A Pocket Guide to

uditing a
Pharmaceutical Water System
A
P
harmaceutical water may which may have occurred but
Control of water be the only utility from a were overlooked for documenta-
facility to be administered tion requirements or procedural
production and its to a patient. Even if the water is changes. It should be modified
removed in processing the water, and updated as necessary to
usage are critical it is still regarded as a raw mate- support the system and maintain
rial and has the potential to leave a state of compliance with cur-
in producing impurities in the product. As with rent Good Manufacturing
all raw materials of a product, Practices (cGMPs).1 The second
a product . . . the water must meet predefined audience is the auditor, who may
specifications but, unlike other use the list as a reference point
raw materials, it may be used as on which to base an audit while
it is produced. Some systems leaving the specific details to the
produce water on a batch basis individual.
which is tested and released, for Procedures and problems
use, but others continuously feed encountered in the microbiology
water to a storage tank. Water is laboratory are outside the scope
also used in many different of this article but can be found in
cleaning processes, and, if con- “Guide to the Inspections of
taminated, could affect multiple Microbiological Pharmaceutical
batches. Control of water produc- Quality Control Laboratories”
tion and its usage are critical in (FDA 1993). An introduction to
producing a product that meets regulatory requirements of water
predefined specifications and systems can be found in the
regulatory expectations. “Guide to Inspection of High Purity
The pocket checklist included Water Systems” (FDA 1993).
with this guide is designed for This pocket guide is intended
two audiences. The first is the to provide a baseline for auditing
user of the system and those water systems. It is not an all-
who have responsibility for main- inclusive list of possible items
by tenance and testing of the sys- and areas to be examined. The
Graham Bunn tem. The list may be used as a content should be adapted and
Manager, GMP Audit proactive tool on a periodic basis updated as necessary for indi-
AstraZeneca to identify and monitor changes vidual systems and situations.

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Graham Bunn

Documentation manufacturing dates in batch records. The

water system must be approved for use
All systems require complete and accurate doc- before it can be used in the manufacturing
umentation including qualification, maintenance, process. Outstanding requests for change
change control, investigations, and analytical/micro- controls may indicate that there are alterna-
biological results to provide evidence that the sys- tive reasons for the delays. If the changes
tem is in a state of control. Documentation should were not performed, the potential impact on
be checked against the SOP requirements applica- the integrity of the system should be
ble at the time the work was performed and against assessed.
current industry standards. The current revision of ■ Chemical and microbial testing raw data and
the schematic diagram must accurately reflect the trend reports. Compare the data against
actual system and be authenticated by a suitably release documents, and check that the trends
qualified person. The auditor can use a copy of the are being suitably monitored and the neces-
diagram as a checklist during the tour. The date of sary people informed of the results.
the diagram should correlate with the last change ■ Out-of-specification results. The laboratory
control if physical changes were made that required out-of-specification investigations should be
changes to the diagram. A typical water system is reviewed against the SOP requirements. They
shown in Figure 1. must be of a suitable depth, and the conclu-
The following documentation and SOPs can be sions must be supported by adequate data
requested for review in the audit conference room: and information. Documentation is required to
support any follow-up actions with defined
■ Maintenance records for system components. time lines.
These must be completed in compliance with
the SOP requirements and provide a com- Manufacturing requirements will determine the
plete record. water quality and capacity requirements of the sys-
■ Qualification documentation (installation, tem. Supply of water-for-injection (WFI) to a large
operational, and performance). The qualifica- manufacturing site will have different physical
tion must be performed against a suitably requirements than the purified water supplying a
approved protocol before the initiation of the small solid oral dosage pilot plant. A note should be
work. The results must meet predefined made of the manufacturer, and model numbers of
acceptance criteria or be adequately justified. components of the system for comparison against
■ Change control log and supporting documen- the validation protocol and change control requests.
tation. The dates that the system was During the facility tour, the general conditions of the
approved for use should be compared to any areas should be observed. Excessive water on the

Figure 1
Basics of a Typical High Purity Water System
Cationic /
Softener Reverse Anionic
Filtered City Acid Osmosis UV 254 nm Exchange
Water Beds

Circulation Steam Mixed Bed

UV 254 nm Loop with Jacketed Ion Filter
Points of use Storage Exchange
Tank

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 Graham Bunn

floor and especially from leaking pipes is cause for ing, often referred to as “dead-legs,” are found
concern. This is the first indication of the care and where changes in the distribution have been made
attention the area receives from the maintenance or in the removal of a section of the loop. Hard pip-
staff. Some of these areas are operated and main- ing of equipment without a non-return valve and
tained to a high standard. In a larger facility this drainage of isolated piping back into the system
may be maintained by the dedicated engineering can also cause similar problems.
staff compared to the smaller unit, which may be A suitable number of the points of use and the
supported by other staff, but cGMP requirements environment around them should be examined.
are the same irrespective of the water being pro- Points of use requiring tubing must not provide the
duced by the system. Area and equipment log opportunity for water to be siphoned back into the
books may be requested at this time, as it is some- system and cause contamination. The classic
times more useful for the auditor to examine these example of this is the tubing reaching into a sink
in situ. This also enables assessment of the individ- below the overflow level. Equipment joined directly
uals responsible for the areas in their own environ- to the water source has the potential to allow
ment. The SOPs applicable to the individual plant water to re-enter the system (back-flushing) and
areas should be easily accessible so that users can cause possible contamination. One-way flow
refer to them whenever necessary. valves minimize the possibility of this occurring.
Air breaks are essential to ensure that there is no
Generation possibility that waste water discharged to a drain
can possibly be siphoned or forced to enter the
Resin bed cartridges sent to a contractor for system or pieces of equipment from back-flow. All
regeneration should be dedicated to the company piping in the generation plant must be suitably
to minimize any potential for contamination from an labeled with a description of the contents and
unknown user. Any chemicals used in the system direction of flow.
for sanitization, regeneration of resins, etc., must Points of use must also have clear labeling to
be adequately stored, labeled, and as with any ensure there is no confusion in the water quality
component of a pharmaceutical product, quaran- delivered from the outlet. Multiple outlets labeled
tined, tested, and released for use by Quality “water” are major problem areas, especially when
Control. A note of readings on gauges and digital potable and WFI may both be available in an
readouts should be made for future reference and equipment cleaning area.
checked against operating ranges in the qualifica- An explanation of the procedure and any physi-
tion documentation. Any readings that appear to be cal controls should be requested when two storage
at the upper or lower end of the ranges or are fluc- tanks are released individually on a batch system
tuating erratically should be investigated further. All by QC. There must be adequate controls in place
major components of the system should be exam- to ensure that only water that has been released
ined for general condition and appearance. can be used. This may only administered by QC or
Excessive leaking or rusting are an indication of a by QC providing documentation to another group
problem area, which warrants further investigation (engineering). It should be determined if water has
and explanation. ever been released for use before all testing has
been complete. If this was allowed, it is defined as
Distribution and Storage manufacturing at risk if the water was used as a
component of a product. Manufacturing at risk is
During the walk-through, the auditor should ask not permitted under the cGMPs and has been
general questions concerning the frequency of clearly explained by the Commissioner in the
changing resins, sanitation, filter changes, integrity preamble to the cGMPs.2
testing of vent filters, and general cleaning of Major maintenance work on the water system
areas. The appropriate individuals should be asked may be performed annually when the entire plant
how the frequencies were established and what is closed for scheduled maintenance. There must
documentation supports the justifications. There be SOPs describing the procedure for decommis-
must be no place in the distribution pipes where sioning (i.e., stopping the production of water) and
water can remain stagnant and provide the oppor- then bringing the system back to its original quali-
tunity for microbial growth. These segments of pip- fied state again. This must also include the quar-

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Graham Bunn

antine and subsequent testing against an

approved protocol with predefined acceptance cri-
Water Systems Terms
teria and ultimately release for use by QA.
Activated Charcoal: Used to remove odor,
chlorine, and some organics.
Sampling and Testing
Adsorption: The process of physical, not
chemical, adherence to a surface by particles,
At the beginning of the audit, it would be benefi-
colloids, or molecules.
cial to inquire if daily water sampling is being per-
formed. If possible, the sampling process should Bactericide: A substance capable of killing
be observed in conjunction with the sampling SOP. bacteria.
The internal auditor is able to request this at rela- Bacteriostat: A substance which inhibits bac-
tively short notice in their own facility, as they terial growth and metabolism but will not neces-
would have performed background checks to sarily kill the cell.
determine the collection times. A contractor should Chlorination: The addition of chlorine in a
have no problem with the auditor observing the concentration of about 0.2 to 2 ppm to render the
process if they are confident that the sampling is in water bacteriostatic.
a state of control and compliance with SOPs. The Conductivity: The ability of a substance to
sampler’s name should be noted so that the indi- conduct electricity. Measurements are in
vidual’s training records can be requested and veri- microSiemens/cm.
fied later. Deionization: The process of removing ion-
Procedures used by operators to draw water ized salts from water using ion exchange resins.
from the system should be observed where possi- Ion exchange is the preferential adsorption of
ble, with special attention to the flushing time/vol- ions from water for equivalently charged ions
ume before usage. The time/volume should be which are held on resins.
defined in an SOP and concur with those samples
Endotoxin: A lipopolysaccharide found in the
taken for chemical and microbial testing. A longer
cell walls of viable and nonviable bacteria which
time/larger volume before sampling will create a
is a heat-resistant pyrogen.
bias for a more favorable result. This is because
any potential contamination is sent to waste in Hardness: The amount of calcium and mag-
sampling but, in practice, would have been added nesium salts.
to the product. The handling process of the water Limulus Amoebocyte Lysate (LAL): A
samples should be followed to ensure that it com- reagent derived from horseshoe crab blood used
plies with the SOP requirements. The process for the detection of endotoxins (pyrogens).
must be validated and include container type and Mixed-bed resin: Both cation and anion resins
storage of the samples which are not tested within mixed together for the deionization of water. The
a set time frame. The container surface must not bed is usually used to polish the water.
add anything to or remove any constituents from Pyrogen: A substance, e.g., endotoxin that
the water while it is awaiting analysis. The key is will induce fever in mammals.
to minimize any influences so that they are Resistivity: The ability of a substance to
insignificant and that there is evidence to support resist the flow of electricity. Measurements are in
this conclusion. megaohms/cm.
Reverse osmosis: The application of pres-
Summary sure across a semipermeable membrane so as
to produce purer water on one side of the mem-
Water systems are complex and one of the criti-
brane and a more concentrated solution of ion-
cal components in a sterile manufacturing facility.
ized salts on the other.
Failure of any part of the system could cause mul-
tiple problems and potentially result in a product Total Organic Carbon (TOC): The concentra-
recall. Adherence to SOPs, strict maintenance of tion of the carbon bound as organic compounds.
change control, and clear definition of responsibili- UV light: Ultra violet light at 254 nm used to kill
ties will assist in minimizing potential problems. bacteria and destroy ozone in the water system.
Meeting expectations of this guide and checklist

80 Special Edition: Utilities Qualification

 Graham Bunn

will not ensure that your facility will not receive an References
FDA form 483. Auditing is based on education, 1. Current Good Manufacturing Practice for the
experience, competency, and instinct. It cannot Manufacture, Processing, Packaging or Holding of
solely be taught in the classroom but also has to Drugs; General. 21 CFR part 210. Current Good
Manufacturing Practice for Finished Pharmaceuticals.
be learned by practical application. 21 CFR part 211.
Good luck in passing your next inspection as I 2. Preamble, 1978 GMPs: Federal Register, 29
may be the auditor at your door. ❏ 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 employ-
ers, either past or present.

The Auditor’s Pocket

Literature Sources Checklist for
Pharmaceutical
1. Guide to Inspections of Microbiological Water Systems Follows
Pharmaceutical Quality Control
Laboratories. (FDA 1993).
2. USP, current edition.

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• Quality Based on Conformance to Requirements • Statistics-Based Quality – Reduction of Variability
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• Preventing “Risk Creep” • Maintaining a Sense of Criticality • Rotate Jobs • Actively Participate in Industry Groups • Establish Clear and
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Graham Bunn

The Auditor’s 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 company’s 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?

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The Auditor’s 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 ºC), 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 welder’s 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.

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The Auditor’s 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?

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The Auditor’s 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.)

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The Auditor’s 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
1.3μS/cm. On-line method.
Stage 2: Carbon dioxide and temperature corrected. Sample limit is 2.4μS/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 1.3μS/cm. On-line method.
Stage 2: Carbon dioxide and temperature corrected. Sample limit is 2.4μS/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 comm-
ensurate with their formulation.

86 Special Edition: Utilities Qualification