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Clean Steam in the Pharmaceutical Industry

Tim Latham, M.Sc., C.Eng., MIChemE.

COURSE CONTENT
1. What is Clean Steam ?
Clean steam is used in the pharmaceutical and healthcare industries in
processes where the steam or its condensate can come into contact with a
pharmaceutical or medical product and cause contamination. In such cases,
steam from a conventional boiler (often called utility or plant steam) is
unsuitable because it may contain boiler additives, rust or other undesirable
materials.
The use of clean steam is determined by the rules of Good Manufacturing
Practice (GMP). These are general rules applicable to pharmaceutical
manufacture, detailed in the Code of Federal Regulations (CFR Title 21, Part
211). They do not provide any specific recommendations regarding steam,
but do present the general requirements of facilities, systems, equipment and
operation needed to prevent contamination of pharmaceutical products
during their manufacture.
2. Uses of Clean Steam
The main use of clean steam in pharmaceutical manufacturing is for the
sterilization of products or, more usually, equipment. Steam sterilzation is
encountered in the following processes :
Manufacture of injectable or parenteral solutions, which are always
sterile.
Biopharmaceutical manufacturing, where a sterile environment must
be created to grow the biological production organism (bacterium,
yeast or animal cell).
Manufacture of sterile solutions, such as ophthalmic products.
Typically in these processes, clean steam is injected into equipment or
piping to create a sterile environment, or into autoclaves where loose

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equipment, components (such as vials and ampoules) or products are

sterilized.
Clean steam may be used for some other functions where conventional
utility steam might cause contamination, such as :
Humidification in some clean rooms.
Injection into high purity water for heating prior to Clean-in-Place
(CIP) operations.
3. Clean Steam purity
Before discussing the purity required of clean steam, it is first worth
discussing the requirements for the purity of water used in pharmaceutical
manufacturing. This is because clean steam purity is often defined by the
purity of the condensate, and this is often referenced to one of the published
water purity standards. Additionally, the parameters by which
pharmaceutical water purity is measured (conductivity, total organic carbon,
endotoxins and microbial content) are those usually used for defining clean
steam purity.
There are statutory requirements regulating the purity of water used in
pharmaceutical manufacture, and two grades of high purity water are defined
in the US Pharmacopoeia, namely Purified Water (PW) and Water for
Injection (WFI). PW must meet a chemical specification for conductivity
and total organic carbon (TOC), and a microbial specification. WFI is a
higher purity water. It must meet the same chemical specification as PW, but
a much higher microbial specification. Additionally, it must meet a
specification for endotoxins, and must be produced by a defined method
(either distillation or reverse osmosis).
TABLE 1 : USP 24 Specification for Water Purity
Purified Water
< 2.1 S/cm at 25 0C
<500 ppm

Conductivity
Total Organic Carbon
(TOC)
Microbial (recommended 100 cfu/ml
Action Limit)
Endotoxin
No requirement
Production Method
Not Specified
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Water for Injection

< 2.1 S/cm at 25 0C
<500 ppm
10 cfu/100 ml
< 0.25 EU/ml
Either distillation or
reverse osmosis

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Microbial content is measured in colony forming units, or cfu this

reflects the test method, in which water samples are spread on plates of
growth medium and incubated, the number of microbial colonies that
develop then being counted under a microscope. The microbial specification
for PW and WFI is set for each system by the pharmaceutical manufacturer,
but the pharmacopoeia guidelines for PW would be 100 cfu/ml, whereas for
WFI it would be 10 cfu/100 ml.
Endotoxins are breakdown products of dead microbes, often
lipopolysaccharides from the cell walls of Gram negative bacteria. They are
also called pyrogens, which is indicative of the main problem that they cause
in patients pyrexia, or fever. The avoidance of endotoxins is therefore
mainly of concern for parenteral pharmaceutical products, which are injected
into the patients.
In contrast to water, there is no pharmacopoeia standard for clean steam (or
any type of steam for use in pharmaceutical manufacturing). A specification
for the purity of such steam must be prepared by each manufacturer, and the
specification must be such that they meet the GMP requirement to avoid
contamination of the product. In theory, there could be a wide range of
different clean steam specifications, applicable to products of different
degrees of purity and different stages of manufacture. In practice, the
pharmaceutical industry has tended to consolidate around specifications
where the steam condensate meets the pharmacopoeia specification for PW
or WFI.
Probably the commonest clean steam specification is that the condensate
meets WFI requirements for conductivity, TOC and endotoxin (The
microbial limit is normally excluded as it is acknowledged that viable microorganisms cannot survive, indeed are killed, in steam systems). The WFIbased specification is used where an endotoxin limit is required, and this is
important for injectables and parenteral products. These are produced as
sterile solutions and, since clean steam is primarily used for sterilization,
they make-up the majority of manufacturing facilities where clean steam is
used.
A specification for clean steam may be based on the PW specification, and
will thus be confined to chemical composition (TOC and conductivity). This
would be appropriate in facilities producing products, or using processes,
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which must be sterile, but where endotoxin in the final product is not a
concern. Example might include some biopharmaceutical processes, or the
production of sterile ophthalmic solutions. Increasingly, processes of some
bulk ingested liquids, such as mouthwashes, is undertaken in steamsterilized plant.
Finally in this section, it is important to discuss nomenclature. Although
Clean Steam has been used throughout this course, and is used in the ISPE
Baseline Guide, it is not used universally, and can have different meaning to
different people. Terms such as Pure Steam, Pyrogen-free Steam and
Low Endotoxin Steam are encountered in the pharmaceutical industry, and
may have specifications that are the same or different to those of Clean
Steam used on other sites. The important point is that each site or facility
must have its own written specification for a grade of steam used in its
processes, and that that specification is appropriate to the manufacturing
process in which it is used.
In March 2000 the Water & Parenterals Subcommittee of the United States
Pharmacopeia established definitions for Pure Steam and Pure Steam for
Injection and recommended inclusion of these definitions in the "Water for
Pharmaceutical Purposes" section of the USP. At the time of writing this
course, that recommendation had not yet been enacted.
You may also encounter the term Clean Steam used for some types of
utility steam for example, it may be used for a type of steam used in food
manufacture, where the boiler additives used are approved by the FDA for
food processing.
Where nomenclature becomes confusing, concentrate on the purity
specification, and from that develop the type of feedwater, generator and
distribution system needed to meet that requirement.
4. Fundamentals of Clean Steam system design
Before describing the details of generator and distribution design, it is worth
reviewing some of the fundamental principles upon which their design is
based.
Avoidance of corrosion
Unlike utility steam, clean steam has no corrosion inhibitors. Also, low
conductivity water or condensate is hungry for ions, causing it to be
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corrosive to many materials commonly used in utility steam systems. Carbon

steel, gunmetal and bronze, all commonly found in utility steam
components, would all be rapidly corroded. Metal components for clean
steam systems are therefore usually AISI 316L stainless steel, or sometimes
titanium. Non-metallic materials used include EPDM and PTFE.
The need to avoid corrosion is not only necessary for safeguarding the
integrity of equipment. Corrosion products entering the clean steam could
potentially cause contamination of the pharmaceutical product, either as
chemical or particulate contamination.
Even where 316l stainless steel is used, a particular form of corrosion, called
rouging, is often encountered in clean steam systems. The passive layer on
the steel surface is disrupted and a red/brown/black film develops over time.
Often this film is stable and does not pose a threat to the pharmaceutical
product. Sometimes a powdery film develops and this can detach from the
steel surface and cause discoloration of equipment which the steam contacts.
If this occurs, and the manufacturer feels that there is a risk of contamination
or discoloration of the product, then the clean steam generator or even the
full distribution system may be cleaned (derouging). A variety of of
methods are used, but they all involve a chemical treatment to remove the
surface layer of steel this is essentially an etching process. After
derouging, a passivation process must be used to restore the passive layer on
the steel surface, since it is the passive layer that is responsible for corrosion
resistance.
Preventing entry of contaminants into the system
Clean steam must be free of contaminants at the point of use. Chemical and
microbial contaminants can enter steam systems in a variety of ways, and in
the design of clean steam systems this must be avoided. Pathways for
contamination include leakage, air being piulled into the system and grow
through from a contaminated external environment.
Preventing microbial growth in the system
Steam at typical operating pressures will kill bacteria and their spores, so the
parts of a clean steam system that are continuously exposed to steam will be
sterile. However, if condensate is allowed to collect in the system, and it
cools, then stagnant water can provide a suitable environment for bacterial
growth. Though these bacteria may be killed when the condensate is
discharged into equipment, followed by steam, their breakdown products,
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including endotoxins, may still be present. Endotoxins are not destroyed by

typical clean steam system temperatures.
5. Clean Steam generation
Generation of clean steam relies on the evaporation of good quality
feedwater. Contaminants remain in the concentrated feedwater within the
generator, and are periodically removed by blowdown. Clean steam
generators are designed to prevent droplets (which may contain
contaminants) being carried forward with the clean steam. Fig. 1 shows an
example of one type of clean steam generator.

FIGURE 1 : Clean Steam Generator (Thermosyphon)

Feedwater
Feedwater must be pumped into the generator, typically at 10 psig above the
operating pressure. The flow is usually controlled by level.
For pharmaceutical manufacturing, it is a regulatory requirement that
feedwater must be derived from water that is drinking quality. It is treated to
remove the bulk of dissolved solids and any hardness and silica, which could
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cause scaling of the generator. A typical manufacturers specification for

feedwater is defined in Table 2.
TABLE 2 : Typical generator manufacturers requirement for
feedwater
Source :
Treatment :
Amines, chlorine and chlorides
Silica
Total hardness
Conductivity

Drinking Water
Deionisation or Reverse Osmosis
Free of amines, chlorine and
chlorides
< 1ppm
< 1ppm
< 5 S/cm

Amines must be removed because they are volatile and could be carried
forward with the steam.
Chlorine must also be removed because it could cause corrosion of a
stainless steel generator. Chlorine is present in water as a biocide, to control
the level of micro-organisms, and its removal may allow microbial levels to
increase. Feedwater treatment must therefore include some other, nonchemical, means of controlling micro-organisms, and often the final
treatment is a membrane process such as reverse osmosis (RO). The
acceptable microbial level in the feedwater is debatable, but clearly gross
contamination could overwhelm the generator. In practice, a microbial
content of less than 500 cfu/ml (the recommended maximum limit for
drinking water) should allow a generator to produce clean steam with
condensate meeting the WFI specification for endotoxin. The ISPE Baseline
Guide states that a typical generator can make a 3 to 4 log10 reduction in
endotoxin from the feedwater level.
It is probably the case that most clean steam generators used in
pharmaceutical facilities are fed with Purified Water. This is a matter of
convenience rather than necessity. PW is much higher purity, both in
chemical and microbial terms, than is required. However, most facilities
using clean steam also need a PW system, the water and steam plant is often
located in the same utility room and the capacity and daily usage of steam
generators is usually much lower than that of the PW system. In some plants
with large steam usage, or which only use WFI, there may be an economic
case for providing a separate feedwater system of lower purity than PW, and
often RO water is used in those situations.
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Heating
Most clean steam generators use utility steam for heating, though for low
capacity systems electric heating may be used.
The utility steam must be at higher pressure than the required clean steam
pressure, in order to provide the temperature differential for heat transfer.
Typically utility steam will be at least 30 psi higher for economic reasons.
The generator design must prevent contamination from the utility steam,
which might occur by leakage at the tubesheet. Usually a double tubesheet
exchanger is provided (see Fig. 2).

FIGURE 2 : Double tubesheet exchanger construction

Generation Pressure
Clean steam pressure is usually defined by the requirements of autoclaves.
Sterilisation in pharmaceutical manufacturing is usually carried out at 121
0
C (equivalent to 15 psig for saturated steam). Typically autoclaves have
their own pressure control valve at the steam inlet, and this has a pressure
drop. Therefore autoclave manufacturers typically demand a supply pressure
of 40 psig or thereabouts.
Lower pressure steam is used for sterilization-in-place (SIP) of vessels,
equipment and pipelines, where there is often no pressure control and
achieving sterilization temperature is entirely dependent on the supply
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pressure of the clean steam. In such cases a clean steam header at 25 psig is
provided (higher pressure/temperature is not only wasteful of energy, but
may have an adverse effect on valve diaphragms and other equipment
components).
Since most facilities using SIP also have autoclaves, often the clean steam is
generated at 40 to 50 psig and a sub-header, supplied through a pressure
reducing valve, is provided at about 25 psig g.
Droplet Removal
The ability of a clean steam generator to remove contaminants is dependent
on preventing droplets of liquid being carried forward in the steam. Different
types of generator use different mechanisms to achieve this.
One type uses a disengagement space and a demister. The evaporation vessel
is made wide (to reduce steam velocity) and long (to allow droplets to
separate) see Fig. 1.
Another type of generator employs a thin film evaporator (Fig.3), in which
the clean steam is channelled through a cyclonic arrangement of baffles in
the annulus of the evaporator. The cyclone increase the distance the steam
must travel and also provides a centrifugal effect, enhancing droplet
separation.
Since droplet removal is essential to generator function and steam is
produced dry and saturated, a separator is not required on the steam
distribution piping.
Filtration is not essential in a clean steam system, as there are no particulates
in the generated steam and correct choice of materials and a suitable
maintenance program should eliminate the risk of corrosion. Some
pharmaceutical manufacturers, fearing the consequence of a damaged gasket
or O-ring contaminating their products, will install a filter at the point of use.

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FIGURE 3 : Clean Steam Generator (Evaporator with cyclone)

Materials of Construction
Most generators have AISI 316L stainless steel contact parts to avoid
corrosion. Titanium is sometimes used.
Blowdown
The concentrated contaminants from the feedwater are removed from the
generator by periodic blowdown. This is usually done on a timed basis, or
may be triggered by conductivity measurement. Typically 10 to 15% of the
feedwater is discharged in this way. The blowdown is hot and may be used
to preheat the feedwater.
6. Clean Steam distribution
They key requirements of a distribution system for clean steam is that it
delivers uncontaminated, dry, saturated steam, without superheat, to the
point of use. The general principles of steam distribution that apply to utility
steam system also apply to clean steam, but there are some significant
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differences, primarily in the materials of construction and, to a degree, the

need for sanitary design.
Materials of Construction
Invariably piping and other contact materials are AISI 316L stainless steel,
to resist corrosion. Lower grades of stainless steel such as 304L are will
suffer more quickly from rouging and may even be subject to other forms of
corrosion. To enhance the corrosion resistance of stainless steel itneeds to be
passivated by a procedure such as that described in ASTM380. Whilst
electropolishing has been shown to reduce the rate of rouging, it is otherwise
of doubtful benefit for a clean steam system.
Removal of Condensate
In utility steam systems, condensate must be removed because it leads to
water hammer, and because it reduces the efficiency of the steams function,
usually heating. In clean steam systems the same factors are present, but
additionally cold condensate can allow the growth of micro-organisms,
which may cause a failure to meet the endotoxin specification.
Removal of condensate relies on :
Pipes sloped to direct the condensate to low points where steam traps
are used to remove the condensate from the system. Typically
horizontal pipes are sloped with a minimum gradient of 1:100. For
long pipe runs, one trap manufacturer recommends placing traps at no
greater than 100 feet apart.
Pipes must be properly supported to prevent sagging, should be
regularly trapped, and steam traps should be placed at the bottom of
vertical risers.
Traps are also placed on branches to user points if these are at a low
point, and especially if they are infrequently used. One neat way of
reducing the number of these traps is to run the clean steam header at
low level, thus allowing condensate that forms in the rising branch to
the user to drain back to the main header, which is itself trapped.
Other deadlegs where condensate could accumulate are designed out,
such as placing instrument branches vertically upwards.
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Traps are used which efficiently remove condensate at or near the

steam temperature. Traps which rely on the physical difference
between steam and water (float traps, thermodynamic traps) are
therefore suitable. That said, there is a particular type of thermostatic
trap, the balanced pressure thermostatic trap, which has been
developed for clean steam systems. It requires only a small temperture
difference to operate, and because of other advantages (good air
removal, resistance to blockage, fails open) it seems to have become
the preferrred choice for clean steam systems.
The system should also be designed to reduce condensate formation,
so adequate insulation is important, especially where clean steam
pipes are run through unheated service areas.
Separators are not essential for clean steam systems, unless some
aspect of poor design has to be addressed. A properly functioning
generator will produce saturated steam without droplet carryover, and
good pipe insulation should prevent excessive condensate formation.
Removal of Air
Air in steam systems should be avoided. If it mixes with steam it reduces the
effective temperature at any given pressure, and consequently could lead to
sterilization failures.
In clean steam systems usually air is removed through the steam traps. For
removal of large amounts of air at start-up, an air vent or air eliminator
(effectively an inverted steam trap) can be installed at the high point on a
distribution system.
Prevention of Superheat
Steam becomes superheated when it is reduced in pressure, such as might
occur when a low pressure header is supplied through a pressure reducer, or
where there is large pressure drop through piping. Energy from the higher
temperature steam released by the pressure reduction raises the steam above
its saturation temperature.
Conversely, there are features in a steam system that act against
superheating. The presence of condensate reduces the tendency to superheat,
as steam endeavours to evaporate the condensate and move back towards a
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saturated state. Also, heat losses from piping cause the steam temperature to
fall, again allowing the steam to move back towards saturation.
In practice, a rule of thumb that pressure should not drop to below 50% of
the absolute supply pressure seems to avoid adverse superheat (for example,
if steam is supplied at 65 psia (50 psig), then the reduced pressure should not
be less than 33 psia (18 psig).
Sanitary Design
Steam at 121 0C kills micro-organisms and their spores. In a well-designed
clean steam system adequate removal of air and condensate will allow the
steam to contact all surfaces, and sanitary design is therefore less important
than it is in PW and WFI systems, or in pharmaceutical process piping.
Historically, clean steam systems were once built using conventional flanged
piping, unpolished, and with conventional stainless steel components. Many
of these systems functioned perfectly adequately.
Modern clean steam systems are usually fabricated from sanitary tubing
(ASME BPE-2002) using orbitally welded joints. Bolted Triclamp
connections are often used for instrument connections or other situations
where welded joints are inappropriate. It could be argued that such a degree
of sanitary design is unnecessary, but tubing is usually less expensive than
pipe, and it is usually convenient to use a standard that is consistent with the
piping used for process and water systems.
A high degree of internal polish is unnecessary for clean steam systems. The
ISPE Baseline Guide recommends mill finish or 180 grit mechanical polish.
Diaphragm valves have achieved almost universal acceptance for PW and
WFI systems, but ball valves are usually used for clean steam. They have
crevices in their internal construction (which may retain contaminants) and
they can retain condensate in their internal cavities. Whilst unsuitable
therefore for sanitary process and water systems, they are adequate for use
where steam provides a constant sterilising effect. A perceived advantage of
ball valves is that their handle position is an obvious indication of valve
position (open or closed), whilst this is less so for diaphragm valves.
Whilst ball valves are considered to be safer and more reliable in steam
applications than diaphragm valves, appropriate PTFE/EPDM diaphragms
are available and some systems utilise these. The diaphragms have to be
regularly inspected and are changed when they degrade, but there are several
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advantages over ball valves diaphragm valves are lighter and require less
support, they are cheaper, and it is often convenient that they can be
maintained by plant operators rather than mechanical fitters.
Sanitary butterfly valves are sometimes used for clean steam. Valves which
hold up condensate or which have many internal crevices or screw threads,
such as gate and globe valves, are usually avoided.
Special components of sanitary design, such as pressure reducers,
instruments and relief valves, are available for use in clean steam systems.
Instrumentation
There are normal operating/maintenance requirments for installing pressure
and temperature instruments in clean steam systems, usually at or near the
point of generation and at pressure reducing stations. Validation of the
system may also demand that these are also placed at the end of long
headers, or at other critical points.
Examples of sanitary components
Line Sizing
Normal economic pipe sizing criteria apply, and often a maximum velocity
criterion of 120 ft/sec is suitable. Pressure drops should be checked on very
long distribution headers to ensure that superheat is not generated, and that
the rquired delivery pressure at the point of use is maintained.
7. Clean Steam Sampling
Sampling of clean steam is achieved by condensing the steam with cold
water. The sampling device may be portable, connected to the steam system
by a hose, or may be permanently installed.
Example of a Portable Sampling Device
Example of Permanent Sampler Installations
8. Condensate systems
The function of the condensate system is primarily to remove condensate
quickly from the system, and it also has a part to play in the removal of air.
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Care must be taken to prevent contamination flowing back from the

condensate system to the clean steam system. Often an air break is used after
the trap to prevent backflow. If an open air break is used, this should be
located where flash steam will not be a problem.
Condensate from clean steam systems is often discharged as waste water,
and is never recycled, untreated, to the generator (it would create a
contamination risk). Heat recovery may be used if the condensate is
produced consistently and at sufficient capacity.
9. Impact of Foreign Regulations
The preceding part of this course has concentrated on US requirements. For
a pharmaceutical facility located in the US producing products for the US
market, or for the small number of countries with which the US has bilateral
agreements, then this is all that is required. However, pharmaceutical
manufacturing typically is aimed at multinational markets and the facility
then must meet the equivalent regulations of those markets. It may also be
subject to inspection by foreign regulatory authorities. In practice, this
should not create many problems with a well-designed clean steam system,
but there are a few points worth noting.
Other national pharmacopoeias exist, and may have differences in their
purity requirements for PW or WFI. For example, the European
Pharmacopoeia, applicable to the countries of the European Community, has
slightly different chemical standards for PW and WFI. They both must meet
specifications for heavy metals and nitrates, and the conductivity
specification is slightly different. These differences should be included in a
clean steam purity specification.
In Europe there is a standard for steam supply to autoclaves (EN285). This
standard gives limits and testing methods for three physical characteristics of
steam, namely dryness factor, superheat and non-condensible gases. A welldesigned pharmaceutical clean steam system should have no problem
meeting these requirements (which were originally defined for hospital
autoclaves using utility steam), but the requirements should be included in a
clean steam specification. Whilst EN285 is only variably enforced in some
European countries, it is a key concern in others. In particular, inspectors
from the United Kingdom will demand that it is met.
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The use of US engineering standards, for piping, pressure vessels etc. would
not be an issue with which the regulatory authorities would be concerned.

10. Validation of Clean Steam systems

A clean steam system in a pharmaceutical manufacturing facility would
normally be classified as a critical system ie. it can have a direct impact on
the purity of the pharmaceutical product. As it a critical system, it needs to
be validated.
There is no universal system of nomenclature, but the following example
includes all the principal activities needed for qualification.
The typical activities of a validation process can be described sequentially as
follows :
Develop a User Requirement Specification (URS)
Develop a Functional Specification (FS)
Undergo Design Qualification (DQ)
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PfQ)
User Requirement Specification
This document defines the users requirements for the system, and is usually
generated by the pharmaceutical manufacturing company and approved by
their QA team.
For a clean steam system the user requirements would include :
The steam purity required, usually defined in terms of condensate
purity (TOC, conductivity, endotoxins), and sometimes including
requirements for saturation, dryness and non-condensables.
Flow, pressure and temperature requirements at point of use.
Relevant standards and legislation which must be met, such as which
national GMPs need to be met, and requirements to comply with
GAMP or 21 CFR Part 11 requirements for automation systems.
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Sampling requirements
Sometimes URSs will include significant detail on the design of a system,
such as valve types to be used, surface finish of piping etc. However, these
items are better included in the FS, which defines how the URS is going to
be met in engineering terms.
Functional Specification
The FS defines how each requirement of the URS is to be met. It is usually
generated by the system designer or supplier. For example, if the URS
included a requirement that :
The clean steam system shall be constructed of materials that are inert, nonadsorbent, resistant to corrosion and do not contaminate the steam.
Then the FS might answer that with a statement listing the product contact
materials to be used, and any specifications with which they must comply,
for example :
Piping will be 316L stainless steel, to ASME BPE-2002 standard etc.
Gaskets will be EPDM, complying with USP requirements for
biocompatability and Code of Federal Regulations requirements for
elastomers (21 CFR 177.2600).
Design Qualification
DQ is a review process, held once the system has been designed and
specified. It allows the design, and particularly the FS, to be reviewed for
compliance with the URS. It is often conducted as a meeting, and is attended
and approved by the QA team of the pharmaceutical manufacturer.
For DQ of a clean steam system the documents reviewed would typically
include :
The Piping & Instrumentation Diagram
The Functional Specification
The specifications for major equipment items (the clean steam
generator), piping and valves
Control System specifications
Documentation requirements for suppliers
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Installation Qualification
IQ is the process of proving that the system has been supplied and installed
correctly, and meets the requirements of the URS and the standards
identified in the FS and approved at DQ. It usually involves the generation
of an IQ protocol, effectively a test and inspection plan for the system.
For a clean steam system IQ the following would be typical :
Assemble documentation on system components, including materials
data, welding documentation, calibration certificates.
Verify compliance of the installation with the P & ID and assembly
drawings, including pipe slopes, valve and trap orientation, deadlegs,
instrument orientation.
Operational Qualification
OQ is the process of demonstrating the correct operation of the system. It
tests not only the correct operation of the system, but also the adequacy of
SOPs
For a clean steam system OQ the following would be typical :
Determine system pressure and temperature at points of use, including
fluctuation between minimum and maximum capacity.
Demonstrate acceptable system capacity.
Modify (if found necessary) and issue initial SOPs for use.
Performance Qualification
PfQ is the process of demonstrating that the system performance is
acceptable when being operated by initial SOPs. It is usually achieved by
testing of the steam and condensate. It is often performed by the QA/QC
team from the pharmaceutical manufacturing organistion. The PfQ protocol
will include sampling requirements (location, frequency and tests to be
undertaken). Specific acceptance criteria will be included.

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For example, a clean steam PfQ might include the requirement to test
condensate from all traps and sampling points, by testing each point once per
week over a period of two weeks. The tests might be defined to include
conductivity, TOC and endotoxin, and the acceptance criteria would be that
all tests meet the relevant USP requirements for WFI.
At the end of PfQ the SOPs will be approved for use.
10. Operation & maintenance of Clean Steam systems
As a critical system in pharmaceutical manufacturing a clean steam system
must be subject to a regular scheme of maintenance and supervision. Key
aspects of this scheme would include :
Ongoing revalidation of the system, including regular confirmation
that the system meets the user requirements. Typically a revalidation
exercise would be undertaken every two years.
Inspection requirements to meet national standards for pressure
systems.
Instrument recalibration
Verification of correct functioning of steam traps
Inspection for rouging, and possible derouging of the generator or the
complete system.

References
1. ISPE Baseline Pharmaceutical Engineering Guide : Volume 4 Water
& Steam Systems (2001).
2. Clean Steam Systems, Tim Latham, in Pharmaceutical Engineering
Vol.15, No.2, March/April 1995.
3. Bioprocess Engineering Systems, Equipment and Facilities, edited
by Lydersen, DElia & Nelson, published by John Wiley & Sons, Inc.
(1994) Chapter 15 Utilities for Biotechnology Production Plants.

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