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Utilities Qualification

The document is a special edition of Utilities Qualification that contains articles on validating utilities systems used in pharmaceutical manufacturing. It includes articles on validating water, HVAC, hydrogen peroxide and other gas systems. The document provides guidance to pharmaceutical companies on qualifying utilities according to cGMP regulations to ensure utilities systems are suitable for their intended uses.

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Utilities Qualification

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UTILITIES QUALIFICATION
Systems: The Basics - Part 1: Design as a Prelude to Validation
4 Water
by Bob Elms and Cindy Green
Systems: The Basics - Part 2: Validation and Maintenance
11 Water
by Bob Elms and Cindy Green
to Validating Purified Water or Water-For-Injection System
21 AbyGuide
Benjamin J. Roczniak
Validation of a Water Purification System: An Inherently Flawed Process?
25 Proper
by William V. Collentro
of HVAC Systems in Pharmaceutical & Biotechnology Facilities - Part I
32 Validation
by Brian Scott, Jeff Hargroves and Jerry Bauers
of HVAC Systems in Pharmaceutical & Biotechnology Facilities - Part II
38 Validation
by Brian Scott, Jeff Hargroves and Jerry Bauers
and Endotoxins: Their Generation and Prevention in Pharmaceutical Water Systems
53 Pyrogens
by Drew Coleman and Douglas Burns
a Water Quality Failure/Incident Investigation
63 Conducting
by Shahid T. Dara
Building Controls Systems
73 Validating
by Jeffrey L. Waters
Report: A Pocket Guide to Auditing Pharmaceutical Water Systems
77 Special
by Graham Bunn
Validation: Validating USP Purified Water, Compressed Air and HVAC Systems
87 Facility
by Jean-Pierre Thiesset
Aspects of Validating Hydrogen Peroxide Gas Cycles in Isolator Systems
99 Key
by James R. Rickloff, M.S.
of Process Gas Systems
110 Validation
by Jeff Hargroves
Water Systems: A System Perspective Under the New USP Quality Requirements
116 Purified
by Tod E. Ransdell
Considerations in Water Purification Systems Validation
122 Management
by Shahid T. Dara
Study of the Design of Production Systems of Purified Water for the Pharmaceutical Industry
130 The
~ Negre and J.R. Tic Grau
by I. Lerin Riera, R. Salazar Macian, J.M. S un
Qualification: Some Practical Advice
149 Autoclave
by Gamal Amer, Ph.D. and Robert G. Beane, Jr.
of Purified Water Systems
153 Qualification
by David W. Vincent

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Special Edition: Utilities Qualification

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52

Special Edition: Utilities Qualification

Conducting a

Water
Quality
This article, based
on various
procedures
developed by the
author over the
years, will provide
an overview of
such an SOP with
special references
to water
quality failure
investigation...

by
Shahid T. Dara
President
COMPLIANCE Consulting Inc.

Failure/
Incident
Investigation

uality systems and procedures are implemented to

minimize quality defects,
with an the aim of creating a
zero-defect manufacturing environment. In reality, there is no
such thing as a perfect system.
Quality defects and failures are
part of any manufacturing operation, and pharmaceutical manufacturing is no exception. cGMPs
require that all quality
failures/incidents should be
investigated, documented, and
corrective actions implemented
to prevent recurrence of the quality defects. Most pharmaceutical
manufacturers have established
detailed procedures on how to
investigate out-of-specification
data originating in analytical laboratory following the Barr Decision. However, there is a need
to have separate procedures to
address other operational quality
issues, i.e., quality failure/incidents. Quality failure incident
investigation procedures offer a
number of benefits, such as:
Standardized investigation
formats
Useful communication and
training tools
Improved processes and
procedures

Long term cost savings

Enhanced overall compliance
Timely resolution of quality
issues
This article, will provide an
overview of such an SOP, with
special reference to water quality
failure investigation, both during
validation and routine monitoring
of the system. Considering the
depth of the subject, this article
will be divided into two sections:
Section I will address general
quality failure incident investigation procedure, and Section II will
address water quality failure
investigation. This article is based
on various procedures developed
by the author over the years.

What is Quality
Failure/Incident?
Quality failure refers to a situation where a finished drug product, process, or service does not
meet its expected attributes or
specifications. Quality incident, on
the other hand, could be a failure
of the quality system practices,
which may or may not lead to a
quality failure of a product, process, or service. Both cases,
however, should be fully investigated and documented.

Special Edition: Utilities Qualification

Shahid T. Dara

Section I
Quality Failure/Incident
Investigation Procedure
A quality failure/incident investigation procedure
should address the following areas as appropriate,
(see Figure 1 for a summarized list):

Figure 1

Elements of Quality
Failure/Incident Investigation
Procedure
Define quality failure/incident
Define quality significance of the failure/incident
Define the cause of quality failure/incident
Facilities
Utilities
Components
Equipment
Process
Drug product
Analytical
Personnel
Quality failure/incident investigation
Facilities
Utilities
Components
Equipment
Process
Drug product
Personnel
Procedures and documentation practices
Corrective action plan
Summary, conclusion, and sign off

Define quality failure/incident

It is extremely important that the quality
failure/incident be defined in a clear and concise
manner, detailing exactly what happened.
Define quality significance of the failure/incident
Most quality failure/incidents can be classified as
critical, major, minor, or for information only. In some
cases, the quality data is also measured against
alert and action limits, e.g., total aerobic count for an
environmental monitoring sample for a given area.
This classification can be a useful tool in determining the extent of the investigation as well as the
scope of corrective actions needed, including disposition of drug product or products involved.
Define the cause of quality failure
A quality failure/incident could be caused by
one or more of the following; however, use the pro64

Special Edition: Utilities Qualification

cess of elimination to narrow down this list as

much as possible.
Facilities
An example of facilities as a possible cause of
quality incident/failure could be improper
cleaning/sanitization of manufacturing areas leading to increased bioburden in the environment with
the potential for drug product contamination.
Utilities
Malfunction of any of the following utility systems can cause a quality failure/incident leading to
a drug product failure:
HVAC system
Water purification system
Compressed air system
Dust collection system
Components
Both chemical raw materials and packaging/
labeling components can cause a quality
failure/incident.
Equipment
Equipment breakdown, as well as improper
cleaning, can lead to quality failure/incident.
Process
Manufacturing process, as well as process conditions, can contribute to a quality failure/incident.
Drug Product
Failure to meet drug product specifications is
the ultimate quality failure/incident.
Analytical
Most analytical laboratory quality issues are
related to analytical data and are usually investigated
according to an out-of-specification (OOS) data
investigation SOP. An OOS investigation will likely
involve some of the aspects being discussed here.
Personnel
Personnel expertise and level of training can
also significantly contribute to quality failures.
This listing should not be considered all inclusive, and there could be other factors involved.
One should review all possibilities and attempt to
define the most probable causes of the quality failure/incident.

Shahid T. Dara

Quality Failure Investigation

A quality failure/incident investigation should
include a review of the following, depending on the
most probable causes. Concentrate on those areas
that may have contributed to a given quality failure/incident. The investigation phase is, in fact,
already underway as the probable causes of a
given quality failure/incident are being defined, and
therefore, the two cannot be totally separated from
each other. Quality Assurance must lead the investigation phase in cooperation with other departments, as these findings will be the basis of any
corrective action plan.
Facilities
If facilities are a possible cause of quality failure/incident, review the state of repair of manufacturing and packaging areas as well as the temperature and humidity conditions in the plant. Also, if
the microbial environment is monitored, the data
for the particular incident should be reviewed along
with data for the past four to six weeks to identify
any adverse trends.
Utilities
If any of the utility systems is a potential cause
for a quality failure incident, review the system in
question in detail. Some items to be checked if one
or more of the following utility systems is under
suspicion:
HVAC System Temperature/humidity profile
of the area and potential temperature/humidity exposure of the components and drug
product(s) involved.
Water purification system Both chemical
and microbial quality of purified water and
water for injection can impact the quality of
the finished drug product. Quality failure investigation for a water purification system will be
discussed in detail in Part II of this article.
Compressed air system Possible presence
of oil droplets in an oil-free compressed air
system can cause contamination.
Dust Collection System Malfunction of a dust
collection system can cause excessive dust in
the area with potential for cross contamination,
especially where conditioned air is recirculated.
Components
Always review the sampling/inspection and
release processes if a component is a potential

cause for a quality failure/incident. Sample manipulation can have potential negative impact on the
quality of the material being sampled.
Both active and inactive raw materials can have
a direct bearing on drug product quality if these
are not of desired quality or their quality is compromised either during sampling process or due to
improper storage conditions.
Packaging/labeling component quality defects
can cause potential stability concerns as well as
mislabeling situations. Almost one-third of all the
drug product recalls in recent years were due to
mislabeling of drug products, per FDA enforcement
reports.
Equipment
If manufacturing/packaging equipment is a
potential cause for a quality failure/incident, review
the following:

Cleaning and sanitization records

Calibration status of critical equipment
Maintenance records
Performance history
Equipment qualification records

Process
Review the manufacturing process in detail to
see if there were any deviations or anomalies. Also
review the process conditions, like temperature,
humidity, machine speed set ups, order of addition
of ingredients, process time limits, etc. A review of
process validation records might well be in order if
considered necessary.
Drug Product
Review other batches of the same drug product
to see if this is a product-specific quality issue or
an isolated incident. Also review batches of related
drug products manufactured under a similar set of
conditions. This will help determine if other drug
products are also involved. This part of the investigation demands extreme diligence on the part of
the quality management team, as it can have farreaching implications. In recent years, FDA has
repeatedly cited pharmaceutical manufacturers for
failure to perform an in-depth investigation of quality failure/incidents.
Personnel
This is an issue that is difficult to measure, as it
tends to indirectly validate the effectiveness of an
Special Edition: Utilities Qualification

Shahid T. Dara
employee training program. Make sure that the
individuals involved in all phases of a given quality
failure/incident have the knowledge, expertise, and
training to carry out their assignments, and there is
documented evidence to support this claim. If not,
an isolated quality failure/incident could be an indication of a major systemic quality problem within
the organization.
Procedures and Documentation Practices
A review of the SOPs, batch records, analytical
procedures, etc., is also required to complete this
investigation. This assures that the procedures are
detailed enough and easy to follow for the operator; if not, revisions might be needed.

Corrective Action Plan

Quality Assurance management, in collaboration with other appropriate departments within the
organization, should develop a corrective action
plan with definite time lines for implementation.
Such a plan should clearly define the responsibilities and accountability profile of assignments and
should include:
Does the incident/failure fall under OOS investigation? If so, is there a need for a separate investigation?
In such cases, the two investigations should
complement each other in resolving the issue.

Identify procedural changes required

Identify documentation to be revised
Identify additional training requirements
Disposition of the drug product(s) involved

Summary, Conclusion, and Final Sign Off

A critical step in the successful conclusion of
any investigation is that a summary report and conclusion is written up. Before finalizing such a report,
Quality Assurance should verify that all the corrective actions have been (or are being) implemented
per their time lines. The effectiveness of completed
corrective actions can be evaluated by verification
that the procedures and systems were revised, and
the employees were retrained by responsible personnel, the new equipment was purchased, or
there was a change in a raw material supplier, etc.
Documentation supporting that a given corrective action was completed should be reviewed
and referenced or attached to the investigation
report, like employee training records, copies of
66

Special Edition: Utilities Qualification

the purchase order, copy of the approved change

control, etc.
The report should be reviewed and approved by
the appropriate departments within the organization. Quality Assurance and other pertinent departments should sign off on the report and sign-off
responsibilities should be delineated in an SOP.
The summary report should be used to inform the
upper management of any critical quality issues,
especially those which would involve capital investments as part of their corrective action plan.

Section II
Water Quality Failure
Investigation Procedure
Water purification systems are designed and
qualified to assure a consistent supply of purified
water of the desired quality. However, despite our
best efforts, a water sample may fail to meet its
specifications.
Water quality failure/incident has far-reaching
implications, as purified water and water-for-injection are widely used in drug product manufacturing
and facilities and equipment cleaning. In Section I
of this article, quality failure/incident investigation
procedure was discussed. Section II of this article,
based on the authors personal experiences in
handling water system quality failures, will provide
a detailed overview of water quality failure investigation procedure, both during validation and routine monitoring of the water purification system.
In order to accomplish a comprehensive investigation of a water quality failure incident, it is important that different aspects of the investigation be
assigned to different departments within an organization according to their expertise. This is especially true if the incident happens during validation
or major revalidation of a water purification system.
The investigation team should include:
Engineering and Maintenance along with
Validation to review the water purification system for physical and functional integrity from
an engineering, as well as, a validation point
of view.
Quality Assurance to review the procedural
and training issues, as well as the drug product(s) involved from a compliance point of
view.
Quality Control to review the chemical and
microbiological testing issues, as well as the

Shahid T. Dara
water sampling techniques.
Drug safety and information to review the
safety concerns to decide the disposition of
affected drug product(s).
The investigation should be led by Quality
Assurance and may also involve Manufacturing if
needed. The investigation team should discuss all
findings of the investigation before designing a corrective action plan and deciding the disposition of
the drug product(s) involved.

Water Quality Failure Investigation

A water quality failure investigation should
address the following areas as appropriate (see
Figure 2 for a summarized list).

Define water quality failure/incident

Water quality failure/incident could involve one
or more of the following scenarios:
Purification system malfunction
Chemical
Microbiological
In most instances, it is the failure of a water sample for chemical or microbiological specifications
which triggers an investigation. Since purified water
is being constantly used in production, there is
always a chance that the suspect quality water might
have been used in equipment cleaning or manufacture of a drug product, thereby putting it at risk.

Define quality significance of the water quality

failure/incident
Water quality failure incidents can be classified as
critical, major, minor, or for information only, depending on the nature and severity of the incident. For
microbiological tests, the quality data is measured
against alert and action limits, e.g., total aerobic
count for a purified water sample. If the water sample
fails pH specification or total organic carbon (TOC),
and the purified water was used to manufacture a
solid oral dosage, the impact on quality, strength,
identity, and safety of the drug product will be much
less if the water sample fails for microbiological specifications and is used to manufacture a liquid or sterile drug product. This classification can be a useful
tool in determining the extent of the investigation as
well as the scope of corrective actions including disposition of drug product(s) involved.

Figure 2

Elements of Water Quality

Failure/Incident Investigation
Define water quality failure/incident
System malfunction
Chemical
Microbiological
Define quality significance of the water quality
failure/incident
Define the cause of water quality failure/incident
Purification system
Sampling
Analytical issues
Quality failure/incident investigation
Purification system
Source water
Pretreatment
Purification system
Storage and distribution
Controls, alarms, etc.
Sanitization cycle
Sampling
Sampling procedure
Sampling technique
Sample container prep
Analytical procedures
Instruments
Analytical procedures
Analyst training
Sample prep
Media prep and tracking
Drug product/s involved
Personnel
Procedures and documentation practices
Corrective action plan
Summary, conclusion, and sign off

Define water quality failure/incident

Water quality failure/incident could be caused
by one or more of the following; however, try to
narrow down this list as much as possible.
Purification system
Each water purification system is designed per
individual plant requirements but does have so
constants which should be looked into when investigating a water quality failure/incident.
Source Water
Quality of source water as supplied by local
water authorities changes with the time of the year
and geographic location of the plant. Microbial
quality and the total dissolved solids in source
water play a vital role in determining the capability
of a given water purification system. Source water
Special Edition: Utilities Qualification

Shahid T. Dara
test data should be part of the validation file for a
given water purification system. Sudden changes
in source water quality can cause purified water
failure, especially after natural disasters like floods.
Source water test data from the local water authority and in-house periodic source water test results
should be reviewed to determine any sudden
change in source water quality. This review should
also indicate any trends that might be developing
over recent weeks, especially after heavy rains or
floods in the area, as they can affect the composition of natural water reservoirs.

Water Softeners or Deionizers

Water softeners or deionizers are used to
remove the heavy metal ions from source
water to avoid scaling downstream during the
purification process. Deionizing resins need to
be regenerated periodically, and the regeneration process should be controlled to assure
that a deionizer tank does not sit idle for long
periods of time after regeneration, as it could
promote microbial growth. If such a tank is
used in water purification, it might overburden
the system and the water produced could fail.

Pretreatment
Source water is pretreated to minimize the level
of both organic and inorganic impurities before
water is actually processed through the final purification step. If pretreatment steps are not precisely
controlled and routinely monitored for performance
within preset limits, these could cause quality failure of the water produced.

Carbon Filter
Activated carbon filters are used to remove dissolved chlorine and other gases from source
water, along with organic materials before water
is subjected to the final purification process.
However, carbon filters can promote microbial
growth and, therefore, foul the downstream
components. Frequent monitoring and sanitization of carbon filters should be carried out to
prevent this situation. Nonetheless, carbon filters can be a cause of water quality failure.

Chlorination
Chlorine is added to the source water to
decrease its bioburden. It also helps to minimize microbial growth in the pipes and storage
equipment. Local water authorities usually add
a chlorine gas generating chemical to water to
produce 1 2 PPM of chlorine gas, like
sodium hypochlorite. However, there is a downside to the presence of chlorine in water, as it
tends to corrode stainless steel surfaces and
will deteriorate reverse-osmosis membranes. It
is, therefore, very important that chlorine be
removed from water before it actually reaches
the purification and storage stage.
However, if there is insufficient or no chlorine in
the source water, the purification system downstream may not be able to remove all the microbial contaminants, thereby causing a quality failure of the water produced.
Depth Filters
Source water is passed through a series of
coarse filters to remove suspended solids. The
filtration media could be different grades of
sand. However, such filters tend to harbor
microbes and should be periodically backwashed to remove all the trapped waste. If left
unsanitized, these filters could contaminate
the water with microbes, causing failure of the
water produced after purification.
68

Special Edition: Utilities Qualification

Purification System
Deionization
Deionization is not considered an acceptable
water purification process by FDA to produce
water-for-Injection (WFI); however, it is used to produce purified water. Cation, anion, and mixed bed
resins are used to remove ionic impurities from
source water. The quality of these resin beds can
be monitored by determining the conductivity of
effluent water. A sudden increase in effluent water
conductivity indicates that a resin bed needs to be
regenerated. Ion exchange resin tank regeneration
should be controlled, and regenerated tanks should
not sit idle, as this can promote microbial growth.
Also, if there is a leakage of sodium ions from a
cation exchange resin, the water produced will have
a higher pH, greater than 7.0.

Reverse Osmosis
Reverse osmosis membranes are efficient water
purifiers when used in series. However, these can
harbor microbial growth, as they are chlorine sensitive and, therefore, can produce water of suspect
quality. Also, if the membranes are not periodically
backwashed, these would become overloaded and
let organic and inorganic impurities pass through.
Distillation

Shahid T. Dara
Distillation is the method of choice for producing
WFI, assuming it is a continuous process. If, for some
reason, the system is idle for a period of time, the
feed sections of the still can become dead legs and
promote microbial growth. On start up, if used unsanitized, this could produce WFI with high endotoxins.
Storage and Distribution
Storage tank, distribution piping, and associated
controls are critical to maintaining the quality of the
water being produced. If there are leaks in the system, these could contaminate the entire system.
Likewise, the vent filter on the storage tank should
be checked for integrity and also to see that it is not
harboring any microbes in the condensate, as both
could compromise the quality of water. There should
be a procedure in place for changing the sterile vent
filter on the storage tank. Many times, water quality
is compromised by the addition of foreign material
during filter changeover. Typically, filter change is
followed by a complete sanitization cycle. The
heating and cooling system is another critical part
of this puzzle, as the water quality is totally dependent on its storage temperature before it is used.
Sanitization process
Water purification systems are periodically
sanitized to remove any biofilm and organic build
up on different water contact surfaces. If a chemical sanitizing agent is used, there is potential for
residual chemicals in the purified water, unless
the system is thoroughly flushed and drained.

areas believed to have contributed most to a given

quality failure/incident.
Source water
Source water test data from the local water
authority and in-house periodic source water test
results should be reviewed to determine any sudden changes in source water quality. This review
should also indicate any trends that might be
developing over recent weeks, especially after
heavy rains or floods in the area, as they can affect
the composition of natural water reservoirs.
Pretreatment
Review all pretreatment steps to see if the quality of source water was compromised at any stage.
Also check for any leaks or malfunction of any
alarms, controls, or autoregeneration of deionizing
tanks, etc.

Chlorination
Review the source water data to see if there
was sufficient chlorine in the water. Also, review
the residual chlorine level of pretreated water processed downstream, especially in case of a
reverse osmosis water purification system.
Depth Filters
Check the backwash records to see if the depth
filters were backwashed and sanitized per requirements, as these can cause both microbial and
chemical contamination of the water being purified.

Sampling
Water samples are drawn during validation and
routine monitoring of a water purification system.
This step is very critical and can cause water
quality failure if sampling procedure(s) are not
strictly adhered to. Details will be discussed in the
investigation section of this article.

Water Softeners or Deionizers

Review the regeneration procedure and schedule for water softener and deionizing tanks to
detect any deviation, especially if the tanks were
sitting idle for a long period of time after regeneration, promoting microbial growth and thereby causing contamination of water.

Analytical issues
Both chemical and microbiological testing have
their own set of variables which could cause a
water sample to fail. It could be the instrument,
sample prep, or the procedure. Details will be discussed in the investigation section of this article.

Carbon Filter
Review the monitoring data for post carbon bed
to see if there was any proliferation of microbes,
which could have contaminated the system downstream.

Water quality failure investigation

Water quality failure/incident investigation
should include a review of the following, depending
upon the probable cause. Concentrate on those

Purification System
Deionization
Review the regeneration procedure and schedule for cation, anion, and mixed bed resin tanks to
detect any deviation, especially if the tanks were
Special Edition: Utilities Qualification

Shahid T. Dara
sitting idle for a long period of time after regeneration, thereby causing microbial contamination of
water. Also, the conductivity data for effluent water
should be reviewed to determine if the tanks were
changed as per schedule and not totally exhausted
before replacement.

Sanitization process
Review the water purification system sanitization procedure and frequency to determine if they
could be contributing factors in water quality failure, especially when residual chemicals or high/low
pH values are detected.

Reverse Osmosis
The reverse osmosis membranes should be
checked for integrity if these were exposed to high
chlorine source water. Also, the membrane backflushing procedure should be reviewed to determine
if it is effective in removing all the build up. The
reverse osmosis system sanitization procedure and
frequency should be checked to see if they need
any revisions, both in procedure and frequency.

Sampling
Draw multiple water samples on a daily basis
during validation and routine monitoring of a
water purification system. The sampling procedure and the individual samplers technique are
key to obtaining uncompromised water samples.
While investigating a water quality failure/incident,
the sampling process should be scrutinized in
detail. Review the following to determine if there
is any chance to compromise the integrity of the
sample:

Distillation
Ensure that the system was in operation per
approved specifications. If there was a shutdown,
was the system sanitized before start up? Check
that all the alarms and controls are functioning and
within calibration. Look for any dead legs in the
system as potential breeding grounds for microbes.
Storage and Distribution
Check the storage tank, distribution piping, and
all points of use for leaks or other physical defects.
Examine the vent filter on the storage tank for
integrity and to see if it is harboring any microbes
in the condensate. Check the heat exchanger and
chiller controls for proper function to assure the
water is maintained at its desired storage and circulation temperature.
If plastic pipes are used, like PVDF, etc., these
should be checked, as they tend to sag over time,
leading to potential dead legs and, therefore, could
promote microbial growth. The drain pipe from the
storage tank should have at least a two-inch gap or
twice the pipes diameter, whichever is greater,
between the pipe and the floor drain to prevent
back siphon of floor drain.
Controls, Alarms
Todays water purification systems have a number of controls and alarms to operate the system
within specifications while controlling the costs.
One should review all the controls and alarms in
case of a water quality failure/incident to see if they
are functioning properly and are within calibration,
where applicable.

Special Edition: Utilities Qualification

Sampling procedure
The sampling procedure should be reviewed to
determine the level of detail and clarity of statement for a nontechnical person to understand it.
Also review the training requirements spelled out in
the SOP and audit training records.
Sampling technique
If sampling is a potential cause for water quality
failure, QA should review the sampling technique
and perhaps have a microbiologist watch the individual sampler conduct the actual sampling under realtime conditions. This will provide a wealth of information as to the effectiveness of sampling technique
as described in the sampling procedure and how
people are trained. The sampling procedure should
simulate actual practice when the system is used to
draw water for manufacturing or cleaning activities,
i.e., flush the system for 10 seconds before withdrawing water, etc.
Sample container prep
Water sample containers are specially prepared. Microbiological samples are taken in sterile
containers, while chemical samples are taken in
containers which have been specially cleaned and
rinsed with WFI to minimize contamination. While
investigating a water quality failure/incident, one
should also review the sample container prep practices. This could involve reviewing cleaning procedures and any studies done on these containers
after cleaning to determine the effectiveness of the
cleaning procedure. If presterilized containers are

Shahid T. Dara
obtained from an outside vendor, obtain access to
the vendors sterilization procedure and supporting
validation documents. Nonsterile sample containers have been blamed for false failures of water
samples.
Analytical issues
Chemical and microbiological tests are usually
performed by the quality control laboratory, and
this phase of investigation is best accomplished
if a chemist and a microbiologist are asked to
review different aspects of the analytical work. In
particular, the following should be closely examined:
Analytical instruments
Review analytical instruments to determine if
they are within calibration and performance limits.
Also check for any unusual repair or maintenance activity that might have affected the performance of the instrument.
Analytical procedures
Analytical procedures should be reviewed for
both chemical and microbiological testing to determine if there are any issues and if the procedures
adequately guide the analyst in a step-by-step process to execute the test.
Analyst training
Review training records for the analyst to make
sure he/she was qualified to perform the test under
review.
Sample storage and preparation
Water samples are usually transported to the
quality control laboratory, where they might sit for
a while before testing is conducted. Review sample storage conditions as well as the time elapsed
before testing was performed. Some companies
refrigerate water samples upon receipt and may
test them after 24 hours or so. This practice
should be discouraged, as it could result in suspect data. Also, review the sample preparation
techniques in the laboratory to assure that they do
not compromise the integrity of the sample.
Testing time limits
Water samples should be tested as soon as
they are received by the quality control laboratory.
However, if the company has a practice that allows
the samples to be stored for a limited time before

analysis, review the records to determine if the

samples were tested within the time limit.
Media preparation and storage
For microbiological testing, media preparation,
storage, and expiration dating issues are critical in
defining the success or failure of a test. Review
media preparation procedures as well as the expiration date assigned to a given lot of in-house prepared media to assure that it is used within its
expiration date. Other issues to be considered
when reviewing microbiological testing should
include:
Incubation conditions
Qualification status of incubator
Use of positive/negative controls
Isolation and speciation of the microbial
contaminants
Drug product(s) involved
As part of the investigation, the drug product(s)
manufactured with suspect water should be
reviewed to determine if the safety, quality, and
efficacy of the drug product has been compromised. The following points should be considered
in this review:

Dosage form of the drug product involved

Route of administration
Therapeutic class
Presence or absence of a preservative system in the drug product
Safety history of the drug product(s)

Personnel
This part of the investigation should determine if
there are any deficiencies in the training program
and if the people are qualified to perform their
assignments.
Procedures and Documentation Practices
All the procedures and documentation
involved should be reviewed to see if there is
need for revisions, or new procedures should be
prepared to supplement ones already in existence. Also, a determination should be made to
assess whether all critical data is being reviewed
by the appropriate people to make critical decisions (if needed).

Special Edition: Utilities Qualification

Shahid T. Dara

Corrective Action Plan

Once all the facts are known, Quality Assurance
should develop an appropriate corrective action
plan in consultation with other departments. The
corrective action plan could involve one or more of
the following, depending upon the cause of the
water quality failure/incident:
If the water purification system is operating
within specifications, additional water samples should be taken from source water, storage tanks, and all points of use for three to
five days and the system released if all samples meet specifications.
If part(s) of the water purification system
need to be replaced, a determination should
be made if this change is covered under system parts change program or if it would
necessitate a requalification of the system.
Revise water sampling procedures and
retrain employees.
Revise the analytical procedures.
Recalibrate the instruments, etc.

Summary, Conclusion, and Sign-Off

A summary report should be prepared detailing
the water quality failure/incident, probable or definite
cause, corrective action plan, and disposition of the
drug product(s) involved. Such a report should be
prepared by Quality Assurance and reviewed and
approved by appropriate members of management.
The investigation report, along with a summary,
should become part of the water purification system file. However, a brief management summary
might be prepared to inform upper management if
the situation so warrants.

Special Edition: Utilities Qualification

Validating Building
Controls Systems
By Jeffrey L. Waters
Landis & Staefa

hy should a company
These recommendations must
validate its Building
be interpreted and implemented by
Controls System? Tothe individual facility operators,
Environmental
days international competition and
but other industry guidelines are
wary consumers mandate some kind
more specific. The ASHRAE 1995
control in drug
of quality control in almost every
Handbook HVAC Applications
industry. Voluntary compliance with
(pg. 13.8), [for chemical] Labmanufacturing
the International Organization for
oratory Ventilation Systems, states,
facilities
has
drawn
Standardization (ISO) is one of the
Minimum ventilation rates are
hallmarks of many successful busiincreased attention generally in the range of 6 to 10 air
nesses. The ISO 9000 standard is
changes per hour [ACPH] when
from the FDA in
even recognized by the Food and
occupied. Actual air change rates
Drug Administration (FDA) in
may be significantly higher in labs
the 1990s.
its internet file (ftp://ftp.fda.gov/
with a high concentration of fume
CBER/ misc/cgmp.txt). The princihoods. For example, a 30-by-50ples and practices elucidated in the
foot lab with 10-foot ceilings
ISO standards are not in conflict with those provided
(15,000 square feet) containing 10 fume hoods
by the cGMP (current Good Manufacturing Practices) exhausting 1000 cubic feet per minute each (a total
regulations, the FDA states in the file. Indeed, the
of 10,000 CFM) would experience a ventilation
voluntary ISO standards share common principles
rate of 40 ACPH. On the other hand, labs with a
with FDAs cGMP requirements.
single fume hood or bio-safety cabinet may require
Environmental control in drug manufacturing
supplementary general exhaust ducts to provide
facilities has drawn increased attention from the adequate air changes. Simple mechanical Constant
FDA in the 1990s. The cGMP (21CFR 211.46), last
Air Volume (CAV) systems are less expensive to
modified in 1995, says in part:
install and start up, but a computerized Building
Controls System (BCS) provides dynamic control
(a) Adequate ventilation shall be provided.
and monitoring of parameters such as air pressure
(b) Equipment for adequate control over air presand humidity. Variable Air Volume (VAV) controls
sure, micro-organisms, dust, humidity and tem- minimize energy usage by reducing supply and
perature shall be provided when appropriate for exhaust flow when fume hoods are closed or the
the manufacture, processing, packing, or holdfacility is unoccupied.
ing of a drug product.
Air filtration in most critical applications is pro(c) Air filtration systems, including pre-filters and
vided by High Efficiency Particulate Air (HEPA) filparticulate matter air filters, shall be used on air ters. Strict specifications (such as Military Standard
supplies to production areas when appropriate.
MIL-F-51079B for fire resistant biological filters)
Special Edition: Utilities Qualification

Jeffrey L. Waters

business sense to make

sure the facility operates as designed to
Work Flow
ensure quality products
Hardware and Software Change Control
are consistently produced.
IQ
OQ
PQ
Sean Chuckas, LanValidation
dis & Staefas operaProtocols (CDS) Calibration
tions manager for valiDevelopmental Processes
dation, explains it this
Commissioning
way, Aside from the
(SOPs)
risk to the life and
Point-to-Point
Start-up
health of employees,
Checkout
the cost of product failure due to not meeting
define the properties of a HEPA filter. The National quality standards can be very high. Years ago,
Sanitation Foundation requires (in its NSF-49 stan- humidity, pressure, and temperature were not considdard for biohazard cabinetry) that aerosol penetra- ered part of quality control. Today we realize that
tion not exceed 0.01% at any point on the filter, so
production yield is boosted by controlling the enviNSF-49 certified HEPAs are at least 99.99% effi- ronment. Its not just the process (that must be valicient. Pre-filters (to prevent loading the more expen- dated).
sive HEPAs) are simple bag or box filters that trap
Now that we have established the necessity of
dust and large particulates such as animal hair. validating HVAC equipment, it is vital to understand
Alternatives for less critical applications include the difference between commissioning environmenHigh Efficiency filters (95% efficient), and charcoal tal controls and validating their performance. A
filters for organic vapor or odor control.
chart will help explain the difference.
The cGMPs have governed drug manufacturing
The purpose of Figure 1 is to show the work flow
facilities since 1963. According to the FDAs World
in a linear fashion while separating the Validation
Wide Web site (www.cgmp.com), proposed changes
Protocols (contained in the Controlled Documents
may require construction of separate facilities and System) from the Commissioning Process.
control systems for highly toxic agents:
Standard Operating Procedures (SOPs) are used in
Penicillin has long been subject to specific the commissioning of everyday projects. After the
cGMP regulations designed to reduce the danger of
HVAC mechanical equipment and controls are
cross-contamination. Because other substances installed, the process should begin with a point-to[cephalosporins, cytotoxic anti-cancer agents, and point check-out of every component (i.e, verifying
infectious agents] pose at least as great a risk of tox- that every input and output device is connected to
icity due to cross-contamination, FDA is proposing
the proper terminals). The jagged line on the chart
to expand the contamination control requirements. represents the ups and downs of a typical construcSection 211.240(b) would require dedicated production project. A method that reduces cost and time is
tion, which may include facilities, air handling, or
utilization of commissioning documentation to supprocess equipment, in those circumstances in which port validation. For example, commissioning checkcontaminants pose a special danger to human or anilists can be referenced in the Installation Qualmal health.
ification (IQ). According to Sean Chuckas, The
Fear of FDA intervention certainly is a com- alternative is to do them separately and duplicate a
pelling reason for a company to validate its environlot of paperwork. If calibration is required, the promental controls. Accomplishing business goals may
cedures and documentation must be referenced in
be a better reason. According to Landis & Staefa val- the validation protocols.
idation consultant Irene Miess, It just makes good
Once Installation Qualification is satisfactorily
Figure 1

Special Edition: Utilities Qualification

Jeffrey L. Waters

completed, start-up of the HVAC system can begin,

and then sealed behind drywall during construction,
in accordance with the companys SOPs. The
calibration will be a very expensive and time-conmechanical equipment must be up and running
suming process. RTDs, which can be calibrated in
before Operational Qualification (OQ) can begin.
place and have field replaceable parts, may be more
This is where verification that the various mechacost effective in the long run even though the initial
nisms operate as intended must be done (for examcost is higher. If the software change control proceple, when the room thermostat calls for heat, does
dure requires re-validation with every minor modifithe hot water valve open?).
cation, updates will be very difficult and costly. One
Performance Qualification (PQ) must be carried should remember that the maintenance staff must
out by the owner. This is where verification is done
live with the change control procedures for the life
to insure that all systems work together under asof the facility. Flexibility should be built in, and subused conditions to meet the User Requirement contractors also must be trained on proper proceSpecification. Do room temperature, humidity, and
dures. Change control procedures should address
pressure stay in spec with production under way and
such issues as scheduling and documentation of
people entering and leaving the facility? All systems
maintenance, and re-certification of calibrated senmust be operational to complete PQ.
sors. How will one insure that a calibrated sensor is
Cooperation between the various contractors
available if one fails, or that the control program
(mechanical, controls, etc.) is vital to completing PQ in
changes stick to standard formats? This is the nature
a timely and cost-effective manner. Sean Chuckas
of Building Control System Change Control.
stresses, The owner and the designer must sit down at
The following quote from the Proposed Changes
the beginning of the project and determine critical [valfile of the cGMP web site emphasizes the FDAs
idated] and non-critical areas. You dont want to waste
viewpoint: To preserve the validated status of a proresources and dollars validating non-critical areas.
cess, measures must be taken that will allow any sigTo help make this determination, one should ask, Which
areas are critical to the producCooperation between the various
tion and storage of the product? and validate only those
contractors (mechanical, controls, etc.)
areas. If more than one building
is vital to completing PQ in a timely
will be constructed, all processes
that must be validated by Good
and cost-effective manner.
Laboratory Practice (GLP) or
Current Good Manufacturing
Practice (cGMP) should be segregated to the same
nificant process changes to be recognized and
building, and non-critical facilities housed in the
addressed promptly. Such change control measures
other. If critical and non-critical areas are mixed can apply to equipment, standard operating procewithin the building, the critical processes should be
dures, manufacturing instructions, environmental
segregated to one area. Do offices, research-and conditions, or any other aspect of the process system
development-labs, storage areas, and corridors really
that has an effect on its state of control, and therefore
need to be validated? And finally, are only the rooms
on the state of validation.
critical, or should the HVAC equipment be validated
An auditor must be able to evaluate the current
as well (air handling units, filters, temperature senstatus of a facility based on the owners documentasors, etc.)? One should be sure to coordinate these
tion, and compare it to the specifications, but the
decisions with the supervisors of each affected area.
processes also have to work smoothly and allow
Hardware and software change control also must
improvement. Irene Miess has this advice for anyone
be addressed early on, because it will affect the
responsible for validated processes; The owner
entire process. If thermistors are specified (they should get involved as early as possible and look at
must be replaced when they are out of specification)
what the desired end result will be, not just the corSpecial Edition: Utilities Qualification

Jeffrey L. Waters

rectness of the specification. The User Requirement

Specification is not always exactly what he wants,
and what he wants is not always what he gets.
Some aspects of validation are unique to HVAC
control systems. Sean Chuckas elaborates,
Although the controls are one of the last things to
go in on new construction, they must not be
planned last. The owner must make many decisions before the controls are installed and there
should be meetings early in the process. Quality
cant be tested into a process. It has to be designed
into each system.
The HVAC controls for critical (validated) areas
should be grouped in specified field panels. One may
want to label these panels, Critical Process Controls:
Please follow Change Control Procedures, or something similar. This will prevent the necessity of having to validate non-critical controls.
Electric and other utilities must also be evaluated.

One may need an Uninterrupted Power Supply

(UPS) for critical field panels and PC workstations
to continuously monitor critical equipment such as
refrigerators, incubators, and particle counters
with the Building Controls System.
When choosing an HVAC controls vendor, one
should have experience in the validation process
as a prerequisite. A close working relationship
can save time and money beyond the initial cost
of installation. Irene Miess sums it up thusly, A
primary criterion for choosing a building automation vendor should be the ability to provide support for the life of the facility. Their attitude
should be, We dont walk away after commissioning.

What are you working on Today?

We want to hear about it!
The Journal of GXP Compliance and the Journal of Validation Technology are looking for readers to share their expertise. Industry needs more practical information.
All papers submitted are
reviewed by a panel of industry
experts. The contact information for
each author is included with each
article. If you are interested, please
fill out this form and fax it to the
Institute of Validation Technology,
Phone: 218-740-7028,
U.S. Only: 888-524-9922
and fax: 218-740-6308 or send us
an e-mail: [email protected].

Name: _______________________________________________
Title:_________________________________________________
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Address: _____________________________________________
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Special Edition: Utilities Qualification

A Pocket Guide to

uditing a
Pharmaceutical Water System
Control of water
production and its
usage are critical
in producing
a product . . .

by
Graham Bunn
Manager, GMP Audit
AstraZeneca

harmaceutical water may

be the only utility from a
facility to be administered
to a patient. Even if the water is
removed in processing the water,
it is still regarded as a raw material and has the potential to leave
impurities in the product. As with
all raw materials of a product,
the water must meet predefined
specifications but, unlike other
raw materials, it may be used as
it is produced. Some systems
produce water on a batch basis
which is tested and released, for
use, but others continuously feed
water to a storage tank. Water is
also used in many different
cleaning processes, and, if contaminated, could affect multiple
batches. Control of water production and its usage are critical in
producing a product that meets
predefined specifications and
regulatory expectations.
The pocket checklist included
with this guide is designed for
two audiences. The first is the
user of the system and those
who have responsibility for maintenance and testing of the system. The list may be used as a
proactive tool on a periodic basis
to identify and monitor changes

which may have occurred but

were overlooked for documentation requirements or procedural
changes. It should be modified
and updated as necessary to
support the system and maintain
a state of compliance with current Good Manufacturing
Practices (cGMPs).1 The second
audience is the auditor, who may
use the list as a reference point
on which to base an audit while
leaving the specific details to the
individual.
Procedures and problems
encountered in the microbiology
laboratory are outside the scope
of this article but can be found in
Guide to the Inspections of
Microbiological Pharmaceutical
Quality Control Laboratories
(FDA 1993). An introduction to
regulatory requirements of water
systems can be found in the
Guide to Inspection of High Purity
Water Systems (FDA 1993).
This pocket guide is intended
to provide a baseline for auditing
water systems. It is not an allinclusive list of possible items
and areas to be examined. The
content should be adapted and
updated as necessary for individual systems and situations.

Special Edition: Utilities Qualification

Graham Bunn

Documentation
All systems require complete and accurate documentation including qualification, maintenance,
change control, investigations, and analytical/microbiological results to provide evidence that the system is in a state of control. Documentation should
be checked against the SOP requirements applicable at the time the work was performed and against
current industry standards. The current revision of
the schematic diagram must accurately reflect the
actual system and be authenticated by a suitably
qualified person. The auditor can use a copy of the
diagram as a checklist during the tour. The date of
the diagram should correlate with the last change
control if physical changes were made that required
changes to the diagram. A typical water system is
shown in Figure 1.
The following documentation and SOPs can be
requested for review in the audit conference room:
Maintenance records for system components.
These must be completed in compliance with
the SOP requirements and provide a complete record.
Qualification documentation (installation,
operational, and performance). The qualification must be performed against a suitably
approved protocol before the initiation of the
work. The results must meet predefined
acceptance criteria or be adequately justified.
Change control log and supporting documentation. The dates that the system was
approved for use should be compared to any

manufacturing dates in batch records. The

water system must be approved for use
before it can be used in the manufacturing
process. Outstanding requests for change
controls may indicate that there are alternative reasons for the delays. If the changes
were not performed, the potential impact on
the integrity of the system should be
assessed.
Chemical and microbial testing raw data and
trend reports. Compare the data against
release documents, and check that the trends
are being suitably monitored and the necessary people informed of the results.
Out-of-specification results. The laboratory
out-of-specification investigations should be
reviewed against the SOP requirements. They
must be of a suitable depth, and the conclusions must be supported by adequate data
and information. Documentation is required to
support any follow-up actions with defined
time lines.
Manufacturing requirements will determine the
water quality and capacity requirements of the system. Supply of water-for-injection (WFI) to a large
manufacturing site will have different physical
requirements than the purified water supplying a
small solid oral dosage pilot plant. A note should be
made of the manufacturer, and model numbers of
components of the system for comparison against
the validation protocol and change control requests.
During the facility tour, the general conditions of the
areas should be observed. Excessive water on the

Figure 1

Basics of a Typical High Purity Water System

Filtered City
Water

UV 254 nm

Softener

Circulation
Loop with
Points of use

Acid

Steam
Jacketed
Storage
Tank

Special Edition: Utilities Qualification

Reverse
Osmosis

UV 254 nm

Mixed Bed
Ion
Exchange

Cationic /
Anionic
Exchange
Beds

Filter

Graham Bunn
floor and especially from leaking pipes is cause for
concern. This is the first indication of the care and
attention the area receives from the maintenance
staff. Some of these areas are operated and maintained to a high standard. In a larger facility this
may be maintained by the dedicated engineering
staff compared to the smaller unit, which may be
supported by other staff, but cGMP requirements
are the same irrespective of the water being produced by the system. Area and equipment log
books may be requested at this time, as it is sometimes more useful for the auditor to examine these
in situ. This also enables assessment of the individuals responsible for the areas in their own environment. The SOPs applicable to the individual plant
areas should be easily accessible so that users can
refer to them whenever necessary.

Generation
Resin bed cartridges sent to a contractor for
regeneration should be dedicated to the company
to minimize any potential for contamination from an
unknown user. Any chemicals used in the system
for sanitization, regeneration of resins, etc., must
be adequately stored, labeled, and as with any
component of a pharmaceutical product, quarantined, tested, and released for use by Quality
Control. A note of readings on gauges and digital
readouts should be made for future reference and
checked against operating ranges in the qualification documentation. Any readings that appear to be
at the upper or lower end of the ranges or are fluctuating erratically should be investigated further. All
major components of the system should be examined for general condition and appearance.
Excessive leaking or rusting are an indication of a
problem area, which warrants further investigation
and explanation.

Distribution and Storage

During the walk-through, the auditor should ask
general questions concerning the frequency of
changing resins, sanitation, filter changes, integrity
testing of vent filters, and general cleaning of
areas. The appropriate individuals should be asked
how the frequencies were established and what
documentation supports the justifications. There
must be no place in the distribution pipes where
water can remain stagnant and provide the opportunity for microbial growth. These segments of pip-

ing, often referred to as dead-legs, are found

where changes in the distribution have been made
or in the removal of a section of the loop. Hard piping of equipment without a non-return valve and
drainage of isolated piping back into the system
can also cause similar problems.
A suitable number of the points of use and the
environment around them should be examined.
Points of use requiring tubing must not provide the
opportunity for water to be siphoned back into the
system and cause contamination. The classic
example of this is the tubing reaching into a sink
below the overflow level. Equipment joined directly
to the water source has the potential to allow
water to re-enter the system (back-flushing) and
cause possible contamination. One-way flow
valves minimize the possibility of this occurring.
Air breaks are essential to ensure that there is no
possibility that waste water discharged to a drain
can possibly be siphoned or forced to enter the
system or pieces of equipment from back-flow. All
piping in the generation plant must be suitably
labeled with a description of the contents and
direction of flow.
Points of use must also have clear labeling to
ensure there is no confusion in the water quality
delivered from the outlet. Multiple outlets labeled
water are major problem areas, especially when
potable and WFI may both be available in an
equipment cleaning area.
An explanation of the procedure and any physical controls should be requested when two storage
tanks are released individually on a batch system
by QC. There must be adequate controls in place
to ensure that only water that has been released
can be used. This may only administered by QC or
by QC providing documentation to another group
(engineering). It should be determined if water has
ever been released for use before all testing has
been complete. If this was allowed, it is defined as
manufacturing at risk if the water was used as a
component of a product. Manufacturing at risk is
not permitted under the cGMPs and has been
clearly explained by the Commissioner in the
preamble to the cGMPs.2
Major maintenance work on the water system
may be performed annually when the entire plant
is closed for scheduled maintenance. There must
be SOPs describing the procedure for decommissioning (i.e., stopping the production of water) and
then bringing the system back to its original qualified state again. This must also include the quarSpecial Edition: Utilities Qualification

Graham Bunn
antine and subsequent testing against an
approved protocol with predefined acceptance criteria and ultimately release for use by QA.

Sampling and Testing

At the beginning of the audit, it would be beneficial to inquire if daily water sampling is being performed. If possible, the sampling process should
be observed in conjunction with the sampling SOP.
The internal auditor is able to request this at relatively short notice in their own facility, as they
would have performed background checks to
determine the collection times. A contractor should
have no problem with the auditor observing the
process if they are confident that the sampling is in
a state of control and compliance with SOPs. The
samplers name should be noted so that the individuals training records can be requested and verified later.
Procedures used by operators to draw water
from the system should be observed where possible, with special attention to the flushing time/volume before usage. The time/volume should be
defined in an SOP and concur with those samples
taken for chemical and microbial testing. A longer
time/larger volume before sampling will create a
bias for a more favorable result. This is because
any potential contamination is sent to waste in
sampling but, in practice, would have been added
to the product. The handling process of the water
samples should be followed to ensure that it complies with the SOP requirements. The process
must be validated and include container type and
storage of the samples which are not tested within
a set time frame. The container surface must not
add anything to or remove any constituents from
the water while it is awaiting analysis. The key is
to minimize any influences so that they are
insignificant and that there is evidence to support
this conclusion.

Summary
Water systems are complex and one of the critical components in a sterile manufacturing facility.
Failure of any part of the system could cause multiple problems and potentially result in a product
recall. Adherence to SOPs, strict maintenance of
change control, and clear definition of responsibilities will assist in minimizing potential problems.
Meeting expectations of this guide and checklist
80

Special Edition: Utilities Qualification

Water Systems Terms

Activated Charcoal: Used to remove odor,
chlorine, and some organics.
Adsorption: The process of physical, not
chemical, adherence to a surface by particles,
colloids, or molecules.
Bactericide: A substance capable of killing
bacteria.
Bacteriostat: A substance which inhibits bacterial growth and metabolism but will not necessarily kill the cell.
Chlorination: The addition of chlorine in a
concentration of about 0.2 to 2 ppm to render the
water bacteriostatic.
Conductivity: The ability of a substance to
conduct electricity. Measurements are in
microSiemens/cm.
Deionization: The process of removing ionized salts from water using ion exchange resins.
Ion exchange is the preferential adsorption of
ions from water for equivalently charged ions
which are held on resins.
Endotoxin: A lipopolysaccharide found in the
cell walls of viable and nonviable bacteria which
is a heat-resistant pyrogen.
Hardness: The amount of calcium and magnesium salts.
Limulus Amoebocyte Lysate (LAL): A
reagent derived from horseshoe crab blood used
for the detection of endotoxins (pyrogens).
Mixed-bed resin: Both cation and anion resins
mixed together for the deionization of water. The
bed is usually used to polish the water.
Pyrogen: A substance, e.g., endotoxin that
will induce fever in mammals.
Resistivity: The ability of a substance to
resist the flow of electricity. Measurements are in
megaohms/cm.
Reverse osmosis: The application of pressure across a semipermeable membrane so as
to produce purer water on one side of the membrane and a more concentrated solution of ionized salts on the other.
Total Organic Carbon (TOC): The concentration of the carbon bound as organic compounds.
UV light: Ultra violet light at 254 nm used to kill
bacteria and destroy ozone in the water system.

Graham Bunn
will not ensure that your facility will not receive an
FDA form 483. Auditing is based on education,
experience, competency, and instinct. It cannot
solely be taught in the classroom but also has to
be learned by practical application.
Good luck in passing your next inspection as I
may be the auditor at your door.

References
1. Current Good Manufacturing Practice for the
Manufacture, Processing, Packaging or Holding of
Drugs; General. 21 CFR part 210. Current Good
Manufacturing Practice for Finished Pharmaceuticals.
21 CFR part 211.
2. Preamble, 1978 GMPs: Federal Register, 29
September 1978 (Vol. 43, No. 190, pp. 45013-45336).

The opinions expressed in this article are those of

the author and are not related in any way to employers, either past or present.

Literature Sources
1.

Guide to Inspections of Microbiological

Pharmaceutical Quality Control
Laboratories. (FDA 1993).
USP, current edition.

The Auditors Pocket

Checklist for
Pharmaceutical
Water Systems Follows

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The Auditors Pocket Checklist for Pharmaceutical Water Systems

Facility:
Address:
Audit Date(s):
Auditor(s):
Product(s):
Water Quality

General Audit Requests

Request the following information from facility management, if applicable:
History of business and corporate affiliations.
Establishment Registration Number.
Organizational chart with names and titles of key management.
Facility floor plans.
List of products manufactured in the facility.
Results of FDA inspections since last audit or, if an initial audit, for the previous two years. Also
request companys responses.
Master File, if applicable.
Quality Manual.
Complete SOP list.

Yes, No, NA
or Information
Feed Water
What is the source for the plant water (city or private supply well ground water,
or surface water)?
Is source water entering the facility, whether from a municipal supply or a private
well, tested for microbiological contamination, and what are the specifications?
Is coliform bacteria testing performed according to 40 CFR 141.14; 141.21?
Is source water entering the facility tested for chemical contamination, or are
municipality reports provided?
Does the water meet the EPA specifications for potable water?
What is the frequency of testing?
If the results are provided by the water supplier, are they reviewed and approved
by a suitably qualified user?
What actions are taken if specifications are not met?
If the water is being tested by the user, is a written SOP describing sampling
and testing available?

Special Edition: Utilities Qualification

Graham Bunn

The Auditors Pocket Checklist for Pharmaceutical Water Systems

General Water System Requirements
What water purification system is used?
Is the system a one-way flow (i.e., not recirculating)? These are more
problematic and difficult to maintain as they are basically a dead leg.
What is the velocity of the circulating system (6 fps recommended)?
What is the temperature range of the water in a recirculating system (normally
65 to 80 C), and how is this monitored?
What is the temperature of the water in the tank?
Is the tank storage time less than or equal to 24 hours for room temperature
batch processing?
Is there a continuous temperature recorder and controller for each storage tank?
How often is the tank vent filter integrity tested and checked for condensate
blockage?
Is the vent filter a hydrophobic 0.2 um?
What type of tubing is used? (316L Stainless Steel piping is common in WFI and
purified water. Some plastics (e.g., PVDF can also be used but must be
checked for compatibility.)
Is there acceptable documentation/video of the stainless steel welding and
unique identification of each welded joint?
Is there a copy of the welders certification and the welding procedure on file?
Are there any dead legs or potential areas where air can become trapped or
where water can stagnate?
Does the system contain screw-threaded fittings instead of the required
sanitary fittings?
Does the system contain ball valves or other fittings that can possibly retain
water from the main system and cause potential microbial problems?
Does the heat exchanger, with the exception of a double concentric tube or double
sheet tube, have a greater pressure on the water system side than the coolant?
Do any of the use points in the system have 0.2 um filters (FDA prefers no in-line
filters)? Actual water microbial counts may be masked by filters.
Review water sampling results for at least six months preceding and two months
following the manufacture of lots selected during the audit. If specifications were
not met, review investigation and corrective actions. Are the results, investigations,
and corrective actions acceptable?
Are the sampling locations and frequency of testing suitable for the system?
Who performs sampling for the chemical and microbial samples?
Check that the sampling personnel are adequately trained and the training
is appropriately documented.
Are chemical and microbial results being trended? Are the results acceptable?
Have changes been made to the water system since the last audit? Since the
system was initially qualified? If major system changes have occurred, have
the changes been evaluated for the need for re-qualification?
Are any pumps only used periodically? These can be a source of bacterial
contamination from stagnant water.
Are thorough and complete records of the system cleaning, passivation, and
maintenance maintained? The records should include who performed and
supervised the cleaning, date, cleaning agents used, pH, conductivity, and
microbial results.
Special Edition: Utilities Qualification

Graham Bunn

The Auditors Pocket Checklist for Pharmaceutical Water Systems

What chemical sanitization is used, and is it adequate?
How often are the reverse osmosis membrane seals checked for integrity to
prevent bypass and contamination?
Is there a maintenance program for the reverse osmosis to prevent membrane
fouling and integrity failure?
If resins are regenerated on site, what SOP is followed?
Are the ion-exchange beds tested microbiologically and chemically after
regeneration?
What is the quality of the regenerant chemicals? Are they released by
QC before use?
Is regeneration of the cation/anion/mixed-bed resins documented?
If the resins are regenerated off site, does the manufacturer have written
certification that the units have been used for treatment of water in only
systems such as this?
Are cation/anion/mixed-bed resins regenerated, or are virgin resins always used?
Has the correlation between in-line and laboratory testing for conductivity and
TOC been established?
What is the minimum output of the UV light in the system before
replacement is required? (normally 40-50% of original)
What wavelength of light is used? (254nm; germicidal, 185nm; TOC reduction)
Is there a maintenance program for the UV lamp, especially cleaning of
the lens to maintain effectiveness?
Are the established specifications and corresponding action and alert levels
suitable and based on historical/statistical data?
Have any vendors supplying products for the system been qualified?
Are any of the components controlled/monitored by a computer or programmed
logic controller? If so, has the system been validated?

Water For Injection (WFI)

Is the water prepared by distillation or reverse osmosis?
Is clean steam (free of additives) used to generate the WFI?
How is the feed water treated prior to the distillation? Is the source water
chlorinated, carbon treated, deionized?
Is endotoxin testing performed on the tank, pre/post-final treatment step and
points of use?
What is the level of endotoxins from the feed water, and is it appropriate to
feed the still or reverse osmosis? (Stills normally only affect a 2.5 to 3 log
reduction in endotoxin content.)
Is the system in a state of control and producing water of a quality suitable
for its intended use?

Special Edition: Utilities Qualification

Graham Bunn

The Auditors Pocket Checklist for Pharmaceutical Water Systems

Documentation
Water board testing results at regular intervals according to SOP
Microbial and analytical test results
Are these acceptable or acceptable with investigations and corrective actions?
Are sampling plans defined which include a defined purpose and evidence for:
Verification of quality attributes in treatment, distribution, and points of use?
Supporting the compliance profile?
Gathering validation samples?
Verifying continued quality of source water supply?
Is trending of results done, and does it indicate anything?
Installation Qualification
Approved protocol?
Meet acceptance criteria?
Operational Qualification
Approved protocol?
Meet acceptance criteria including daily sampling after each step of the purification
process at each point of use for two to four weeks?
Are the operational SOPs approved?
Repeat testing as above.
Performance Qualification
Approved protocol?
Meet acceptance criteria including: WFI sampling one point of use
each day with all points tested weekly. Complete a year of testing
and meet specifications?
Change control requests
Review decision where revalidation of the system was not performed.
Were these justifiable?
Does the level of testing relate to the type of change made?
Was water used before the final approval of the documentation? If so, why?
Quality investigations relating to the system or any water-related problems
Note any open investigations that have not been closed within 30 days. This
must be defined in the SOP. Why are they still open, and is senior management
aware of the situation?
Are the investigations adequate?
Were the corrective actions suitable and effective in preventing repeat occurrences?
Is trending done and reported to senior management and QA on a regular basis?
Are problems of a similar/same type being reported more than once?
(This could indicate a more serious underlying problem.)

Special Edition: Utilities Qualification

Graham Bunn

The Auditors Pocket Checklist for Pharmaceutical Water Systems

Area, equipment, and maintenance log books
Are the SOP requirements being met?
Are the books complete?
Calibration records
Select equipment and examine the records. Are outside vendor records
reviewed and approved by suitably qualified personnel of the company
owning the equipment?
What actions are taken when a result is out of calibration?
SOPs:
Operation and maintenance of the system
Sampling and handling
Change control
Review content and completeness
Do the SOPs reflect actual procedures observed or being documented?
Batch release SOP (if applicable)
What documentation is required to release the batch?
Who physically releases the batch and how?
Are batches ever used before receiving the quality release documentation?
Shut Down and power failure
Current Specifications
WFI
For sample volumes of 100 to 300ml.
Microbial > 5CFU/100ml alert level. >10CFU/100ml action level.
(Note: These may vary by company).
Conductivity
Stage 1: Uncorrected for temperature or carbon dioxide. Sample limit is
1.3S/cm. On-line method.
Stage 2: Carbon dioxide and temperature corrected. Sample limit is 2.4S/cm.
Stage 3: Utilizes a sliding pH scale to determine conductivity acceptability.
Apparent Total Organic Carbon 500ppb limit response.
Endotoxins <0.25EU/ml.

Purified Water
Microbial >50CFU/ml alert level. >100 CFU/ml action limit. (Note: These may
vary by company).
Conductivity
Stage 1: Uncorrected for temperature or carbon dioxide. Sample limit
is 1.3S/cm. On-line method.
Stage 2: Carbon dioxide and temperature corrected. Sample limit is 2.4S/cm.
Stage 3: Utilizes a sliding pH scale to determine conductivity acceptability.
Apparent Total Organic Carbon 500ppb limit response.
Note that water usage may direct the appropriate specification e.g., antacids
do not have an effective preservative system and require an action limit commensurate with their formulation.
86

Special Edition: Utilities Qualification

Facility Validation
Validating USP Purified Water, Compressed
Air and HVAC Systems
By Jean-Pierre Thiesset
Alcon Laboratories, Inc.

acility validation is a tremendous task in which many

different processes and
pieces of equipment must be considered.
The processes addressed within
this article include:

A validation plan
does not necessarily
need to be an
all-encompassing
100-page
document.

A United States Pharmacopoeia (USP) purified water system that produces USP purified
water for use in component and
final product cleaning. This water
is not used as a constituent of the product itself.
A compressed air system, which generates oil
free air, used in manufacturing processes to blow off
components and final products. This system also supplies compressed air to manufacturing equipment.
A heating, ventilation and air conditioning
(HVAC) system that controls temperature, humidity
and differential pressure for a class 100,000 controlled manufacturing environment (CME).

Successful facility validation requires organization, attention to the different systems and processes
one-at-a-time, and patience. It is important not to try
to complete the validation before it starts.
The first step is forming a validation team. The
importance of assembling a team that includes all
interested parties at the beginning of the project is
obvious. At a minimum, this team should include, representatives from facilities, manufacturing, quality,
validation engineering and information technology.

The next important step is developing a validation project plan. This

will not decrease the amount of work
to perform, but it will significantly
contribute to successful validation.

Validation Project Plan

A validation plan does not necessarily need to be an all-encompassing 100-page document. A

more concise document, which
clearly states the projects purpose,
the validation approach, and the overall acceptance
criteria may be more useful. A validation project
plan should be developed so that it serves as a road
map. It ensures that each required task has been executed as planned. Specific qualification protocols,
which contain the detailed testing, can be developed
separately for each piece of equipment.
An effective validation project plan must contain:
1. Validation project plan number, subject and
approval blocks.
2. Project purpose.
3. Project scope.
4. Facility and system: Define what the system
does (system description and intended use)
and how the system does what it is required to
do (design description).
5. Project responsibilities: Define project manager/leader, team members and their respective responsibilities.
Special Edition: Utilities Qualification

Jean-Pierre Thiesset

6. Planning and organization: project goals, objectives and expected benefits, project organization, constraints, impact on existing systems
and operations, proposed time line and major
milestones.
7. Validation methodology: broad overview of
the validation approach to be taken.
8. Validation responsibilities: consider the suppliers responsibilities as well as those of the
validation team.
9. Validation procedure. Installation Qualification (IQ), Operational Qualification
(OQ) and Performance Qualification (PQ)
requirements. List the specific protocols
which must be implemented, (usually one
per system, or one for each specific IQ, OQ
and PQ). Note: List only major tests that
must be included in each qualification. It is
not necessary to provide explicit detail
within the scope of this document. (The
detailed procedure for executing a qualification of a particular system will be specified
within a specific protocol for that qualification).
10. Validation deliverables. These might include
supplier qualification, operational procedures,
process documents, preventive maintenance
schedules for each piece of equipment, training plans, and other documentation.
11. Acceptance criteria. List the acceptance criteria for the validation project plan.
12. Attachments. It may be helpful to use a check
sheet format that contains the list of specific
protocols to implement. This section should refer to supporting documentation, such as drawings, flowcharts, and Gantt charts.

tem. A multi media depth filter which filters the city

water with an automatic backwash system when
pressure drop exceeds a predefined value. This filter
removes particulate matter greater than 10 microns.
A carbon filter removes organic contaminants and
chlorine from the water by absorption.
A deionized (DI) water production system. A
cation/anion unit removes dissolved ions in the
water by ion exchange. First, the water passes
through a strong acid cation exchanger, (cation
exchange resin regenerated with acid HCl). Then,
the water flows through a strong base anion
exchanger, (anion exchange resin regenerated with
caustic soda NaOH). When the resistivity of the
water after the cation/anion unit is lower than a predefined value, a regeneration cycle is triggered. A
one micron filter completes this DI water production system.
A water temperature maintenance and distribution system. This system includes: a sanitary pump,
a hot water generator for sanitizing, an ultra violet
(UV) disinfecting lamp, a 0.1 micron filter, a bank of
three parallel mixed polishing beds, a one micron filter, a second UV disinfecting lamp, a second 0.1
micron filter, and two distribution loops which are
connected back to the sanitary pump.
A monitoring system. The resistivity of the
water is monitored at several points in the system
ensuring that the water delivered by the system is
greater than a predefined value, and a system of yellow and red indicators alerts maintenance technicians and users if resistivity goes below this predefined value.

After the project plan is approved, the team can

begin executing the plan.

The most difficult part of a USP purified water system validation is not the OQ, but the IQ. An important
part of a quality USP purified water system resides in
its architecture, piping, valves characteristics, and
installation method. Knowing that, it becomes evident
that the validation must start even before the first pipe
is installed by the choice of the right company to perform the soldering, installation and verification.
It is recommended that vendor selection criteria
include a requirement for the vendor to provide a
quality assurance plan for the project. Their plan

USP Purified Water System Validation

This system is described as two stainless steel piping distribution loops which provide continuously recirculating, ambient temperature, USP purified water
to manufacturing areas. This system consists of:
A supply water (city water) pretreatment sys88

Special Edition: Utilities Qualification

USP Purified Water System

Installation Qualification (IQ)

Jean-Pierre Thiesset

Figure 1

Classic Installation Qualification (IQ) Testing

Test #
1

4
5
6

Test Designation
Drawings and
schematics review.
Manuals review.
Major components
identification.
Major components installation.
Connections verification.
Wiring verification.

Tagging verification.

Utilities verification.

Plant capacity.

Personal computer
software installation
(if applicable).

Program review
(if applicable).

Supplier validation
questionnaire review.

Equipment verification
by a safety officer.
Calibration verification.

2
3

Test Description
Verify that drawings and schematics are available for the following when
applicable: major components, connections, wiring, inter-connections, piping.
Verify that a manual is available for each major component.
Record the following for each major component: designation, brand,
model, serial number.
Verify that each major component is correctly installed.
Verify that connections conform to drawings and schematics.
Verify that wiring conforms to drawings and schematics, and wires
and cables are identified at both ends.
Verify that valves, gauges, relays, contractors and fuses are identified
and tagged according to drawings and schematics.
Verify that the following utilities conform to manufacturer specifications
when applicable: power supply (voltage), air pressure and quality,
water pressure and quality.
Verify that the plant has the capacity to produce the required utilities
without impacting the existing processes.
Verify that the computer is in compliance with the minimum software
requirements, that the software is available on appropriate medium (e.g.,
CD-ROM, diskette), that no error message is displayed during the
software installation, and the software main menu can be displayed
after installation. Verify that the software is compatible Year 2000 (i.e.,
will continue to operate correctly on January 01, 2000 and the years after).
Verify that program listing (source code) and functional flowchart are
available for review, that the program is correctly commented and
contains no dead code, and the program has been saved for backup
(current and previous versions saved on separate directories or drives).
This is a questionnaire sent to the supplier of pieces of equipment which
contain hardware or software ensuring that the supplier has a software
quality assurance system in place. It is used to evaluate the extent of validation
testing required.
A safety officer must verify that the equipment is safe for use in a
manufacturing environment.
A representative from the metrology department must verify that pieces of
equipment which required calibration have been calibrated, and that a
rationale has been written for the pieces of equipment which do not
require calibration.

should address the following:

Material and equipment receipt and acceptance
procedures ensuring that materials conform to their
specifications. The program should include methods
for lot number tracking, review of certificates of
conformance and material test reports.
Inspection procedures. These must be detailed,
referencing the equipment to use, the technician certification and/or training required, the methods, the
sampling plans, and the acceptance criteria for each
test. For example, stainless steel welded pipe tests

are done in accordance with the appropriate

American Society for Testing and Materials
(ASTM) specification. The inspections may include
verification of outside diameter and wall thickness,
inspection of inner diameter surface anomalies
(minor pits only, no porosity, no inclusions), cleanliness (e.g., no dirt, grease, grit, oil), and chemistry.
Most of these tests require the use of sophisticated
instrumentation by certified technicians. Examples
of water system tests include: slope verification and
pressure testing.
Special Edition: Utilities Qualification

Jean-Pierre Thiesset

Welders performance qualification procedures and records.

Welding procedures. These may include, but
are not limited to, cutting, facing, deburring, cleaning, pipe fitting, purging, and alignment.
Weld documentation. May include a weld numbering system, welder identification, time and date.
Choosing the right company ensures that the
water system IQ will be completed practically at the
same time of the installation itself. The only part that
will be left to organize is a classic IQ (see Figure 1
Installation Qualification (IQ) testing). During a
review of drawings, make sure to verify that your
installation has no dead legs. It is not as easy as it
seems, because dead legs can be hidden everywhere.
(For example, a dead leg can be created when a
valve is closed.) Verification that the system has
been correctly pasteurized will complete the IQ testing portion of the water system qualification.

USP Purified Water System

Operational Qualification (OQ)
The OQ of a USP purified water system is time
consuming, but not really complicated, due to the
fact that this type of system does not contain a lot of
complex pieces of equipment.
Start by checking each component separately to
ensure that it functions as it is supposed to operate:
Verify pump is capable of producing the specified flow rate.
Verify on/off sequence of the UV lights.
Verify the hot water generator is capable of
producing the required temperature for the
sanitizing cycle.
Verify valves open and close as intended.
Verify alarms are activated as intended.
Once every component has been checked and
deemed acceptable, the water system OQ can begin.
The system tests consist of the sanitizing cycle test,
chemical tests, microbial tests and documentation
and training verification. Before conducting any
other tests, it is important to check the sanitizing
cycle ensuring that the system maintains circulating
water at a minimum temperature of 85C (185F) for
90

Special Edition: Utilities Qualification

30 minutes. It is critical to ensure that the power supply to the UV lights is shut off during the sanitizing
cycle preventing a deterioration of the UV lights.
Ideally, the system is designed to automatically cut
the power supply to the UV lights when the temperature reaches 50C, (122F), and turns it back on
when the temperature comes back under 40C
(104F). For safety, it is important to install a pressure release valve in order to allow the release of the
excess pressure generated during the sanitizing cycle
when the temperature increases. This valve must be
checked ensuring it is working properly.
The next step is verifying that the control system is
operating as necessary. The control of the resistivity,
temperature and other parameters are performed by a
computerized system. First, it is necessary to verify
that the values recorded by the control system conform
to the actual values. One method to do this is measuring all the parameters with calibrated instruments.
Record the date and time the measurements are taken,
along with the values obtained. Compare these manually obtained values to those recorded and saved by the
control system during the same period. During the
OQ, it is necessary to verify that the control system
acts and reacts as it is intended. For example, the system must maintain temperature at an acceptable range,
activate correct indicator lights based resistivity readings. The system may also generate customized special reports or exception reports. An important fact to
remember is that all computerized systems, including
most of todays USP purified water systems, contain
software programs which need to be validated.
During the operational qualification, chemical
and microbial tests will be performed. It is important
to define the testing frequency conducted at each
point-of-use. At a minimum, chemical tests consist
of the following:

Description
Resistivity
pH
Total solids
Chloride
Sulfate
Ammonia
Calcium
Carbon dioxide
Heavy metals

Jean-Pierre Thiesset

Figure 2

Chemical and Microbial Test Matrix

Test
C
H
E
M

M
I
C
R
O
B
I
A
L

POU
X

Loop
N/A
A
A
B
B
A
A
B
B
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B

Days
Ctrl
Begin
End
Begin
End
Begin
End
Begin
End
POU-A1
POU-A2
POU-A3
POU-A4
POU-A5
POU-A6
POU-A7
POU-A8
POU-A9
POU-A10
POU-B1
POU-B2
POU-B3
POU-B4
POU-B5
POU-B6
POU-B7
POU-B8
POU-B9
POU-B10

1
X
X
X
X
X
X
X
X
X
X

Operational
Qualification
2
3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

4
X
X
X
X
X
X
X
X
X
X

5
X
X
X
X
X
X
X
X
X
X

X
X

X
X
X

X
X

Performance Qualification
Phase 1
6
7
8
9 10
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

11 12
X X
X X
X X
X X
X X
X X
X X
X X
X X
X
X
X
X
X
X

X
X
X
X
X
X

= Point of Use
= Test to be performed
= Sanitizing Cycle to be Performed

Oxidizable substances
As the system is stated to be a USP purified water
system, the acceptance criteria for these chemical tests
must comply with the USP purified water specifications.
The chemical tests must be performed at points located
as close as possible to the beginning and end of each

loop, and at a control point located before the purification system. (This control point should fail the test, as it
is located before the purification system). The microbial
tests must be performed at each point of use. The validation acceptance level for Colony Forming Units
(CFUs) per ml should be below the alert level. For examSpecial Edition: Utilities Qualification

Jean-Pierre Thiesset

ple, action levels may be established at 50 CFUs/ml, and

alert levels may be 40 CFUs/ml. The acceptance level
would then be < 40 CFUs/ml. It may be useful to use a
matrix such as the one shown in Figure 2 to define testing frequency. In the example shown in Figure 2, each
point of use is tested at least once during the three days
of the OQ/chemical and microbial testing and a sanitizing cycle is performed after day three.
The OQ phase will be concluded by verification
that appropriate procedures and training are in place.
It is important to verify that all required procedures
for water system operation, monitoring, and maintenance are applicable and approved (see Figure 3,
procedures required during facility validation). It is
also important that individuals who utilize, and/or
maintain the system have been trained appropriately
and that this training is documented.

USP Purified Water System

Performance Qualification (PQ)
The PQ of a USP purified water system could be
conducted in two phases. The first phase consists of an
intensive chemical and microbial testing during nine
days with a sanitizing cycle between day three and day
four. In the example shown in Figure 2 (chemical and

microbial tests matrix) each point of use is tested at

least three times during the PQ phase. (Once before the
sanitizing cycle and twice after the sanitizing cycle). A
recalibration of each piece of equipment calibrated at
the end of the IQ must be performed ensuring that the
measurement performed during the validation test was
valid. If some devices are found to be out of calibration,
an investigation of the impact on the validity of the tests
performed must be conducted, and a few or all OQ and
PQ tests may have to be performed again.
The second phase of the PQ consists of a less
intensive, (but more than routine monitoring) of the
chemical and microbial conditions during three
months to ensure that the system continues to produce
the required water quality. Once the second phase of
the PQ is completed, routine monitoring starts.
Routine monitoring consists of the control of each
critical point of use once a week and is used to ensure
that the system continues to produce the required
water quality. It also allows the assessment of the
effect of seasonal changes on source water routinely
recommended by industry experts.

Compressed Air System Validation

The compressed air system consists of the following:

Figure 3

Procedures Required During Facility Validation

Procedures
Water Sampling Method
Air Sampling Method
Chemical Test Method
Microbial Test Method
Hydrocarbon Test Method
Viable Particulate Test Method
Non-Viable Particular Test Method
Monitoring Procedures
Sanitizing Procedures
Excursion Reporting & Investigation
Calibration Procedures
Training Procedures
Standard Operating Procedures
Change Control Procedures
Preventive Maintenance Procedures
92

Special Edition: Utilities Qualification

USP Purified
Water System
Yes
No
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Compressed
Air System
No
Yes
No
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes

Air
Handling System
No
Yes
No
No
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes

Jean-Pierre Thiesset

Oil free air compressor unit. This eliminates

hydrocarbon content in the compressed air and eliminates or reduces the need for coalescing type filters.
Closed loop cooling system. In order to avoid
contamination, the cooling system does not have
contact with the compressed air.
A dryer. Serves to remove as much water as
possible, decreasing the dew point.
A copper piping network. This network is oil
free and has been cleaned with alcohol. (Note that
the use of galvanized piping, which is porous, is
avoided. Such pipe materials will retain moisture.)
Several 0.5 micron Millipore filters at each
potential product-contact point of use.
A few coalescing type filters may be installed
before the Millipore filters at any point of use where
particularly high levels of cleanliness may be required
due to the nature of product contact at that point.

Compressed Air System

Installation Qualification (IQ)
The IQ of a compressed air system is much easier
than the IQ of a USP purified water system. It consists
of the Installation Qualification (IQ) testing described
in Figure 1. The first step is verifying that all components and materials received conform to what was
specified. One thing to consider is the installation of
quick disconnects at each point of use or each monitoring point. This facilitates sample collection that
will be necessary during the validation and any future
monitoring. It is important to have appropriate
instruction manuals and maintenance manuals with a
spare parts list for each major component of the system (such as the compressor).
Correct installation of the piping, according to
the compressed air network drawings must be verified. During verification, assure that the piping has
been efficiently cleaned (flushed) with alcohol to
removed any trace of oil, and/or other materials used
during manufacturing and installation.
It is also necessary to consider utilities for each
piece of equipment. Verify that the utilities comply
with manufacturers requirements. The overall plant
capacity must be verified to ensure that it can safely
provide the power supply required for each piece of
equipment without affecting the functioning of the
new and/or existing systems. Compressed air system

leak testing followed by verification that all equipment and measurement tools were appropriately calibrated will conclude the IQ.

Compressed Air System

Operational Qualification (OQ)
The OQ of a compressed air system consists of
two phases:
Functional qualification at component and systems-levels.
Air quality testing.
During the first phase, each component and each
specific piece of equipment must be checked to verify functional operation. Accordingly, it is necessary
to design tests that challenge each major function.
The ultimate test is one that verifies all functions of
a piece of equipment in one unique operation. Unfortunately, this is difficult, and realistically, it will
probably be necessary to perform many specific
tests to thoroughly challenge each function.
The classic functional tests of compressed air
system components might include, but are not limited to, the following:
Verification that mechanical moving parts
move freely.
Verification that all necessary adjustments can
be performed.
Verification that normal operating adjustments are
not at the minimum or the maximum of the range.
Low and high alarm testing.
On/off sequences testing.
Simulation of a power supply shut down and
recovery.
Systems-level testing consists of verifying that
the compressed air system delivers the required
cubic feet per minute (cfm) at the specified working
pressure, and is capable of achieving and maintaining the specified dew point.
The air quality testing phase can be planned in the
same manner as the water quality testing by generating
a matrix of tests to perform. The following tests should
be performed on samples taken immediately after the
dryer, and at each product-contact point of use:
Special Edition: Utilities Qualification

Jean-Pierre Thiesset

Viable particulates. A typical acceptance level

could be less than 0.1 colony forming units per cubic feet
(CFUs/ft3) if the alert level is equal to or greater than 0.1
CFUs/ft3, and the action level exceeds 0.15 CFUs/ft3.
Non-viable particulates. A typical acceptance level
could be less than 9,000 parts per cubic feet (ppcf) for 0.5
micron particulates if the alert level is equal to or greater
than 9,000 ppcf for 0.5 micron particulates, and the action
level exceeds 10,000 ppcf for 0.5 micron particulates.
Hydrocarbon content.
As with any OQ, conclude by verifying that all
required operational and maintenance procedures
are in place, applicable and approved (see Figure 3,
procedures required during facility validation).
Verify that training of personnel who utilizes, and/or
maintain the system has been documented.

Compressed Air System

Performance Qualification (PQ)
As with the compressed air system OQ, the PQ is
conducted in two phases. The first phase consists of
performing the following tests at least one week
after the OQ on samples taken just after the dryer,
and at each product-contact point of use:
Viable particulates.
Non-viable particulates.
Hydrocarbons content.
The system components should be recalibrated as
appropriate in order to ensure that the measurements
performed during the validation tests are valid. If some
devices are found out of calibration, an investigation of
the impact on the validity of the tests performed must
be conducted, and a few or all of the OQ and PQ tests
may have to be performed again. The second phase of
the PQ consists of a less intensive, (but more than routine) monitoring of viable and non-viable particulate
levels over at least a three month period ensuring that
the system continues to produce the compressed air
meeting documented specifications.

HVAC System Validation

The HVAC system considered as part of this validation project supplies conditioned air to a Class
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Special Edition: Utilities Qualification

100,000 controlled manufacturing environment

(CME) by way of a duct network. Areas are pressurized to achieve the required differential pressures
between manufacturing rooms, corridors and gowning rooms.
The system consists of:
An air handling unit (AHU). This provides filtered air, and consists of fans and their motors, high
efficiency particulate air (HEPA) filters, dampers, a
condenser unit with its refrigerant piping, an indirect
fired gas heating unit with its gas piping, and an
electric panel.
A temperature and humidification system.
Primary humidifiers inject low pressure steam into
the main branches of the duct network in quantities
sufficient to produce slightly less than the nominal
percent of relative humidity (%RH) required when
the air stream temperature is raised to the rooms
nominal temperatures. Electric duct heaters and terminal trim humidifiers respectively reheat and rehumidify the air prior to being distributed into each
area in order to maintain each rooms specified temperature and %RH.
HEPA filters at the end of the ducts just before
the distribution of the air into the room.
A sensor system. This consists of temperature
and humidity sensors located down-stream from the
main stream distributors. Temperature and humidity
sensors are located in each room. Differential pressure sensors are located between adjacent manufacturing rooms, between manufacturing rooms and
adjacent gowning rooms, between manufacturing
rooms and adjacent corridors, and between gowning
rooms and adjacent corridors. All these sensors are
connected to a computerized control unit.
A computerized control unit. This serves to monitor temperature, the %RH and the differential pressure.
It also controls the AHU, the primary humidifiers, the
trim humidifiers and the heaters. This system is built
within a computer-type environment with a lot of hardware components (electronics and printed circuit
boards). A complex interconnection network between
the unit and the sensors and between the unit and the
AHU, the humidifiers and the heaters allows the monitoring and control by this computerized control unit.
Of course, the computerized control unit contains several software components which must be validated.

Jean-Pierre Thiesset

HVAC System Installation

Qualification (IQ)
The IQ of a HVAC System may take more than a
week, since it involves many different pieces of
equipment. However, this does not necessarily mean
that the IQ will be difficult to execute. As in any
installation qualification, begin by addressing the
tests and tasks defined in the installation qualification (IQ) testing described in Figure 1. Customize
the IQ protocols as necessary for the unique system.
It will usually be necessary to add a few tests that are
specific for the type of system that has been
installed. In the case of the HVAC system described
in this article, the system-specific tests consists of,
but are not limited to, the following:
Duct network verification. Assures the correct
duct sections are installed according to drawings and
cleaned as defined in cleaning procedure.
Room verification. Requires checking that the
rooms have been prepared correctly, so that no air
leak can compromise the differential pressure that is
established by the system.
Filter performance. Challenges for leaks and
filter integrity. A certified company that is familiar
with the appropriate standards, and utilizes only calibrated test equipment must perform testing on all
filters. It is critical to use a non-cancerous aerosol
agent for HEPA filters integrity testing,
Dioctylphthalate (DOP) is questionable, and should
not be used.
The validation of a HVAC system, as with any
system, could be compromised if scientifically
sound measurement principles are not followed.
Basic measurement principles require verification
and documentation that all measurement instruments utilized have been calibrated, and that the calibration is traceable to National Institute of
Standards and Technology (NIST). The calibration
must be within the due date. The accuracy of the
instrument must be sufficient given the characteristic being measured. The rule of thumb is that the tolerance accuracy ratio (TAR) should ideally be equal
to ten. The TAR is the ratio between the total tolerance of the characteristic measured, divided by the
accuracy of the instrument utilized. Calibration is a

critical part of the IQ, which includes verification

that calibration of all components and equipment
within the system is calibrated appropriately.

HVAC System Operational

Qualification (OQ)
The OQ of a HVAC system will also be very time
consuming as it requires that several pieces of equipment be functionally challenged. The OQ of this
HVAC System will be conducted in six phases:
Functional challenge of the components and
pieces of equipment.
Room balancing.
Testing temperature and %RH monitoring and
control systems
Temperature and %RH mapping.
Testing differential pressure monitoring system.
Testing air quality.
The first phase, the functional challenges of components and equipment is unique and specific for
each system. The following will outline only a few
of the functional tests that are required. As stated in
previous sections, each specific function of each
component or piece of equipment needs to be challenged. As a guideline, ask the following question:
do the tests performed establish confidence that this
piece of equipment operates as it is intended to function? It may be very useful to generate a table with
two columns. The first column contains the list of all
major functions of the system, and the second specifies which test is performed to challenge the function. Special attention must be given to the safety
checks, and the alarms verifications. These aspects
must be thoroughly tested ensuring a safe working
environment, and establishing confidence that
abnormal or unsafe conditions will be detected
before they reach critical levels.
Room balancing, the second phase, must be done
by specialists. As with HEPA filter performance testing mentioned above, a certified company familiar
with the appropriate standards must conduct these
tasks, and utilize only traceable calibrated test equipment. Differential pressure specifications depend on
the rooms usage and the type of product manufacSpecial Edition: Utilities Qualification

Jean-Pierre Thiesset

tured. The purpose of the operational qualification is

not determining whether or not the specifications are
correct, but in establishing confidence that the system conforms to the specifications. The PQ demonstrates that there is a high probability that the system
will continue to conform to these specifications.
The third phase, testing the temperature and
%RH monitoring and control system, consists of a
verification that the values of the actual temperature,
and %RH in the rooms are:
Correctly measured.
Correctly sent to and received by the control
system.
Correctly interpreted by the control system (i.e.,
control system sent back the appropriate control
signal to AHU, humidifiers and heaters.)
The easiest method of verifying that the values
are correctly sent and received by the control systems is for one person to record the actual value
within the room being tested and another person to
record the value registered by the control station at
the exact same time. It is helpful if these two persons
maintain communication through portable receivers
and transmitters or other similar wireless devices. It
is extremely important that they record the values at
precisely the same time in order to obtain meaningful data. Remember to repeat this procedure for each
instrument, and/or sensor that transmits data to the
system. Never assume that if the value measured by
one temperature sensor, for example, is correctly
transmitted, the values measured by the other temperature sensors will also be correctly transmitted.
There are many potential causes for a single sensor
to fail, thus preventing accurate data transmission
(for example, an improper connection, defective output in the transmitting unit, or defective input in the
receiving unit).
Verifying that the values are correctly interpreted
by the control system can be performed by testing
whether the control system responds as defined by the
specifications. Events for which a response can be
evaluated might include: decrease or increase in the
ambient room temperature, change in ambient room
%RH; decrease or increase in the room temperature
set points, and temperature or %RH reaching predefined alarm limits. It is important to test each room,
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Special Edition: Utilities Qualification

and verify that each humidifier and heater is turned on

and off, when (and only when) it is expected.
The fourth phase, temperature and %RH mapping, requires verifying that the entire room is in
compliance with its specifications, not only the specific area where the sensor is physically located.
This is performed by measuring the temperature and
%RH in various locations throughout the room; for
example, the middle of the room, each corner, and at
three feet and eight feet points within each location.
A data sheet like the one shown in Figure 4 (temperature and %RH mapping) could be used to record
the values measured.
The fifth phase, testing the differential pressure
monitoring system, consists of a verification that the
differential pressure values are:
Correctly measured.
Correctly sent to and received by the control
system.
Correctly interpreted by the control system.
Verifications of correct measurement and receipt by the control system can be performed in a
manner similar to that described previously for the
temperature and %RH verifications. In order to
verify the interpretation of the data received, it is
necessary to check that the system generates an
exception report. Such reports must correctly document any instance where differential pressure
goes above or below the predefined alarm levels,
identify the fault, identify the location, and the time
of the event (date, time).
In the final phase, air quality testing will be conducted in each room and consists of measuring:
viable particulates and non-viable particulates.
Typical acceptable parameters for viable particulate
might be < 0.1 CFUs/ft3 if the alert level is equal to
or greater than 0.1 CFUs/ft3, and the action level
exceeds 0.15 CFUs/ft3. Typical acceptable parameters for non-viable particulates might be an acceptance level < 9,000 ppcf for 0.5 micron particulates,
if the alert level is equal to or greater than 9,000 ppcf
for 0.5 micron particulates, and the action level
exceeds 10,000 ppcf for 0.5 micron particulates.
The OQ will conclude, as described in the other
OQ sections of this article, with verification that
appropriate procedures are in place, applicable,

Jean-Pierre Thiesset

Figure 4

Temperature and %RH Mapping

%RH at 3:
Temp at 3:
%RH at 8:
Temp at 8:

________.
________.
________.
________.

Room #:__________.
Date: ____________.
Performed by:________________________.

%RH at 3:
Temp at 3:
%RH at 8:
Temp at 8:

East
North

South

%RH at 3: ________.
Temp at 3: ________.
%RH at 8: ________.
Temp at 8: ________.

______.
______.
______.
______.

West
%RH at 3:
Temp at 3:
%RH at 8:
Temp at 8:

________.
________.
________.
________.

Instrument ID #: __________________.
Calibration Date:__________________.
Calibration Due Date:______________.

%RH at 3: ________.
Temp at 3: ________.
%RH at 8: ________.
Temp at 8: ________.

approved, and personnel who utilize, and/or maintain

the system, have been trained appropriately.

Validation of New Systems

vs. Existing Systems

HVAC System Performance

Qualification (PQ)

The validations described are pertinent to the

qualification of new systems; however, the
approach to qualifying existing systems will not be
significantly different. It is still necessary to form a
multidisciplinary team, develop and document validation project plans, and perform IQ, OQ & PQ.
The IQ phase will be modified because the systems
are already installed. For example, during an IQ of
an existing system, it is necessary to verify that the
original architectural drawings are consistent with
the equipment, as it is currently installed. This is in
contrast to an IQ of a newly installed system, in
which the equipment is compared to approved
drawings.
The OQ and PQ phases will be approached in the
same manner for a newly installed system or an
existing system. Do not make the mistake of assuming that a review of historical data is a sufficient
method of meeting OQ and PQ requirements for an
existing system. The only means to competently
perform an OQ and a PQ is thoroughly establishing
documented evidence that the system operates in
accordance with approved specifications and that it
will reliably continue to do so.

The PQ of the HVAC system consists of the monitoring of the following parameters every hour over
at least thirty consecutive days:
Temperature. A typical acceptance criteria
could be > 20C (68F) and < 25C (77F).
%RH. A typical acceptance criteria could be >
30 %RH, and < 65 %RH.
Differential pressures. Acceptance criteria is
very specific and based on use and product requirements.
Always assure that all acceptance criteria is consistent with those defined in the approved system
specification for each particular case
A temperature and %RH Mapping might be performed for each room at the end of the thirty day
testing period to confirm that the entire room is still
in compliance with its specifications.
The PQ concludes with verification of calibration
status of all equipment, and assuring that all measurements made during the testing phase are acceptable.

Special Edition: Utilities Qualification

Jean-Pierre Thiesset

References
1.

2.
3.
4.

Food and Drug Administration; 21 CFR Part 820; Medical

Devices; Current Good Manufacturing Practice (CGMP);
Final Rule; Monday October 7, 1996; Quality System
Regulation.
IEEE Standards Collection Software Engineering 1994
Edition; September 14, 1994.
ISO 9001-1994(E); Quality Systems Model for Quality
Assurance in Design, Development, Production, Installation
and Servicing.
ANSI/ASQC Q9001-1994; Quality Systems Model for

Quality Assurance in Design, Development, Production,

Installation and Servicing.
ISO 9000-3-1991(E); Quality management and quality
assurance standards Part 3: Guidelines for the application
of ISO 9001 to the development, supply and maintenance of
software.
Food and Drug Administration; Design Control Guidance
For Medical Device Manufacturers; March 11, 1997.

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109

Validation of Process Gas Systems

By Jeff Hargroves
Alza Corporation

alidation of process gas systems involve documenting

the expected system behavior, and verifying that the system
performs as expected. This article
covers the pertinent aspects of IQ,
OQ, and PQ related to process gas
systems and many of the potential
problem areas. The validation of
nitrogen and compressed air systems, including breathing air systems, is used as an example which
can be extended to the validation of
most other process gas systems.

Why Validate Process

Gases?

This articles
covers the
pertinent aspects
of IQ, OQ, and
PQ related to
process gas
systems and many
of the potential
problem areas.

Process gas systems may include compressed air,

nitrogen, oxygen, helium, or other inert gases. If the
gas is used to operate product related system(s), or
directly affects the manufacture of drug products, we
must demonstrate the system can continuously operate in a state of control.
Inspection agencies require that we demonstrate
control over utilities that can potentially impact a product. However, the methods we use to document and
demonstrate control of utilities are currently a source of
debate in the field of validation. For example,
Will contractor start-up documents suffice?
Is commissioning, using Good Engineering
Practices adequate?
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Special Edition: Utilities Qualification

Are traditional, preapproved

validation protocols necessary?
There is no pat answer. Generally, we must demonstrate that
the process gas delivered at the
point-of-use meets the predetermined user requirements. As long
as we demonstrate this, it does not
matter what we call the demonstration documents.

Design Considerations

As with any other cGMP system

or equipment, we must design
nitrogen and compressed air systems so that they can
be qualified. The design process begins and ends
with documentation of the point-of-use requirements for the system.
A typical compressed air system consists of the
air compressor(s), driers (desiccant or refrigerated),
distribution piping, and filtration systems. A typical
nitrogen system consists of either a liquid nitrogen
storage tank and vaporizer or nitrogen bottles, distribution piping and filtration systems.
Breathing air systems are becoming more commonplace as our industry increases the research
and production of potent and toxic drugs. The qualification of breathing air systems is generally similar to that of other process gases. However, there
are some specific, generally accepted requirements

Jeff Hargroves

Figure 1

Minimum Requirements of a Compressed Air or Nitrogen System

Characteristic
Pressure, min. & max.

Typical
Acceptance Criteria
90-110 psig

Flow, min.

10 scfm

Temperature, max.

90F

Purity
Particulate

Meets USP Monograph

Meets particulate class level as
defined by Federal Std. 209E
Meets microbial limits, as
defined by your company, for
given room classifications
-40F

Microbial

Dewpoint
Hydrocarbon

Characteristic
Pressure, min. & max.
Dewpoint
Carbon Monoxide
Carbon Dioxide

Non-detectable, (eg 25ppm

as measured with Draeger 10a/P
hydrocarbon tubes)
Typical Breathing Air
Acceptance Criteria
20-25 psig
0-45F
< 10 ppm
< 500 ppm

for breathing air systems.

Figure 1 lists the minimum requirements that
should be considered during design of a compressed
air or nitrogen system.

Process Gas Standards

Currently, there are no universally recognized
standards for the validation of process gases.
However, a group within ASTM subcommittee
48.06 is developing validation standards for the process gases, and for the methods used to test the
gases. There are several places to go for direction on
the requirements of process gas systems. Generally,
process gas systems must meet the chemical, microbial, and purity requirements of the products they
will potentially contact, and the requirements of the
room into which they are exhausted, if applicable.
The USP has developed test monographs for process gases, such as medical air, nitrogen-99%, nitrogen-75%, and oxygen. Care should be taken to con-

When to be concerned about

this characteristic
Usually to meet equipment needs; max. is important
if equipment is not capable of throttling pressure.
Usually to meet equipment needs; max. is important
if equipment is not capable of throttling flow.
Seldom important, except for breathing air, unless
there is a specific process requirement.
Use only if required.
Same requirement as the room in which the gas is
introduced, tighter if product contact issues dictate.
Same requirement as the room in which the gas is
introduced, tighter if product contact issues dictate.
Process driven. (Dont claim -40F if your process
doesnt need it).
Process driven, generally non-detectable for process
applications. Specify the lower non-detectable limit.

When to be concerned about

this characteristic
At points-of-use (e.g., hookups to air hoods)
NFPA 99 guideline
NFPA 99 guideline
NFPA 99 guideline

sider the particular process application before

assuming that conformance to USP specifications is
required. Some of these methods are difficult to execute in the field (e.g., Nitrogen-99%), and should not
be attempted unless they are required.
For microbial and particulate monitoring, the specific criteria developed in our respective facilities for
class 100,000, 10,000, 100 and so on, should be consulted. In general, the process gas must not negatively impact the room into which it is exhausted.
For breathing air systems, the NFPA 99 specifications for breathing air is used as the basis for
acceptance criteria. Additional guidance can be
found in the journals of the Compressed Gas
Association.

Use of Final Filters

The use of the air should always be considered
when deciding what type of filter, if any, is required.
Compressed air and nitrogen are often used to power
Special Edition: Utilities Qualification

111

Jeff Hargroves

equipment and motors in the process areas. In classified (such as 100,000, 10,000, and 100) areas,
where process gases directly contact the product,
final filters are advisable.
Point-of-use filters should be in place, or at least
considered during PQ of the system. Many companies qualify the system without the point-of-use filters in place to ensure system integrity even if the filter develops a leak during its use.
Filter model numbers should be documented, and
controls should be established to ensure the same filters are used over the life of the system. The manufacturer may vary, but critical characteristics, such as filter materials, flow rate, and particulate filtration levels
must be maintained. This information can be documented in the system or equipment SOPs, or in the
maintenance management system. The filters found in
the system two years after the initial qualification must
have the same critical characteristics as the filters that
were originally designed, specified, and qualified.
Final filters serving class 100, or cleaner areas,
should be integrity tested. The frequency of testing
should be commensurate with their use. For this reason, it is often advisable to locate the filters outside
the process area. A common design approach is
using medical grade copper in the distribution system, transitioning to stainless before entering into
process areas, with dielectric couplings at the transition. This transition point is usually a good place to
locate the systems final filters.

Installation Qualification Issues

As with any cGMP system or equipment, every
inch of the system should be checked to verify conformance with as-built drawings, construction materials, valves, cross-connection to other systems, and
unused portions of the system. In any large, unused
portion of the system, adequate protection preventing fluid buildup during system shutdown, which
could compromise the microbial purity of other
parts of the system, must be ensured.
All alarms must be tested, including those on the
compressors and desiccant driers for the compressed
air system, on the storage tanks and vaporizer for
nitrogen systems, as well as on the distribution system itself. It is often useful to hire the service representative to conduct these tests. These experienced
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personnel can test the alarms much faster than someone who is unfamiliar with, and could possibly damage the equipment. Plus, the tests usually take only a
few hours with someone familiar with the equipment, versus a few days for someone who does not
work regularly with the equipment.
For high purity gas systems, requirements for the
material in product contact closely mirror those of a
high purity water system. All new high purity systems should be pressure tested, cleaned, and flushed
according to preapproved procedures. For stainless
steel lines serving aseptic process areas (downstream of final filters), the weld maps should be
matched to the weld logs and to the material certifications. If passivation has been specified, its proper
execution and flushing should be verified.

Operational Qualification Issues

As with any system, all critical instruments should
be calibrated prior to the performance of operational
tests. Critical instruments on a process gas system are
those instruments used to measure the parameters
listed in Figure 1. However, an instrument need not
be permanently installed for each characteristic. For
example, if diversity testing is done well, the permanent installation of flowmeter(s) should not be
required. But a pressure switch used in maintaining
the minimum system pressure by turning on the lag
compressor, should be calibrated.
The instruments used to monitor the critical characteristics of a breathing air system should also be
calibrated. These include on-line carbon monoxide
(CO), carbon dioxide (CO2), and dewpoint monitors.
CO and CO2 monitors can be easily calibrated by
using standardized test gas canisters which trigger
the alarms at the appropriate levels. The manufacturer of the respective monitor can usually provide
the certified gas canisters. The gases are typically
provided in concentrations that correspond to the
alert and action alarm levels. They can be easily input
to the monitor, and then flushed from the system.

Sequence of Operation Testing

For complex systems, such as multiple air compressors or multiple liquid nitrogen vaporizers, care
should be taken to test, or at least bracket, all oper-

Jeff Hargroves

ational scenarios. This includes testing each compressor in a lead and lag position.
Backup compressors or gas cylinders should be
tested with the rest of the system. All potential operating scenarios should be explored during the operational qualification process. If an operating scenario
affects the quality of the gas produced, it should be
incorporated into the hydrocarbon, dewpoint, and
microbial testing.

Testing of System Characteristics

The following sections review specific measurement techniques and issues for each system characteristic listed in Figure 1.
Each measurement technique should be carried out
with calibrated instrumentation. Although Draeger
tubes and some accessories will not come with NIST
certificates, the flowmeter and timer used to capture the
sample should be calibrated. The results obtained from
accessories, such as Draeger tubes, should be reported
with a corresponding error based on the manufacturers
statement of accuracy. Test results are only as good as
the sum of the errors introduced during measurement.
Testing must be performed so that additional
error is not introduced into the system. For example,
during microbial sampling, an uninformed protocol
executor might put the flowmeter between the pointof-use and the agar plate, but this introduces potential additional microbial contamination from the
flowmeter. Whenever possible, valves, flowmeters,
flow restriction devices and pressure gauges should
be placed downstream of the variable being tested.
By minimizing introduced errors, the certainty of the
final test result is supported.
Test methods should be thoroughly documented, so
that qualification can be repeated years after the original
tests. For a small start-up company, this may mean simply writing down the test procedure in the comments
section of the protocol. For more mature companies that
will be routinely performing these tests, the methods
should be codified in a company guideline or SOP.

Pressure
Although pressure is probably the simplest characteristic to measure for a large system, a bucket full
of fittings may be needed to provide connections to

all the points of use. Qualification should not be

destructive. If the gas lines are already connected to
process equipment, the reading from the instruments
on the equipment may be obtained, and the line need
not be broken.
Nothing should be taken for granted. If there is a
pressure or flow specification at a point-of-use, that
point-of-use should be tested. One cannot assume
that because the correct pressure appears at one drop
in a room, it applies to all drops in the room.
Pressure considerations during diversity testing
are discussed in the following section.

Flow
The flow rate of each point-of-use should be
measured to verify that user requirements are met.
However, for many drops, there may be no predetermined user requirement. Typically, a baseline
flow measurement is taken for each drop, whether
or not it has a predetermined specification. By
obtaining a flow rate measurement for each use
point, a comprehensive document is established,
which can be used in the future to help make decisions about whether the system can support a new
piece of equipment. For example, if on initial test,
only 10 scfm could be obtained, it is clear that the
line size or supply pressure will need to be increased
to support equipment that requires 25 scfm.
Performing the flow test at each drop also provides a visual check for large pockets of stagnate
water in the pipeline. This can be important because
dewpoint measurements may not be performed at
all locations. Condensate may form in the lines
during the initial installation of a system, or after an
old portion of an existing system has not been used
for an extended period. If water is found in the line,
the system may not have been adequately cleaned
and flushed.
Flow rate diversity tests should also be performed
to identify how many (and which) points-of-use can
be operated simultaneously. For a new system,
diversity values should be predefined in the design
documents. For existing systems, a few interviews
with the equipment users should provide sufficient
information for educated assumptions about simultaneous use of equipment. Simultaneous recording
of flow rate and supply pressure at critical points-ofSpecial Edition: Utilities Qualification

113

Jeff Hargroves

use provides very useful information about the ability of the system to perform as designed.
Flowmeters can be found in most process equipment and instrumentation catalogues. A good contract calibration company should be able to calibrate
the flowmeter, and provide a standardization table
for each process gas.

Purity

ageable level. For example, in a room with three

compressed air drops, a sample from location one on
day one, from location two on day two, and location
three on day three should be adequate to ensure that
portion of the line is hydrocarbon free.

Dewpoint

Dewpoint can be a difficult characteristic to measure. The equipment used to measure dewpoint
If claims are made about the purity of the process include chilled mirror, moisture level conversions, and
gas, then testing should be performed to demon- others. The chilled mirror method is usually accurate
strate that the appropriate specifications are met. A enough to meet the process requirements. Alternsample is typically obtained into a vacuum conatively, Draeger tubes (or their equivalent) can be used
tainer or bag that can be transported to a laboratory.
to measure moisture levels in ppm, which can be converted
to
dewpoint.
Additionally, there are handFor more reliable, precise data, a gas
held measurement instruments that can be submerged
sample can be obtained for
in the process gas to provide
laboratory analysis.
dynamic measurements.
It is important that the
The methods used to obtain the sample, and to
dewpoint measurement be taken at the correct temperdemonstrate purity should be carefully documented
ature and pressure. The dewpoint conversion informaand reproducible.
tion provided by manufacturers is often only applicable at atmospheric pressure and standard temperature.
Hydrocarbon
Measurements taken at other pressures and temperatures must be converted to ensure that the system specAmong the many ways that hydrocarbon tests can
ifications are met. Measurements taken at high presbe performed, the most common is the use of Draeger,
sure can also damage the measurement equipment.
or equivalent, tubes to indicate the approximate level
Particulate
of contamination. These indications are generally not
traceable to a standards bureau, such as NIST, but
Most standard particle counters can be used to
they are a reliable, repeatable, and commonly
measure particulate levels in process gases. The
accepted method for discerning system contaminasame caution with respect to pressure also applies to
tion.
For more reliable, precise data, a gas sample can particle monitors. The supply gas is limited to very
low pressure thresholds. The monitors usually conbe obtained for laboratory analysis. This is usually
necessary for demonstrating compliance with tain their own pump because they are mainly used
for collecting samples from room air.
breathing air standards. Most large contract environFlow must also be carefully controlled during
mental testing laboratories provide the vacuum conparticulate measurement. Particle counters are usutainers used to obtain and transport the sample.
ally designed to pull the sample at 0.1 or 1.0 cfm.
Hydrocarbon measurements should be taken near
Most particle counter manufacturers can provide a
the source during maximum load conditions to
ensure that minimum system requirements are met. dispersion tube that can be used to bring the gas
down to the required flow and pressure.
They should be tested at points-of-use where prodThe calculations provided in Federal Standard
uct will be contacted. Bracketing should be used on
209E can be used to translate the sample measurelarge systems to keep the number of tests to a man114

Special Edition: Utilities Qualification

Jeff Hargroves

ment to a specific confidence level for the room classification being tested. Again, the particulate level
should correspond to the particulate level of the room
into which the process gas is being exhausted.

Microbial
Microbial air samples can also be difficult to
obtain. A variety of sampling devices, such as slit-toagar, centrifugal, and direct impact, can be used. The
best method will closely mirror the sampling technique used for open air measurements in your facility.
In recent years, sampling devices have been
designed specifically for process gas sampling. A
sampling atrium can be used to pull samples directly
from the process gas line. The sampling atrium can
be sterilized between uses to ensure that it does not
add to the microbial load of the sample. An agar
plate, such as that used for room air sampling, can be
easily and aseptically placed into the atrium for sample capture. The amount of air that passes over the
agar plate should match that of a typical room air
sample, usually at least 40 liters.

Summary
If it is approached methodically, validation of process gas systems should not be an overwhelming task.
The potential impact of the specific system on the
product and the process must be considered.
Execution of a well-developed plan that demonstrates
conformance to the predefined criteria should be simply a milestone on the way to a validated facility.

Post Validation
After the initial qualification, process gas systems
should be maintained in a qualified state. To accomplish this, the following actions should be taken:
Utilize change control.
Develop preventive maintenance (PM) and
operational SOPs.
Calibrate any critical instruments.
Train mechanics and operators on the SOPs.
Point-of-use filters should be included in a PM
program. All point-of-use filters can be changed by
maintenance personnel at a specified frequency,
such as semiannual. Alternatively, point-of-use filters are considered part of the process equipment
that it serves. In this method, production operators
are responsible for checking and replacing the filter
as part of the equipment setup. The main benefit of
this approach is that filters are maintained with the
same frequency as the equipment. If equipment is
not used, money is not wasted on filters, but if equipment is used frequently, the filters receive a corresponding level of attention.
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115

Purified Water
Water Systems:
Systems: AASystem
Purified
System
PerspectiveUnder
Underthe
theNew
New
Perspective
USPQuality
QualityRequirements
Requirements
USP
By Tod E. Ransdell
Sanofi Pasteur

O
Editors Note: Figure 1 has been
included to define specific terms
appearing in this article.

reliable, consistent supply of

high-purity process water is
essential in the regulated
health care industry. Concepts of
quality assurance and sound system
management, including a rigorous
monitoring program, should be applied to the operation
of all in-house, high-purity water production systems.
The issuance of the Eighth Supplement to USP 23
(official as of May 15, 1998) will complete the process
of radically changing how a large portion, if not all, of
the regulated health care industry monitors and tests
for basic purified water quality. The days of simple
tabletop, color chemistry are definitely over. Now we
will be utilizing selective testing for discretely measurable quality attributes. In addition to the current pH
and bioburden requirements, Purified Water (PW) and
Water for Injection (WFI) requirements will now
include conductivity and Total Organic Carbon (TOC)
testing to replace the panel of testing that has been in
place almost since the inception of the official compendia for water quality.

Design, Installation, and Operation

of a Water Treatment System
Purity of process water is critical to product integrity. The proper design, installation, and operation of a
high-purity water system is the primary consideration.
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The first challenge is to define highpurity water as it relates to the

process in question. There are a
series of very comprehensive flow
charts on pages 75427544 of the
MayJune 1994 Pharmacopoeial
Forum that includes a scheme for the
Water System Validation Life Cycle.
d The charts show the logical steps to
be taken during a high-purity water
system definition and validation effort.
The many phases for the qualification of a water
system has been extensively covered in previous
issues of the Journal of Validation Technology, as
well as many other professional publications. I will
not regurgitate any of that information in this article.
Suffice it to say that this process is well characterized.

Review of the Water System

Monitoring Program
So whats first? In reviewing the current water system monitoring program here at Sanofi Diagnostics
Pasteur (Sanofi), we observed that the major changes
were considerations for conductivity requirements and
the establishment of TOC analysis as part of our ongoing testing capability program. We already have in-line
resistivity monitoring of our Deionized Water (DIW)
loops at our two primary production facility locations.
This information has been historically used to trigger
change out of the deionization and activated charcoal
beds. Up until this point, it was not effectively used as
one of the key quality release criteria for our DIW.

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117

Figure 2

Table of Laboratory, Reagent and Electronic Grade Waters

Type
TOC
Conductivity
Resistivity
pH
4,5,6,7
USP Purified Water
<.05 ppm
1.3 @25C
NS
5.07.0
NCCLS Type I
NS
NS
*10 @ 25C
NS
NCCLS Type II
NS
NS
1.0
NS
NCCLS Type III
NS
NS
0.1
5.08.0
CAP Type I
NS
0.1
10
NS
CAP Type II
NS
0.5
2.0
NS
CAP Type III
NS
10
0.1
5.08.0
ASTM Type I
NS
0.06
16.6
NS
ASTM Type II
NS
1.0
1.0
NS
ASTM Type II
NS
1.0
1.0
6.27.5
ASTM E-1
0.075 ppm
NS
17 @ 25C
NS
ASTM E-2
0.5 ppm
NS
10 @ 25C
NS
ASTM E-3
1 ppm
NS
1.0 @ 25C
NS
NS = Not specified in resource material
*Specifies an in-line measurement

on a number of occasions that the method that we

employ as an indicator of water quality is comparable to the method that has found its way into the latest revision of the USP 23. Measurement of this particular aspect of water quality is appropriate using
either method.
It is clearly stated in the Fifth Supplement of USP
23, Conductivity expressed in S/cm (or moh/cm)
is the reciprocal of Resistivity, expressed in
MegOhm*cm. Therefore, the higher the quality the
water, the higher the resistance or the lower the conductivity. DIW should fall in a resistivity range of 410 MegOhm*cm because of the carbon adsorption.2
The in-line measurement of the DIW resistivity at
Sanofi runs between 10 and 18 MegOhm*cm, which
translates to 0.1 and 0 S/cm Conductivity. The
Stage 1 Conductivity Requirements for USP Purified
Water between the temperatures of 3035C (average
system operating temperature at Sanofis Redmond
Main Facility) is 1.41.5 S/cm. The USP requirement is a relatively less stringent quality than the
standards already maintained at Sanofi.
In comparison to other previously recognized
standards, the DIW at Sanofi conforms to various
grades of Laboratory, Reagent, and Electronics
Waters. National Committee for Clinical Laboratory
Standards (NCCLS) Type I Water is very similar to
USP Purified Water, with a slightly higher resistivity
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Special Edition: Utilities Qualification

requirement; NCCLS Type II Water is of lesser quality, but is generally good quality DIW; NCCLS Type
III Water is deionized water that is primarily required
for glassware rinsing functions.3 (See Figure 2).

Selection of a TOC Analyzer

To send the samples away to an outside testing
laboratory seemed at first blush to be the easiest
approach. There were a couple of items that presented themselves that weighed against this option. The
first was the expense. We have approximately 30
sites we sample every month at only one of our two
facility sites. Cost of analysis by an outside laboratory comes to over $1,000.00/month for that one facility alone. At this rate, we figured that we would be
able to pay for an in-house analyzer in approximately a year, processing all samples from all facilities.
The next consideration was the timeliness of the
reporting. We are already tied to a three-day lag for
bioburden analysis. The outside lab results can take
a week or more to come back for review. We could
have all the samples put on a special high priority
test schedule, but that service could potentially double the cost of the analysis. If the TOC analyzer were
part of our in-house QC laboratory services, we
could in effect have results within 24 hours of initial
sampling.

On the other hand, on-line or in-line sampling

provides instantaneous readouts. We are then limited to possibly just a few monitoring sites, like we
are with our resistivity measurement. Is that adequate? We opted for the multiple site, off-line analysis for our TOC, because we felt it was a higher priority quality aspect to monitor on a continuous basis.
To bring a new analysis system in-house was still
an awesome task. It is no small chunk of change to
first qualify the analyzer in association with all the
peripheral accouterments, then maintain the system
over each ensuing year. Even with all that, for our
particular company, an in-house system was clearly
the preferred alternative.
Selecting the TOC analyzer was really a very
straightforward approach. There have been a plethora of articles that specified a number of specific
manufacturers. Along with that basic source information, many of these same manufacturers were saturating the trade journals with advertising touting
their ability to meet the new USP standards and
offering a wide variety of different styles of analyzers, methods of analysis, and installation formats.
The basic techniques for the determination of
TOC in water samples have remained well understood and stable for nearly two decades. Organic
compounds are converted to carbon dioxide (CO2)
utilizing a number of methods either singly or in
some combination that may include chemical oxidizers, UV radiation, or combustion. The CO2 is in
turn measured by conductometric, microcoulometric, or IR absorption techniques as total carbon (TC).
Through other methods, total inorganic carbon
(TIC) is removed, the effluent measured, and the
resulting difference yields a value for TOC in the
sample (i.e., TOC = TC - TIC).
Performance Considerations: The measurement of TOC in high-purity waters is of particular
importance. TOC assays are used to evaluate the
level of contamination in a wide variety of water,
from feed water to high- and ultra-high purity water.
Characteristic TOC concentrations can range from 1
microgram per liter and lower (<1 ppb TOC) to well
over 1,000 milligrams per liter (>1,000 ppm TOC),
depending upon the type of water in use. Generally
in the regulated health care industry, we are looking
for water that has a contamination level 500 ppb
TOC.5,6,7 Other types or sources of samples may be

processed, so the upper end of the capability range is

equally as important.
Vendor selection was a snap. We contacted the
top three vendors to obtain as much promotional
material as possible. This was reviewed by a select
panel of people from our cross-functional Validation
Committee. We selected two systems to be more
closely scrutinized and invited vendor representatives in to demonstrate their systems. These in-house
demonstrations gave us a snap-shot of our in-house
water quality and also answered the nagging question about our ability to produce water that was 500
ppb TOC.
We reviewed the demonstration sessions and invited our primary candidate back again for a more
rigorous on-site trial with a variety of samples from
all around our facility. We again reviewed the two
top contenders and processed the request for funding. The selection process took far less time than the
funding process, but we finally received our shiny
new TOC Analyzer System.

In-line Sampling vs. Auto-Sampler

vs. Grab Sample
The choice is really yours. For our particular set
of needs, an in-line system just was not a practical
consideration. We were looking for the greatest level
of versatility and flexibility possible for our TOC
analyzer system. To be able to stretch our limited
budget as far as possible and be able to use the system for as many different functions as possible, we
selected an analyzer with the autosampler option.
With the autosampler, it is possible to set up a full
set of samples, start the machine at the end of the
day and collect the finished analysis reports the next
morning when you return to work. Proper set up of
the series of samples is the primary consideration. It
is a good idea to run your lowest expected
TOC/contamination levels first, then graduate to
samples with a higher potential for contamination.
This potential to walk away and allow the machine
to carry out its programming assumes that you have
that level of confidence in the machine and its capability to perform as it is intended, with minimal
human intervention. This may not happen initially,
but will come with time and experience with your
particular system.
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119

We also wanted to have the capability to process

cleaning process qualification samples, cleaning
process monitoring program samples, and perform
our regular DIW analysis, all on the same test platform. The system that we chose has the widest range
possible and still maintains the capability to achieve
accuracies below the 100 ppb level.

Validation of the Analyzer System

Several vendors offer a validation package.
Depending upon the level of expertise within an individual company, the amount of value your company
places on the time and effort it would take to replicate a comparable qualification package and the
availability of resources within your company, these
packages can be very valuable, despite the sometimes outrageous price that is attached to them. Since
this is a relatively new technology for us, we face
time and resource limitations. We chose to purchase
the vendor validation package. However, we did not
use all of the information made available to us in the
validation package. We instead prepared a protocol
that directed which sections we would be using and
how each section would be used to complete our
qualification effort. We attached copies of the appropriate vendor test sections and data collection sheets
to our protocol and approved it for execution.
Editorial Advisory Board Reviewers Commentary:
There is a need to evaluate the TOC vendors ability to
supply a compliant and usable protocol. Part of the
selection/purchase process should be an assessment of
the vendors validation capabilities. If the vendor
understands the cGMPs and has a good track record,
then their supplied protocols or validation services will
probably be adequate for your needs. Many vendor
protocols concentrate on validating of the functionali ty of their system, which should already be established,
as the system is in wide distribution. The intent of vali dation should be to assess the compliance and reliabil ity of the system as it is installed at the customer site.

Instituting Changes to the

Current Monitoring Program
If you already have a water system monitoring
program established, it will be a relatively straightforward revision of your current documentation. To
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swap one method of quality determination for

another should be directed by your in-house Document Change Control Program. The industry has
had a year to get this new program into place and
possibly exercise the new procedures for a month or
two. Be sure that your organization establishes a
clear cut-over date that is as close to the official initiation of the newest revision of the regulation. It
should, of course, follow the validation of the new
analyzer system and personnel training on any
change to sampling techniques and on the new
instrument(s) as well.
Since Sanofi currently (at the time of this writing),
does not have a crystal-clear understanding of the
performance of the entire system under this new
method of testing at all its points of use, and system
monitoring locations, we have chosen to approach
the implementation much like we did during a relatively recent system qualification following the
expansion of one of the DIW distribution loops.
Bioburden, pH, and resistivity will remain as we
have previously established in our program. We will
use the 500 ppb TOC as our Action Limit, but wait
to establish a meaningful Alert Limit based on a time
intensified system sampling plan. The entire system
will be sampled for 20 consecutive workdays. From
this data population we will establish our Preliminary
Alert Limit. The normal monitoring program will
kick in at that point, and the Environmental
Monitoring Committee will review the results as part
of the regular monthly environmental review schedule. At the end of the first year, the Preliminary Alert
Limit will be reviewed and adjusted if necessary to
more accurately reflect the actual system performance over the previous years sampling period.
If your company does not already have a water
system monitoring program established, get one
started.
Editorial Advisory Board Reviewers Commentary:
Look carefully at implementation schedules. Validation
and related programs using water quality monitoring
might end up with remnants of the old methods in addi tion to the new TOC methods. That means SOPs, train ing, and records might exist for both methods at the
same time. This would be very difficult to document
and defend in a final validation report. It may also be
necessary to implement the TOC program early in
some evaluations to assure continuity of the program.

Special Edition: Utilities Qualification

121

Management Considerations
in Water Purification
Systems Validation
By Shahid T. Dara
Schwarz Pharma Inc.

alidation is a multidiscidesign of a water system depends

plinary effort, especially
on the quality of water desired and
for a complicated system
is influenced by the physiochemiIn 1996, 27.5%
like water purification. In order to
cal and microbiological characterof
all
warning
accomplish a successful water sysistics of source water. (See Figure
tem validation, it is essential that
2 for Water Quality Designations).
letters
issued
to
the validation manager or profesA water purification system is a
the pharmaceutical living, breathing system, and the
sional assigned to head up this project must understand the complexvalidation cycle never ends with
manufacturers
ity of this endeavor from concept to
the initial qualification of the syscommissioning. This article is an involved citations for tem. As a matter of fact, between
overview of water purification sysroutine monitoring and periodic
water
systems
tems with a life cycle approach to
revalidation efforts, it is one of the
its validation and highlights the
most resource-consuming projects
deficiencies.
importance of a validation team
within a pharmaceutical manufacconcept in achieving the ultimate
turing operation. However, it is
goal, i.e., the consistent supply of purified water of
critical that a water system must be validated prior
desired quality.
to its commissioning and then be maintained in a
qualified state for its life. In 1996, 27.5% of all
Introduction
warning letters issued to pharmaceutical manufacWater is the source of life on this planet. For the
pharmaceutical industry, the importance of water
is unmatched, as it is used in huge quantities in
everyday operations, both in manufacturing and
cleaning (see Figure 1). Water quality determines
the ultimate quality of drug products manufactured.
Each water purification system is unique for a
given manufacturing facility, and the process itself
is a complex operation consisting of a series of
elaborate, multistep purification processes. The
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Special Edition: Utilities Qualification

Figure 1
Cleaning Agent:
Universal rinsing agent for equipment, solvent
for detergents/sanitizers.
Solvent:
Base for all aqueous liquids, injectables,
suspensions, ointments.
Granulating Agent:
For wet granulation preparation.
Diluent:
For lyophilized powders, reconstitution of
suspensions.

Shahid T. Dara

Figure 2
Potable Drinking Water: Meets EPA specifications
for drinking water (40 CFR 141).
USP Purified Water: USP 23, 1995, pp 1637.
USP Water-for-Injection: USP 23, 1995, pp 1635-1636,
USP Bacteriostatic Water-for-Injection: USP 23,
1995. pp 1636.
USP Sterile Water-for-Injection: USP 23, 1995, pp
1636-1637.
USP Sterile Water for Inhalation: USP 23, 1995,
pp 1636.
USP Sterile Water for Irrigation: USP 23, 1995, pp
1636.

turers involved citations for water system deficiencies. It is therefore prudent, both for regulatory
compliance and business profitability, to have a
team of experts to manage and conduct this validation.

Management of Water Purification

System Validation
If and when a pharmaceutical manufacturer
decides to install a new water system or to upgrade
an existing system, the validation department
should be involved from the earliest possible stage
to avoid undue delays caused by poor execution of
any phase of this mammoth project. A team
approach is the most effective way to accomplish
this very complicated undertaking, with clear lines
of communication and areas of responsibility and
accountability defined up front for each member
of the team. Basic project management assures
that the task will be finished on time per organizational requirements and within budgetary limits.
The validation team should be in place as soon as
the project is given a go ahead and there must be a
back up designated for each member of the team.

Validation Team
Who should be part of the Water System Validation Team?
Considering the technical aspects of the project,
the following disciplines should be represented
along with their primary areas of responsibility:

Engineering:
Concept and design of water system
Water system drawings per design
Installation, operation, and performance qualification of the system
Instrument calibration
Preventive maintenance schedules and
procedures
Water system drawings as built
Manufacturing:
End user of the product
System capabilities and limitations vs. plant
manufacturing needs
Operation of the system and usage criteria, i.e.,
flushing before use, etc.
Sampling of water
Quality Assurance:
Define SOP requirements for each phase of
validation
Change control procedures
Water sampling procedures
Employee training requirements
Quality Control Laboratories:
Chemical and microbiological testing
Test methods
Alert and action limits
Validation:
Project supervision
Prepare the protocols
Coordinate all validation activities
Collect all documents
Manage validation change control
Compile final reports
Coordinate review and approval of protocols
and final reports
Commissioning of the water system
Once the water system validation team is assembled, the project should be defined in detail, with
timelines established for completion and review/approval of all critical phases. Also, it should
be established who will be responsible for final
review and approval of the water system validation
before the system is commissioned for use.
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123

Shahid T. Dara

Life Cycle Approach

Water system validation is best accomplished via
a life cycle approach. Once the quality of water to be
produced is established, the project should be
divided into the following phases:

Concept
System design
Vendor/s selection
Water system drawings
Sampling plan
Installation qualification (IQ)
Operation qualification (OQ)
Performance qualification (PQ)
Final reports, reviews, and approvals
Ongoing monitoring
Revalidation

Concept:
The quality of water produced and the manufacturing needs of the plant determine the purification
technology to be used. While defining the desired
water quality and the manufacturing needs, one must

authority to ensure the source water meets the compendial requirements for drinking water. During
the design phase, the team should consider the initial cost of the system components as well as their
long-term maintenance costs. The design team
should consider the following when defining the
design specifications:
Pretreatment of Feed Water:
This is especially true for reverse osmosis membrane systems and is also needed to account for seasonal variation in source water quality. Pretreatment
is intended to minimize maintenance of the actual
purification system and could include the use of
dechlorination, depth filters, carbon filters, and
water softeners. Each step of pretreatment should be
duly documented along with operating procedures
for cleaning and sanitization to comply with validation requirements.

Purification of Water:
Source water can be purified by deionization,
reverse osmosis, or distillation. Each purification
technique has its merits and demerits. However, the
selection should be based on
eventual use of the purified
A team approach is the most effective
water and the compliance
benefit/risk analysis, as there
way to accomplish this very
could be a substantial cost
difference in switching from
complicated undertaking.
one purification technology
to another. Generally, USP
Purified Water is water obtained by deionization,
consider current requirements, as well as any future
reverse osmosis, or distillation, while USP Waterexpansion possibilities, thereby building flexibility
for-Injection is water purified by distillation or by
in the system to expand if needed. Validation should
reverse osmosis.
have a thorough understanding of the purification
technology, as it will help in preparing effective valDeionization:
idation protocols.
Deionizers remove solids that are ionic in nature
from source water. Cation exchangers replace posWater Purification System Design
itively charged ions, like calcium and magnesium,
with hydrogen ions. Anion exchangers replace negIn designing a water purification system, the
atively charged ions, such as phosphate and sulfate,
quality of the source water must be considered.
with hydroxide ions. When used in series, a cation
Local water authorities can provide some vital
exchanger and an anion exchanger combine to
information as to the historical data on source
deliver nearly pure water. Use of mixed bed deionwater quality as well as any seasonal variations in
izers, containing both cation and anion resins, genthe water quality. Also, periodic water test reports
erally generate the best quality water. In deionizashould be obtained routinely from the local water
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Shahid T. Dara

tion based water purification systems, the purified

water is passed through a UV lamp and a 0.2
micron filter to reduce the microbial count.
Deionization can be used as the primary purification technique when the USP Purified Water is to
be produced in limited quantity and is therefore
cost effective compared with reverse osmosis or
distillation. However, deionization is usually the
first step in the purification process and is either
followed by reverse osmosis or distillation to
obtain water of desired purity.
Ion exchange resins regeneration schedules can
be defined by measuring the conductivity of feed
water vs. conductivity of effluent. By trending these
values, one can predict the regeneration cycles with
reasonable accuracy.
Deionization has its limitations:
Limited capacity based on the ion exchange
resin volume and type
Regeneration of ion exchange resin
Hazards of handling caustic regeneration
chemicals
Potential of idle resins to harbor microbial
growth
Need for a close monitoring of automatic
regenerating cycles
Reverse Osmosis:
The principle of reverse osmosis is pretty simple:
Under pressure certain membranes pass water
molecules while rejecting others. It is filtration
under pressure and leads to separation of suspended
and dissolved solids from water. Flow across the
membrane is tangential, and large quantities of the
feed water are rejected. To make it feasible, a very
large filtration surface area is required, and that is
accomplished by rolling into alternate layers of
inert porous material and filtration membrane. A
single pass RO filter can remove more than 95% of
dissolved solids from feed water. Usually a multipass filtration schematic is used so that initially
rejected water is refiltered. Using conductivity measurements of the feed water and the effluent, the
rate of water purification can be determined, and a
trending of these values can also be used to establish cleaning schedules for RO systems. When used
in series, RO systems can produce very high quality

water, meeting the USP Water-for-Injection monograph. However, reverse osmosis has its own limitations:
High pressure of feed water can damage the
filter membrane.
Reverse osmosis filter membranes are not
absolute and can let microbes pass through.
Fine contaminants, like silica, can pass
through these membranes.
Most reverse osmosis filter membranes are not
resistant to chlorine. Therefore, the feed water
has to be dechlorinated, leading to a high
bioload for the membrane to handle. This
could cause microbial contamination of the filter membrane and would require periodic sanitization.
Scale formation at the filter membrane surface
is another problem which could limit the effective filtration area.
Distillation:
Distillation is the most popular method of water
purification and can produce both USP Purified
Water as well as USP Water-for-Injection. Feed
water is boiled to make steam, leaving behind the
contaminants in a liquid state. The steam is removed
from the boiler and condensed into water, either
using a cooling heat exchanger or compression.
Distillation can purify up to 95% of feed water and
the efficiency can be increased by using multiple
stills. The liquid concentrate of the contaminants is
removed from the still by a process referred to as
Blowdown. Distillation does reduce the endotoxins
level of feed water: however, the feed water must be
reasonably free of microbes and endotoxins to produce Water-for-Injection.
Initial cost of a distillation unit and attendant controls along with ongoing maintenance is a major
investment and can run into hundreds of thousands
of dollars. Inappropriate design or operation of a distillation unit can be very costly. If the system is idle
for any reason (routine maintenance) for a period of
time, the feed sections of stills become dead legs and
could harbor microbes. The still must be cleaned and
sanitized before restarting, otherwise a mixture of
water and microbes can enter the still and contaminate the whole system.
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125

Shahid T. Dara

Heat Exchangers:
If purified water is to be stored after production
and has to be recirculated, then there will be a
need for heat exchangers to maintain the water
temperature above 80C 85C during storage.
Also, there will be a need for heat exchangers
(with adequate chill water flow), to cool the hot
water to ambient temperatures before it is used.
For a facility working eight to ten hours a day, the
system should be designed to operate in a thermal
cycling mode. At the beginning of a work day, the
heat exchanger with adequate flow of chill water
will decrease the temperature of stored and recirculating water to 25C. The inlet temperature for
the chill water should be about 12 13C and the
outlet temperature would be about 18C. The flow
rate of the chill water is determined by the volume
of water to be cooled. At the end of a work day, the
recirculating loop operating at 25C is heated to 80
85C, using facility maintenance steam which
also maintains the temperature of water in the storage tank. All heating and cooling operations are
performed and controlled by a dedicated heat
transfer and control system associated with the
jacketed and insulated water storage tank.
For continuous-use operations, the water in the
storage tank and the recirculation loop is maintained at 80-85C, and it is at the point of use drops
where the water is cooled down to 25C using
chiller water.
Storage Tank:
The purified water storage tanks material of construction should be such that it does not compromise
the integrity of the purified water stored inside.
Preferably, it should be constructed from stainless
steel and should be equipped with vent filter attachments which allow for easy replacement of the filter.
Distribution Piping:
Purified water is distributed over varying distances in a manufacturing facility. The piping
could be made of stainless steel or PVDF. Both
materials are inert and easy to sanitize. One
should be aware of the dead legs in the piping system and should keep these to a minimum. System
sanitization could be a routine activity based on
the data gathered during validation and daily
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operation of the system.

Sanitization might also be required in response to
a contamination of the system with microbes. Steam
sanitization is the best way, as it will not leave any
residue but could cause problems by removing the
biofilm built up on the inner surface of distribution
piping. Also, it may not remove all the microbes
either.
A number of chemical agents have been used
alone or in combination for water system sanitization. However, chemicals can have adverse reactions
with stainless steel or PVDF, generating chemical
impurities while removing microbes. Also, the
chemical sanitizers could leave residues in the water
stream which could have an adverse effect on the
drug product stability, especially if it is a highly
potent oxidizing agent. Hydrogen peroxide has been
used successfully in varying concentrations (0.2%
10.0%) in sanitizing water purification systems, as it
is an effective biocide and degrades into water and
oxygen.
Other chemicals mentioned in literature include
sodium hydroxide, mineral acids, sodium hypochlorite, peracetic acid, etc. Sanitizer selection and frequency of sanitization should be established during
validation of the water system.

Vendor Selection
Selecting vendors of a water system components
should be based on a vendors reputation in the pharmaceutical industry, and consideration should be
given to the following:
Prior experience in pharmaceutical industry
water system design, installation, and operation
Knowledge of pertinent regulatory requirements
Ability to provide documentation when required
Training capabilities
On-site technical support
The design team should develop a standardized
questionnaire for prospective vendors. Also, it
should ensure that each vendor has the ability to
document the work performed per validation protocols. Suppliers/vendors should be paid only when

Shahid T. Dara

validation certifies that all necessary services, documents, etc., have been provided and meet the validation requirements.

Water System Drawings Per Design

Once the water system design is finalized, the
vendor must provide detailed drawings of the system before starting the installation. This drawing
per design should be used as a blueprint to compare the actual installation of all the components
to the design specifications and should be redlined whenever necessary to reflect any deviations from approved design. Once the installation
is complete, a final as built water system drawing should be provided by the vendor and become
part of the validation package as a required document.

Sampling Plan
Sampling plans should be critically evaluated
before adoption in validating a water purification
system. The FDA Guide to Inspection of High
Purity Water Systems details the Agencys
expectations. The initial sampling plans during
OQ are meant to assess the systems ability to perform as a unit and produce water of desired quality. The samples should be taken daily (seven days
a week) and analyzed for both microbial and
chemical contents. If the system is equipped with
heat exchangers/water chillers, the water temperature profile should also be determined at this
point.
During PQ, sampling and testing can be divided
into two phases. Initially, the samples should be
taken seven days in a row. During this time, multiple samples might be pulled from each site each
day. If the results are satisfactory, the sampling
could be reduced to five days a week for the next
four weeks. This will mimic the routine operational
activities, when there is no activity over the weekend and holidays. The samples are again tested for
chemical and microbial contents. The water temperature profile is also established during this
period, measuring the water temperature distribution within the storage tank, distribution loop, and
at the points of use drops.

Installation Qualification
As the design is finalized, validation personnel
should start developing the qualification protocols.
This will enable the engineering personnel to
obtain all necessary documents from the different
vendors as the components are being purchased.
Also, this will help technicians to verify that the
water system components are being installed per
design and each component meets its specifications. If the vendor is involved in the installation
of the equipment, a copy of the IQ protocol should
be provided to their technical staff. This ensures
that the vendors engineers and technicians understand the validation requirements and are familiar
with the documentation.
The IQ protocol should detail the following:
System description
Scope of qualification
Responsibilities
Incoming components specifications and inspection
Installation verification
Utilities installation
Critical instrumentation calibration
Software qualification, if needed
Preventive maintenance procedures
Documentation
System drawings as installed
SOPs
Summary report and conclusions

Operational Qualification
Following successful installation of all the components, the water system should be commissioned
for operation after testing each component ( and the
water system as a whole), assuring that it operates
per manufacturers instructions and specifications.
All the controls should be operating within limits,
and critical instruments should be within their calibration period. The IQ must be completed before
starting the OQ.
The OQ protocol should detail the following:
System description
Scope of qualification
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127

Shahid T. Dara

Responsibilities
Critical instrumentation calibration
System cleaning/sanitization procedures and
frequency
Sampling plan
Daily for two weeks
Sampling points
Source water
After each critical step in the purification
process
Storage tank (temperature profile and
water quality)
Circulation loop (temperature profile only)
At each point of use (temperature profile
and water quality)
Sampling procedures
Testing requirements
Testing methodologies
Acceptance criteria
Documentation
SOPs
Summary report and conclusions

Performance Qualification
Once the IQ and OQ are completed, the water
system should be qualified to prove that it is capable of producing water of desired quality consistently over a period of time under varying seasonal
conditions.
The OQ protocol should detail the following:

System description
Scope of qualification
Responsibilities
Critical instrumentation calibration
Sampling plan
Initially one week
Daily for four weeks
Sampling points
Source water, initially and every week
thereafter
After each critical step in the purification
process
Storage tank (temperature profile and
water quality)
Recirculation loop (temperature profile
only)
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Special Edition: Utilities Qualification

At each point of use (temperature profile

and water quality)
Sampling procedures
Testing requirements
Testing methodologies
Acceptance criteria
Documentation
SOPs
Summary report and conclusions

Commissioning of Water System

Following a successful campaign of IQ, OQ, and
PQ, the water system can be commissioned for routine production of water of desired quality. However,
all the validation protocols must be completed and
the summary reports with conclusions be reviewed
and approved by all the pertinent organizational
units before the water is used in manufacturing.

Ongoing Monitoring:
In order to complete the validation cycle, the
sampling and testing of water should continue after
the water system has been qualified and commissioned to produce water of known quality. This is
necessary to account for any seasonal variation in
the quality of feed water.
Sampling plan
Routine sampling frequency
Sampling points
Source water once a month
For Water-for-Injection, one point of use
daily and all points of use once a week

Revalidation
Water systems are periodically revalidated.
However, revalidation might be called for if there is
a critical change in equipment or there are persistent water quality issues. In such cases, depending
on the cause, the revalidation effort might be a
repeat of the PQ alone or could involve IQ/OQ
also. Each case should be duly investigated and
system requalification be performed per company
policies.

Shahid T. Dara

Call for More Details

PO Box 6004
Duluth, MN 55806
Tel. 218-740-7028 U.S. Only 888-524-9922
Fax: 218-740-6308
E-Mail: [email protected]
Web Site: www.ivthome.com
Special Edition: Utilities Qualification

129

TheStudy
Studyofofthe
theDesign
Design
The
ProductionSystems
Systems
ofofProduction
Purified Water for
ofofPurified
thePharmaceutical
Pharmaceutical
Industry
the
Industry
By I. Lerin Riera,
R. Salazar Macian,
J.M. Su Negre,
and J.R. Tic Grau
University of Barcelona

O
Part I

ater used in the pharmaceutical industry,

especially water used to
manufacture drug products (purified water and water-for-injection)
is vital to the manufacture of these
products and, therefore, should be
considered as a raw material that
needs to comply, at a minimum,
with specifications set out in Pharmacopeia.
Presently, validation is essential to ensure the reliability of any
system to produce water of pharmaceutical quality. The first step to ensure the correct functioning of the system is that each instrument, each component, all the building materials,
and all other considerations in the design of these
systems should comply with ruling Pharmacopeias
and the current Good Manufacturing Practice
(cGMP).
This study examines the design of the production
systems of purified water for the pharmaceutical
industry in three pharmaceutical plants where a study
130

on the design (description of functioning) is carried out for each of

them, together with a report on the
design.

Special Edition: Utilities Qualification

General Considerations

The chosen pharmaceutical plants

have been labeled Pharmaceutical
Plant A, Pharmaceutical Plant B, and
Pharmaceutical Plant C.
The study for each of the three
plants has been separated into two
distinct sections:

1. Study of the design: A description of the functioning of the system. To examine the
design of each production system of Purified Water,
the study has been divided into two phases:
Production and storage of purified water
Distribution of purified water to points of use
2. Report on design: Contains recommendations
for each point of improvement* (both critical and
noncritical) detected by the study in the design.

Pharmaceutical Plant A
In Figure 1, the fundamental stages to carry out a
systematic follow up on the flow of the water have
been numbered, from the moment it enters the system as feed water to the moment the purified water
enters the distribution loop where the different
points of use are found.

Study of the Design

Description of the functioning of the system
Production of Purified Water
Chlorination flocculation filtration
decalcification adding sodium hypochlorite
carbon filter 2 m filtration reverse osmosis
Osmotic water storage tank ionic exchange 2
m filtration UV lamp 0.22 m filtration
Purified Water storage tank.
Water purification is carried out in two funda-

mental stages, a first stage of purification by means

of reverse osmosis and a second stage of polishing
by means of ionic exchange resins.
The dechlorination of the water prior to the
reverse osmosis step is carried out through the action
of a carbon filter.
Note that in the system there are two recirculations: R1 and R2. These recirculations prevent the
water from remaining stagnant in critical equipment,
such as reverse osmosis membranes and the ionic
exchange resins, during periods when production is
stopped.
R1: The R1 water recirculation refers to the
recirculation from the exit of reverse osmosis to the
intermediate storage tank. This recirculation is put
into operation if the osmotic water tank is full,
which occurs when there is no consumption of
purified water, i.e., during the night, at weekends,
and holiday periods. At the same time, this recirculation is also put into operation in case the conduc-

Figure 1

Production System for Purified Water Design Diagram:

Pharmaceutical Plant A
1

1.
2.
3.
4.

5.
6.
7.
8.

Glossary
Chlorination
9. Ionic exchange
storage tank
resins
Sand filter
10. UV lamp
Decalcification
11. 2 micrometer
equipment
and 0,22
Intermediate
micrometer filters
storage tank
12. Purified storage
(adding of soditank
um hipochloride) 13. UV lamp
Carbon filter
14. 0,22 micrometer
Intermediate
filters
storage tank
15. Heat exchanger
Reverse
16. Distribution ring
Osmosis
to points of use
Osmotic water
storage tanks

13 14 15

R1:
R2:
R3:

Recirculation 1
Recirculation 2
Recirculation 3 (Distribution loop)

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131

tivity values of the water when leaving the reverse

osmosis are higher than those of the established
limit.
R2: R2 water recirculation refers to the access to
the purified water tank to the osmotic water storage
tank. This recirculation is put into operation when
the purified water tank is full, which occurs when
there is no consumption of purified water.
With the aim to avoid excessive loss of water
due to the rejection of the reverse osmosis, this goes
into operation cyclically for 15 minutes every 120
minutes, recirculating through the R1 recirculation
to the storage tank.
Storage and Distribution of Purified Water to
Points of Use
Purified Water storage tank UV lamp 0.22
m filtration heat exchanger distribution loop
Purified Water storage tank
The microbiological quality of both the purified
water from the storage tank and that of the water
flowing through the distribution loop is assured by
the UV lamp and the two high efficiency filters of
0.22 m installed in parallel before the water enters
into the distribution loop where, except during holiday periods, the water is constantly recirculating.
After any holiday period, sterilization with clean
steam is carried out at 121C for one hour. In addition, the loop is cleaned for sanitary purposes every
15 days with purified water heated to 80 85C for
90 minutes.

Report on the Design of Plant A

Conclusions
Having studied the detailed description of the
functioning of the system, some points of improvement are proposed, and a series of recommendations
for each are set down.
Recommendations
1. Carbon filter: Although carbon filters are a
technological option for water dechlorination, they
invite a high risk of microbiological contamination
in the system. It is then advisable to eliminate such
filters and obtain dechlorinated water by means of a
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Special Edition: Utilities Qualification

system of bisulfite dosifications together with the

corresponding controls. It is advisable in the actual
situation to:
a) Strictly control cleaning and sanitization
procedures, which should occur at least once
a week in the beginning, then using experience to indicate the necessary frequency to
ensure that microbiological levels are within
limits.
b) Control water leaving the carbon filter twice a
week to establish the microbiological level.
2. Stainless steel tanks: These cannot be sterilized
with clean steam, so it is recommended that they be
replaced with storage tanks that can be. Considering
the possibility of the intermediate tank, an alternative solution is to install a UV lamp at the entrance
to the reverse osmosis. This would achieve a much
lower microbiological contamination and provide
greater safety for the system.
3. Return of the distribution loop to the purified
water storage tank: Installing a UV lamp will avoid
accidental contamination which might arise at any
points of use. In this way, the correct microbiological quality of the water entering the purified water
tank coming from the return of the distribution loop
could be ensured.
4. The 0.22 m filters: Can be eliminated,
which would represent an economy, as the UV
lamps are considered to be enough to assure
microbiological quality. Keep in mind that
although applying the high efficiency filters is a
technologically correct option to ensure microbiological quality of the water in the last stages, these
filters represent a high-maintenance cost (sterilizing and regular changing). The use of ultraviolet
technology along the pretreatment phase and at
distribution is considered an adequate technology,
as it maintains the microbiological quality level at
lower maintenance costs.

Pharmaceutical Plant B
The study carried out is similar to that for Plant
A. See Figure 2.

Figure 2

Production System for Purified Water Design Diagram:

Pharmaceutical Plant B
1

R2
Glossary
1. Chlorination storage
7. Reverse Osmosis
tank
8. Osmotic water
2. Adding of flocculant
storage tanks
3. Dechlorination by
9. Ionic exchange resins
means of sodium
10. 1 and 0.22 micrometer
bisulfate
filters
4. 10 micrometer filter
11. Heat exchanger
5. Adding of chelating
12. Purified storage tank
agent
13. Distribution loop to
6. 5 micrometer filter
points of use

Study of the Design:

Description of the functioning of the system
Production of Purified Water
Sand filter decalcification equipment chlorination Flocculation adding of bisulfite 10
m filtration adding of abductor 5 m filtra tion reverse osmosis intermediate storage
tanks ionic exchange resins 1 m filtration
0.22 m filtration Heat exchanger Purified
Water storage tank.
As in Plant A, purification of water is carried in
two stages, first, by a reverse osmosis unit and second, refining by means of ionic exchange mixed bed
resins.
Water dechlorination prior to reverse osmosis is
carried out by adding sodium bisulfite. At the same
time, note the addition of the chelating agent, which
avoids the precipitation of carbonates and calcium
sulphate on the membranes of reverse osmosis due
to a possible excess of sodium bisulfate.
There is a double recirculation, R1, which
includes the two storage tanks of osmotic water and

13
R1

R1:
R2:

Recirculation 1
Recirculation 2 (Distribution loops)

the two installations for demineralizing. In this way,

possible microbiological contamination in the inner
layers of resin is diminished when the equipment does
not produce water, whether there is no need for consumption or simply because it is in reserve.
The microbiological quality of the water that
goes into the purified water tank and comes from the
ionic exchange resins is ensured first by a 0.22 m
filter and later by the heat exchanger. The water is
stored at 80C in the heat-resistant storage tank,
which is made of AISI 316 L stainless steel.
Storage and Distribution of Purified Water to
Points of Use
Purified Water storage tank distribution loop
Purified Water storage tank
It should be noted that the microbiological quality
of both the water in the purified water tank and that of
the water flowing through the distribution loop in this
plant is assured by increasing the temperature of the
water carried out by the heat exchanger to 80C.
Starting from the stainless steel storage tank the water is
pumped to the entire plant, flowing at 80C in a closed

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133

loop so as to ensure that the water is sterile in practice.

To maintain the temperature, the storage tank for the
purified water and the distribution loop are insulated.

such a way that any possibility of microbiological

contamination of the water entering the osmosis
module is avoided.

As the flow of water is thermostatically controlled at 80C through the loop, no stoppages in the
recirculation of the distribution loop are forecasted
for its sanitization as supported by the microbiological data of this plant. In practice, the distribution
loop is sterilized by means of clean steam at 121C
for an hour after holiday periods.

2. Regarding the R1 recirculation: Recirculation

of water through the reverse osmosis module during
periods when production is stopped is not contemplated. This implies the risk that the membranes in
such modules could be microbiologically contaminated. Install two UV lamps-one at the entrance of
the reverse osmosis modules and one at the exit-to
ensure the microbiological quality of the water
entering and leaving.

Report on the Design of Plant B

Conclusions
Having carried out and studied the detailed
description of the system according to the design
diagrams, the design can be considered to be correct.
In this design, the microbiological quality of the
water in the distribution loop and the purified water
storage tank is assured by heating the water to 80C,
in contrast to the design of Plant A, where quality
was ensured by the combined use of sterilizing filters and ultraviolet technology.
Keep in mind that the FDA(Guideline 1993) considers that heat, as an assurance of microbiological
quality in the distribution loop, can turn out to be
more expensive than other systems. At the same
time, it states that maintenance and control costs,
together with the potential problems that other systems might incur, could be higher than the cost of
power saved.
Some points that could be improved upon have
been detected. A series of recommendations are set
out for each of them.
Recommendations
1. Dechlorination by means of bisulfite:
Dechlorination using bisulfite after the flocculation
and prior to the entry of the water into the modules
of reverse osmosis could entail a risk of microbiological contamination by use, as it is considered that
the dechlorination is carried out at a stage excessively distant from the reverse osmosis. It is advisable for the chlorination to be carried out prior to the
entry of the water into the reverse osmosis or, otherwise, for a UV lamp to be installed at the point
where the water enters into the osmosis module in
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Special Edition: Utilities Qualification

3. Section of the pipe in which water could remain

stagnant while the R1 is functioning: If the R1 recirculation is started up, there is a section of pipe
between the beginning of said recirculation (after the
ionic exchange resins module) and the purified water
storage tank where water could remain stagnant. One
possible solution calls for not starting the water recirculation exactly as it has been designed (immediately
after the exit of the ionic exchange resins module),
but at the point where the water enters the purified
water tank. In this way, the dead leg can be avoided.
4. 0.22 micrometer filter at the entrance to the
purified water storage tank: Its elimination is recommended. Despite being an option to ensure the final
microbiological quality of the water coming into the
tank of purified water, the thermostatic control of the
water by means of the heat exchanger is considered
to be sufficient assurance. It should be kept in mind
that the water at the entrance to the purified water
storage tank must comply with the microbiological
limits of Pharmacopoeia.

Pharmaceutical Plant C (Figure 3)

Study of the Design:
Description of the functioning of the system
Production of Purified Water
Flocculation chlorination filtration carbon
filters 5 m filtration decalcification ozonation 5 m and 1 m filtration UV lamp 1ST
reverse osmosis UV lamp 2ND reverse osmosis ozonation Purified Water storage tank.

Figure 3

Production System for Purified Water Design Diagram:

Pharmaceutical Plant C
1 2

11.a 10

11.b

14.a
7
R1

7
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Glossary
Adding of flocculant
11.a.Reverse Osmosis
Adding of chloride
11.b.Double reverse osmosis
Silex anthracite filter
12. Purified water storage
Carbon filters
tank
5 micrometer filter
13. UV lamps
Decalcification equipment
14.a.Distribution loop 1:
Ozonation
Production
5 and 1 micrometer filters
14.b.Distribution loop 2:
UV lamp
Laboratory
UV lamp

In this plant, water is also purified in two

stages, but differently from the other plants and,
because of the low conductivity of feed water, it is
carried out through double reverse osmosis.
Dechlorination of the water is carried out using
two carbon filters in a parallel installation.
Note that from the moment the decalcified
water is obtained, its microbiological quality is
ensured by the combined treatment of ozone (bactericidal and oxidizing agent) and of ultraviolet technology.
Throughout the system, the water is ozonated
several times, specifically at the entry points to the
purified water storage tank, at the entry point coming from the production plant, and in all the returns
in the two distribution loops. Water is also ozonated
when it leaves the tank of purified water before the
water enters each of the two loops, just prior to the
last treatment with ultraviolet lamps.
Keep in mind that the use of ozone as a bactericidal agent is far more convenient than treatment with
chloride; the effect of the ozone is not influenced by
the pH in the medium. On the other hand, it does not

R1
14.b

R1:

Recirculation 1: Distribution loops

leave residual compounds, add odor or flavor, nor

does it attack the membranes in the ionic exchange
nor those in the osmosis stage. In this sense there
should be no concern regarding the elimination of
ozone after treating the water. However, it does have
a drawback when compared to chloride: Its effect is
not as lasting, which implies that the water should be
treated later with chloride at a smaller dose (as a
result of the prior treatment with ozone) or, as in this
case, repeat treatment along the entire system to ensure the bacteriological quality of water thus treated.
Nevertheless, it is well known that UV wavelengths
employed in water treatment are 254 nm and 185
nm; 254 nm UV light is employed in disinfection
and ozone destruction applications.
Storage and Distribution of Purified Water to
Points of Use
Purified Water storage tank ozonation UV
lamp distribution loop ozonation Purified
Water storage tank
The design shows two independent distribution
loops from a sole tank of purified water. The micro-

Special Edition: Utilities Qualification

135

biological quality of the water in the purified water

storage tank and the water flowing through each of
the two loops is ensured by the joint action of ozonation and UV lamps. At the same time, in each of the
returns of the two loops and before the water enters
the tank of purified water, the water is again ozonated. A flow of ozone also goes to the tank for its sterilization. After holiday periods, sterilization of the
two distribution loops is carried out by means of
clean steam at 121C for one hour.

Report on the Design of Plant C

Conclusion
After studying the design of Pharmaceutical Plant
C, it can be said that it is correct to achieve water of
microbiological and chemical quality as set out in
the norms for purified water to be used in the pharmaceutical industry.
Note that there are two differences between the
design of the Pharmaceutical Plant C and that of the
Pharmaceutical Plants A and B.
The first difference is that once the water has been
decalcified, ozone is used together with ultraviolet
technology to assure microbiological quality. The other
difference lies in the double-sequenced reverse osmosis treatment, which enables correct conductivity of the
water. The high quality level of the water obtained by
double osmosis makes the ionic exchange resins in the
system unnecessary, thus avoiding the drawbacks they
represent in the regeneration of same.
Keep in mind that the application of doublereverse osmosis is recommended only for water with
low conductivity (under 600 (s/cm), as an increase
of concentration will overcome the retention capacity of the reverse-osmosis, thus causing the water
leaving the osmosis modules to have a conductivity
over the limits.
Should the water have a high conductivity
(6001500 (s/cm), employ ionic exchange resins or
electrodeionization equipment (CDI), as these methods have a greater power of retention than that of
reverse osmosis.
There are several points where improvements can
be made.
Recommendations
1. Recirculation between the purified water storage
136

Special Edition: Utilities Qualification

tank and the modules of reverse osmosis: There is no

recirculation of water between the purified water tank
and the modules of reverse osmosis in case of stoppage,
whether caused by the tank of purified water being full
or by stoppages at weekends or holiday periods. In both
cases, the water will remain stagnant in the pipes and
equipment from the entry of feed water to the modules
of reverse osmosis (inclusive), with all the dangers of
microbiological contamination that this entails.
A system for water recirculation should be placed
between the tank of purified water and the two modules of reverse osmosis, like the one in Pharmaceutical
Plant A.
2. Carbon filters: To avoid the problems of microbiological contamination and maintenance these
systems require, it is preferable to remove them and
obtain dechlorinated water by means of a system of
bisulfite dosage with its corresponding controls. It is
advisable to:
a) Strictly record the cleaning and sanitization
processes, which should be carried out at least
once a week. Experience will suggest the most
adequate frequency to ensure that the microbiological levels are within limits.
b) Check the microbiological level of the water
twice a week at the point it leaves the carbon
filter.
3. Ozonation: Bear in mind that, in this plant, the
ozone and UV treatments are used consecutively.
Although apparently this is contradictory to previous statements; as a general rule, a UV dosage of
90,000 (W-s/cm2 is required to completely destroy 1
ppm (1 mg/l) of residual ozone.
The bactericidal treatment of water by using
ozone is a technologically correct option, but it is far
too expensive. Therefore, it is recommended to
replace this treatment with one less expensive, such
as ultraviolet lamps, as these represent much lower
maintenance costs.
Points of improvement are understood to be those
points where the final quality of the product as well
as the productivity of the process might be affected.
These points of improvement are divided into critical and noncritical points.
Critical points are those which affect or might

Special Edition: Utilities Qualification

137

The European Pharmacopoeia still requires the

determination of salts, oxidizable substances, and pH.
Microbiological specifications for purified water
determined by the European Pharmacopoeia and the
USP 23 are very similar. The only difference
between them is that the USP 23 establishes two
kinds of limits-alert and action limits-and the
European Pharmacopoeia establishes only one,
which coincides with the USP 23 action limit.

Study of the Design:

Diagram and description of
the functioning of the system
Figures 5, 6, and 7 show the design of each system.
Description of the Functioning

Two clearly distinct phases were set:

Phase 1:
Phase 2:

Production of purified water

Storage and distribution of purified
water to points of use

Phase 1: Production of Purified Water (see Figure 5).

Production of Osmotic Water
Chlorination flocculation filtration
decalcification dechlorination (by bisulfite) 5
rim filtration W lamp reverse osmosis.
Feed water (drinking water or from the well) is
submitted to chlorination in tank. From this tank,
water is driven along the circuit by two alternative
pumps.

Figure 5

Optimized Design (Plan 1/2)

Production of Purified Water
Vent
FIlter
1

3 SilexAnthracite
Filter
3

6
Chloride
Detector

1
Chlorination
Tank

Feed
Water

2 Adding of
Flocculant
Return from the
Distribution Loop

7
5 m
Filter
4

8
Decalcified
Water
Storage
Tank

5 Dechlorination
Through
4 Decalcification Bisulfite
Equipment

Clean
Steam

TOC

Clean
Steam

10
14 UV

Sterile Vent
FIlter HEPA
R1: Recirculation 1

Distribution
Loop

15
Purified
Water
Storage
Tank

9
13 UV

7
11 UV

12
CDI: Electrodeionization
Equipment

138

Special Edition: Utilities Qualification

6
10
Reverse
Osmosis

9 UV

C:
Conductivity meter on-line
TOC: (Total Organic Carbon)
TOC measurer on-line

Figure 6

Optimized Design (Plan 2/2)

Storage and Distribution of Purified Water to Points of Use
16

17
19 UV

R2: Recirculation 2

Points of Use

Clean
Steam

15
Purified
Water
Storage
Tank

18 Distribution Loop

TOC

HEPA Sterile
Vent Filter

11
From
Production
Plant

17 UV
16
Heat
Exchanger

When leaving the tank, the flocculant is added to

cause a flocculation of solid matter, easing its elimination through filtration by silex-anthracite, the function of which is to retain suspended solids.
The water, once filtered, goes through decalcification equipment, which retains calcium and magnesium in the water. The equipment is made up of a
double cationic resin in sodium cycle, with the aim of
carrying out an automatic regeneration of resins, i.e.,
when one of these goes into a regeneration period,
the other column starts functioning. This means that
it is not necessary to stop the production of purified
water to allow for the regeneration of these resins.
Once the water has gone through the decalcification
equipment and just before it enters the decalcified water
storage tank, dechlorination of the water takes place by
injecting bisulfite into the system, avoiding the chloride
attacking the membranes of the reverse osmosis.
As chloride, even at low concentrations, could damage the membranes of the reverse osmosis module,
there is a chloride detector after the dechlorination module and just before the entry of water into the decalcified
water storage tank. This ensures that the process is
stopped should there be a high level of chloride in the
water and thus preventing it from entering the tank.
Prior to the water entering the decalcified water

TOC: (Total Organic Carbon)

TOC measurer on-line

tank, it flows through a 5 m filter to retain particles which might break away from the decalcification equipment.
The water enters the decalcified water storage
tank, which is sterilized by clean steam.
After the water leaves the decalcified water tank
and prior to it flowing into the reverse osmosis, the
water flows through an ultraviolet lamp to ensure its
microbiological quality before entering the reverse
osmosis modules.
Water is driven by two autonomous high-pressure
sanitary pumps (15/20 atmospheres) into the
polyamide membranes of the reverse osmosis modules to carry out the first stage of deionization, eliminating 95 97% of the salts in the water, thus
allowing the desired quality to be attained in an economical way.

Purification of Osmotic Water

Into Purified Water
Reverse osmosis W lamp electrodeionization (CDI) Wlamp Purified Water storage tank.
Once it has gone through the reverse osmosis, the
water passes the ultraviolet lamp, ensuring its microSpecial Edition: Utilities Qualification

139

biological quality before it enters the electrodeionization equipment (CDI) This eliminates salts which
may remain in the water after going through the
reverse osmosis modules. It should be noted that
there is a conductivity meter installed on-line at the
exit of the CDI equipment which stops the production of purified water should the specified values of
conductivity be surpassed as specified by the USP
23 (1 3 s/cm at T=25C).
Once it has left the electrodeionization equipment, the water flows through an ultraviolet lamp to
ensure its microbiological quality before it enters the
purified water tank.

Phase 2: Storage and Distribution of

Purified Water to Points of Use
(See Figures 6 and 7)

In the return of the distribution loop to the purified water tank and before it enters the tank, the
water is again treated by a UV unit to ensure its
microbiological quality before arriving at the storage tank. Before the water enters the purified water
tank, there is an on-line TOC (Total Organic
Carbon) measurer that allows control of the level of
organic substances present in the purified water.
Another possibility to ensure the microbiological
quality of the purified water to points of use consists
of changing the ultraviolet treatment units by water
heating to 80C by means of a heat exchanger.
Keep in mind that, in this sense, the FDA
(Guideline 1993) considers that although the use of
heat could turn out to be more expensive than other
systems, it does lower control and maintenance costs
and reduces potential problems in the production
system for purified water.

Purified Water storage tank Heat exchanger

W lamp distribution loop UV lamp
Purified Water storage tank
The water leaves the purified water storage tank
and passes through a heat exchanger before it reaches the points of use in the distribution loop. The heat
exchanger sanitizes the loop. Later, the water is driven by two independent pumps to a UV unit and,
finally, to the distribution loop.

Recirculation
This design in Figure 8 shows the recirculations
which ensure the quality of the water in case of stoppage in the production of purified water.
R1 recirculation: R1 recirculation starts after the
ultraviolet lamp and before the purified water storage tank (and creates a closed circuit.)

Figure 7

Optimized Design (Plan 2/2) Storage and Distribution of

Purified Water to Points of Use Heated Water to 80C
Recirculation of
Purified Water
Heated to 80C

Clean
Steam

TOC

HEPA Sterile
Vent Filter
RS

Purified
Water
Storage
Tank

Points of Use

Heat
Exchanger

From
Production
Plant

Recirculation for Sterilization of the loop with

water overheated at 121C
TOC: (Total Organic Carbon) TOC measurer on-line

RS:

140

Special Edition: Utilities Qualification

The installation of the ultraviolet lamp. Located

in the recirculation circuit at the entry to the storage
tank, it ensures the microbiological quality of the
water entering the tank.
Rl recirculation functions during periods of nonproduction, i.e., when the purified water tank is full,
during holiday periods, and during stoppages for
sanitization of the distribution loop
The recirculation is continuous to avoid the risk
of the contamination of the water when there is no
production. So, when there is no demand for purified
water, the water does not remain stagnant in the
membranes of the reverse osmosis modules and in
the resins of electrodeionization.
Another way to avoid water remaining stagnant
in the membranes of the reverse osmosis module and
the resins in the electrodeionization equipment during periods of production stoppage is to have the reverse osmosis module function cyclically for short
periods of time. For example, reverse osmosis
would start to function every two hours and do so for
10 minutes. In this way, there could be power and
water saving as a result of the losses caused by the
recoils in the reverse osmosis and electrodeionization equipment.
It should also be noted that the functioning of the

R1 recirculation decreases the water level in the

tank. When the tank reaches its minimum level, it
causes the system to start, filling the tank till it
reaches its maximum level.
It should be pointed out that some industrial
plants that utilize recoils coming from the reverse
osmosis module and electrodeionization (CDI), collects and recycles them. In fact, this practice is
presently being studied by the pharmaceutical
industry for application in those cases where there
is a water shortage or in which the cost of water is
very high.
R2 recirculation: Recirculation in the distribution loop. The water is constantly recirculating within the distribution loop, from the points of use to the
purified water storage tank. Stoppage of recirculation in this distribution loop is only contemplated
during holiday periods and for sanitization purposes.
Before starting the recirculation after stoppages in
the system after holiday periods, the distribution
loop should be sterilized by clean steam at 121C for
60 minutes. Sanitization of the distribution loop
should be carried out once a month by means of
purified water at 80C for 120 minutes using the heat
exchanger.
The data collected during routine use will con-

Figure 8

Recirculation 1
Water Coming
from the
Decalcification
Equipment

8
Decalcified
Water
Storage
Tank

14 UV

Distribution
Loop

10
Reverse
Osmosis

9 UV

11 UV

R1 Recirculation
12 CDI

Vent
Filter
HEPA
15
Purified
Water
Storage
Tank

Conductivity
Meter

13 UV

Special Edition: Utilities Qualification

141

142

Special Edition: Utilities Qualification

143

Figure 12

Chemical Critical Points 1, 4, 7, 11, 15, and 17

Point
1
4
7
11
15
17

Situation

Determinations and Specifications

Entry of feed water into system

Entry to decalcified water storage tank (8)
Exit from reverse osmosis
Entry into purified water storage tank (15)
Entry into distribution loop, after UV lamp (17)
Return to purified water tank (15), after UV lamp (19)

All controls: Drinking water

Total chloride (0.0 ppm)
Conductivity < 150 s/cm
All those determinations for Purified Water

Figure 13

Weekly Sampling Criterion (Microbiological)

Points in the
System

Total
Points

Monday

Tuesday

Wednesday

Thursday

Friday

Total Points
Sampled

A. Pre-Treatment

B. Points in Loop:
B.1 Control Points
B.2 Points of Use
In such a way that:

6
40

1
8

2
8

6
40

Every week all the pre-treatment points and all points in the distribution ring are sampled.
At the end of the 4 weeks validation period, four samples from each point will have been taken

9. An on-line TOC measuring apparatus is placed

in the return of the distribution loop, before the entry
of water into the purified water storage tank. It
ensures that the organic substances in the water do
not exceed the specifications.
10. R1 recirculation function:. It is convenient
and economical to program a 10-minute recirculation every two hours at weekend stoppages
instead of having the water circulating constantly. This would recoil the minimum amount of
water caused by the functioning of the reverse
osmosis module and in the electrodeionization
equipment.

Recommended Sampling Plan

for the Validation
Introduction
Sampling points
Microbiological sampling plan and specifications
Chemical sampling plan and specifications

144

Special Edition: Utilities Qualification

Introduction
The FDA, in its 1993 Guideline, recommends
that the validation of the system (PQ) is carried out
in three phases. In the first and second, samples are
obtained every day, for two/four weeks at each pretreatment point and at the distribution loop. The
third phase consists of compiling the data attained
from the routinary control plan over one year.
Because of the great number of points of use and
pretreatment points (before the distribution loop)
found in pharmaceutical plants, it is very difficult to
comply with this FDA recommendation. Therefore,
develop a sampling plan which does not totally correspond with this recommendation but which is
considered to be enough to prove that the system
operates in accordance with the established standard operating procedures (SOPs).

Sampling Points
The sampling points in the system are divided
into two groups:

Special Edition: Utilities Qualification

145

146

Special Edition: Utilities Qualification

147

148

Special Edition: Utilities Qualification

The Ultimate
Resource
Glossary of Computerized
System and Software
Development Terminology
F HEALTH
TO
&
H
EN

This document serves

as a glossary of terminology applicable to software development and
computerized systems in
Glossary of
FDA-regulated indusComputeri
zed System
tries. It will facilitate
an
Software D d
evelop
consistency in describTerminolog ment
y
ing the requirements of

the law and regulations

Reference
ma
investigator terial for
s
applicable to such
FDA/Indus and other
try personn
el
products and systems.
The organization of
this document is alphabetical.
Acronyms are grouped at the beginning of each alphabetical section, and are followed by words, terms, and
phrases. Acronyms are expanded at the beginning of
each alphabetical section and defined with the full
term or phrase. The terms are defined, as much as possible, using available standards. Over 850 terms,
phrases, and acronyms are included in this document.
SERVICE
S
AN
U
UM

1. Faure M. Une installation deau purified par dminralization,

STP Pharma Pratiques. 1991; 1 (2) 166
2. LAcqua nellindustria Farmaceutica. Manuali Tecnici, 1st
edition, Associazione Farmaceutici delindustria, Roma, 1991.
3. Collentro W., Angelucci L., Coordinating Validation Requirements for Pharmaceutical Water Purification Systems,
Pharmaceutical Technology, Sept 1992, pp. 68-78.
4. Good Manufacturing Practices for Pharmaceutical Products,
Annex: Guidelines on the Validation of Manufacturing Processes.
WHO Expert Committes on Specifications for Pharmaceutical
Preparations, Thirty-second Report, Genova, 1992.
5. Guide of Correct Norms for the manufacture of medicine in
the European Community, Ministry of Health and Consumption, General Management of Pharmacy and Sanitary
Products, General Sub-management of Pharmaceutical
Control, Madrid, 1992.
6. FDA, Guide to Inspections of High Purity Water Systems, July
1993.
7. Berry I.R., Nash R.A., Pharmaceutical Process Validation,
Second Ed. Marcel/Dekker Inc. Cap 9: Ward Journal,
Validation of Water Systems for Sterile and Non Sterile
Products, 1993: 299-317.
8. Gibes S., The Second European Pharm Tech Conference,
Barcelona, October 1994.
9. Net Martinez J., Processes for Obtaining Water-for-Injection
(WFI) Through Destilation, Lifelong Training Course Les
Heures, Barcelona 1995.
10. Validation Occupies Center Stage in GMPProposal, Drug and
GMP reports, #46. May 1996, pp. 2-3
11. United States Pharmacopeia, 23 revision: Water for Pharmaceutical Purposes, Fifth Supplement, November 1996.
12. Rosser M. FDA in Europe, Pharmaceutical Technology
Europe, Vol. 8, No. 11, December 1996, pp 16-21.
13. European Pharmacopeia, 3RD Edition, Maisonneuve, SA
Sante Ruffme, 1997, pp. 808.
14. King P., Equipment Validation: A Logical Approach to the
Pharmaceutical Validation Life Cycle Journey: Part One of
a Series, Journal of Validation Technology, Vol. 3, No. 4,
1997.
15. Angelucci L., Master Planning: How to Get Started, Journal
of Validation Technology , Vol. 3, No. 2, February 1997, pp.
167-175.
16. Neal C., Back to the Basics, Journal of Validation
Technology, Vol. 3 No. 3, May 1997.
17. Tisak D., Koster R., Validation Commissioning Documents:
a Checklist Approach for Facility Validation, Journal of
Validation Technology, Vol. 3, No. 4, August 1997.
18. Flint C., Melanson P., Retzick M., Stiller S y colt, Using a
Single Sensor to Measure Conductivity and Total Organic
Carbon (TOC) in Pharmaceutical Water, Pharm.Tech. Europe
1997.
19. Beaus R., Cortes F., Design of Production and Distribution
Systems for Pharmaceutical Quality Waters, Lifelong
Training Course Les Heures, Barcelona, June 1998.
20. Retzik M., The Mesurement of Total Organic Carbon (TOC)
and Conductivity in USP 23 Grade Pharmaceutical Water,
European Journal of Parenteral Sciences, Vol. 3 No. 1, 1998:
13-20.
21. Srikanth B., Chen Eng MS., The Application of UV
Technology to Pharmaceutical Water Treatment, European
Journal of Parenteral Sciences, Vol. 3 No. 4, 1998: 97102
22. Bruno R., Lorenz M., An Ambient-Temperature USPPurified
Water System Using Ozone Sanitization, Pharmaceutical
Technology, January 1999, pp. 36-44.

DEPA
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Special Edition: Utilities Qualification

Qualification of Purified
Water Systems
David W. Vincent
Validation Technologies, Inc.

here are various types of water

This article
used in the pharmaceutical
Water Requirements
industry. Their usage in the
Potable: Environmental Partdiscusses
the
actual formulation, in processing
iculate Aggregates (EPA)
operations, and as a final rinse of a

United
States Pharmacopeia
basic steps in
product contact surface, enables them
(USP) Purified
validating
to truly be considered a product ingre USP
Water-For-Injection
dient. Purified water can be produced
(WFI)
various water
many different ways and with various
different designs and equipment. The
The following table lists the four
systems, and
usage of pharmaceutical grade water
basic water types and classification.1
once they are
is very important in the production of
Type I
Well water
pharmaceutical drug products. Therevalidated,
Type II Potable water
fore, the validation and routine monType III Purified water used for crititoring of these systems are critical in
establishing
ical batch applications
maintaining the quality of the final
a routine
Type IV Food and Drug Adminiproduct. This article discusses the
stration (FDA) water for
basic steps in validating various water
monitoring
final rinse and formulation
systems, and once they are validated,
WFI
establishing a routine monitoring proprogram to
gram to maintain them. In addition
various types of water and their appli- maintain them. Type I Water
Type I is untreated water used for
cations, design, validation requireutilities (fire protection, lawn sprinklers, etc.), and may
ments, steps for validating purified water systems, roube from a well or surface source.
tine monitoring program, Preventative Maintenance
Type II Water
(PM) and revalidation program.
Type II is drinking water (potable) that must meet the
Water is classified into many different groups, deEnvironmental Protection Agency (EPA) requirements
pending on its source, quality, treatment, or use. It is also
necessary to define each classification by the minimum for quality. Its source is from a private or city supply that
quality requirements, especially with regards to chemi- has a variable degree of hardness and added chlorine for
microbial control.
cal and microbiological purity. The following is an
Type III Water
example of the different types of water and their usage.
Type III is purified water, which is the most diffiWater Usage in Pharmaceutical Production
Special Edition: Utilities Qualification

153

David W. Vincent

cult to control from a microbial standpoint, and usually used for bulk batch application where there is no
reasonable alternative and for non-parenteral product formulation. It is sometimes used as the initial
cleaning agent for some processes.
Type IV Water
Type IV water is the most critical quality level. It
is commonly used in final formulation for parenteral
applicants and as final rinse water for critical product
contact surfaces. This water must satisfy the specifications for WFI as defined by USP compendia

Design Requirements for Water Systems

The first step in designing a water system is to
define what the systems intended use will be. Once the
systems use has been determined, it is important to
test the incoming water source. This data will be used
to determine what type water treatment is needed. The
design, installation, and operation of water systems
used to produce Purified and WFI include similar
components, controls, and procedures. Usually WFI
systems are designed to produce high quality water,
and the most common methods employed are by distillation and Reverse Osmosis (RO). The design of
these systems can vary from system to system. The
following description is of a typical system, which
only contains pretreatment and WFI. The pretreatment
system is only used to create water to service the WFI
distillation system.
Incoming City Water
The incoming source water is usually from the city
municipal water treatment facility. The water quality
must meet their own water quality standards (ERC-2),
plus the EPA regulations on drinking water quality.
The following table is a summary of the major contaminants found in some city water systems.
Contaminant
Total Dissolve
Solids (TDS)
Total Hardness
Total Organic
Carbon (TOC)
pH
Microbial Limits

154

City Feed Water Results

125.74 mg/l
77.71 mg/l
10.45 ppm
9.23
500 cfu/ml

Special Edition: Utilities Qualification

It is also important to monitor the incoming city

water flow rates or pressures.
Purified Water System
To maintain a high level of biological and chemical control, it is necessary to limit the load by pretreating the water source before it enters into the
still. This is accomplished through several purification steps in the pretreatment sequence. The following components are typical components found in a
pretreatment system:
Multimedia filter
Duplex water softener with brine tank, and brine
feed pump
Hot water sanitizable carbon filter skid with circulation pump
Heat exchanger
Activated carbon filter
Multi-cartridge filters
RO feed tank with break tank and vent filter; RO
feed pump
Single pass RO unit
Deionization bottles
0.5 micron filter
Ultraviolet (UV) sterilizer
0.2 micron final filter
Multimedia Filter
A multi-media filter is used to remove or reduce turbidity, suspended solids, and sediment from the feed
water (incoming city water). The filtration also removes
particles with a nominal size of 10 microns or greater.
Duplex Water Softener
A duplex water softener, brine tank, and feed pump
system produces a sodium cycle, that will remove
scaling and other trace minerals from the water to improve RO operation and extend the life of the filter
membrane.
Carbon Filter Skid
The hot sanitizable carbon filter is used to remove
organic material and residual chlorine from the incoming softened water. The carbon bed is installed in a loop
that consists of a recirculation pump, heat exchanger,
and activated carbon filter. In order to minimize the risk
of microbial contamination from the carbon bed, the
contents of the loop are heated to 176F periodically to
sanitize the carbon bed and associated components.

David W. Vincent

Break Tank System

A 100 gallon RO feed break tank provides an air
break and reserve capacity for the RO system. The
pump delivers feed water through two 1.0-micron
multi-cartridge filters, which are used to remove carbon fines or other particulate matter from the water
before it passes through the RO unit.
Reverse Osmosis (RO)
A single pass RO unit is used to remove 99% of
particulate matter, silica, bacteria and endotoxins. The
operation of the RO unit is continuous in order to minimize bacterial load. When the still does not require
feed water, the RO unit will operate in a high recovery
mode in order to minimize water consumption.
Deionization System
The Deionization (DI) recirculation loop provides pressurized RO/DI water to the still feed system. The water in this system is flowing constantly
through the DI recirculation pump, two deionization
bottles in series, an UV sterilizer, and a 0.5-micron
resin trap filter.
UV Sterilizer and Final Filtration System
A 0.5-micron filter is used to decrease the bioburden levels, and prevent resin particles from the DI
bottles from being deposited onto the surface in the
UV sterilizer. A UV sterilizer and a 0.2-micron final
filter are used to decrease the bioburden levels in the
water before it enters into the still.
Pretreatment Programmable Logic Controller (PLC)
Some pretreatment systems are controlled by a
PLC. The PLC is monitored by a Supervisory Control
And Data Acquisition (SCADA) system. The SCADA
system allows access to all visual and audible alarms
for all equipment associated with the WFI system.
The pretreatment system is designed to purify
incoming city water from USP EPA drinking water
standards to meet the following still feed water specification summarized in the table below.
Purified Water Specifications
Conductivity
Endotoxins
Microbial
pH
Total Solids
Chlorine

< 5 microsiemens/cm
< 25 EU/ml
< 200 CFU/ml
5.5 to 7.0
< 5 mg/l
Non-detected

The previous specifications are those of the still

manufacturer, and are not regulatory requirements.
These still requirements can vary from system-tosystem. It also depends on the quality of the feed
water.
Water Purification System
Usually, the components associated with purification systems are similar to WFI systems with the exception of the method of water production (distillation
verse RO/DI) and the final quality output. The components that comprise the purified water system are skid
mounted multimedia, water softener, carbon filter, dual
pre-filters, UV sterilizer, RO unit, bioburden reduction
filter, and storage tank. Below is a list of major components for a typical purified water system:
Multimedia filter
Duplex water softener with brine tank, and brine
feed pump
Hot water sanitizable carbon filter skid with circulation pump
Heat exchanger
Activated carbon filter
Multi-cartridge filters
RO feed tank with break tank and vent filter; RO
feed pump
Single pass RO unit
Deionization bottles
0.5 micron filter
Ultraviolet sterilizer
0.2-micron final filter
Storage tank
Tank vent filter
Purification Water Storage System
Purified water is supplied to a storage vessel from
the purification system. Purified water quality is maintained within the storage system by constant recirculation of the storage system. The purified water is
dumped after 24 hours to prevent proliferation of bacteria.
The purified water distribution loop returns to the
storage vessel after being further polished and filtered. A 0.2-micron hydrophobic vent filter is usually employed on the purified water storage vessel to
filter any incoming air into the storage vessel during
purified water system draw down.
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David W. Vincent

Purified Distribution Loops

The generated purified water is distributed throughout in a continuous loop. In distribution systems, where
the water circulates at a specified controlled temperature, dead legs and low flow should be avoided, and
valves tie-in points should have length to diameter
ratios of six or less. Components and distribution lines
should be sloped and fitted with drain points. The distribution loops tubing may be composed of stainless
steel or plastic. The purification system is designed to
purify water to meet USP 23 specifications. The following point of use specification is summarized in the
following table.
Purified Water Specifications
Conductivity
Endotoxins
Bacteria
pH
TOC

USP 24 Specification
No Specifications
100 cfu/ml
5.0 7.0
500 ppb

Water-for-Injection (WFI) Systems

The components that comprise the WFI system are
four effect distillation unit, jacket storage tank, vent
filter, cold, hot, and ambient WFI distribution loops
with associated pumps, heat exchanger with cooling
water, heat exchanger with chilled glycol, and a heat
exchanger with chilled water.
Distillation System
USP 23 WFI is produced by a four-effect distillation unit. The WFI storage tank level transmitters
control operation of the still. RO/DI treated water
flows into the WFI still feed and produce WFI quality
distillate.
The multi-effect still is capable of producing clean
steam for periodic clean steam sterilization of the
WFI storage and distribution systems. The distillation process provides a three-log reduction in endotoxin and a five-log reduction in bacteria to meet
USP 23 requirements.
WFI Storage System
WFI is supplied to a storage vessel from the multieffect still. WFI quality water is maintained within the
storage system by constant recirculation of the storage system contents at greater than 80C. Tempera156

Special Edition: Utilities Qualification

ture of the WFI within the storage system is maintained by a plant steam jacket on the WFI storage vessel. The temperature of the vessel contents is maintained above 80C.
The hot WFI distribution loop returns to the WFI
storage vessel through a spray ball. The spray ball constantly rinses the dome and sidewalls of the storage
vessel with hot WFI to maintain cleanliness within the
storage tank.
A 0.2-micron hydrophobic vent filter is usually
employed on the WFI storage vessel to filter any incoming air into the storage vessel during WFI system draw
down. The filter is provided with a low-pressure plant
steam jacket to prevent filter plugging. Valves and ports
are provided on the vent filter for clean steam sanitization of the vent filter after cartridge replacement. A rupture disk on the storage vessel protects it from over pressurizing. A burst monitor indicates rupture disk over
pressure and activates an alarm. The WFI storage tank
temperature is continuously monitored.
WFI Distribution Loops
The generated WFI distributed throughout the
facility can be in three different loops; hot distribution,
ambient distribution, and cold distribution. In distribution systems where the water circulates at high temperature, dead legs and low flow should be avoided,
and valve tie-in points should have length to diameter
ratios of six or less. Components and distribution lines
should be sloped and fitted with drain points.
Water-For-Injection (WFI) Specifications
Conductivity
Endotoxins
Bacteria
pH
TOC

USP 24 specification
0.25 EU/ml
10 cfu/100ml
5.0 7.0
500 ppb

Validation Requirements for

Purified Water Systems
The validation of water systems assures that the
system will consistently produce water of predicable
quality when operated in the prescribed manner. The
validation of critical water systems involves a great
deal of time and planning. The initial phase involves
verifying that all related components, process moni-

David W. Vincent

tors, and controls are installed and functioning as per

design. The second phase is called the performance
phase, which involves testing the systems for microbial and chemical qualities over certain periods of
time. The final phase is the routine monitoring that is
performed over the life of the system. At this stage,
data is compiled and reviewed to determine trends,
which will give a more accurate system profile. The
data compiled includes seasonal variations, maintenance, and sanitation of the system.
Each water system is designed differently, and therefore, must be validated according to its intended design
and use. This section of the article will only cover
Levels II, III, and IV water systems, since these are the
most commonly used in pharmaceutical applications.

After all the equipment and piping has been verified as installed correctly and working as specified,
the initial phase of the water system validation can
begin.
During the initial phase, the operational parameters and cleaning/sanitation procedures and frequencies will be developed. Sampling should be daily after
each step in the purification process, and at each point
of use for two to four weeks.
The sampling procedures for point of use should
reflect how they are taken, e.g., use of hose, and time
for flushing. At the end of two (2) or four (4) weeks,
the firm should have developed its Standard Operating Procedures (SOPs) for operation and maintenance
of the water system.

Water Purification Systems

1. Pretreatment
Water softener
Depth filtration
Activated carbon and/or bisulfite injection
Demineralization
RO
2. Purification
Deionization
Distillation
RO
Ultrafiltration

Phase 2
The second phase of the water system validation
is to demonstrating that the system will consistently
produce the desired water quality when operated in
conformance with SOPs. The sampling is performed as
in the initial phase and for the same period. At the end
of this phase, the data should demonstrate that the system consistently produces the desired quality of water.

A basic reference used for the validation of high

purity water systems is the Parenteral Drug Association (PDA) Technical Report No. 4 titled, Design
Concepts for the Validation of a Water for Injection
Systems. The validation of water systems can be time
consuming and very costly. In realizing that the pharmaceutical industry needed some guidance in the validation of critical water systems, the FDA published
the Guide to Inspections of High Purity Water
Systems in 1993.3 The following are some points to
consider from the FDAs perspective when validating
critical water systems as per the above guidelines.
Phase 1
All water systems should have documentation
containing a system description and accurate drawing. The drawing needs to show all equipment in the
systems from water input to points of use. It should
also show all sampling points and their designations.

Phase 3
The third phase of validation is designed to
demonstrate that when the water system is operated, in
accordance with the SOPs, over a long period of time,
it will consistently produce water of desired quality.
Any variations in the quality of the feed water that
could affect the operation, and ultimately the water quality, will be noticed during this phase of the validation.
Sampling is performed according to routine procedures and frequencies. For WFI systems, samples
should be taken daily from a minimum of one point of
use, with all points of use tested weekly.
The validation of the water system is completed
when the firm has collected data for a full year.
The FDA states that: while the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system.
First, there must be data to support the SOPs.
Second, there must be data demonstrating that
the SOPs are valid, and that the system is capaSpecial Edition: Utilities Qualification

157

David W. Vincent

ble of consistently producing water that meets

the desired specifications.
Finally, there must be data to demonstrate that
seasonal variations in the feed water do not adversely affect the operation of the system or water
quality. This last part of the validation is the compilation of the data, with any conclusions written
into the final report.
Once all regulatory concerns are addressed, it is
important to consider microbiological and chemical
requirements for each system. Figure 1 contains limits for each level of water system.
Figure 1

Microbiological/Chemical Limits

Figure 2

Water System Validation Lifecycle

Define Water
Quality Attributes
Define System and Subsystems
Including Processing Technologies,
Operating Parameters, and
Corrective Action Features to Meet
Water Quality Attributes

Changes
Install Equipment
Piping and Control
Systems

Identify Critical
Process Parameters
and Establish
Operating Ranges

Changes
Tests

Potable
Water
pH
N/A
TOC
N/A
Conductivity N/A

Bacteria
Endotoxins

Purified
Water
5.0 - 7.0
500 ppb
4.7 to 5.8
S/cm

Water-for
injection
5.0 - 7.0
500 ppb
USP 24
Specification/
Method
500 cfu/mL 100 cfu/mL
10 cfu/100mL
N/A
Not Specified 0.25 EU/mL

cfu: Colony Forming Units

A validation program qualifies the design, installation, operation, and performance of the system. It begins when the system design moves through different
phases: Construction Qualification (CQ), Installation
Qualification (IQ), Operational Qualification (OQ),
Performance Qualification (PQ) and routine monitoring program. The USP-NF fifth supplement <1231>,
Water for Pharmaceutical Purposes, defines a typical
water system validation lifecycle which is shown in
the graphical representation of Figure 2.

Steps for Validation of Water Systems

There are many ways of qualifying a water system.
The following is one typical method:
Construction Qualification (CQ)
During the CQ phase of the validation, material
certification on tubing and components should be collected. Welding logs should be inspected to insure that
the welders are conforming to their own quality pro158

Special Edition: Utilities Qualification

Installation
Qualification
(IQ)

Establish Alert and

Action Levels for Key
Quality Attributes

Changes
Operational
Qualification
(OQ)

Establish
Corrective Action
Response

Performance
Qualification
(PQ)

Prospective
Phase-Confirm
Appropriateness of
Critical Process
Parameters
Operating Ranges

Concurrent/Retrospective Phase
Establish reproducibility and reliability of system
Evaluate effects of seasonal changes
Confirm appropriateness of alert an
action levels and corrective action
program

Validation
Maintenance
Change Control
Periodic Review

David W. Vincent

gram. Certain test procedures, such as hydrostatic testing, should be witnessed and documented. Verification
that piping is sloped to drain according to specifications and code should be completed.
Installation Qualification (IQ)
An IQ phase consists of field verifying that instruments, valves, heat exchangers, and major components are installed as per design specifications. The
system should be inspected to verify that the drawings
accurately depict the as-built configuration of the
water system. The system should be checked to verify
that there are no dead legs. A dead leg is a length of
piping that should be less than six inches of the pipe
diameters length. The data and reports for the cleaning and passivation activities should be reviewed, and
the test results included in the final report. Passivation
of the stainless steel piping and tank is important in
removing various metal contaminates, which can
cause oxidization of the surface areas. After the passivation process is complete, it is important to assure that
there are no residues remaining in the system. Finally,
check that distribution system and points of use valves
are labeled and tagged. The water system should be
fully commissioned before the OQ phase can start.2
Operational Qualification (OQ)
During the OQ phase, it is important to test and
verify the following functions:
Flow and pressure rates
Temperature and conductivity
Sanitization and/or Steam-In-Place (SIP) procedures
Computer control functions
Alarms
Pumps
Major components function as per design specifications
Filter integrity
It is important to verify that all instrument and devices have been calibrated before starting the OQ.
After all functions are verified, it is important to perform preliminary testing on the systems. This involves
sampling the system for two weeks for microbial and
chemical quality. It is also important to verify the efficiency of each major component to insure they per-

form according to their design specifications. For

example, the carbon bed should be tested or monitored
to insure it is capable of removing chlorides to an
acceptable level. During the execution of the OQ protocol, its important to verify that all valves function
properly, and pumps are capable of meeting their
appropriate pump curve requirements. Its also important to verify that all computerized control points are
functioning per operational specifications. By performing this step, you will be able to determine if your
system is ready for the PQ phase of the validation.
This step will prevent unnecessary cost and time
wasted on a system that may not be ready for the PQ
study. All system SOPs should be developed and finalized during the OQ phase.
Testing the system before starting the PQ gives
valuable information on the systems ability to produce high quality water.
It is important to qualify the microbiological and
chemical test methods before starting the PQ Study.
Performance Qualification (PQ)
The PQ phase involves monitoring the system for
microbial and chemical quality over a specific
period of time. Most companies perform this study
for 30 to 60 consecutive days. After 30 days, the
system is shut down for 24 hours (stagnation test).
After 24 hours testing continues for another 30 days
to determine how long it takes for the system to
recover. Sampling should be daily after each step in
the purification process and at each point during the
extent of the PQ. Again, it is important to monitor
the incoming water source, in-between each major
piece of equipment, and at the points of use. This is
to insure each component is performing per design.
By testing in between each major component, it will
also be easier to detect the source of any problems,
should they occur. Sampling for microbial and endotoxin levels should be performed on a daily basis,
whereas chemical analysis can be rotate for each use
point.
Test Methods and Materials Used During PQ Study
The use of proper test methods and materials are
critical to any validation project. That is why it is
important to qualify them before the actual PQ study.
The USP fifth supplements, USP-NF, <1231> Water
for Pharmaceutical Purposes recommended methodSpecial Edition: Utilities Qualification

159

David W. Vincent

ologies are derived from the Standard Methods for

the Examination of Water and Wastewater, 18th Edition,
American Public Health Association, Washington,
DC 20005.4 These methodologies are considered appropriate for establishing trends in the number Colony
Forming Units (CFUs) observed in the routine microbiological monitoring of ingredient water. They do
however, recognize, that other combinations of media,
time, and temperature of incubation may occasionally or even consistently result in higher number of
CFUs being observed. The following are some of the
recommended methods that are generally satisfactory
for monitoring pharmaceutical water systems:5
Drinking Water:

Pour Plate Method

Minimum sample 1.0 ml
Plate count agar
42 to 72 hours at 30 to 35C
Purified Water:
Pour Plate Method
Minimum sample 1.0 ml
Plate count agar
42 to 72 hours at 30 to 35C
Water-For-Injection: Pour Plate Method
Minimum sample 1.0 ml
Plate count agar
42 to 72 hours at 30 to 35C
While the above methodology may be considered
acceptable, it is also important to consider other alternative methodologies. For example, low nutrient media
may be compared with high nutrient media, especially during the validation of a water system. The use
of high (enriched) nutrient media is normally used for
the isolation and enumeration of hetetrophic bacteria.
It is also important to consider slow growth bacteria
that are living in an environment with very little nutritional supplements or that are under stress from
chemical agents. Therefore, it may be important to
consider the use of a low nutrient media. High nutrient media requires a higher temperature and shorter
incubation period; whereas low nutrient media requires lower temperature and a longer incubation
period. Since the amount of bacteria detected in a 100
ml sample may be very low, a larger sample volume
(250 300 ml) should especially be considered for
WFI systems.
When testing drinking water for microbial quality,
it is also important to inactivate the chlorine that is
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Special Edition: Utilities Qualification

normally used to treat the water. By not doing so, one

may not get an accurate count because of the bactericidal affect the chlorine will have on the microbial
results.

Routine Monitoring Program for

Purified Water Systems
Once the PQ is completed, the real time validation of the critical utilities begins. Usually the PQ study
is performed over a short period of time, and with intensive sampling. But the routine Environmental Monitoring (EM) is performed during the life of the facility, and usually involves less intense sampling. The
data collected from routine EM programs includes
seasonal variations, and manufacturing activities,
along with maintenance and cleaning activities. The
most effective EM programs are the ones with clear
and precise procedures.
Routine Environmental Monitoring Program
When establishing a routine EM program, the data
for the PQ study should have the starting point for
determining the sampling sites and frequencies of
testing. It is also important to have an accurate drawing indicating the sampling sites. The program
should also include environmental worksheets to
record test results. The worksheet data can be
entered into a computer-aided software program that
can be used to trend and perform queries on environmental data.
Establishment of Alert and Action Limits
Alert Limits The concentration of viable and
non-viable particulate in a controlled environment
that, when exceeded, signal a potential drift from
normal operating conditions.
Action Limits The concentration of viable and
non-viable particulate in a controlled environment that,
when exceeded, signal a potential drift from normal
operating conditions, and which require an investigation and corrective action.
Alert and action limits are usually derived statistically from historical data. These limits are conservative measures designed to signal potential drift
from historical or design performance characteristics.
The establishment of the alert action limits should
be written and utilized in a consistent, non-arbitrary

David W. Vincent

manner. It is important to remember that alert/action

times. Acceptable levels are reattained if three conlevels should not be extensions of product specificasecutive retests meet acceptable levels. Once the systions. If an alert level is exceeded, correct action may
tem is operating in a compliant state, QA is responsinot be required, but records should show that the
ble for releasing the system to manufacturing
excursion was recognized. But if alert levels are consistently exceeding their limits, an investigative action Corrective Action Program for Purified Water Systems
should be taken.
The purpose of a corrective action program is to
If an excursion occurs above an
action level, as a minimum, one
The most effective EM
should review the data. An investi[Environmental Monitoring]
gation should be undertaken, and
corrective and alert notices to
programs are the ones with
responsible parties and departments.
clear and precise procedures.
When an action limit is
exceeded, an investigation and corrective action should be performed. The following
investigate critical system failures, and reporting and
actions may be taken, but are not limited to the foldocumenting these failures, and making the neceslowing:
sary corrective action to bring the system into a compliance state.
Generate an Environmental Deviation Report
The following program is applicable to purified
(EDR) form
water, and WFI, systems.
Issue an alert notice
Investigate the environmental deviation
Program Procedures
Perform corrective action
An environmental investigation applies to any sit Resample Out-of Limit (OOL) locations
uations not considered an immediate threat to a criti Review maintenance and cleaning logs
cal system, but which, if allowed to continue, may
Perform gram stain/identification of isolated or- become serious. An EDR must be filled out under the
ganism(s)
following or similar circumstances.
Determine sensitivity of isolate to disinfectant
being used
Water Systems
Review risk of product contact
When QC sample consistently exceeds alert
limits for all QC test results.
No further action is usually required when accept When a QC sample of water exceeds the action
able levels are re-attained. The results from the retest
level for bacterial count.
are recorded on the EDR form, disposition as pass and
When a QC sample of water exceeds the action
file future for reference.
level for endotoxins limits.
If the retest indicates that acceptable levels have not
When a QC sample of water exceeds the limit
been met, the Quality Control (QC) department will
for USP 24 chemistry.
initiate an investigation report with the description of
When a possible minor malfunction in the water
the deviation to directors of Quality Assurance (QA)
system is observed.
and manufacturing. It is the responsibility of manufacturing and/or facility department to conduct an immeInvestigation and Corrective Action
diate investigation, and initiate corrective actions to
The following steps should be taken:
restore the area to normal operating conditions. QA is
QA and the responsible facility (facility related)
responsible for evaluating the impact of the conditions
and/or production (process or equipment
on product quality.
related) department will investigate the system
After corrective actions have been taken, the
and recommend corrective action.
affected location(s) should be retested at least three
Document the proposed corrective action on the
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161

David W. Vincent

EDR form
The facilities and/or production manager will sign
the EDR form, and return it to QA for review and
approval of corrective action.
Perform the corrective action immediately, if
possible. If the action requires planning, materials, or time to implement, perform it as soon as
possible.
QA will review the proposed corrective action and
any subsequent QC retesting data. If the investigation or the data shows that the system is in control,
QA will sign the form, distribute copies, and file
the QA copy of the form.
Distribute copies to QA, facility manager, production, and the system and/or product file.
Manufacturing Alert Notice For Action Limit Failures
A manufacturing alert notice applies to any situation that is considered an immediate threat to a critical
system or process equipment, and which may have a
direct impact on the quality of the product. A manufacturing alert notice is issued to the manufacturing
department notifying them that a system may or may
not be used (depending on the circumstance and severity of the problem) until corrective action has been
taken to bring it back into compliance. A manufacturing alert notice form must be filled out under the following or similar circumstances:
When two or more retest samples exceed the action
limits
When you observe a questionable condition (sanitation, potential contamination)
When you observe a possible minor or major malfunction in the utility system, which could possibly
compromise the integrity of the production area
When a QC test sample exceeds the action limits
If a system is still not in compliance after the first
environmental corrective action or investigation
was taken
Corrective Action Program
An EDR form is initiated immediately when action
levels are exceeded. A number is assigned to the deviation for traceability. The number consists of four
groups of digits; the first group represents the system,
the second group represents the year, and the third
group a sequential number (i.e., Water-For-Injection;
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Special Edition: Utilities Qualification

WF-96-01, and USP purified water).

The manufacturing manager and/or appropriate
individual(s), are notified immediately of the type of
deviation, and their signature/date obtained, along
with the appropriate corrective actions are taken.
An EDR form will usually include the following
section:
Section 1
1. The EDR number
2. System affected
3. Location where levels have been exceed
4. Room number
Section 2
1. Sample location, (i.e., point of use)
2. System sampled (WFI, USP purifed)
Section 3
1. Initial sample data
2. QC test results (collection data, site, sample data
action levels)
3. Recommended corrective actions (if applicable)
Section 4
1. Corrective actions taken (requires a description
of the action taken)
Section 5
1. Retest sample data
2. QC test results (collection data, site, sample data
action levels)
3. EDR disposition (resampling results pass/fail)
Section 6
1. Other action taken (if applicable)
2. Results acceptable (no further steps required)
3. Not acceptable (investigation continues
After the investigation is completed, include any
supporting documentation with the report. Also maintain a history file on each system to determine if there
are any reoccurring failures, which may require modification or redesign of the system.
Water Systems Corrective Action
Corrective actions for pretreatment water, purified water and WFI systems may be included, but
are not limited to, the following:
Additional sampling and testing
Review/repeat sanitization procedures
Review sampling/testing technique

David W. Vincent

Review validation data

Check on possible unusual events during sampling
and/or testing
Review 0.2m filter and tank vent filter integrity
test results
Review maintenance and sanitization logs
Perform gram stain/identification of isolated organism(s)
SIP the entire system
Inspect all major components on the pretreatment,
purified, and WFI system
Review risk of product contact
No further action is required when acceptable levels are reattained. Record retest results on the EDR
form, disposition as Pass, and file future for reference.
If the retest indicates that acceptable levels have
not been met, initiate another investigation report to
directors of QA and manufacturing with the description of the deviation. It is the responsibility of manufacturing to conduct an immediate investigation, and
to initiate corrective actions to restore the area to normal operating conditions. QA should be responsible
for evaluating the impact of the conditions on product
quality.
After corrective actions have been taken, the
affected location(s) will be retested at least three times.
Acceptable levels are reattained if three consecutive
retests meet acceptable levels.
Preventative Maintenance (PM) Program
Once the purified systems is qualified, its important
to place the system and its components in the PM program. This requires placing the system under a routine
maintenance schedule. Normal PM may require filters
being replaced, gauges and devices calibrated, loop
being sanitized, pumps being inspected, and softener or
carbon beds replaced. For WFI systems, a routine passivation schedule must be implemented as part of the
PM. The purified water systems with stainless steel
piping may require passivation every two to three
years, depending on the age of the system. If the system is shut down for PM or emergency repairs, a procedure should be developed to determine if the system
is still in a validated state. This may require sample
testing the water for two three days. The water may
be used at risk for GMP activities if one-day results for
chemistry is acceptable.

Revalidation of Critical Systems

Revalidation will occur when any significant
changes or alterations occur to any above systems.
(i.e., modification of purified water system major
components). The extent of the testing will be determined on a case-by-case basis, and will be properly
documented and filed. Revalidation for a critical utility should be performed annually or semi-annually,
depending on the criticality of the system. The revalidation SOP should be written, which includes the
extent of testing and the system under the program.
Once the water system IQ is completed, its important to place the system in the change control program. Changes to the system and drawings should be
reviewed annually to determine if some degree of
requalification is required. An annual summary
report should be written that includes yearly trended
QC data, changes or modifications made to the system, or any major maintenance issues. The final
report should include a statement that the system is
still in state of control and fully qualified for manufacturing use.

References
1.
2.
3.
4.
5.

Center for Drugs and Biologics, Center for Devices and Radiographic Health. Guidelines on General Principles of Process Validation. FDA Rockville, Maryland. 1987.
cGMP Compliance in Architecture and Construction of Biopharmaceutical Manufacturing Facilities. BioPharm. Prepared
January-February. 1993.
FDA. Guide to Inspections of High Purity Water Systems. (1993).
Standard Methods for the Examination of Water and Wastewater, 18th Edition. American Public Health Association.
Washington, DC 20005.
PDA Environmental Task Force. Fundamentals of a Microbiological Environmental Monitoring Program. Vol. 44. Supplement 1990.

Special Edition: Utilities Qualification

163

David W. Vincent

Article Acronym Listing

CFU:
CQ:
DI:
EDR:
EM:
EPA:
EPA:
FDA:
IQ:
TDS:
OOL:
OQ:
PDA:
PLC:
PM:
PQ:
QA:
QC:
RO:
SCADA:
SIP:
SOP:
TOC:
USP:
UV:
WFI:

164

Colony Forming Unit

Construction Qualification
Deionization
Environmental Deviation Report
Environmental Monitoring
Environmental Particulate Aggregates
Environmental Protection Agency
Food and Drug Administration
Installation Qualification
Total Dissolve Solids
Out-of Limit
Operational Qualification
Perenteral Drug Association
Programmable Logic Controllers
Preventative Maintenance
Performance Qualification
Quality Assurance
Quality Control
Reverse Osmosis
Supervisory Control And Data
Acquisition
Steam-In-Place
Standard Operating Procedure
Total Organic Carbon
United States Pharmacopeia
Ultraviolet
Water-For-Injection

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Utilities Qualification

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TABLE OF CONTENTS

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

A Must Have for

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Brian Scott, Jeff Hargroves and Jerry Bauers

Special Edition: Utilities Qualification

Save 20% Off the Regular Price of $99.00

Defines FDA terminology and compares it to

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

Special Edition: Utilities Qualification

uality systems and procedures are implemented to

Long term cost savings

Special Edition: Utilities Qualification

Define quality failure/incident

Special Edition: Utilities Qualification