VALIDATION AND QUALIFICATION OF WATER PURIFICATION,

STORAGE, AND DISTRIBUTION SYSTEMS: Establishing the dependability

of pharmaceutical water purification, storage, and distribution systems
requires an appropriate period of monitoring and observation. Ordinarily,
few problems are encountered in maintaining the chemical purity of Purified
Water and Water for Injection Nevertheless, the advent of using conductivity
and TOC to define chemical purity has allowed the user to more
quantitatively assess the water's chemical purity and its variability as a
function of routine pretreatment system maintenance and regeneration.
Even the presence of such unit operations as heat exchangers and use point
hoses can compromise the chemical quality of water within and delivered
from an otherwise well-controlled water system. Therefore, an assessment of
the consistency of the water's chemical purity over time must be part of the
validation program. However, even with the most well controlled chemical
quality, it is often more difficult to consistently meet established
microbiological quality criteria owing to phenomena occurring during and
after chemical purification. A typical program involves intensive daily
sampling and testing of major process points for at least one month after
operational criteria have been established for each unit operation, point of
use, and sampling point.

VALIDATION AND QUALIFICATION OF WATER PURIFICATION,

STORAGE, AND DISTRIBUTION SYSTEMS

An overlooked aspect of water system validation is the delivery of the water

to its actual location of use. If this transfer process from the distribution
system outlets to the water use locations (usually with hoses) is defined as
outside the water system, then this transfer process still needs to be validated
to not adversely affect the quality of the water to the extent it becomes unfit
for use. Because routine microbial monitoring is performed for the same
transfer process and components (e.g., hoses and heat exchangers) as that of
routine water use (see Sampling Considerations), there is some logic to
include this water transfer process within the distribution system validation.

Validation is the process whereby substantiation to a high level of assurance

that a specific process will consistently produce a product conforming to an
established set of quality attributes is acquired and documented. Prior to and
during the very early stages of validation, the critical process parameters and
their operating ranges are established. A validation program qualifies and
documents the design, installation, operation, and performance of
equipment. It begins when the system is defined and moves through several
stages: installation qualification (IQ), operational qualification (OQ), and
performance qualification (PQ). A graphical representation of a typical water
system validation life cycle is shown in Figure.

Pharmaceutical Water system validation life cycle.

A validation plan for a water system typically includes the following steps:
(1) establishing standards for quality attributes of the finished water and the
source water; (2) defining suitable unit operations and their operating
parameters for achieving the desired finished water quality attributes from
the available source water; (3) selecting piping, equipment, controls, and
monitoring technologies; (4) developing an IQ stage consisting of instrument
calibrations, inspections to verify that the drawings accurately depict the
final configuration of the water system and, where necessary, special tests to
verify that the installation meets the design requirements; (5) developing an
OQ stage consisting of tests and inspections to verify that the equipment,
system alerts, and controls are operating reliably and that appropriate alert
and action levels are established (This phase of qualification may overlap
with aspects of the next step.); and (6) developing a prospective PQ stage to
confirm the appropriateness of critical process parameter operating ranges
(During this phase of validation, alert and action levels for key quality
attributes and operating parameters are verified.); (7) assuring the adequacy
of ongoing control procedures, e.g., sanitization frequency; (8)
supplementing a validation maintenance program (also called continuous
validation life cycle) that includes a mechanism to control changes to the
water system and establishes and carries out scheduled preventive
maintenance including recalibration of instruments (In addition, validation
maintenance includes a monitoring program for critical process parameters
and a corrective action program.); (9) instituting a schedule for periodic
review of the system performance and requalification, and (10) completing
protocols and documenting Steps 1 through 9.

PURIFIED WATER AND WATER FOR INJECTION SYSTEMS

The design, installation, and operation of systems to produce Purified Water

and Water for Injection include similar components, control techniques, and
procedures. The quality attributes of both waters differ only in the presence
of a bacterial endotoxin requirement for Water for Injection and in their
methods of preparation, at least at the last stage of preparation. The
similarities in the quality attributes provide considerable common ground in
the design of water systems to meet either requirement. The critical
difference is the degree of control of the system and the final purification
steps needed to ensure bacterial and bacterial endotoxin removal.

Production of pharmaceutical water

Production of pharmaceutical water employs sequential unit operations
(processing steps) that address specific water quality attributes and protect
the operation of subsequent treatment steps. A typical evaluation process to
select an appropriate water quality for a particular pharmaceutical purpose
is shown in the decision tree in Figure 2. This diagram may be used to assist
in defining requirements for specific water uses and in the selection of unit
operations. The final unit operation used to produce Water for Injection is
limited to distillation or other processes equivalent or superior to distillation
in the removal of chemical impurities as well as microorganisms and their
components. Distillation has a long history of reliable performance and can
be validated as a unit operation for the production of Water for Injection, but
other technologies or combinations of technologies can be validated as being
equivalently effective. Other technologies, such as ultrafiltration following
other chemical purification process, may be suitable in the production of
Water for Injection if they can be shown through validation to be as effective
and reliable as distillation. The advent of new materials for older
technologies, such as reverse osmosis and ultrafiltration, that allow
intermittent or continuous operation at elevated, microbial temperatures,
show promise for a valid use in producing Water for Injection.

Validation plan Pharmaceutical Water System

The validation plan should be designed to establish the suitability of the

system and to provide a thorough understanding of the purification
mechanism, range of operating conditions, required pretreatment, and the
most likely modes of failure. It is also necessary to demonstrate the
effectiveness of the monitoring scheme and to establish the documentation
and qualification requirements for the system's validation maintenance.
Trials conducted in a pilot installation can be valuable in defining the
operating parameters and the expected water quality and in identifying
failure modes. However, qualification of the specific unit operation can only
be performed as part of the validation of the installed operational system.
The selection of specific unit operations and design characteristics for a
water system should take into account the quality of the feed water, the
technology chosen for subsequent processing steps, the extent and
complexity of the water distribution system, and the appropriate compendial
requirements. For example, in the design of a system for Water for Injection,
the final process (distillation or whatever other validated process is used
according to the monograph) must have effective bacterial endotoxin
reduction capability and must be validated.
INSTALLATION, MATERIALS OF CONSTRUCTION, AND
COMPONENT SELECTION

Installation techniques are important because they can affect the

mechanical, corrosive, and sanitary integrity of the system. Valve installation
attitude should promote gravity drainage. Pipe supports should provide
appropriate slopes for drainage and should be designed to support the piping
adequately under worst-case thermal and flow conditions. The methods of
connecting system components including units of operation, tanks, and
distribution piping require careful attention to preclude potential problems.
Stainless steel welds should provide reliable joints that are internally smooth
and corrosion-free. Low-carbon stainless steel, compatible wire filler, where
necessary, inert gas, automatic welding machines, and regular inspection
and documentation help to ensure acceptable weld quality. Follow-up
cleaning and passivation are important for removing contamination and
corrosion products and to re-establish the passive corrosion resistant
surface. Plastic materials can be fused (welded) in some cases and also
require smooth, uniform internal surfaces. Adhesive glues and solvents
should be avoided due to the potential for voids and extractables. Mechanical
methods of joining, such as flange fittings, require care to avoid the creation
of offsets, gaps, penetrations, and voids. Control measures include good
alignment, properly sized gaskets, appropriate spacing, uniform sealing
force, and the avoidance of threaded fittings.

Materials of construction should be selected to be compatible with control

measures such as sanitizing, cleaning, and passivating. Temperature rating
is a critical factor in choosing appropriate materials because surfaces may be
required to handle elevated operating and sanitization temperatures. Should
chemicals or additives be used to clean, control, or sanitize the system,
materials resistant to these chemicals or additives must be utilized. Materials
should be capable of handling turbulent flow and elevated velocities without
wear of the corrosion-resistant film such as the passive chromium oxide
surface of stainless steel. The finish on metallic materials such as stainless
steel, whether it is a refined mill finish, polished to a specific grit, or an
electropolished treatment, should complement system design and provide
satisfactory corrosion and microbial activity resistance as well as chemical
sanitizability. Auxiliary equipment and fittings that require seals, gaskets,
diaphragms, filter media, and membranes should exclude materials that
permit the possibility of extractables, shedding, and microbial activity.
Insulating materials exposed to stainless steel surfaces should be free of
chlorides to avoid the phenomenon of stress corrosion cracking that can lead
to system contamination and the destruction of tanks and critical system
components.

Specifications are important to ensure proper selection of materials and to

serve as a reference for system qualification and maintenance. Information
such as mill reports for stainless steel and reports of composition, ratings,
and material handling capabilities for nonmetallic substances should be
reviewed for suitability and retained for reference. Component (auxiliary
equipment) selection should be made with assurance that it does not create
a source of contamination intrusion. Heat exchangers should be constructed
to prevent leakage of heat transfer medium to the pharmaceutical water and,
for heat exchanger designs where prevention may fail, there should be a
means to detect leakage. Pumps should be of sanitary design with seals that
prevent contamination of the water. Valves should have smooth internal
surfaces with the seat and closing device exposed to the flushing action of
water, such as occurs in diaphragm valves. Valves with pocket areas or
closing devices (e.g., ball, plug, gate, globe) that move into and out of the flow
area should be avoided.

SANITIZATION - Pharmaceutical Water System

Microbial control in water systems is achieved primarily through sanitization

practices. Systems can be sanitized using either thermal or chemical means.
Thermal approaches to system sanitization include periodic or continuously
circulating hot water and the use of steam. Temperatures of at least 80 are
most commonly used for this purpose, but continuously recirculating water
of at least 65 has also been used effectively in insulated stainless steel
distribution systems when attention is paid to uniformity and distribution of
such self-sanitizing temperatures. These techniques are limited to systems
that are compatible with the higher temperatures needed to achieve
sanitization. Although thermal methods control biofilm development by
either continuously inhibiting their growth or, in intermittent applications,
by killing the microorganisms within biofilms, they are not effective in
removing established biofilms. Killed but intact biofilms can become a
nutrient source for rapid biofilm regrowth after the sanitizing conditions are
removed or halted. In such cases, a combination of routine thermal and
periodic supplementation with chemical sanitization might be more
effective. The more frequent the thermal sanitization, the more likely biofilm
development and regrowth can be eliminated. Chemical methods, where
compatible, can be used on a wider variety of construction materials. These
methods typically employ oxidizing agents such as halogenated compounds,
hydrogen peroxide, ozone, peracetic acid, or combinations thereof.
Halogenated compounds are effective sanitizers but are difficult to flush
from the system and may leave biofilms intact. Compounds such as hydrogen
peroxide, ozone, and peracetic acid oxidize bacteria and biofilms by forming
reactive peroxides and free radicals (notably hydroxyl radicals). The short
half-life of ozone in particular, and its limitation on achievable
concentrations require that it be added continuously during the sanitization
process. Hydrogen peroxide and ozone rapidly degrade to water and oxygen;
peracetic acid degrades to acetic acid in the presence of UV light. In fact,
ozone's ease of degradation to oxygen using 254-nm UV lights at use points
allow it to be most effectively used on a continuous basis to provide
continuously sanitizing conditions.

In-line UV light at a wavelength of 254 nm can also be used to continuously

“sanitize” water circulating in the system, but these devices must be properly
sized for the water flow. Such devices inactivate a high percentage (but not
100%) of microorganisms that flow through the device but cannot be used to
directly control existing biofilm upstream or downstream of the device.
However, when coupled with conventional thermal or chemical sanitization
technologies or located immediately upstream of a microbially retentive
filter, it is most effective and can prolong the interval between system
sanitizations.

It is important to note that microorganisms in a well-developed biofilm can

be extremely difficult to kill, even by aggressive oxidizing biocides. The less
developed and therefore thinner the biofilm, the more effective the biocidal
action. Therefore, optimal biocide control is achieved by frequent biocide use
that does not allow significant biofilm development between treatments.

Sanitization steps require validation to demonstrate the capability of

reducing and holding microbial contamination at acceptable levels.
Validation of thermal methods should include a heat distribution study to
demonstrate that sanitization temperatures are achieved throughout the
system, including the body of use point valves. Validation of chemical
methods require demonstrating adequate chemical concentrations
throughout the system, exposure to all wetted surfaces, including the body
of use point valves, and complete removal of the sanitant from the system at
the completion of treatment. Methods validation for the detection and
quantification of residues of the sanitant or its objectionable degradants is
an essential part of the validation program. The frequency of sanitization
should be supported by, if not triggered by, the results of system microbial
monitoring. Conclusions derived from trend analysis of the microbiological
data should be used as the alert mechanism for maintenance.The frequency
of sanitization should be established in such a way that the system operates
in a state of microbiological control and does not routinely exceed alert levels
(see Alert and Action Levels and Specifications).

Pharmaceutical Water System OPERATION, MAINTENANCE,

AND CONTROL

A preventive maintenance program should be established to ensure that the

water system remains in a state of control. The program should include (1)
procedures for operating the system, (2) monitoring programs for critical
quality attributes and operating conditions including calibration of critical
instruments, (3) schedule for periodic sanitization, (4) preventive
maintenance of components, and (5) control of changes to the mechanical
system and to operating conditions.

Operating Procedures—

Procedures for operating the water system and performing routine

maintenance and corrective action should be written, and they should also
define the point when action is required. The procedures should be well
documented, detail the function of each job, assign who is responsible for
performing the work, and describe how the job is to be conducted. The
effectiveness of these procedures should be assessed during water system
validation.

Monitoring Program—

Critical quality attributes and operating parameters should be documented

and monitored. The program may include a combination of in-line sensors
or automated instruments (e.g., for TOC, conductivity, hardness, and
chlorine), automated or manual documentation of operational parameters
(such as flow rates or pressure drop across a carbon bed, filter, or RO unit),
and laboratory tests (e.g., total microbial counts). The frequency of sampling,
the requirement for evaluating test results, and the necessity for initiating
corrective action should be included.

Sanitization—

Depending on system design and the selected units of operation, routine

periodic sanitization may be necessary to maintain the system in a state of
microbial control. Technologies for sanitization are described above.

Preventive Maintenance—

A preventive maintenance program should be in effect. The program should

establish what preventive maintenance is to be performed, the frequency of
maintenance work, and how the work should be documented.

Change Control—

The mechanical configuration and operating conditions must be controlled.

Proposed changes should be evaluated for their impact on the whole system.
The need to requalify the system after changes are made should be
determined. Following a decision to modify a water system, the affected
drawings, manuals, and procedures should be revised.

Auxiliary Information— Staff Liaison : Gary E. Ritchie, M.Sc., Scientific

Fellow

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

Phone Number : 1-301-816-8353