Validating High-Purity Water Systems By: Dan Laux January 2001
A2C2 --
In the production of pharmaceuticals, the most widely used raw
material is water. As a raw material, high purity water is unique
in that it is the only component, which must be produced by the
manufacturer, because it is not available from a vendor in a ready-to-use
form. Water is utilized in the production of every type of pharmaceutical;
in some products, such as parenterals, it is a critical component.
In such applications Water-For-Injection (WFI) systems are used
to generate water for use in manufacturing applications.
Regadess of the system used to generate high purity water, under
Federal regulations 21CFR 210 and 211, it must be validated. One
of the primary references used in the validation of high purity
water systems is the Parenteral Drug Association’s Tech nical
Report No. 4, “Design Concepts for the Validation of a Water
for Injection Sys tem.” According to the report,
Validation often involves the use of an appropriate challenge.
In this situation, it would be undesirable to introduce micro organisms
into an on-line system; therefore, reliance is placed on periodic
testing for microbiological quality and on the installation of monitoring
equipment at specific checkpoints to ensure that the total system
is operating properly and continuously fulfilling its intended function.
So while there are several strategies that may be employed in the
validation of high purity water systems, the following strategy
contains all the necessary elements.
A Design/installation review. While not always considered an actual
part of the validation process, the installation review is a critical
step in ensuring that the validation is not put at risk and is successfully
completed. Once the installation is finalized, a complete and up-to-date
description and design drawing of the system should be added to
the file and included in the final report. It is important that
the design drawing include all components of the system and clearly
identify all sample points and their designations. If the design
drawing does not include these elements, the water system is considered
to be in an “objectionable condition” and the validation
is at risk.
It is advisable to review the design drawing annually to ensure
that it is accurate and up to date. These reviews often identify
unreported changes and are effective in confirming reported changes
to the system.
B SOP development and confirmation. Once the system design and
installation has been finalized, the next step is to develop the
operational parameters and cleaning and sanitizing protocols. Once
developed, these procedures become the SOPs for the system’s
normal operation. During this step, data are collected over a period
of two to four weeks, and samples should be collected daily after
each purification step and from all points of use. At the end of
the period, if the system has successfully generated water of the
appropriate quality, these procedures are established as the water
system’s SOPs.
C Demonstration of effectiveness. During this phase of the validation
the objective is to demonstrate that the water system consistently
produces water of the desired quality when operated within the parameters
outlined in the SOPs over a long period of time. It is important
that the data is collected in accordance with the SOPs. WFI system
samples are taken daily at a minimum from one point of use and weekly
from all points of use. This type of operation should identify any
inconsistencies in the feedwater quality due to seasonal variations
or other changes in the quality of the source water. A water system
cannot be considered validated until the manufacturer has a year’s
worth of operational data.
D Data compilation and sign-off. The final step in validating a
high purity water system is assembling the data into a validation
report. The final report should include all the data collected in
Steps B and C, along with any conclusions derived from the data.
Once the final report is complete, it is important to ensure that
the appropriate personnel review and sign off on it.
Any validation strategy should include the elements outlined above:
development of the SOPs through data collection, a demonstration
that the SOPs are effective, and assurance that the system is capable
of consistently producing, over a long period, water that meets
the quality specifications. While including these elements in the
validation strategy increases the odds of successfully validating
the water system, even a well thought out strategy is susceptible
to failure because of often overlooked details. The validation process
is long and complex and small details can often be overlooked.
The following are some of the more commonly overlooked considerations:
1 Feedwater. During a water system validation, consideration has
to be given to the quality and seasonal variation of the feedwater.
In some instances, it is also beneficial to consider the quality
of water in surrounding municipalities in the event that water must
be diverted from an alternate, neighboring source. (Feedwater may
be diverted as a result of such events as construction or an emergency
such as a major fire. In such cases, the feedwater entering the
facility may be contaminated with elevated levels or different types
of flora.)
2 Air contamination. A common omission from SOPs is a list of the
correct procedures to preclude contamination from non-sterile air
after a water system is drained. Point-of-use piping extensions,
particularly those that utilize tubing or hoses for application,
can allow non-sterile air to come in contact with the system when
the valves are not opened in the proper sequence. The SOPs should
be reviewed to ensure that proper valve sequencing prevents contamination
from non-sterile air.
3 Component design is an important consideration. While component
design has become more sophisticated in recent years, each of the
following system elements can benefit from further thought:
Carbon beds remove organic compounds from the feedwater. One of
the most common organic compound removed is chlorine, which municipalities
use to control bacterial growth in drinking water. Since carbon
beds filter the organic material needed for bacterial growth, this
material becomes concentrated in the carbon beds; if the beds are
not properly maintained, they can harbor bacteria and endotoxins.
Hot water or steam should be used periodically to purge the system
of such contaminants. It is important that the SOPs include these
maintenance procedures.
Holding tanks. The design element that causes the most concern
vis-a-vis the holding tank is the vent filter. Most new tanks utilize
jacketed vent filters to prevent condensate or water from blocking
the hydrophobic filter. It is important that maintenance SOPs include
procedures for regular checking of the vent filter integrity. For
this reason, the filter should be located in a position that provides
easy access for testing. The SOPs should also include complete flushing
or draining of the holding tanks on a regular basis.
Heat exchangers should be designed to prevent distillate contamination
from feedwater. Double tubesheet design and positive pressure are
the two most common methods used; if positive pressure is utilized
in the design, monitoring systems should ensure that higher pressure
is constantly maintained on the distillate side.
Distillation stills are used in the production of WFI because they
kill microbial organisms, deactivate endotoxins, and eliminate dissolved
solids not removed by previous filtration steps. It is important
that the condenser be designed with double tubesheet to ensure that
the distillate will not come in contact with the coolant, thus preventing
recontamination. Another consideration for distillation stills is
the quality of the steam supplied to the process; the quality of
the steam must be controlled to prevent recontamination.
Pumps. All pumps experience wear and some burn out; it is therefore
important that the maintenance SOPs include a program for the upkeep
of all pumps in the system. If a pump is not in continuous operation,
the reservoir is a potential source of contamination; when the pump
is not in use, water may collect in the low point of the pump housing,
potentially harboring microorganisms. It may be advisable to install
a drain in the low point of the pump housing.
Piping. Most WFI and other high purity water systems utilize stainless
steel (SS) piping in their construction. Where low level metal contamination
is a concern, polyvinylidene fluoride (PVDF) piping has been used
in place of the SS piping. Systems utilizing PVDF piping, however,
require additional support in the piping layout. While the system
is in use, the circulation of hot water may reduce the rigidity
of the piping, causing it to sag. In cases where the piping sags
or bends, stress can create fissures in joints, which may result
in leakage and/or contamination. Other considerations for the piping
include the elimination of “dead-legs” and the use of
welding or sanitary fittings for all joints and connections in the
system design.
4 Microbial Limits. When establishing the microbial specifications
for a high purity water system, the most commonly used reference
is the USP 24 (Table 1). It is important to understand that the
limits set forth by USP 24 are not absolute, and as such the FDA
does not view them as pass/fail limits. Instead, they are viewed
as action limits and in some cases may not be stringent enough.
It is important that users take into account not only the USP guidelines
but also their understanding of the dosage form in which the high
purity water will be used when setting alert or action limits. In,
for example, situations in which the final dosage form does not
have a preservative system, more stringent action limits may be
required to produce safe and effective products. Conversely, some
dosage forms that have low moisture content may tolerate higher
microbial levels and as such the action limits may be established
at higher values.
In WFI systems it is possible that a system may pass either the
microbial or endotoxin action limit but fail the other. It is therefore
import that both endotoxin and microbial levels are closely monitored.
When alert and action limits have been established, it is imperative
that the user have an SOP for investigating deviations. Once a deviation
is detected, the user must investigate the cause, determine a corrective
action, and assess the impact of the contamination on adulterated
product. Throughout this process, the findings and conclusion should
be documented and assembled in a corrective action report. Finally,
there should be a process in place to confirm any changes to the
system or SOPs as a result of the corrective action.
5 Cost of operation. While not a factor in validation, cost considerations
are important. High purity water systems, which operate between
65Þ and 80Þ C, are generally recognized as self-sanitizing.
While these systems cost more initially than “cold” systems,
the savings realized through reduced operations, maintenance, and
testing—and the prevention of potential problems—may make
the investment worthwhile.
The quality of the high purity water generated by WFI and other
systems is critical to the processing of pharmaceuticals. Validation
of the high purity water system and close adherence to the SOPs
are essential to maintaining the quality and integrity of the generated
water. When conducting a high purity water system validation, considering
the points outlined in this article will increase the odds of a
successful validation and preserve the integrity of process water.
