Qualification of Purified Water Systems
Qualification of Purified Water Systems
Qualification of Purified Water Systems
Water Systems
David W. Vincent
Validation Technologies, Inc.
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, routine monitoring program, Preventative Maintenance be from a well or surface source.
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
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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
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David W. Vincent
< 5 microsiemens/cm
< 25 EU/ml
< 200 CFU/ml
5.5 to 7.0
< 5 mg/l
Non-detected
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USP 24 Specification
No Specifications
100 cfu/ml
5.0 7.0
500 ppb
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
David W. Vincent
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.
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.
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
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David W. Vincent
Microbiological/Chemical Limits
Figure 2
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
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.
Installation
Qualification
(IQ)
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-
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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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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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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.
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