Pure Steam Generation

This article
presents an Design of Pure Steam Generation and
overview
of design Distribution Systems
requirements of
pharmaceutical
pure steam by Hugh Hodkinson
generation and
distribution
systems with
particular
emphasis on
recommended What is Pure Steam?

P
takes place with saturated steam. The most
terminology ure steam is a clean utility used in effective method of heat transfer from steam
(clean vs. pure the pharmaceutical industry with two is due to condensation. Therefore, the lower
steam) and feed primary uses: the dryness level, the less steam is available
to condense. On the other hand, superheated
water quality steam will have to cool sufficiently prior to it
• sterilization of product contacting compo-
requirements. nents condensing and non-condensable gases will
• humidification of cleanroom and isolator air never condense. All three of these are factors
supplies which reduce the efficiency of the heat transfer
process.
Since the above two categories are both critical Note that while, as stated above, pure steam
to the production of pharmaceutical products, is most commonly used for air humidification
the design of pure steam generation and distri- in pharmaceutical facilities, the ISPE Baseline®
bution systems is a very detailed process, which Pharmaceutical Engineering Guide on Water
must include a wide range of considerations and Steam Systems3 states “Pure steam is com-
to ensure the steam generated is suitable for monly utilized in the industry for humidification
product contact and that the distribution system of “cleanroom” process areas due to possible
maintains this quality. exposure to the drug product. However, produc-
Pure steam has traditionally been defined tion areas where exposure to the drug product
as having Water For Injection (WFI) quality is of less concern commonly utilize chemical
condensate. While this is still the case for the free steam for humidification.”
European Pharmacopoeia (EP), the United
States Pharmacopoeia (USP) has more recently Pure Steam vs. Clean Steam
defined pure steam specifically. However, this There is a lot of debate throughout the industry
definition of pure steam lists the quality require- as to which term is more appropriate: “clean
ments of its condensate, which actually ties in steam” or “pure steam.” In many circles, both
Reprinted from terms are acceptable and are often used inter-
with USP WFI requirements. Furthermore, if
PHARMACEUTICAL changeably. However, it is the strong recom-
the pure steam is to be supplied to sterilizers
ENGINEERING® mendation of this author to use the term pure
downstream, it should meet the quality require-
The Official Magazine of ISPE
ments defined in European Norm (EN) 285 and steam for the following reasons:
July/August 2009, Health Technical Memorandum (HTM) 2010.1,
Vol. 29 No.4 2
(Note: these are European and UK standards, • Some parties (especially equipment suppli-
but are generally used internationally.) These ers) use the term “pure steam” to refer to a
©Copyright ISPE 2009 unit that produces steam, which is suitable
requirements are summarized in Table A.
www.ISPE.org for pharmaceutical product contact applica-
The characteristics in Table A are listed
because it is important that steam sterilization tions (e.g., for Sterilize In Place processes),
Table A. EN 285 and
but use the term “clean steam” to
HTM 2010 Steam Characteristic Requirement refer to units which produce steam
Quality Requirements. Dryness 0.9 (0.95 for metal loads) that is suitable for use in hospitals
and similar environments.
Superheat < 25°C
This situation became problematic
Non Condensables < 3.5% when a contractor ordered a Clean
Continued on page 10.
8 PHARMACEUTICAL ENGINEERING July/August 2009
 Pure Steam Generation
Steam Generator for a pharmaceutical facility, which was
Characteristic Requirement
actually not suitable for pharmaceutical steam production
and it had to subsequently be replaced. pH @ 2 ºC 6.5 - 8.5
• The ASME Bioprocessing Equipment (BPE) 2007 Guide4 Conductivity @ 20ºC < 10 µS/cm
defines clean steam as “steam free from boiler additives Dissolved Solids < 5 mg/L
that may be purified, filtered, or separated. Usually used
Chlorides < 50 ppb
for incidental heating in pharmaceutical applications.”
The same guideline defines pure steam as “steam that is Free Chlorine < 50 ppb
produced by a steam generator, which when condensed, Ammonia < 50 ppb
meets requirements for Water For Injection (WFI).” Total hardness < 2 ppm
• Many equipment suppliers use the term “pure steam” or
Silica as SiO2 < 1 ppm
“pyrogen-free pure steam” exclusively throughout their
documentation. If a pharmaceutical facility refers to “clean Endotoxins < 250 EU/ml
steam” throughout all of their documentation and draw- Table B. Recommended feed-water quality for pure steam generators.
ings, but “pure steam” is referred to throughout all of the
generation skid documentation and drawings, it creates as to which water supply in the facility would give the most
an undesirable disparity. cost effective feed water. To take a hypothetical example: If
• The quality of the feed water is in no way related to whether there was a de-ionized water loop, a Purified Water loop, and
the steam produced is called “clean steam” or “pure steam” a WFI loop, where all three met the minimum feed water
so the name used should never be based on the feed water quality requirements, the de-ionized loop would generally be
quality. the most economic to extend to supply the PSG. Additionally,
• Although there are variations throughout the relevant producing one liter of de-ionized water as feed is substantially
guidance documents, it is common for pure steam to be less expensive than producing one liter of WFI. However, it
defined as higher quality than clean steam or at least the must be stressed that before this decision can be made, the
same quality. Using the term “pure steam” is unlikely to water quality must be confirmed as acceptable for the PSG.
cause any confusion, but the term “clean steam” is a lot The water quality characteristics listed in Table B can be
more ambiguous due to different definitions throughout used as a guideline for the quality of water typically required
the industry. for supply to a PSG. This has been collated based on feedback
from several leading PSG suppliers to the pharmaceutical
Feed Water Quality for industry. Note that this is purely a guideline and that the final
Pure Steam Generators decision for feed water quality must be made in accordance
This is another controversial item in the pharmaceutical with the recommendations of the PSG supplier.
industry. There is widespread debate over the quality of the
feed water required by a Pure Steam Generator (PSG). The Notes:
most common feed water used by PSGs is USP and EP Puri- 1. Pure steam generators will typically give a 3 to 4 log
fied Water. The reason that purified water is normally used reduction in Endotoxin Level (which will be stated in the
is because it is available in and distributed through most upcoming revision to ISPE Baseline® Guide: Water and
pharmaceutical facilities. In fact, purified water is a much Steam Systems3) which is why this is a requirement for
higher quality than is typically required by a PSG; therefore, feed water quality. One manufacturer confirmed that they
it is a needlessly expensive water supply if there is a lower achieve a minimum 3 log reduction in endotoxin levels
quality supply available which still meets the PSG feed water through their PSGs.
requirements. There also are parties who advocate using Wa- 2. Non-condensable levels in the feed water will ideally be
ter For Injection (WFI) to feed a PSG. However, this does not less than 3.5% v/v, but if this requirement is not met, the
make sense since the most common method of producing WFI PSG can be fitted with a degasser.
is from a WFI Still, which operates on the same principles as
a PSG. Therefore, the WFI produced is condensed steam so Specification of a Pure Steam Generator
the feed would have been distilled twice. It should be noted The key activities of a Pure Steam Generator are to evaporate
that USP states that the feed water supplied to the PSG must the feed water, remove non-condensable gases from the system,
be in accordance with feed water required for a WFI Still or and remove entrained droplets from the steam, while keeping
Purified Water Skid. According to USP, for a WFI Still: “The the steam saturated. Removal of non-condensable gases is
minimum quality of source or feed water for the generation necessary because there is a non-condensables limit specified
of Water for Injection is Drinking Water as defined by the US in HTM 2010. Removal of entrained droplets is necessary
EPA, EU, Japan, or the WHO.” However, in practice, many because dryness is another key quality criterion, but also
PSGs require a higher standard of feed water than that. because these droplets will carry over contamination from
The recommendation of this author is to contact the the feed water. Saturation is important for effective steam
supplier (or potential suppliers) of the PSG to confirm the sterilization because most of the energy transferred is from
acceptable feed water quality. Then a decision must be made latent heat of condensation.
Continued on page 12.
10 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
Common methods of reducing entrained droplets include on the requirements of the distribution system users).
using demister plates in the main evaporator, designing the • Passivated 316L stainless steel is the recommended mate-
evaporator column to be long and wide enough that the steam rial of construction as pure steam is a very corrosive sub-
upflow is low enough that droplets fall back into the boiling stance. Non-metallic piping materials of PVDF and PTFE
feed water, and/or using a cyclone effect so that centrifugal could be used if rated for the pressure and temperature.
force drives entrained droplets against the evaporator wall Schedule 80 would be preferable.
(baffles can be used to augment this process). • A surface finish of Ra < 0.5 µm (20 microinch) is recom-
It is good practice to degas the pure steam produced. If there mended for pure steam contacting parts.
is a feed water tank on the skid, it is common to heat the feed • Hygienic connections to be used throughout. High pressure
water and recirculate it so that it sprays back into the feed water clamps which require a tool to remove are recommended
tank, enabling non-condensable gases to be released through over clamps which can be removed merely by hand.
a stack vent on the tank. If there is no feed water tank, some • Any interaction with the upstream feed water distribution
suppliers can feed a degassing vent directly to the evaporator system should be specified, such as feed water request
column. These can operate by means of a falling film on the signals sent from the PSG control system and feed water
infeed line to the PSG, where the hot feed water releases non- available signals returned to the PSG control system.
condensable gases which rise up through a degassing vent. The • A small stream should be taken off the pure steam outlet,
advantage of fitting this directly to the evaporator is a smaller condensed and monitored continuously for conductivity.
overall footprint for the PSG, but the vent stack is generally Note that the ISPE Baseline® Guide3 states that tempera-
more difficult to remove than from the feed water tank. ture compensated conductivity sensors cannot be used for
Prior to ordering a PSG, it is wise to meet with one or critical quality assurance testing of purified water, highly
more leading PSG suppliers to discuss the details and exact purified water, WFI, and pure steam condensate.
requirements of your application. Some key items that should • It is common to record the PSG pure steam condensate
be considered for the PSG specification are summarized below. conductivity and temperature for a facility’s batch records.
Note that the below list is aimed at design items which are Since most PSGs are Programmable Logic Controller
specific to PSGs and is not intended to be an all encompassing (PLC) based and do not have permanent data storage, it is
list covering items common to specifying any piece of sanitary recommended that this data is stored either by connecting
equipment, such as documentation requirements, testing re- the PLC to a Supervisory Control and Data Acquisition
quirements, safety requirements, construction requirements, (SCADA) system or alternatively that the conductivity
etc. Key items to consider when specifying a PSG are: and temperature signals are routed in parallel to a data
logging system. In the case of the latter, it is recommended
• The quality of the feed water proposed for the PSG. that a signal is also sent from the PSG PLC to confirm that
• Ensure the PSG outlet is fitted with EN 285/HTM 2010 good quality steam is being produced. Otherwise, it will
test points, as well as a test point for taking pure steam not be clear from the data logged when the PSG is running
condensate samples. If the pure steam does not meet these properly and when it is in alarm or shut down.
quality requirements at the facility user points, the first • One item that must be considered when designing a pure
check that should be performed is that the PSG is produc- steam system is whether and how the feed water system
ing sufficiently high quality steam. is sanitized. If the feed water is normally cold, but is
• Ensure the PSG is fitted with a degasser. This gives con- sanitized by heating the feed water distribution, this can
fidence that non-condensable requirements will be met in generally be catered for in the PSG design if the vendor is
the system. informed up front. However, if a different method of feed
• State the feed water minimum supply pressure. PSGs water sanitization is used (e.g., chemical sanitization),
require a feed water tank and booster pump if the feed then it could be necessary to stop feeding the PSG for the
water pressure is not a sufficient quantity greater than the duration of sanitization. If there is no feed to the PSG for
pure steam generation pressure – commonly 1 bar (14.5 a sufficient period, it will have to shut down. This would
psi), but this varies between suppliers. obviously have a drastic effect if the facility air handling
• It is recommended that inlet feed water is used to condense units depend on the PSG for pure steam. Note that feed
pure steam for inline conductivity monitoring and offline water sanitization depends on the design of the feed water
analysis. Otherwise, a separate cooling water supply is system and is not a requirement of the PSG.
required to the PSG skid. • It is typical for the pure steam distribution system header
• Effluent from the PSG is going to be hot, and if it is not cooled, to be a purely mechanical system. That is, the distribution
a plume of steam will be generated at the waste connection does not have its own control system. The key parameter
from the skid. So it is recommended to include a blow down that must be controlled in the distribution header is the
vessel in the skid where the effluent is cooled by process pressure, which is set in the PSG control system.
water or similar. Also note that the vent from this blow down • The most common temperature used for sterilization processes
vessel will typically be exhausting hot water vapor so it is is 121°C. 134°C is used for some processes, but this is much
normal to pipe this vent outside the building. less common.These temperatures correspond to steam supply
• The flowrate and pressure required at the PSG outlet (based pressures of ~1.1 barg (16.0 psig) and ~2.0 barg (29.0 psig)
Continued on page 14.
12 PHARMACEUTICAL ENGINEERING July/August 2009
 Pure Steam Generation
respectively. To allow for pressure losses in the distribution tion line for sizes up to 4 inch (100 mm) and one or two
system and to buffer the distribution system, it is common sizes smaller for lines of 6 inch (150 mm) or larger.
to run distribution headers at pressures in the range of 2.5 • 30 cm (~1 ft) of uninsulated piping above each steam trap.
– 3.0 barg (36.3 psig – 43.5 psig). However, it is important to Thermostatic traps release condensate which is a few degrees
check the pressure required by each of the downstream users colder than the steam saturation temperature would be at
before deciding on the pressure required in the header and the operating pressure. Therefore, the condensate must be
corresponding pressure setpoint at the PSG outlet. allowed to cool so that it is released through the trap.
• Full bore ball valves used throughout, but diaphragm valves
Design of a Pure Steam Distribution System are advisable at the sterile boundary of an aseptic system,
The design of a pure steam distribution system is more com- e.g., the last valve on a line for SIP of a vessel would be a
plex than might first appear. The following design guidelines diaphragm valve, but the preceding valves would be ball
assume that the pure steam generator has been correctly valves. Diaphragm valves used in a pure steam system
specified and will produce pure steam of a quality that meets require far more maintenance than ball valves.
USP and EN 285 requirements (as well as meeting EP WFI • Sanitary pressure regulators are to be used where required.
quality limits for Pure Steam condensate). Sanitary pressure regulators typically have a bottom mounted
Once the PSG has been correctly specified, designed, and inlet and side mounted outlet so that any condensate built
installed, it is critical that the distribution system delivers up in the regulator flows back through the regulator inlet.
pure steam of a sufficient quality to the facility user points. A • No direct connections to unhygienic systems. Air gaps to
poorly designed distribution system can reduce the quality of be used at all drain points.
the steam so that it does not meet the regulations pertaining • Hygienic connections used throughout. High pressure
to pure steam. clamps which require a tool to remove are recommended
over clamps which can be removed merely by hand.
Header Design • Passivated 316L is the recommended material of construc-
Headers must be designed so that they minimize condensate tion as pure steam is low in ions and is a very corrosive
formation and any condensate which is formed is routed out substance.
of the distribution system, maintaining a dry steam supply • User point take offs are piped off the top of headers to
to each user point. To this end, the following design features minimize entrained condensate.
are recommended: • Headers and take offs are typically sized to give a steam
velocity in the range of 20 to 30 m/s (~65 to 100 ft/s) to
• Piping runs slope to at least 1% minimized entrained condensate in the pure steam flows.
• Steam traps are recommended: Note lower velocities also are acceptable.
- at the end of each header or branch • Sample points to be easily accessible.
- every 30m (~100 ft) on any straight run • It is often stated that pure steam distribution systems are
- at each user point or sample cooler self sterilizing and the benefits of polished tubing is ques-
- where the line transitions from horizontal to vertical tioned. However, it is very common throughout the industry
(at the bottom of the vertical riser) (and recommended by this author) to polish distribution
- at thermal expansion loops systems to finishes of Ra < 0.5 µm (20 microinch) or less
- anywhere condensate could build up and would not (depending on the site standard) and is recommended.
otherwise be removed (i.e., there should be no dead legs Sometimes for smaller components such as steam traps,
where condensate can build up) this requirement cannot be met and can be relaxed to Ra
• Thermostatic steam traps to be used throughout. These are < 0.8 µm (32 microinch).
the most common sanitary traps for pure steam distribu- • Air breaks to be at least twice the size of the relevant pipe
tion systems and have the ability to remove air from the diameter.
system. Float traps and thermodynamic traps are not free • Eccentric reducers used for any horizontal reductions in
draining and do not release air from the system so they pipe diameter.
are not recommended.
• Never group steam traps. This means that multiple users A typical autoclave user point is shown in Figure 1. Note that this
are not run to a single trap (this often leads to preferential includes HTM 2010 test points and a pressure gauge as well as
draining for one piece of equipment, because different local condensate sampling. Not all of these features are required
pieces of equipment will release condensate at different at every user point, as described in the sampling section below.
temperatures and pressures). It also means that the dis- Also note that 50 mm (2") air breaks are used in this example.
charge lines from traps must not be connected. Each of This is a common length, but air breaks should always be at least
these should go to drain through a separate air gap since twice the pipe diameter used in the given application.
linking these lines can hinder the release of condensate
through one or more of the traps. Sampling
• Trap legs for the collection of condensate from the steam It is recommended to take samples to prove compliance with
distribution system should be of equal size to the distribu- the following:
Continued on page 16.
14 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
a. Pure steam condensate complies with USP and/or EP (as it is generally acceptable to sample at the end of the
relevant) relevant header.
b. Pure steam quality complies with HTM 2010/EN 285
dryness, superheat, and non-condensable requirements It is advisable to fit a hygienic needle valve immediately
as described in the introduction to this article upstream of the sample cooler so as to control the sample
flowrate. It also is recommended to normally fit a steam trap
With respect to a. above: Sample coolers are recommended at the outlet of the sample cooler so that it is continuously
at the following locations: self sterilizing, but to have a spool piece which can be used
to replace the steam trap during sampling (obviously after
- At the end of each header the system has been isolated and allowed to depressurize
- At each critical user take off, i.e., where pure steam is and cool sufficiently).
used on product contacting surfaces such as for equip- With respect to b. above: HTM 2010/EN 285 test points
ment SIP or for autoclaves. However, for non-product are recommended at the following locations, at a minimum:
contacting users such as steam used for humidification,

Figure 1. Typical pure steam supply configuration for an autoclave.

Concludes on page 18.
16 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
this is not recommended for a continuously running pure
steam system. While it is possible that a high point trap, such
as this, will accelerate the de-aeration of the system, this is
not a worthwhile gain for a system which will only be shut
down and started up once or twice a year. It must be noted
that once hot, air is heavier than steam and that thermostatic
traps operate based on temperature. In other words, the low
point steam traps will pass air until the system is de-aerated.
These types of high point air vents can make sense in plant
steam systems which use thermodynamic or float traps which
are based on velocity and density respectively (i.e., will not
pass air), but do not make sense for a distribution system
which uses thermostatic traps throughout.
Furthermore, the ideal location of the high point venting
trap is frequently in a very inaccessible location at the top of
the building, often at the top of a pipe rack. Over time, these
Figure 2. Typical HTM 2010 sampling arrangement.
traps can begin to leak. If the trap begins to leak, it will have
to be removed for maintenance. Since these are generally
- At each autoclave (as stipulated in the above stan- difficult to access, they are often permanently removed after
dards) they have leaked a few times.
- At each lyophilizer (not specified in the above standards,
but good practice) Conclusion
- At the PSG outlet. Normally, in the scope of the PSG The above article is intended as a guideline to some of the
supplier. key issues to consider when designing a pure steam genera-
tion and distribution system. In particular, it aims to discuss
Three ½" hygienic clamp connections are required for these many of the contentious issues which come up repeatedly in
sample points. It is recommended to have an isolation valve the design of pure steam systems. However, it is recommended
immediately upstream and a pressure gauge to confirm that to seek the advice of a professional designer when designing
the line has been depressurized before clamp blind caps are or modifying such systems.
removed to connect sampling equipment. It cannot be stressed
enough that these sample points must be accessible. They are References
often installed as an afterthought and can then be extremely 1. EN 285: 2006 Sterilization. Steam Sterilizers. Large Steril-
difficult to connect with the relevant sampling equipment. izers.
During the initial piping layout design, it must be anticipated 2. Health Technical Memorandum (HTM) 2010 Crown Copy-
to locate these sample points as close to the autoclave (or other right 1994.
equipment) as possible, but certainly within 2 or 3 meters. 3. ISPE Baseline® Pharmaceutical Engineering Guide, Vol-
These HTM 2010/EN 285 test points are used to take ume 4 - Water and Steam Systems, International Society
samples manually. Non-condensables are measured by con- for Pharmaceutical Engineering (ISPE), First Edition,
densing a quantity of steam and then measuring the volume January 2001, http://www.ispe.org.
of this which is water and the volume which is gas. Superheat 4. ASME BPE 2007 Bioprocessing Equipment.
is measured by routing steam through an expansion tube and 5. United States Pharmacopoeia 32-NF27, 1 November
checking that there is not an excessive temperature difference 2009.
between that temperature and the main header temperature.
Dryness is measured by condensing steam from the header. About the Author
A typical HTM 2010 test connection is shown in Figure 2. Hugh Hodkinson is a Lead Process Engineer
Note that the dryness HTM 2010 test in particular is very for DPS Engineering. Educated at University
sensitive to entrained moisture, and if there are flaws in the College Dublin, he holds a BE in chemical
design or installation of the pure steam distribution system, engineering. He has been with the company
this is the test that is most likely to fail. Even if an upstream since 1999 and has led aseptic design projects
pipe has been stepped on during construction and bent (even in Ireland, the UK, and the Netherlands. His
if it is almost imperceptible to the naked eye) so that there is experience includes a variety of facilities for
slight pooling of condensate in the line, this amount of conden- vaccine production, cell culture production,
sate can be enough to make the system fail its dryness test. downstream processing, and fill finish products. He can be
contacted by telephone: +353-86-8185589 or by email: hugh.
Air Venting [email protected].
There are sources which recommend installing a high point DPS Engineering, Landscape House, Baldonnell Business
trap for venting air out of the pure steam system. However, Park, Baldonnell, Co. Dublin, Republic of Ireland.

18 PHARMACEUTICAL ENGINEERING July/August 2009

 Pure Steam Generation

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July/August 2009 PHARMACEUTICAL ENGINEERING 19

 WFI Production Methods
This article
presents the Methods of Producing Water for
advantages and
disadvantages Injection
of distillation-
based and
membrane- by Henry Brush and Gary Zoccolante
based methods
for producing
WFI, outlines
international
WFI regulatory
requirements, Introduction

W
been successful in attainment of the water qual-
discusses ater For Injection (WFI) interna- ity specifications. Yet, most other high-purity
historical market tional pharmacopoeial standards industries use reverse osmosis, deionization,
penetration and have been brought closer through and ultrafiltration, not distillation, to produce
harmonization efforts, but sig- WFI equivalent or higher quality water. ASTM
performance nificant differences still exist. The USP WFI Type A laboratory water limits for total bacte-
of distillation monograph allows production by “distillation rial count and endotoxin are respectively ten
and membrane- or a purification process proven to be equal and eight times lower than WFI. ASTM Type
based WFI to or superior to distillation.” USP language 1.2 water for microelectronics has similar mi-
is the least restrictive in terms of acceptable crobial restrictions with total organic carbon
systems, and processes among the major pharmacopoeial and conductivity limits well below WFI. Those
includes a groups. The Japanese Pharmacopeia (JP) applications are routinely satisfied with mem-
membrane case allows distillation or Reverse Osmosis (RO) brane-based systems producing water at ambi-
study. followed by UltraFiltration (UF). Distillation ent temperature. However, those industries do
is the only WFI method of production that is not have regulated process limitations.
approved by the European Pharmacopoeia This article will discuss the advantages and
(EP). disadvantages of distillation-based and mem-
Historically, distillation has been the brane-based methods for producing WFI; outline
preferred method for producing WFI in the international WFI regulatory requirements; and
biopharmaceutical industry, and today, most discuss historical market penetration and per-
pharmaceutical WFI is produced by distilla- formance of distillation and membrane-based
tion. Regulatory requirements have helped WFI systems. Also included is a membrane case
significantly in the domination of WFI produc- history from US biopharmaceutical company
tion by distillation, but distillation also has Alkermes, Inc.

Table A. WFI Requirements

for USP, EP, JP. USP EP JP Distillation-Based
WFI Systems
Method of WFI Distillation or Distillation only Distillation or
Production purification RO/UF To meet USP requirements, WFI
process proven must be produced by “distillation
to be equal to or or a purification process proven to
superior to
distillation be equal to or superior to distilla-
tion.” Additionally, the water must
Conductivity, µS/ 1.3 1.3 1.3
Reprinted from cm @ 25 °C or pass conductivity and Total Organic
PHARMACEUTICAL equiv. @ other Carbon (TOC) tests, and the bacteria
temps. endotoxin level must be below 0.25
ENGINEERING®
The Official Magazine of ISPE TOC, ppb <500 <500 <500 endotoxin units per milliliter (EU/
Endotoxin 0.25 EU/mL 0.25 EU/mL 0.25 IU/mL mL). The microbial level must not
July/August 2009, be above 10 Colony-Forming Units
Vol. 29 No.4 Bacteria, 10 10 10
cfu/100 mL (CFU) per 100 mL. Distillation is
©Copyright ISPE 2009 effective at quantitative reduction
Nitrates, ppm N/A 0.2 N/A
www.ISPE.org of most water contaminants and can
Ammonium, mg/L N/A N/A 0.05 produce water with low conductivity,
Continued on page 22.
20 PHARMACEUTICAL ENGINEERING July/August 2009
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Answers for industry.

 WFI Production Methods
low TOC, low microbial levels, and low endotoxin levels. water-sanitizable RO, and finally, a vapor compression still. The
Almost all pharmaceutical distillation-based systems key design consideration is inclusion or exclusion of RO.
implement either multiple effect or vapor compression stills. RO is excluded when ionized solids and endotoxin reduction
Both still types employ various techniques for recovery of is not deemed necessary for reliable, consistent attainment of
latent and sensible heat to minimize energy consumption. WFI quality parameters. RO is implemented when the user
Both technologies produce WFI quality water when properly believes that reduction of endotoxin and ionized solids in the
implemented and operated. Each still type has advantages and still feed assures that WFI quality is consistently attained,
disadvantages and each has significant successful operational maintenance is minimized, and hot blowdown is minimized.
history. Many systems of both types are in operation. If only endotoxin
While stills are reliable, they are not perfect, and can reduction is desired in the still pretreatment system, UF may
produce pyrogenic product water when operated incorrectly, be substituted for RO.
when they fail mechanically or when the feed water contains In addition to meeting all pharmacopoeial requirements,
contaminant levels beyond the still reduction capability. If vapor compression distillation offers the following advan-
fed with high endotoxin feed water from the raw supply or tages:
pretreatment equipment, in cases where there is no mem-
brane-based system pre-treating the still, the product water • generally reliable operation
from the still may fail the endotoxin test. Many successful • typically more energy efficient than multiple-effect distil-
distillation systems exist with no membrane pretreatment, lation
but several other systems have required retrofit of Reverse • can be operated on softened/dechlorinated feed
Osmosis (RO) or UltraFiltration (UF) pretreatment after • may not require a complex system design
periodic product water endotoxin failures due to high still • relatively low maintenance
feed endotoxin levels.
The FDA Guide for Inspections of High-Purity Water Potential disadvantages of vapor compression stills include:
Systems recognizes the still pretreatment design question
regarding potential use of a membrane process. Section V • may be more labor intensive than multiple-effect distilla-
of the Guide states, “Many of the still fabricators will only tion with compressor and associated drive gear
guarantee a 2.5-log to 3-log reduction in the endotoxin content. • may have higher life cycle cost than membrane based
Therefore, it is not surprising that in systems where the feed systems
water occasionally spikes to 250 EU/mL, unacceptable levels
of endotoxins may occasionally appear in the distillate (WFI). Multiple-Effect Distillation
For example, three new stills, including two multi-effect, were A Multiple-Effect Distillation (MED) system often consists of
recently found to be periodically yielding WFI with levels a multi-media filter, softening, break tank, heat exchanger,
greater than 0.25 EU/mL.” hot-water-sanitizable activated carbon, prefilter, optional
The FDA Guide further states, “Pre-treatment systems pH adjustment, 254-nanometer ultraviolet (UV) light,
for the stills included only deionization systems with no RO, hot-water-sanitizable RO, continuous electrodeionization
ultrafiltration, or distillation. Unless a firm has a satisfactory (CEDI), followed by the multiple-effect distillation unit. The
pre-treatment system, it would be extremely difficult for them pretreatment system is generally comprehensive because the
to demonstrate that the system is validated.” high operating temperature makes MED stills susceptible to
The decision to implement or not implement reverse osmo- chloride stress corrosion and scale. The pretreatment system
sis in still pretreatment is generally more relevant to vapor typically minimizes chloride, silica, and total dissolved sol-
compression stills than multiple effect stills. Vapor compres- ids levels. Membrane based pretreatment typically reduces
sion stills operate at a lower temperature than Multiple- endotoxin to very low levels, such that the still endotoxin
Effect (ME) stills and are less susceptible to chloride stress challenge is negligible.
corrosion and scale; therefore, reverse osmosis is not always
necessary for scale and corrosion prevention. Multiple effect • In addition to meeting all pharmacopoeial requirements,
stills generally require feed water with low levels of chloride, multi-effect distillation has the advantage of few moving
silica, and total solids, and are almost always pretreated with parts and this can minimize maintenance requirements.
reverse osmosis and/or an ion exchange process. Since reverse
osmosis is present in almost all ME still feed systems, the Potential disadvantages include:
feed endotoxin levels are quite low.
• generally requires high-quality feed water: less than 0.5
Vapor Compression Distillation ppm chloride; less than 1.0 ppm silica; less than 5.0 µS/
Vapor compression distillation systems generally implement cm conductivity
scale control, dechlorination, and in some cases, reduction of • typically higher energy costs than vapor compression
ionized solids and/or endotoxin. A vapor compression distil- distillation
lation system often consists of softening, heat exchanger, • typically higher cooling water requirements than vapor
hot-water-sanitizable activated carbon, prefilter, optional hot- compression

22 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

“Most alternative designs to distillation have used one or two passes of RO, often with an
ion exchange process and in virtually all cases, final polishing with UF or RO. The system
designs over decades have been driven by practicality and regulation.”

• may have higher life cycle costs than membrane-based systems were more popular prior to the presence of conduc-
system tivity and TOC tests. At that time, the USP WFI monograph
only allowed distillation or RO for process and it was accepted
What Other Treatment Methods Work? that the still or RO would be the terminal process. The FDA
A number of separation methods, such as RO and UF, can re- had noted in “The FDA Guide for Inspections of High-Purity
move endotoxin. Oxidation with ozone also removes endotoxin. Water Systems” that if RO was used for WFI, two stages should
Heat, distillation, UF, RO, filtration, ozone, UV, and chemical be used to assure attainment of the quality specifications.
methods can all achieve low microbial levels in the product TPRO can typically meet all of the required water quality
water. Other market applications, such as microelectronics and parameters, but consistent attainment of Stage 1 conductivity
select laboratory water types have water quality specifications can be an issue with some feed waters. TPRO systems often
far tighter than WFI including extremely low endotoxin limits. consist of a multi-media filter, softening, break tank, heat
Almost all of these systems utilize membrane technologies exchanger, hot-water-sanitizable activated carbon, prefilter,
for primary treatment. Membrane systems may offer lower optional pH adjustment, 254-nm UV, and two stages of hot-
operating economics as no water evaporation occurs. Systems water-sanitizable reverse osmosis.
either operate at ambient temperature normally or are heated The implementation of a WFI conductivity test requirement
to high temperature without evaporation and condensation. and the liberalization of the USP WFI allowable processes
The content of stainless steel is often less with membrane increased use of systems implementing reverse osmosis,
systems compared to distillation. ion exchange processes, and ultrafiltration or a final stage
of RO. The logic of this type of system configuration is that
Membrane-Based WFI Systems the combination of reverse osmosis and ion exchange easily
Most alternative designs to distillation have used one or meet the conductivity and TOC specifications while the final
two passes of RO, often with an ion exchange process and in ultrafilter or RO stage assures compliance with the endotoxin
virtually all cases, final polishing with UF or RO. The system and microbial requirements. Systems of this type have had a
designs over decades have been driven by practicality and lengthy history in production of “WFI quality water” prior to
regulation. The first alternative to distillation allowed by USP acceptance as a method to produce WFI to pharmacopoeial
decades ago was RO. RO technology was generally not up to standards. The basic system capability for production of water
the task of consistent WFI performance and the technology did with low contaminant levels has been long proven in other
not flourish. Hot water sanitizable membranes did not exist markets, such as microelectronics, for decades.
and chemical sanitization was often inconsistent, allowing Most membrane based systems have several components
periodic microbial excursions beyond WFI specification. Some that are either intermittently hot water sanitized or main-
validated systems existed, but placements were few. tained continuously at a self sanitizing high temperature.
The presence of membrane systems was enhanced when Some systems have a final membrane stage that operates at
the Japanese Pharmacopoeia allowed RO followed by UF the same elevated temperature as the storage and distribu-
as an alternative to distillation. Hot water sanitizable and tion system. Several systems of this type have been in opera-
continuous hot ultrafiltration elements were available and tion for more than 10 years with water quality performance
contributed to successful operation. Ultrafiltration had a equivalent to distillation based systems.
lengthy, successful history in pharmaceutical manufacturing A typical membrane based WFI system includes dechlori-
and was accepted. This technology change led to implemen- nation, softening, a hot-water-sanitizable RO device followed
tation of more systems that produced “WFI quality” water by a hot water sanitized CEDI device. A continuous hot-water
where pharmacopoeial WFI compliance was not required. UF device polishes the water prior to storage and use as WFI
The change by USP to open WFI production to “distillation if the water will be stored hot. A hot water sanitized UF or RO
or a purification process proven to be equal to or superior to serves as the final stage if the product water will be stored
distillation” has helped to increase interest in membrane at ambient temperature. Advantages of using RO/RO or RO/
based WFI systems. UF to produce WFI are as follows:
EP has created a monograph for Highly Purified Water
with no process limitations and water quality specifications • may be the lowest life cycle cost alternative
identical to WFI. This has helped to increase membrane • typically low energy requirements
system placement for production of “WFI quality” water. • typically very low conductivity, TOC, endotoxin, and mi-
Two-Pass RO (TPRO), also known as product staged RO, crobial levels
was one of the earliest WFI membrane configurations. TPRO • generally reliable operation
Continued on page 24.
July/August 2009 PHARMACEUTICAL ENGINEERING 23
 WFI Production Methods
• can be intermittently or continuously hot sanitized manufacturing often greatly exceed WFI quality require-
• there is some history in the U.S. Pharmacopeia and Japa- ments.
nese Pharmacopoeia of using RO and UF for WFI USP and JP allow membrane based designs as well as
distillation. The EP requirement for distillation eliminates
The most significant disadvantage is that EP does not allow a any choice of alternate technologies for companies wanting
WFI production method other than distillation and therefore, to comply with EP. Therefore, membrane based systems
WFI membrane use is limited to non-EP applications. The are only employed where EP compliance is not required or
history of membrane based WFI system usage is significantly where “WFI quality” water is desired, such as for meeting
less than with distillation, and this has negatively affected the requirements of EP Highly Purified Water, preparation
confidence in membrane systems among some pharmaceuti- of intermediates, or other uses.
cal companies. Additionally, the RO system requires periodic Although some successful membrane-based systems have
cleaning, the membranes must be replaced at some point, been in operation for several years, the historical database is
and membranes can fail just as any technology has failure not nearly as large as for distillation. Membrane-based systems
mechanisms. are beginning to be placed and are considered more frequently
Capital and operating cost comparison for distillation and because membrane-based systems may offer lifecycle cost
membrane based systems is a key element of system choice advantages in reduced capital or operating costs. The choice
when regulatory requirements do not dictate distillation only. is one of many risk-based decisions in the pharmaceutical
This article does not provide costs for several key reasons. industry. Users need to consider product, market, capital cost,
Equipment specifications for materials of construction, in- utility costs, commissioning/qualification, maintenance, and
strumentation, control, and other major cost factors impact risk to make an informed decision.
capital costs significantly and capital costs are meaningless
without detailed specifications. Operating costs are directly Case Study for WFI Production:
impacted by utility costs for water, wastewater, power, steam, Alkermes, Inc.
chilled water, and others and vary tremendously site to site. The following case study is for a membrane-based WFI
These costs are best based upon actual conditions case to case system in a US facility. A case study for distillation is not
for accurate analysis. The significant possibility of lower life presented because distillation is well established. The distil-
cycle economics for membrane based systems is based upon lation operating history is generally good and advantages and
the relative absence of distillation based systems in non- disadvantages are well understood.
regulated high purity applications.
Background
Why Has Membrane-Based WFI Production Alkermes pulmonary drug delivery platform technology
Failed to Flourish? enables delivery of both small molecules and complex mac-
With all the potential advantages of using membrane-based romolecules to the lungs. This system can provide efficient
technologies for producing WFI, why has it not caught on in the dry-powder delivery of small molecule, peptide, and protein
industry? For one reason, when RO was first approved for use containing drug particles to either the deep lung or the upper
in WFI production, the technology was not completely “ready” respiratory tract, based on the product needs. Alkermes de-
for this application. Hot-water-sanitizable RO did not exist, signed and built a manufacturing facility to support production
and chemical sanitization is not as effective as heat. Full-fit of late stage clinical supplies as well as commercial production
RO membrane elements were not available and neither was of its pulmonary drug delivery products. The manufacturing
continuous hot operation. Early failures discouraged use, and operations at the site include spray drying to produce the bulk
while endotoxin control was not a problem, microbial control dry powder, capsule filling, packaging, CIP systems for clean-
was. Ultrafiltration technology, while “ready,” did not have ing, and a clean steam system. The purified water system was
USP or EP approval. designed to support the formulation activities associated with
Membrane technology has a significant successful history production of the bulk powder in the spray drying operation,
in production of WFI in Japan and in the US, but membrane the CIP system for cleaning process equipment, and as feed
system implementation is limited to facilities or applications water to the clean steam system.
where the EP requirements are not a factor. Since a significant
percentage of pharmaceutical manufacturers produce for the Introduction
European market, the EP distillation requirement stifles Dry powder inhalation products are typically not produced
membrane implementation. under aseptic manufacturing conditions. Based on this, the
initial project requirements specified USP Purified Water as
Conclusions the appropriate grade of water for the manufacturing site.
Most WFI systems are distillation based. Distillation has a This decision was revisited after detailed engineering had
lengthy successful history in WFI production. Most other high been completed on the project. The review team identified a
purity systems in other markets use membrane processes potential for tightening of microbial specifications in the final
rather than distillation, but no regulatory requirements exist. drug product, particularly for products that might be used in
Water quality specifications for use such as microelectronics patients with compromised immune systems. Based on this

24 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods
assessment, it was decided that the microbial specifications unit and hardware also had short lead times, which further
of the water should be tightened to support the current as minimized the impact to the overall project schedule. In ad-
well as any future drug product microbial and endotoxin dition, the capital cost of the ultrafilter system was relatively
requirements. small. This minimized the impact to the project cost.
The water system had already been ordered and was in
fabrication when the system requirements were changed. System Description and Discussion
The Alkermes engineering team met with the system sup- The Alkermes water system is designated as an EP Highly
plier to identify solutions that could meet the revised water Purified Water (HPW) System. The system consists of a gen-
system requirements, while minimizing the impact on the cost eration system that is supplied with city water and produces
and schedule of the project. Several options were discussed, up to 8 gpm of highly purified product water that meets USP,
including the option of the reverse osmosis and continuous WFI test specifications. The product water is supplied from
electrodeionization (CEDI) systems that were already specified the HPW generation system to the top of a 3,000 gallon hot
as being able to meet the new requirements, and installation storage tank that is maintained at 80°C. The hot water stor-
of a still to produce WFI grade water. The team identified the age loop is continuously circulated by pumping water from
addition of an ultrafiltration step as the best way to meet the the bottom of the storage tank, through a heat exchanger, and
tightened water specifications, while minimizing the cost and back into the top of the storage tank. If the storage tank is full,
schedule impact to the project. The system supplier was will- the product water is circulated back to the HPW generation
ing to guarantee that with the addition of an ultrafiltration system as feed water.
step, the water generation system would be able to meet USP The HPW distribution loop is self contained and nor-
Water for Injection specifications with regard to microbial and mally maintained at room temperature or 24°C. The HPW
endotoxin requirements. distribution loop and hot storage loop are connected so that
The ultrafilter unit operation is relatively small physically when water is drawn from the distribution loop, hot water
and had a minimal impact on the layout of the generation is supplied from the storage loop to the distribution loop.
and distribution system. This minimized any costs associated A heat exchanger in the HPW distribution loop cools the
with piping layout changes. It also minimized the schedule water prior to feeding the water out into the plant and to
impact because it did not require significant re-piping to ac- the use points. Every 24 hours the cooling heat exchanger
GEAI CV the
commodate Ad - Pharm Eng
ultrafilter unitJul-Aug 09:Layout
into the layout. 1 6/12/2009
The ultrafilter is11:13 AMoffPage
turned 1 HPW loop is heated to 80°C and held
and the
Continued on page 26.

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July/August 2009 PHARMACEUTICAL ENGINEERING 25

 WFI Production Methods
for microbiological growth once the chlorine is removed. The
heat sanitization cycles for the carbon filters are designed to
control the bioburden levels in the carbon filters.
Ultraviolet (UV) lamp units are installed downstream of
the carbon filters for inhibiting microbial growth after the
chlorine has been removed by the carbon beds and prior to
feeding the RO membranes with the in process water. The
intensity of the UV lamps is monitored and documented in
rounds sheets during routine operations of the system.
The next stage in the HPW generation system is the reverse
osmosis process, which is part of the final treatment system.
Figure 1. Process flow diagram for the HPW generation system. The system includes single pass RO membranes. The RO
at temperature for 60 minutes. The system design is based process is a pressure driven process with a semi-permeable
on the “Hot Storage – Self Contained Distribution” design membrane designed to remove minerals, organics, particulates,
that is described in the ISPE Baseline® Guide on Water and microbiological material, and endotoxin. The RO membranes
Steam Systems. reject a significant portion of the feed stream, while allowing
The overall water system includes several unit operations a portion of the purified water stream to pass through the
to meet the required product specifications. City water from membrane. The daily performance of the RO membrane is
the Massachusetts Water Resource Authority system is fil- monitored by measuring the percent rejection of conductive
tered using a multi-media filtering system to remove coarse elements in the feed water to the reverse osmosis unit.
particulates. The first unit operation in the HPW generation The CEDI unit is located downstream of the RO membranes
system is the particulate filter system. The particulate filters and removes ionized species from water using electrically
are nominal 5.0 µm cartridge filters designed to remove large active media and electrical potential to effect ion transfer.
particulates from the incoming feed water. The particulate The CEDI system is a continuous process in that the ions
filter system includes two banks of five cartridge filters, each are continuously removed and the ion exchange resins are
of which can be operated in parallel with either one or two regenerated continuously. In addition, there is a UV unit as
units in operation. part of the CEDI skid. As discussed above, the UV unit is
The next stage in the HPW generation system is a duplex designed to limit microbial growth.
water softening system. The water softening system is an The last unit operation in the final treatment portion of
ion exchange process that is designed to remove divalent the HPW generation system is the ultrafiltration system. The
and trivalent ions from the incoming city water and replace ultrafilter (UF) includes a 0.05 µm single pass filter and is
them with a monovalent sodium ion. The softening process designed to provide the final step in meeting the WFI speci-
prevents scale in the reverse osmosis unit downstream. fications. Figure 1 includes a process flow diagram indicating
Two activated carbon filter skids in parallel are located down- the different unit operation steps in the HPW generation
stream of the water softeners. The carbon filters are designed system.
to remove chlorine from the feed water. Chlorine is added by Heat is used to sanitize both the HPW generation system
municipal authorities to the city water as a microbial control and the HPW distribution system. The carbon filter, reverse
agent. Chlorine can oxidize the reverse osmosis membranes osmosis skid, and associated piping are sanitized weekly using
and negatively impact system performance. In addition, it is 80°C water. The entire generation system, including the carbon
recognized that the carbon beds can serve as an environment filter, RO skid, CEDI system, ultrafilter, and associated piping

Figure 2. HPW generation system outlet. Figure 3. Formulation tank supply valve.

26 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

Figure 4. HPW generation system outlet.

Figure 5. Formulation tank supply port.
is heat sanitized monthly. The distribution system is sanitized
nightly by heating the entire distribution loop to 80°C. generation system outlet. Figure 3 illustrates data from a
The HPW generation and storage and distribution system charge port on the distribution system which is used to fill
was routinely monitored with a combination of inline and a formulation tank. In both cases, all samples were found to
offline testing to confirm that the system was performing as be below the detection limit of 0.05 EU/mL, which satisfies
expected. Critical performance attributes were identified for the alert limit of Not More Than (NMT) 0.13 EU/mL.
the unit operations within the generation system, along with Total aerobic bioburden test data is presented from two
appropriate test methods and acceptance criteria. The perfor- different locations in the HPW system for the period Janu-
mance attributes were routinely monitored to confirm that the ary through December of 2007. Figure 4 includes data from
system was performing as expected. This includes, for example, the outlet of the HPW generation system. Figure 5 includes
routinely monitoring the free chlorine and bioburden levels Concludes on page 28.
after the carbon filter. In addition, the storage and distribu-
tion system was monitored at various points throughout the
system. This included a rotating schedule of sampling various
use points and testing for bioburden, endotoxin, conductivity,
TOC, heavy metals, and nitrates. Appropriate specifications
were established for the use point monitoring that included
alert and action levels for the various attributes. Data and
acceptance criteria are presented below.

Data Discussion
As discussed above, the HPW was used for cleaning opera-
tions, clean steam feed water, and for formulation activities
in producing dry powders used for inhalation therapies. Alk-
ermes identified test attributes and specifications along with
acceptance criteria that were appropriate for the intended use
of the water. The specifications met the standards outlined
for WFI compendial grade water.
The HPW storage and distribution system was sampled and
tested on a routine basis to monitor the quality of the water.
The schedule included sampling and testing of water from
various points in the HPW storage and distribution system.
Data is presented below from the January through December
2007 period that demonstrates the overall performance of the
system. The data includes test points from the outlet of the
generation system before the product water enters the stor-
age and distribution system as well as at use points within
the storage and distribution system.
Endotoxin test data is presented from two different sample
points in the HPW system. Figure 2 includes data from the

July/August 2009 PHARMACEUTICAL ENGINEERING 27

 WFI Production Methods
cal production operations, manufacturing plant design and
commissioning, and manufacturing technical support. Prior
to Alkermes, Brush has developed manufacturing technology
at Acusphere, PerSeptive Biosystems, and Polaroid. Brush is
currently a member of ISPE and has served on the Board of
Directors for the ISPE Boston Chapter. He received his BS in
materials science and engineering from MIT, and his MS in
chemical engineering from Northeastern University. He can
be contacted by email: [email protected].
Alkermes Inc., 88 Sidney St., Cambridge, Massachusetts,
02139-4137.

Gary Zoccolante is Pharmaceutical Techni-

cal Manager at Siemens Water Technologies.
He has more than 30 years of experience in
the design, operation, and trouble-shooting of
Figure 6. Formulation tank supply port.
pharmaceutical water systems, and has been
involved in the development of equipment for
data from a charge port on the distribution system, which is pretreatment, reverse osmosis, deionization,
used to supply a formulation tank. In both cases, all test data ultrafiltration, and distillation. Zoccolante
from the ports were non-detectable for bioburden or below was a task team member of the original ISPE Baseline® Wa-
the alert limit of NMT 1 CFU/100 mL. ter and Steam Systems Guide and is part of the task team
Total Organic Carbon (TOC) data is presented for the currently updating the guide. He has been part of the Guide
formulation tank charge port, which is located on the HPW Presentation Team on several occasions. He was involved in
distribution system. The data is plotted in Figure 6. The ac- face-to-face meetings with the FDA to help resolve many of
ceptance criteria include an alert limit of NMT 250 ppb. All the Guide principles. He is a member of the ISPE Critical
values tested during the January to December 2007 period Utilities Community of Practice Steering Committee. He
were below the alert limit of 250 ppb. worked on the development of the ISPE Good Practice Guide:
Commissioning and Qualification of Pharmaceutical Water
Conclusions and Steam Systems. He has been selected to deliver the first
This case study presented data demonstrating that WFI can public presentation of the Guide. Zoccolante developed the four
be produced using a membrane-based water purification day ISPE Pharmaceutical Water course and has presented
system. Monitoring data from a calendar year are presented the course to hundreds of pharmaceutical industry person-
for several critical performance attributes of the HPW genera- nel, including the FDA. He is a frequent lecturer for many
tion and distribution system. All of the critical performance pharmaceutical groups and has chaired many courses. He has
attributes met the standards outlined for WFI compendial presented for ISPE, Interphex, American Institute of Chemi-
grade water. cal Engineers, American Society of Mechanical Engineers,
A membrane-based water purification system was chosen Institute for International Research, Center for Professional
to minimize cost and schedule impact when the design basis Advancement, PDA, Pharmtec, Barnett International and
was changed during the construction phase of Alkermes’ many others. He has conducted several in-house courses on
manufacturing site. The addition of an ultrafiltration unit pharmaceutical water production and regulatory require-
operation, which is compact in size, minimized the impact ments for pharmaceutical companies. He has authored and
on the design and layout of the overall water system. The co-authored many papers on pharmaceutical water production
ultrafilter had a relatively short lead time and the capital cost and system operation and maintenance. He holds several
was low. In addition, the operating cost of the ultrafiltration patents for pharmaceutical water processes. He has previous
unit is significantly lower than the operating cost of a still, experience as manager of engineering and manager of appli-
minimizing the impact on operating costs. cation engineering. He holds a BS in mechanical engineering
from Northeastern University. He can be contacted by email:
About the Authors [email protected].
Henry Brush is the Director of Manufactur- Siemens Water Technologies Corp., 10 Technology Dr.,
ing and Process Development at Alkermes, Lowell, Massachusetts 01851-2728.
where he has developed the manufacturing
process technology for the pulmonary drug de-
livery platform. This includes leadership roles
in the scale-up of the manufacturing process
to a high volume commercial operation, clini-

28 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

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July/August 2009 PHARMACEUTICAL ENGINEERING 29

 Amplified Media Circulation
This article
describes Amplified Media Circulation – A New
Amplified Media
Circulation Way for Enhancing Sterilization Cycles
(AMC), which
is an alternative
option to the by David A. Karle, Gerald McDonnell, and
use of intrinsic Teppo Nurminen
sterilizer fans.

Introduction

A
for sealing purposes in powering the fans. Even
ny mechanical moving part in a clean with magnetic coupling technology, problems
environment can present unique chal- with particulate emissions, lubricant contami-
lenges to a manufacturing facility. For nation, and bearing endurance can be a concern
example, in the terminal sterilization with traditional fan designs. In this article, an
of fluids, the associated sterilizer moving parts alternative option to the use of intrinsic steril-
can include conveyors (for loading/unloading izer fans is presented, which is referred to as
of the chamber) and impellers (or fans) within Amplified Media Circulation (AMC).
the sterilization chamber for heating/cooling
purposes. Sterilizer fans are widely used to Alternative Method and Design
optimize the steam sterilization of loads (e.g., Recently, a new method for enhancing air, steam,
for providing laminar steam and air flow for liquid, and/or gas movement in sterilization
good temperature distribution or for enabling processes has been developed. The movement
enhanced cooling times), but are a particular of air or other process fluids within a chamber,
problem as they are enclosed within the chamber such as steam, can be amplified by methods other
of steam sterilizers. In addition to the require- than mechanical agitation (the use of fans). An
ment for emission-free operation for the fans, example is using the “venturi” effect. The venturi
the hot, moist, pressurized conditions associ- effect is actually a rather old concept, named
ated with steam sterilization result in an extra after the Italian physicist Giovanni Battista
stress on these mechanical devices to include Venturi (1746-1822). It is based on the premise
the bearings, shafts, and in the routine main- that a high-speed liquid or gas generates a lo-
tenance (e.g., lubrication) of such components. cal vacuum through the kinetic energy of the
Further, chamber penetrations associated with flowing molecules. Although this might not be
fans require extra design requirements and obvious, this phenomenon is used in many com-
utility supply, e.g., ultra pure water or distillate mon devices, such as car carburetors, gas stoves,
Figure 1. Principle of
venturi effect.

Reprinted from
PHARMACEUTICAL
ENGINEERING®
The Official Magazine of ISPE

July/August 2009,
Vol. 29 No.4

©Copyright ISPE 2009

www.ISPE.org

Continued on page 32.

30 PHARMACEUTICAL ENGINEERING July/August 2009
 Pharmaceutical
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 Amplified Media Circulation

Figure 2. Principle of the AMC ejector.

or paint atomizers. In Figure 1, the venturi effect manifests steam pressure is routinely applied in order to maintain product
itself as the hydrostatic pressure difference (h) between high integrity. Producing compressed air is relatively inexpensive,
and low velocity areas of the demonstration device. especially when compared to the requirements for producing
For specific application to enhanced sterilization cycles, AMC distillate or similar quality water for fan installations. In
differs from the traditional venturi pipe system due to the con- sterilizer applications, the AMC devices’ primary air consump-
figuration of the associated flow channels. Whereas in a basic tion is typically from 22 to 72 m3/h at 4 bar working pressure
venturi design the primary flow in the main channel induces (equaling 13-32 cfm at 58 psig), depending on the sterilizer
a negative pressure component into the side channel(s); in the size. These values are essentially equivalent to the typical
case of AMC for sterilizer applications, the channel arrange- air pressure required for an associated sterilization process,
ment is the opposite. Primary media (like air) is injected into a i.e., any process designed for processing liquid loads. The dif-
narrow side channel, from which it flows into the main channel ference is that with AMC, the peak consumption is sustained
through a radially-symmetric capillary gap at the inlet end of throughout the cooling stage and the air compressor should
the channel. The concave shape of the final section of the side be able to support this level of air consumption on a continu-
channel redirects the flow, making it enter the main channel in ous basis. Essentially, this can be achieved when planning
a skewed angle, pointing toward the other end (outlet end) of the utilities for process support to verify that the compressor
the channel - Figure 2. The subsequent angled flow generates capacity for generating required amounts of pressurized air
a local vacuum into the main channel. This vacuum draws air exists. In a medium or large plant, these rates would not be
(or other fluid) into the inlet end of the main channel, and as considered unusual or high, and in most cases, an existing
a result, the combined main flow (priming air and venturi- compressor would already possess the additional capacity
induced main flow) is typically about 20 to 30 times higher in required. As energy consumption is always a consideration, it
volume flow rate than the primary flow was. In this way, the is important that the additional electrical energy consumed by
higher pressure in the compressed air supply is converted into air compressor is below that of the energy consumed by most
higher, “amplified” flow rates in the main channel. conventional fan motors; this is despite the fact that the AMC
The primary air needed for powering the AMC device(s) approach does not require the pure water supply for sealing
can be taken from any source; for example, a typical steam the required penetration. Typically, the cost of the electrical
sterilizer air supply. The air quality requirements are the same energy consumed is estimated to be around one dollar ($0.33
as for any air-powered process component, being dry, oil-free, - $1.13 or 0.25 - 0.85 E depending on the chamber size) for
and passed through a 0.22 micron filter to ensure its sterility. each cooling hour.
This arrangement is practically no different than any other Utilization of AMC devices is not limited to process air.
terminal steam-air-mix sterilizing process or any associated Steam also can be injected into the chamber through such
liquid process for that matter since all of these require air devices, which also may be considered as “ejectors,” which can
to provide and maintain over-pressure. For example, in the result in enhanced temperature distribution and shortened
sterilization of closed liquids, a pressure higher than saturated heating up times. Steam itself can be efficient in its own

32 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation
right, but nevertheless a definite improvement in heating up
times can be witnessed when the steam flow was amplified by
directing it through AMC devices. Also, the higher the steam
velocities, the more dynamic and effective the penetration into
the load items can be. As stated in a steam sterilizer validation
guide, “determining which load items are the most difficult
to sterilize and which location(s) within the items presents
the worst-case conditions can be a daunting task.”2 Steam
penetration speed during standard operating conditions can
be calculated. Calculations are based on simple diffusion
and convective flow,3 but dynamic disturbances improve the
penetration further by agitating the atmosphere mechanically.
Consequently, in order to achieve an optimal performance, Figure 3. Ejector installation in the sterilizer ceiling.
arrangements can be made for toggling the utility supplies
automatically between ejector/no ejector inlets based on the associated disadvantages. Figure 5 presents tests results with
process phase. Figure 3 illustrates a typical ejector pair in- unaided natural cooling, indirect jacket cooling, fan-enhanced
stallation in the ceiling of the sterilizer chamber. cooling, and cooling assisted with AMC.
Ejector design and function can be maximized for optimal
Practical Applications performance and programmed permanently for that applica-
An example of the practical use of the AMC principle has been tion. An added advantage is that the ejectors do not require
shown for the rapid cooling of liquid loads. Figure 4 presents a maintenance, periodical checks, safety precautions, special
typical liquid load with sealed bottles. A traditional, indirect cleaning, spare parts, or adjustments during the lifetime of
(jacket) cooling of such load can take many hours. Enhanced the sterilizer. Importantly, they do not contain moving parts
with fans or other mechanical devices, the cooling stage can nor require lubrication. The entire ejector assembly to include
routinely be shortened by 50 to 60%. The AMC system meets both the external and internal surfaces, such as the capillary
or even exceeds the performance of currently used mechanical gap, is fully within the steam contact area. Consequently, the
convection systems (fans), but does not possess any of their ejector(s) are sterilized each and every sterilization cycle, as
Continued on page 34.

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July/August 2009 PHARMACEUTICAL ENGINEERING 33

 Amplified Media Circulation

Figure 5. Comparison of various cooling methods.

including AMC devices have been independently verified not

to exceed the OSHA or other safe criteria for operation.
Traditional terminal sterilization applications with fans
have attempted to maximize laminar flow to optimize their
use. This approach most often requires guides or baffles,
thus restricting and redirecting the air flow and consuming
chamber space. With AMC, the penetration is based on high
air velocities which create the necessary turbulence within
the chamber. During the cooling phase of a steam steriliza-
tion cycle, for instance, this turbulence prohibits stratification
without the need for particularly guided flow patterns. Smooth
and efficient cooling has been proven for representative full
loads. Figure 6 illustrates the flow patterns during the cooling

Figure 4. Typical liquid load configuration.

with the chamber and associated piping. Actually, the steril-

izing steam enters the pressure vessel through the ejector(s),
meaning that they are intrinsically the hottest spot in the
chamber and therefore, inevitably become sterile. Contrary
to this design, traditional impellers with water sealing may
become a focus area in the sterility qualification as cold spots
within the chamber. FDA guidelines suggest that special at-
tention should be given to the sterilization of those locations
slowest to heat.1 The sealing water flowing through the shaft
penetration, although not intended for cooling, may induce
colder spots into that particular area.
Another advantage of AMC is that it occupies minimal
space within the chamber. Whereas a fan assembly can be
rather bulky and require auxiliary stainless steel constructions
around it, the AMC ejectors are stand-alone devices extruding
only a couple of inches from the chamber ceiling. Further, the
ejectors do not require any associated electric motors on the
top of the sterilizer, thus minimizing the height and installa-
tion size of the unit. The noise levels of the entire sterilizer, Figure 6. AMC flow patterns during cooling stage.

34 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation

Figure 7. Typical temperature distributions with a full liquid load.

stage. Forced convection is induced by conveying the hot air into account when designing the room ventilation. Often, the
rising through the load to the cold walls. pressure differentials between various rooms are controlled
On the other hand, for some other stages of typical steril- accurately, and in cases like this, the air exhaust may not be
ization cycles (e.g., during the steam sterilization or holding allowed directly into the room, but must be piped either to
phase) turbulent conditions should be avoided. The value the safety relief device line or to the drain line. In the latter
of a pressure difference-driven device, such as AMC, is that case, the air exhaust should be segregated from the room with
when the pressure difference diminishes, the amplifying a water lock (siphon) to prevent the flow from disturbing the
effect decreases in parallel. In this way, the flow rates come pressure differentials between controlled or clean rooms.
intrinsically down when the highest (or desired) pressures are Concludes on page 36.
approached. Subsequently, during the sterilization phase, the
counter pressure in the chamber is at its highest, and the ejec-
tor flow rates are at their lowest and the delicate temperature
balance can easily be maintained through this critical stage.
Also, in the absence of shaft penetrations or cooling water for
the shaft seal, cold spots or undesired convection of heat from
the vessel are easier to avoid. Consequently typical, verified
maximum distribution with a full load has been confirmed to
be in the ± 0.35°C range (Figure 7) including the probe in the
drain line. In an empty chamber, the distribution is normally
within ± 0.15°C - Figure 8.
The same automatic adaptation applies to other phases
of a typical sterilization cycle. During the post-sterilization
cooling stage, higher flow rates are again desired (to enhance
the forced convection and the heat transfer from the load),
and the rates can be artificially boosted by allowing some air
to escape from the vessel in a controlled manner. Mechani-
cal agitators, such as fans, are typically running at the same
speed throughout the cycle, and even though speed variation
solutions that involve frequency drives can be implemented,
the flow rates still do not adapt automatically to the process
conditions as observed with the AMC devices. During the cool-
ing phase, air is also exhausted from the vessel. The ASME
pressure vessel codes state that the exhaust from the vessel
must be piped to a safe place. Usually, the air exhaust from the
chamber can be connected to the same pipeline, often leading
to the outside of the building. If the safety device pipeline for
some reason does not exist, the air could be vented directly
into the room. In this case, the air flow rates must be taken

July/August 2009 PHARMACEUTICAL ENGINEERING 35

 Amplified Media Circulation

Figure 8. Typical temperature distributions with an empty chamber.

Summary became Steris Corporation. He can be contacted by telephone:

Mechanical fans have been the traditional method for forced +1-814-870-8578 or by email: [email protected].
convection within steam sterilizer chambers. More modern Steris Corporation, 2424 W. 23rd St., Erie, Pennsylvania
alternatives to conventional fan, such as the AMC devices 16506 USA.
described in this article, can provide the same if not more ef-
ficient operation, but with less space within the chamber, with Dr. Gerald McDonnell has a BSc. (Hons.)
no moving parts to fail, requiring fewer utilities to operate in medical laboratory sciences from the
and being virtually maintenance free. These advantages also University of Ulster and a PhD in microbial
can be provided to low temperature sterilization and other genetics from Trinity College Dublin. He is
applications with similar technology. currently Vice President of Technical Affairs
and Research for Steris Corporation, based
References at their European headquarters in Basing-
1. U.S. Department of Health and Human Services, Food and stoke, UK. McDonnell is widely published
Drug Administration, Guidance for Industry: Sterile Drug in the decontamination and sterilization area. His research
Products Produced by Aseptic Processing – Current Good interests include infection prevention, decontamination
Manufacturing Practice, Rockville, Maryland, 2004. microbiology, emerging pathogens, and the mode of action/
2. Lewis, R.G., “Practical Guide to Autoclave Validation,” resistance to biocides. McDonnell is a member of the Ameri-
Pharmaceutical Engineering, July/August 2002, Vol. 22, can Society of Microbiology, Society for Applied Microbiology,
No. 4, http://www.ispe.org/pe. Hospital Infection Society, Council of Healthcare Advisors,
3. Nordhauser, F.M. and Olson, W.P., Sterilization of Drugs European Biological Safety Association, PDA, and ISPE. He
and Devices, Interpharm Press Inc., 1998, pp. 65-71. can be contacted by telephone: +44-1256-866560 or by email:
4. Morrissey, R.F. and Phillips, G.B., A Practical Guide for [email protected].
Manufacturers and Users of Health Care Products, Ster- Steris Limited, Steris House, Jays Close, Viables, Basing-
ilization Technology, 1993. stoke, Hampshire RG22 4AX, United Kingdom.

About the Authors Teppo Nurminen has a Master of Science

David A. Karle is a Senior Product/Mar- (Eng) in applied electronics and control
keting Manager for Steris Corporation. He techniques from the Helsinki University of
also is responsible for managing a team of Technology. He has held various managerial
professionals who work with pharmaceutical positions at Steris Finn-Aqua since 1994,
companies to develop sterilization cycles for and he is currently a Manager for Research
their products. Karle started his career with and Development at the Tuusula facility,
AMSCO in 1974 as a senior research scientist. Finland. Prior to Finn-Aqua, he worked as
He maintained that position for 11 years an engineering consultant. He is the inventor or co-inventor
before joining the marketing group as a product manager in numerous international patents related to pharmaceuti-
for healthcare steam sterilizers. Since 1985, Karle has held cal water treatment, steam sterilization, and biohazardous
various positions in product and marketing management of effluent decontamination. He can be contacted by telephone:
consumables and capital equipment in both healthcare and +358-9-2585227 or by email: [email protected].
in the pharmaceutical businesses at AMSCO, which in 1996 Steris Finn-Aqua, Teollisuustie 2, 04300 Tuusula, Fin-
land.

36 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation

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July/August 2009 PHARMACEUTICAL ENGINEERING 37

 Maintenance and Facilities Outsourcing
This article
presents a case Maintenance and Facilities
study on the
area of utilities Outsourcing Excellence –
and facilities
maintenance An Industry Case Study
outsourcing
within the
pharmaceutical by Padraig Liggan
industry. This
approach
shows how
the future for
outsourcing is
moving toward Introduction

A
activities of developing and producing product.
full ownership ccording to Jones,1 it was found that Outsourcing the maintenance function can
of utilities in the early 1990s, as little as five reduce costs by eliminating direct company
and facilities percent of world class manufacturing headcount; enabling management to enforce
organizations outsourced maintenance change quickly, drive continuous improvement,
systems through and facilities services. Within 10 years, by the and improve service levels. This is possible be-
long-term fixed end of the 1990s, this figure had risen to around cause the outsourcing company then becomes
contracts which 30%, particularly in the area of utility systems the ‘customer’ of this activity and is in a better
have shown operations and maintenance. The outsourcing of position to demand the most for their money
maintenance at this time had started to reveal from subject experts.
clear benefits itself as a relatively new trend. Currently, in The outsourcing of utility services within
for both parties 2009, the number of world class manufactur- the pharmaceutical industry will in most cases
involved. ing organizations who are outsourcing utili- include clean utility systems such as high purity
ties and facilities operation and maintenance water and steam systems (purified water, water
is estimated to be in excess of 40% and still for injection, clean steam) and cleanroom Heat-
growing. ing Ventilation and Air Conditioning (HVAC).
The main reasons for outsourcing utilities Facilities services will typically include build-
and facilities maintenance are to allow the ing fabric maintenance, cleaning, and general
manufacturing company to focus on its core building services administration. For the main-
Figure 1. The Wyeth
Biopharma Campus at
Grange Castle.

Reprinted from
PHARMACEUTICAL
ENGINEERING®
The Official Magazine of ISPE

July/August 2009,
Vol. 29 No.4

©Copyright ISPE 2009

www.ISPE.org

Continued on page 40.

38 PHARMACEUTICAL ENGINEERING July/August 2009
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 Maintenance and Facilities Outsourcing
tenance outsource provider, customer satisfaction is a primary who monitors contract performance and contract spend. This
area of focus, which is a motivation for the expert service structure is beneficial to Wyeth and they don’t need to get
provider to deliver a best in class, value for money service, involved in the day to day running of the plant. Through the
not necessarily felt as deeply as in-house staff. Outsourcing cost center owner, Wyeth management has a good visibility of
partners are generally non-unionized and so the risks of strike the performance of the contract and the areas that may need
or halts to manufacturing as a result are extremely low. to be addressed. Performance is measured through areas, such
By setting out clear objectives and outsourcing to an expe- as availability, planned work vs. actual, safety and regulatory
rienced company, great results can be achieved. Outsourcing requirements. For clean utility systems (which are qualified
should not be mistaken with relinquishing of overall respon- systems and feed manufacturing areas directly), high level
sibilities. For example, in the pharmaceutical industry, legal compliance is ensured through Wyeth subject matter experts
aspects such as regulatory compliance for drug manufacturing and the Quality Assurance group in each area. Wyeth has
must be maintained and closely monitored and the outsourc- overall responsibility for the safety of their products and this
ing company must provide safe systems of work. Outsourcing structure needs to exist. Figure 2 details the type of organi-
of utilities (particularly clean utilities) and facilities should zational structure that has been set up for the outsourcing
be a risk-based approach where over time, the contract com- of utility systems in manufacturing areas.
pany becomes more empowered through satisfaction by the The outsourced teams interact with local quality groups
client company that high quality services can be consistently and manufacturing area owners on a daily basis as would
delivered. The company also should employ people to monitor occur in any pharmaceutical organization. Overall, the con-
performance of the outsourced contract and to develop service tract is overseen by a client operations manager along with
level agreements. All the major manufacturing companies in client quality support. One of the key advantages of this
Ireland have adopted various degrees of maintenance and structure is that the outsourced company can be measured
facilities outsourcing as part of their business strategy. This directly against the equipment/system uptime that is being
has paved the way for a new emerging industrial services provided; this is because they own every activity within the
business sector in Ireland: outsourcing services, such as facili- maintenance organization. In some outsourcing situations,
ties, maintenance, and security. Competition in these areas only certain tasks are contracted (also known in industry as
is healthy, which of course encourages the industry-wide “body shopping”). In this scenario, it can be difficult for the
provision of better value for money. This is allowing Irish company to achieve full accountability from the contractor
companies to build expertise in these areas by being able to for systems performance. Where the outsourced company has
support large multinational companies who wish to set up a high degree of ownership of systems, continuous improve-
in Ireland. This ability of these service companies can be a ment is a natural evolution, and this should be supported
positive factor in the decision-making process of a company and encouraged by the client company.
potentially choosing Ireland as a location. A service level agreement sets out clear expectations
and tasks to be performed by the outsourcing partner. The
Building Outsourcing Excellence manufacturing companies’ measurement of the contract is
In 2001, it was announced that pharmaceutical giant Wyeth important; company’s can’t manage what they don’t measure,
was to invest E1.8 billion ($1.8 billion) in a state of the art and this is where Key Performance Indicators (KPIs) have
biopharmaceutical plant at Grange Castle, West Dublin. Later a part to play. The KPIs can be structured in terms of plant
that year, the construction of one the world’s largest biophar- availability, scheduled work completion, and safety and compli-
maceutical plants began at Grange Castle - Figure 1. ance with specific targets, among others. Penalty clauses can
In 2002, maintenance outsourcing began with the external- be employed for performance targets that are not met, this
ization of the utilities and facilities maintenance organization approach creates a mutual gain “win-win” (i.e., both share
in order to operate plant utilities and to setup maintenance the risks and rewards) environment in which all parties see
programs for the site. Although we don’t often see plants of the benefit of high performance.
this size being constructed, this is the best time to form an alli-
ance partnership with the maintenance outsourcing company,
working together from the start, regardless of plant size.
Since 2002 to the present, Wyeth and its outsourcing
strategies have evolved to form one of the best examples of
outsourcing excellence in Ireland today. There are a number
of key areas that have contributed to this success.

Utilities and Facilities Outsourcing:

A Self-Managed Service
Wyeth expects and encourages the outsourcing companies to
have a high degree of ownership when it comes to operating and
maintaining utility/facilities systems. In each manufacturing
area, the contract is overseen by one Wyeth cost center owner Figure 2. Typical outsourcing organization chart for utilities/facilities.

40 PHARMACEUTICAL ENGINEERING July/August 2009

 Maintenance and Facilities Outsourcing
Within the outsourcing structure, the internal site train- company is often referred to as “those maintenance people”
ing systems should be adopted by the contract company for and this stigma creates an “us versus them” relationship,
areas such as procedural, GMP, and safety compliance. There which can inhibit improvement, hinder trust, and have a
should be an expectation that the outsourced company will negative effect on overall plant performance.
continually develop their own employees by providing ad- All of the above approaches by Wyeth create a true partner-
ditional technical/equipment specific training. ship between the client and the outsourced partner, and the
By creating the outsourced maintenance function as a relationship is based on mutual trust and mutual gains.
separate entity, it means that whatever is happening in pro-
duction, good or bad, the utilities and facilities equipment/ Building for the Future
systems performance is not compromised. In cases where the At present in Irish industry, companies are in the process of
maintenance function is in-house, the company departments negotiating long-term contracts with utilities and facilities
have tendencies to abandon the maintenance function tem- service companies who take over full ownership of the plant.
porarily in order to sort out problems in production, which This type of approach can provide for a “Black Box” service,
can potentially lead to system performance and regulatory which further enables the client company to reduce overall
compliance suffering due to lack of focus. costs and focus on their core business. This sort of contract
arrangement is set to become the future for outsourcing of
An ‘Alliance Partner’ not ‘Contractor’ utilities and facilities.
Utilities and facilities outsourcing plays an important role Again this is a win-win situation for both parties; on one
in the day-to-day operation of the Wyeth plant in Grange hand, the manufacturing company has an ability to set long
Castle and for this reason, high recognition is given to the term fixed budget costs for each year in return for the supply
outsourced company by providing them with internal facilities of utilities and facilities services. For the outsourced company,
such as training, computer network access, and opportunities an operational profit is made over the term of the contract,
to become involved in site business initiatives. Instead of be- and investment can be made for the long term development
ing “housed away in the back-yard,” the outsourced company of its people without the fear of losing them through loss of
operates alongside Wyeth on a daily basis. short term contracts. Typical KPI measurements are as fol-
The term “contractor” is very rarely used, rather an “Al- lows:
liance Partner” with Wyeth. In many plants, the outsourced
Concludes on page 42.

July/August 2009 PHARMACEUTICAL ENGINEERING 41

Hach-PAT700-inuse-halfpg.indd 1 12/23/2008 11:13:18 AM

 Maintenance and Facilities Outsourcing
• Utility Systems Plant availability (expectations >99.5%) In 2009, a CHP is set to be constructed at the Wyeth Grange
• Quality Compliance (CAPA Investigations timely closure, Castle plant. This project is an example of the design, build,
maintenance scheduled Vs complete) finance, and operate/maintain model mentioned above.
• Safety (number of incidents, no lost time injury)
• Innovations/plant efficiencies/energy savings (bonus pay- Summary and Conclusion
ment provisions in place) Following research and from the author’s own experience,
• Facilities response times and timely closure of logged the area of maintenance outsourcing has been identified
items as a major part of modern industry. As discussed earlier,
the main driver for manufacturing companies to outsource
With a strong outsourcing partnership in place, it is estimated maintenance is to reduce costs and to enable them to focus
that the pharmaceutical company can expect to make savings on the core activity of making product, while gaining best
in excess 20% in comparison with the alternative internal service performance. However, this is only the baseline of
structure. With a long term fixed price contract, it is within possibilities – so much more can be achieved by approaching
the outsourced company’s own initiative to continuously outsourcing correctly, leading to a high degree of ownership
improve in order to gain a higher profit margin on best ef- by the outsourcing partner, continuous improvement, and a
ficiency and performance of high availability utilities being win-win culture which promotes open/honest communication.
sold back to the client. The future for outsourcing is moving toward full ownership of
utility systems through long-term fixed contracts that have
Design, Finance, Operate, and Maintain shown clear benefits for both parties involved.
During the construction of a new plant, another popular op-
tion is to completely outsource the plant core utilities. Some References
outsourcing companies can design, build, finance, and operate 1. Jones, K.E., “10 Key Indicators of Maintenance Perfor-
and maintain the central utilities plant, which can include mance,” Information Service Centre for Energy Industry,
steam, electricity, air, water, etc. With this arrangement the 1999.
client company can focus on getting its manufacturing fa- 2. Welch, S., “A Plan for Maintenance Success,” Advanced
cilities up and running and be supplied with plant utilities Technology Services, 2002.
which can be purchased at unit cost. At an operating level, 3. Martin, H.H., “Contracting out Maintenance and a Plan
the outsource partner, in close cooperation with the client, can for Future Research,” Journal of Quality in Maintenance
offer ongoing savings and efficiencies in the area of energy Engineering, 1997, Vol. 3, No. 2, pp. 1355 -2511.
use and consumption. 4. Durand, A., “The Benefits of Outsourcing Maintenance,”
This package often includes a Combined Heat and Power Caribbean Business (Industrial Maintenance Supplement),
(CHP) plant, also known as co-generation CHP, which is the 2003.
simultaneous generation of usable heat and power (electric- 5. Ireland, B., “Outsourcing Options,” Electrical Contractors
ity) in a single process. & Maintenance (EC&M) Magazine, 2006.
An overview of a CHP plant is shown in Figure 3; CHP 6. Liggan, P., “The Research and Implementation of Mainte-
plants are over twice as efficient as a traditional power plant. nance Excellence on Clean Utility Systems in the Pharma-
The CHP plants are built on the factory premises, electricity ceutical Industry,” Dublin Institute of Technology, 2008.
is sold back to both the factory and the national grid, and 7. http://www.dalkia.ie – Combined Heat and Power
heat generated by the plant is then re-used in the factory. Plants.

About the Author

Padraig Liggan, MEng, BSc (H), has
worked in maintenance engineering within
the pharmaceutical and dairy industries for
the past decade. He is currently employed
with the energy and facilities management
engineering company, Dalkia Ireland Ltd.,
where since 2003, he has been heavily involved
in setting up start-up maintenance programs
at the new Wyeth, Grange Castle plant. The Wyeth plant at
Grange Castle is currently one of the largest integrated Bio-
pharmaceutical campus’ in the world and is still undergoing
further expansion. He can be contacted by telephone: +353-
1-4648959 or by email: [email protected].
Dalkia Ireland Ltd., 145 Lakeview Drive, Airside Business
Figure 3. CHP power generation. Park, Swords, Co. Dublin, Eire, Ireland.

42 PHARMACEUTICAL ENGINEERING July/August 2009

 Maintenance and Facilities Outsourcing
2010

2010
Facility of the Year
Awards
The Facility of the Year Awards program
celebrates state-of-the-art pharmaceutical
was a winner from manufacturing projects utilizing innovative
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was a winner from the Greater Awards program and your firm may win the
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program and each of the Facility of the Year
was a winner from China. Award winners will receive high-profile attention
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www.facilityoftheyear.org

July/August 2009 PHARMACEUTICAL ENGINEERING 43

 Industry Interview
A veteran
quality
Pharmaceutical Engineering Interviews
executive,
Sharon Bleach
Sharon Bleach, Vice President, Global
discusses her
philosophy on Quality, Operations, AstraZeneca
quality, her
experience
as previous by Rochelle Runas, ISPE Technical Writer
chair of ISPE’s
International
Leadership
Forum, and
insight into
AstraZeneca’s
strategic
approach to
Sharon Bleach fol-
lowed her degree in
biophysics from Sus-
Q What are your primary responsibilities in
your current position as VP, Global Quality,
Operations, AstraZeneca?
significant sex University with a

changes in the
role in research at the
Max Planck Institute
A As a member of the leadership team for
Operations, which is the manufacturing
and supply operation, I am responsible for
industry. in Berlin, then West
the strategy and delivery of quality activities
Germany.
across Operations. I have the additional role
On her return to the
of overseeing all GxP activities throughout
UK, Bleach joined Well-
AstraZeneca.
come’s biotechnology R&D organization at Beck-
enham and then moved into developing deep
cell culture plants in the UK, Spain, Canada,
Japan, and the US. During this time, she also
Q What experiences and training best pre-
pared you for your current position?

studied and earned her MBA from Warwick

University.
Moving from R&D to Quality, Bleach led
A Life itself! I’ve been very fortunate and had
many different roles in my career so I have a
broad experience base. I’ve done both site-based
activities in a number of project and line man- and corporate roles, as well as having R&D and
agement roles across both biotechnology and quality experience. I’ve also been extremely
small molecule areas. fortunate in working with many different na-
After the GlaxoWellcome merger, Bleach tionalities and cultures through the course of my
held quality roles covering UK and European career. That has provided a tremendous learning
sites. Following the merger of GlaxoWellcome experience and opportunity to understand dif-
and SmithKline Beecham, she became Head of ferent things about the different cultures and
Quality for European sites in eight countries, countries, which is very useful in a leadership
later moving on to quality associated with new role such as this.
product introduction in Europe, US, and Puerto
Rico.
Before joining AstraZeneca in July 2008,
she completed 28 years with GSK as Head of
Q What are the major challenges faced by a
senior quality executive in a pharmaceuti-
cal organization?
Reprinted from Quality Strategy, introducing a revised Quality
PHARMACEUTICAL
ENGINEERING®
Management System, leading Quality Training
and Development and involvement in External
A I guess there’s always the “not enough time
in the day,” which is probably typical of
many senior roles in many industries. I think
The Official Magazine of ISPE Relations.
part of it is that regulators look on the quality
July/August 2009, Bleach believes that quality is about keeping
organization as almost a surrogate for them
Vol. 29 No.4 things simple, getting them right the first time,
in the industry, yet you’re operating within a
and working with motivated people who do the
©Copyright ISPE 2009 company, understanding the company perspec-
right things.
www.ISPE.org tives and priorities. Really it’s about how do you
balance what regulators are expecting with the

44 PHARMACEUTICAL ENGINEERING July/August 2009

 Industry Interview
company’s need to be successful and, lines in 2007, so I’m going to assume around how we do that. Essentially, I
in doing all that, making sure patients that the Quality Management System think that’s in line with many different
get the right product when and where at AstraZeneca is based on Q10. Am I companies in the industry.
they need it. correct in that assumption?

Q Please elaborate on your philosophy,

“Quality is about keeping things
A That’s correct! I’ve only been at
AstraZeneca since last July, but the
Q Do you feel ICH guidelines are be-
coming part of the culture within
the quality organizations of pharma-
Quality Management System is linked
simple, getting them right first time, ceutical companies?
to Q10. However, we’re also doing work
and working with motivated people
who do the right things.”
on our quality system to put it into a
new format and to emphasize the pro- A Yes, I think so. I think the poten-
tial benefits from ICH Q8, Q9, and

A Regulations are complex, whether

you take one country, such as the
US and the FDA regulations there, or
cess thinking across the company and Q10 are a significant opportunity for
Continued on page 46.

Sterile Clean Steam Sampling

whether it’s Europe with the European
Medicines Agency (EMEA) and authori-
ties in each member state, or whether
it’s Japan, Canada, Australia, etc. One of
the biggest challenges is how you inte-
grate those different requirements and
how you make sure you’re in line with
all of those different requirements.
I also think you have to have people
who want to come to work, because if
they aren’t enjoying what they’re do-
ing, if they don’t think it’s important,
if they don’t recognize the value that
patients get from what we’re doing in
this industry, then you don’t have the
differentiator that people will keep fo-
cused. So, for me, you’ve got to motivate
people to want to improve, to want to
constantly be looking for the next idea,
the good way of doing things, and how
you can simplify. And the more we sim-
plify the more of a chance we’ve got to
get it right.

Q Do you think that industry and

regulators are understanding that GEMÜ BioStar® Steam Sampler, the innovative automated
keeping things simple is the best way sampling system for the monitoring of pure steam quality
and is that reflected in how they’re revis-
ing and coming up with regulations?
■ Sterile from the steam pipe to the laboratory
Sterilization prior to sampling, sterilized sample container, sterile sample transport
A I think the dialogue is much more
about continuous improvement
now and I don’t think that people
■ Automated, programmable and safe
Hands-off auto sampling method eliminates potential contamination of the sample
think that continuous improvement and minimizes risk of injury to operating personnel
necessarily means adding complexity. ■ Consistent, reliable and time saving
Whether or not as an industry – taking Automation of the activity provides consistency and repeatability while reducing
regulators and suppliers together – we the time required to complete the sampling by plant personnel
have focused enough on simplicity and ■ Easy to install - easy to operate
simplification: No, I think there’s more Simplified connections, easy plug and start, air-cooled, mobile or fixed installation,
we can do there. repeatable and programmed process

Q You’ve presented on ICH Q10 and

been involved in the ISPE and PIC/S
joint conference focusing on ICH guide-
GEMÜ Gebr. Müller Apparatebau GmbH & Co. KG · Fritz-Müller-Str. 6-8 · D-74653 Ingelfingen
Phone +49(0)7940/123-0 · Telefax +49(0)7940/123-224 · [email protected] · www.gemue.de

July/August 2009 PHARMACEUTICAL ENGINEERING 45

 Industry Interview
industry and regulators. So, it would be teams, which enabled us to have some these changes in the best way we can.
shortsighted, perhaps, of companies to energy from ILF Members focused on At AZ we are seeking more partnerships
ignore the opportunities that are there. the key topics that were of concern to and collaborations, as well as driving
You can either say, “Well, we’ll start by industry and to regulators. down our operating costs as much as we
working on these things now and it may can without compromising our quality
not be perfect, but we’ll improve as we
go on,” or you can say, “We’ll hang back
and wait and see how it works.” We’ve
Q What are some of those key top-
ics?
focus, to ensure our approach to drug
development is cost effective, as well
as being sensitive to the unmet needs
decided we’re going to be in the forefront
of this because we think there are some
A One of our major pieces of work is
around supply chain security and
teams looking at what industry can do
of patients.

significant benefits and I know there are

a number of companies that are doing
exactly the same thing.
to more actively engage with supply
chain security initiatives that regula-
Q In light of these challenging eco-
nomic times, some predict that
pharmaceutical companies will build
tors are highlighting they’re particu-
themselves horizontally rather than
larly concerned about. And obviously it

Q Your career has encompassed posi-

tions in R&D and quality. Did your
experiences in R&D help you bring
came a lot from the discussion around
contaminated milk, or melanin, or the
vertically with outsourcing playing
a bigger role in that change. In your
experience with different companies
Heparin situation.
different perspectives to positions and certainly now, are you seeing this
We had a very good discussion
you’ve held in Quality? What are those happen?
about 18 months ago with some of the
perspectives?

A When you’re in R&D you learn very

clearly: You only ever make one
regulators who basically said, “Look,
this is our top priority.” It was really
satisfying to be able to say to the regu-
A Yes. We’re actively outsourcing some
activities, where the activity is not
core and we think another organiza-
change at a time in an experiment oth- lators, “Actually, the ILF has already tion can do it in a more effective way,
erwise you don’t know what impact it’s discussed this and we’ve got a piece of and actively consolidating in house for
had. And that lesson, I think, has stood work we are going to be undertaking others that we see as a core strength
me in good stead when going through a that you’re welcome to be part of and for us. The key is to maintain great
lot of quality changes and initiatives. If provide us with input and we’ll have quality and a focus on delivering great
you make multiple changes at the same dialogue with you about what we’re medicines for patients.
time, you have no idea which ones have doing.” The next step will be during
any impact.
I think in general, it is about under-
standing the whole product develop-
this year’s Washington Conference with
a seminar on Supply Chain Integrity
and Anti-Counterfeiting.
Q In what ways do you believe a
global organization such as ISPE
can assist regulators, pharmaceuti-
ment lifecycle. Understanding the early cal companies, and individuals in the
stages and how you work some of those
things through is helpful in terms of Q In your opinion, what have been the
significant changes in the industry
international arena?

looking at the lifecycle management of

products and what you need to think
in the past decade and what are the
challenges for the future?
A I think one of the greatest opportu-
nities for ISPE is that it provides
a whole series of different forums for
about at different stages.
I also think it’s valuable not to think
of there being some big brick or glass
A One of the big challenges over the
past decade has been that the in-
dustry as a whole seems to have moved
discussion between regulators and in-
dustry and individuals as peers. You can
have very good dialogue about the chal-
wall between R&D and manufacturing
from being perceived as adding value lenges that face the industry either at a
organizations, because the skill sets are
and doing the right thing for patients high level and global picture, or you can
very transferable between the differ-
and people around the world, to being an take it down to an extremely detailed
ent areas. I think it’s great to be able
industry that is not valued in the same technical level and make sure that we’ve
to encourage people to move between
way at all. That image and reputation got a common, good understanding of
different parts of a business to see those
shift and damage is really unfortunate good ways of addressing a technical
different perspectives.
because the majority of people in this issue. And it’s that breadth in terms of
industry are here to do the right thing the range of people who are involved,

Q What was your experience like as

previous Chair of ISPE’s Interna-
tional Leadership Forum (ILF)?
for patients and to make a positive
difference to peoples’ lives.
the range of issues, and the levels of the
dialogue that can take place.
The other thing is the consolida-

A I thought it was a tremendous op-

portunity and really enjoyed doing
it. It was great to have the opportunity
tion that’s going on in the industry
at the moment. Companies across the
industry understand that the future is
Q Coming from a biotechnology
background, what technological
and operational breakthroughs do you
to actively shape where ILF went for a going to be very different, and that we anticipate within the next five years?
period. We set up some different work all have to approach our response to

46 PHARMACEUTICAL ENGINEERING July/August 2009

 Industry Interview

A First, I’d say that my direct biotech

experience was quite a long time
ago. I think one of the things about
really good challenge for the company to
make sure that you don’t just have an
internal perspective. You need to keep
I think that quality organization has
a real opportunity always to shape how
a business is working, to add value to
biotech is that it’s been a long time an eye on what’s going on in the external the business. I think in the past people
coming and we’re still not quite there environment and challenge yourself all used to see quality, at best as a necessary
yet. We’ll see more biotech products the time with that. This role is great cost, and at worst as an unnecessary
coming through as there is a greater and I’m thoroughly enjoying it. encumbrance. Today, it is considered
push for more complex medicines that much more of an opportunity to add
respond to those areas where there is
unmet medical need. But that will be
balanced by the pressure on healthcare
Q What kind of career advice can you
offer to our readers who are pursu-
ing careers in quality?
value to product flow and to corporate
reputation.

budgets and the cost of developing

these biological medicines, which are
more complex and therefore cost more
A I think quality provides a great
grounding and a great way into the
Q What kind of activities do you enjoy
in your free time?

to deliver.
industry. There are technical skills that
people can learn which they can apply
to multiple other roles in the industry.
A I love spending time with family
and friends. I love to garden, to sit
and read, and to have a good glass of

Q What has been your most fulfilling

role so far in your career?
The thinking in a quality group is a
good education and helpful in terms of
wine.
I also enjoy traveling with my family;

A Well of course the one I’m in now,

because it really brings together a
lot of the points I learned, the skills
looking at different perspectives.
I also think there should be a very dy-
namic flow with people coming through
we are planning a trip to Jordan later
in the year to see Petra, the Dead Sea,
and Wadi Rum. I have to get really fit
and experiences that I’ve picked up quality as part of a career or part of an for that I’m told, because my daughter
along the way. It’s great to be able to education process and into other roles. has grand plans about climbing up huge
work in a global role with many dif- So it’s a two way flow in and out of qual- numbers of steps in Petra to get good
ferent countries and different groups ity. Some will be there all their careers, views!
internally. Also, I find it really good to some will spend only a short while there;
be able to work externally. I think it’s a both are perfectly valid.

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• Isolation at product loading and
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all O.E.B. categories.
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HANDLING • GRANULATION • TABLETING • CAPSULE FILLING AND BANDING • WEIGHT CHECKING • COATING • WASHING

July/August 2009 PHARMACEUTICAL ENGINEERING 47

 Water and Steam Systems
This article
presents the Rouge in Pharmaceutical Water and
outcome of
a series of Steam Systems
workshops
on the effects
of rouging in by ISPE Critical Utilities D/A/CH COP
pharmaceutical
water and
steam systems.

Introduction

T
• Pickling, passivation, rinsing
he ISPE Critical Utilities D/A/CH
COP held a series of workshops on Each method should be executed, tested, and
pharmaceutical water and steam. The documented in accordance with a Standard
discussions focused on three aspects of Operating Procedure (SOP). The SOP can be
rouge, including: created with the support of the expert/qualified
company. The responsibility for the execution
• Choice of materials, quality control should be defined in the SOP.
• Engineering, system design
• Service and maintenance Methods
Compressed air
Fifty experts participated in the workshops • Removal of large debris
with a range of experience in various fields, • Check for blockage
including OEM, engineering, material produc-
tion, instrument manufacturing, consulting, QC, Rinsing
and pharmaceutical manufacturing. • Rinsing is used to remove:
- Loose debris or water soluble substances
Choice of Materials, QC-Service - Detergents, etc.
System Startup • Rinse after each treatment step.
The desired condition for new systems (zero or • The water quality for each rinse step should
initial-state) should be well defined. be defined individually. Purified Water (PW)
is usually sufficient.
• Sufficiently detailed specifications should • The PW should have a pH of five to seven at
be available for all components (material, the end of the rinsing cycle.
surface roughness, and tolerances) and these
should be tested during the qualification Degreasing with Alkaline Detergents
phase. The thermal and chemical resis- • Removal of debris
tance also should be checked. Furthermore, • Wash out fatty or oily substances
special care should be taken regarding the
cleanliness of all components from the time Chemical Cleaning/Pickling
of delivery onward. • The makeup of the chemical solution should
• If possible (cost feasibility), the materials be suitable for the surface roughness of the
for pipes, fittings, and valves should be the system (qualified SOP).
Reprinted from same to avoid different behavior (welding). • Removal of contaminants (nonalloyed ferrous
PHARMACEUTICAL components, shavings (alloy and nonalloy),
ENGINEERING® Definition of “Treatment” construction dust, discoloration, etc.)
The Official Magazine of ISPE At the end of the installation phase, the entire • In special cases, such as surface damage,
assembly must be dry. removal by chemical reaction (erosive)
July/August 2009, The following methods are considered treat- • Electro polished systems, if pickled, are pick-
Vol. 29 No.4 ments: led without material removal (see following
©Copyright ISPE 2009 comments).
www.ISPE.org • Removal of any installation debris, i.e., using “Pickling:”
compressed air, degreasing, etc. Pickling (cleaning) with weak acids (citric acid,

48 PHARMACEUTICAL ENGINEERING July/August 2009

 Water and Steam Systems
phosphoric acid) dissolve just surface contamination without is required for the production, then the final rinse should
damaging the material. The passive layer remains intact. be conducted using WFI.
Erosive pickling only takes place using reducing acids or acid
mixtures, such as nitric acid or nitric and hydrofluoric acid Handover Criteria
mixtures and results in the chemical removal of the passive • The success of the rinse should be proven using suitable
layer. This is usually not necessary for the pharmaceutical acceptance criteria, for instance, conductivity and TOC are
industry. frequently used. The tolerance range should correspond to
In general, the comments regarding erosive and non-erosive the same predefined range as the rinsing water.
pickling are necessary because pickling always removes some- • Visual control at accessible points or with video endoscope
thing. A film or discoloring could be seen, but are removed can be used to ensure that no installation debris (non-
during pickling, revealing the layer below. suspended particles) has been left behind.

Passivation Measures for Existing Installations

• The passive layer is always present in a neutral, water The system components for existing installations should have
based system at ambient temperatures, even at atmo- documented specifications. If this isn’t the case, then the cur-
spheric exposure with air (oxygen environments, chemical rent state of the system components should be documented
equilibrium). through a detailed system analysis. At least the following
• The stability and homogeneity of the passive layer is de- aspects should be considered as adapted treatment methods
pendent on the redox potential. or processes may be required:
- An oxygen supply is necessary for an optimal redox
potential. • Material qualities
- A low pH is unfavorable. Since CO2 reduces the pH - Corrosion resistance is dependant on these character-
value, its concentration should be minimized. istics. Therefore, if rouging is corrosion, it follows that
Developing the Passive Layer the material quality influences the rouging tendency.
• The presence of O2 or other oxidizing agents, such as ozone, • Surface condition (surface roughness, visual evaluation of
supports the development of the passive layer. the surface condition, type and extent of the rouging)
• The passive layer can be artificially developed with
chemical treatment. The results of such a treatment are Continued on page 50.
only temporary and not permanent. In time, the system
will return to the equilibrium state dictated by the redox www.ISPE.org/innovationshowcase
system.
Register today!
Testing the Passive Layer (Thickness)

ISPE
• The passive layer doesn’t normally need to be tested since
it is naturally present.
• There is no regulatory requirement to test the passive Facility of the Year:
layer.
• The thickness of the passive layer is dependant on the
Innovation Showcase
surrounding conditions; therefore, varies according to the

2–3 November
conditions in the pipe (for example, if the pipe is filled with
liquid or air). Due to this variability, testing the thickness
of the passive layer only gives information on the state of Ulm, Germany
the layer at the time of the testing.
• Possible measuring methods can be conducted by quali- Learn about the latest
fied experts. Laboratory tests (destructive testing), such state-of-the-art developments
as X-ray photoelectron spectroscopy, are time consuming being implemented by
and expensive. manufacturers in the region.
• Non-destructive online measurements, which character-
ize the condition of the material, have been proven in the • Seminar on innovation in pharmaceutical engineering
chemical industry. These are indirect measurements, using
and manufacturing
• Case studies on innovation presented by recent
sensors made of the same material, which are evaluated Facility of the Year Awards winners
using complex algorithms. • Background on projects
• Q&A sessions
Final Rinse • Networking reception
• With water for injection, highly purified water, or purified
• Site visits to award-winning sites
water the minimum required water quality should be
defined (potential cost savings). This quality should be at Sponsorship and Table Top Exhibit
least equal to the operating medium. For instance, if WFI Opportunities Available

July/August 2009 PHARMACEUTICAL ENGINEERING 49

 Water and Steam Systems
• Safety aspects, such as solid connections rather than flex- tolerances must be observed, regarding the piping connec-
ible tubing tions.
• Disposal of treatment and rinsing solutions • Mix of materials – for instance, a stainless steel tank, pip-
ing in PVDF. A rouging layer can be transported onto the
System analysis and evaluation should regularly take place plastic surfaces.
using existing monitoring results. • The chemical tolerance of PVDF is limited to a maximum
of pH 12 (relevant for treatment chemicals).
Definition of Treatment
If the system analysis shows a need to take action, suitable Metal Alloys
treatment methods from the list above should be used. The austenitic stainless steels used most frequently in the
pharmaceutical industry are 1.4404/1.4435 (316L), 1.4571
Measures for Derouging (316Ti).
De-rouging of Existing Installations Pros:
The derouging method should be conducted, tested, and docu- • They can be used for cold and hot media. Almost all com-
mented in accordance with a Standard Operating Procedure ponents are available in these materials.
(SOP). If necessary, existing warranty conditions should be Cons:
taken into consideration. • Stainless steel is susceptible to rouging.

• The SOP can be developed with qualified experts. Specific characteristics of individual alloys:
• The responsibility for the execution should be decided in • 1.4404 – somewhat less Mo (0.5%), slightly reduced corro-
advance. sion resistance in hot systems. Good availability (tubing,
fittings, instruments, valves, etc.)
The recipe should be based on the following: • 1.4435 – limited availability of fittings and instruments.
Expensive material. Also susceptible to rouging.
• Current state (see above)
• Suitability tests (effectiveness) should influence the choice Other alloys also are possible; however, they may be more
of the process. difficult to procure and are significantly more expensive.
1.4539, 1.4462 (Ferritic-Austenitic Duplexsteel), Ni-Basic-
The frequency of derouging should be based on the following Alloy, Alloy 33 (high content of chromium), Titanium.
criteria: Pros:
• These special materials could be more resistance to roug-
• In accordance with monitoring results (months, years) ing; however, this has not been proven yet.
• In accordance with experience and knowledge of the instal- • 1.4462 is resistant to rouging for a wide redox range in
lation pure water systems, but doesn’t solve all problems.
• Dependent on the state • Optimizing the passive layer through higher chromium
content. The Alloy 33 with 33% Cr shows a chromium
Testing and documentation can be assigned to the contract- content in the passive layer of 83% after exposure to 95°C
ing company. pure water.
• No experience with Nickel based alloys. Rouging has been
• Visual inspection in accordance with agreed acceptance observed with Hastelloy C-276, which is not surprising
criteria (colors, film, etc.) considering the lower Cr content.
• Wipe test • Titanium stabilized materials: valves and regulating valves
• Photos, etc. in WFI systems are often made of 316Ti.
Cons:
Choice of Materials and • Due to cost and availability, 1.4539 und 1.4462 are only
Processing/Machining used in special cases.
The choice of materials influences the formation of rouging.
Delta Ferrite Content
Plastics • The delta ferrite criteria can be traced back to the BN
Pros: 2 (Basler Norm, a guideline of the Swiss Chemical and
• No rouging because it is a nonmetallic material Pharmaceutical Industries), where a very low delta ferrite
Cons: content of 0.5% is defined. The original intention of BN2
• Thermal deformation from variance in temperature (hot was to just take the delta ferrite content into account. The
operation or sanitization) delta ferrite limit was specified as a preventive measure
• New design of piping supports (high expansion value) and is not based on scientific proof. The limit is too strict
• Aging stability (hot sanitizations) and is not practical. It dictates the use of steel, which is
• Not always feasible for hot systems. Pressure and vacuum considerably more expensive and compliant welds are

50 PHARMACEUTICAL ENGINEERING July/August 2009

 Water and Steam Systems
considerably more difficult to achieve. Surface Quality
• Many of the participants have found that 3% is a more fea- Stainless steel is always produced with a specific surface qual-
sible limit. Since several participants also have had positive ity. The many variations, which are common for piping, are
experience with considerably higher delta ferrite levels (no well defined in industry standards. There also are standards
unusual rouging observed), 5% was suggested as the maximum which described terms and conditions for delivery.
for a preventive measure. It should be noted that calling 5%
a preventive measure against rouging is not quite correct Common Design:
as lower delta ferrite levels won’t have a negative effect on • Seamless tubing or longitudinal welds
rouging, but could drive up the material costs. • Mechanically polished or honed (bright finish, bright rolled,
• The goal (specification) should be 3%. Specifying < 3% is and cold drawn)
not recommended based on the experience of the group. An • Not pickled, just rinsed with water
absolute maximum value of 5% should not be exceeded.
• A complete lack of iron can result in a significantly higher Pros:
susceptibility to heat cracks and require the use of special • More economical than electro polished tube
weld filler metal. Cons:
• This aspect is overvalued regarding its potential negative • These surface qualities are often treated in situ.
influence on rouging. The delta ferrite has a more elevated With the exception Ti or Nb stabilized steel, all steel is
Cr content and is fundamentally more resistant to rouging available with electro polished surfaces, which can lead to
than austenitic (bulk) structure. further improvement
• This does not protect against rouging! • A roughness of Ra < 0.8 µm should be specified
• The limit for delta ferrite was created as a measure of
corrosion resistance and it can be used as proof of weld Pros:
quality. The delta ferrite measurement is an economical • Due to the reduced surface area and the more compact,
and useful method to test weld quality if the weld filler clean (free from defects) passive layer in comparison to
material is fully alloyed. non electropolished surfaces, electro polished surfaces
• The delta ferrite content does not have an effect on the generally show less tendency to rouging.
prevention of rouging.
Continued on page 52.

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July/August 2009 PHARMACEUTICAL ENGINEERING 51
 Water and Steam Systems
• Better cleanability with higher surface quality Engineering, System Design
Cons: Influencing Factors
• Treatment with strong acids roughens the surface. How can rouging be avoided through engineering and system
• Special care must be taken if any secondary welding is design of the water treatment plant?
required. Various aspects under consideration of possible influencing
• The welds in the pipe system can influence the surface factors, such as the design itself and monitoring, should be
quality. considered.
The following factors, which all could possibly effect the
Welding Procedures development of rouging, were considered in the workshop:
The Processing of the materials should be clearly defined,
while taking into account the following criteria: 1. CO2
2. Temperature
• Goods-in quality control (QM, QS, documentation) 3. Nitrogen
• Storage conditions and environment (low dust) should be 4. Oxygen
specified 5. Particle Carryover
6. Ozone
A. Weld Preparation 7. Feedwater
• Cutting of non alloyed ferritic materials à these develop 8. Choice of Materials
very aggressive particles. 9. Sanitization Process
• Cutting of alloyed materials leads to conversion to mar-
tensite (magnetic, less corrosion resistant). 1. CO2
• Do not use a cutting disc, grinder. Elevated CO2 concentrations cause a decrease in pH. This
can lead to destabilization of the passive layer, particularly
B. Welding Procedure in hot systems (80°C).
• Define welding procedure in advance (orbital or manual)
• Develop and qualify site specific welding procedures 2. Temperature
• Welder’s qualifications should correlate to the qualified Since rouging is a form of corrosion, it is expected that there
welding procedures (see above) is a system specific temperature above which the rouging will
• Automatic welding procedures (MIG, WIG) increase with further temperature increase.
• Laser, plasma welding procedures (tanks, etc.)
• Manual welds allowed as exceptions 3. Nitrogen
Nitrogen blanketing of storage tanks removes the presence
C. Weld Filler Metal of oxygen in the tank atmosphere. This leads to a drop in the
The corrosion resistance is improved when higher alloyed filler oxygen concentration of the water, reducing the redox potential,
metal in comparison to the welded material is used. This also which results in a change in the passive layer.
helps maintain a low delta ferrite content (experience: of the
same kind as basic material). 4. Oxygen
Oxygen facilitates the natural continuous re-passivation of
D. Weld Testing and Documentation the steel surface.
• All welds should be visually examined (naked eye, endo-
scope). A predetermined percentage of the welds should 5. Particle Carryover
be documented with photos, DVD, or video. Possible particle carryover from the water purification equip-
• Examination of the weld formation and any discoloration ment or WFI still into the distribution system can be avoided
should be included. or minimized through proper design.
• An alternate testing method should be set for welds, which
can not be visually examined (X-ray, sample weld before • For example: by avoiding the use of non-alloyed steels for
and after the true welding, etc.). construction or piping material as well as through appro-
priate operating conditions.
Further Documentation: • Further measures can only be defined once the possible
• Risk analysis, sample welds formation mechanisms for ferrous compounds have been
• Weld plan, weld supervision, work instructions, welding fully identified.
procedure qualification
• Welder qualification It is assumed that semi- intermediate- and final products
• “Technische Regel TR 153,“ Gütesicherung von Schweißnäht- (bulk) will pass particle filtration steps during the produc-
en an Apparaten und Rohrleitungen“ issued by the Basel tion process.
Chemical Industry (BCI). Available in German only.

52 PHARMACEUTICAL ENGINEERING July/August 2009

 Water and Steam Systems
6. Ozone -The material is more susceptible to local corrosion
Ozone, frequently used in cold storage and distribution sys- depending on the degree of cold forming; however, this
tems, is thought to favorably effect the formation of the passive isn’t relevant for high purity water systems.
layer on the steel surface. However, ozone concentrations over - Bending pipework is often preferred, due to economic
about 1 ppm can lead to corrosion when chlorides are present reasons.
and standard alloys, such as AISI 304 and 316 are used. • CO2 elimination
- Protecting WFI stills and pure steam generators by
7. Feed Water installing selective degassing steps upstream
A detailed examination of the feed water quality is necessary - CO2 traps can be installed on the product water storage
during the equipment engineering phase to identify possible tanks to prevent CO2 from entering the distribution
corrosion sources. system. The CO2 trap shouldn’t be allowed to collect
The goal is to eliminate iron, manganese, silica, CO2, and moisture as this can cause blockage.
chlorides.
Monitoring
8. Choice of Materials • Visual inspection using sight glasses, inspection pieces, or
The choice of materials is handled in detail under “Choice of opening the pump housing
materials, QC.” • Inline measurement
- Direct quantitative measurement of rouge is not com-
9. Sanitization Process mercially available. Such monitoring technologies are
Since high temperatures support corrosion, the temperature currently in development.
in a given system should be kept as low as possible without • Other parameters and measurements
compromising safe operation. Frequent steam or hot water - Measuring methods for parameters, such as pH, par-
sanitizations could support rouge formation with the tem- ticle quantification and size, and CO2 concentration
perature and time being the deciding factors. Reasonable are available. Their influence on rouging has not been
sanitization intervals should be set based on monitoring results conclusively studied or proven.
(qualification phase, performance qualification, routine).
Service and Maintenance
Design Suggested Procedure
The following design criteria should be critically analyzed A risk analysis is a valuable starting point for the selection
as part of a risk analysis. The focus should be on the effects or determination of measures, which are to be implemented
on the equipment itself, on the operation of the equipment, in the service and maintenance plan. The experience of the
and on the product. operator as well as the previous actions of the engineering
or maintenance and quality control departments also should
• Sanitization and Cleanability be taken into account.
- Drainability The risk analysis should work out which parts of the sys-
- Rinsable pure steam piping, for example, design the tem are critical and define the necessary treatment (to what
condensate piping system in a way in which it can extant, in which intervals, to which time point, and with which
be used to provide circulation during future chemical measures).
treatments (passivation, de-rouging). Figure 1 shows a possible procedure for the development
- Optimization of the cleaning procedure to simplify and of a plant specific service and maintenance plan.
reduce the amount of cleaning agent needed It is generally accepted that suspended particles in low con-
• Allow for removable inspection spool pieces in the piping centrations can be present and will be removed at filters.
- Installation of easy to access spool pieces, such as elbows The usual sample methods based on the Pharmacopeia
or bends at reference points in the piping system where will usually not discover the presence of particles.
rouging is expected The current findings show no influence of rouging on the
- These pieces should be easily replaceable to allow de- mechanical stability of piping and components. It seems
tailed analysis with destructive testing in the lab when prudent to involve all parties, for instance, operator, quality
necessary. control, engineering, and maintenance in the risk analysis
• Demisters in the form of wire mesh should be avoided process. Some of the issues and problems which they will
when possible, due to their large surface areas. Cyclone address are:
separators are acceptable.
• Welds are seen as a risk factor. • What are the possible effects on the product? Is it an API,
Correctly welded seams using WIG-process and with suf- end product?
ficient weld seam protection (inert gas shielded) do not • Can dissolved metallic ions occur (such as ferric ions) and
add to the corrosion risk. what influence would this have on the product?
- Cold bending offers a possibility to reduce the number • Can adherent metal hydroxides occur (Fe-, Ni-, Cr-) and
of welds in a system, particularly for smaller pipe di- what influence would this have on the product?
ameters (i.e., up to DN25). Continued on page 54.
July/August 2009 PHARMACEUTICAL ENGINEERING 53
 Water and Steam Systems
Both on and off-line tests can be used as well as testing
the surface of spool pieces removed from the system.
An inspection plan can be created in order to collect enough
information and empirical test results to allow optimiza-
tion.
The following inspection and evaluation methods can be
defined and used primarily:

• General visual inspection, e.g., through an inspection glass

or with endoscope
- Possible assessment: color (yellow, orange, red, brown,
etc.) or surface finish (dull, shiny, morbid)
• Swab test (results: particles are removable, partly remov-
able, not removable)
• Optical inline measurement
• Particle measurement, online/inline
• Filter: the water is filtered offline at 0.1 µm and the filter
membrane then undergoes laboratory analysis and evalua-
tion, for instance, checking if discoloration or particles are
present. This type of test should be carried out at prede-
termined intervals and the test results should influence
the testing intervals.
• Inspection spool pieces: the following should be taken into
account:
- The piece should be representative of the system in
terms of surface finish, material, etc.
Figure 1. Flow chart risk analysis.
- Critical points in the system
• Are filters in place which would be negatively impacted - They do not necessarily need to be built into straight
by particles? piping segments.
• Can deposits form on measuring probes and sensors? - It is better to use pieces with elbows, valves, or instru-
• If rouging occurs, could it negatively impact downstream ments. Procedure and use of spool pieces:
plants or equipment? à The spool piece is removed during maintenance and
• Are heat exchangers present and could these be negatively is used as a reference which is used as a sample for
impacted? testing different cleaning methods.
• Are components, such as injectors, present whose func- • Electro-chemical methods
tion would be negatively impacted by the presence of
particles? Monitoring data can be regularly evaluated on the basis of
• Further critical parts could be: pumps, instrument ports, the monitoring plan. The results are used defining objective
tanks, valves, spray balls, forged components, vacuum acceptance criteria and specifying the required state of the
molded components. system.
• Are unplanned events expected whose frequency would
influence the availability of a plant, for example, when a Maintenance Plan
cause analysis and subsequent service and maintenance One of the most important goals for evaluating the inspection
measures are necessary after an OOS finding? results is their further use toward development of a system
• Are measures to restore the defined state necessary after specific maintenance plan.
repairs or planned expansions or changes to the system, All results from the inspection, particularly from the spool
such as rinsing, passivation, pickling etc., after welding pieces, should be taken into account in the development of
work has been done? the plan and in determining the steps which are to be taken.
• Could the surface finish be changed by deposits? Will this Depending on the actual situation, the plan can contain the
favor biofilm formation? following points and actions to be taken:

Inspection Program • location of the inspection or actions to be taken

A periodic monitoring program should be established to provide • responsibility
regular controls at the critical points of the system, which • frequency or interval of the inspection or execution of the
were defined in the risk analysis, to collect experience and actions to be taken
information, for instance, through photo documentation. This • experience from previous cleanings, when available
provides the basis for the service and maintenance plan. • execution of a cleaning procedure, when necessary

54 PHARMACEUTICAL ENGINEERING July/August 2009

 Rouge
• For especially critical cases in clean steam systems, a
particle filter can be installed at the point of use. For this
application, a filter size of < 0.1 µm is generally accept- Your Single Source Solution Provider
able. Director Series
• Carbon dioxide absorbers can be used, for instance, on
water storage tanks. Reactor Temperature
Control Module
If the decision has been made that cleaning is necessary, the
following issues should be decided, where appropriate:

• Should a general chemical clean take place?

• choice of the cleaning media (anodic clean, electro polish-
ing)
• definition of success factors, using monitoring methods,
such as conductivity, inspection spools etc., or use of pas-
sive layer measuring device, Ferroxyl test (ASTM-A380)
• definition of cycles and time periods, dependent on pro-
cess
• In the case of older systems, special attention should be
placed when defining parameters to take into account
design, material, and components.

The operator must ensure that the following is met:

• Execution description exists and is accepted.

• Critical parameters, such as the treatment temperature
and soak time are defined.
• The execution is properly documented. Features Include:
• The scope of documentation is defined. � Temperature Range from -80º to +285ºC
• The execution and scope of evaluating if the treatment
was a success is defined. � Stainless Steel Construction
• Procedure or maintenance plan is approved. � Sizes from 20 Liter to 500 Gallon Reactors
Regulatory Aspects � Jacket Delivery Pressure Control
In order to ensure that the current regulatory requirements
� Single Loop or Cascade Control
are understood, it is advisable to keep up to date on the
available audit information (FDA Warning Letters) as well � General Duty or Explosion Proof
as literature and publications. Classification
Should the regulatory agency check how rouging is handled,
� PLC Control, Data Logging & Trending
it should be possible to present and explain how the procedure
defining the maintenance and inspection plan was conducted
Software, Self Tuning for Accuracy ±1ºC
as well as the results.
The operator must ensure that cleaning (derouging), moni- Budzar Industries has specialized in process
toring, etc. is documented. In particular, a treatment report fluid heat transfer systems since 1975 and has
should be available which documents the results (also with earned a global reputation for quality and
photos) and in which all relevant points are systematically ingenuity in the design, engineering, and
addressed. manufacturing of temperature control systems.
Budzar Industries systems are found throughout
About the Authors the world, delivering accurate temperature
The Critical Utilities D/A/CH is a local ISPE Community measurement and control to the production of
of Practice (COP) comprised of individuals from Germany/ pharmaceuticals, chemicals, petroleum, rubber,
Austria/Switzerland with expertise in pharmaceutical water power, steel, food, and plastics.
and steam.
Budzar Industries
Visit the Critical Utilities (CU) COP on the ISPE Web site 38241 Willoughby Parkway
for discussions on other related topics --- Willoughby, Ohio 44094
http://www.ispe.org/communitiesofpractice 440-918-0505 • www.Budzar.com

July/August 2009 PHARMACEUTICAL ENGINEERING 55

 Reprinted from

Global Regulatory News PHARMACEUTICAL

ENGINEERING®
The Official Magazine of ISPE

July/August 2009,

Europe Dealing Regulations SI 2005 No 2789 International Vol. 29 No.4

Denmark was replaced by the regulation SI 2009 ASEAN Countries ©Copyright ISPE 2009
www.ISPE.org
Defects Medicines – No 1164 in May 2009. GMP Inspection Reports6
Packaging1 Amendments have been made which In April at the Pattaya summit in Thai-
The annual report on product defects affect the labelling requirements for land, a mutual recognition agreement
and recalls for 2008 covering both antiviral medicines for children under was signed by 10 ASEAN countries
marketed and non-marketed medicines the age of one year in a pandemic situ- agreeing to recognise certifications and/
was published by the Danish Medicines ation, allow for notice of urgent safety or inspection reports on good manu-
Agency. This report showed most of measures to be given as soon as possible facturing practice of pharmaceutical
the recalls were issued because of to the licensing authority and an ethics companies within the region.
wrapping defects. Reports on the lack committee during a period in which a All ASEAN member states are
of adherence to good manufacturing disease is pandemic and is a serious expected to fully implement this mu-
practice regulations also were sent to risk to human health, and enable the tual recognition agreement by the 1st
the agency as a result of inspections wholesale distribution of unauthorised January 2011 and the GMP certificates
carried out by various European medi- medicinal products in response to the and reports will be used as the basis
cines agencies. suspected or confirmed spread of health- granting approvals, delivering licenses
The most current defect reported harming substances. to the manufacturer, supporting post
was regarding packaging. Most of the The regulation came into force on 8 market assessments of conformity for
defects were related to packaging or May 2009. products and providing information
repackaging processes and to wrap- on manufacturer facilities or testing
ping – usually plastic – and mainly EudraGMP Database4 laboratories in the ASEAN region.
concerned the printing of incorrect The Medicines and Healthcare prod- In this agreement, the format that
expiry dates on packaging. ucts Regulatory Agency (MHRA) drug regulatory authorities will have
Only five side effects related to implemented a new system that will to follow when issuing the GMP inspec-
product defects were reported in the automatically transfer data from its tion reports is specified. Information on
177 reports filed with the agency. medicines database Sentinel onto the dosage forms manufactured at the
the European database EudraGMP facility and manufacturer compliance
United Kingdom launched in 2007 and maintained by with the GMP requirements will be
Notifying the GLPMA of the European Medicines Agency.1 The captured in inspection reports.
Changes within a GLP Test EudraGMP database was launched Under this agreement, where a
Facility2 in order to facilitate the exchange of manufacturing facility has not been
In April 2009, the Good Labora- information on compliance with good inspected recently, a Member state
tory Practice Monitoring Authority manufacturing practice. can request its counterpart to carry
(GLPMA) released a guidance advising Information on manufacturing and out a specific and detailed inspection.
manufacturers about the declaration importation authorisations and post- The aim of this GMP mutual recogni-
form to the GLPMA that needs to inspection good manufacturing practice tion agreement is to move closer to its
be filled out when there are changes certificates issued by the MHRA will 2015 goal of a single Southeast Asian
made within a GLP test facility. This be automatically published on the market. The agreement will help to
GLP TEST FACILITY form was part of EudraGMP. ensure the safety, quality and efficacy
the risk assessment process settled by The MHRA Director of Informa- of medicinal products manufactured in
the GLPMA in order to ensure public tion Alison Davis said this system will the region.
safety and compliance with the Good ensure the information in EudraGMP Consumers will benefit from greater
Laboratory Practices (GLP) standards. remains current while reducing the confidence in the safety of medicines
Changes to be notified to the GLPMA burden of data transfer. being sold and the business costs of
will be the volume of GLP work un- manufacturers will be lowered by the
dertaken, types of GLP activities Turkey mutual recognition of inspection reports
undertaken, contracting out of GLP GMP5 as they will not be required to undergo a
functions, facilities and equipment, The GMP guideline was revised in repeated testing or certification process
personnel aspects and other changes accordance with the EMEA and ICH for marketing their products in the dif-
such as changes in company owner- Guidelines and the specific condi- ferent member states.
ship or changes to the management or tions in Turkey. It was approved and
organization structure. published on 11 May 2009. During Brazil
inspections performed by the MoH, Manufacturing Resolutions for
GMP – Update to Labeling the manufacturers of pharmaceutical Influenza A Vaccines (H1N1)7
Requirements for Pandemic preparations and active ingredients will The National Health Surveillance
Antivirals3 be required to comply with provisions Agency (ANVISA) issued on 7 May 2009
The Manufacturing and Wholesale of this Guideline. the Resolution RDC 18 for Manufactur-

56 PHARMACEUTICAL ENGINEERING July/August 2009

 Global Regulatory News
ers of influenza A vaccines (H1N1) in pharmaceutical trading hub. ment – for example, validation and
Brazil. An area of approximately 3,700 qualification activities; and to support
This resolution states that the m2 will be allocated for this zone and provision of GMP certification to New
manufacturing of influenza A vaccines among other things, it would include a Zealand's mutual recognition aggree-
(H1N1) in Brazil will be previously cold room facility with varied tempera- ment partners on behalf of New Zealand
authorized in Brazil provided that the ture zones (-20° to 8°C), a comfort zone manufacturers exporting medicines to
following requirements are fulfilled: (with temperatures below 25ºC) for the other countries.
examination of pharmaceuticals, and a Stakeholders were expected to be
• manufacturers hold a Marketing Au- basic testing facility to check samples informed by Medsafe of its final deci-
thorization granted by ANVISA for of pharma products. sion on 15 June and will publish the
manufacturing seasonal influenza Separately, new measures have updated edition of the NZ Code of GMP
A vaccines been initiated by the Indian Ministry on 1 July, which will come into effect
• manufacturing takes place in sites of Commerce and Industry in order to on 1 September.
authorized by ANVISA for the manu- combat criticism from some countries
facturing of influenza vaccines that drugs being exported by Indian Philippines
• the Influenza A viral strain (H1N1) manufacturers do not meet interna- Streamlining Drug Registration
used for the manufacturing is the tional quality standards. Processes9
one issued by the World Health A public notice was issued by the Measures to streamline the registration
Organization Directorate General of Foreign Trade process of pharmaceutical products
to inform new procedures/guidelines to have been proposed by the Philippines
ANVISA will need to be formally noti- strengthen the enforcement mechanism Bureau of Food And Drugs. These mea-
fied by the Marketing Authorization available under the Drugs and Cosmet- sures aim at improving patient access to
Holder/ manufacturer immediately ics Act 1940, to ensure that counterfeit medicines. The use and implementation
after reception of the viral strain for drugs do not get exported from India. of electronic data messages, documents,
production of the vaccine. As per this notification a copy of the and signatures for product registra-
From the reception of the strain, certificate of analysis issued by the tion can be implemented in July if the
the whole manufacturing process of manufacturer for the subject product proposal is finalised.
the vaccine will be under supervision along with other documents will be The proposed measures have been
by a Regulatory Technical Committee requested to every exporter of drugs outlined in the form of a draft admin-
formally established by ANVISA. and pharmaceuticals, at the time of istrative order, which would apply
This resolution came into force on 7 shipment. to all pharmaceutical products for
May 2009. human use (except traditional and
New Zealand herbal medicines). It would also cover
India GMP Code Updated10 all manufacturers, traders, importers,
"Pharma Zones"8 Proposals to change the New Zealand exporters and distributors of these
The Indian Central Drugs Standard Code of Good Manufacturing Practice products.
Control Organisation (CDSCO) is have been announced by the New By this order for a drug not registered
seeking feedback on its plans to create Zealand's regulatory agency Medsafe. with the agency, manufacturing, im-
dedicated climate controlled "pharma Comments on the proposals from porting, exporting, selling, distributing,
zones" within the cargo area of all major Stakeholders were until 15 May 2009. transferring, promoting or advertising
airports and seaports. These proposals aim to bring the New would become illegal. Comments on the
Proper storage and examination of Zealand Code of Good Manufacturing proposed measures were accepted until
pharmaceutical products meant for Practice in line with the international 30 April 2009.
import or export in accordance with GMP codes.
good manufacturing and distribution These updates intend to incorporate United States
practices will be performed in these developments in international codes of OTC – New Labeling for
zones mentioned by the CDSCO. This GMP and developments with respect Analgesics, Antipyretics and
system aims to preserve the quality, to new or improved technologies; to Antirheumatics11
safety and efficacy of pharmaceuticals ensure New Zealand's requirements The Food and Drug Administration
being transported and this will ensure and manufacturers remain up to date (FDA) released on 28 April 2009 final
no cross contamination of medicines in an increasingly global manufactur- rule 21 CFR Part 201 (Final rule) for
with other products. The deadline for ing environment; improve the specific manufacturers of Over-The-Counter
comments on the draft plan was 15 guidance for particular industry sectors (OTC) Internal Analgesic, Antipyretic,
June 2009. - for example, manufacturers of sterile and Antirheumatic (IAAA) drug prod-
In India, the Indira Gandhi Inter- medicines and of active pharmaceutical ucts. Manufacturers of these drugs will
national airport in Delhi will be the ingredients; improve the guidance for need to revise their labeling in order to
first zone to be set up which is a major key components of quality manage- include warnings about potential safety
Concludes on page 58.
July/August 2009 PHARMACEUTICAL ENGINEERING 57
 Global Regulatory News
risks such as internal bleeding and liver References • CDSCO, Presentation on Phar-
damage, associated with the use of these 1. The Regulatory Affairs Journal, ma Zone, 14 May 2009, http://
popular drugs like acetaminophen and May 2009. www.cdsco.nic.in/Pharma%20
nonsteroidal anti-inflammatory drugs DMA, Report: Product Defects Zone.pdf
(NSAIDS) like aspirin, ibuprofen, and Recalls of Pharmaceuticals • Pharmexcil, Circular to mem-
naproxen, and ketoprofen. in 2008, 31 March 2009, http:// bers, Ref: PXL/H.O./CIR-
This new labeling is required for all www.laegemiddelstyrelsen.dk/1024/ 013/2009-10, 14 May 2009,
OTC IAAA drug products whether mar- visLSArtikelBredSkema.asp?artikel http://www.pharmexcil.com/
keted under an OTC drug monograph ID=14893#forfalskede v1/aspx/viewNewsBulletin.
or an approved new drug application aspx?ID=540
(NDA). 2. http://www.mhra.gov.uk • Directorate General of Foreign
According to the rule manufacturers Trade, Public Notice No. 173
must relabel their products within one 3. Published by the Stationery Office, (RE-2008) /2004-2009, 13 April
year to include a warning and ensure http://www.opsi.gov.uk 2009, http://164.100.9.245/
that the active ingredients of these exim/2000/pn/pn08/pn17308.
drugs are prominently displayed on 4. The Regulatory Affairs Journal, htm
the drug labels on both the packages May 2009.
and bottles. MHRA press release, 6 May 2009, 9. The Regulatory Affairs Journal,
This final rule from the FDA is http://www.mhra.gov.uk/NewsCen- May 2009.
aimed at helping consumers to use tre/Pressreleases/CON046496 • BFAD, Streamlined Rules and
these products safely. Regulations on the Registration
5. IEGM (General Directorate of System of Pharmaceutical Prod-
Ongoing Safety Review of Pharmaceuticals and Pharmacy), ucts for Human Use Amending
Botox and Botox Cosmetic12 http://www.iegm.gov.tr for this Purpose Administrative
The FDA published a safety review Order No 67 s. 1989, Issuances
in April 2009 – a follow up to the 8 6. The Regulatory Affairs Journal, Supplementing the same, and
February 2008 Early Communication May 2009. for other purposes, 23 April 2009,
about an Ongoing Safety Review of The ASEAN member states are http://www.bfad.gov.ph/default.
Botox and Botox Cosmetic (Botulinum Brunei Darussalam, Cambodia, In- cfm?isdraft=1&cid=673
toxin Type A) and Myobloc (Botulinum donesia, Laos, Malaysia, Myanmar, • BFAD circular, 21 January 2009,
toxin Type B). Philippines, Singapore, Thailand http://www.bfad.gov.ph/cfc/pdf.
As the result of an ongoing safety and Vietnam. cfm?pdfid=1108
review, the FDA has notified manu- • ASEAN Bulletin, 10 April • Philippines government press re-
facturers of licensed botulinum toxin 2009, http://www.aseansec.org/ lease, 21 May 2009, http://www.
products of the need to strengthen Bulletin-Apr-09.htm#Article-6 gov.ph/index.php?option=com_c
warnings in product labeling, and add • ASEAN, Fact sheet on the MRA, ontent&task=view&id=200061
a boxed warning, regarding the risk of 10 April 2009, http://www. 7&Itemid=2
adverse events when the effects of the aseansec.org/Fact%20Sheet/
toxin spread beyond the site where it AEC/2009-AEC-026.pdf 10. The Regulatory Affairs Journal,
was injected. • ASEAN Sectoral Mutual Rec- May 2009.
FDA also has notified the manufac- ognition Arrangement for good Medsafe, Proposed update to the
turers that development and imple- manufacturing practice (GMP) New Zealand Code of Good Manu-
mentation of a Risk Evaluation and inspection of manufacturers of facturing Practice, 16 March 2009,
Mitigation Strategy (REMS) is neces- medicinal products, 10 April http://www.medsafe.govt.nz/hot/
sary to ensure that the benefits of the 2009, http://www.aseansec. Consultation/GMP%20Review.asp
product outweigh the risks. org/22481.pdf
In addition, FDA is requiring the 11. http://www.Idrac.com; FDA, Medi-
manufacturers to submit safety data 7. The Regulatory Affairs Journal, cines Agency, http://www.fda.gov
after multiple administrations of the May 2009.
product in a specified number of chil- Diário Oficial da União (DOU) No. 12. http://www.Idrac.com; FDA, Medi-
dren and adults with spasticity to as- 85, of 7 May 2009, http://www.in. cines Agency, http://www.fda.gov
sess the signal of serious risk regarding gov.br
distant spread of toxin effects. This information was provided by Frank
8. • CDSCO, General Notice, 14 May Sayala and Rohini Chari, Pharmaceuti-
2009, http://www.cdsco.nic.in/ cal Research Associates (UK).
General%20Notice.doc

58 PHARMACEUTICAL ENGINEERING July/August 2009

 Global Regulatory News

ISPE
Annual Meeting

Thriving In A Survival Environment

8 - 11 November • Manchester Grand Hyatt San Diego • San Diego • California, USA

Eleven Session Tracks:

• Product development • Supply chain management • Quality systems • Suppliers
• Facilities and equipment • Production systems • Project management • Survival-focused
• Information systems • Regulatory compliance • Investigational products

Wa t c h f o r d e t a i l s a n d o n l i n e r e g i s t r a t i o n a t w w w. I S P E . o r g / a n n u a l m e e t i n g .

Exhibit and Sponsorship Opportunities Available

July/August 2009 PHARMACEUTICAL ENGINEERING 59

 ISPE Update

PQLI Tours Asia Reprinted from

PHARMACEUTICAL
ENGINEERING®
The Official Magazine of ISPE

A
s a key part of PQLI’s global strat- following the in- July/August 2009,
egy spearheading with practical troduction of ICH Vol. 29 No.4

implementation examples of ICH Q8, Q9, and Q10 ©Copyright ISPE 2009
guidelines Q8, Q9, and Q10, interac- in Japan, particu- www.ISPE.org

tive sessions were held at the Indian larly the status of

Affiliate Annual Meeting in Mumbai the various MHLW
on 13 and 14 April and at the Japan work groups.
Affiliate Annual Meeting in Tokyo on Spavins led the
16 and 17 April. Western team with
A Western team was active at both a presentation on
meetings and included Jim Spavins, the benefits and value to the industry dation and scale-independent design
Vice President, Global CMC, Pfizer Inc.; of conducting enhanced approaches space being very clear winners.
Roger Nosal, Executive Director, Regu- using Quality by Design (QbD). Nosal The Indian organizing committee
latory CMC, Pfizer Global Research; provided Pfizer’s experiences in filing was led by Gopal Nair, under the overall
and Chris Potter, CMC Consultant and QbD submissions and also summarized leadership of Ajit Singh. Nair was sup-
Technical Project Manager for ISPE’s the latest activities of PQLI teams ported by Manasi Baindur from ISPE
PQLI® Initiative. Ranjit Deshmukh, working on Critical Quality Attributes/ India. The PQLI session was chaired by
Senior Director of Wyeth, was a member Critical Process Parameters (originally R. Raghunandanan, Director of ISPE
of the team in Mumbai. Criticality), Design Space, and Control India.
Input was provided by US FDA Strategy topics. Potter provided an In Japan, the meeting organizing
speakers Rick Friedman, Director, FDA/ overview of the PQLI vision and status, committee was chaired by Tatsuro
DMPQ, who discussed global supply discussed the recently published Jour- Miyagawa, Executive Vice-President,
chain challenges for regulators and nal of Pharmaceutical Innovation (JPI) Daiichi Sankyo Propharma, who was
industry, and Tara Gooen, Compliance paper on application of QbD to existing supported by Natsumi Sahara from
Officer, FDA/DMPQ, who discussed the products, as well as summarized a case ISPE Japan. Yoshio Kitazawa, Chair-
recent FDA draft guidance on process study on the application of real-time man of the Japanese PQLI Steering
validation at both meetings. Both pre- release testing to a solid dosage form Committee, co-chaired the PQLI session
sentations were pre-recorded. In Tokyo, provided by AstraZeneca. In Mumbai, with Potter.
Yukio Hiyama, Chief, Third Section, Deshmukh presented a Wyeth case
Division of Drugs, NIHS, presented and study. The recorded version of the PQLI
was part of the Q&A session. Hiyama- In Japan, a vote was held on potential webinar available is at www.ISPE.
san summarized the current position PQLI future topics, with process vali- org/pqli.

Global Regulators and ISPE Members Make for Washington

Conference Success

M ultiple time zones and great distances could not stop

pharmaceutical industry leaders from sharing their
knowledge at ISPE’s Engineering Regulatory Compliance
This seminar brought together a panel of industry leaders
and US FDA regulators to help the pharmaceutical industry
address recent concerns about the integrity of today’s complex
Conference held in Washington, D.C., USA from 1–4 June. pharmaceutical supply chain and to help companies assure
For the first time at an American ISPE conference, select a safe, efficacious drug supply.
content from among its lineup of speakers was recorded and Industry leaders from around the world were also able to
is accessible as downloadable webinars for those industry deliver their content virtually via live Webcasts, during which
professionals who were unable to attend. Content was also on-site and off-site participants could participate in Question
delivered virtually via live Webcasts and live online speaker and Answer periods with speakers located in India and Italy.
presentations. To access the selection of Washington Webcasts Attendees rated these sessions very highly and felt that the
and Webinars, visit www.ispe.org. virtual Q&A exchanges were as good as if every participant
A popular seminar was “Global Supply Chain Integrity was on site.
and Anti-counterfeiting” – co-sponsored by IPEC–Americas.

60 PHARMACEUTICAL ENGINEERING July/August 2009

 ISPE Update
ISPE Strasbourg
ISPE Launches Three New Conference to
Online Learning Product Lines Focus on Managing
Knowledge through
I
SPE has introduced three new Online Learning products: the ISPE 2009
Washington Conference Session series, the Certified Pharmaceutical
Industry ProfessionalTM (CPIPTM) Online Course series, and the Good Science and Risk
Manufacturing Practices (GMP) Online Training Course series.
“With the increased restrictions placed on executive travel, and the demand Assessment
for education remaining stronger than ever, ISPE’s latest Online Learning
offerings will truly accommodate a multitude of training needs in today’s chal-
lenging economy,” said Robert P. Best, President and CEO of ISPE. “Having
access to an expert directly from their desktops is what most pharmaceutical
professionals want, and as the leader in pharmaceutical education, ISPE can
T he ISPE Strasbourg Conference will
be held 28 September – 1 October
at the Palais des Congrès, Strasbourg,
supply that with its expanding library of Online Learning opportunities.” France. The conference will feature the
ISPE has made select sessions from its successful 2009 Washington Confer- following seminars:
ence available as downloadable Webinars. Those industry professionals who
were unable to attend the conference can still benefit from the numerous • Commissioning and Qualification:
global regulators – including those from the World Health Organization and Practical Applications of Science and
the U.S. Food and Drug Administration – who shared their expertise with Risk-based Approaches to Valida-
participants on topics ranging from global supply chain integrity to validation tion
and quality by design.
• Disposables and Containment
“With the increased restrictions placed on executive Technology in Biomanufacturing:
travel, and the demand for education remaining stronger Managing Risk, Reducing Cost
than ever, ISPE’s latest Online Learning offerings will
• GAMP® 5 Operational Aspects
truly accommodate a multitude of training needs in
today’s challenging economy...”
• Barrier Isolation Forum, Innovation
Robert P. Best, President and CEO of ISPE Updates and New Case Studies

The Certified Pharmaceutical Industry Professional (CPIP) Online Course • Investigational Medicinal Product
series provides a broad range of learning opportunities for career growth and (IP) Innovation in a Regulated En-
professional development. The CPIP series of self-directed online courses is vironment
designed for two groups: those pharmaceutical professionals who are hoping
to obtain general pharmaceutical industry knowledge from drug product • PQLI ®: Global Realisation and
development through manufacturing, as well as to those who are seeking Implementation of the ICH Quality
industry-wide recognition of accumulated experience via the CPIP creden- Vision
tial.
Developed in cooperation with the global leader in GMP training, the GMP Training Courses:
Institute, the pre-recorded Good Automated Manufacturing Practice Training
Online Course series is being developed and reviewed by expert instructors • Basic Principles of Computerised
and international regulatory advisors. Each 60 or 90 minute event will pro- System Compliance (GAMP 5)
vide an interactive learning experience that includes a pre-assessment to
identify knowledge gaps, a downloadable course presentation for note-taking, • Cleaning Validation Principles
learning reviews/assessments highlighting important points, links to various
web pages, an online resource handout as a quick reference for all web links
discussed, and a summary of the assessments to gauge knowledge gained. More detailed information
Each of these webinars can be found in ISPE’s Online Learning Catalog, about this event
which features course titles for every recorded ISPE webinar and online course is available at
sorted by topic, title, and area of interest. Each event is led by an industry www.ISPE.org.
leader, subject matter expert, or a member of one of ISPE’s Communities of
Practice (COPs) and is available in a convenient and cost-effective recorded
format at www.ISPE.org/onlinelearning.

Continued on page 62.

July/August 2009 PHARMACEUTICAL ENGINEERING 61
 ISPE Update

Event to
New ISPE Technical Document and
Showcase Webinar Offer Pragmatic Solutions to
Facility of the Maintenance Issues
Year Award
T
he new ISPE Good Practice Guide:

Winners from Maintenance provides current, es-

tablished practices to help achieve

DACH Region technical and regulatory accuracy and

cost-effective compliance whether in a
new maintenance program or reviewing
an existing program for effective strategy

I n the last three years, compa-

nies from the ISPE Germany/
Austria/Switzerland (DACH)
and efficiency. The Guide is intended to be
used as a tool for the development, imple-
mentation, and execution of a maintenance
Affiliate have won many of the
program in a manufacturing environment.
awards presented by ISPE’s Facil-
The Guide is focused on maintenance in
ity of the Year Awards program,
cGMP areas where maintenance strate-
including an Overall Winner
gies, plans, SOPs, and quality procedures
award. To highlight the latest
and policy application are developed.
state-of-the-art developments
Because the Guide was written by a
being implemented by these
group of maintenance professionals from
award-winning manufacturers
many pharmaceutical companies from
and their suppliers, the Facility
around the world – and reviewed by the US Food and Drug Administration – it is
of the Year: Innovation Show-
in fact a benchmarking tool. The key concepts in this Guide can be used knowing
case will be held 2-3 November
that they have general acceptance in the industry.
2009 in Ulm, Germany.
As with all ISPE technical documents, the ISPE Good Practice Guide: Mainte-
nance utilizes a practical, pragmatic, non-theoretical approach, giving the reader
guidance on solving problems and serving as a valuable tool for addressing regula-
tory inspections and compliance issues. Of particular interest in the Guide is the
“Reliability Curve” graphic illustration and the Table of Regulatory Citations.
In tandem with the global release of the ISPE Good Practice Guide: Maintenance,
is the offering of a 60-minute webinar, “Launch of the ISPE Good Practice Guide:
Maintenance.” This webinar identifies how the new guide can provide solutions
for structuring a maintenance program and provides practical tools that will help
ensure quality and compliance of maintenance operations. More detailed informa-
The event will include case stud-
tion on the Guide and Webinar is available at www.ISPE.org.
ies on innovation and background
on the projects, Q&A sessions,
a networking reception, and
site visits to some of the award- Sichuan University Student Chapter Takes on
winning facilities. Presentations
will cover research, development, Glossary Translation
clinical trials manufacturing,
biologics, vaccines, sterile fill/
finish, and oral solid dosage pro- T he ISPE Student Chapter at Sichuan University is still new, but the Student
Members have already completed a major project that will significantly impact
the pharmaceutical engineering industry in China. At the request of the China Af-
duction. Speakers will illustrate
innovative project execution, filiate Steering Committee, members of the Student Chapter agreed to undertake
facility integration, process de- the translation of the ISPE glossary from English to Mandarin Chinese. They began
sign, and operational excellence. work in the middle of January and finished at the end of April. The translation
More detailed information about from A to Z totaled 5,963 words and phrases. In addition, they helped combine the
this event is available at www. material into several convenient groups for upcoming review by industry experts.
ISPE.org. The Sichuan University Student Chapter has 107 members and is led by President
Zhang Yiwen. For more information, visit the ISPE China Affiliate Web site, which
can be accessed through www.ISPE.org.

62 PHARMACEUTICAL ENGINEERING July/August 2009

 ISPE Update

New Knowledge Briefs Published

I
SPE just released the Overview: Regulatory Framework – PIC/S and ICH
Removal of “Use by by Dr. Kate McCormick
Dates” from Clini- This Knowledge Brief provides a basic overview of the es-
cal Trial Material La- tablishment and purpose of these two organizations and
bels in the European PIC/S and ICH publications pertinent to the pharmaceutical
Union by Michael A. manufacturer.
Arnold. This Knowledge
Brief explains how – Packaging Equipment: Slat Fillers
through a risk analysis by James Hills
– IVR/IWR technology This Knowledge Brief provides a basic overview of the general
may be a better alterna- concept and design of the slat filler and addresses several
tive to the conventional considerations important to achieving maximum operational
method of managing efficiency.
“use by dates.” Guidance
is also provided on how to Reducing the Cost of Manufacturing
notify authorities of an by John Nichols
intent to use IVR/IWR This Knowledge Brief provides an overview of how Targeted
technology. Processes, Process Intensification, and Lean/Continuous
Also new and avail- Manufacturing will serve as key techniques and technologies
able is Dry Powder to reduce the cost of pharmaceutical manufacturing today
Sampling and the Containment of Hazardous Com- and in the future.
pounds by Jonathan Lind. This Knowledge Brief provides
a high level review of the requirements for the successful Risk-Based Approaches to Cross Contamination
containment of hazardous compounds associated with dry by Stephanie Wilkins
powder sampling activities. The concepts presented in this Knowledge Brief were developed
Knowledge Briefs are concise, summary documents that from the ISPE Baseline® Guide, the Risk-Based Manufacture
provide general information on issues, processes, and technolo- of Pharmaceutical Products (Risk-MaPP) – A Guide to Man-
gies impacting the contemporary pharmaceutical industry. aging Risks Associated with Cross Contamination, which is
Although it may contain technical content, Knowledge Briefs currently being reviewed by the US FDA.
are written in terms a non-technical reader can understand
and are intended to help industry professionals get up-to- Biotechnology Basics
speed quickly on a particular topic. Each brief includes links Adapted from the ISPE Training Course on Biotech Basics
to additional ISPE resources such as technical documents, This Knowledge Brief provides basic concepts explaining the
Pharmaceutical Engineering articles, webinars, Communities science of biotechnology and how science and process are
of Practice, and educational seminars and training courses combined to lead to the manufacture of a human therapeutic
to provide more specific and detailed information on the product.
subject.
Knowledge Briefs are available for immediate download Commissioning and Qualification of Biopharmaceuti-
(free to ISPE Members, $5 US / E3 for nonmembers) from cal Facilities
www.ISPE.org/knowledgebriefs. The following is a list of ad- The information contained in this Knowledge Brief was ex-
ditional Knowledge Briefs: tracted from the ISPE Baseline® Guide: Biopharmaceutical
Facilities, authored by the Biopharmaceutical Manufacturing
Overview: Regulatory Framework – US FDA Facilities Baseline® Guide Task Team
by Dr. Kate McCormick This Knowledge Brief summarizes the considerations
This Knowledge Brief provides a basic overview of the US FDA's involved in the commissioning and qualification of a biop-
organizational structure and licensing procedures relevant to harmaceutical manufacturing facility.
pharmaceutical manufacturing and regulation.
Quality by Design
Overview: Regulatory Framework – EMEA by John Berridge, PhD
by Dr. Kate McCormick This Knowledge Brief provides and explains the basic ele-
This Knowledge Brief provides a basic overview of the EMEA's ments of Quality by Design (QbD).
organizational structure, responsibilities, and regulations
relevant to the manufacture of medicinal products.

July/August 2009 PHARMACEUTICAL ENGINEERING 63

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64 PHARMACEUTICAL ENGINEERING July/August 2009

 Classified Advertising
Validation Services Vial Traying Systems

Commissioning Agents, Inc., 1515 Hurst Corp., Box 737, Devon, PA 19333.
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For
Sale Advertising Space
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Pharmaceutical Engineering
Call ISPE Director
January/February 2009 of Sales Dave Hall
at Tel: +1-813-960-2105.
March/April 2009
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July/August 2009 PHARMACEUTICAL ENGINEERING 65

 Advertiser's Index
Thank You to our Sponsors ACTIVE CHEMICAL.................................... 65

ISPE Washington Conference AES CLEAN TECHNOLOGY........................... 7

Platinum Sponsors
BUDZAR INDUSTRIES................................. 55

CAL-CHEM CORP....................................... 64

CHEM SHOW............................................ 39

Gold Sponsors COMMISSIONING AGENTS........................... 9

CRB CONSULTING ENGINEERS...................... 3

JIM CRUMPLEY & ASSOCIATES.................. 64

Lanyard Sponsor EI ASSOCIATES......................................... 65

ELETTRACQUA.......................................... 11

FARR AIR POLLUTION CONTROL................... 2

Onsite Advertising Sponsor FIKE CORP................................................ 33

GE WATER & PROCESS TECHNOLOGIES...... 25

GEA PROCESS ENGINEERING...................... 31

ISPE Strasbourg Conference GEMU GMBH............................................. 45
Host Sponsor
HACH COMPANY....................................... 41

France Affiliate Networking Event Sponsor HOWORTH AIR TECHNOLOGY.................... 13

HURST CORP............................................ 65

IMA ACTIVE.............................................. 47

IP COP Networking Event Sponsors INTELLIGEN............................................... 15

INTERPHEX............................................... 29

MECO....................................................... 17

MURRAY COMPANY.................................. 27

NNE PHARMAPLAN.................................... 68

PARSONS................................................... 5

PHARMACEUTICAL ONLINE........................ 51

PLASCORE................................................ 35

SIEMENS WATER TECHNOLOGIES............... 21

66 PHARMACEUTICAL ENGINEERING July/August 2009

more

Pharmaceutical Engineering
than engineering
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reductions of 40% or more. NNE Pharmaplan is a thought leader and unique in its
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 On-Line Exclusive Article
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE Electro Membrane Technology
July/August 2009, Vol. 29 No. 4

This article
presents electro Electro Membrane Technology
membrane
technology for Boosting Bioreactor Processes
improving yield
of bioreactor
processes. by René Fuhlendorff, Arvid Garde, and Jens-Ulrik Rype

Introduction

E
bacteria, yeast, plant, and mammalian cells.
lectrochemical processes are chemical Electro membrane processes have been
processes in which an electrical poten- developed to fit such manufacturing lines both
tial is acting as the driving force for the on the upstream and on the down-stream sides.
electrochemical reactions involved in Examples are the use of electro membrane
the process. Historically, such electrochemical separation in the production of recombinant
processes have had its industrial use in the proteins, therapeutic proteins, enzymes, probi-
manufacturing and purification processes in- otics, among other secondary metabolites.
volving almost exclusively small molecules and New inventions and new types of polymers
salts supporting the widespread use of such in have opened up for a range of new separation
the chemical industry. techniques that could not have been foreseen
Electrochemical principles have been ap- only 20 years ago. The developments made
plied in processes of various purposes; includ- of such polymer based techniques benefit not
ing the formation of new compounds by using only the biopharmaceutical industry, but also
the electrical potential to drive the reduction many other industries; including, food and food
and oxidation processes toward such entities; ingredient industry, medico technical indus-
and within separation technology by using the try, biopolymer industry, packaging industry,
electrical potential to separate compounds from down-stream processes in general, and many
a complex solution as in electro membrane sepa- environmental processes in these industries.
rations; and with the developments and shift In striving to meet higher demands of prod-
in the manufacturing industry from chemical uct quantity and improved efficiency of such
syntheses toward biochemical processes and production processes, it is becoming ever more
microbial cell factories strong focus on larger important to scale up processes and bioreactors
molecules, primary metabolites, and secondary volume. However, design, construction, testing,
metabolites. and evaluation are both costly and time con-
A widespread use of fermentation and bio- suming endeavors and much effort is required
reactor processes are seen today across several to handle these challenges. Computational ap-
industries. Examples of products are bio ethanol, proaches based on fluid dynamics can be used
amino acids, nucleotides, vitamins, organic to simulate and optimize some critical limiting
acids, vaccines, polysaccharides, antibiotics, factors such as non-ideal mixing, nutrient and
and therapeutic proteins from cell-culture oxygen distribution, and mass transfer in such
processes. Fermentative production of vitamins bioreactors.1 Metabolic and genetic engineering
has replaced many synthetic vitamin produc- are other means to improve process efficiency
tion processes and enzymatic and cell-based and lower costs in specific applications.
bioconversions are becoming essential for the The concern with bioreactor productions
is not only focused on capital and operational
©Copyright ISPE 2009

production of fine chemicals single isomers and

bio energy. The discovery of recombinant DNA expenditures (low volume, high purity product
techniques has led to biochemical processes is desired), but also on technical and practical
for large scale production of various secondary issues like microbial contamination, viruses,
metabolites and products. Today, recombinant etc. Substantial R&D resources are required
proteins can be produced by several different in order to achieve the mandatory specificity,
host and their expression systems, such as selectivity, and productivity of such processes.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 1

 Electro Membrane Technology
Biopharmaceutical companies also are challenged by the advantages can be associated with the Gram positive organ-
time-to-market with new products and by demonstrating ism as it allows proteins to be secreted directly to the extra-
sufficient business growth for shareholders and investors. cellular milieu with only a limited number of side products.
And clearly because of the enormous costs for bringing a new Also, downstream processing is considerably less complex
product to the market as well as the implementation of small in contrast to Gram negative bacteria as Lactococcus lactis
changes in a pre-approved production process, initiatives in does not produce endotoxins or forms inclusion bodies. Hence,
improving productivity and yield are quite substantial to the expressed recombinant protein can be isolated from the
counter the additional costs related to documentation and fermentation broth through simple purification processes. The
administrative processes. last couple of decades has resulted in the development of a
number of Lactococcus lactis based gene expression systems
Bioreactor Growth Rate Inhibition because of such advantages.10,11
Fermentation processes are often inhibited by a number of However, the production of lactic acid – the primary end
expressed products either being the end-products in ques- product of glucose metabolism – will have a limiting effect on
tion or by-products limiting growth rate, cell density, and biomass production in Lactococcus lactis. Lactic acid inhibits
productivity. In the typical batch fermentation with unlimited growth even when the acid is neutralized by the addition
nutrients, the biomass growth rate strongly depends on the of base to keep pH constant resulting in relatively low cell
stage of the cell system, from lag phase to the exponential density, which also has been the primary drawback for Lac-
phase and finally to the stationary phase where product tococcus lactis as a host organism for producing heterologous
inhibition becomes controlling. proteins.
Inherent to such bioreactor processes are the fundamental Various attempts to overcome growth rate inhibition have
challenge to achieve and prolong the exponential growth rate been made during the past decade12 both genetically as well
of the cell system in the production of biomass, products or as physically, resulting in sub-optimal solution: Removal of
various by-products at optimal growth conditions. After the inhibiting substances in bioreactor processes is an option
initialization of the fermentation process, the microorgan- when higher cell densities and product yields are demanded.
ism should ideally stay in exponential phase as long as pos- Removing such inhibiting compounds directly (online) from
sible. the fermentation broth by a membrane separation process
Escherichia coli (E. coli) is one of the most important host makes it possible to operate at much higher biomass concen-
organisms for production of recombinant proteins and con- tration, thereby increasing the production rate as well as the
siderable effort has been made to improve the efficiency and final product concentration. Attempts to solve the problem of
to extend the application range of E. coli-based expression inhibitor induced growth rate reduction have led to numerous
systems. Acetate formation in aerobically grown cultures development designs and new separation techniques, which are
of Escherichia coli continues to be a major problem in the also beneficial in the subsequent down-stream processes.
industrial application of this microorganism; the presence of
acetate inhibits growth2 and the production of recombinant Reverse Electro-Enhanced Dialysis (REEDTM)
proteins,3 and induces stress response even at low concen- – Combining Driving Forces from Simple
trations.4 Acetate formation occurs not only under anaerobic Dialysis into Electro Membrane Processes
conditions (mixed acid fermentation), but also under fully For the direct removal of inhibitors from fermentation broth,
aerobic conditions with excess carbon source. When glucose several separation techniques have been investigated. While
is the carbon source, E. coli predominantly generates acetate microfiltration, ultra filtration, and nano filtration are tech-
as a result of overflow metabolism.5,6 niques primarily used in the down-stream fermentation pro-
Acetate formation has several other disadvantages in ad- cesses, various dialysis techniques have been coupled directly
dition to the inhibition on production; acetate has a negative to the bioreactor, including Diffusion Dialysis or Donnan
effect on the stability of intracellular proteins7 and accumula- Dialysis (DD), and electro assisted dialysis techniques like
tion of acetate will acidify the medium. When the pH is below Electro Dialysis (ED) and Electro Dialysis Reversal (EDR).
5.0, cell lysis will appear due to the irreversible denaturation Donnan Dialysis (DD) or Diffusion Dialysis employs the
of proteins and DNA.8 The level of acetate produced during same type of ion-exchange membranes, but differs from electro
aerobic fermentation is depending on the E. coli strain, the dialysis in electro-membrane processes in that the driving
growth conditions, the actual glucose concentration in the force is not an electrical current, but simply a difference in
medium, and the overall composition of the fermentation chemical potential. As an example, a negative ion (A-) can be
medium.9 Acetate formation can be circumvented through driven out of a feed solution or fermentation broth through
different means, e.g., making the carbon source rate limiting/ Donnan Dialysis equipped with anion-exchange membranes,
©Copyright ISPE 2009

managing oxygen supply, but under optimal growth conditions, by utilizing a second alkaline stream. The concentration dif-
acetate formation will at length lead to growth inhibition. ference of hydroxide ions (OH-) between the two solutions
Similarly, for several years Lactococcus lactis (a.o. LAB) drives the hydroxide ions to diffuse into the Feed solution.
has played a role as major production host in the food and This creates an oppositely directed electrical field driving an
food ingredient industry and today is Generally Recognized extraction of negative ions (A-) from the Feed solution.
As Safe (GRAS) for these applications worldwide. A number of On the other hand, Electro Dialysis (ED) utilizing the

2 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Electro Membrane Technology
electrical potential as the main driving force in separations the REED system is able to regulate pH of the fermentation
limits the possible targeted solutes for recovery separation broth by exchanging hydroxide ions with the expressed product
to charged compounds. The charged compounds must be mo- anions, thus reducing the need for a titration agent.
bile, and the separation media must be able to transfer the Electro membrane technology including the REED technol-
electrical current with relatively low resistance. Traditional ogy can be integrated into the fermentation processes either
applications of Electro Dialysis are based on its ability to as fully integrated solutions (REED controlled fermentation)
desalinate or concentrate a liquid process stream containing or as simple modular device solutions (REED Add on).
salts. ED is very useful for water treatments by removal of The REED controlled fermentation setup is a build-in
mineral salts, sulphates, nitrates among others in making solution where the REED unit is fully integrated and control-
drinking water from brackish water or sea water or for waste ling the fermentation process, either fed-batch or continuous
water reduction or recovery. fermentation. The REED unit is connected directly (on-line)
Drawbacks of the simple ED set-up lies in the fact that to the fermenter and separates the process inhibiting acid
liquid process streams must be free of particles and high or- continuously. Though the REED controlled fermentation setup
ganic content in order to avoid membrane fouling. For complex generates the best output in active biomass (actually more
process streams the benefits from Electro Dialysis Reversal than a factor of 10 times compared to unassisted fermentation),
(EDR) must be taken into account. EDR is operated like ED, it also requires significant changes to the existing process.
but when fouling has grown to a certain level, the setup is Obviously, such changes should be considered as early in the
altered by reversing the direction of the constant current design phase as possible.
driving the separation and either operating with “negative” In the modular REED add on setup, the REED unit is act-
reversed separation effect for a short period until returning ing as a passive unit on the fermenter; the batch fermentation
to normal operation or by subsequently switching the dilu- setup and control is left basically untouched. Fermentation
tion and concentration chambers. This way, it is possible to broth will pass through the REED unit removing as much
prolong the ED operation without having to stop and clean organic acid as possible during the cause of the fermentation.
the equipment. Benefits of the acid removal are prolonged exponential growth
In general, Electro membrane techniques have in common and production of more biomass.
the fundamental ability to separate charged small molecules When applied for the specific production of organic acids
from process streams using the electrical field as the driving like high purity lactic acid for Poly Lactic Acid (PLA) produc-
force across selective ion-exchange membranes. Advanced tion, the REED add on setup leaves two product streams; one
combinations of separation techniques and designs have been directly from the REED and one from the fermenter itself.
developed, which compensates for some of the drawbacks of Due to the pre-filtration in the REED unit, the stream from
the individual techniques. the REED unit is of acid salt (lactate) form separated from
Across several industries and in various bioreactor bio matter, while the fermenter stream is unaffected. Hence,
processes, the combinations of driving forces from dialysis this setup provides two options of producing separate product
techniques, innovative designs of cell stacks, and material qualities and/or pooling both streams for the conventional
technology for electro-membrane separations have resulted Down Stream Process (DSP).
in alternative routes in achieving better biomass and product In contrast to simple Electro Dialysis, more advanced elec-
yields. tro membrane solutions are typically exploited in high-end
Reverse Electro Enhanced Dialysis (REEDTM) is a technol- biopharmaceutical production processes to boost bioreactor
ogy that combines the principles of Donnan Dialysis (DD) and processes of high valued products like therapeutic proteins,
Electro Dialysis Reversal (EDR). enzymes, and various others.
With the REED technology, fermentation processes can Due to the highly scalable nature of such electro membrane
be handled without the build-up of fouling layers on the systems, the fundamental setup can be the same: from small
membrane surfaces seen during fermentation as the REED scale bioreactor productions (lab scale), pilot scale productions,
technology has a built-in anti-fouling mechanism, which or even to industrial applications with 100 m3 tanks.
automatically removes deposited organic components from Presented in the following are case studies and results from
the membrane surfaces. specific REED applications from lactic acid for food ingredi-
Using current developments in membrane technology, the ent production to various small scale biopharmaceutical gene
REED process is able to extract small, charged molecules like expressions of recombinant proteins.
the corresponding bases of, e.g., organic acids (lactate, acetate
from lactic, and acetic acid among others) separating these REED Technology in Lactic Acid Production
from larger or non-charged components like proteins, sugars, The present case study is a suggestion for a process for pro-
©Copyright ISPE 2009

cells, yeast, etc. duction of lactic acid by lactic acid bacteria using a combina-
REED-assisted fermentation processes with continuous tion of electro membrane processes including the REED.13
extraction of growth rate reducing substances allows for The process itself is generic in nature and can with very few
significant extensions of the exponential growth phase. Such modifications be adapted for a wide variety of other applica-
applications result in higher yields and improved capacities of tions. These include production of various organic acids and
the existing fermenter or bioreactor equipment. Furthermore, bases and especially pharmaceutical and biotech products

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 3

 Electro Membrane Technology

Figure 1. Process flow sheet of a lactic acid production process.

made by fermentation. However, the targeted species in the collected lactate.

broth must be charged and have an approximate molecular Membrane fouling, a drawback of conventional electro
weight of less than 500 g/mol. membrane separation processes, is avoided with the current
In the application, the electro membrane separation is reversals in the REED technology. Without pre-filtration of
operated and combined with the fermentation, which makes the broth, the membranes will quickly be fouled, resulting
it possible to extract the targeted ionic species, and at the in increasing electrical resistance. However, by periodically
same time, control the pH of the fermenter. A major advantage changing the direction of the current, fouling of the membranes
of the process is that no treatment to remove cells, proteins, is reversibly removed and significantly prolonged operation
macromolecules, calcium, magnesium, etc. is required prior times are achieved. Figure 3 shows the effect of reversing the
to the extraction of product due to the integrated anti-fouling current, the resistance (voltage drop) returns to its original
mechanism in the extraction unit. The lactic acid production level after one period. Hence, continuous lactate removal is
process is shown in Figure 1. possible directly from the unfiltered broth.
From the feed tank, T-1, substrate is fed to the recycle fer- Shown in Figure 4 is the potential drop across a REED-
menter where the sugar is fermented to lactic acid. A stream, stack containing three cell pairs during removal of lactate
S-2, is taken out, and in the Reverse Electrically Enhanced from fermentation broth at constant current density. The
Dialysis (REED), stack lactate ions are replaced with OH- resistance of the membranes is steadily increasing during the
before it is sent back to the fermenter for pH control (S-3). first 55 minutes as fouling is building up on the membrane
The alkaline stream, S-4, containing lactate is pumped to a surface. However, as soon as current reversal is applied every
Bipolar Electro Dialysis (EDBM) system where lactate and any
inorganic anions are concentrated in the acid compartment.
The base is regenerated and returned to the REED after a
make-up addition of base from T-2. Lactic acid is concentrated
in the acid circuit of the EDBM to approximately 20 to 25%.
The synergy effect of combining REED with an EDBM
system offers the possibility to continuously regenerate al-
kaline solution for the REED system and recover and acidify
organic acids extracted from the fermentation. A less complex
solution for operating the REED without the EDBM system is
to add premixed alkaline solution directly to the REED and
then employ other means for after-treatment of the acid salt
leaving the REED.

Unit Operations
Placed in the recycle loop of the fermenter is the REED unit,
©Copyright ISPE 2009

which can be adapted to conventional fermenter types.

Figure 2 shows how the electrical current through the broth
feed compartments enhances the flux of acid ions (lactate),
which migrates into the base compartment. In the base com-
partments, the hydroxide ions have a dominating transport
number and are transported back to the broth instead of the Figure 2. Ion transport in the REED unit.

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 Electro Membrane Technology
The following examples present the research of the com-
bination of the REED technique with a specific expression
system: P170 Expression System.15

Lactococcus lactis with a REED Assisted

P170 Expression System
The P170 Expression System16 is a Lactococcus lactis based
expression platform with an auto-induced promoter being
activated when a certain threshold of lactate is reached in
the Lactococcus lactis culture. Auto-induction eliminates
the need for the addition of exogenous components to induce
recombinant protein production. Optimized P170 promoter
variants have been combined with optimized signal peptides,
resulting in secretion of recombinant proteins.
Figure 3. The curve shows the electrical potential across a cell pair
Due to the growth rate reduction by Lactic acid, the final
upon current reversal every 60 seconds during REED operation.
biomass concentrations are often below 6 g/L cell Dry Weight
(DW), whereas respiring organisms easily reach 100 g/L (DW).
The low cell density has been the major drawback for Lacto-
coccus lactis as a host organism for producing heterologous
proteins. The yield in biomass production is below that of
other expression systems with cell densities of approximately
20 OD600 units. With this limited cell density, the expression
system has reached 300 mg/L of secreted protein. Although
this level is acceptable for some high value proteins, in most
cases, higher production levels are desirable.
While the accumulation of lactate gradually reduces the
growth rate of Lactococcus lactis, it also induces protein produc-
Figure 4. Potential drop across a REED-stack. tion controlled by P170. The optimal lactate concentration for
recombinant protein production is pH and protein dependent.
300 seconds, the self cleaning effect sets in and the potential Therefore, a method that can control the lactate concentration
drop (resistance) returns to near its original level. during fermentation will serve dual purposes: to achieve high
Furthermore, by using the REED setup with anion exchange cell densities and to prolong the phase of P170 controlled pro-
membranes, problems caused by divalent cations, such as Ca2+ tein production. The described REED technology has recently
and Mg2+ in the subsequent EDBM, which can not operate helped to overcome this cell density problem in a combined study
when these ions are present, is eliminated. with the P170 Expression System. The effect of the REED unit
The current efficiency in the REED is very much dependent resulted in a nine-fold increase in biomass and an increase from
on the amount of other unwanted anions in the broth and 300 mg/L to 2,000 mg/L for a secreted test protein.
time between current reversals. Typically, the REED operates
at current efficiencies of 80 to 90%. The energy consumption Expression of
(kWh/kg acid extracted) is dependent on the current density, Protein S. aureus nuclease, SNase
but is typically 0.25 to 0.75 kWh/kg for lactic acid. In another study, the synergistic effect of the REED system
combined with the P170 Expression System was tested in the
REED Technology in Biopharmaceutical
Gene Expression of Recombinant Proteins
The increased use of bioreactor technology in the manu-
facturing of biopharmaceuticals has put the focus on the
development of the production system and its elements, e.g.,
the biopharmaceutical cell factories, the gene expressions
systems, and further developments of genetic engineering
technologies.
Coupling of advanced electro membrane techniques like
©Copyright ISPE 2009

REED with such biopharmaceutical gene expression systems

can be seen as a supplement to or an alternative to the genetic
engineering approach; when the work of genetic manipulation
no longer can lead to further improvements of the productivity
of the cell systems; such electro membrane systems can help
Figure 5. SDS-PAGE analyses of SNase from production in yeast
in achieving the targeted higher productivities. extract medium.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 5

 Electro Membrane Technology

Figure 6. SDS-PAGE analyses of malaria hybrid antigen, GLURP-MSP3.

production of a secreted model protein S. aureus nuclease, The yield of secreted GLURP-MSP3 was increased four
SNase. Traditional batch fermentation was done in parallel to six fold resulting in approximately 140 mg/L in the REED
for comparison. In the first phase, the REED unit was used fermentation.
to keep the lactate concentration below 150 mM, allowing
rapid exponential growth. When a certain cell density was Production of a Sugar Converting Enzyme,
achieved (70 OD600), the lactate concentration was increased L-arabinose isomerase
and kept between 250 to 350 mM for 21 hours. During this The conversion of D-galactose to the low-calorie sweetener
phase, cell growth continued at a reduced rate due to lactate D-tagatose is catalyzed by L-arabinose isomerase (araA).
inhibition, while the specific production rate of recombinant A thermostable L-arabinose isomerase from Thermoanaer-
protein was continuously kept at an optimal level. obacter mathranii was expressed intracellularly in the P170
By applying REED technology, the growth phase could be Expression System and the yield of araA was evaluated in
prolonged resulting in a final cell density of 180 OD600 units REED vs. batch fermentations. By applying the REED system
in the REED assisted fermentation in contrast to 20 OD600 for production of araA both yield and biomass (OD600) were
units in the standard batch fermentation, i.e., a nine fold im- increased approximately six fold from ~ 100 mg/L to ~ 600
provement. Furthermore, the yield was increased more than mg/L and ~ 15 to 90 (OD600), respectively.
10 fold using REED vs. batch, resulting in 2 g/L of secreted
nuclease in the REED fermentation. Conclusion
Electro membrane technology can be used in bioreactor based
Malaria Vaccine Antigen, GLURP-MPS3 processes for the production of both biomass and products
In a recent study, the malaria vaccine antigen, GLURP-MPS3, leading to very pure biopharmaceuticals and chemicals.
was produced in the P170 Expression System using standard The REED technology is a general technology based on
batch fermentation. In this study, the REED assisted P170 combinations of ion-exchange membrane processes, which
Expression System was evaluated for increased secretion of is applicable to removing inhibitors of bioreactor processes
GLURP-MSP3 with promising results. resulting in the production of biomass; the raw material and
starting material for various biopharmaceuticals and pure
chemicals in biopharmaceutical and food applications.
In contrast to other ED systems, the inherent antifouling
mechanism of the REED technology allows REED modules
to be directly coupled to a bioreactor/fermenter in upstream
processes without the use of any other filtration and mem-
branes techniques.
Until now, focus has been mainly on documenting the
REED technology in L Lactis production of lactic acid and in
the production of recombinant proteins with the P170 Expres-
©Copyright ISPE 2009

sion systems. Recently, the REED technology also has proven

to be favorable in the removal of expressed inhibitors as well
as general bioreactor pH control for E. coli based systems.
Primary REED-applications have been indentified for
production of Starter Cultures, metabolic enzymes, antibiotics
Figure 7. Production of L-arabinose isomerase (AraA) in chemically
defined medium in REED assisted vs. unassisted batch productions. or other proteins, organic acids and pure chemicals, and in

6 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Electro Membrane Technology
general, in separations and purifications in the recovery of pH-Inducible and Growth-Phase Dependent Promoter
high end value products in downstream processes of complex P170 of Lactococcus lactis MG1363,” Mol Microbiol, 1999,
process streams. Vol. 32, pp. 75-87.

References About the Authors

1. Dhanasekharan, K., “Design and Scale-Up of Bioreactors René Fuhlendorff obtained his MSc in
Using Computer Simulations,” BioProcess International, 1989 in organic electro analytical chemistry
2006, pp. 34-41. and physics from the University of Aarhus,
2. Mey, M.D., et al., “Minimizing Acetate Formation in E. coli Denmark, and partly from University of East
Fermentations,” J Ind Microbiol Biotechnol, 2007, Vol. 34, Anglia, UK. His professional career began at
pp. 689-700. the Technological Institute, Denmark, where
3. Contiero, J., et al., “Effects of Mutations in Acetate Metabo- he worked as an analytical chemist and as
lism on High-Cell-Density Growth of Escherichia coli.,” J project manager. In 1994, he became Depart-
Ind Microbiol Biotechnol, 2000, Vol. 24, pp. 421-430. ment Manager at Hedeselskabet with responsibility for various
4 Gschaedler, A., et al., “Effects of Pulse Addition of Carbon projects, including QA/QC activities. After that Fuhlendorff
Sources on Continuous Cultivation of Escherichia coli became Division Manager for Industrial lab activities and later
Containing a Recombinant E. coli GapA Gene,” Biotechnol on when the company was integrated in Eurofins Scientific
Bioeng, 1999, Vol. 63, pp. 712-720. Group, Business Manager at Eurofins Pharma. He played
5. Doelle, H.W., Ewings, K.N., and Hollywood, N.W.., “Regu- a major role in the development of the Eurofins’ business
lation of Glucose Metabolism in Bacterial Systems,” Adv activities, including the work for authorities’ and clients’
Biochem Eng, 1982, pp. 1-35. inspections and GMP-approval of the laboratories. In 2008,
6. El-Mansi, E.M.T., and Holms, W.H., “Control of Carbon after nearly 20 years in the laboratory sector, Fuhlendorff
Flux to Acetatet Excretion During Growth of Escherichia decided to do business development for Jurag Separation
coli in Batch and Continuous Cultures,” J Gen Microbiol, A/S, where he is Director of Business Development. He is a
1989, Vol. 11, pp. 2875-2883. member of ISPE, BioProcessing Professionals, and Pharma
7. Stephanopoulos, G., “Metabolic Engineering,” Biotechnol Business Development. He can be contacted by telephone:
Bioeng, 1998, Vol. 58, pp. 199-120. +45-4816-9608 or by email: [email protected].
8. Cherrington, C., et al., “Shortchain Organic Acids at pH
5.0 Kill Escherichia coli and Salmonella spp. without Arvid Garde obtained his MsC in 1997 fol-
Causing Membrane Pertubation,” J Appl Bacteriol, 1991, lowed by a PhD in 2002 in the field of electro
Vol. 70, pp. 161-165. membrane filtration technology from the
9. Wolfe, A.J., “The Acetate Switch,” Microbiol Mol Biol Rev, Technical University of Denmark (DTU).
2005, Vol. 69, pp. 12-50. His cooperation with Jens-Ulrik Rype and
10. Bredmose, L., et al., Development of a Heterologous Gene Associate Professor Gunnar Jonsson, DTU,
Expression System for use in Lactococcus lactis on Host within this field resulted in the patented
Physiology. [book auth.] Merten OW et al., Recombinant REED technology, upon which the company
Protein Production with Prokaryotic and Eukary- Jurag Separation was founded by the three inventors in 2001.
otic Cell. A Comparative View, Doordrecht : Kluwer He started his professional carrier as Managing Director
Academic Press, 2001. of Jurag Separation and in 2005, Garde became Technical
11. Mierau, I., and Kleerebezem, M., “10 Years of the Nisin- Director focusing on R&D and implementation of the REED
Controlled Expression System (NICE) in Lactococcus lactis,” technology. He can be contacted by email: [email protected].
Appl Microbiol Biotechnol, 2005, Vol. 68, pp. 705-717.
12. Narayanan, N., “L (+) Lactic Acid Fermentation and its Jens-Ulrik Rype obtained his MsC in 1997
Product Polymerization,” Journal of Biotechnology, 2004, followed by a PhD in 2002 in the field of elec-
Vol. 7, pp. 167-179. tro membrane filtration technology from the
13. Rype, J.-U., Modelling of Electrically Driven Mem- Technical University of Denmark (DTU). His
brane Processes, Department of Chemical Engineering, cooperation with Arvid Garde and Associate
Technical University of Denmark, Copenhagen: s.n., 2002. Professor Gunnar Jonsson, DTU, within this
pp. 147-166, Ph.D. Thesis. field resulted in the patented REED technol-
14. Straathof, A. J.J. et al., “Feasibility of Acrylic Acid Produc- ogy, upon which the company Jurag Separa-
tion by Fermentation,” Appl Microbiol Biotechnol, 2005, tion was founded by the three inventors in 2001. He started
©Copyright ISPE 2009

Vol. 67, pp. 727-734. his professional carrier as a Product Developer for Immunolex,
15. Madsen, S.M., and MacDonald, S.A., “Bacterial Systems and later AntiBodyShop, before he returned to a position as
Breed New Expectation,” s.l.: Samedan LTD Pharmaceuti- Project Manager for Jurag Separation with responsibility for
cal Publishers, Autumn 2006, European BioPharmaceuti- product development and development projects. He can be
cal Review, pp. 122-126. contacted by email: [email protected].
16. Madsen, S.M., et al., “Molecular Characterization of the Jurag Separation A/S, Gydevang 4, Alleroed DK-3450,
Denmark.
www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 7
 On-Line Exclusive Article
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE Working Height Velocity Studies
July/August 2009, Vol. 29 No. 4

This article
presents the Working Height Velocity Measurement
methods and
results from in Conventional Cleanrooms
performing
Working Height
Velocity studies by William Mason, Bernard McGarvey, PhD,
in conventional Thomas R. Spearman, PE
cleanrooms.

Introduction

I
connections. Normally, such conditions are
n conventional pharmaceutical cleanrooms, provided by a laminar air flow work station.
Unidirectional Air Flow (UAF) hoods pro- Laminar air flow systems should provide a
vide air flow to protect critical (e.g., aseptic) homogeneous air speed in a range of 0.36
operations from contaminants. The UAF to 0.54 m/s (guidance value) at the working
hood air flow patterns are tested using visible position in open cleanroom applications.
particles such as theatrical fog (smoke) to ensure
air flows from the cleanest (critical) areas to less Manufacturers have received inspection obser-
clean areas. Routine velocity measurements vations regarding WHV.
are taken at the High Efficiency Particulate
Air (HEPA) filter protective grill and at work- 1. “In parenteral products manufacturing, the
ing height to ensure the air flow pattern is air velocity testing of HEPA filters in criti-
maintained. cal, (Class 100) areas, is done 4 to 6 inches
Measuring WHV is a regulatory concern for from the filter face and not at the critical
conventional cleanrooms used in parenteral working level where sterile product is open
manufacturing. The following paragraph is to the environment.”
from the US FDA Guidance for Industry.1 2. “The firm has not performed any studies
under dynamic conditions to show there
HEPA filter leak testing alone is insufficient is a correlation between air velocity at the
to monitor filter performance. It is important filter face and velocity at the critical working
to conduct periodic monitoring of filter at- area.”
tributes such as uniformity of velocity across
the filter (and relative to adjacent filters). To resolve the observations, several techni-
Variations in velocity can cause turbulence cal studies and industry benchmarking were
that increases the possibility of contamina- performed. Earlier technical studies measured
tion. Velocities of unidirectional air should air velocity using an electronic manometer and
be measured 6 inches from the filter face and self-averaging pitot array. This instrument has
at a defined distance proximal to the work an air velocity accuracy of ± 3% of reading ± 7
surface for HEPA filters in the critical area. feet per minute (fpm) [0.036 meters per second
Velocity monitoring at suitable intervals (m/s)] from 50 to 2500 fpm (0.25 to 12.7 m/s).3
can provide useful data on the critical area This instrument also is used to measure High
in which aseptic processing is performed. Efficiency Particulate Air (HEPA) filter air
The measurements should correlate to the velocity during Preventive Maintenance (PM)
velocity range established at the time of in execution.
situ air pattern analysis studies. The previous technical studies’ conclusions
were:
©Copyright ISPE 2009

The following paragraph is from the European

Medicines Agency (EMEA) Annex 1.2 • Data included a significant number of velocity
readings below 50 fpm (0.25 m/s), which is
Grade A: The local zone for high risk op- below the measurable range of the electronic
erations, e.g., filling zone, stopper bowls, manometer and self-averaging pitot array.
open ampoules and vials, making aseptic • Individual WHV readings are heavily de-

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 1

 Working Height Velocity Studies

Figure 1. Time constant effects. Figure 2. Probe alignment effects.

pendent upon the geometric shape of the items within the Meter Performance
critical area. Theory of Operation
• Small position changes in the X – Y – Z planes cause sig- “The thermal (hot-wire or hot-film) anemometer consists of
nificant variation in the individual readings. a heated RTD, thermocouple junction, or thermistor sensor
constructed at the end of a probe. It is designed to provide a
Industry benchmarking with eight pharmaceutical firms and direct, simple method of determining air velocity at a point in
three cleanroom certifiers was performed from June 2005 to the flow field. The probe is placed into an airstream, and air
February 2006. The benchmarking revealed: movement past the electrically heated velocity sensor tends
to cool the sensor in proportion to the speed of the airflow.
• Most pharmaceutical firms do not measure WHV. Some The electronics and sensor are commonly combined into a
firms measure WHV during initial qualification, but very portable, hand-held device that interprets the sensor signal
few re-measure on a routine basis. and provides a direct reading of air velocity in either analog
• When WHV readings were measured, acceptance criteria or digital display format.”4
was not established. The thermal anemometer used has a range of 0 to 9999
• Experience shows that “WHV is not something that can fpm (0 to 50 m/s); an accuracy of ±3% of reading or ±3 fpm
be repeated reliably.” (±0.015 m/s), whichever is greater; and a resolution of 1 fpm
• The ‘gold standard’ remains Air Flow Pattern Testing (0.0051 m/s).5
(AFPT) correlated to filter face velocities. The filter face
velocities are tested routinely, at least every six months. Time Constant Effects
AFPT is repeated when significant changes are made and The effect of the thermal anemometer time constant was
on a routine schedule, from every one to three years. tested using a UAF hood protecting a capping line accumula-

Since the previous studies had a significant number of velocity

readings below the measurable range of the electronic ma-
nometer and self-averaging pitot array, a thermal anemometer
was selected for its capability to measure low velocities. This
report shares the results of the testing performed with the
thermal anemometer.
©Copyright ISPE 2009

Figure 3. Bubble level. Figure 4. Test setup.

2 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Working Height Velocity Studies
tor table. The time constant is the averaging period of the air roll of 0 degrees. The test results comparing the average and
flow velocity measurement. The probe was placed 18 inches standard deviation for each test are shown in Figure 2.
[45.7 centimeters (cm)] from the HEPA filter protective grill. The probe roll alignment effects are apparent in the lower
The anemometer probe was held using a ring stand and was average readings and the higher standard deviations. Based
visually aligned. The air flow velocity was approximately on these results, a method of assuring the proper roll align-
100 fpm (0.51 m/s). Ten readings were taken for each time ment is critical to obtaining consistent measurements. The
constant setting of 1, 2, 5, 10, 15, and 20 seconds. The test probe pitch alignment has very little effect.
results comparing the time constant settings to the standard A bubble level tool, shown in Figure 3, was developed for
deviations of the 10 readings are shown in Figure 1. Based roll alignment. The bubble level includes a groove that fits
on these results, a time constant of 10 seconds was chosen for in the anemometer probe slot. The ring stand clamp aligns
subsequent testing. This time constant achieves good results the probe for pitch.
when balanced against the time required for execution.
Test Setup
Alignment Effects The test setup subsequently used is shown in Figure 4. The
The effect of the probe alignment was tested using the ther- plumb bob is used to determine the location of the velocity
mal anemometer under a UAF hood protecting a capping line measurement in relation to a horizontal plane. The hori-
accumulator table. The probe was placed 30 inches (76.2 cm) zontal plane is parallel to the face of the UAF Hood HEPA
from the HEPA filter protective grill. The anemometer probe filter protective grill. This test setup measures the vertical
was held using a ring stand. A time constant of 10 seconds was component of air velocity.
used. The air velocity was approximately 60 fpm (0.30 m/s).
Ten readings were taken for each probe orientation. The probe Air Flow Testing
orientations tested were a roll of 0, 9, and 11.5 degrees with Obstructed and Unobstructed Air Flow
a pitch of 0 degrees, and a pitch of 1.5 and 3 degrees with a These tests were executed using an autoclave UAF hood. A
©Copyright ISPE 2009

Figure 5. Test locations and setup.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 3

 Working Height Velocity Studies
40 inches (101.6 cm) from the filter face. The P1 Obstructed
velocity begins diverging from the P1 Unobstructed velocity
at 40 inches (101.6 cm) from the filter face. The P1 Obstructed
velocity reaches 0 fpm (0 m/s) at 52 inches (132.1 cm) from the
filter face. This reflects the air flow changing direction from
vertical to horizontal as it nears the obstruction surface.
As supporting data a Computational Fluid Dynamics (CFD)
model of the testing was created. Figure 7 shows the model
results. At Test Point 1 and Test Point 2, the streamlines indi-
cate more horizontal components at 47 inches (119.4 cm) from
the filter face, indicating the velocity changing from vertical
to horizontal as the air nears the obstruction surface.
Figure 6. Obstructed and unobstructed air flow.
The P3 Obstructed and P4 Obstructed velocities begin to
simulated wind tunnel was created around one HEPA filter increase at 46 inches (116.8 cm) from the filter face until the
using semi-rigid material. The wind tunnel was 60 inches last test point at 58 inches (147.3 cm). This reflects that the
(152.4 cm) in length. Readings were taken at varying distances locations where air can escape show an increase in velocity.
from the filter face, with and without an obstruction inserted Figure 8 indicates the CFD model also reflects this air flow
into the air stream. The obstruction was a solid cylinder with behavior by showing the increased number of streamlines
a square top surface. Figure 5 shows the test setup and the accumulating at Test Point 4, as they approach the obstruc-
test point locations. On the 38 inch (96.5 cm) lengths, the filter tion, resulting in an increased velocity.
framing reduced the filter surface area by 1.75 inches (4.45
cm) on each end; therefore, there is no air flow at the wider Working Height Velocity Procedure
side edges. The test results are shown in Figure 6. Considerations
Figure 6 shows the air velocities at each test point, with The following considerations were used to determine routine
and without the obstruction. For the four test points, the ob- WHV measurement locations and acceptance criteria.
structed and unobstructed air velocities do not diverge until Sample site locations (critical points) are selected based
on but not limited to the following criteria:

• microbial dispersion patterns (e.g., personnel traffic, mate-

rial flow, airflow)
• potential for microbial contamination during actual pro-
duction
• potential to impact product quality
• monitoring location to allow for reproducible sampling

Technical studies are performed to determine the low and

high WHV limits for each critical point location. The studies
must ensure that:

• Testing is performed using a thermal anemometer.

• Testing is performed with the UAF hood set at low, nominal,
and high velocities. The velocities are based on the UAF
hood acceptance limits established by AFPT.
• The HEPA filter face velocity readings are within tolerance
before testing.
©Copyright ISPE 2009

Figure 7. CFD model of obstructed air flow. Figure 8. Test location pattern.

4 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Working Height Velocity Studies
• The Heating Ventilation and Air-Conditioning (HVAC) understanding the variability due to a 3 inch (7.6 cm) differ-
system serving the area, as well as differential pressures, ence in test locations.
are functioning normally. The data for this area does not follow a logical pattern of
• Testing includes taking 10 velocity readings at the criti- values where the high velocity setting is greater than the
cal point to obtain a reasonable sample set to account for nominal velocity followed by the low velocity. For this area,
measurement variability. all the velocities at the critical point A-5 are essentially the
• Sampling, including equipment setup between each test same. The characteristics of Area A with a 75% enclosed area
run, is repeated three times to account for any variability and a significant physical feature to obstruct the air flow may
in equipment setup and alignment. account for the inconsistency in readings. The high standard
• Test points are 12 inches (30.5 cm) above the working deviations of 1.7 to 10.9 fpm (0.009 to 0.055 m/s) and vari-
surface. ability in readings are a measure of this inconsistency.
• All data values used to determine acceptance limits reflect The data for this area follows a logical pattern; however,
conditions representing acceptable airflow patterns. the inconsistency in readings is significant. The logical pat-
tern of values where the high velocity setting is greater than
Case Study the nominal velocity followed by the low velocity is present.
As a case study for developing WHV acceptance criteria, the The characteristics of Area B with a 50% enclosed area and
following shows the testing application for three locations. a significant physical feature to influence air pattern may
account for the inconsistency in readings. The standard devia-
Tests Executed tions from 1.5 to 4.9 fpm (0.008 to 0.025 m/s) and variability
Testing was performed with the UAF hood set at low, nomi- in readings are a measure of this inconsistency.
nal, and high velocities for AFPT. All three settings were The data for this area shows the maximum velocity set-
ultimately determined to provide acceptable air flow patterns. ting being equal to the nominal velocity and both just slightly
The testing included taking 10 readings around the critical greater than the minimum velocity. Variability in readings
point (point 5) in the test pattern plan view shown in Figure is significant. The characteristics of Area C with a 50% en-
8. The test pattern also is shown in Figure 4. The thermal closed area and a significant physical feature to influence
anemometer probe was placed 12 inches (30.5 cm) above the air pattern may account for the inconsistency in readings.
work surface. A plumb bob, shown in Figure 4, is used to align The high standard deviations from 1.2 to 8.7 fpm (0.0061 to
the anemometer probe above the test point. 0.044 m/s) and variability in readings are a measure of this
Generally, at each velocity setting, two tests were executed inconsistency.
at each of the points shown in Figure 8 and three additional
tests at the critical location (point 5) only. Testing was executed General Conclusion
at three test locations identified as: These results indicate the average values and variability are
influenced by physical features or adjacent environments.
Area A – Accumulator Although the areas are relatively well enclosed by corrugated
Area B – Filler polycarbonate sheets, the consistent physical obstructions
Area C – Stopper Bowl appear to be causing significant variability in the readings.

Test Conditions Establishing Criteria for Working Height Velocity

No differential pressure alarms or HVAC system issues were Measurements
encountered during testing. The HEPA filter face velocities Statistical analysis software was used to calculate WHV ac-
that comprised the Air Flow Pattern Testing (AFPT) low, ceptance criteria using the data from Tables B, C, and D. Based
nominal, and high velocity settings are shown in Table A. The on acceptable AFPT results, all readings recorded represent
HEPA filter face air velocity was measured using an electronic acceptable WHV values. To view and determine these results,
manometer and self-averaging pitot array. a histogram is supplied for each critical location with the
Quantiles showing the minimum and maximum values.
Results for Individual Tests The WHV acceptance criteria from the histograms in
The following tables contain the velocity readings used to Figures 9 to 11 is summarized in Table E.
establish WHV acceptance criteria. Acceptance criteria are
only calculated for the critical point (point 5). The data col- Potential Causes for Failure
lected at the other points is supplied as reference to help in In the event readings are outside the acceptance criteria, sev-
eral potential causes should be investigated. These include:
©Copyright ISPE 2009

Test Area Low Nominal High

1. Test location
A 98 fpm (0.50 m/s) 122 fpm (0.62 m/s) 147 fpm (0.75 m/s)
2. Test method
B 97 fpm (0.50 m/s) 116 fpm (0.59 m/s) 146 fpm (0.74 m/s) 3. HEPA filter velocities
C 98 fpm (0.50 m/s) 118 fpm (0.60 m/s) 142 fpm (0.72 m/s) 4. Adjacent area
Table A. AFPT low, nominal, and high settings.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 5

 Working Height Velocity Studies
Average Standard Deviation Velocity
A-1 A-2 A-3 A-4 A-5 A-1 A-2 A-3 A-4 A-5 Setting
59.0 52.0 45.9 31.6 49.9 2.4 4.5 7.2 7.9 6.0 Low
(0.30) (0.26) (0.23) (0.16) (0.25) (0.012) (0.023) (0.037) (0.040) (0.030)
62.0 54.5 47.7 38.6 53.9 1.7 4.8 3.9 7.2 3.0 Low
(0.31) (0.28) (0.24) (0.20) (0.28) (0.009) (0.024) (0.020) (0.037) (0.015)
54.4 4.2 Low
(0.28) (0.021)
54.8 3.4 Low
(0.28) (0.017)
52.8 3.6 Low
(0.27) (0.018)
41.5 3.7 Low
(0.21) (0.019)
40.2 8.8 Low
(0.20) (0.045)
41.5 4.8 Low
(0.21) (0.024)
43.7 4.9 Low
(0.22) (0.025)
37.8 7.2 Low
(0.19) (0.037)
65.4 44.3 37.7 21.2 44.2 2.7 7.8 5.3 5.4 7.7 Nominal
(0.33) (0.23) (0.19) (0.11) (0.22) (0.014) (0.040) (0.027) (0.027) (0.039)
52.2 5.6 Nominal
(0.27) (0.028)
45.8 7.6 Nominal
(0.23) (0.039)
49.4 5.7 Nominal
(0.25) (0.029)
45.7 7.3 Nominal
(0.23) (0.037)
74.1 36.6 50.2 29.3 41.1 2.1 8.9 9.1 5.1 10.9 High
(0.38) (0.19) (0.26) (0.15) (0.21) (0.011) (0.045) (0.046) (0.026) (0.055)
69.5 64.5 43.9 13.7 40.6 3.6 6.6 4.1 6.5 6.6 High
(0.35) (0.33) (0.22) (0.07) (0.21) (0.018) (0.034) (0.021) (0.033) (0.034)
37.3 9.9 High
(0.19) (0.050)
47.8 6.4 High
(0.24) (0.033)
50.3 7.7 High
(0.26) (0.039)
Table B. Area A results in fpm (m/s).

©Copyright ISPE 2009

Figure 9. Area A histogram.

6 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Working Height Velocity Studies
Average Standard Deviation Velocity
B-1 B-2 B-3 B-4 B-5 B-1 B-2 B-3 B-4 B-5 Setting
20.6 12.9 30.8 30.4 25.5 2.8 3.3 1.8 2.4 3.7 Low
(0.10) (0.07) (0.16) (0.15) (0.13) (0.014) (0.017) (0.009) (0.012) (0.019)
26.5 16.4 32.2 28.8 24.7 3.6 4.2 1.5 2.3 4.9 Low
(0.13) (0.08) (0.16) (0.15) (0.13) (0.018) (0.021) (0.008) (0.012) (0.025)
27.3 2.7 Low
(0.14) (0.014)
24.3 3.6 Low
(0.12) (0.018)
27.8 3.1 Low
(0.14) (0.016)
30.7 2.9 Low
(0.16) (0.015)
30.6 1.7 Low
(0.16) (0.009)
30.7 3.5 Low
(0.16) (0.018)
30.5 3.2 Low
(0.15) (0.016)
31.3 3.9 Low
(0.16) (0.020)
27.3 15.1 37.7 38.2 33.5 3.4 3.6 2.1 2.7 4.0 Nominal
(0.14) (0.08) (0.19) (0.19) (0.17) (0.017) (0.018) (0.011) (0.014) (0.020)
31.8 3.6 Nominal
(0.16) (0.018)
32.3 2.3 Nominal
(0.16) (0.012)
33.3 2.5 Nominal
(0.17) (0.013)
34.1 1.7 Nominal
(0.17) (0.009)
35.2 15.7 46.7 43.2 38.0 2.6 3.6 1.6 2.7 2.2 High
(0.18) (0.08) (0.24) (0.22) (0.19) (0.013) (0.018) (0.008) (0.014) (0.011)
35.0 15.5 45.9 43.8 34.6 2.1 2.4 1.9 2.3 2.7 High
(0.18) (0.08) (0.23) (0.22) (0.18) (0.011) (0.012) (0.010) (0.012) (0.014)
39.0 3.5 High
(0.20) (0.018)
39.6 2.2 High
(0.20) (0.011)
40.4 2.3 High
(0.21) (0.012)
Table C. Area B results in fpm (m/s).
©Copyright ISPE 2009

Figure 10. Area B histogram.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 7

 Working Height Velocity Studies
Average Standard Deviation Velocity
C-1 C-2 C-3 C-4 C-5 C-1 C-2 C-3 C-4 C-5 Setting
22.1 31.0 4.2 14.6 21.5 2.5 5.2 1.3 3.9 2.2 Low
(0.11) (0.16) (0.21) (0.074) (0.11) (0.013) (0.026) (0.0066) (0.020) (0.011)
22.9 3.8 Low
(0.12) (0.019)
21.3 3.2 Low
(0.11) (0.016)
23.0 1.2 Low
(0.12) (0.0061)
22.5 3.8 Low
(0.11) (0.019)
21.0 3.6 Low
(0.11) (0.018)
23.8 5.5 Low
(0.12) (0.028)
18.4 3.2 Low
(0.093) (0.016)
20.4 4.0 Low
(0.10) (0.020)
21.1 3.2 Low
(0.11) (0.016)
31.1 39.7 26.3 30.4 24.1 5.0 5.8 3.3 5.4 2.3 Nominal
(0.16) (0.20) (0.13) (0.15) (0.12) (0.025) (0.029) (0.017) (0.027) (0.012)
24.4 2.5 Nominal
(0.12) (0.013)
26.5 3.2 Nominal
(0.13) (0.016)
25.9 2.1 Nominal
(0.13) (0.011)
26.4 4.8 Nominal
(0.13) (0.024)
38.8 51.2 28.9 29.9 22.4 8.7 4.2 3.4 5.9 2.3 High
(0.20) (0.26) (0.15) (0.15) (0.11) (0.044) (0.021) (0.017) (0.030) (0.012)
33.5 46.1 28.6 29.4 23.0 2.6 4.9 5.2 6.2 3.2 High
(0.17) (0.23) (0.15) (0.15) (0.12) (0.013) (0.025) (0.026) (0.031) (0.016)
28.6 2.6 High
(0.15) (0.013)
27.6 3.2 High
(0.14) (0.016)
24.6 2.0 High
(0.12) (0.010)
Table D. Area C results in fpm (m/s).

©Copyright ISPE 2009

Figure 11. Area C histogram.

8 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Working Height Velocity Studies
Critical Point Minimum Air Velocity Maximum Air Velocity Acknowledgments
The contributions of the following people to the development
A - Accumulator 19 fpm (0.097 m/s) 61 fpm (0.31 m/s) of this technical report are greatly appreciated:
B - Filler 14 fpm (0.071 m/s) 46 fpm (0.23 m/s)
C - Stopper Bowl 13 fpm (0.066 m/s) 38 fpm (0.19 m/s) Beverly K. Flick
John W. Masengale
Table E. Case study WHV acceptance criteria.
Peter K. Meginnis, PE
Donald R. Moore, PE
Verification that the critical point tested matched the test Douglas A. Schrader
location in the technical study should be confirmed. Critical
elements of the test method include the anemometer time About the Authors
constant and probe alignment. The HEPA filter face velocities William G. Mason is an Engineering Consultant with Eli
will affect the working height velocities. The velocities of the Lilly and Company. Since joining Lilly in 1989, he has held a
HEPA filters were recorded from the AFPT that proceeded variety of assignments in technical services, process control
the WHV testing. Subsequent adjustments to these velocities and automation, and process engineering. He can be contacted
can impact WHV readings. All tests used to determine the by telephone: +1-317-277-7350 or by email: mason_william_g@
critical limits were executed with corrugated polycarbonate lilly.com.
sheet doors closed.
Bernard McGarvey, PhD, is an Engineer-
Conclusions ing Advisor with Eli Lilly and Company.
1. Velocity can vary significantly with relatively small loca- Currently, he leads a group that focuses on
tion change. This is especially important using thermal the use of modeling within manufacturing
anemometers. and process development. This group ap-
2. Velocity measurements at the HEPA filter protective grill plies process modeling to such diverse areas
are a better indictor of UAF hood performance than velocity as capacity simulation, flowsheet modeling,
measurements at working height due to the high standard computational fluid dynamics, optimization,
deviation and variability in velocity readings at the work- and operations research. He has 25 years of experience in
ing height. The correlation of HEPA filter face velocity to the pharmaceutical industry and has held previous posi-
air flow pattern testing is a more reliable and repeatable tions in technical services, process control and automation,
method than the correlation of working height velocity to and process engineering. He can be contacted by telephone:
air flow pattern testing. +1-317-433-2293 or by email: [email protected].
3. Thermal anemometry can be used to obtain detailed multi-
directional spatial variation of air flow velocities in complex Thomas R. Spearman, PE is an Associ-
flow environments. Also, it provides data that can be used ate Engineering Consultant at Eli Lilly and
to compare with CFD models. Company. Since joining Lilly in 1978, he has
held a variety of engineering assignments
References and is currently the responsible engineer
1. Sterile Drug Products Produced by Aseptic Processing – for facilities, HVAC, and utility systems in
Current Good Manufacturing Practice, Food and Drug Indianapolis Parenteral Operations. He also
Administration, 2004, p.9. leads the global Parenteral HVAC Technology
2. EC Guide to Good Manufacturing Practice Revision to Annex Team. He obtained a BSc in mechanical engineering from Pur-
1 – Manufacture of Sterile Medicinal Products, European due University at Indianapolis. He obtained his professional
Commission, 2008, p. 2. engineering license in Indiana in 1998. He is a member of
3. Shortridge AirdataTM Multimeter Electronic Microman- ISPE and is a member of the ISPE Sterile Products Processing
ometer with Velgrid, Model ADM-880C, “Specifications,” Community of Practice (COP) Steering Committee. He is a
February 2007, page 2. member of the American Society of Heating, Refrigerating and
4. 2005 ASHRAE Handbook – Fundamentals, page 14.15. Air-Conditioning Engineers (ASHRAE) and is a corresponding
5. TSI VELOCICALC® Plus Air Velocity Meter Model 8384 member of the ASHRAE Clean Space Technical Committee.
/8384A/8385/8385A/8386/8386A, “Operation and Service He was a member of the Board of Directors of the Controlled
Manual,” P/N 1980321, Revision H, June 2006, page 21. Environment Testing Association (CETA) from 2005 to 2008.
He can be contacted by telephone: +1-317-276-8750 or by
©Copyright ISPE 2009

email: [email protected].
Eli Lilly and Company, Lilly Corporate Center, Indianapolis,
Indiana 46285, USA.

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 9

 On-Line Exclusive Article
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE Planning an API Production Factory
July/August 2009, Vol. 29 No. 4

This article
presents an A Risk Assessment Approach to
overview of the
planning of an Planning an API Production Factory
API production
factory from the
risk assessment by Kazuo Tozaki
viewpoint.
Three risk
assessment
factors of
severity,
probability of Introduction

A
of maintaining API specific qualities, namely,
occurrence, and long period of time and many steps are equivalency, efficacy, quality, purity, and safety.
detectability necessary to plan and construct an API But, as is well known, many contamination risks
are discussed. production plant (Figure 1). Of particu- exist in the API production process - Figure 2.
lar concern is the construction of the The significance of these contamination risks
An example hardware that goes into the plant. The results lies in the fact that they constitute threats to
of conceptual of design work during the basic planning and/or the maintenance of the desired API specific
layout planning basic design phase play a key role in determin- qualities. The materials that pose a hazard and
is presented. ing the ultimate cost of the plant. the mechanisms of occurrence of contamination
This article will summarize important items are the main features of these risks.
to be considered and the process to be followed
in the early stages of planning an API produc- Risk Assessment and Assessment
tion facility that qualify it in terms of GMP. Factors of Contamination
The main discussion will center around ICH Q9 presents a typical example of a quality
the risk assessment approach of how to give risk management process and explains that risk
shape to the GMP concept from the viewpoint is generally understood as the combination of
of contamination control for the API production the assessment factors, that is, the probability
process. For the purposes of this discussion, the of occurrence of harm and the severity of the
product is assumed to be a chemically synthe- harm. It also includes a reference to a ‘Failure
sized non-aseptic API. Mode Effect and Criticality Analysis’ (FMECA),
which incorporates “detectability” (the ability
Contamination Risk in the API to detect the presence of contamination) as an
Production Process additional factor. According to this idea, risk
During the production of API, control measures will be expressed as a combination of the risk
like process control and quality control are factors, that is, the severity of harm, the prob-
employed in order to build quality-creating ability of occurrence, and the detectability of
factors into the process steps, with the aim contamination.
Figure 1. Schematic
diagram of the project
flow for the construction
of an API production
facility.
©Copyright ISPE 2009

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 1

 Planning an API Production Factory
als, intermediate materials, significant intermediate
materials, and final intermediate materials.

The impact of any contamination will differ according to

the stage in the process at which the contamination takes
place.Note 1

Probability of Occurrence
It is difficult to evaluate the probability of occurrence quan-
titatively. However, it becomes easier to understand if it is
considered as being divided into two parts, that is, the nature
of the contamination threat (causes difficulty in the event of
occurrence) and the fragility of the production facility (weak-
ness of the production facility).
The mechanism of the contamination threat is considered
as including phenomena, such as generation, growth, remain-
ing, mingling, invasion, and cross-contamination.
On the other hand, the fragility is considered to be re-
lated to non-conformance with the contamination prevention
measures. Accordingly, the occurrence of contamination is
considered to be a phenomenon in which the threat of the
occurrence of contamination becomes apparent through the
trigger represented by the fragility of the production facility
and production management system.
The following is an example of the occurrence of contamina-
tion. “Waste material on a beam flange drops into the reaction
liquid through an open inspection-hole of the reactor and is
Figure 2. Contamination risks in the API production process. mixed with the process material, because the inspection-hole
is located directly under the beam.” The waste material on the
Risk = Severity of Harm × beam flange will be the cause of the threat (cause material of
Probability of Occurrence × Detectability harm) and is mixed with the process liquid resulting in the
occurrence of the contamination.
These factors may be combined as the product, the sum of The fact that that there was a reactor directly underneath
the elements, or in the form of a matrix. The form selected and no protective measures were in place will be the fragil-
should be decided upon on a case-by-case basis. The following ity.
are the important elements to be aware of in order to assess The fragility will exist in the hardware elements, such as
the risk factors. equipment and facilities and also in software elements, such
as rules or a standard operating procedure.
Severity of Harm If the situation is left in the present (fragile) condition,
Severity is assessed by the potential magnitude of the harm it is necessary to assume the possibility of the occurrence of
that will be caused. The harm which can be brought about contamination every time the inspection-hole is opened.
due to the occurrence of contamination includes, for example, The contamination has its own mechanism of occur-
the delays in production owing to the reprocessing work, rence.
disposal of the batch, the impact on other products, and the Clarification of the mechanisms on a scientific basis and
occurrence of drug-induced ill-effects resulting from use of complementing and/or reinforcing of the fragility are neces-
the product. sary.
In order to assess the magnitude of harm, understanding In the above example, a software-type countermeasure of
the significance of the production process that will suffer regularly cleaning the area, including the beam flange, will
contamination by evaluating the materials being handled be one effective way of preventing the occurrence.
and the process steps will be of key importance. Assessing Also, as the mechanism of contamination occurrence is
the impact of the contamination on the materials handled considered to be the mingling of the waste material, which
©Copyright ISPE 2009

will include: has dropped into the opening just beneath the beam, a design
change that alters the relative positions of the beam and open-
• Evaluating the impact on the specific qualities of the API: ing, or action that provides proper protection to the existing
- Finding the status of the materials handled, such as raw opening will remove the threat of contamination.
materials (chemical substances), API starting materi-

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 Planning an API Production Factory
Materials Causing Contamination Weak points in the process (fragility) are subject to con-
The types of materials which are viewed as causing the threat tamination. A variety of hardware/software items in the
of contamination are listed in Figure 3, “Classification of production process will be related and are summarized as
Contaminants and Corresponding Measures.” follows:
In Figure 3, the contaminants are classified into three
groups of potential contaminants, that is, contaminants re- Treatment of Raw Materials
lated to source control, the contaminants related to protection • level of quality control at suppliers and the results of
control, and those involved in cross-contamination. audits
• quality of the raw materials received
Mechanisms of Contamination will include: • effectiveness and performance level of receiving checks
• generation, growth, remaining, mingling, invasion, cross- • effectiveness and performance level of warehouse con-
contamination trols
• defects in the quality control system or the manufacturing
control system Physico-Chemical Properties, State, and Characteristics
of the Materials Handled
The assessment of these mechanisms will need the knowledge • physico-chemical properties: the sensitivity of the materials
of the materials handled and the detailed information about handled to changes of process conditions.
the production facility. • state of materials: powder, wet powder, gas/vapor, liquid
• characteristics: coagulation, adhesiveness, volatility,
The Fragility Toward Contamination change in quality, etc.
Fragility, as shown in Figure 4, will act as a loophole through
which the protection measures against the threat are un- Characteristics of the Reaction Process
dermined. The difficulty that may exist in controlling the reaction.
©Copyright ISPE 2009

Figure 3. Classification of contaminants and corresponding measures.

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 Planning an API Production Factory
• level of the facility maintenance
• level of practical application of good work practices (the
5S)Note 2
• level of training for operators and its effectiveness
• nature and effectiveness of the measures included in pro-
cedures to cope with any instances of nonconformity
• state of preparation of the Standard Operation Procedures
are raised as examples

Conditions of the Surrounding Environment (External

to the Equipment)
Given below are well known examples of conditions for which
parameters should be set.
Figure 4. Contamination risks of API.
• temperature
Robustness Against Contamination of the Process • humidity
System • cleanliness
• Whether the contamination affects the quality of the • ability to withstand the effects of external disturbances
product directly or indirectly will be assessed.
• For example, the contamination of the clean steam or the Detectability
process water will directly affect API quality, but will affect Detectability is the ability to discover or determine the exis-
it indirectly in a case involving jacket cooling water of the tence, presence, or fact of hazards, together with the degree
reactor. of severity, related to critical quality risk. The waste material
on a beam flange may happen to drop into a powder product,
Level of Operation exposure to the External not into the liquid in the reactor. In this case, we cannot find
Environment the waste materials easily, making detectability low and the
The level of exposure of the operation to the external envi- risk higher than in the case of liquids.
ronment will differ depending upon the operation status, In the case of liquids, usually we can easily detect and
specifically, whether it is in closed operation, in briefly opened remove the waste with a filter. And we may assume that the
operation, in completely opened operation or in common use severity of harm and probability of occurrence are to be the
operation. same level.
The following are important examples of factors that will
Quality of the Construction/Fabrication of the Facility have significant influence on detectability:
The assessment factors for the quality of fabrication or how
well-built the facility is have relation to a number of areas, in- • state of the materials handled (powder, wet powder, liquid,
cluding the level of technology employed and cost performance gas/vapor)
issues. The typical assessment factors will be: cleanability, • existence of detection mechanisms or detection process
ease of washing, ease of overhaul, toughness, corrosion resis- steps and their accuracy
tance, ease of maintenance, weather-proofing, protection level • existence of monitoring mechanisms
against the external environment, contamination resistance/ • position among the production steps (For example, after the
self cleaning capacity, operability, safety, etc. final purification step or final sterilization step, there exist
However, the purpose of the facility must be paid careful no detection mechanisms before shipping inspection.)
attention to in actual practice. (For example, the capacity for
complete overhaul does not justify itself; it must be assessed Countermeasures Against
in terms of its necessity for the purpose of the facility). Contamination Risks
The contamination threat will comprise the occurrence of
Process and the Process Devices for Quality Control generation, growth, remaining, mingling, invasion, and cross-
The detection process for impurities, the analytical processes contamination, and that fragility will be related to the inap-
applied to monitor the quality of the API and the intermedi- propriateness of the hard and software aspects of the facility.
ates, and the process for the confirmation of the completion To prevent contamination risks from actually causing harm,
of the reactions can be raised as examples. it will be necessary to identify the cause materials of contami-
©Copyright ISPE 2009

nation, to make clear on a scientific basis the mechanisms

Facility Maintenance of contamination, and to determine the degree of fragility of
The maintenance and the quality of the fabrication will be the facility that may be threatened by contamination. It also
inevitably complementary to each other, otherwise both may will be necessary to take proper countermeasures which are
be the source of malfunctions. balanced from both the hard- and software standpoints and
plan a production facility/system that is resistant to contami-

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 Planning an API Production Factory
nation. The above measures enable the construction of the Prevent Cross-Contamination
GMP qualified production facility, and through the PDCA (Cross-Contamination Control)
cycle of GMP management during the operation phase, GMP The contaminants involved in cross-contamination have a
will be realized. relation to the former two types of contaminants.
The countermeasures to the contamination risk can be
summarized in the four steps below: Integrate with Hazard Control
In recent years, as the number of new, highly potent drugs has
Step 1 - identify the contaminants increased rapidly, it is generally acknowledged that not only
the protection of the drugs, but also the protection of person-
Step 2 - make clear the mechanisms of contamination and nel/the environment are indispensable. So, it is important to
evaluate the threat. incorporate hazard control in order to attain the purpose of
“the protection of personnel/external environment” together
Step 3 - evaluate the risk with consideration given to the with the source control, the protection control, and the cross-
severity and detectability. contamination control, which are to attain “the assurance of
drug quality.” Thus, the protection of the drugs from contami-
Step 4 - take concrete measures, which are balanced from the nants and the protection of personnel/the environment must
viewpoint of hardware/software aspects to reduce the necessarily be realized in one set of hardware. A system of
fragility of the production facility. anti-hazard countermeasures has been developed that estab-
lishes exposure levels based on the safety data like MSDS,
Planning Contamination and determines the barrier levels that protect operators/the
Prevention Measures environment from drugs, and is in use for the designing of
The planning of the contamination prevention measures are commercial plants.
studied according to the following five policies. During this The purpose of the contamination control for API is con-
study, three management concepts of source control, protec- sidered to realize the countermeasures against the various
tion control, and hazard control are proposed. contaminants shown in Figure 3 in one facility according to
three management factors below in a way which satisfies the
Classify and Group Contaminants hardware/software balance.
The source materials of contamination include those from a
wide range of origins. Hence, clear classification and grouping Control of Contaminants
will be essential. Therefore, each contaminant is identified and In this paragraph, the outline of the contamination control
classified according to the cause and place of generation. will be given below according to Figure 3 and three manage-
A sample of the result of the above classification is shown ment concepts are detailed.
in Figure 3 in which countermeasures and management policy
for each contaminant also are indicated. Source Control
The contaminants of API are classified into three groups, The Analysis of Critical Process StepsNote 4
the contaminants which originate in the production process Source control is aimed at maintaining API specific qualities
(hereinafter referred to as “internal origin contaminants”), the through the control of the generation/removal of undesired
contaminants which originate outside the production process materials within the production process. In the case of chemi-
(hereinafter referred to as “external origin contaminants”), cally synthesized API, the impurity profile and the physico-
and those involved in cross-contamination. chemical properties are controlled within the established
Source control, protection control, and cross-contamination control limits. The strictness of process control is not the same
control correspond mainly to each of the types of contaminants with each process step, because the GMP significance is not
mentioned above. In Figure 3, undesired materialsNote 3 also are
included as well as the foreign materials that have mingled
or invaded from outside of the process. The production facility
itself also is included as a source of contaminants.

Control the Generation and Removal of

Contaminants (Source Control)
It is to control the generation and removal of contaminants
within the production process.
©Copyright ISPE 2009

Protect the API or Intermediate Product from

the Mingling and Invasion of Contaminants
(Protection Control)
It is to protect the API or intermediate products from exist-
ing contaminants. Figure 5. Three management concepts of contamination control.

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 Planning an API Production Factory
the same throughout the API production process. derive from the cause materials outside the process plant,
The analysis of critical process steps gives an effective tool and “chemical reaction with or dissolution from the produc-
for this type of analysis. It enables the classification of the tion facility.”
level of control according to the significance of the process
step using the concept of critical process steps and critical Production Plant Origin Contaminants
parameters. These can be defined as undesirable materials, such as excess
The following process steps are raised in general as the raw reaction materials, by-product, decomposed product,
critical process steps.Note 5 The manufacturer will decide these denatured materials, residual intermediates, and recovered
in detail, while taking into consideration the significance and solvent.
characteristics of the production process together with the Through the control of the generation/removal of these
practice of process control. contaminants, the impurity profile will be controlled.
Through the analysis of critical process steps, the object of Lot control of the recovered solvent will be carried out
control to avoid the threat of contamination – which will be so that identification of the solvent used for each lot can be
brought about by any deviation, operational mistake, or failure, made.
and the places in the production process where contamination Here, in the case of mixing the solvents between lots, the
risks exist – will be identified. In order to give shape to the equivalence of the solvent to be added must be tested and
countermeasures against the risks posed by contamination, confirmed before it is mixed with the original solvent.
establishing the level of management required to control the
occurrence of contamination based on the evaluation of the Outside Production Plant Origin Contaminants
degree of harm is necessary. For this reason, establishing the Contaminants may be generated through the chemical reac-
allowable impurity levels, which are the basis of evaluation, tions involving the API, reaction materials, and intermediates,
is indispensable. which will occur by the mingling of or stimulation by the cause
Accordingly, in the source control, establishing the allow- materials of contamination, which will come from the produc-
able level mentioned above and the process control in order tion room where the production facility is installed and from
to control the generation/removal of undesired materials is outdoors, such as ultraviolet rays, oxygen in the air, water,
necessary. For the process steps downstream of critical steps, and micro-organisms, which are well known examples.
strict control is required. In the case of ultraviolet rays, wavelengths will be evaluated
Some changes with an impact on the API specific quali- as to whether they have a potential contaminating effect or
ties established in the development phase are likely. These not, and concentrations left behind in the reaction liquid will
may be as a result of the increased scale, the altered process be evaluated for the amount of contaminants generated.
conditions, and different surrounding environment as well If necessary, process control limits will be established based
changes made in the process when the investigational plant on this information in order to contribute to contamination
is replaced by its commercial successor. prevention.
It is desirable to remove the influences of these changes
beforehand so that the generation/removal control of the Chemical Reaction With or Dissolution From the Production
undesired materials will be carried out effectively through Facility
the daily operation control and maintenance work during the Contaminants may be generated through chemical reaction
production phase. between the raw/reaction materials and the materials used
Thus, the verification and documentation ensuring the in manufacturing the equipment or by the liquation from the
equivalenceNote 6 will become necessary at the test operation construction materials, e.g., the chemical reaction between
and validation phase. raw materials and glass-lined vessels, or trace metals in
rubber stoppers, etc. These contaminants are caused by the
Internal Origin Contaminants lack of reliability and conformity with respect to mechanical
Internal origin contaminants are classified into two groups: 1. and material issues of the production equipment against the
the contaminants which originate in the process unit operation, chemical compound handled.
such as chemical reaction, extraction, cell culture, fermenta-
tion, and enzymatic reaction, and 2. the residuals. Residuals Inside the Production Facility
Among internal origin contaminants, the contamination It is generally well known that residual solvents, residuals
which will be generated by genetic recombination is not within left behind after washing, additives, and residuals torn or
the scope of this classification in accordance with the GMP which have fallen from the production equipment represent a
Guide for API (ICH Q7). potential contaminant effect. Protective countermeasures will
©Copyright ISPE 2009

be necessary based upon the significance of the process steps,

Contaminants which Originate in the Process Unit the dangerousness of the residues, and the ease of removal.
Operation
These include “the production plant origin contaminants,” Residual Solvent
which derive from the cause materials in the process plant, Control through the impurity profile, if necessary, will be
“the outside production plant origin contaminants,” which carried out, as well as control through the allowable control

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 Planning an API Production Factory
limit in order to manage the amount of the residual solvent. the production process, the foreign materials which mingle
The ways of treating residual solvents are different in the and invade from outside of the production process, and cross-
case of intermediates and API. In the case of intermediates, contamination.
their specifications will be established depending upon each The analysis of critical steps also is effective for protection
case in terms of the impact on their stability, the degree of control. Through the analysis of critical process steps, the
influence on the next process step or crystallization, and knowledge about the place (process steps) and the magnitude
whether it will, if carried over to the API, have a poisonous of contamination risks, which will be caused by the residuals,
effect or cause mutagenicity or carcinogenicity, etc. On the mingling, invasion, and cross-contamination in the process
other hand, it is required to carry out control of the residu- steps can be obtained.
als in the API in accordance with “Impurities: Guideline for For the residuals, protection control will be carried out ac-
Residual Solvents”(ICH Q3C). cording to the method described above. For the external origin
contaminants, as well as cross-contamination, the necessary
Cleaning Residuals protection levelNote 7 will be established to protect the process
The examples are: steps concerned by considering the significance of each process
step and the level of exposure to the external environment,
• residuals left behind in the reactors or vessels after between- prior to carrying out each protection measure.
lot-cleaning Establishing the protection level means building the frame-
• residuals on the filters of a centrifuge, the use of which work of the protection measures necessary to protect drugs
extends over several lots from residuals and foreign materials that will be sufficient
• cleaning residuals left following a product switching opera- to cope with and be appropriate to the contamination risks.
tion This will be materialized by a combination of enclosing the
• cleaning residuals at product switching operation for equipment together with the use of containment, protection
producing several intermediates in the same equipment by structures, and HVAC as well as changing rules/SOPs.
of a dedicated API plant Thus, not all the required protection measures are neces-
sarily achieved with the process equipment only.
The control of the allowable amount of residuals will be carried In order to evaluate the probabilities of contamination oc-
out through the performance of the cleaning validation. In currence and the magnitude of harm caused by the exposure,
the facility planning, the best design efforts to remove dead the characteristics specific to the API production process
spots in piping, vessels, and ducting are essential. described below will have to be studied.

Residuals of Additives Key Elements in Deciding the Characteristics of

These include additives, catalysts, heavy metals, and filtra- the API Production Process
tion agents. The process steps to remove these additives are • The production know-how and the experience accumulated
foreseen so that they are removable generally by means of from work conducted with the investigational production
physico-chemical methods, such as filtration and precipita- plant:
tion. These will be included in the impurity profile control if - This work provides basic knowledge on the risk of
necessary. exposure and the necessary level of enclosure for the
facility, and also provides a basis for determining the
Production Plant Origin Residuals requirements for equivalency of the facility.
The examples are exfoliated lining materials from agita- • The process steps where the drug effect is generated
tors in the reactors, filter fiber debris, mingling of foreign • Information on the critical process steps:
materials resulting from damage to equipment (bolts, pieces
of metal), fragments detached from rotating parts of equip-
ment, mingling of harmful sealant liquids, and residuals from
construction work.
To control the occurrence of contaminants originating
within the production plant, it is necessary to plan equipment
with sufficient toughness and reliability (maintenance obvia-
tion). Referred to as “maintenance prevention” in Japan this
process is based on experience with similar work and detailed
equipment structure information from the design stage, and
©Copyright ISPE 2009

maintain its reliability through adequate maintenance work

(preventive maintenance).

Protection Control
Establishing the Protection Level
Protection control will protect drugs from the residuals in Figure 6. Typical example of a protection level framework.

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 Planning an API Production Factory
- The investigational plant provides knowledge on the people. In order to cope with these issues, establishing an
places where contamination risks with a serious influ- appropriate layout based on the routes for movement and
ence on the quality of the API exist, and on the objects zoning planning (see section on Factory Layout Planning) and
that need control. establishing appropriate changing rules and enter/exit rules
• The state of the materials handled: will be effective together with the proper strategy to enclose
- The state of the materials handled, such as gas, liquid, the production plant. The proper training of operators involved
wet powder, or powder form (and whether in large or in the production process and the effective management of
small quantity) will provide knowledge on the risk fac- measures such as sanitary control also will be effective.
tors.
• The level of enclosure of the production plant and existing Fine Particles, Gas, Bacteria, Mold, etc. from
within it will provide knowledge on how, and to what de- Business Places External to the Factory
gree, the production plant itself and the equipment within Contaminants may invade from external business places ow-
it should be enclosed against the external environment. ing to the factory layout and site conditions. Measures may
• The method of operation: be adopted to decide the direction of air intakes or installing
- Provides knowledge on the level of exposure to the ex- appropriate filters taking into consideration the existence/
ternal environment from the operational standpoint. location of plants producing poisonous/toxic substances
• Classification of the production facility: around the API production factory and of the waste liquid
- Typical examples are “dedicated” or “common use” treatment facilities.
plants, and according to the classification of the role of In preventing the growth of mold in the factory, paying
the production facility in terms of which kind of drugs attention to humidity control will be of key importance. This
are produced, such as non-proprietary drugs, highly relates especially to the prevention of dew condensation on
potent drugs, or high sensitizing agents. The necessary the inside surfaces of walls and windows.
countermeasures against cross-contamination are dif-
ferent. Contaminants Originating from the Building or its
Fittings
External Origin Contaminants Materials or substances originating from the building itself
External origin contaminants include those introduced or its fittings, such as paint which has peeled from the steel
through mingling and through invasion from outside the frame, rust, or items like bolts or nuts, may mingle as for-
production process. eign materials. It will be important to take countermeasures
through maintenance work on the factory, as well as paying
Raw Material Origin Contaminants attention to these issues at the design phase and the quality
The threat of the mingling of impurities, adhesives, denatured control at the construction phase.
materials, etc. contained in raw materials, and indication of The subject of maintenance can be approached in two
mistakes or management mistakes, such as mislabeling and ways, namely maintenance obviation, which will mainly be a
inaccurate/incomplete directions for use are potential risks. concern during the design phase and preventive maintenance
Receiving checks and warehouse management must be carried that will be practiced during operation of the facility. Improv-
out so as to prevent foreign materials from being introduced ing the quality of the facility from a maintenance viewpoint
into the production process and the control of the impurity by changing materials from carbon steel to stainless-steel to
profile, as well as appropriate advice to the contracted factories prevent rust is an example of maintenance obviation.
involved will be important.
Airborne Particles, Gas
Insect, Animal Origin Contaminants These contaminants represent the main factors in the cross-
Every stage, from the factory construction phase to opera- contamination threat.
tion, offers chances of invasion. So, many kinds of measures The magnitude of the harm will be different for proprietary
may be adopted as deemed necessary, such as the removal of and non-proprietary drugs even if the contamination may be
places where growth/breeding occurs, the blocking of potential the same (same contaminants and same mechanism of occur-
routes of entry, and extermination measures using chemicals rence) so that measures which are appropriate to each case
in accordance with each invasion route (pest control). will be necessary. For example, the class level of cleanroom
Also from the viewpoint of factory planning, the designers will be different according to the drugs handled.
must be aware of the impact of many factors, such as the pres- In the consideration of planning of the factory, establishing
ence of trees around the factory, the location of septic tanks an appropriate layout, changing rules, and enter/exit rules
©Copyright ISPE 2009

and effluent points, the layout plan of ante-rooms, the sealing based on the routes for movement, zoning, and HVAC plan-
of openings of doors and rooms, warehouse management, the ning will be necessary.
planning of carry-in/carry-out areas, and other precautions.
Process Water Origin Contaminants
Human Origin Contaminants The use of suitable water that fits the requirements of the
Contaminants may move and mingle with the movement of API being produced is important, as there are various kinds

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 Planning an API Production Factory
of process water, such as drinking water, purified water, UF For high sensitizing API at present, because the quantita-
water, and WFI. According to the equipment used for pro- tive evaluation method for allowable contamination limits has
ducing the water, adequate measures like bacteria control, not yet been established, a containment facility for the API
pressure control, temperature control, and maintenance, etc. or the use of a dedicated facility may be studied as options.
will be required.
Cross-Contamination at a Common Facility at
Apparatus for Cleaning the Time of Product Switching
Residuals of foreign materials which are related to cleaning The common facilities in a multi-product plant require cleaning
operations like detergents and brushes are potential contami- at the time of product switching. This cleaning work will be
nants. The automation of the factory has a limit in terms of carried out based on the allowable residual amount inside the
costs and performance so manual cleaning is inevitable. An plant which is established to maintain the required level of
appropriate SOP will be necessary. purity for the drugs. In the case of highly potent or poisonous
drugs, adding to the control based on the allowable residu-
The above measures have been summarized individually so als mentioned above, the treatment to make it harmless by
far, as prevention of the introduction of foreign materials, deactivation will be necessary.
pest control, cleanliness control, sanitation control, factory The containment of the API or the use of a dedicated plant
planning, and facility control. From the protection control may be studied as options.
viewpoint, prior to carrying out these countermeasures, the
location of contamination risks and their magnitude will be Factory Layout Planning
evaluated and based on this knowledge, the required protection In this paragraph, the application of the contents discussed
levels for the API will be set up, followed by establishment of so far to the factory layout design will be introduced. The
the corresponding hardware/software. outline of the design procedure is shown in Figure 7 and
Figure 8 together with an applied example in Figure 9. Lay-
Cross-Contamination Control out planning is one of the concrete measures for protection
The threat of cross-contamination is related to both internal control and it is aimed at external origin contaminants and
origin contaminants and external origin contaminants. As those introduced by cross-contamination. Thus, it provides
the mechanisms of this threat become apparent, the follow- only a part of the necessary protection control. However, it
ing points are raised: raises issues that must be considered at an early stage of the
construction project for an API production factory, and has
• Cases where contaminations are caused by operators or significant importance in deciding the quality of the produc-
by air moving between different facilities by way of such tion environment.
common facilities as corridors and elevators.
• Cases where contaminations occur due to residual raw Outline of Factory Layout Planning
materials, intermediates, and APIs when products are To start factory layout planning, the basic production scale
switched. and functions will be decided by the company management
according to their requirements, such as the factory concept
The concrete measures are different according to the follow- and the allocation of resources.
ing cases. Factory layout planning will be divided into two levels:
• Where protection measures for the API itself will be enough, the overall layout for the factory area as a whole and the
such as with non-proprietary drugs and additives. layout for the production factory itself. The overall layout for
• Where drugs are poisonous or highly potent and protec- the factory area will be an input condition for planning the
tion of personnel and the environment from the API is internal layout of the production factory, and they are obvi-
required. ously closely related to each other as can be understood by the
matter of the selection of the setting of the production factory
Human/Air Origin Contaminants Carried within the overall area. In the study of overall factory area
between Different Facilities and by Means layout, material/energy balances, required factory functions,
of Common Facilities such as Corridors and such as production, management, distribution, research and
Elevators development, zoning, and people/material/energy flows are
In the case of non-proprietary drugs, necessary protection examined in relation to each other.
levels will be established based on the knowledge of the loca- The following three requirements will decide the basic
tions of contamination risks within the process steps. In the specifications although limits on the amount of space avail-
©Copyright ISPE 2009

case of poisonous or highly potent drugs, necessary barrier able or revision of the functions may occur owing to budget
levels will be established for the protection of personnel/the restrictions on the construction cost.
environment. The requirements which apply in these two kinds
of cases may conflict with each other so facility specifications Production Process Requirements Decided from
must be established through the integration of API protection the Production Capacity Required
and protection of personnel/the environment. • Establishment of process flows [material/energy bal-

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 Planning an API Production Factory

Figure 7. Procedure of factory layout planning.

ances, batch/lot size, selection of unit operation, selection production), and production phase (raw materials ~ interme-
of cleaning methods, establishment of operation time diate ~ significant intermediate ~ final intermediate ~ API)
schedule, working out the Piping and Instrument Diagram are assigned to the scope of the factory.
(P&ID)] Also, in the case of planning a multi-purpose factory, which
• Material distribution planning produces multiple APIs or intermediates, different consider-
• Specifying of warehouse stock conditions ations from those for a dedicated plant will be necessary from
• Waste water/gas, waste treatment planning the viewpoint of cross-contamination prevention.
• Planning of utility systems Risk assessment will be considered to be carried out from
an overall scale level to a detailed scale level stepwise, such
Regulatory Requirements as from the entire factory to process systems, sub-process sys-
Satisfying the regulatory requirements that apply to the tems, unit operations, and sub-systems which constitute unit
layout is indispensable. operations. Figure 8 shows the procedure of risk assessment
up to the figuring out of the concept layout planning based on
The Requirements of “GMP Guide for API (ICH Q7)” the information regarding process steps and contaminants.
• Identification of API starting materials and the scope of The start is made from the identification of the API starting
GMP management materials and establishing the scope of ICH Q7.
• Identification of critical process steps and the scope of The next step is risk assessment from the viewpoint of
validation source control, protection control, cross-contamination control,
and establishing provisional control area classifications by
As the items that need studying mentioned above will influence analyzing zoning and finding necessary buffer zones.
each other, various professional engineers need to cooperate During these procedures, critical process steps will be
to work out the layout. Figure 7 shows an outline of these identified, establishing building/HVAC zoning, and movement
procedures. However, in actual designing, project engineering route analysis will be carried out.
©Copyright ISPE 2009

techniques will be employed effectively as trial-and-error and After completing risk assessment based on the given pro-
coordination work between professionals are indispensable. cess information, and getting the conclusion that residual
Figure 7 shows an example where the scope of factory risks are within allowable limits, a conceptual layout will
planning is downstream of the scope of ICH Q7. The scope of be set up together with control area classifications and its
planning will differ depending upon which stage of develop- specifications.
ment phase (Phase I ~ Phase II ~ Phase III ~ commercial After that, the design output of the above mentioned pro-

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 Planning an API Production Factory
cedure in turn becomes the input conditions of the following • Finding necessary protection levels (Level I ~ III) and
risk assessment at the detailed design phase and operation establishing provisional area classifications
phase making use of assessment techniques appropriate to • Selecting the HVAC system (re-circulating, all fresh)
each phase. Risk will be assessed for the contaminants and • Establishing changing rules
mechanisms of contamination identified, carrying out ad-
ditional hard/soft-ware measures. Zoning Plan of each Class of Area
It will be a more practical planning tool by incorporat- The plot plan of each area class will be in accordance with
ing in advance the knowledge acquired by the experience of the movement route plan for the entire factory complex. The
project execution from detailed design to test operations, and following are points to which attention must be paid:
the knowledge of additional preventive measures acquired
by the risk analysis, into the specifications of control area • Concentrate as much as possible on the areas requiring
classifications. equal protection levels and the areas requiring equal clean
Various well-known risk assessment methods exist in ad- levels. In this way, the prevention of cross-contamination,
dition to that proposed in this article. Failure Mode, Effects, the clarification of the routes of movement, and the ratio-
and Criticality Analysis (FMECA) may be applicable to the nalization of HVAC systems can be achieved.
risk assessment of unit operations at the detailed design • Concentrate on those areas where hazardous/poisonous
phase. Also, HACCP, which at present is applied mainly in materials are handled.
the food production industry, may be efficiently applied at the • Separate the areas legally defined as “hazardous” and
operation phase. “non-hazardous” so that the regulations that apply to
hazardous areas will not need to be applied to the whole
Zoning factory area.
Zoning is divided into entire factory area zoning and the • The supporting areas that include washrooms, toilets, rest
production factory zoning. rooms, and storage for waste materials will be positioned
so as not to face directly to the production area in a way
Entire Factory Area Zoning that may cause contamination.
It is the plot plan which lays out all the elements which make
up the factory area complex, such as the production area, Moving Route Planning
research and development area, energy center, distribution In the planning of routes for movement, the routes for the
center, and welfare area. The following are points to which entire factory area and those inside the production factory
attention should be paid: itself will naturally influence each other. The basic structure
of the layout will be established by studying the combination
• The configuration of the factory site area, the surrounding of the zoning requirements and the routes for movement
environment, natural conditions (sunshine, wind direction), inside the factory.
the distance from each contaminant source (production area In the analysis of personnel/material/air flows, attention
of highly potent substances and/or agricultural chemicals, will be paid to work procedures, handling volume, and work ef-
waste water treatment facilities, etc.), wind direction, and ficiency in studying the prevention of cross-contamination.
movement routes inside the factory area must be taken
into consideration in the site planning. Entire Factory Area Movement Routes
• Personnel/material movement routes in the site and tie-in The following are the points of concern for the analysis of the
points of utilities movement routes in the entire factory area.
• If necessary, expansion/increase must be taken into con-
sideration. • The receiving routes for raw materials and other materi-
als
Production Factory Zoning • The routes followed by transportation and pick-up ve-
Zoning has as its aim the protection of the production plant by hicles
ensuring a proper production environment. Thus, prior to zon- • The product shipping route
ing, an analysis of the production process is indispensable. • Routes for the movement of wastes
The zoning of a production factory will be established based • Routes of movement to be followed by factory personnel
on provisional area classification, which is the result of risk and visitors
assessment work based on the process conditions – Figure 9. • Energy flows such as electricity and heat sources
This work will includes such steps as:
©Copyright ISPE 2009

Personnel/Material/Air Flow Inside the Factory

• Clarifying process steps (production flow, properties of Based on the zoning, the moving route analysis will be carried
materials handled, equipment specifications, transport out in order to find that moving of materials, humans, and air
system, etc.) across the different zones will give no contamination risks to
• Identifying critical process steps and a rough plot plan of the production environments and the products that cannot be
necessary rooms allowed. In case such risks are found, proper counter measures

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 11

 Planning an API Production Factory
have to be provided. Such buffer zones or areas such as pass such as ante-rooms or A/L owing to zone control reasons,
boxes/pass rooms and ante-rooms may be raised as examples. but also to the area of the cleanroom or that of the building
Also, movement analysis may find the necessity for additional and the HVAC loadings.
areas like corridors owing to the operational necessity. This classification also is relevant to the frequency of
The following are the points of concern for the study involved changing for operators, which raises issues of operability and
in the analysis of movement routes inside the factory: cost incompatibility. Thus, case studies on these issues will
be important before deciding the building configuration or
• The corridors and elevators for personnel and materials the number of stories and going into details of the layout.
will be installed according to necessity, and consistent with • The physical dimensions of corridors and loading condi-
each protection level, within each protected area. Whether tions will be set up according to the purpose of use, such
such areas should be classified as level I or level III is as personnel only, materials only, common for personnel/
relevant to not only the needs of additional buffer areas, materials, and equipment installation at maintenance.

©Copyright ISPE 2009

Figure 8. Risk assessment procedure.

12 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Planning an API Production Factory

Figure 9. Example of conceptual layout.

• By installing buffer areas such as changing rooms, ante- Equipment Plot Plan
rooms, air-locks, pass-rooms, and pass-boxes, issues on The equipment plot plan will be planned according to the
air-flows will be settled. Also, enforcement of enter/exit process flows and work flows so that the operation will be
control to the protected area will ensure protection from carried out effectively, while also paying attention to station-
human origin cross-contamination. ary operations that make up the regular production activities
• The routes for the movement of personnel and those for and non-stationary operations, such as maintenance, cleaning,
materials should be made separate as much as possible and emergency measures.
and decrease the risk of cross-contamination. In the event
that less than ideal routes for movement cannot be avoided, • Equipment will be positioned according to the production
operation procedures like time difference control will be steps as far as practicable.
effective to remove the possibilities of contamination. • Sufficient space for maintenance work will be ensured
• Also necessary is the securing of sufficient space and routes around the equipment as well as planning a layout which
for movement that will enable easy checking, repairing, satisfies the need for easy workability and safety by clarify-
and cleaning. ing work flows. Routes for movement for emergencies must
be taken into consideration, as well.
In Figure 9, a table of input conditions for risk assessment • Supplementary equipment for production and piping will
(process conditions) and the result of assessment with control desirably be installed as much as possible outside of pro-
measures is shown. tected areas so as to increase the cleanability.
A sample of a conceptual layout developed through zoning • If necessary, future extension of the plant will be fore-
©Copyright ISPE 2009

and moving route analysis also is shown. seen.

During the process of these works, the experienced risk
factors described in this article are to be examined. Establishing Control Area Classifications
An appropriate framework will be helpful to evaluate the After setting up the basics of the layout through zoning and
contaminants and manage the risks, and is shown in Figure movement route analysis, a provisional control area classifi-
5 and summarized in Figure 3. cation will be established. Then, specifications for the basic

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 13

 Planning an API Production Factory
Control Definition Building HVAC Changing Rule Equipment Reference
Classification Specification
0.0 An area equivalent to the --- Ventilation Factory Clothes, Equipment is operated ---
external of the factory: Glasses, Outdoor Shoes under closed system
External Area
0.5 An area where APIs or Walls : ALC + Ventilation Factory Clothes, Equipment is operated Clean-Up Air
intermediates will be Painting Glasses, Outdoor Shoes under closed system
exposed to the Floors: Concrete +
environment and not be Dust-Proof Painting
separated by walls: An
area where cleaning-up of
the outer surface will be
carried out, Pass-room to
external area
1.0 An area where APIs or Walls : ALC + 30% ASHRAE Factory Clothes, Equipment is operated Insect Proof Device
intermediates will not be Painting Air Pressure: Glasses, Indoor Shoes under closed system
exposed to the area Floors: Steel Floor + ±0 Pa
except in emergency Painting, Concrete +
Dust-Proof Painting
1.5 An area where protective Factory Clothes, Equipment, or part of ---
measures exist to protect Glasses, Indoor Shoes equipment, is protected
APIs exposed to the area with sheets or curtains
(wet powder, liquid)
2.0 Anteroom for control Walls: Gypsum Board 85% ASHRAE Changing Room --- Hand Washer, Locker
class 3.0: Pass Room of Ceilings: Gypsum Air Pressure:
product, anteroom Board +12.5 Pa
Floors: Concrete +
Dust-Proof Painting
3.0
An area for which specific Walls: Gypsum Board 85% ASHRAE Over-Gown, Over- Open system No difference in
environmental conditions Ceilings: Gypsum Air Pressure: Shoes, Glasses, Dust- equipment, Stainless grade
are defined, controlled, Board +25.0 Pa Proof Mask, Gloves steel is adopted in the
and monitored to prevent Floors: Concrete + Monitoring with part which is exposed
contamination of exposed Dust-Proof Painting Air Conditioning to the environment
APIs or intermediates Device
Class: 100,000
Table A. Example of control area classifications.

conditions of the production facility, building facility, HVAC and this control requires the identification and grouping of
system, and electrical, as well as changing rules will be made. contaminants and the study of protection measures through
This specifying work is to be carried out at the basic planning three contamination management concepts.
phase or at the beginning of the basic design phase. This is to Then, integration of these countermeasures in one set
develop the prerequisite conditions for each element involved of hardware, enabling the building up of hardware which
in the techniques which constitute plant engineering. These complies with the concept of contamination control, can be
techniques will concern the design of equipment, machinery, achieved.
buildings, HVAC, electricals, etc. The specifications at this An appropriate factory layout will play a significant role
stage will decide the major part of the construction cost fac- as an actual countermeasure in decreasing contamination
tors for the facilities. Hereafter, in the project of creating an risks for the API.
API production factory, detailed design work will be carried
out with the specifications of this stage as input conditions. Notes
Table A is an example of area classifications and related Note 1: These process steps will include those such as the
specifications which are developed for buildings, HVAC, and purification steps for raw materials, the process step where
facilities. the drug effect is activated, process steps where significant
impurities are generated or removed, the final purification
Summary step, and the final sterilization step.
In order to plan the GMP qualified API production factory,
identifying contaminants and establishing the countermea- Note 2: The 5S are the first letters of the Japanese words
©Copyright ISPE 2009

sures based on the mechanisms of contamination, and plan- ‘Seiri,’ ‘Seiton,’ ‘Seiketsu,’ ‘Seisou,’ ‘Shitsuke,’ and they refer
ning production facilities which are effective in preventing to the basic activities necessary to build a good working envi-
contamination from both hardware and software viewpoints ronment and will be of importance as one of the prerequisite
are necessary elements. conditions of GMP practice.
In order to give shape to the GMP concept in the factory
planning, the “Contamination control of API” is important, Note 3: This refers to the chemical substances, which the

14 PHARMACEUTICAL ENGINEERING On-Line Exclusive July/August 2009 www.ISPE.org/PE

 Planning an API Production Factory
production process is not intended to generate, such as excess References
raw reaction materials, by-product, decomposed product, 1. Pharm Stage, Vol.6, No.1, 2006.
denatured materials, and residual intermediates. 2. Tozaki, K., Chap. 3, Iyakuhin API kojo no GMP ha-do taiou
ni. kansuru gaido-bukku, Dai 2 han GMP ha-do kenkyu-
Note 4: A critical process step is a step where the API with kai, JIHOU-kabu, 2009.
the scheduled quality and impurity profile cannot be attained 3. Good Manufacturing Practice Guide for Active Pharma-
in the event that operation mistakes or mingling of foreign ceutical Ingredients (ICH Q7A), 2001.
materials should occur. 4. ISPE Baseline® Pharmaceutical Engineering Guide, Vol-
ume 1 - Active Pharmaceutical Ingredients, International
Note 5: Examples of critical process steps: Society for Pharmaceutical Engineering (ISPE), Second
1. Process step where the basic structure of the chemical Edition, June 2007, www.ispe.org.
compound is established.
2. Process step where significant impurity is generated. About the Author
3. Process step where significant impurity is removed. Kazuo Tozaki, PE, is a Project Manager
4. Final purification step. with JGC Project Service Co., Ltd. (JPS) for
pharmaceutical and food production factory
Note 6: The following are examples of the change factors on construction projects. He has worked for 26
the equivalence at the commercialization phase and after years at JGC Corp. of Japan in that area as
approval: well as in chemical plant projects and has
spent the last six years with JPS. He holds
1. The equivalence of the drug quality: impurity profile and a BS and a MS from Kyoto University in
physico-chemical properties sanitary engineering and finished his PhD course in 1976. He
2. The equivalence of the facility: the change of the production is a member of ISPE and PDA. He worked as a member of a
facility, process step, or unit operation, the scaling-up of the national project which studied the countermeasures on GMP
facility with the accompanying changes in heat transfer hardware aspects in 2002. As an ISPE member, he served on
rate, changes in the methods of material handling, speci- the API COP working group that developed the Japanese
fications or handling differences from those of the pilot translation of the second edition of the API Baseline Guide. As
plant on raw materials, utilities and solvent, the change a Project Manager, he has executed more than 10 EPC projects
of construction materials, and physical properties of the for API production plants as well as food plants in the past 20
powders. years. He also executed a project for an anti-chemical hazard
parenteral drug production plant, together with a number
Note 7: A typical example of a protection level framework, of basic design jobs. He is a registered consulting engineer
which makes use of two-dimensional evaluation axes of the (chemical) and a registered management consultant. He is a
level of exposure of process steps to the external environment, registered provisional auditor of ISO22000 of IRCA /JFARB
and the significance of the process steps - Figure 6.4 and is a registered Japan Quality Award self assessor. He
can be contacted by telephone: +81-45-743-7469 or by email:
[email protected].
JGC Project Service Co., Ltd., 13-1 Saido 1-chome, Kounan-
ku, Yokohama 233-8550, Japan.
©Copyright ISPE 2009

www.ISPE.org/PE July/August 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 15

more

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4 PHARMACEUTICAL ENGINEERING July/August 2009

 Table of Contents
The Global Information Source for Pharmaceutical Science and Manufacturing Professionals

The Official
Magazine of
ISPE

July/august 2009 Volume 29, Number 4

Cover Photo
Articles
Courtesy of CRB
Consulting Engineers. 8
Design of Pure Steam Generation 48
Rouge in Pharmaceutical Water
and Distribution Systems and Steam Systems
Cover Design by Hugh Hodkinson by ISPE Critical Utilities D/A/CH COP
Lynda Goldbach, ISPE
20Methods of Producing Water for
Publications Manager
Injection Departments
Current Issue/Theme by Henry Brush and Gary Zoccolante 56 Global Regulatory News
July/August 2009
Utilities 30 Amplified Media Circulation – 60 ISPE Update
A New Way for Enhancing PQLI Tours Asia
Next Issue/Theme Sterilization Cycles Global Regulators and ISPE Members Make for
Washington Conference Success
September/october 2009 by David A. Karle, Gerald McDonnell,
ISPE Launches Three New Online Learning Product
Management of and Teppo Nurminen Lines
Globalization
ISPE Strasbourg Conference to Focus on
Publishes 21 September 38 Maintenance and Facilities Managing Knowledge through Science and Risk
2009 Outsourcing Excellence – Assessment
An Industry Case Study Event to Showcase Facility of the Year Award
by Padraig Liggan Winners from DACH Region
New ISPE Technical Document and Webinar Offer
44Industry Interview Series: Pragmatic Solutions to Maintenance Issues
Sichuan University Student Chapter Takes on
Sharon Bleach, Vice President, Glossary Translation
Global Quality, Operations, New Knowledge Briefs Published
AstraZeneca
by Rochelle Runas 64 Classified Advertising

66 Advertiser’s Index
On-Line Exclusive Articles
Electro Membrane Technology Boosting Bioreactor Processes
by René Fuhlendorff, Arvid Garde, and Jens-Ulrik Rype
Working Height Velocity Measurement in Conventional Cleanrooms
by William Mason, Bernard McGarvey, PhD, Thomas R. Spearman, PE
A Risk Assessment Approach to Planning an API Production Factory by Kazuo Tozaki
visit www.ISPE.org/PharmaceuticalEngineering

6 PHARMACEUTICAL ENGINEERING July/August 2009

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 Pure Steam Generation
This article
presents an Design of Pure Steam Generation and
overview
of design Distribution Systems
requirements of
pharmaceutical
pure steam by Hugh Hodkinson
generation and
distribution
systems with
particular
emphasis on
recommended What is Pure Steam?

P
takes place with saturated steam. The most
terminology ure steam is a clean utility used in effective method of heat transfer from steam
(clean vs. pure the pharmaceutical industry with two is due to condensation. Therefore, the lower
steam) and feed primary uses: the dryness level, the less steam is available
to condense. On the other hand, superheated
water quality steam will have to cool sufficiently prior to it
• sterilization of product contacting compo-
requirements. nents condensing and non-condensable gases will
• humidification of cleanroom and isolator air never condense. All three of these are factors
supplies which reduce the efficiency of the heat transfer
process.
Since the above two categories are both critical Note that while, as stated above, pure steam
to the production of pharmaceutical products, is most commonly used for air humidification
the design of pure steam generation and distri- in pharmaceutical facilities, the ISPE Baseline®
bution systems is a very detailed process, which Pharmaceutical Engineering Guide on Water
must include a wide range of considerations and Steam Systems3 states “Pure steam is com-
to ensure the steam generated is suitable for monly utilized in the industry for humidification
product contact and that the distribution system of “cleanroom” process areas due to possible
maintains this quality. exposure to the drug product. However, produc-
Pure steam has traditionally been defined tion areas where exposure to the drug product
as having Water For Injection (WFI) quality is of less concern commonly utilize chemical
condensate. While this is still the case for the free steam for humidification.”
European Pharmacopoeia (EP), the United
States Pharmacopoeia (USP) has more recently Pure Steam vs. Clean Steam
defined pure steam specifically. However, this There is a lot of debate throughout the industry
definition of pure steam lists the quality require- as to which term is more appropriate: “clean
ments of its condensate, which actually ties in steam” or “pure steam.” In many circles, both
with USP WFI requirements. Furthermore, if terms are acceptable and are often used inter-
the pure steam is to be supplied to sterilizers changeably. However, it is the strong recom-
downstream, it should meet the quality require- mendation of this author to use the term pure
ments defined in European Norm (EN) 285 and steam for the following reasons:
Health Technical Memorandum (HTM) 2010.1,
2
(Note: these are European and UK standards, • Some parties (especially equipment suppli-
but are generally used internationally.) These ers) use the term “pure steam” to refer to a
requirements are summarized in Table A. unit that produces steam, which is suitable
The characteristics in Table A are listed for pharmaceutical product contact applica-
because it is important that steam sterilization tions (e.g., for Sterilize In Place processes),
Table A. EN 285 and
but use the term “clean steam” to
HTM 2010 Steam Characteristic Requirement refer to units which produce steam
Quality Requirements. Dryness 0.9 (0.95 for metal loads) that is suitable for use in hospitals
and similar environments.
Superheat < 25°C
This situation became problematic
Non Condensables < 3.5% when a contractor ordered a Clean
Continued on page 10.
8 PHARMACEUTICAL ENGINEERING July/August 2009
 Pure Steam Generation
Steam Generator for a pharmaceutical facility, which was
Characteristic Requirement
actually not suitable for pharmaceutical steam production
and it had to subsequently be replaced. pH @ 2 ºC 6.5 - 8.5
• The ASME Bioprocessing Equipment (BPE) 2007 Guide4 Conductivity @ 20ºC < 10 µS/cm
defines clean steam as “steam free from boiler additives Dissolved Solids < 5 mg/L
that may be purified, filtered, or separated. Usually used
Chlorides < 50 ppb
for incidental heating in pharmaceutical applications.”
The same guideline defines pure steam as “steam that is Free Chlorine < 50 ppb
produced by a steam generator, which when condensed, Ammonia < 50 ppb
meets requirements for Water For Injection (WFI).” Total hardness < 2 ppm
• Many equipment suppliers use the term “pure steam” or
Silica as SiO2 < 1 ppm
“pyrogen-free pure steam” exclusively throughout their
documentation. If a pharmaceutical facility refers to “clean Endotoxins < 250 EU/ml
steam” throughout all of their documentation and draw- Table B. Recommended feed-water quality for pure steam generators.
ings, but “pure steam” is referred to throughout all of the
generation skid documentation and drawings, it creates as to which water supply in the facility would give the most
an undesirable disparity. cost effective feed water. To take a hypothetical example: If
• The quality of the feed water is in no way related to whether there was a de-ionized water loop, a Purified Water loop, and
the steam produced is called “clean steam” or “pure steam” a WFI loop, where all three met the minimum feed water
so the name used should never be based on the feed water quality requirements, the de-ionized loop would generally be
quality. the most economic to extend to supply the PSG. Additionally,
• Although there are variations throughout the relevant producing one liter of de-ionized water as feed is substantially
guidance documents, it is common for pure steam to be less expensive than producing one liter of WFI. However, it
defined as higher quality than clean steam or at least the must be stressed that before this decision can be made, the
same quality. Using the term “pure steam” is unlikely to water quality must be confirmed as acceptable for the PSG.
cause any confusion, but the term “clean steam” is a lot The water quality characteristics listed in Table B can be
more ambiguous due to different definitions throughout used as a guideline for the quality of water typically required
the industry. for supply to a PSG. This has been collated based on feedback
from several leading PSG suppliers to the pharmaceutical
Feed Water Quality for industry. Note that this is purely a guideline and that the final
Pure Steam Generators decision for feed water quality must be made in accordance
This is another controversial item in the pharmaceutical with the recommendations of the PSG supplier.
industry. There is widespread debate over the quality of the
feed water required by a Pure Steam Generator (PSG). The Notes:
most common feed water used by PSGs is USP and EP Puri- 1. Pure steam generators will typically give a 3 to 4 log
fied Water. The reason that purified water is normally used reduction in Endotoxin Level (which will be stated in the
is because it is available in and distributed through most upcoming revision to ISPE Baseline® Guide: Water and
pharmaceutical facilities. In fact, purified water is a much Steam Systems3) which is why this is a requirement for
higher quality than is typically required by a PSG; therefore, feed water quality. One manufacturer confirmed that they
it is a needlessly expensive water supply if there is a lower achieve a minimum 3 log reduction in endotoxin levels
quality supply available which still meets the PSG feed water through their PSGs.
requirements. There also are parties who advocate using Wa- 2. Non-condensable levels in the feed water will ideally be
ter For Injection (WFI) to feed a PSG. However, this does not less than 3.5% v/v, but if this requirement is not met, the
make sense since the most common method of producing WFI PSG can be fitted with a degasser.
is from a WFI Still, which operates on the same principles as
a PSG. Therefore, the WFI produced is condensed steam so Specification of a Pure Steam Generator
the feed would have been distilled twice. It should be noted The key activities of a Pure Steam Generator are to evaporate
that USP states that the feed water supplied to the PSG must the feed water, remove non-condensable gases from the system,
be in accordance with feed water required for a WFI Still or and remove entrained droplets from the steam, while keeping
Purified Water Skid. According to USP, for a WFI Still: “The the steam saturated. Removal of non-condensable gases is
minimum quality of source or feed water for the generation necessary because there is a non-condensables limit specified
of Water for Injection is Drinking Water as defined by the US in HTM 2010. Removal of entrained droplets is necessary
EPA, EU, Japan, or the WHO.” However, in practice, many because dryness is another key quality criterion, but also
PSGs require a higher standard of feed water than that. because these droplets will carry over contamination from
The recommendation of this author is to contact the the feed water. Saturation is important for effective steam
supplier (or potential suppliers) of the PSG to confirm the sterilization because most of the energy transferred is from
acceptable feed water quality. Then a decision must be made latent heat of condensation.
Continued on page 12.
10 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
Common methods of reducing entrained droplets include on the requirements of the distribution system users).
using demister plates in the main evaporator, designing the • Passivated 316L stainless steel is the recommended mate-
evaporator column to be long and wide enough that the steam rial of construction as pure steam is a very corrosive sub-
upflow is low enough that droplets fall back into the boiling stance. Non-metallic piping materials of PVDF and PTFE
feed water, and/or using a cyclone effect so that centrifugal could be used if rated for the pressure and temperature.
force drives entrained droplets against the evaporator wall Schedule 80 would be preferable.
(baffles can be used to augment this process). • A surface finish of Ra < 0.5 µm (20 microinch) is recom-
It is good practice to degas the pure steam produced. If there mended for pure steam contacting parts.
is a feed water tank on the skid, it is common to heat the feed • Hygienic connections to be used throughout. High pressure
water and recirculate it so that it sprays back into the feed water clamps which require a tool to remove are recommended
tank, enabling non-condensable gases to be released through over clamps which can be removed merely by hand.
a stack vent on the tank. If there is no feed water tank, some • Any interaction with the upstream feed water distribution
suppliers can feed a degassing vent directly to the evaporator system should be specified, such as feed water request
column. These can operate by means of a falling film on the signals sent from the PSG control system and feed water
infeed line to the PSG, where the hot feed water releases non- available signals returned to the PSG control system.
condensable gases which rise up through a degassing vent. The • A small stream should be taken off the pure steam outlet,
advantage of fitting this directly to the evaporator is a smaller condensed and monitored continuously for conductivity.
overall footprint for the PSG, but the vent stack is generally Note that the ISPE Baseline® Guide3 states that tempera-
more difficult to remove than from the feed water tank. ture compensated conductivity sensors cannot be used for
Prior to ordering a PSG, it is wise to meet with one or critical quality assurance testing of purified water, highly
more leading PSG suppliers to discuss the details and exact purified water, WFI, and pure steam condensate.
requirements of your application. Some key items that should • It is common to record the PSG pure steam condensate
be considered for the PSG specification are summarized below. conductivity and temperature for a facility’s batch records.
Note that the below list is aimed at design items which are Since most PSGs are Programmable Logic Controller
specific to PSGs and is not intended to be an all encompassing (PLC) based and do not have permanent data storage, it is
list covering items common to specifying any piece of sanitary recommended that this data is stored either by connecting
equipment, such as documentation requirements, testing re- the PLC to a Supervisory Control and Data Acquisition
quirements, safety requirements, construction requirements, (SCADA) system or alternatively that the conductivity
etc. Key items to consider when specifying a PSG are: and temperature signals are routed in parallel to a data
logging system. In the case of the latter, it is recommended
• The quality of the feed water proposed for the PSG. that a signal is also sent from the PSG PLC to confirm that
• Ensure the PSG outlet is fitted with EN 285/HTM 2010 good quality steam is being produced. Otherwise, it will
test points, as well as a test point for taking pure steam not be clear from the data logged when the PSG is running
condensate samples. If the pure steam does not meet these properly and when it is in alarm or shut down.
quality requirements at the facility user points, the first • One item that must be considered when designing a pure
check that should be performed is that the PSG is produc- steam system is whether and how the feed water system
ing sufficiently high quality steam. is sanitized. If the feed water is normally cold, but is
• Ensure the PSG is fitted with a degasser. This gives con- sanitized by heating the feed water distribution, this can
fidence that non-condensable requirements will be met in generally be catered for in the PSG design if the vendor is
the system. informed up front. However, if a different method of feed
• State the feed water minimum supply pressure. PSGs water sanitization is used (e.g., chemical sanitization),
require a feed water tank and booster pump if the feed then it could be necessary to stop feeding the PSG for the
water pressure is not a sufficient quantity greater than the duration of sanitization. If there is no feed to the PSG for
pure steam generation pressure – commonly 1 bar (14.5 a sufficient period, it will have to shut down. This would
psi), but this varies between suppliers. obviously have a drastic effect if the facility air handling
• It is recommended that inlet feed water is used to condense units depend on the PSG for pure steam. Note that feed
pure steam for inline conductivity monitoring and offline water sanitization depends on the design of the feed water
analysis. Otherwise, a separate cooling water supply is system and is not a requirement of the PSG.
required to the PSG skid. • It is typical for the pure steam distribution system header
• Effluent from the PSG is going to be hot, and if it is not cooled, to be a purely mechanical system. That is, the distribution
a plume of steam will be generated at the waste connection does not have its own control system. The key parameter
from the skid. So it is recommended to include a blow down that must be controlled in the distribution header is the
vessel in the skid where the effluent is cooled by process pressure, which is set in the PSG control system.
water or similar. Also note that the vent from this blow down • The most common temperature used for sterilization processes
vessel will typically be exhausting hot water vapor so it is is 121°C. 134°C is used for some processes, but this is much
normal to pipe this vent outside the building. less common.These temperatures correspond to steam supply
• The flowrate and pressure required at the PSG outlet (based pressures of ~1.1 barg (16.0 psig) and ~2.0 barg (29.0 psig)
Continued on page 14.
12 PHARMACEUTICAL ENGINEERING July/August 2009
 Pure Steam Generation
respectively. To allow for pressure losses in the distribution tion line for sizes up to 4 inch (100 mm) and one or two
system and to buffer the distribution system, it is common sizes smaller for lines of 6 inch (150 mm) or larger.
to run distribution headers at pressures in the range of 2.5 • 30 cm (~1 ft) of uninsulated piping above each steam trap.
– 3.0 barg (36.3 psig – 43.5 psig). However, it is important to Thermostatic traps release condensate which is a few degrees
check the pressure required by each of the downstream users colder than the steam saturation temperature would be at
before deciding on the pressure required in the header and the operating pressure. Therefore, the condensate must be
corresponding pressure setpoint at the PSG outlet. allowed to cool so that it is released through the trap.
• Full bore ball valves used throughout, but diaphragm valves
Design of a Pure Steam Distribution System are advisable at the sterile boundary of an aseptic system,
The design of a pure steam distribution system is more com- e.g., the last valve on a line for SIP of a vessel would be a
plex than might first appear. The following design guidelines diaphragm valve, but the preceding valves would be ball
assume that the pure steam generator has been correctly valves. Diaphragm valves used in a pure steam system
specified and will produce pure steam of a quality that meets require far more maintenance than ball valves.
USP and EN 285 requirements (as well as meeting EP WFI • Sanitary pressure regulators are to be used where required.
quality limits for Pure Steam condensate). Sanitary pressure regulators typically have a bottom mounted
Once the PSG has been correctly specified, designed, and inlet and side mounted outlet so that any condensate built
installed, it is critical that the distribution system delivers up in the regulator flows back through the regulator inlet.
pure steam of a sufficient quality to the facility user points. A • No direct connections to unhygienic systems. Air gaps to
poorly designed distribution system can reduce the quality of be used at all drain points.
the steam so that it does not meet the regulations pertaining • Hygienic connections used throughout. High pressure
to pure steam. clamps which require a tool to remove are recommended
over clamps which can be removed merely by hand.
Header Design • Passivated 316L is the recommended material of construc-
Headers must be designed so that they minimize condensate tion as pure steam is low in ions and is a very corrosive
formation and any condensate which is formed is routed out substance.
of the distribution system, maintaining a dry steam supply • User point take offs are piped off the top of headers to
to each user point. To this end, the following design features minimize entrained condensate.
are recommended: • Headers and take offs are typically sized to give a steam
velocity in the range of 20 to 30 m/s (~65 to 100 ft/s) to
• Piping runs slope to at least 1% minimized entrained condensate in the pure steam flows.
• Steam traps are recommended: Note lower velocities also are acceptable.
- at the end of each header or branch • Sample points to be easily accessible.
- every 30m (~100 ft) on any straight run • It is often stated that pure steam distribution systems are
- at each user point or sample cooler self sterilizing and the benefits of polished tubing is ques-
- where the line transitions from horizontal to vertical tioned. However, it is very common throughout the industry
(at the bottom of the vertical riser) (and recommended by this author) to polish distribution
- at thermal expansion loops systems to finishes of Ra < 0.5 µm (20 microinch) or less
- anywhere condensate could build up and would not (depending on the site standard) and is recommended.
otherwise be removed (i.e., there should be no dead legs Sometimes for smaller components such as steam traps,
where condensate can build up) this requirement cannot be met and can be relaxed to Ra
• Thermostatic steam traps to be used throughout. These are < 0.8 µm (32 microinch).
the most common sanitary traps for pure steam distribu- • Air breaks to be at least twice the size of the relevant pipe
tion systems and have the ability to remove air from the diameter.
system. Float traps and thermodynamic traps are not free • Eccentric reducers used for any horizontal reductions in
draining and do not release air from the system so they pipe diameter.
are not recommended.
• Never group steam traps. This means that multiple users A typical autoclave user point is shown in Figure 1. Note that this
are not run to a single trap (this often leads to preferential includes HTM 2010 test points and a pressure gauge as well as
draining for one piece of equipment, because different local condensate sampling. Not all of these features are required
pieces of equipment will release condensate at different at every user point, as described in the sampling section below.
temperatures and pressures). It also means that the dis- Also note that 50 mm (2") air breaks are used in this example.
charge lines from traps must not be connected. Each of This is a common length, but air breaks should always be at least
these should go to drain through a separate air gap since twice the pipe diameter used in the given application.
linking these lines can hinder the release of condensate
through one or more of the traps. Sampling
• Trap legs for the collection of condensate from the steam It is recommended to take samples to prove compliance with
distribution system should be of equal size to the distribu- the following:
Continued on page 16.
14 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
a. Pure steam condensate complies with USP and/or EP (as it is generally acceptable to sample at the end of the
relevant) relevant header.
b. Pure steam quality complies with HTM 2010/EN 285
dryness, superheat, and non-condensable requirements It is advisable to fit a hygienic needle valve immediately
as described in the introduction to this article upstream of the sample cooler so as to control the sample
flowrate. It also is recommended to normally fit a steam trap
With respect to a. above: Sample coolers are recommended at the outlet of the sample cooler so that it is continuously
at the following locations: self sterilizing, but to have a spool piece which can be used
to replace the steam trap during sampling (obviously after
- At the end of each header the system has been isolated and allowed to depressurize
- At each critical user take off, i.e., where pure steam is and cool sufficiently).
used on product contacting surfaces such as for equip- With respect to b. above: HTM 2010/EN 285 test points
ment SIP or for autoclaves. However, for non-product are recommended at the following locations, at a minimum:
contacting users such as steam used for humidification,

Figure 1. Typical pure steam supply configuration for an autoclave.

Concludes on page 18.
16 PHARMACEUTICAL ENGINEERING July/August 2009
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 Pure Steam Generation
this is not recommended for a continuously running pure
steam system. While it is possible that a high point trap, such
as this, will accelerate the de-aeration of the system, this is
not a worthwhile gain for a system which will only be shut
down and started up once or twice a year. It must be noted
that once hot, air is heavier than steam and that thermostatic
traps operate based on temperature. In other words, the low
point steam traps will pass air until the system is de-aerated.
These types of high point air vents can make sense in plant
steam systems which use thermodynamic or float traps which
are based on velocity and density respectively (i.e., will not
pass air), but do not make sense for a distribution system
which uses thermostatic traps throughout.
Furthermore, the ideal location of the high point venting
trap is frequently in a very inaccessible location at the top of
the building, often at the top of a pipe rack. Over time, these
Figure 2. Typical HTM 2010 sampling arrangement.
traps can begin to leak. If the trap begins to leak, it will have
to be removed for maintenance. Since these are generally
- At each autoclave (as stipulated in the above stan- difficult to access, they are often permanently removed after
dards) they have leaked a few times.
- At each lyophilizer (not specified in the above standards,
but good practice) Conclusion
- At the PSG outlet. Normally, in the scope of the PSG The above article is intended as a guideline to some of the
supplier. key issues to consider when designing a pure steam genera-
tion and distribution system. In particular, it aims to discuss
Three ½" hygienic clamp connections are required for these many of the contentious issues which come up repeatedly in
sample points. It is recommended to have an isolation valve the design of pure steam systems. However, it is recommended
immediately upstream and a pressure gauge to confirm that to seek the advice of a professional designer when designing
the line has been depressurized before clamp blind caps are or modifying such systems.
removed to connect sampling equipment. It cannot be stressed
enough that these sample points must be accessible. They are References
often installed as an afterthought and can then be extremely 1. EN 285: 2006 Sterilization. Steam Sterilizers. Large Steril-
difficult to connect with the relevant sampling equipment. izers.
During the initial piping layout design, it must be anticipated 2. Health Technical Memorandum (HTM) 2010 Crown Copy-
to locate these sample points as close to the autoclave (or other right 1994.
equipment) as possible, but certainly within 2 or 3 meters. 3. ISPE Baseline® Pharmaceutical Engineering Guide, Vol-
These HTM 2010/EN 285 test points are used to take ume 4 - Water and Steam Systems, International Society
samples manually. Non-condensables are measured by con- for Pharmaceutical Engineering (ISPE), First Edition,
densing a quantity of steam and then measuring the volume January 2001, http://www.ispe.org.
of this which is water and the volume which is gas. Superheat 4. ASME BPE 2007 Bioprocessing Equipment.
is measured by routing steam through an expansion tube and 5. United States Pharmacopoeia 32-NF27, 1 November
checking that there is not an excessive temperature difference 2009.
between that temperature and the main header temperature.
Dryness is measured by condensing steam from the header. About the Author
A typical HTM 2010 test connection is shown in Figure 2. Hugh Hodkinson is a Lead Process Engineer
Note that the dryness HTM 2010 test in particular is very for DPS Engineering. Educated at University
sensitive to entrained moisture, and if there are flaws in the College Dublin, he holds a BE in chemical
design or installation of the pure steam distribution system, engineering. He has been with the company
this is the test that is most likely to fail. Even if an upstream since 1999 and has led aseptic design projects
pipe has been stepped on during construction and bent (even in Ireland, the UK, and the Netherlands. His
if it is almost imperceptible to the naked eye) so that there is experience includes a variety of facilities for
slight pooling of condensate in the line, this amount of conden- vaccine production, cell culture production,
sate can be enough to make the system fail its dryness test. downstream processing, and fill finish products. He can be
contacted by telephone: +353-86-8185589 or by email: hugh.
Air Venting [email protected].
There are sources which recommend installing a high point DPS Engineering, Landscape House, Baldonnell Business
trap for venting air out of the pure steam system. However, Park, Baldonnell, Co. Dublin, Republic of Ireland.

18 PHARMACEUTICAL ENGINEERING July/August 2009

 Pure Steam Generation

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July/August 2009 PHARMACEUTICAL ENGINEERING 19

 WFI Production Methods
This article
presents the Methods of Producing Water for
advantages and
disadvantages Injection
of distillation-
based and
membrane- by Henry Brush and Gary Zoccolante
based methods
for producing
WFI, outlines
international
WFI regulatory
requirements, Introduction

W
been successful in attainment of the water qual-
discusses ater For Injection (WFI) interna- ity specifications. Yet, most other high-purity
historical market tional pharmacopoeial standards industries use reverse osmosis, deionization,
penetration and have been brought closer through and ultrafiltration, not distillation, to produce
harmonization efforts, but sig- WFI equivalent or higher quality water. ASTM
performance nificant differences still exist. The USP WFI Type A laboratory water limits for total bacte-
of distillation monograph allows production by “distillation rial count and endotoxin are respectively ten
and membrane- or a purification process proven to be equal and eight times lower than WFI. ASTM Type
based WFI to or superior to distillation.” USP language 1.2 water for microelectronics has similar mi-
is the least restrictive in terms of acceptable crobial restrictions with total organic carbon
systems, and processes among the major pharmacopoeial and conductivity limits well below WFI. Those
includes a groups. The Japanese Pharmacopeia (JP) applications are routinely satisfied with mem-
membrane case allows distillation or Reverse Osmosis (RO) brane-based systems producing water at ambi-
study. followed by UltraFiltration (UF). Distillation ent temperature. However, those industries do
is the only WFI method of production that is not have regulated process limitations.
approved by the European Pharmacopoeia This article will discuss the advantages and
(EP). disadvantages of distillation-based and mem-
Historically, distillation has been the brane-based methods for producing WFI; outline
preferred method for producing WFI in the international WFI regulatory requirements; and
biopharmaceutical industry, and today, most discuss historical market penetration and per-
pharmaceutical WFI is produced by distilla- formance of distillation and membrane-based
tion. Regulatory requirements have helped WFI systems. Also included is a membrane case
significantly in the domination of WFI produc- history from US biopharmaceutical company
tion by distillation, but distillation also has Alkermes, Inc.

Table A. WFI Requirements

for USP, EP, JP. USP EP JP Distillation-Based
WFI Systems
Method of WFI Distillation or Distillation only Distillation or
Production purification RO/UF To meet USP requirements, WFI
process proven must be produced by “distillation
to be equal to or or a purification process proven to
superior to
distillation be equal to or superior to distilla-
tion.” Additionally, the water must
Conductivity, µS/ 1.3 1.3 1.3
cm @ 25 °C or pass conductivity and Total Organic
equiv. @ other Carbon (TOC) tests, and the bacteria
temps. endotoxin level must be below 0.25
TOC, ppb <500 <500 <500 endotoxin units per milliliter (EU/
Endotoxin 0.25 EU/mL 0.25 EU/mL 0.25 IU/mL mL). The microbial level must not
be above 10 Colony-Forming Units
Bacteria, 10 10 10
cfu/100 mL (CFU) per 100 mL. Distillation is
effective at quantitative reduction
Nitrates, ppm N/A 0.2 N/A
of most water contaminants and can
Ammonium, mg/L N/A N/A 0.05 produce water with low conductivity,
Continued on page 22.
20 PHARMACEUTICAL ENGINEERING July/August 2009
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 WFI Production Methods
low TOC, low microbial levels, and low endotoxin levels. water-sanitizable RO, and finally, a vapor compression still. The
Almost all pharmaceutical distillation-based systems key design consideration is inclusion or exclusion of RO.
implement either multiple effect or vapor compression stills. RO is excluded when ionized solids and endotoxin reduction
Both still types employ various techniques for recovery of is not deemed necessary for reliable, consistent attainment of
latent and sensible heat to minimize energy consumption. WFI quality parameters. RO is implemented when the user
Both technologies produce WFI quality water when properly believes that reduction of endotoxin and ionized solids in the
implemented and operated. Each still type has advantages and still feed assures that WFI quality is consistently attained,
disadvantages and each has significant successful operational maintenance is minimized, and hot blowdown is minimized.
history. Many systems of both types are in operation. If only endotoxin
While stills are reliable, they are not perfect, and can reduction is desired in the still pretreatment system, UF may
produce pyrogenic product water when operated incorrectly, be substituted for RO.
when they fail mechanically or when the feed water contains In addition to meeting all pharmacopoeial requirements,
contaminant levels beyond the still reduction capability. If vapor compression distillation offers the following advan-
fed with high endotoxin feed water from the raw supply or tages:
pretreatment equipment, in cases where there is no mem-
brane-based system pre-treating the still, the product water • generally reliable operation
from the still may fail the endotoxin test. Many successful • typically more energy efficient than multiple-effect distil-
distillation systems exist with no membrane pretreatment, lation
but several other systems have required retrofit of Reverse • can be operated on softened/dechlorinated feed
Osmosis (RO) or UltraFiltration (UF) pretreatment after • may not require a complex system design
periodic product water endotoxin failures due to high still • relatively low maintenance
feed endotoxin levels.
The FDA Guide for Inspections of High-Purity Water Potential disadvantages of vapor compression stills include:
Systems recognizes the still pretreatment design question
regarding potential use of a membrane process. Section V • may be more labor intensive than multiple-effect distilla-
of the Guide states, “Many of the still fabricators will only tion with compressor and associated drive gear
guarantee a 2.5-log to 3-log reduction in the endotoxin content. • may have higher life cycle cost than membrane based
Therefore, it is not surprising that in systems where the feed systems
water occasionally spikes to 250 EU/mL, unacceptable levels
of endotoxins may occasionally appear in the distillate (WFI). Multiple-Effect Distillation
For example, three new stills, including two multi-effect, were A Multiple-Effect Distillation (MED) system often consists of
recently found to be periodically yielding WFI with levels a multi-media filter, softening, break tank, heat exchanger,
greater than 0.25 EU/mL.” hot-water-sanitizable activated carbon, prefilter, optional
The FDA Guide further states, “Pre-treatment systems pH adjustment, 254-nanometer ultraviolet (UV) light,
for the stills included only deionization systems with no RO, hot-water-sanitizable RO, continuous electrodeionization
ultrafiltration, or distillation. Unless a firm has a satisfactory (CEDI), followed by the multiple-effect distillation unit. The
pre-treatment system, it would be extremely difficult for them pretreatment system is generally comprehensive because the
to demonstrate that the system is validated.” high operating temperature makes MED stills susceptible to
The decision to implement or not implement reverse osmo- chloride stress corrosion and scale. The pretreatment system
sis in still pretreatment is generally more relevant to vapor typically minimizes chloride, silica, and total dissolved sol-
compression stills than multiple effect stills. Vapor compres- ids levels. Membrane based pretreatment typically reduces
sion stills operate at a lower temperature than Multiple- endotoxin to very low levels, such that the still endotoxin
Effect (ME) stills and are less susceptible to chloride stress challenge is negligible.
corrosion and scale; therefore, reverse osmosis is not always
necessary for scale and corrosion prevention. Multiple effect • In addition to meeting all pharmacopoeial requirements,
stills generally require feed water with low levels of chloride, multi-effect distillation has the advantage of few moving
silica, and total solids, and are almost always pretreated with parts and this can minimize maintenance requirements.
reverse osmosis and/or an ion exchange process. Since reverse
osmosis is present in almost all ME still feed systems, the Potential disadvantages include:
feed endotoxin levels are quite low.
• generally requires high-quality feed water: less than 0.5
Vapor Compression Distillation ppm chloride; less than 1.0 ppm silica; less than 5.0 µS/
Vapor compression distillation systems generally implement cm conductivity
scale control, dechlorination, and in some cases, reduction of • typically higher energy costs than vapor compression
ionized solids and/or endotoxin. A vapor compression distil- distillation
lation system often consists of softening, heat exchanger, • typically higher cooling water requirements than vapor
hot-water-sanitizable activated carbon, prefilter, optional hot- compression

22 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

“Most alternative designs to distillation have used one or two passes of RO, often with an
ion exchange process and in virtually all cases, final polishing with UF or RO. The system
designs over decades have been driven by practicality and regulation.”

• may have higher life cycle costs than membrane-based systems were more popular prior to the presence of conduc-
system tivity and TOC tests. At that time, the USP WFI monograph
only allowed distillation or RO for process and it was accepted
What Other Treatment Methods Work? that the still or RO would be the terminal process. The FDA
A number of separation methods, such as RO and UF, can re- had noted in “The FDA Guide for Inspections of High-Purity
move endotoxin. Oxidation with ozone also removes endotoxin. Water Systems” that if RO was used for WFI, two stages should
Heat, distillation, UF, RO, filtration, ozone, UV, and chemical be used to assure attainment of the quality specifications.
methods can all achieve low microbial levels in the product TPRO can typically meet all of the required water quality
water. Other market applications, such as microelectronics and parameters, but consistent attainment of Stage 1 conductivity
select laboratory water types have water quality specifications can be an issue with some feed waters. TPRO systems often
far tighter than WFI including extremely low endotoxin limits. consist of a multi-media filter, softening, break tank, heat
Almost all of these systems utilize membrane technologies exchanger, hot-water-sanitizable activated carbon, prefilter,
for primary treatment. Membrane systems may offer lower optional pH adjustment, 254-nm UV, and two stages of hot-
operating economics as no water evaporation occurs. Systems water-sanitizable reverse osmosis.
either operate at ambient temperature normally or are heated The implementation of a WFI conductivity test requirement
to high temperature without evaporation and condensation. and the liberalization of the USP WFI allowable processes
The content of stainless steel is often less with membrane increased use of systems implementing reverse osmosis,
systems compared to distillation. ion exchange processes, and ultrafiltration or a final stage
of RO. The logic of this type of system configuration is that
Membrane-Based WFI Systems the combination of reverse osmosis and ion exchange easily
Most alternative designs to distillation have used one or meet the conductivity and TOC specifications while the final
two passes of RO, often with an ion exchange process and in ultrafilter or RO stage assures compliance with the endotoxin
virtually all cases, final polishing with UF or RO. The system and microbial requirements. Systems of this type have had a
designs over decades have been driven by practicality and lengthy history in production of “WFI quality water” prior to
regulation. The first alternative to distillation allowed by USP acceptance as a method to produce WFI to pharmacopoeial
decades ago was RO. RO technology was generally not up to standards. The basic system capability for production of water
the task of consistent WFI performance and the technology did with low contaminant levels has been long proven in other
not flourish. Hot water sanitizable membranes did not exist markets, such as microelectronics, for decades.
and chemical sanitization was often inconsistent, allowing Most membrane based systems have several components
periodic microbial excursions beyond WFI specification. Some that are either intermittently hot water sanitized or main-
validated systems existed, but placements were few. tained continuously at a self sanitizing high temperature.
The presence of membrane systems was enhanced when Some systems have a final membrane stage that operates at
the Japanese Pharmacopoeia allowed RO followed by UF the same elevated temperature as the storage and distribu-
as an alternative to distillation. Hot water sanitizable and tion system. Several systems of this type have been in opera-
continuous hot ultrafiltration elements were available and tion for more than 10 years with water quality performance
contributed to successful operation. Ultrafiltration had a equivalent to distillation based systems.
lengthy, successful history in pharmaceutical manufacturing A typical membrane based WFI system includes dechlori-
and was accepted. This technology change led to implemen- nation, softening, a hot-water-sanitizable RO device followed
tation of more systems that produced “WFI quality” water by a hot water sanitized CEDI device. A continuous hot-water
where pharmacopoeial WFI compliance was not required. UF device polishes the water prior to storage and use as WFI
The change by USP to open WFI production to “distillation if the water will be stored hot. A hot water sanitized UF or RO
or a purification process proven to be equal to or superior to serves as the final stage if the product water will be stored
distillation” has helped to increase interest in membrane at ambient temperature. Advantages of using RO/RO or RO/
based WFI systems. UF to produce WFI are as follows:
EP has created a monograph for Highly Purified Water
with no process limitations and water quality specifications • may be the lowest life cycle cost alternative
identical to WFI. This has helped to increase membrane • typically low energy requirements
system placement for production of “WFI quality” water. • typically very low conductivity, TOC, endotoxin, and mi-
Two-Pass RO (TPRO), also known as product staged RO, crobial levels
was one of the earliest WFI membrane configurations. TPRO • generally reliable operation
Continued on page 24.
July/August 2009 PHARMACEUTICAL ENGINEERING 23
 WFI Production Methods
• can be intermittently or continuously hot sanitized manufacturing often greatly exceed WFI quality require-
• there is some history in the U.S. Pharmacopeia and Japa- ments.
nese Pharmacopoeia of using RO and UF for WFI USP and JP allow membrane based designs as well as
distillation. The EP requirement for distillation eliminates
The most significant disadvantage is that EP does not allow a any choice of alternate technologies for companies wanting
WFI production method other than distillation and therefore, to comply with EP. Therefore, membrane based systems
WFI membrane use is limited to non-EP applications. The are only employed where EP compliance is not required or
history of membrane based WFI system usage is significantly where “WFI quality” water is desired, such as for meeting
less than with distillation, and this has negatively affected the requirements of EP Highly Purified Water, preparation
confidence in membrane systems among some pharmaceuti- of intermediates, or other uses.
cal companies. Additionally, the RO system requires periodic Although some successful membrane-based systems have
cleaning, the membranes must be replaced at some point, been in operation for several years, the historical database is
and membranes can fail just as any technology has failure not nearly as large as for distillation. Membrane-based systems
mechanisms. are beginning to be placed and are considered more frequently
Capital and operating cost comparison for distillation and because membrane-based systems may offer lifecycle cost
membrane based systems is a key element of system choice advantages in reduced capital or operating costs. The choice
when regulatory requirements do not dictate distillation only. is one of many risk-based decisions in the pharmaceutical
This article does not provide costs for several key reasons. industry. Users need to consider product, market, capital cost,
Equipment specifications for materials of construction, in- utility costs, commissioning/qualification, maintenance, and
strumentation, control, and other major cost factors impact risk to make an informed decision.
capital costs significantly and capital costs are meaningless
without detailed specifications. Operating costs are directly Case Study for WFI Production:
impacted by utility costs for water, wastewater, power, steam, Alkermes, Inc.
chilled water, and others and vary tremendously site to site. The following case study is for a membrane-based WFI
These costs are best based upon actual conditions case to case system in a US facility. A case study for distillation is not
for accurate analysis. The significant possibility of lower life presented because distillation is well established. The distil-
cycle economics for membrane based systems is based upon lation operating history is generally good and advantages and
the relative absence of distillation based systems in non- disadvantages are well understood.
regulated high purity applications.
Background
Why Has Membrane-Based WFI Production Alkermes pulmonary drug delivery platform technology
Failed to Flourish? enables delivery of both small molecules and complex mac-
With all the potential advantages of using membrane-based romolecules to the lungs. This system can provide efficient
technologies for producing WFI, why has it not caught on in the dry-powder delivery of small molecule, peptide, and protein
industry? For one reason, when RO was first approved for use containing drug particles to either the deep lung or the upper
in WFI production, the technology was not completely “ready” respiratory tract, based on the product needs. Alkermes de-
for this application. Hot-water-sanitizable RO did not exist, signed and built a manufacturing facility to support production
and chemical sanitization is not as effective as heat. Full-fit of late stage clinical supplies as well as commercial production
RO membrane elements were not available and neither was of its pulmonary drug delivery products. The manufacturing
continuous hot operation. Early failures discouraged use, and operations at the site include spray drying to produce the bulk
while endotoxin control was not a problem, microbial control dry powder, capsule filling, packaging, CIP systems for clean-
was. Ultrafiltration technology, while “ready,” did not have ing, and a clean steam system. The purified water system was
USP or EP approval. designed to support the formulation activities associated with
Membrane technology has a significant successful history production of the bulk powder in the spray drying operation,
in production of WFI in Japan and in the US, but membrane the CIP system for cleaning process equipment, and as feed
system implementation is limited to facilities or applications water to the clean steam system.
where the EP requirements are not a factor. Since a significant
percentage of pharmaceutical manufacturers produce for the Introduction
European market, the EP distillation requirement stifles Dry powder inhalation products are typically not produced
membrane implementation. under aseptic manufacturing conditions. Based on this, the
initial project requirements specified USP Purified Water as
Conclusions the appropriate grade of water for the manufacturing site.
Most WFI systems are distillation based. Distillation has a This decision was revisited after detailed engineering had
lengthy successful history in WFI production. Most other high been completed on the project. The review team identified a
purity systems in other markets use membrane processes potential for tightening of microbial specifications in the final
rather than distillation, but no regulatory requirements exist. drug product, particularly for products that might be used in
Water quality specifications for use such as microelectronics patients with compromised immune systems. Based on this

24 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods
assessment, it was decided that the microbial specifications unit and hardware also had short lead times, which further
of the water should be tightened to support the current as minimized the impact to the overall project schedule. In ad-
well as any future drug product microbial and endotoxin dition, the capital cost of the ultrafilter system was relatively
requirements. small. This minimized the impact to the project cost.
The water system had already been ordered and was in
fabrication when the system requirements were changed. System Description and Discussion
The Alkermes engineering team met with the system sup- The Alkermes water system is designated as an EP Highly
plier to identify solutions that could meet the revised water Purified Water (HPW) System. The system consists of a gen-
system requirements, while minimizing the impact on the cost eration system that is supplied with city water and produces
and schedule of the project. Several options were discussed, up to 8 gpm of highly purified product water that meets USP,
including the option of the reverse osmosis and continuous WFI test specifications. The product water is supplied from
electrodeionization (CEDI) systems that were already specified the HPW generation system to the top of a 3,000 gallon hot
as being able to meet the new requirements, and installation storage tank that is maintained at 80°C. The hot water stor-
of a still to produce WFI grade water. The team identified the age loop is continuously circulated by pumping water from
addition of an ultrafiltration step as the best way to meet the the bottom of the storage tank, through a heat exchanger, and
tightened water specifications, while minimizing the cost and back into the top of the storage tank. If the storage tank is full,
schedule impact to the project. The system supplier was will- the product water is circulated back to the HPW generation
ing to guarantee that with the addition of an ultrafiltration system as feed water.
step, the water generation system would be able to meet USP The HPW distribution loop is self contained and nor-
Water for Injection specifications with regard to microbial and mally maintained at room temperature or 24°C. The HPW
endotoxin requirements. distribution loop and hot storage loop are connected so that
The ultrafilter unit operation is relatively small physically when water is drawn from the distribution loop, hot water
and had a minimal impact on the layout of the generation is supplied from the storage loop to the distribution loop.
and distribution system. This minimized any costs associated A heat exchanger in the HPW distribution loop cools the
with piping layout changes. It also minimized the schedule water prior to feeding the water out into the plant and to
impact because it did not require significant re-piping to ac- the use points. Every 24 hours the cooling heat exchanger
GEAI CV the
commodate Ad - Pharm Eng
ultrafilter unitJul-Aug 09:Layout
into the layout. 1 6/12/2009
The ultrafilter is11:13 AMoffPage
turned 1 HPW loop is heated to 80°C and held
and the
Continued on page 26.

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July/August 2009 PHARMACEUTICAL ENGINEERING 25

 WFI Production Methods
for microbiological growth once the chlorine is removed. The
heat sanitization cycles for the carbon filters are designed to
control the bioburden levels in the carbon filters.
Ultraviolet (UV) lamp units are installed downstream of
the carbon filters for inhibiting microbial growth after the
chlorine has been removed by the carbon beds and prior to
feeding the RO membranes with the in process water. The
intensity of the UV lamps is monitored and documented in
rounds sheets during routine operations of the system.
The next stage in the HPW generation system is the reverse
osmosis process, which is part of the final treatment system.
Figure 1. Process flow diagram for the HPW generation system. The system includes single pass RO membranes. The RO
at temperature for 60 minutes. The system design is based process is a pressure driven process with a semi-permeable
on the “Hot Storage – Self Contained Distribution” design membrane designed to remove minerals, organics, particulates,
that is described in the ISPE Baseline® Guide on Water and microbiological material, and endotoxin. The RO membranes
Steam Systems. reject a significant portion of the feed stream, while allowing
The overall water system includes several unit operations a portion of the purified water stream to pass through the
to meet the required product specifications. City water from membrane. The daily performance of the RO membrane is
the Massachusetts Water Resource Authority system is fil- monitored by measuring the percent rejection of conductive
tered using a multi-media filtering system to remove coarse elements in the feed water to the reverse osmosis unit.
particulates. The first unit operation in the HPW generation The CEDI unit is located downstream of the RO membranes
system is the particulate filter system. The particulate filters and removes ionized species from water using electrically
are nominal 5.0 µm cartridge filters designed to remove large active media and electrical potential to effect ion transfer.
particulates from the incoming feed water. The particulate The CEDI system is a continuous process in that the ions
filter system includes two banks of five cartridge filters, each are continuously removed and the ion exchange resins are
of which can be operated in parallel with either one or two regenerated continuously. In addition, there is a UV unit as
units in operation. part of the CEDI skid. As discussed above, the UV unit is
The next stage in the HPW generation system is a duplex designed to limit microbial growth.
water softening system. The water softening system is an The last unit operation in the final treatment portion of
ion exchange process that is designed to remove divalent the HPW generation system is the ultrafiltration system. The
and trivalent ions from the incoming city water and replace ultrafilter (UF) includes a 0.05 µm single pass filter and is
them with a monovalent sodium ion. The softening process designed to provide the final step in meeting the WFI speci-
prevents scale in the reverse osmosis unit downstream. fications. Figure 1 includes a process flow diagram indicating
Two activated carbon filter skids in parallel are located down- the different unit operation steps in the HPW generation
stream of the water softeners. The carbon filters are designed system.
to remove chlorine from the feed water. Chlorine is added by Heat is used to sanitize both the HPW generation system
municipal authorities to the city water as a microbial control and the HPW distribution system. The carbon filter, reverse
agent. Chlorine can oxidize the reverse osmosis membranes osmosis skid, and associated piping are sanitized weekly using
and negatively impact system performance. In addition, it is 80°C water. The entire generation system, including the carbon
recognized that the carbon beds can serve as an environment filter, RO skid, CEDI system, ultrafilter, and associated piping

Figure 2. HPW generation system outlet. Figure 3. Formulation tank supply valve.

26 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

Figure 4. HPW generation system outlet.

Figure 5. Formulation tank supply port.
is heat sanitized monthly. The distribution system is sanitized
nightly by heating the entire distribution loop to 80°C. generation system outlet. Figure 3 illustrates data from a
The HPW generation and storage and distribution system charge port on the distribution system which is used to fill
was routinely monitored with a combination of inline and a formulation tank. In both cases, all samples were found to
offline testing to confirm that the system was performing as be below the detection limit of 0.05 EU/mL, which satisfies
expected. Critical performance attributes were identified for the alert limit of Not More Than (NMT) 0.13 EU/mL.
the unit operations within the generation system, along with Total aerobic bioburden test data is presented from two
appropriate test methods and acceptance criteria. The perfor- different locations in the HPW system for the period Janu-
mance attributes were routinely monitored to confirm that the ary through December of 2007. Figure 4 includes data from
system was performing as expected. This includes, for example, the outlet of the HPW generation system. Figure 5 includes
routinely monitoring the free chlorine and bioburden levels Concludes on page 28.
after the carbon filter. In addition, the storage and distribu-
tion system was monitored at various points throughout the
system. This included a rotating schedule of sampling various
use points and testing for bioburden, endotoxin, conductivity,
TOC, heavy metals, and nitrates. Appropriate specifications
were established for the use point monitoring that included
alert and action levels for the various attributes. Data and
acceptance criteria are presented below.

Data Discussion
As discussed above, the HPW was used for cleaning opera-
tions, clean steam feed water, and for formulation activities
in producing dry powders used for inhalation therapies. Alk-
ermes identified test attributes and specifications along with
acceptance criteria that were appropriate for the intended use
of the water. The specifications met the standards outlined
for WFI compendial grade water.
The HPW storage and distribution system was sampled and
tested on a routine basis to monitor the quality of the water.
The schedule included sampling and testing of water from
various points in the HPW storage and distribution system.
Data is presented below from the January through December
2007 period that demonstrates the overall performance of the
system. The data includes test points from the outlet of the
generation system before the product water enters the stor-
age and distribution system as well as at use points within
the storage and distribution system.
Endotoxin test data is presented from two different sample
points in the HPW system. Figure 2 includes data from the

July/August 2009 PHARMACEUTICAL ENGINEERING 27

 WFI Production Methods
cal production operations, manufacturing plant design and
commissioning, and manufacturing technical support. Prior
to Alkermes, Brush has developed manufacturing technology
at Acusphere, PerSeptive Biosystems, and Polaroid. Brush is
currently a member of ISPE and has served on the Board of
Directors for the ISPE Boston Chapter. He received his BS in
materials science and engineering from MIT, and his MS in
chemical engineering from Northeastern University. He can
be contacted by email: [email protected].
Alkermes Inc., 88 Sidney St., Cambridge, Massachusetts,
02139-4137.

Gary Zoccolante is Pharmaceutical Techni-

cal Manager at Siemens Water Technologies.
He has more than 30 years of experience in
the design, operation, and trouble-shooting of
Figure 6. Formulation tank supply port.
pharmaceutical water systems, and has been
involved in the development of equipment for
data from a charge port on the distribution system, which is pretreatment, reverse osmosis, deionization,
used to supply a formulation tank. In both cases, all test data ultrafiltration, and distillation. Zoccolante
from the ports were non-detectable for bioburden or below was a task team member of the original ISPE Baseline® Wa-
the alert limit of NMT 1 CFU/100 mL. ter and Steam Systems Guide and is part of the task team
Total Organic Carbon (TOC) data is presented for the currently updating the guide. He has been part of the Guide
formulation tank charge port, which is located on the HPW Presentation Team on several occasions. He was involved in
distribution system. The data is plotted in Figure 6. The ac- face-to-face meetings with the FDA to help resolve many of
ceptance criteria include an alert limit of NMT 250 ppb. All the Guide principles. He is a member of the ISPE Critical
values tested during the January to December 2007 period Utilities Community of Practice Steering Committee. He
were below the alert limit of 250 ppb. worked on the development of the ISPE Good Practice Guide:
Commissioning and Qualification of Pharmaceutical Water
Conclusions and Steam Systems. He has been selected to deliver the first
This case study presented data demonstrating that WFI can public presentation of the Guide. Zoccolante developed the four
be produced using a membrane-based water purification day ISPE Pharmaceutical Water course and has presented
system. Monitoring data from a calendar year are presented the course to hundreds of pharmaceutical industry person-
for several critical performance attributes of the HPW genera- nel, including the FDA. He is a frequent lecturer for many
tion and distribution system. All of the critical performance pharmaceutical groups and has chaired many courses. He has
attributes met the standards outlined for WFI compendial presented for ISPE, Interphex, American Institute of Chemi-
grade water. cal Engineers, American Society of Mechanical Engineers,
A membrane-based water purification system was chosen Institute for International Research, Center for Professional
to minimize cost and schedule impact when the design basis Advancement, PDA, Pharmtec, Barnett International and
was changed during the construction phase of Alkermes’ many others. He has conducted several in-house courses on
manufacturing site. The addition of an ultrafiltration unit pharmaceutical water production and regulatory require-
operation, which is compact in size, minimized the impact ments for pharmaceutical companies. He has authored and
on the design and layout of the overall water system. The co-authored many papers on pharmaceutical water production
ultrafilter had a relatively short lead time and the capital cost and system operation and maintenance. He holds several
was low. In addition, the operating cost of the ultrafiltration patents for pharmaceutical water processes. He has previous
unit is significantly lower than the operating cost of a still, experience as manager of engineering and manager of appli-
minimizing the impact on operating costs. cation engineering. He holds a BS in mechanical engineering
from Northeastern University. He can be contacted by email:
About the Authors [email protected].
Henry Brush is the Director of Manufactur- Siemens Water Technologies Corp., 10 Technology Dr.,
ing and Process Development at Alkermes, Lowell, Massachusetts 01851-2728.
where he has developed the manufacturing
process technology for the pulmonary drug de-
livery platform. This includes leadership roles
in the scale-up of the manufacturing process
to a high volume commercial operation, clini-

28 PHARMACEUTICAL ENGINEERING July/August 2009

 WFI Production Methods

Sponsored By: Media Sponsors:

July/August 2009 PHARMACEUTICAL ENGINEERING 29

 Amplified Media Circulation
This article
describes Amplified Media Circulation – A New
Amplified Media
Circulation Way for Enhancing Sterilization Cycles
(AMC), which
is an alternative
option to the by David A. Karle, Gerald McDonnell, and
use of intrinsic Teppo Nurminen
sterilizer fans.

Introduction

A
for sealing purposes in powering the fans. Even
ny mechanical moving part in a clean with magnetic coupling technology, problems
environment can present unique chal- with particulate emissions, lubricant contami-
lenges to a manufacturing facility. For nation, and bearing endurance can be a concern
example, in the terminal sterilization with traditional fan designs. In this article, an
of fluids, the associated sterilizer moving parts alternative option to the use of intrinsic steril-
can include conveyors (for loading/unloading izer fans is presented, which is referred to as
of the chamber) and impellers (or fans) within Amplified Media Circulation (AMC).
the sterilization chamber for heating/cooling
purposes. Sterilizer fans are widely used to Alternative Method and Design
optimize the steam sterilization of loads (e.g., Recently, a new method for enhancing air, steam,
for providing laminar steam and air flow for liquid, and/or gas movement in sterilization
good temperature distribution or for enabling processes has been developed. The movement
enhanced cooling times), but are a particular of air or other process fluids within a chamber,
problem as they are enclosed within the chamber such as steam, can be amplified by methods other
of steam sterilizers. In addition to the require- than mechanical agitation (the use of fans). An
ment for emission-free operation for the fans, example is using the “venturi” effect. The venturi
the hot, moist, pressurized conditions associ- effect is actually a rather old concept, named
ated with steam sterilization result in an extra after the Italian physicist Giovanni Battista
stress on these mechanical devices to include Venturi (1746-1822). It is based on the premise
the bearings, shafts, and in the routine main- that a high-speed liquid or gas generates a lo-
tenance (e.g., lubrication) of such components. cal vacuum through the kinetic energy of the
Further, chamber penetrations associated with flowing molecules. Although this might not be
fans require extra design requirements and obvious, this phenomenon is used in many com-
utility supply, e.g., ultra pure water or distillate mon devices, such as car carburetors, gas stoves,
Figure 1. Principle of
venturi effect.

Continued on page 32.

30 PHARMACEUTICAL ENGINEERING July/August 2009
 Pharmaceutical
Processing
Systems
GEA Pharma Systems supplies
the world’s pharmaceutical companies
with state-of-the-art solutions for the
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 Amplified Media Circulation

Figure 2. Principle of the AMC ejector.

or paint atomizers. In Figure 1, the venturi effect manifests steam pressure is routinely applied in order to maintain product
itself as the hydrostatic pressure difference (h) between high integrity. Producing compressed air is relatively inexpensive,
and low velocity areas of the demonstration device. especially when compared to the requirements for producing
For specific application to enhanced sterilization cycles, AMC distillate or similar quality water for fan installations. In
differs from the traditional venturi pipe system due to the con- sterilizer applications, the AMC devices’ primary air consump-
figuration of the associated flow channels. Whereas in a basic tion is typically from 22 to 72 m3/h at 4 bar working pressure
venturi design the primary flow in the main channel induces (equaling 13-32 cfm at 58 psig), depending on the sterilizer
a negative pressure component into the side channel(s); in the size. These values are essentially equivalent to the typical
case of AMC for sterilizer applications, the channel arrange- air pressure required for an associated sterilization process,
ment is the opposite. Primary media (like air) is injected into a i.e., any process designed for processing liquid loads. The dif-
narrow side channel, from which it flows into the main channel ference is that with AMC, the peak consumption is sustained
through a radially-symmetric capillary gap at the inlet end of throughout the cooling stage and the air compressor should
the channel. The concave shape of the final section of the side be able to support this level of air consumption on a continu-
channel redirects the flow, making it enter the main channel in ous basis. Essentially, this can be achieved when planning
a skewed angle, pointing toward the other end (outlet end) of the utilities for process support to verify that the compressor
the channel - Figure 2. The subsequent angled flow generates capacity for generating required amounts of pressurized air
a local vacuum into the main channel. This vacuum draws air exists. In a medium or large plant, these rates would not be
(or other fluid) into the inlet end of the main channel, and as considered unusual or high, and in most cases, an existing
a result, the combined main flow (priming air and venturi- compressor would already possess the additional capacity
induced main flow) is typically about 20 to 30 times higher in required. As energy consumption is always a consideration, it
volume flow rate than the primary flow was. In this way, the is important that the additional electrical energy consumed by
higher pressure in the compressed air supply is converted into air compressor is below that of the energy consumed by most
higher, “amplified” flow rates in the main channel. conventional fan motors; this is despite the fact that the AMC
The primary air needed for powering the AMC device(s) approach does not require the pure water supply for sealing
can be taken from any source; for example, a typical steam the required penetration. Typically, the cost of the electrical
sterilizer air supply. The air quality requirements are the same energy consumed is estimated to be around one dollar ($0.33
as for any air-powered process component, being dry, oil-free, - $1.13 or 0.25 - 0.85 E depending on the chamber size) for
and passed through a 0.22 micron filter to ensure its sterility. each cooling hour.
This arrangement is practically no different than any other Utilization of AMC devices is not limited to process air.
terminal steam-air-mix sterilizing process or any associated Steam also can be injected into the chamber through such
liquid process for that matter since all of these require air devices, which also may be considered as “ejectors,” which can
to provide and maintain over-pressure. For example, in the result in enhanced temperature distribution and shortened
sterilization of closed liquids, a pressure higher than saturated heating up times. Steam itself can be efficient in its own

32 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation
right, but nevertheless a definite improvement in heating up
times can be witnessed when the steam flow was amplified by
directing it through AMC devices. Also, the higher the steam
velocities, the more dynamic and effective the penetration into
the load items can be. As stated in a steam sterilizer validation
guide, “determining which load items are the most difficult
to sterilize and which location(s) within the items presents
the worst-case conditions can be a daunting task.”2 Steam
penetration speed during standard operating conditions can
be calculated. Calculations are based on simple diffusion
and convective flow,3 but dynamic disturbances improve the
penetration further by agitating the atmosphere mechanically.
Consequently, in order to achieve an optimal performance, Figure 3. Ejector installation in the sterilizer ceiling.
arrangements can be made for toggling the utility supplies
automatically between ejector/no ejector inlets based on the associated disadvantages. Figure 5 presents tests results with
process phase. Figure 3 illustrates a typical ejector pair in- unaided natural cooling, indirect jacket cooling, fan-enhanced
stallation in the ceiling of the sterilizer chamber. cooling, and cooling assisted with AMC.
Ejector design and function can be maximized for optimal
Practical Applications performance and programmed permanently for that applica-
An example of the practical use of the AMC principle has been tion. An added advantage is that the ejectors do not require
shown for the rapid cooling of liquid loads. Figure 4 presents a maintenance, periodical checks, safety precautions, special
typical liquid load with sealed bottles. A traditional, indirect cleaning, spare parts, or adjustments during the lifetime of
(jacket) cooling of such load can take many hours. Enhanced the sterilizer. Importantly, they do not contain moving parts
with fans or other mechanical devices, the cooling stage can nor require lubrication. The entire ejector assembly to include
routinely be shortened by 50 to 60%. The AMC system meets both the external and internal surfaces, such as the capillary
or even exceeds the performance of currently used mechanical gap, is fully within the steam contact area. Consequently, the
convection systems (fans), but does not possess any of their ejector(s) are sterilized each and every sterilization cycle, as
Continued on page 34.

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 Amplified Media Circulation

Figure 5. Comparison of various cooling methods.

including AMC devices have been independently verified not

to exceed the OSHA or other safe criteria for operation.
Traditional terminal sterilization applications with fans
have attempted to maximize laminar flow to optimize their
use. This approach most often requires guides or baffles,
thus restricting and redirecting the air flow and consuming
chamber space. With AMC, the penetration is based on high
air velocities which create the necessary turbulence within
the chamber. During the cooling phase of a steam steriliza-
tion cycle, for instance, this turbulence prohibits stratification
without the need for particularly guided flow patterns. Smooth
and efficient cooling has been proven for representative full
loads. Figure 6 illustrates the flow patterns during the cooling

Figure 4. Typical liquid load configuration.

with the chamber and associated piping. Actually, the steril-

izing steam enters the pressure vessel through the ejector(s),
meaning that they are intrinsically the hottest spot in the
chamber and therefore, inevitably become sterile. Contrary
to this design, traditional impellers with water sealing may
become a focus area in the sterility qualification as cold spots
within the chamber. FDA guidelines suggest that special at-
tention should be given to the sterilization of those locations
slowest to heat.1 The sealing water flowing through the shaft
penetration, although not intended for cooling, may induce
colder spots into that particular area.
Another advantage of AMC is that it occupies minimal
space within the chamber. Whereas a fan assembly can be
rather bulky and require auxiliary stainless steel constructions
around it, the AMC ejectors are stand-alone devices extruding
only a couple of inches from the chamber ceiling. Further, the
ejectors do not require any associated electric motors on the
top of the sterilizer, thus minimizing the height and installa-
tion size of the unit. The noise levels of the entire sterilizer, Figure 6. AMC flow patterns during cooling stage.

34 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation

Figure 7. Typical temperature distributions with a full liquid load.

stage. Forced convection is induced by conveying the hot air into account when designing the room ventilation. Often, the
rising through the load to the cold walls. pressure differentials between various rooms are controlled
On the other hand, for some other stages of typical steril- accurately, and in cases like this, the air exhaust may not be
ization cycles (e.g., during the steam sterilization or holding allowed directly into the room, but must be piped either to
phase) turbulent conditions should be avoided. The value the safety relief device line or to the drain line. In the latter
of a pressure difference-driven device, such as AMC, is that case, the air exhaust should be segregated from the room with
when the pressure difference diminishes, the amplifying a water lock (siphon) to prevent the flow from disturbing the
effect decreases in parallel. In this way, the flow rates come pressure differentials between controlled or clean rooms.
intrinsically down when the highest (or desired) pressures are Concludes on page 36.
approached. Subsequently, during the sterilization phase, the
counter pressure in the chamber is at its highest, and the ejec-
tor flow rates are at their lowest and the delicate temperature
balance can easily be maintained through this critical stage.
Also, in the absence of shaft penetrations or cooling water for
the shaft seal, cold spots or undesired convection of heat from
the vessel are easier to avoid. Consequently typical, verified
maximum distribution with a full load has been confirmed to
be in the ± 0.35°C range (Figure 7) including the probe in the
drain line. In an empty chamber, the distribution is normally
within ± 0.15°C - Figure 8.
The same automatic adaptation applies to other phases
of a typical sterilization cycle. During the post-sterilization
cooling stage, higher flow rates are again desired (to enhance
the forced convection and the heat transfer from the load),
and the rates can be artificially boosted by allowing some air
to escape from the vessel in a controlled manner. Mechani-
cal agitators, such as fans, are typically running at the same
speed throughout the cycle, and even though speed variation
solutions that involve frequency drives can be implemented,
the flow rates still do not adapt automatically to the process
conditions as observed with the AMC devices. During the cool-
ing phase, air is also exhausted from the vessel. The ASME
pressure vessel codes state that the exhaust from the vessel
must be piped to a safe place. Usually, the air exhaust from the
chamber can be connected to the same pipeline, often leading
to the outside of the building. If the safety device pipeline for
some reason does not exist, the air could be vented directly
into the room. In this case, the air flow rates must be taken

July/August 2009 PHARMACEUTICAL ENGINEERING 35

 Amplified Media Circulation

Figure 8. Typical temperature distributions with an empty chamber.

Summary became Steris Corporation. He can be contacted by telephone:

Mechanical fans have been the traditional method for forced +1-814-870-8578 or by email: [email protected].
convection within steam sterilizer chambers. More modern Steris Corporation, 2424 W. 23rd St., Erie, Pennsylvania
alternatives to conventional fan, such as the AMC devices 16506 USA.
described in this article, can provide the same if not more ef-
ficient operation, but with less space within the chamber, with Dr. Gerald McDonnell has a BSc. (Hons.)
no moving parts to fail, requiring fewer utilities to operate in medical laboratory sciences from the
and being virtually maintenance free. These advantages also University of Ulster and a PhD in microbial
can be provided to low temperature sterilization and other genetics from Trinity College Dublin. He is
applications with similar technology. currently Vice President of Technical Affairs
and Research for Steris Corporation, based
References at their European headquarters in Basing-
1. U.S. Department of Health and Human Services, Food and stoke, UK. McDonnell is widely published
Drug Administration, Guidance for Industry: Sterile Drug in the decontamination and sterilization area. His research
Products Produced by Aseptic Processing – Current Good interests include infection prevention, decontamination
Manufacturing Practice, Rockville, Maryland, 2004. microbiology, emerging pathogens, and the mode of action/
2. Lewis, R.G., “Practical Guide to Autoclave Validation,” resistance to biocides. McDonnell is a member of the Ameri-
Pharmaceutical Engineering, July/August 2002, Vol. 22, can Society of Microbiology, Society for Applied Microbiology,
No. 4, http://www.ispe.org/pe. Hospital Infection Society, Council of Healthcare Advisors,
3. Nordhauser, F.M. and Olson, W.P., Sterilization of Drugs European Biological Safety Association, PDA, and ISPE. He
and Devices, Interpharm Press Inc., 1998, pp. 65-71. can be contacted by telephone: +44-1256-866560 or by email:
4. Morrissey, R.F. and Phillips, G.B., A Practical Guide for [email protected].
Manufacturers and Users of Health Care Products, Ster- Steris Limited, Steris House, Jays Close, Viables, Basing-
ilization Technology, 1993. stoke, Hampshire RG22 4AX, United Kingdom.

About the Authors Teppo Nurminen has a Master of Science

David A. Karle is a Senior Product/Mar- (Eng) in applied electronics and control
keting Manager for Steris Corporation. He techniques from the Helsinki University of
also is responsible for managing a team of Technology. He has held various managerial
professionals who work with pharmaceutical positions at Steris Finn-Aqua since 1994,
companies to develop sterilization cycles for and he is currently a Manager for Research
their products. Karle started his career with and Development at the Tuusula facility,
AMSCO in 1974 as a senior research scientist. Finland. Prior to Finn-Aqua, he worked as
He maintained that position for 11 years an engineering consultant. He is the inventor or co-inventor
before joining the marketing group as a product manager in numerous international patents related to pharmaceuti-
for healthcare steam sterilizers. Since 1985, Karle has held cal water treatment, steam sterilization, and biohazardous
various positions in product and marketing management of effluent decontamination. He can be contacted by telephone:
consumables and capital equipment in both healthcare and +358-9-2585227 or by email: [email protected].
in the pharmaceutical businesses at AMSCO, which in 1996 Steris Finn-Aqua, Teollisuustie 2, 04300 Tuusula, Fin-
land.

36 PHARMACEUTICAL ENGINEERING July/August 2009

 Amplified Media Circulation

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July/August 2009 PHARMACEUTICAL ENGINEERING 37

 Maintenance and Facilities Outsourcing
This article
presents a case Maintenance and Facilities
study on the
area of utilities Outsourcing Excellence –
and facilities
maintenance An Industry Case Study
outsourcing
within the
pharmaceutical by Padraig Liggan
industry. This
approach
shows how
the future for
outsourcing is
moving toward Introduction

A
activities of developing and producing product.
full ownership ccording to Jones,1 it was found that Outsourcing the maintenance function can
of utilities in the early 1990s, as little as five reduce costs by eliminating direct company
and facilities percent of world class manufacturing headcount; enabling management to enforce
organizations outsourced maintenance change quickly, drive continuous improvement,
systems through and facilities services. Within 10 years, by the and improve service levels. This is possible be-
long-term fixed end of the 1990s, this figure had risen to around cause the outsourcing company then becomes
contracts which 30%, particularly in the area of utility systems the ‘customer’ of this activity and is in a better
have shown operations and maintenance. The outsourcing of position to demand the most for their money
maintenance at this time had started to reveal from subject experts.
clear benefits itself as a relatively new trend. Currently, in The outsourcing of utility services within
for both parties 2009, the number of world class manufactur- the pharmaceutical industry will in most cases
involved. ing organizations who are outsourcing utili- include clean utility systems such as high purity
ties and facilities operation and maintenance water and steam systems (purified water, water
is estimated to be in excess of 40% and still for injection, clean steam) and cleanroom Heat-
growing. ing Ventilation and Air Conditioning (HVAC).
The main reasons for outsourcing utilities Facilities services will typically include build-
and facilities maintenance are to allow the ing fabric maintenance, cleaning, and general
manufacturing company to focus on its core building services administration. For the main-
Figure 1. The Wyeth
Biopharma Campus at
Grange Castle.

Continued on page 40.

38 PHARMACEUTICAL ENGINEERING July/August 2009
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 Maintenance and Facilities Outsourcing
tenance outsource provider, customer satisfaction is a primary who monitors contract performance and contract spend. This
area of focus, which is a motivation for the expert service structure is beneficial to Wyeth and they don’t need to get
provider to deliver a best in class, value for money service, involved in the day to day running of the plant. Through the
not necessarily felt as deeply as in-house staff. Outsourcing cost center owner, Wyeth management has a good visibility of
partners are generally non-unionized and so the risks of strike the performance of the contract and the areas that may need
or halts to manufacturing as a result are extremely low. to be addressed. Performance is measured through areas, such
By setting out clear objectives and outsourcing to an expe- as availability, planned work vs. actual, safety and regulatory
rienced company, great results can be achieved. Outsourcing requirements. For clean utility systems (which are qualified
should not be mistaken with relinquishing of overall respon- systems and feed manufacturing areas directly), high level
sibilities. For example, in the pharmaceutical industry, legal compliance is ensured through Wyeth subject matter experts
aspects such as regulatory compliance for drug manufacturing and the Quality Assurance group in each area. Wyeth has
must be maintained and closely monitored and the outsourc- overall responsibility for the safety of their products and this
ing company must provide safe systems of work. Outsourcing structure needs to exist. Figure 2 details the type of organi-
of utilities (particularly clean utilities) and facilities should zational structure that has been set up for the outsourcing
be a risk-based approach where over time, the contract com- of utility systems in manufacturing areas.
pany becomes more empowered through satisfaction by the The outsourced teams interact with local quality groups
client company that high quality services can be consistently and manufacturing area owners on a daily basis as would
delivered. The company also should employ people to monitor occur in any pharmaceutical organization. Overall, the con-
performance of the outsourced contract and to develop service tract is overseen by a client operations manager along with
level agreements. All the major manufacturing companies in client quality support. One of the key advantages of this
Ireland have adopted various degrees of maintenance and structure is that the outsourced company can be measured
facilities outsourcing as part of their business strategy. This directly against the equipment/system uptime that is being
has paved the way for a new emerging industrial services provided; this is because they own every activity within the
business sector in Ireland: outsourcing services, such as facili- maintenance organization. In some outsourcing situations,
ties, maintenance, and security. Competition in these areas only certain tasks are contracted (also known in industry as
is healthy, which of course encourages the industry-wide “body shopping”). In this scenario, it can be difficult for the
provision of better value for money. This is allowing Irish company to achieve full accountability from the contractor
companies to build expertise in these areas by being able to for systems performance. Where the outsourced company has
support large multinational companies who wish to set up a high degree of ownership of systems, continuous improve-
in Ireland. This ability of these service companies can be a ment is a natural evolution, and this should be supported
positive factor in the decision-making process of a company and encouraged by the client company.
potentially choosing Ireland as a location. A service level agreement sets out clear expectations
and tasks to be performed by the outsourcing partner. The
Building Outsourcing Excellence manufacturing companies’ measurement of the contract is
In 2001, it was announced that pharmaceutical giant Wyeth important; company’s can’t manage what they don’t measure,
was to invest E1.8 billion ($1.8 billion) in a state of the art and this is where Key Performance Indicators (KPIs) have
biopharmaceutical plant at Grange Castle, West Dublin. Later a part to play. The KPIs can be structured in terms of plant
that year, the construction of one the world’s largest biophar- availability, scheduled work completion, and safety and compli-
maceutical plants began at Grange Castle - Figure 1. ance with specific targets, among others. Penalty clauses can
In 2002, maintenance outsourcing began with the external- be employed for performance targets that are not met, this
ization of the utilities and facilities maintenance organization approach creates a mutual gain “win-win” (i.e., both share
in order to operate plant utilities and to setup maintenance the risks and rewards) environment in which all parties see
programs for the site. Although we don’t often see plants of the benefit of high performance.
this size being constructed, this is the best time to form an alli-
ance partnership with the maintenance outsourcing company,
working together from the start, regardless of plant size.
Since 2002 to the present, Wyeth and its outsourcing
strategies have evolved to form one of the best examples of
outsourcing excellence in Ireland today. There are a number
of key areas that have contributed to this success.

Utilities and Facilities Outsourcing:

A Self-Managed Service
Wyeth expects and encourages the outsourcing companies to
have a high degree of ownership when it comes to operating and
maintaining utility/facilities systems. In each manufacturing
area, the contract is overseen by one Wyeth cost center owner Figure 2. Typical outsourcing organization chart for utilities/facilities.

40 PHARMACEUTICAL ENGINEERING July/August 2009

 Maintenance and Facilities Outsourcing
Within the outsourcing structure, the internal site train- company is often referred to as “those maintenance people”
ing systems should be adopted by the contract company for and this stigma creates an “us versus them” relationship,
areas such as procedural, GMP, and safety compliance. There which can inhibit improvement, hinder trust, and have a
should be an expectation that the outsourced company will negative effect on overall plant performance.
continually develop their own employees by providing ad- All of the above approaches by Wyeth create a true partner-
ditional technical/equipment specific training. ship between the client and the outsourced partner, and the
By creating the outsourced maintenance function as a relationship is based on mutual trust and mutual gains.
separate entity, it means that whatever is happening in pro-
duction, good or bad, the utilities and facilities equipment/ Building for the Future
systems performance is not compromised. In cases where the At present in Irish industry, companies are in the process of
maintenance function is in-house, the company departments negotiating long-term contracts with utilities and facilities
have tendencies to abandon the maintenance function tem- service companies who take over full ownership of the plant.
porarily in order to sort out problems in production, which This type of approach can provide for a “Black Box” service,
can potentially lead to system performance and regulatory which further enables the client company to reduce overall
compliance suffering due to lack of focus. costs and focus on their core business. This sort of contract
arrangement is set to become the future for outsourcing of
An ‘Alliance Partner’ not ‘Contractor’ utilities and facilities.
Utilities and facilities outsourcing plays an important role Again this is a win-win situation for both parties; on one
in the day-to-day operation of the Wyeth plant in Grange hand, the manufacturing company has an ability to set long
Castle and for this reason, high recognition is given to the term fixed budget costs for each year in return for the supply
outsourced company by providing them with internal facilities of utilities and facilities services. For the outsourced company,
such as training, computer network access, and opportunities an operational profit is made over the term of the contract,
to become involved in site business initiatives. Instead of be- and investment can be made for the long term development
ing “housed away in the back-yard,” the outsourced company of its people without the fear of losing them through loss of
operates alongside Wyeth on a daily basis. short term contracts. Typical KPI measurements are as fol-
The term “contractor” is very rarely used, rather an “Al- lows:
liance Partner” with Wyeth. In many plants, the outsourced
Concludes on page 42.

July/August 2009 PHARMACEUTICAL ENGINEERING 41

Hach-PAT700-inuse-halfpg.indd 1 12/23/2008 11:13:18 AM

 Maintenance and Facilities Outsourcing
• Utility Systems Plant availability (expectations >99.5%) In 2009, a CHP is set to be constructed at the Wyeth Grange
• Quality Compliance (CAPA Investigations timely closure, Castle plant. This project is an example of the design, build,
maintenance scheduled Vs complete) finance, and operate/maintain model mentioned above.
• Safety (number of incidents, no lost time injury)
• Innovations/plant efficiencies/energy savings (bonus pay- Summary and Conclusion
ment provisions in place) Following research and from the author’s own experience,
• Facilities response times and timely closure of logged the area of maintenance outsourcing has been identified
items as a major part of modern industry. As discussed earlier,
the main driver for manufacturing companies to outsource
With a strong outsourcing partnership in place, it is estimated maintenance is to reduce costs and to enable them to focus
that the pharmaceutical company can expect to make savings on the core activity of making product, while gaining best
in excess 20% in comparison with the alternative internal service performance. However, this is only the baseline of
structure. With a long term fixed price contract, it is within possibilities – so much more can be achieved by approaching
the outsourced company’s own initiative to continuously outsourcing correctly, leading to a high degree of ownership
improve in order to gain a higher profit margin on best ef- by the outsourcing partner, continuous improvement, and a
ficiency and performance of high availability utilities being win-win culture which promotes open/honest communication.
sold back to the client. The future for outsourcing is moving toward full ownership of
utility systems through long-term fixed contracts that have
Design, Finance, Operate, and Maintain shown clear benefits for both parties involved.
During the construction of a new plant, another popular op-
tion is to completely outsource the plant core utilities. Some References
outsourcing companies can design, build, finance, and operate 1. Jones, K.E., “10 Key Indicators of Maintenance Perfor-
and maintain the central utilities plant, which can include mance,” Information Service Centre for Energy Industry,
steam, electricity, air, water, etc. With this arrangement the 1999.
client company can focus on getting its manufacturing fa- 2. Welch, S., “A Plan for Maintenance Success,” Advanced
cilities up and running and be supplied with plant utilities Technology Services, 2002.
which can be purchased at unit cost. At an operating level, 3. Martin, H.H., “Contracting out Maintenance and a Plan
the outsource partner, in close cooperation with the client, can for Future Research,” Journal of Quality in Maintenance
offer ongoing savings and efficiencies in the area of energy Engineering, 1997, Vol. 3, No. 2, pp. 1355 -2511.
use and consumption. 4. Durand, A., “The Benefits of Outsourcing Maintenance,”
This package often includes a Combined Heat and Power Caribbean Business (Industrial Maintenance Supplement),
(CHP) plant, also known as co-generation CHP, which is the 2003.
simultaneous generation of usable heat and power (electric- 5. Ireland, B., “Outsourcing Options,” Electrical Contractors
ity) in a single process. & Maintenance (EC&M) Magazine, 2006.
An overview of a CHP plant is shown in Figure 3; CHP 6. Liggan, P., “The Research and Implementation of Mainte-
plants are over twice as efficient as a traditional power plant. nance Excellence on Clean Utility Systems in the Pharma-
The CHP plants are built on the factory premises, electricity ceutical Industry,” Dublin Institute of Technology, 2008.
is sold back to both the factory and the national grid, and 7. http://www.dalkia.ie – Combined Heat and Power
heat generated by the plant is then re-used in the factory. Plants.

About the Author

Padraig Liggan, MEng, BSc (H), has
worked in maintenance engineering within
the pharmaceutical and dairy industries for
the past decade. He is currently employed
with the energy and facilities management
engineering company, Dalkia Ireland Ltd.,
where since 2003, he has been heavily involved
in setting up start-up maintenance programs
at the new Wyeth, Grange Castle plant. The Wyeth plant at
Grange Castle is currently one of the largest integrated Bio-
pharmaceutical campus’ in the world and is still undergoing
further expansion. He can be contacted by telephone: +353-
1-4648959 or by email: [email protected].
Dalkia Ireland Ltd., 145 Lakeview Drive, Airside Business
Figure 3. CHP power generation. Park, Swords, Co. Dublin, Eire, Ireland.

42 PHARMACEUTICAL ENGINEERING July/August 2009

 Maintenance and Facilities Outsourcing
2010

2010
Facility of the Year
Awards
The Facility of the Year Awards program
celebrates state-of-the-art pharmaceutical
was a winner from manufacturing projects utilizing innovative
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For additional information about the Awards

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www.facilityoftheyear.org

July/August 2009 PHARMACEUTICAL ENGINEERING 43

 Industry Interview
A veteran
quality
Pharmaceutical Engineering Interviews
executive,
Sharon Bleach
Sharon Bleach, Vice President, Global
discusses her
philosophy on Quality, Operations, AstraZeneca
quality, her
experience
as previous by Rochelle Runas, ISPE Technical Writer
chair of ISPE’s
International
Leadership
Forum, and
insight into
AstraZeneca’s
strategic
approach to
Sharon Bleach fol-
lowed her degree in
biophysics from Sus-
Q What are your primary responsibilities in
your current position as VP, Global Quality,
Operations, AstraZeneca?
significant sex University with a

changes in the
role in research at the
Max Planck Institute
A As a member of the leadership team for
Operations, which is the manufacturing
and supply operation, I am responsible for
industry. in Berlin, then West
the strategy and delivery of quality activities
Germany.
across Operations. I have the additional role
On her return to the
of overseeing all GxP activities throughout
UK, Bleach joined Well-
AstraZeneca.
come’s biotechnology R&D organization at Beck-
enham and then moved into developing deep
cell culture plants in the UK, Spain, Canada,
Japan, and the US. During this time, she also
Q What experiences and training best pre-
pared you for your current position?

studied and earned her MBA from Warwick

University.
Moving from R&D to Quality, Bleach led
A Life itself! I’ve been very fortunate and had
many different roles in my career so I have a
broad experience base. I’ve done both site-based
activities in a number of project and line man- and corporate roles, as well as having R&D and
agement roles across both biotechnology and quality experience. I’ve also been extremely
small molecule areas. fortunate in working with many different na-
After the GlaxoWellcome merger, Bleach tionalities and cultures through the course of my
held quality roles covering UK and European career. That has provided a tremendous learning
sites. Following the merger of GlaxoWellcome experience and opportunity to understand dif-
and SmithKline Beecham, she became Head of ferent things about the different cultures and
Quality for European sites in eight countries, countries, which is very useful in a leadership
later moving on to quality associated with new role such as this.
product introduction in Europe, US, and Puerto
Rico.
Before joining AstraZeneca in July 2008,
she completed 28 years with GSK as Head of
Q What are the major challenges faced by a
senior quality executive in a pharmaceuti-
cal organization?
Quality Strategy, introducing a revised Quality
Management System, leading Quality Training
and Development and involvement in External
A I guess there’s always the “not enough time
in the day,” which is probably typical of
many senior roles in many industries. I think
Relations.
part of it is that regulators look on the quality
Bleach believes that quality is about keeping
organization as almost a surrogate for them
things simple, getting them right the first time,
in the industry, yet you’re operating within a
and working with motivated people who do the
company, understanding the company perspec-
right things.
tives and priorities. Really it’s about how do you
balance what regulators are expecting with the

44 PHARMACEUTICAL ENGINEERING July/August 2009

 Industry Interview
company’s need to be successful and, lines in 2007, so I’m going to assume around how we do that. Essentially, I
in doing all that, making sure patients that the Quality Management System think that’s in line with many different
get the right product when and where at AstraZeneca is based on Q10. Am I companies in the industry.
they need it. correct in that assumption?

Q Please elaborate on your philosophy,

“Quality is about keeping things
A That’s correct! I’ve only been at
AstraZeneca since last July, but the
Q Do you feel ICH guidelines are be-
coming part of the culture within
the quality organizations of pharma-
Quality Management System is linked
simple, getting them right first time, ceutical companies?
to Q10. However, we’re also doing work
and working with motivated people
who do the right things.”
on our quality system to put it into a
new format and to emphasize the pro- A Yes, I think so. I think the poten-
tial benefits from ICH Q8, Q9, and

A Regulations are complex, whether

you take one country, such as the
US and the FDA regulations there, or
cess thinking across the company and Q10 are a significant opportunity for
Continued on page 46.

Sterile Clean Steam Sampling

whether it’s Europe with the European
Medicines Agency (EMEA) and authori-
ties in each member state, or whether
it’s Japan, Canada, Australia, etc. One of
the biggest challenges is how you inte-
grate those different requirements and
how you make sure you’re in line with
all of those different requirements.
I also think you have to have people
who want to come to work, because if
they aren’t enjoying what they’re do-
ing, if they don’t think it’s important,
if they don’t recognize the value that
patients get from what we’re doing in
this industry, then you don’t have the
differentiator that people will keep fo-
cused. So, for me, you’ve got to motivate
people to want to improve, to want to
constantly be looking for the next idea,
the good way of doing things, and how
you can simplify. And the more we sim-
plify the more of a chance we’ve got to
get it right.

Q Do you think that industry and

regulators are understanding that GEMÜ BioStar® Steam Sampler, the innovative automated
keeping things simple is the best way sampling system for the monitoring of pure steam quality
and is that reflected in how they’re revis-
ing and coming up with regulations?
■ Sterile from the steam pipe to the laboratory
Sterilization prior to sampling, sterilized sample container, sterile sample transport
A I think the dialogue is much more
about continuous improvement
now and I don’t think that people
■ Automated, programmable and safe
Hands-off auto sampling method eliminates potential contamination of the sample
think that continuous improvement and minimizes risk of injury to operating personnel
necessarily means adding complexity. ■ Consistent, reliable and time saving
Whether or not as an industry – taking Automation of the activity provides consistency and repeatability while reducing
regulators and suppliers together – we the time required to complete the sampling by plant personnel
have focused enough on simplicity and ■ Easy to install - easy to operate
simplification: No, I think there’s more Simplified connections, easy plug and start, air-cooled, mobile or fixed installation,
we can do there. repeatable and programmed process

Q You’ve presented on ICH Q10 and

been involved in the ISPE and PIC/S
joint conference focusing on ICH guide-
GEMÜ Gebr. Müller Apparatebau GmbH & Co. KG · Fritz-Müller-Str. 6-8 · D-74653 Ingelfingen
Phone +49(0)7940/123-0 · Telefax +49(0)7940/123-224 · [email protected] · www.gemue.de

July/August 2009 PHARMACEUTICAL ENGINEERING 45

 Industry Interview
industry and regulators. So, it would be teams, which enabled us to have some these changes in the best way we can.
shortsighted, perhaps, of companies to energy from ILF Members focused on At AZ we are seeking more partnerships
ignore the opportunities that are there. the key topics that were of concern to and collaborations, as well as driving
You can either say, “Well, we’ll start by industry and to regulators. down our operating costs as much as we
working on these things now and it may can without compromising our quality
not be perfect, but we’ll improve as we
go on,” or you can say, “We’ll hang back
and wait and see how it works.” We’ve
Q What are some of those key top-
ics?
focus, to ensure our approach to drug
development is cost effective, as well
as being sensitive to the unmet needs
decided we’re going to be in the forefront
of this because we think there are some
A One of our major pieces of work is
around supply chain security and
teams looking at what industry can do
of patients.

significant benefits and I know there are

a number of companies that are doing
exactly the same thing.
to more actively engage with supply
chain security initiatives that regula-
Q In light of these challenging eco-
nomic times, some predict that
pharmaceutical companies will build
tors are highlighting they’re particu-
themselves horizontally rather than
larly concerned about. And obviously it

Q Your career has encompassed posi-

tions in R&D and quality. Did your
experiences in R&D help you bring
came a lot from the discussion around
contaminated milk, or melanin, or the
vertically with outsourcing playing
a bigger role in that change. In your
experience with different companies
Heparin situation.
different perspectives to positions and certainly now, are you seeing this
We had a very good discussion
you’ve held in Quality? What are those happen?
about 18 months ago with some of the
perspectives?

A When you’re in R&D you learn very

clearly: You only ever make one
regulators who basically said, “Look,
this is our top priority.” It was really
satisfying to be able to say to the regu-
A Yes. We’re actively outsourcing some
activities, where the activity is not
core and we think another organiza-
change at a time in an experiment oth- lators, “Actually, the ILF has already tion can do it in a more effective way,
erwise you don’t know what impact it’s discussed this and we’ve got a piece of and actively consolidating in house for
had. And that lesson, I think, has stood work we are going to be undertaking others that we see as a core strength
me in good stead when going through a that you’re welcome to be part of and for us. The key is to maintain great
lot of quality changes and initiatives. If provide us with input and we’ll have quality and a focus on delivering great
you make multiple changes at the same dialogue with you about what we’re medicines for patients.
time, you have no idea which ones have doing.” The next step will be during
any impact.
I think in general, it is about under-
standing the whole product develop-
this year’s Washington Conference with
a seminar on Supply Chain Integrity
and Anti-Counterfeiting.
Q In what ways do you believe a
global organization such as ISPE
can assist regulators, pharmaceuti-
ment lifecycle. Understanding the early cal companies, and individuals in the
stages and how you work some of those
things through is helpful in terms of Q In your opinion, what have been the
significant changes in the industry
international arena?

looking at the lifecycle management of

products and what you need to think
in the past decade and what are the
challenges for the future?
A I think one of the greatest opportu-
nities for ISPE is that it provides
a whole series of different forums for
about at different stages.
I also think it’s valuable not to think
of there being some big brick or glass
A One of the big challenges over the
past decade has been that the in-
dustry as a whole seems to have moved
discussion between regulators and in-
dustry and individuals as peers. You can
have very good dialogue about the chal-
wall between R&D and manufacturing
from being perceived as adding value lenges that face the industry either at a
organizations, because the skill sets are
and doing the right thing for patients high level and global picture, or you can
very transferable between the differ-
and people around the world, to being an take it down to an extremely detailed
ent areas. I think it’s great to be able
industry that is not valued in the same technical level and make sure that we’ve
to encourage people to move between
way at all. That image and reputation got a common, good understanding of
different parts of a business to see those
shift and damage is really unfortunate good ways of addressing a technical
different perspectives.
because the majority of people in this issue. And it’s that breadth in terms of
industry are here to do the right thing the range of people who are involved,

Q What was your experience like as

previous Chair of ISPE’s Interna-
tional Leadership Forum (ILF)?
for patients and to make a positive
difference to peoples’ lives.
the range of issues, and the levels of the
dialogue that can take place.
The other thing is the consolida-

A I thought it was a tremendous op-

portunity and really enjoyed doing
it. It was great to have the opportunity
tion that’s going on in the industry
at the moment. Companies across the
industry understand that the future is
Q Coming from a biotechnology
background, what technological
and operational breakthroughs do you
to actively shape where ILF went for a going to be very different, and that we anticipate within the next five years?
period. We set up some different work all have to approach our response to

46 PHARMACEUTICAL ENGINEERING July/August 2009

 Industry Interview

A First, I’d say that my direct biotech

experience was quite a long time
ago. I think one of the things about
really good challenge for the company to
make sure that you don’t just have an
internal perspective. You need to keep
I think that quality organization has
a real opportunity always to shape how
a business is working, to add value to
biotech is that it’s been a long time an eye on what’s going on in the external the business. I think in the past people
coming and we’re still not quite there environment and challenge yourself all used to see quality, at best as a necessary
yet. We’ll see more biotech products the time with that. This role is great cost, and at worst as an unnecessary
coming through as there is a greater and I’m thoroughly enjoying it. encumbrance. Today, it is considered
push for more complex medicines that much more of an opportunity to add
respond to those areas where there is
unmet medical need. But that will be
balanced by the pressure on healthcare
Q What kind of career advice can you
offer to our readers who are pursu-
ing careers in quality?
value to product flow and to corporate
reputation.

budgets and the cost of developing

these biological medicines, which are
more complex and therefore cost more
A I think quality provides a great
grounding and a great way into the
Q What kind of activities do you enjoy
in your free time?

to deliver.
industry. There are technical skills that
people can learn which they can apply
to multiple other roles in the industry.
A I love spending time with family
and friends. I love to garden, to sit
and read, and to have a good glass of

Q What has been your most fulfilling

role so far in your career?
The thinking in a quality group is a
good education and helpful in terms of
wine.
I also enjoy traveling with my family;

A Well of course the one I’m in now,

because it really brings together a
lot of the points I learned, the skills
looking at different perspectives.
I also think there should be a very dy-
namic flow with people coming through
we are planning a trip to Jordan later
in the year to see Petra, the Dead Sea,
and Wadi Rum. I have to get really fit
and experiences that I’ve picked up quality as part of a career or part of an for that I’m told, because my daughter
along the way. It’s great to be able to education process and into other roles. has grand plans about climbing up huge
work in a global role with many dif- So it’s a two way flow in and out of qual- numbers of steps in Petra to get good
ferent countries and different groups ity. Some will be there all their careers, views!
internally. Also, I find it really good to some will spend only a short while there;
be able to work externally. I think it’s a both are perfectly valid.

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• Isolation at product loading and
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all O.E.B. categories.
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HANDLING • GRANULATION • TABLETING • CAPSULE FILLING AND BANDING • WEIGHT CHECKING • COATING • WASHING

July/August 2009 PHARMACEUTICAL ENGINEERING 47

 Water and Steam Systems
This article
presents the Rouge in Pharmaceutical Water and
outcome of
a series of Steam Systems
workshops
on the effects
of rouging in by ISPE Critical Utilities D/A/CH COP
pharmaceutical
water and
steam systems.

Introduction

T
• Pickling, passivation, rinsing
he ISPE Critical Utilities D/A/CH
COP held a series of workshops on Each method should be executed, tested, and
pharmaceutical water and steam. The documented in accordance with a Standard
discussions focused on three aspects of Operating Procedure (SOP). The SOP can be
rouge, including: created with the support of the expert/qualified
company. The responsibility for the execution
• Choice of materials, quality control should be defined in the SOP.
• Engineering, system design
• Service and maintenance Methods
Compressed air
Fifty experts participated in the workshops • Removal of large debris
with a range of experience in various fields, • Check for blockage
including OEM, engineering, material produc-
tion, instrument manufacturing, consulting, QC, Rinsing
and pharmaceutical manufacturing. • Rinsing is used to remove:
- Loose debris or water soluble substances
Choice of Materials, QC-Service - Detergents, etc.
System Startup • Rinse after each treatment step.
The desired condition for new systems (zero or • The water quality for each rinse step should
initial-state) should be well defined. be defined individually. Purified Water (PW)
is usually sufficient.
• Sufficiently detailed specifications should • The PW should have a pH of five to seven at
be available for all components (material, the end of the rinsing cycle.
surface roughness, and tolerances) and these
should be tested during the qualification Degreasing with Alkaline Detergents
phase. The thermal and chemical resis- • Removal of debris
tance also should be checked. Furthermore, • Wash out fatty or oily substances
special care should be taken regarding the
cleanliness of all components from the time Chemical Cleaning/Pickling
of delivery onward. • The makeup of the chemical solution should
• If possible (cost feasibility), the materials be suitable for the surface roughness of the
for pipes, fittings, and valves should be the system (qualified SOP).
same to avoid different behavior (welding). • Removal of contaminants (nonalloyed ferrous
components, shavings (alloy and nonalloy),
Definition of “Treatment” construction dust, discoloration, etc.)
At the end of the installation phase, the entire • In special cases, such as surface damage,
assembly must be dry. removal by chemical reaction (erosive)
The following methods are considered treat- • Electro polished systems, if pickled, are pick-
ments: led without material removal (see following
comments).
• Removal of any installation debris, i.e., using “Pickling:”
compressed air, degreasing, etc. Pickling (cleaning) with weak acids (citric acid,

48 PHARMACEUTICAL ENGINEERING July/August 2009

 Water and Steam Systems
phosphoric acid) dissolve just surface contamination without is required for the production, then the final rinse should
damaging the material. The passive layer remains intact. be conducted using WFI.
Erosive pickling only takes place using reducing acids or acid
mixtures, such as nitric acid or nitric and hydrofluoric acid Handover Criteria
mixtures and results in the chemical removal of the passive • The success of the rinse should be proven using suitable
layer. This is usually not necessary for the pharmaceutical acceptance criteria, for instance, conductivity and TOC are
industry. frequently used. The tolerance range should correspond to
In general, the comments regarding erosive and non-erosive the same predefined range as the rinsing water.
pickling are necessary because pickling always removes some- • Visual control at accessible points or with video endoscope
thing. A film or discoloring could be seen, but are removed can be used to ensure that no installation debris (non-
during pickling, revealing the layer below. suspended particles) has been left behind.

Passivation Measures for Existing Installations

• The passive layer is always present in a neutral, water The system components for existing installations should have
based system at ambient temperatures, even at atmo- documented specifications. If this isn’t the case, then the cur-
spheric exposure with air (oxygen environments, chemical rent state of the system components should be documented
equilibrium). through a detailed system analysis. At least the following
• The stability and homogeneity of the passive layer is de- aspects should be considered as adapted treatment methods
pendent on the redox potential. or processes may be required:
- An oxygen supply is necessary for an optimal redox
potential. • Material qualities
- A low pH is unfavorable. Since CO2 reduces the pH - Corrosion resistance is dependant on these character-
value, its concentration should be minimized. istics. Therefore, if rouging is corrosion, it follows that
Developing the Passive Layer the material quality influences the rouging tendency.
• The presence of O2 or other oxidizing agents, such as ozone, • Surface condition (surface roughness, visual evaluation of
supports the development of the passive layer. the surface condition, type and extent of the rouging)
• The passive layer can be artificially developed with
chemical treatment. The results of such a treatment are Continued on page 50.
only temporary and not permanent. In time, the system
will return to the equilibrium state dictated by the redox www.ISPE.org/innovationshowcase
system.
Register today!
Testing the Passive Layer (Thickness)

ISPE
• The passive layer doesn’t normally need to be tested since
it is naturally present.
• There is no regulatory requirement to test the passive Facility of the Year:
layer.
• The thickness of the passive layer is dependant on the
Innovation Showcase
surrounding conditions; therefore, varies according to the

2–3 November
conditions in the pipe (for example, if the pipe is filled with
liquid or air). Due to this variability, testing the thickness
of the passive layer only gives information on the state of Ulm, Germany
the layer at the time of the testing.
• Possible measuring methods can be conducted by quali- Learn about the latest
fied experts. Laboratory tests (destructive testing), such state-of-the-art developments
as X-ray photoelectron spectroscopy, are time consuming being implemented by
and expensive. manufacturers in the region.
• Non-destructive online measurements, which character-
ize the condition of the material, have been proven in the • Seminar on innovation in pharmaceutical engineering
chemical industry. These are indirect measurements, using
and manufacturing
• Case studies on innovation presented by recent
sensors made of the same material, which are evaluated Facility of the Year Awards winners
using complex algorithms. • Background on projects
• Q&A sessions
Final Rinse • Networking reception
• With water for injection, highly purified water, or purified
• Site visits to award-winning sites
water the minimum required water quality should be
defined (potential cost savings). This quality should be at Sponsorship and Table Top Exhibit
least equal to the operating medium. For instance, if WFI Opportunities Available

July/August 2009 PHARMACEUTICAL ENGINEERING 49

 Water and Steam Systems
• Safety aspects, such as solid connections rather than flex- tolerances must be observed, regarding the piping connec-
ible tubing tions.
• Disposal of treatment and rinsing solutions • Mix of materials – for instance, a stainless steel tank, pip-
ing in PVDF. A rouging layer can be transported onto the
System analysis and evaluation should regularly take place plastic surfaces.
using existing monitoring results. • The chemical tolerance of PVDF is limited to a maximum
of pH 12 (relevant for treatment chemicals).
Definition of Treatment
If the system analysis shows a need to take action, suitable Metal Alloys
treatment methods from the list above should be used. The austenitic stainless steels used most frequently in the
pharmaceutical industry are 1.4404/1.4435 (316L), 1.4571
Measures for Derouging (316Ti).
De-rouging of Existing Installations Pros:
The derouging method should be conducted, tested, and docu- • They can be used for cold and hot media. Almost all com-
mented in accordance with a Standard Operating Procedure ponents are available in these materials.
(SOP). If necessary, existing warranty conditions should be Cons:
taken into consideration. • Stainless steel is susceptible to rouging.

• The SOP can be developed with qualified experts. Specific characteristics of individual alloys:
• The responsibility for the execution should be decided in • 1.4404 – somewhat less Mo (0.5%), slightly reduced corro-
advance. sion resistance in hot systems. Good availability (tubing,
fittings, instruments, valves, etc.)
The recipe should be based on the following: • 1.4435 – limited availability of fittings and instruments.
Expensive material. Also susceptible to rouging.
• Current state (see above)
• Suitability tests (effectiveness) should influence the choice Other alloys also are possible; however, they may be more
of the process. difficult to procure and are significantly more expensive.
1.4539, 1.4462 (Ferritic-Austenitic Duplexsteel), Ni-Basic-
The frequency of derouging should be based on the following Alloy, Alloy 33 (high content of chromium), Titanium.
criteria: Pros:
• These special materials could be more resistance to roug-
• In accordance with monitoring results (months, years) ing; however, this has not been proven yet.
• In accordance with experience and knowledge of the instal- • 1.4462 is resistant to rouging for a wide redox range in
lation pure water systems, but doesn’t solve all problems.
• Dependent on the state • Optimizing the passive layer through higher chromium
content. The Alloy 33 with 33% Cr shows a chromium
Testing and documentation can be assigned to the contract- content in the passive layer of 83% after exposure to 95°C
ing company. pure water.
• No experience with Nickel based alloys. Rouging has been
• Visual inspection in accordance with agreed acceptance observed with Hastelloy C-276, which is not surprising
criteria (colors, film, etc.) considering the lower Cr content.
• Wipe test • Titanium stabilized materials: valves and regulating valves
• Photos, etc. in WFI systems are often made of 316Ti.
Cons:
Choice of Materials and • Due to cost and availability, 1.4539 und 1.4462 are only
Processing/Machining used in special cases.
The choice of materials influences the formation of rouging.
Delta Ferrite Content
Plastics • The delta ferrite criteria can be traced back to the BN
Pros: 2 (Basler Norm, a guideline of the Swiss Chemical and
• No rouging because it is a nonmetallic material Pharmaceutical Industries), where a very low delta ferrite
Cons: content of 0.5% is defined. The original intention of BN2
• Thermal deformation from variance in temperature (hot was to just take the delta ferrite content into account. The
operation or sanitization) delta ferrite limit was specified as a preventive measure
• New design of piping supports (high expansion value) and is not based on scientific proof. The limit is too strict
• Aging stability (hot sanitizations) and is not practical. It dictates the use of steel, which is
• Not always feasible for hot systems. Pressure and vacuum considerably more expensive and compliant welds are

50 PHARMACEUTICAL ENGINEERING July/August 2009

 ISPE
Presents:
Technical Documents
for the Pharmaceutical Manufacturing
and Biotechnology Industries

ISPE Good Practice Guide:

Heating, Ventilation, and
Air Conditioning (HVAC)

www.ISPE.org/publications
Item # IGPGHVAC
Member: $145 / €105
Nonmember: $215 / €155
- Anticipated Release: August 2009
HVAC systems can be critical systems that
affect the ability of a pharmaceutical facility
to meet its objective of providing safe and
effective product to the patient. The ISPE Good Practice Guide on HVAC
provides designers and the project team with suggestions to help determine
the user requirements and the functional design that define the facility’s
objectives. It also provides options to be considered in creating a design
that has low life-cycle cost and which is sustainable. The Guide provides:
• an overview of the basic principles of HVAC to facilitate a common
understanding of critical issues and consistent nomenclature
• guidance on accepted industry practices to address HVAC issues
• a common resource for HVAC information currently included in
appendices of the various Baseline® Guides
• an understanding of the differences between HVAC parameters that
address product requirements and “discretionary” HVAC specifications
that tend to be more business driven

ISPE Good Practice Guide:

Maintenance
Item # IGPGMAINT
Member: $145 / €105
Nonmember: $215 / €155
- Published May 2009
The ISPE Good Practice Guide: Maintenance
provides practical solutions and tools for
ensuring quality and compliance of
maintenance operations in a regulated
industry. Covering current and established
practices, this Guide helps achieve technical and regulatory accuracy and
cost-effective compliance in a new or an existing maintenance program for
effective strategy and efficiency. Offering maximum flexibility, this Guide
clearly helps define roles and responsibilities across cross-functional areas
and recommends a systematic approach aimed at continuous improvement
of maintenance operations.
The Guide is focused on maintenance in cGMP areas and provides a
Bookmark: tear along the lines

practical and consistent interpretation of the necessary elements of a

pharmaceutical maintenance program. The Guide seeks to enable
widespread adaptation and encourage innovation.

www.ISPE.org/publications
 ISPE
Presents:
Technical Documents
for the Pharmaceutical Manufacturing
and Biotechnology Industries

ISPE Good Practice Guide: Good

Engineering Practice
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- Published December 2008
This first edition of the ISPE Good Practice
Guide: Good Engineering Practice covers
the complete lifecycle of engineering from
20%
concept to retirement. The Guide aims to promote a common
understanding of the concept and principles of GEP and explains the
term “Good Engineering Practice.” It describes the fundamental
elements existing in pharmaceutical and related industries, and
identifies practices, demonstrating how GEP concepts may be applied
in the pharmaceutical industry considering the entire range of
pharmaceutical engineering activity, as well as key attributes of GEP,
including how GEP relates and interfaces with GxP.

GAMP® 5: A Risk-Based
Approach to Compliant GxP
Computerized Systems
• ISPE Good Practice Guide:

• ISPE Good Practice Guide:

• ISPE Good Practice Guide:

Good Engineering Practice

Maintenance

HVAC

Item # 5BOUNDUS/5BOUNDEU
Member Price: $250 / 185
Nonmember Price: $450 / 375
- Published February 2008
Provides pragmatic and practical industry
guidance to achieve compliant computerized systems fit for intended
use in an efficient and effective manner. Describes a flexible risk-based
approach to compliant GxP regulated computerized systems, based on
scalable specification and verification. Points to the future of computer
systems compliance by centering on principles behind major industry
developments such as PQLI; ICH Q8, Q9, Q10; and ASTM E2500.

ISPE Baseline® Guide:

Active Pharmaceutical
• ISPE Baseline® Guide: Active

• GAMP Good Practice Guide:

• GAMP® 5: A Risk-Based Approach to

of Bulk Pharmaceutical Chemicals
Pharmaceutical Ingredients, a Revision

Electronic Data Archiving

Compliant GxP Computerized Systems

Ingredients, a Revision of Bulk

Pharmaceutical Chemicals
Item # API0607
Member Price: $200 / 145
Nonmember Price: $400 / 335
Bookmark: tear along the lines

- Published June 2007

The first revision in the Baseline Guide series incorporates new regula-
tions and guidance, such as: ICH Q7, ICH Q9, GAMP® 4, 21 CFR Part
11, Guidance for Industry, Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice (cGMP), FDA Draft
Guidance for Industry PAT – Framework for Innovative Pharmaceutical
Manufacturing and Quality Assurance, and much more.
 Water and Steam Systems
considerably more difficult to achieve. Surface Quality
• Many of the participants have found that 3% is a more fea- Stainless steel is always produced with a specific surface qual-
sible limit. Since several participants also have had positive ity. The many variations, which are common for piping, are
experience with considerably higher delta ferrite levels (no well defined in industry standards. There also are standards
unusual rouging observed), 5% was suggested as the maximum which described terms and conditions for delivery.
for a preventive measure. It should be noted that calling 5%
a preventive measure against rouging is not quite correct Common Design:
as lower delta ferrite levels won’t have a negative effect on • Seamless tubing or longitudinal welds
rouging, but could drive up the material costs. • Mechanically polished or honed (bright finish, bright rolled,
• The goal (specification) should be 3%. Specifying < 3% is and cold drawn)
not recommended based on the experience of the group. An • Not pickled, just rinsed with water
absolute maximum value of 5% should not be exceeded.
• A complete lack of iron can result in a significantly higher Pros:
susceptibility to heat cracks and require the use of special • More economical than electro polished tube
weld filler metal. Cons:
• This aspect is overvalued regarding its potential negative • These surface qualities are often treated in situ.
influence on rouging. The delta ferrite has a more elevated With the exception Ti or Nb stabilized steel, all steel is
Cr content and is fundamentally more resistant to rouging available with electro polished surfaces, which can lead to
than austenitic (bulk) structure. further improvement
• This does not protect against rouging! • A roughness of Ra < 0.8 µm should be specified
• The limit for delta ferrite was created as a measure of
corrosion resistance and it can be used as proof of weld Pros:
quality. The delta ferrite measurement is an economical • Due to the reduced surface area and the more compact,
and useful method to test weld quality if the weld filler clean (free from defects) passive layer in comparison to
material is fully alloyed. non electropolished surfaces, electro polished surfaces
• The delta ferrite content does not have an effect on the generally show less tendency to rouging.
prevention of rouging.
Continued on page 52.

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July/August 2009 PHARMACEUTICAL ENGINEERING 51
 Water and Steam Systems
• Better cleanability with higher surface quality Engineering, System Design
Cons: Influencing Factors
• Treatment with strong acids roughens the surface. How can rouging be avoided through engineering and system
• Special care must be taken if any secondary welding is design of the water treatment plant?
required. Various aspects under consideration of possible influencing
• The welds in the pipe system can influence the surface factors, such as the design itself and monitoring, should be
quality. considered.
The following factors, which all could possibly effect the
Welding Procedures development of rouging, were considered in the workshop:
The Processing of the materials should be clearly defined,
while taking into account the following criteria: 1. CO2
2. Temperature
• Goods-in quality control (QM, QS, documentation) 3. Nitrogen
• Storage conditions and environment (low dust) should be 4. Oxygen
specified 5. Particle Carryover
6. Ozone
A. Weld Preparation 7. Feedwater
• Cutting of non alloyed ferritic materials à these develop 8. Choice of Materials
very aggressive particles. 9. Sanitization Process
• Cutting of alloyed materials leads to conversion to mar-
tensite (magnetic, less corrosion resistant). 1. CO2
• Do not use a cutting disc, grinder. Elevated CO2 concentrations cause a decrease in pH. This
can lead to destabilization of the passive layer, particularly
B. Welding Procedure in hot systems (80°C).
• Define welding procedure in advance (orbital or manual)
• Develop and qualify site specific welding procedures 2. Temperature
• Welder’s qualifications should correlate to the qualified Since rouging is a form of corrosion, it is expected that there
welding procedures (see above) is a system specific temperature above which the rouging will
• Automatic welding procedures (MIG, WIG) increase with further temperature increase.
• Laser, plasma welding procedures (tanks, etc.)
• Manual welds allowed as exceptions 3. Nitrogen
Nitrogen blanketing of storage tanks removes the presence
C. Weld Filler Metal of oxygen in the tank atmosphere. This leads to a drop in the
The corrosion resistance is improved when higher alloyed filler oxygen concentration of the water, reducing the redox potential,
metal in comparison to the welded material is used. This also which results in a change in the passive layer.
helps maintain a low delta ferrite content (experience: of the
same kind as basic material). 4. Oxygen
Oxygen facilitates the natural continuous re-passivation of
D. Weld Testing and Documentation the steel surface.
• All welds should be visually examined (naked eye, endo-
scope). A predetermined percentage of the welds should 5. Particle Carryover
be documented with photos, DVD, or video. Possible particle carryover from the water purification equip-
• Examination of the weld formation and any discoloration ment or WFI still into the distribution system can be avoided
should be included. or minimized through proper design.
• An alternate testing method should be set for welds, which
can not be visually examined (X-ray, sample weld before • For example: by avoiding the use of non-alloyed steels for
and after the true welding, etc.). construction or piping material as well as through appro-
priate operating conditions.
Further Documentation: • Further measures can only be defined once the possible
• Risk analysis, sample welds formation mechanisms for ferrous compounds have been
• Weld plan, weld supervision, work instructions, welding fully identified.
procedure qualification
• Welder qualification It is assumed that semi- intermediate- and final products
• “Technische Regel TR 153,“ Gütesicherung von Schweißnäht- (bulk) will pass particle filtration steps during the produc-
en an Apparaten und Rohrleitungen“ issued by the Basel tion process.
Chemical Industry (BCI). Available in German only.

52 PHARMACEUTICAL ENGINEERING July/August 2009

 Water and Steam Systems
6. Ozone -The material is more susceptible to local corrosion
Ozone, frequently used in cold storage and distribution sys- depending on the degree of cold forming; however, this
tems, is thought to favorably effect the formation of the passive isn’t relevant for high purity water systems.
layer on the steel surface. However, ozone concentrations over - Bending pipework is often preferred, due to economic
about 1 ppm can lead to corrosion when chlorides are present reasons.
and standard alloys, such as AISI 304 and 316 are used. • CO2 elimination
- Protecting WFI stills and pure steam generators by
7. Feed Water installing selective degassing steps upstream
A detailed examination of the feed water quality is necessary - CO2 traps can be installed on the product water storage
during the equipment engineering phase to identify possible tanks to prevent CO2 from entering the distribution
corrosion sources. system. The CO2 trap shouldn’t be allowed to collect
The goal is to eliminate iron, manganese, silica, CO2, and moisture as this can cause blockage.
chlorides.
Monitoring
8. Choice of Materials • Visual inspection using sight glasses, inspection pieces, or
The choice of materials is handled in detail under “Choice of opening the pump housing
materials, QC.” • Inline measurement
- Direct quantitative measurement of rouge is not com-
9. Sanitization Process mercially available. Such monitoring technologies are
Since high temperatures support corrosion, the temperature currently in development.
in a given system should be kept as low as possible without • Other parameters and measurements
compromising safe operation. Frequent steam or hot water - Measuring methods for parameters, such as pH, par-
sanitizations could support rouge formation with the tem- ticle quantification and size, and CO2 concentration
perature and time being the deciding factors. Reasonable are available. Their influence on rouging has not been
sanitization intervals should be set based on monitoring results conclusively studied or proven.
(qualification phase, performance qualification, routine).
Service and Maintenance
Design Suggested Procedure
The following design criteria should be critically analyzed A risk analysis is a valuable starting point for the selection
as part of a risk analysis. The focus should be on the effects or determination of measures, which are to be implemented
on the equipment itself, on the operation of the equipment, in the service and maintenance plan. The experience of the
and on the product. operator as well as the previous actions of the engineering
or maintenance and quality control departments also should
• Sanitization and Cleanability be taken into account.
- Drainability The risk analysis should work out which parts of the sys-
- Rinsable pure steam piping, for example, design the tem are critical and define the necessary treatment (to what
condensate piping system in a way in which it can extant, in which intervals, to which time point, and with which
be used to provide circulation during future chemical measures).
treatments (passivation, de-rouging). Figure 1 shows a possible procedure for the development
- Optimization of the cleaning procedure to simplify and of a plant specific service and maintenance plan.
reduce the amount of cleaning agent needed It is generally accepted that suspended particles in low con-
• Allow for removable inspection spool pieces in the piping centrations can be present and will be removed at filters.
- Installation of easy to access spool pieces, such as elbows The usual sample methods based on the Pharmacopeia
or bends at reference points in the piping system where will usually not discover the presence of particles.
rouging is expected The current findings show no influence of rouging on the
- These pieces should be easily replaceable to allow de- mechanical stability of piping and components. It seems
tailed analysis with destructive testing in the lab when prudent to involve all parties, for instance, operator, quality
necessary. control, engineering, and maintenance in the risk analysis
• Demisters in the form of wire mesh should be avoided process. Some of the issues and problems which they will
when possible, due to their large surface areas. Cyclone address are:
separators are acceptable.
• Welds are seen as a risk factor. • What are the possible effects on the product? Is it an API,
Correctly welded seams using WIG-process and with suf- end product?
ficient weld seam protection (inert gas shielded) do not • Can dissolved metallic ions occur (such as ferric ions) and
add to the corrosion risk. what influence would this have on the product?
- Cold bending offers a possibility to reduce the number • Can adherent metal hydroxides occur (Fe-, Ni-, Cr-) and
of welds in a system, particularly for smaller pipe di- what influence would this have on the product?
ameters (i.e., up to DN25). Continued on page 54.
July/August 2009 PHARMACEUTICAL ENGINEERING 53
 Water and Steam Systems
Both on and off-line tests can be used as well as testing
the surface of spool pieces removed from the system.
An inspection plan can be created in order to collect enough
information and empirical test results to allow optimiza-
tion.
The following inspection and evaluation methods can be
defined and used primarily:

• General visual inspection, e.g., through an inspection glass

or with endoscope
- Possible assessment: color (yellow, orange, red, brown,
etc.) or surface finish (dull, shiny, morbid)
• Swab test (results: particles are removable, partly remov-
able, not removable)
• Optical inline measurement
• Particle measurement, online/inline
• Filter: the water is filtered offline at 0.1 µm and the filter
membrane then undergoes laboratory analysis and evalua-
tion, for instance, checking if discoloration or particles are
present. This type of test should be carried out at prede-
termined intervals and the test results should influence
the testing intervals.
• Inspection spool pieces: the following should be taken into
account:
- The piece should be representative of the system in
terms of surface finish, material, etc.
Figure 1. Flow chart risk analysis.
- Critical points in the system
• Are filters in place which would be negatively impacted - They do not necessarily need to be built into straight
by particles? piping segments.
• Can deposits form on measuring probes and sensors? - It is better to use pieces with elbows, valves, or instru-
• If rouging occurs, could it negatively impact downstream ments. Procedure and use of spool pieces:
plants or equipment? à The spool piece is removed during maintenance and
• Are heat exchangers present and could these be negatively is used as a reference which is used as a sample for
impacted? testing different cleaning methods.
• Are components, such as injectors, present whose func- • Electro-chemical methods
tion would be negatively impacted by the presence of
particles? Monitoring data can be regularly evaluated on the basis of
• Further critical parts could be: pumps, instrument ports, the monitoring plan. The results are used defining objective
tanks, valves, spray balls, forged components, vacuum acceptance criteria and specifying the required state of the
molded components. system.
• Are unplanned events expected whose frequency would
influence the availability of a plant, for example, when a Maintenance Plan
cause analysis and subsequent service and maintenance One of the most important goals for evaluating the inspection
measures are necessary after an OOS finding? results is their further use toward development of a system
• Are measures to restore the defined state necessary after specific maintenance plan.
repairs or planned expansions or changes to the system, All results from the inspection, particularly from the spool
such as rinsing, passivation, pickling etc., after welding pieces, should be taken into account in the development of
work has been done? the plan and in determining the steps which are to be taken.
• Could the surface finish be changed by deposits? Will this Depending on the actual situation, the plan can contain the
favor biofilm formation? following points and actions to be taken:

Inspection Program • location of the inspection or actions to be taken

A periodic monitoring program should be established to provide • responsibility
regular controls at the critical points of the system, which • frequency or interval of the inspection or execution of the
were defined in the risk analysis, to collect experience and actions to be taken
information, for instance, through photo documentation. This • experience from previous cleanings, when available
provides the basis for the service and maintenance plan. • execution of a cleaning procedure, when necessary

54 PHARMACEUTICAL ENGINEERING July/August 2009

 Rouge
• For especially critical cases in clean steam systems, a
particle filter can be installed at the point of use. For this
application, a filter size of < 0.1 µm is generally accept- Your Single Source Solution Provider
able. Director Series
• Carbon dioxide absorbers can be used, for instance, on
water storage tanks. Reactor Temperature
Control Module
If the decision has been made that cleaning is necessary, the
following issues should be decided, where appropriate:

• Should a general chemical clean take place?

• choice of the cleaning media (anodic clean, electro polish-
ing)
• definition of success factors, using monitoring methods,
such as conductivity, inspection spools etc., or use of pas-
sive layer measuring device, Ferroxyl test (ASTM-A380)
• definition of cycles and time periods, dependent on pro-
cess
• In the case of older systems, special attention should be
placed when defining parameters to take into account
design, material, and components.

The operator must ensure that the following is met:

• Execution description exists and is accepted.

• Critical parameters, such as the treatment temperature
and soak time are defined.
• The execution is properly documented. Features Include:
• The scope of documentation is defined. � Temperature Range from -80º to +285ºC
• The execution and scope of evaluating if the treatment
was a success is defined. � Stainless Steel Construction
• Procedure or maintenance plan is approved. � Sizes from 20 Liter to 500 Gallon Reactors
Regulatory Aspects � Jacket Delivery Pressure Control
In order to ensure that the current regulatory requirements
� Single Loop or Cascade Control
are understood, it is advisable to keep up to date on the
available audit information (FDA Warning Letters) as well � General Duty or Explosion Proof
as literature and publications. Classification
Should the regulatory agency check how rouging is handled,
� PLC Control, Data Logging & Trending
it should be possible to present and explain how the procedure
defining the maintenance and inspection plan was conducted
Software, Self Tuning for Accuracy ±1ºC
as well as the results.
The operator must ensure that cleaning (derouging), moni- Budzar Industries has specialized in process
toring, etc. is documented. In particular, a treatment report fluid heat transfer systems since 1975 and has
should be available which documents the results (also with earned a global reputation for quality and
photos) and in which all relevant points are systematically ingenuity in the design, engineering, and
addressed. manufacturing of temperature control systems.
Budzar Industries systems are found throughout
About the Authors the world, delivering accurate temperature
The Critical Utilities D/A/CH is a local ISPE Community measurement and control to the production of
of Practice (COP) comprised of individuals from Germany/ pharmaceuticals, chemicals, petroleum, rubber,
Austria/Switzerland with expertise in pharmaceutical water power, steel, food, and plastics.
and steam.
Budzar Industries
Visit the Critical Utilities (CU) COP on the ISPE Web site 38241 Willoughby Parkway
for discussions on other related topics --- Willoughby, Ohio 44094
http://www.ispe.org/communitiesofpractice 440-918-0505 • www.Budzar.com

July/August 2009 PHARMACEUTICAL ENGINEERING 55

 Global Regulatory News
Europe Dealing Regulations SI 2005 No 2789 International
Denmark was replaced by the regulation SI 2009 ASEAN Countries
Defects Medicines – No 1164 in May 2009. GMP Inspection Reports6
Packaging1 Amendments have been made which In April at the Pattaya summit in Thai-
The annual report on product defects affect the labelling requirements for land, a mutual recognition agreement
and recalls for 2008 covering both antiviral medicines for children under was signed by 10 ASEAN countries
marketed and non-marketed medicines the age of one year in a pandemic situ- agreeing to recognise certifications and/
was published by the Danish Medicines ation, allow for notice of urgent safety or inspection reports on good manu-
Agency. This report showed most of measures to be given as soon as possible facturing practice of pharmaceutical
the recalls were issued because of to the licensing authority and an ethics companies within the region.
wrapping defects. Reports on the lack committee during a period in which a All ASEAN member states are
of adherence to good manufacturing disease is pandemic and is a serious expected to fully implement this mu-
practice regulations also were sent to risk to human health, and enable the tual recognition agreement by the 1st
the agency as a result of inspections wholesale distribution of unauthorised January 2011 and the GMP certificates
carried out by various European medi- medicinal products in response to the and reports will be used as the basis
cines agencies. suspected or confirmed spread of health- granting approvals, delivering licenses
The most current defect reported harming substances. to the manufacturer, supporting post
was regarding packaging. Most of the The regulation came into force on 8 market assessments of conformity for
defects were related to packaging or May 2009. products and providing information
repackaging processes and to wrap- on manufacturer facilities or testing
ping – usually plastic – and mainly EudraGMP Database4 laboratories in the ASEAN region.
concerned the printing of incorrect The Medicines and Healthcare prod- In this agreement, the format that
expiry dates on packaging. ucts Regulatory Agency (MHRA) drug regulatory authorities will have
Only five side effects related to implemented a new system that will to follow when issuing the GMP inspec-
product defects were reported in the automatically transfer data from its tion reports is specified. Information on
177 reports filed with the agency. medicines database Sentinel onto the dosage forms manufactured at the
the European database EudraGMP facility and manufacturer compliance
United Kingdom launched in 2007 and maintained by with the GMP requirements will be
Notifying the GLPMA of the European Medicines Agency.1 The captured in inspection reports.
Changes within a GLP Test EudraGMP database was launched Under this agreement, where a
Facility2 in order to facilitate the exchange of manufacturing facility has not been
In April 2009, the Good Labora- information on compliance with good inspected recently, a Member state
tory Practice Monitoring Authority manufacturing practice. can request its counterpart to carry
(GLPMA) released a guidance advising Information on manufacturing and out a specific and detailed inspection.
manufacturers about the declaration importation authorisations and post- The aim of this GMP mutual recogni-
form to the GLPMA that needs to inspection good manufacturing practice tion agreement is to move closer to its
be filled out when there are changes certificates issued by the MHRA will 2015 goal of a single Southeast Asian
made within a GLP test facility. This be automatically published on the market. The agreement will help to
GLP TEST FACILITY form was part of EudraGMP. ensure the safety, quality and efficacy
the risk assessment process settled by The MHRA Director of Informa- of medicinal products manufactured in
the GLPMA in order to ensure public tion Alison Davis said this system will the region.
safety and compliance with the Good ensure the information in EudraGMP Consumers will benefit from greater
Laboratory Practices (GLP) standards. remains current while reducing the confidence in the safety of medicines
Changes to be notified to the GLPMA burden of data transfer. being sold and the business costs of
will be the volume of GLP work un- manufacturers will be lowered by the
dertaken, types of GLP activities Turkey mutual recognition of inspection reports
undertaken, contracting out of GLP GMP5 as they will not be required to undergo a
functions, facilities and equipment, The GMP guideline was revised in repeated testing or certification process
personnel aspects and other changes accordance with the EMEA and ICH for marketing their products in the dif-
such as changes in company owner- Guidelines and the specific condi- ferent member states.
ship or changes to the management or tions in Turkey. It was approved and
organization structure. published on 11 May 2009. During Brazil
inspections performed by the MoH, Manufacturing Resolutions for
GMP – Update to Labeling the manufacturers of pharmaceutical Influenza A Vaccines (H1N1)7
Requirements for Pandemic preparations and active ingredients will The National Health Surveillance
Antivirals3 be required to comply with provisions Agency (ANVISA) issued on 7 May 2009
The Manufacturing and Wholesale of this Guideline. the Resolution RDC 18 for Manufactur-

56 PHARMACEUTICAL ENGINEERING July/August 2009

 Global Regulatory News
ers of influenza A vaccines (H1N1) in pharmaceutical trading hub. ment – for example, validation and
Brazil. An area of approximately 3,700 qualification activities; and to support
This resolution states that the m2 will be allocated for this zone and provision of GMP certification to New
manufacturing of influenza A vaccines among other things, it would include a Zealand's mutual recognition aggree-
(H1N1) in Brazil will be previously cold room facility with varied tempera- ment partners on behalf of New Zealand
authorized in Brazil provided that the ture zones (-20° to 8°C), a comfort zone manufacturers exporting medicines to
following requirements are fulfilled: (with temperatures below 25ºC) for the other countries.
examination of pharmaceuticals, and a Stakeholders were expected to be
• manufacturers hold a Marketing Au- basic testing facility to check samples informed by Medsafe of its final deci-
thorization granted by ANVISA for of pharma products. sion on 15 June and will publish the
manufacturing seasonal influenza Separately, new measures have updated edition of the NZ Code of GMP
A vaccines been initiated by the Indian Ministry on 1 July, which will come into effect
• manufacturing takes place in sites of Commerce and Industry in order to on 1 September.
authorized by ANVISA for the manu- combat criticism from some countries
facturing of influenza vaccines that drugs being exported by Indian Philippines
• the Influenza A viral strain (H1N1) manufacturers do not meet interna- Streamlining Drug Registration
used for the manufacturing is the tional quality standards. Processes9
one issued by the World Health A public notice was issued by the Measures to streamline the registration
Organization Directorate General of Foreign Trade process of pharmaceutical products
to inform new procedures/guidelines to have been proposed by the Philippines
ANVISA will need to be formally noti- strengthen the enforcement mechanism Bureau of Food And Drugs. These mea-
fied by the Marketing Authorization available under the Drugs and Cosmet- sures aim at improving patient access to
Holder/ manufacturer immediately ics Act 1940, to ensure that counterfeit medicines. The use and implementation
after reception of the viral strain for drugs do not get exported from India. of electronic data messages, documents,
production of the vaccine. As per this notification a copy of the and signatures for product registra-
From the reception of the strain, certificate of analysis issued by the tion can be implemented in July if the
the whole manufacturing process of manufacturer for the subject product proposal is finalised.
the vaccine will be under supervision along with other documents will be The proposed measures have been
by a Regulatory Technical Committee requested to every exporter of drugs outlined in the form of a draft admin-
formally established by ANVISA. and pharmaceuticals, at the time of istrative order, which would apply
This resolution came into force on 7 shipment. to all pharmaceutical products for
May 2009. human use (except traditional and
New Zealand herbal medicines). It would also cover
India GMP Code Updated10 all manufacturers, traders, importers,
"Pharma Zones"8 Proposals to change the New Zealand exporters and distributors of these
The Indian Central Drugs Standard Code of Good Manufacturing Practice products.
Control Organisation (CDSCO) is have been announced by the New By this order for a drug not registered
seeking feedback on its plans to create Zealand's regulatory agency Medsafe. with the agency, manufacturing, im-
dedicated climate controlled "pharma Comments on the proposals from porting, exporting, selling, distributing,
zones" within the cargo area of all major Stakeholders were until 15 May 2009. transferring, promoting or advertising
airports and seaports. These proposals aim to bring the New would become illegal. Comments on the
Proper storage and examination of Zealand Code of Good Manufacturing proposed measures were accepted until
pharmaceutical products meant for Practice in line with the international 30 April 2009.
import or export in accordance with GMP codes.
good manufacturing and distribution These updates intend to incorporate United States
practices will be performed in these developments in international codes of OTC – New Labeling for
zones mentioned by the CDSCO. This GMP and developments with respect Analgesics, Antipyretics and
system aims to preserve the quality, to new or improved technologies; to Antirheumatics11
safety and efficacy of pharmaceuticals ensure New Zealand's requirements The Food and Drug Administration
being transported and this will ensure and manufacturers remain up to date (FDA) released on 28 April 2009 final
no cross contamination of medicines in an increasingly global manufactur- rule 21 CFR Part 201 (Final rule) for
with other products. The deadline for ing environment; improve the specific manufacturers of Over-The-Counter
comments on the draft plan was 15 guidance for particular industry sectors (OTC) Internal Analgesic, Antipyretic,
June 2009. - for example, manufacturers of sterile and Antirheumatic (IAAA) drug prod-
In India, the Indira Gandhi Inter- medicines and of active pharmaceutical ucts. Manufacturers of these drugs will
national airport in Delhi will be the ingredients; improve the guidance for need to revise their labeling in order to
first zone to be set up which is a major key components of quality manage- include warnings about potential safety
Concludes on page 58.
July/August 2009 PHARMACEUTICAL ENGINEERING 57
 Global Regulatory News
risks such as internal bleeding and liver References • CDSCO, Presentation on Phar-
damage, associated with the use of these 1. The Regulatory Affairs Journal, ma Zone, 14 May 2009, http://
popular drugs like acetaminophen and May 2009. www.cdsco.nic.in/Pharma%20
nonsteroidal anti-inflammatory drugs DMA, Report: Product Defects Zone.pdf
(NSAIDS) like aspirin, ibuprofen, and Recalls of Pharmaceuticals • Pharmexcil, Circular to mem-
naproxen, and ketoprofen. in 2008, 31 March 2009, http:// bers, Ref: PXL/H.O./CIR-
This new labeling is required for all www.laegemiddelstyrelsen.dk/1024/ 013/2009-10, 14 May 2009,
OTC IAAA drug products whether mar- visLSArtikelBredSkema.asp?artikel http://www.pharmexcil.com/
keted under an OTC drug monograph ID=14893#forfalskede v1/aspx/viewNewsBulletin.
or an approved new drug application aspx?ID=540
(NDA). 2. http://www.mhra.gov.uk • Directorate General of Foreign
According to the rule manufacturers Trade, Public Notice No. 173
must relabel their products within one 3. Published by the Stationery Office, (RE-2008) /2004-2009, 13 April
year to include a warning and ensure http://www.opsi.gov.uk 2009, http://164.100.9.245/
that the active ingredients of these exim/2000/pn/pn08/pn17308.
drugs are prominently displayed on 4. The Regulatory Affairs Journal, htm
the drug labels on both the packages May 2009.
and bottles. MHRA press release, 6 May 2009, 9. The Regulatory Affairs Journal,
This final rule from the FDA is http://www.mhra.gov.uk/NewsCen- May 2009.
aimed at helping consumers to use tre/Pressreleases/CON046496 • BFAD, Streamlined Rules and
these products safely. Regulations on the Registration
5. IEGM (General Directorate of System of Pharmaceutical Prod-
Ongoing Safety Review of Pharmaceuticals and Pharmacy), ucts for Human Use Amending
Botox and Botox Cosmetic12 http://www.iegm.gov.tr for this Purpose Administrative
The FDA published a safety review Order No 67 s. 1989, Issuances
in April 2009 – a follow up to the 8 6. The Regulatory Affairs Journal, Supplementing the same, and
February 2008 Early Communication May 2009. for other purposes, 23 April 2009,
about an Ongoing Safety Review of The ASEAN member states are http://www.bfad.gov.ph/default.
Botox and Botox Cosmetic (Botulinum Brunei Darussalam, Cambodia, In- cfm?isdraft=1&cid=673
toxin Type A) and Myobloc (Botulinum donesia, Laos, Malaysia, Myanmar, • BFAD circular, 21 January 2009,
toxin Type B). Philippines, Singapore, Thailand http://www.bfad.gov.ph/cfc/pdf.
As the result of an ongoing safety and Vietnam. cfm?pdfid=1108
review, the FDA has notified manu- • ASEAN Bulletin, 10 April • Philippines government press re-
facturers of licensed botulinum toxin 2009, http://www.aseansec.org/ lease, 21 May 2009, http://www.
products of the need to strengthen Bulletin-Apr-09.htm#Article-6 gov.ph/index.php?option=com_c
warnings in product labeling, and add • ASEAN, Fact sheet on the MRA, ontent&task=view&id=200061
a boxed warning, regarding the risk of 10 April 2009, http://www. 7&Itemid=2
adverse events when the effects of the aseansec.org/Fact%20Sheet/
toxin spread beyond the site where it AEC/2009-AEC-026.pdf 10. The Regulatory Affairs Journal,
was injected. • ASEAN Sectoral Mutual Rec- May 2009.
FDA also has notified the manufac- ognition Arrangement for good Medsafe, Proposed update to the
turers that development and imple- manufacturing practice (GMP) New Zealand Code of Good Manu-
mentation of a Risk Evaluation and inspection of manufacturers of facturing Practice, 16 March 2009,
Mitigation Strategy (REMS) is neces- medicinal products, 10 April http://www.medsafe.govt.nz/hot/
sary to ensure that the benefits of the 2009, http://www.aseansec. Consultation/GMP%20Review.asp
product outweigh the risks. org/22481.pdf
In addition, FDA is requiring the 11. http://www.Idrac.com; FDA, Medi-
manufacturers to submit safety data 7. The Regulatory Affairs Journal, cines Agency, http://www.fda.gov
after multiple administrations of the May 2009.
product in a specified number of chil- Diário Oficial da União (DOU) No. 12. http://www.Idrac.com; FDA, Medi-
dren and adults with spasticity to as- 85, of 7 May 2009, http://www.in. cines Agency, http://www.fda.gov
sess the signal of serious risk regarding gov.br
distant spread of toxin effects. This information was provided by Frank
8. • CDSCO, General Notice, 14 May Sayala and Rohini Chari, Pharmaceuti-
2009, http://www.cdsco.nic.in/ cal Research Associates (UK).
General%20Notice.doc

58 PHARMACEUTICAL ENGINEERING July/August 2009

 Global Regulatory News

ISPE
Annual Meeting

Thriving In A Survival Environment

8 - 11 November • Manchester Grand Hyatt San Diego • San Diego • California, USA

Eleven Session Tracks:

• Product development • Supply chain management • Quality systems • Suppliers
• Facilities and equipment • Production systems • Project management • Survival-focused
• Information systems • Regulatory compliance • Investigational products

Wa t c h f o r d e t a i l s a n d o n l i n e r e g i s t r a t i o n a t w w w. I S P E . o r g / a n n u a l m e e t i n g .

Exhibit and Sponsorship Opportunities Available

July/August 2009 PHARMACEUTICAL ENGINEERING 59

 ISPE Update

PQLI Tours Asia

A
s a key part of PQLI’s global strat- following the in-
egy spearheading with practical troduction of ICH
implementation examples of ICH Q8, Q9, and Q10
guidelines Q8, Q9, and Q10, interac- in Japan, particu-
tive sessions were held at the Indian larly the status of
Affiliate Annual Meeting in Mumbai the various MHLW
on 13 and 14 April and at the Japan work groups.
Affiliate Annual Meeting in Tokyo on Spavins led the
16 and 17 April. Western team with
A Western team was active at both a presentation on
meetings and included Jim Spavins, the benefits and value to the industry dation and scale-independent design
Vice President, Global CMC, Pfizer Inc.; of conducting enhanced approaches space being very clear winners.
Roger Nosal, Executive Director, Regu- using Quality by Design (QbD). Nosal The Indian organizing committee
latory CMC, Pfizer Global Research; provided Pfizer’s experiences in filing was led by Gopal Nair, under the overall
and Chris Potter, CMC Consultant and QbD submissions and also summarized leadership of Ajit Singh. Nair was sup-
Technical Project Manager for ISPE’s the latest activities of PQLI teams ported by Manasi Baindur from ISPE
PQLI® Initiative. Ranjit Deshmukh, working on Critical Quality Attributes/ India. The PQLI session was chaired by
Senior Director of Wyeth, was a member Critical Process Parameters (originally R. Raghunandanan, Director of ISPE
of the team in Mumbai. Criticality), Design Space, and Control India.
Input was provided by US FDA Strategy topics. Potter provided an In Japan, the meeting organizing
speakers Rick Friedman, Director, FDA/ overview of the PQLI vision and status, committee was chaired by Tatsuro
DMPQ, who discussed global supply discussed the recently published Jour- Miyagawa, Executive Vice-President,
chain challenges for regulators and nal of Pharmaceutical Innovation (JPI) Daiichi Sankyo Propharma, who was
industry, and Tara Gooen, Compliance paper on application of QbD to existing supported by Natsumi Sahara from
Officer, FDA/DMPQ, who discussed the products, as well as summarized a case ISPE Japan. Yoshio Kitazawa, Chair-
recent FDA draft guidance on process study on the application of real-time man of the Japanese PQLI Steering
validation at both meetings. Both pre- release testing to a solid dosage form Committee, co-chaired the PQLI session
sentations were pre-recorded. In Tokyo, provided by AstraZeneca. In Mumbai, with Potter.
Yukio Hiyama, Chief, Third Section, Deshmukh presented a Wyeth case
Division of Drugs, NIHS, presented and study. The recorded version of the PQLI
was part of the Q&A session. Hiyama- In Japan, a vote was held on potential webinar available is at www.ISPE.
san summarized the current position PQLI future topics, with process vali- org/pqli.

Global Regulators and ISPE Members Make for Washington

Conference Success

M ultiple time zones and great distances could not stop

pharmaceutical industry leaders from sharing their
knowledge at ISPE’s Engineering Regulatory Compliance
This seminar brought together a panel of industry leaders
and US FDA regulators to help the pharmaceutical industry
address recent concerns about the integrity of today’s complex
Conference held in Washington, D.C., USA from 1–4 June. pharmaceutical supply chain and to help companies assure
For the first time at an American ISPE conference, select a safe, efficacious drug supply.
content from among its lineup of speakers was recorded and Industry leaders from around the world were also able to
is accessible as downloadable webinars for those industry deliver their content virtually via live Webcasts, during which
professionals who were unable to attend. Content was also on-site and off-site participants could participate in Question
delivered virtually via live Webcasts and live online speaker and Answer periods with speakers located in India and Italy.
presentations. To access the selection of Washington Webcasts Attendees rated these sessions very highly and felt that the
and Webinars, visit www.ispe.org. virtual Q&A exchanges were as good as if every participant
A popular seminar was “Global Supply Chain Integrity was on site.
and Anti-counterfeiting” – co-sponsored by IPEC–Americas.

60 PHARMACEUTICAL ENGINEERING July/August 2009

 ISPE Update
ISPE Strasbourg
ISPE Launches Three New Conference to
Online Learning Product Lines Focus on Managing
Knowledge through
I
SPE has introduced three new Online Learning products: the ISPE 2009
Washington Conference Session series, the Certified Pharmaceutical
Industry ProfessionalTM (CPIPTM) Online Course series, and the Good Science and Risk
Manufacturing Practices (GMP) Online Training Course series.
“With the increased restrictions placed on executive travel, and the demand Assessment
for education remaining stronger than ever, ISPE’s latest Online Learning
offerings will truly accommodate a multitude of training needs in today’s chal-
lenging economy,” said Robert P. Best, President and CEO of ISPE. “Having
access to an expert directly from their desktops is what most pharmaceutical
professionals want, and as the leader in pharmaceutical education, ISPE can
T he ISPE Strasbourg Conference will
be held 28 September – 1 October
at the Palais des Congrès, Strasbourg,
supply that with its expanding library of Online Learning opportunities.” France. The conference will feature the
ISPE has made select sessions from its successful 2009 Washington Confer- following seminars:
ence available as downloadable Webinars. Those industry professionals who
were unable to attend the conference can still benefit from the numerous • Commissioning and Qualification:
global regulators – including those from the World Health Organization and Practical Applications of Science and
the U.S. Food and Drug Administration – who shared their expertise with Risk-based Approaches to Valida-
participants on topics ranging from global supply chain integrity to validation tion
and quality by design.
• Disposables and Containment
“With the increased restrictions placed on executive Technology in Biomanufacturing:
travel, and the demand for education remaining stronger Managing Risk, Reducing Cost
than ever, ISPE’s latest Online Learning offerings will
• GAMP® 5 Operational Aspects
truly accommodate a multitude of training needs in
today’s challenging economy...”
• Barrier Isolation Forum, Innovation
Robert P. Best, President and CEO of ISPE Updates and New Case Studies

The Certified Pharmaceutical Industry Professional (CPIP) Online Course • Investigational Medicinal Product
series provides a broad range of learning opportunities for career growth and (IP) Innovation in a Regulated En-
professional development. The CPIP series of self-directed online courses is vironment
designed for two groups: those pharmaceutical professionals who are hoping
to obtain general pharmaceutical industry knowledge from drug product • PQLI ®: Global Realisation and
development through manufacturing, as well as to those who are seeking Implementation of the ICH Quality
industry-wide recognition of accumulated experience via the CPIP creden- Vision
tial.
Developed in cooperation with the global leader in GMP training, the GMP Training Courses:
Institute, the pre-recorded Good Automated Manufacturing Practice Training
Online Course series is being developed and reviewed by expert instructors • Basic Principles of Computerised
and international regulatory advisors. Each 60 or 90 minute event will pro- System Compliance (GAMP 5)
vide an interactive learning experience that includes a pre-assessment to
identify knowledge gaps, a downloadable course presentation for note-taking, • Cleaning Validation Principles
learning reviews/assessments highlighting important points, links to various
web pages, an online resource handout as a quick reference for all web links
discussed, and a summary of the assessments to gauge knowledge gained. More detailed information
Each of these webinars can be found in ISPE’s Online Learning Catalog, about this event
which features course titles for every recorded ISPE webinar and online course is available at
sorted by topic, title, and area of interest. Each event is led by an industry www.ISPE.org.
leader, subject matter expert, or a member of one of ISPE’s Communities of
Practice (COPs) and is available in a convenient and cost-effective recorded
format at www.ISPE.org/onlinelearning.

Continued on page 62.

July/August 2009 PHARMACEUTICAL ENGINEERING 61
 ISPE Update

Event to
New ISPE Technical Document and
Showcase Webinar Offer Pragmatic Solutions to
Facility of the Maintenance Issues
Year Award
T
he new ISPE Good Practice Guide:

Winners from Maintenance provides current, es-

tablished practices to help achieve

DACH Region technical and regulatory accuracy and

cost-effective compliance whether in a
new maintenance program or reviewing
an existing program for effective strategy

I n the last three years, compa-

nies from the ISPE Germany/
Austria/Switzerland (DACH)
and efficiency. The Guide is intended to be
used as a tool for the development, imple-
mentation, and execution of a maintenance
Affiliate have won many of the
program in a manufacturing environment.
awards presented by ISPE’s Facil-
The Guide is focused on maintenance in
ity of the Year Awards program,
cGMP areas where maintenance strate-
including an Overall Winner
gies, plans, SOPs, and quality procedures
award. To highlight the latest
and policy application are developed.
state-of-the-art developments
Because the Guide was written by a
being implemented by these
group of maintenance professionals from
award-winning manufacturers
many pharmaceutical companies from
and their suppliers, the Facility
around the world – and reviewed by the US Food and Drug Administration – it is
of the Year: Innovation Show-
in fact a benchmarking tool. The key concepts in this Guide can be used knowing
case will be held 2-3 November
that they have general acceptance in the industry.
2009 in Ulm, Germany.
As with all ISPE technical documents, the ISPE Good Practice Guide: Mainte-
nance utilizes a practical, pragmatic, non-theoretical approach, giving the reader
guidance on solving problems and serving as a valuable tool for addressing regula-
tory inspections and compliance issues. Of particular interest in the Guide is the
“Reliability Curve” graphic illustration and the Table of Regulatory Citations.
In tandem with the global release of the ISPE Good Practice Guide: Maintenance,
is the offering of a 60-minute webinar, “Launch of the ISPE Good Practice Guide:
Maintenance.” This webinar identifies how the new guide can provide solutions
for structuring a maintenance program and provides practical tools that will help
ensure quality and compliance of maintenance operations. More detailed informa-
The event will include case stud-
tion on the Guide and Webinar is available at www.ISPE.org.
ies on innovation and background
on the projects, Q&A sessions,
a networking reception, and
site visits to some of the award- Sichuan University Student Chapter Takes on
winning facilities. Presentations
will cover research, development, Glossary Translation
clinical trials manufacturing,
biologics, vaccines, sterile fill/
finish, and oral solid dosage pro- T he ISPE Student Chapter at Sichuan University is still new, but the Student
Members have already completed a major project that will significantly impact
the pharmaceutical engineering industry in China. At the request of the China Af-
duction. Speakers will illustrate
innovative project execution, filiate Steering Committee, members of the Student Chapter agreed to undertake
facility integration, process de- the translation of the ISPE glossary from English to Mandarin Chinese. They began
sign, and operational excellence. work in the middle of January and finished at the end of April. The translation
More detailed information about from A to Z totaled 5,963 words and phrases. In addition, they helped combine the
this event is available at www. material into several convenient groups for upcoming review by industry experts.
ISPE.org. The Sichuan University Student Chapter has 107 members and is led by President
Zhang Yiwen. For more information, visit the ISPE China Affiliate Web site, which
can be accessed through www.ISPE.org.

62 PHARMACEUTICAL ENGINEERING July/August 2009

 ISPE Update

New Knowledge Briefs Published

I
SPE just released the Overview: Regulatory Framework – PIC/S and ICH
Removal of “Use by by Dr. Kate McCormick
Dates” from Clini- This Knowledge Brief provides a basic overview of the es-
cal Trial Material La- tablishment and purpose of these two organizations and
bels in the European PIC/S and ICH publications pertinent to the pharmaceutical
Union by Michael A. manufacturer.
Arnold. This Knowledge
Brief explains how – Packaging Equipment: Slat Fillers
through a risk analysis by James Hills
– IVR/IWR technology This Knowledge Brief provides a basic overview of the general
may be a better alterna- concept and design of the slat filler and addresses several
tive to the conventional considerations important to achieving maximum operational
method of managing efficiency.
“use by dates.” Guidance
is also provided on how to Reducing the Cost of Manufacturing
notify authorities of an by John Nichols
intent to use IVR/IWR This Knowledge Brief provides an overview of how Targeted
technology. Processes, Process Intensification, and Lean/Continuous
Also new and avail- Manufacturing will serve as key techniques and technologies
able is Dry Powder to reduce the cost of pharmaceutical manufacturing today
Sampling and the Containment of Hazardous Com- and in the future.
pounds by Jonathan Lind. This Knowledge Brief provides
a high level review of the requirements for the successful Risk-Based Approaches to Cross Contamination
containment of hazardous compounds associated with dry by Stephanie Wilkins
powder sampling activities. The concepts presented in this Knowledge Brief were developed
Knowledge Briefs are concise, summary documents that from the ISPE Baseline® Guide, the Risk-Based Manufacture
provide general information on issues, processes, and technolo- of Pharmaceutical Products (Risk-MaPP) – A Guide to Man-
gies impacting the contemporary pharmaceutical industry. aging Risks Associated with Cross Contamination, which is
Although it may contain technical content, Knowledge Briefs currently being reviewed by the US FDA.
are written in terms a non-technical reader can understand
and are intended to help industry professionals get up-to- Biotechnology Basics
speed quickly on a particular topic. Each brief includes links Adapted from the ISPE Training Course on Biotech Basics
to additional ISPE resources such as technical documents, This Knowledge Brief provides basic concepts explaining the
Pharmaceutical Engineering articles, webinars, Communities science of biotechnology and how science and process are
of Practice, and educational seminars and training courses combined to lead to the manufacture of a human therapeutic
to provide more specific and detailed information on the product.
subject.
Knowledge Briefs are available for immediate download Commissioning and Qualification of Biopharmaceuti-
(free to ISPE Members, $5 US / E3 for nonmembers) from cal Facilities
www.ISPE.org/knowledgebriefs. The following is a list of ad- The information contained in this Knowledge Brief was ex-
ditional Knowledge Briefs: tracted from the ISPE Baseline® Guide: Biopharmaceutical
Facilities, authored by the Biopharmaceutical Manufacturing
Overview: Regulatory Framework – US FDA Facilities Baseline® Guide Task Team
by Dr. Kate McCormick This Knowledge Brief summarizes the considerations
This Knowledge Brief provides a basic overview of the US FDA's involved in the commissioning and qualification of a biop-
organizational structure and licensing procedures relevant to harmaceutical manufacturing facility.
pharmaceutical manufacturing and regulation.
Quality by Design
Overview: Regulatory Framework – EMEA by John Berridge, PhD
by Dr. Kate McCormick This Knowledge Brief provides and explains the basic ele-
This Knowledge Brief provides a basic overview of the EMEA's ments of Quality by Design (QbD).
organizational structure, responsibilities, and regulations
relevant to the manufacture of medicinal products.

July/August 2009 PHARMACEUTICAL ENGINEERING 63

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64 PHARMACEUTICAL ENGINEERING July/August 2009

 Classified Advertising
Validation Services Vial Traying Systems

Commissioning Agents, Inc., 1515 Hurst Corp., Box 737, Devon, PA 19333.
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Siemens Water Technologies, 10

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For
Sale Advertising Space
Available
Pharmaceutical Engineering
Call ISPE Director
January/February 2009 of Sales Dave Hall
at Tel: +1-813-960-2105.
March/April 2009
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July/August 2009 PHARMACEUTICAL ENGINEERING 65

 Advertiser's Index
Thank You to our Sponsors ACTIVE CHEMICAL.................................... 65

ISPE Washington Conference AES CLEAN TECHNOLOGY........................... 7

Platinum Sponsors
BUDZAR INDUSTRIES................................. 55

CAL-CHEM CORP....................................... 64

CHEM SHOW............................................ 39

Gold Sponsors COMMISSIONING AGENTS........................... 9

CRB CONSULTING ENGINEERS...................... 3

JIM CRUMPLEY & ASSOCIATES.................. 64

Lanyard Sponsor EI ASSOCIATES......................................... 65

ELETTRACQUA.......................................... 11

FARR AIR POLLUTION CONTROL................... 2

Onsite Advertising Sponsor FIKE CORP................................................ 33

GE WATER & PROCESS TECHNOLOGIES...... 25

GEA PROCESS ENGINEERING...................... 31

ISPE Strasbourg Conference GEMU GMBH............................................. 45
Host Sponsor
HACH COMPANY....................................... 41

France Affiliate Networking Event Sponsor HOWORTH AIR TECHNOLOGY.................... 13

HURST CORP............................................ 65

IMA ACTIVE.............................................. 47

IP COP Networking Event Sponsors INTELLIGEN............................................... 15

INTERPHEX............................................... 29

MECO....................................................... 17

MURRAY COMPANY.................................. 27

NNE PHARMAPLAN.................................... 68

PARSONS................................................... 5

PHARMACEUTICAL ONLINE........................ 51

PLASCORE................................................ 35

SIEMENS WATER TECHNOLOGIES............... 21

66 PHARMACEUTICAL ENGINEERING July/August 2009

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Go to where dust and fume pollution meet permanent solutions.
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ISPE’s recognized industry magazine,
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January/February 2010
unique application, or success story that Theme: Process Equipment and Systems
you want to share with your colleagues Manuscripts Due: 4 September 2009
in the biopharmaceutical manufacturing Publishes: 22 January 2010

industry? March/April 2010

Theme: Facilities
Pharmaceutical Engineering is now Manuscripts Due: 3 November 2009
Publishes: 22 March 2010
accepting articles for its 2010 Editorial
Calendar. May/June 2010
Theme: Biotechnology
Manuscripts Due: 2 January 2010
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please visit us on the Web site at
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Manuscripts Due: 3 May 2010
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November/December 2010
Theme: Product Security
The Official Manuscripts Due: 2 July 2010
Magazine of Publishes: 22 Nov 2010
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