[ PQ Forum.

Paul L. Pluta

PQ=Confirmation

Paul L. Pluta

PQ Forum provides a forum for validation practi-
tioners to share information about stage 2 process
qualification (PQ) in validation lifecycle. Information
about supporting activities such as equipment and
analytical validation is shared. The information pro-
vided is intended to be helpful and practical so as
to enable application in actual work situations. Our
objective: Useful information.
Comments from readers are needed to help us
fulfill our objective for this column. Suggestions
for future discussion topics are invited. Please con-
tact column coordinator Paul Pluta at paul.pluta@
comcast.net or journal coordinating editor Susan
Haigney at shaigney@advanstar.com with comments,
suggestions, or topics for discussion.
KEY POINTS
The following key points are discussed:
Validation performance qualification is expected to
be confirmatory (i.e., the validation is expected
to confirm the design, development, and other
support work associated with the respective
validation).
Personnel involved in validation may not know
or understand current validation expectations.
Validation documentation may also be substan-
dard due to incomplete development work.
A strategy to change erroneous understanding of
validation and define current validation expecta-
tions is proposed.
The site validation policy should clearly state
the site strategy and approach to validation and
qualification. Appropriate personnel should be
trained on this policy.
If there is not complete confidence in the future
success of the validation PQ, protocols must not be
approved and validation should not be initiated.
The site validation approval committee (VAC)
should have significant input into development
of the site policy and must then uphold the stated
validation standards and expectations.
The VAC should function as a surrogate regulatory
auditor when reviewing and approving validation
documents.
INTRODUCTION
Validation has evolved over the years; what was com-
mon and accepted practice in validation performance
qualification (PQ) years ago is not acceptable today.
The November 2008 FDA process validation draft guid-
ance (1) clearly states the current expectation for PQ as
follows: Stage 2Process Qualification: During this
stage, the process design is confirmed as being capable
of reproducible commercial manufacture.
The draft guidance also states the following:
During the process qualification stage of process
validation, the process design is confirmed as being
capable of reproducible commercial manufacturing.
This stage has two elements: [1] design of the facility
and qualification of the equipment and utilities, and
[2] performance qualification (PQ). During this stage,
CGMP-compliant procedures must be followed and
successful completion of this stage is necessary before
commercial distribution.

[
ABOUT THE AUTHOR
Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive industrial development, manufac-
For more Author turing, and management experience. Dr. Pluta is also Adjunct Associate Professor at the University of
information, Illinois, Chicago College of Pharmacy. He is also editor-in-chief of the Journal of Validation Technology
go to and the Journal of GXP Compliance. Dr. Pluta has written several chapters and edited Cleaning and
gxpandjvt.com/bios Cleaning Validation, Volume 1, Basics, Expectations, and Principles, published by PDA and DHI Publishing.
He may be contacted by e-mail at paul.pluta@comcast.net.

60 Journal of Validation T echnology [Autumn 2010] iv thome.com


A successful PQ will confirm the process design and
demonstrate that the commercial manufacturing process
performs as expected.
The level of monitoring and testing should be suf-
ficient to confirm uniform product quality throughout
the batch during processing.
After establishing and confirming the process,
manufacturers must maintain the process in a state of
control over the life of the process, even as materials,
equipment, production environment, personnel, and
manufacturing procedures change.
The key word that is restated in these sections of the
guidance is confirm.
There is clear and repeated evidence that the US Food
and Drug Administration expects manufacturers to
thoroughly understand the process and confirm its
acceptability in the PQ. The PQ is expected to confirm
the design, development, and other preliminary work
associated with the validation. The confirmatory PQ
is a decision point that heavily contributes to the judg-
ment to transition responsibility for the process from
development to manufacturing for routine use. The FDA
guidance (1) states, Success at this (PQ) stage signals an
important milestone in the product lifecycle and needs
to be completed before the manufacturer commences
commercial distribution of the drug product.
A successfully completed PQ is a strong statement
that development of the subject operation has been
completed and is ready for manufacture of commercial
product. The most effective way to demonstrate readi-
ness for routine use is through a successfully executed
PQproblem-free and mistake-freethat clearly shows
that the design and development objective has been
achieved.
The FDA guidance was written specifically for manu-
facturing processes. However, validation thought lead-
ers are now applying the validation lifecycle approach
to equipment, facilities, utilities, and other applica-
tions (i.e., any item or system to be validated). The
PQ for each of these items should confirm acceptable
performance. When the PQ for any of these items is
successfully completed, responsibility for the object of
the PQ (i.e., processes, equipment, computer systems,
etc.) is transferred for routine use.
Why Dont We Confirm?
There are several reasons why the validation PQ is
not always confirmatory. The primary reason is
that people involved in the work of validation (i.e.,
research and development [R&D] scientists, engineers,
and other technical people) are not aware of current
gxpandjv t.com
Paul L. Pluta.
regulatory expectations. Validation is performed in
different areas on different things related to manufac-
turing (e.g., manufacturing processes, cleaning pro-
cesses, analytical methods, equipment, HVAC systems,
water systems, computer systems, and so on). Each of
these is performed by people with different expertise,
knowledge, and experience. These people have differ-
ent levels of awareness of regulations and regulatory
expectations for validation. Other factors may also
influence the validation approach. Project timelines
may cause an accelerated initiation of validation.
Commercial demand requirements may also cause
validation to be prematurely initiated. New active
pharmaceutical ingredients (APIs) or other materials
may not be available to perform experimental runs
prior to validation. Costs may be prohibitive, espe-
cially when used material will be destroyed and not
commercially distributed.
All personnel involved in validation must clearly
know that validation is intended to confirm that the
process, equipment, facilities, etc. are well understood,
under good control, and can be expected to perform
reliably and consistently throughout their respective
lifecycle.
Again, the key message: Validation is confirmation.
This discussion addresses the following:
Obsolete attitudes and beliefs. Some specific
examples of misunderstanding validation, obsolete
attitudes, and beliefs about validation.
Validation equals confirmation. A successful
PQ confirms that the subject of the validation can
be expected to reliably perform.
Defining current validation expectations.
A strategy to change erroneous understanding of
validation and clearly define current expectations
is presented. Topics addressed include validation
policy, training, experimental work, management
commitment, and associated topics.
OBSOLETE ATTITUDES AND BELIEFS
Validation managers that attended the IVT Validation
Week Europe conference in Dublin, Ireland in March
2010 discussed obstacles they face in their jobs. The
first subject to be raised by these managers was the
general lack of understanding of current validation
expectations by people at their respective manufac-
turing sites. People do not understand that validation
should confirm process design and development. They
learned validation at different times over the last 20 to
30 years and have not stayed current with regulatory
expectations and industry practice.
Journal of Validation T echnology [Autumn 2010] 61
PQ Forum.
Incomplete Preparation For Validation
Several managers at the conference complained that
R&D, engineering, or technical people never totally
complete a project before initiating validation. These
people often do not understand that validation should
confirm their technical work. Their following state-
ments describe their attitudes and beliefs:
Validation is the final step in the development
process
We may have to do final process optimization in
validation
We will determine the final operating parameters
in validation
The project should be completely finished before
we start validation, but if we see something to
improve during validation, we will do it during
the validation.
These statements demonstrate a fundamental misun-
derstanding of validation expectations. Development
work must be completed before validation is initiated.
Process parameters must be completely defined and
clearly stated in manufacturing process directions.
Processes using finalized defined parameters are then
confirmed in validation.
Documentation Problems
Several managers also commented about validation doc-
umentation problems caused by incomplete technical
work. For example, statements included the following:
If there are major process problems during vali-
dation, we explain them in the protocol. If the
explanation is good, then the process is validated.
It is OK to make mistakes in paperwork because
we will explain them in the write-up.
As long as you sign and date changes in the pro-
tocol, QA will approve them.
Validation documents are fundamental documents
frequently requested by regulatory auditors. Regulatory
expectations for validation documents are high. Docu-
ments should demonstrate that design and development
of process, equipment, or the system being validated
has been completely finished. A successful validation
then confirms that the process, equipment, etc., are
well understood, appropriately controlled, and able to
be used to reliably manufacture commercial product.
Validation documents with process problems, errors,
corrections, and other mistakes suggest the opposite
and the more problems seen in the documentation, the
worse the impression. When one validation manager
62 Journal of Validation T echnology [Autumn 2010]
complained to engineering management about the
quality of validation documentation, she was told that
FDA expects to see mistakes and failures in validation.
Mistakes show that we really performed the validation,
and didnt drylab (falsify) the validation.
Validation professionals must persist in changing the
obsolete attitudes described above and help their col-
leagues to know current requirements and expectations.
VALIDATION EQUALS CONFIRMATION
Validation performance is expected to be confirmatory
(i.e., process, equipment, etc. requirements are expected
to be confirmed in validation). There must be a good
understanding of whatever system is being validated.
Testing and results should demonstrate acceptable
system performance. The PQ is expected to confirm
the design, development, and other preliminary work
associated with the respective validation. There must
be an expectation of successful validation based on
technical knowledge and experience obtained before
validation is initiated. If necessary, development work,
research studies, and even scale-up runs may need to
be conducted prior to initiating the validation protocol.
When the validation protocol is written, we must
know what to test and how to do the testing. Sampling
must be clearly defined, appropriate for use, and justi-
fied. Acceptance criteria must be rational and justified.
There should be complete confidence that validation
tests will pass acceptance criteria. We must not be learn-
ing the performance of our equipment, or determining
the limits of process capability in validation.
We must not be testing something for the first time
when we perform validation. If we need to do some-
thing for the first time, we should do it in develop-
ment or in an engineering study, and then confirm
its acceptability in validation. We must not add a new
requirement or specification to the validation that has
not been previously evaluated. Laboratories must not
be using a new test method that has not been previously
validated. We must not be trying software for the first
time in validation.
To again summarize, validation is confirmation of
what is already known.
Validation Should Be Boring
Consultant Michael Anisfeld, in his program Funda-
mentals and Essentials of Validation (2), teaches that
validation should be boringmeaning that there
should be no surprises in the execution of a validation
protocol, and that the execution of the protocol must
yield expected successful results. Those responsible for
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validation should have no anxiety regarding validation
performance. They should be simply confirming what
they already knowthat all testing in the validation
will meet acceptance criteria. Professionals responsible
for processes, equipment, or systems being validated
as well as the personnel conducting the validations
must approach their work with a confident expecta-
tion of complete success. They should not hope the
validation will pass. They should be bored waiting and other associated documents. These documents
for expected results.
DEFINING CURRENT VALIDATION
EXPECTATIONS
Validation managers at the Dublin meeting discussed
key elements of a strategy to change erroneous or
obsolete understanding of validation and clearly
define current validation expectations. These includ-
ed validation policy, training, validation approval
committee (VAC) responsibilities, experimental trials
ahead of actual PQ runs, personal and organizational
reputations, and senior management support.
Validation Policy
The site validation policy should clearly state the site
strategy and approach to validation and qualification.
These expectations should require that validation pro-
tocols contain requirements that are based on scien-
tific and technical work done in advance of validation.
Design and development work must be completed
before validation is initiated. The validation should
then confirm the design and development work. No
optimization, fine-tuning, or other development work
is allowed to be done in validation. The FDA 2008
process validation draft guidance (1) describes this
approach in the lifecycle approach to validation.
Validation Training
After the policy is written and approved, training of
appropriate associated personnel must be conducted.
These included manufacturing, quality assurance,
technical support, engineering, and other groups.
Personnel involved in support work that is done pre-
liminary to validation are key participants in this
training. They must clearly understand that their
work must be completed before starting validation,
and that validation must confirm their work. This
training will be especially useful to personnel who
had learned validation many years ago but had not
remained current with new developments or regula-
tory expectations. In addition to the aforementioned
site personnel, their respective management must
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Paul L. Pluta.
be part of this training and support compliance to
the policy.
Validation Approval Committee
The site VAC has an important role in the site validation
program. The VAC should have significant input into
development of the site policy. They have responsibil-
ity for approving validation protocols, results packages,
must be in compliance with the site policy. Standards
upheld by the site VAC sends a strong message to those
who are responsible for development work and writing
protocols. Successful validation that confirms design
and development work must be an expectation that is
demanded by the VAC.
Pre-Work, Experimental Studies, And
Engineering Studies
Personnel initiating validation must be completely con-
fident of the future success of their protocols. When
personnel submitting protocols are not highly confident
of future success, protocols must not be approved and
validation should not be initiated. Additional devel-
opment work may be required to address unanswered
questions. Laboratory experimental studies, pilot-scale
work, or even full-scale trials may be warranted depend-
ing on the information available or risk of failure.
Personal And Organizational Reputations
Site personnel, their respective functional organizations,
and site management must support and be commit-
ted to confirmation in PQ validation and its ramifica-
tionscomplete and technically based protocols and
impeccable documentation. Without commitments
from all the aforementioned individuals and groups,
the validation program will not succeed. Good techni-
cally-based validation documentation provides a strong
statement about the organization and its management.
Good validation documentation also conveys a mes-
sage about personnel in the organization. One valida-
tion manager suggested that authors who had written
substandard validation documents be asked to evaluate
the document from a reader perspectivewhat impres-
sion would such substandard documents convey to an
auditor? What judgments would be made about the
authors competency? How significantly would the
authors reputation be damaged? Substandard docu-
ments convey an unwritten message.
Validation documentation also reflects on the site
validation approval committee. The integrity and
competency of the site VAC is also in question when a
Journal of Validation T echnology [Autumn 2010] 63
PQ Forum.
substandard document is approved. The VAC should
serve as a surrogate regulatory auditor when reviewing
validation documents and must require that substan-
dard documents be corrected or rewritten before being
approved. Again, substandard documents convey an
unwritten message.
Senior Management Support
Senior management support of policies that affect
multiple areas in the organization is vital to any
cross-function policy. Topics discussed above may
also affect costs and timelines. However, failures
in validation are often even more costly, required
extensive time and effort for correction, and are an
embarrassment to the organization and all personnel
involved. Without site management support, these
problems will not be corrected.
CONCLUSIONS
Validation performance is expected to be confirmatory.
The PQ is expected to confirm the design, develop-
ment, and other preliminary work associated with the
respective validation.
Personnel may not understand current validation
expectations. R&D or technical people may not under-
stand that development work should be completed
before validation is initiated. This often leads to sub-
standard documentation with process problems, errors,
corrections, and other mistakes.
The validation PQ is expected to be confirmatory.
There must be a good understanding of whatever system
is being validated. There must be an expectation of
success in validation based on technical knowledge and
experience obtained before validation is initiated. New
techniques, sampling, testing, and associated activities
must have been tried before initiating validation. New
acceptance criteria should not be tried without prior
evaluation. New software should not be tried for the
64 Journal of Validation T echnology [Autumn 2010]
first time in validation. Validation is confirmation of
what we already know. Validation should be boring,
meaning that there should be no surprises in the execu-
tion of a validation protocol.
A strategy for changing erroneous or obsolete under-
standing of validation and clearly defining current
validation expectations is proposed. This includes
a validation policy that clearly requires validation
to confirm design and development work. No opti-
mization, fine-tuning, or other development work
must be allowed in validation. If there is not complete
confidence in the future success of the validation PQ,
protocols must not be approved and validation should
not be initiated. Validation training of appropriate
personnel and their management is recommended.
The site validation approval committee should func-
tion as a regulatory auditor to uphold site validation
standards. Substandard validation documents con-
vey a negatively impression of the site, the document
author, and the VAC to regulatory auditors and other
reviewers.
In brief, validation PQ equals confirmation.
REFERENCES
1. FDA, Guidance for Industry, Process Validation: General
Principles and Practices, Draft Guidance, November 2008.
2. Anisfeld, Michael, Fundamentals and Essentials
of Validation, www.Globepharm.org, Deerfield, IL,
USA. JVT
ARTICLE ACRONYM LISTING
APIs Active Pharmaceutical Ingredients
FDA US Food and Drug Administration
PQ Process Validation
R&D Research and Development
VAC Validation Approval Committee
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