Validation Learning Center.
Paul L. Pluta, David W. Vincent, David E. Jones, and Timothy J. Fields
]
Process Performance—
Conformance Lots
EXECUTIVE SUMMARY
This installment of the “Validation Learning Center”
provides a summary of information on demonstration
of process performance (i.e., the manufacturing of conformance lots).
Recent documents and discussions have emphasized
a comprehensive and integrated approach to the validation of manufacturing processes—the lifecycle approach to process validation. This approach includes
process understanding derived from laboratory studies and process development history, confirmatory
process performance at commercial scale using specified process parameter values (conformance lots), and
maintenance of the validated state during routine manufacturing by ongoing process monitoring.
When the process is understood and process parameters are decided, conformance lot manufacturing can
commence. This discussion addresses four topics related to process performance. These include the following:
• Considerations prior to process performance
• Pre process-performance documents
• Manufacturing conformance lots
• Post process-performance documents.
The process performance phase also includes the
qualification of associated equipment, facilities, utilities, and associated control systems. All manufacturing process-related test methods and assays must be
fully developed and validated before commencing the
conformance lot phase.
There must be a general understanding and acceptance of the lifecycle approach to process validation in
the organization. The manufacturing of conformance
lots should confirm the product and process knowl-
For more Author
information,
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[
edge obtained during development. Successful process
performance is achieved through a collaborative effort
of key functional groups in the organization.
Pre-process performance documents include the validation master plan (VMP), the validation plan providing detailed requirements for specific validation activities, and the validation protocol that includes
sampling, testing, and acceptance criteria requirements.
The manufacturing batch record (MBR) provides the
detailed information for the manufacturing process
and process parameters that are to be validated.
Manufacturing conformance lots include the actual
product batches to be manufactured and associated
testing. Planning and communicating activities conducted prior to manufacturing are critical to successful process performance. These include communication to all affected groups and review of associated
equipment/facilities/utilities procedures. Equipment/facility/utility readiness regarding calibration and preventive maintenance, personnel training, use of multiple materials lots, and multiple manufacturing
operators to verify process robustness are discussed.
Post-process performance documents include executed manufacturing batch records, test results, and
summary documents. A plan for maintaining the validated state including monitoring and trending recommendations should be addressed in the final validation report.
Reference presentations and documents supporting
the process performance phase of the validation lifecycle approach are provided.
All work associated with process performance must
be documented. These documents are frequently audited and must be readily retrievable.
ABOUT THE AUTHORS
Paul Pluta, Ph.D., is coordinator of “Validation Learning Center” and has more than 30 years of pharmaceutical
industry experience. He can be reached at paul.pluta@comcast.net. David Vincent is CEO of Validation Technologies, Inc. David Jones is an independent consultant. Tim Fields is President of Drumbeat Dimensions, Inc.
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The terminology associated with process performance
and other areas of validation has had minor changes
over the years and will likely continue to evolve. While
the variety of terminology used may cause difficulties
in communicating, the intent of all validation programs is the same: Formulations and processes must
be developed and understood, process performance is
then confirmed by conformance lots, and thereafter
the validated state must be maintained.
ment to “release the process” for routine commercial
manufacturing and introduce product to the marketplace.
Process performance encompasses the supporting
qualification of associated process equipment and systems including analytical methods utilized in conformance lot manufacturing.
OVERVIEW OF PROCESS PERFORMANCE—CONFORMANCE LOTS
INTRODUCTION
This installment of the “Validation Learning Center”
summarizes validation process performance (i.e., the
manufacturing of validation conformance lots).
Current good manufacturing practice (CGMP) product manufacturers are expected to have sufficient knowledge and experimental data to be confident that the
manufacturing process will consistently deliver a highquality product. Research and development knowledge must yield manufacturing processes that are robust, based on scientific and technical principles, and
appropriately well controlled. Process performance
(i.e., the manufacturing of conformance lots) must be
demonstrated to confirm acceptability of the product
before it can be released for commercial distribution.
Thereafter, quality systems are used to continuously
monitor and maintain the validated state, and thereby
guarantee assurance of continuing high-quality manufacturing and product performance. This integrated
and comprehensive approach to process validation
comprising process understanding, process performance (conformance batches) and validated state monitoring and maintenance describes the lifecycle approach to process validation.
When the process is understood and process parameters are finalized, the process performance phase is
conducted. Process performance confirms the information and process operating parameters determined
in process development. Further, it confirms the effectiveness of technology transfer activities that transition
manufacturing from pilot-scale to large-scale manufacturing. Process performance is not the final step in
development, not the final scale-up trial, and not final
process optimization. Regulatory agencies expect that
all processes be fully developed and well understood
in advance of manufacturing conformance lots (also
called validation lots or demonstration lots). Conformance lots confirm the conclusions and expectations
of the design and development work. The successfully
manufactured conformance lots are the basis for judg60
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Process performance includes the activities and documentation that demonstrate the successful development of a new process or the successful implementation of change to a validated process.
This discussion of process performance includes the
following four separate topics:
• Considerations prior to process performance.
There should be a general understanding and acceptance of the lifecycle approach to process validation by all functions relevant to validation in
the organization (1). In the lifecycle approach,
validation in not completed but is continually ongoing. This approach necessitates good understanding of the product/process; good process understanding is the basis for process performance.
The manufacturing of conformance lots should
confirm the product/process knowledge obtained
during development. The process performance
phase is successful through a collaborative effort
of key organizational groups including the technical function, manufacturing operations, quality
assurance, and the validation group. Each of these
functions has different roles and responsibilities;
all must have a consistent approach for process
performance to succeed.
• Pre-process performance documents. This includes preparation of documents supporting and
specific to validation, and preparation of the product manufacturing batch record. There are several
standard documents routinely used and/or associated with process performance. These include
the VMP, the validation plan for the specific validation and associated activities, and the validation protocol including sampling, testing, and acceptance criteria. These validation documents
provide general supporting information and the
specific details for the validation. The manufacturing batch record provides the detailed process
and critical process parameters to be validated.
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Validation Learning Center.
• Manufacturing conformance lots. These include
the actual product batches to be manufactured and
their associated testing. Considerations and activities conducted prior to manufacturing and testing are critical to successful manufacturing and
process performance. The future actual manufacturing of conformance lots should be a well-communicated event to all affected areas in the organization. All groups, including the technical support,
manufacturing, quality control, analytical laboratories, and other affected groups should be aware
of the future validation and any ramifications of
those validation activities. The procedures and
operational details of qualified associated equipment, utilities, facilities, and systems may need to
be reviewed. Their readiness (i.e., calibration, preventive maintenance, etc.) should be reviewed.
The readiness of personnel for process performance should be reviewed. Manufacturing including planned use of expected variables (material
and personnel) should be considered. All of these
points must be addressed prior to actual conformance lot manufacturing.
• Post-process performance documents. These
documents provide validation test data with discussion and conclusions. After manufacturing of
the conformance lots, data from the executed manufacturing batch records and test results are compiled to develop the validation results report. This
document summarizes and discusses process performance and test results. A final summary report
may be desirable pending the complexity of the
total validation project. A plan for maintaining
the validated state should be discussed in the final
validation report.
Supporting Reference Presentations and Documents
In the recently presented Lifecycle Approach Process
Validation (2) and Benefits of a Pharmaceutical Quality System (3), expectations for process performance
were described. This phase addresses facilities/equipment/utilities qualification and performance qualification of the process to be validated. Equipment/facilities/utilities must be appropriately designed and
qualified to support the manufacturing process. Protocol considerations must go beyond the three lots
manufactured, and must lead to the conclusion that
the process will consistently yield a quality product in
future product manufacturing. The validation lots are
manufactured at commercial scale with qualified equipment/facilities/utilities, approved materials and components, master production and control documents,
and trained personnel. Processes are run at nominal
operating parameters within the acceptable range or
design space. Lots are extensively tested with increased
process control monitoring beyond typical quality control levels of testing. The net results of the process performance phase is that the process is acceptable for
routine commercial manufacturing—“release the
process” for routine commercial manufacturing—based
on supporting process understanding work and the
demonstrated performance. Products may then be introduced to the marketplace.
The July 2004 Pharmaceutical Inspection Convention
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
“Recommendations on Non-Sterile Process Validation”
(4) provides details on process performance. Relevant
comments include the following:
“Master Batch Documentation can be prepared only
after the critical parameters of the process have been
identified and machine setting, component specifications, and environmental conditions have been determined. Using this defined process (including specified components), a series of batches of the final
product should be produced. In theory the number
of process runs carried out and observations made
should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered
acceptable that three consecutive batches/runs within
the finally agreed parameters, giving product of the desired quality, would constitute a proper validation of
the process. In practice, it may take some considerable
time to accumulate this data.”
This document further describes the necessity of a
full-scale production batch size, extensive testing at
various stages, and comprehensive documentation.
Recommendations on the extent of monitoring and
the in-process controls necessary for routine products
are discussed. The discussion of this document is consistent with a lifecycle approach to process validation
including process understanding, process performance,
and maintenance of the validated state.
The January 2004 Global Harmonization Task Force
(GHTF) Quality Management Systems—Process Validation Guidance (5) for medical devices is also consistent
with a lifecycle approach to process validation. Although terminology is different than described for the
various activities of pharmaceutical process validation,
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ing, process performance, and maintaining a state of
validation. Example completed protocols are provided
in this guidance. Statistical methods and tools for
process validation are discussed including process capability, variation input and output, control charting,
and other methods.
The March 12, 2004 revision of the US Food and
Drug Administration’s Process Validation Requirements
for Drug Products and Active Pharmaceutical Ingredients
Subject to Pre-Market Approval (6) discusses validation
conformance batches as follows:
“Before commercial distribution begins, a manufacturer
is expected to have accumulated enough data and knowledge about the commercial production process to support
post-approval product distribution. Normally, this is achieved
after satisfactory product and process development, scale-up
studies, equipment and system qualification, and successful completion of the initial conformance batches. Conformance batches (sometimes referred to as ‘validation’ batches
and demonstration batches) are prepared to demonstrate
that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to
make acceptable product.”
Also, in policy regarding conformance batches, “New
drug applications may be approved by the Center prior
to the completion of the initial conformance batch phase
of process validation. The manufacture of the initial
conformance batches should be successfully completed
prior to commercial distribution.” Allowable exceptions
to the above are discussed in the guidance.
The expectations for process performance have been
published in various regulatory guidances for many
years. The 1987 FDA Guideline on General Principles of
Process Validation (7) defines validation as follows: “A
documented program which provides a high degree of
assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.” The January 1994 FDA
Guide to Inspections of Oral Solid Dosage Forms
Pre/Post Approval Issues for Development and Validation (8) expands on this definition as follows:
“The three components of this definition include
documented evidence, consistency, and predetermined
specifications. Documented evidence includes the experiments, data and analytical results that support the
master formula, the in-process and finished product
specifications, and the filed manufacturing process.
With regard to consistency, several batches would have
to be manufactured, using the full scale batch size, to
demonstrate that a process meets the consistency test.
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sistency. The development of a product and its manufacturing process and specifications, the design of the
validation protocol, and the demonstration (validation) runs of the full scale manufacturing process requires scientific judgment based on good scientific
data. We expect that in-process control and product
specifications will be established during the product
development process, with the test batch serving as the
critical batch used for the establishment of specifications. Specifications, such as hardness and particle
size, should be established prior to validation of the
process; these specifications should be included in the
validation protocol. The use of product development
runs of the process to establish both specifications and
demonstrate that the system is validated often causes
problems. In these cases, more in-depth inspection
and evaluation will be required; some of these process
runs often produce failing product because the product specifications have not been fully established and
tested. The inspection team should observe facilities,
equipment and processes to put data review in proper
context. It is also important that raw data, including
validation and laboratory logbooks be audited or reviewed to verify accuracy and authenticity.”
CONSIDERATIONS PRIOR TO PROCESS
PERFORMANCE
The strategy and approach of the organization toward
validation in general and to the specific validation being
executed is fundamental to the success of validation
performance. Key considerations demonstrating the
organizational strategy and approach include the following:
• Lifecycle approach to process validation
• Validation process performance equals confirmation
• Collaboration—function roles and responsibilities.
Lifecycle Approach to Process Validation
The organization should adopt a lifecycle approach to
process validation as discussed in the referenced regulatory presentations and guidelines. The lifecycle approach to process validation comprises process understanding, process performance by manufacturing
conformance lots, and subsequent maintenance of the
validated state. With respect to process performance,
this means that there is good understanding of the
process or process change being executed, and that
there is a technical basis for performance. See referivthome.com
Validation Learning Center.
ence (1) for an overview discussion on the lifecycle approach to process validation. See reference (9) for an
overview discussion on the process understanding phase
of the lifecycle approach to process validation. Implementation of a lifecycle approach to process validation
includes a comprehensive and integrated approach
rather than a focus only on the specific (usually three)
validation batches.
Validation Process Performance Equals
Confirmation
Process performance should confirm the work of the
process-understanding phase. When the process validation protocol is prepared, there must be knowledge
and understanding of what to test, why the testing is
appropriate, how to do the testing, and what are appropriate acceptance criteria. There must be good confidence that validation tests will meet their pre-determined acceptance criteria. Process performance is not
research, development, scale-up, determination of the
unknown, fine-tuning, optimization, or other exploratory work on the process or associated activities.
The approved process validation protocol must be executed with an expectation of success. All validation
test results must meet their pre-determined acceptance
criteria for the validation to be successful. Validation
should not be initiated unless there is confidence that
tests are appropriate, that they can be performed as
written in the protocol without any changes, and that
test results will be acceptable.
New sampling techniques or new tests should not
be attempted for the first time when performing validation, especially in cases of complex procedures (e.g.,
blend uniformity sampling and testing). If there is a
need for new procedures or methods, these should be
perfected in a pre-validation trial or experimental study.
There should not be new requirements or specifications that have not been previously evaluated. Techniques, sampling, testing, and associated activities
should be tried before being used in validation. There
should not be new acceptance criteria in validation
that have never been evaluated, and these acceptance
criteria should be justified. Validation performance
should confirm the acceptability of the process as previously developed. Validation equals confirmation.
Collaboration—Function Roles and Responsibilities
The successful execution of the process performance
phase of the validation lifecycle requires a collaborative effort of all groups associated with the validation.
While there may be organizational differences in the
group titles, four organization functions are identified
for validation process performance. These include the
technical function including writers of validation documentation, performance (manufacturing) function,
approval function, and validation function. These
groups have the same overall objective: To successfully
complete all validation performance activities. However, each function must have the same general approach to validation within their individual perspectives, roles, and responsibilities. Each group must also
understand and respect the roles, perspectives, and responsibilities of the other groups for the collaboration
to be successful.
• Technical function including writing validation
documents. The technical function group is responsible for technical aspects of the process validation including understanding the process to be
validated. The technical function group is most
knowledgeable of the process and performs the
technical work supportive to validation and subsequent routine manufacturing. The technical
function group must know what is required for
validation and should conduct their development
work with future validation in mind. All development reports and other fundamental
formula/process information are supportive of validation and are considered part of validation documentation. All supporting development documentation must be organized in a logical manner
that best represents the technical effort.
The technical function group includes the writers of validation documentation. The technical
function group has impact on all other functions.
Validation documents must be understandable to
the performance function. Validation documents
must be acceptable to the approval function. Validation documents must meet validation requirements as required by the validation function group.
Protocol writers must prepare their documentation so that all of the organization function groups
will be satisfied with the protocols, results, reports,
and other validation documentation.
The technical function and authors of validation documents must focus on the following three
considerations (i.e., technical, compliance, and
document quality):
1. Technical. Work must demonstrate that validation/qualification and all associated activities are conducted according to scientific and
technical principles, and that there is good understanding of the process to be validated. There
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should be a consistent approach in the performance of validation. Sampling must be adequate
to support the sampling conducted in future
routine manufacturing of commercial product.
Testing must adequately confirm acceptability
for future routine manufacturing. If validation
is acceptable, future routine product manufacturing is expected to be acceptable. Operating
ranges of equipment utilized in product process
validation must be qualified in appropriate
equipment qualification documents.
2. Compliance. The validation must be compliant with company policies and standards, approaches stated in the VMP, and with regulatory
requirements and industry standards.
3. Documentation. Documents must adequately describe the validation and its associated requirements. This includes the scientific
and technical principles that are the bases for
the validation and compliance with standards.
Documentation should demonstrate process
understanding, or provide reference to appropriate documentation. Validation documents
must be written clearly and logically, and must
be written for the future reader of the document.
Rationale for the extent of sampling conducted
in the validation must be provided. Rationale
for the selection of tests conducted in the validation must be provided. There must be adequate evaluation and discussion of results—
more than just stating “results pass.” Validation
documentation must be grammatically correct.
Validation documents must “stand alone” (i.e.,
provide adequate information without additional explanation). Validation documents are
often audited many years after their original
preparation when involved personnel are not
available; the expected useful longevity of these
documents must be considered.
• Performance function. The performance function group executes the manufacturing batch record
and the validation protocol. Production operators execute the manufacturing process that is being
validated. The validation protocol must be carefully prepared, well written, and have clear directions so that the performance function may successfully execute the protocol. The performance
function group should not initiate manufacturing
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unless they clearly understand the manufacturing
directions and protocol requirements, and are confident that both can be successfully executed. All
systems in support of the protocol execution, such
as calibration, preventative maintenance, standard
operating procedures (SOPs), manufacturing batch
records, and other documentation must be accurate, current, and acceptable for use as needed for
protocol execution.
• Approval function. The approval function group
is comprised of multiple disciplines including quality assurance and other appropriate site representatives. Representatives of the technical function
group, performance function group, and validation function group often participate in approval
of validation document. Other appropriate representatives (e.g., regulatory affairs) may be asked
to approve specific validations. The approval function group approves all validation documents such
as validation plans, protocols, results documents,
and summary documents.
The objective of the approval group is to approve documents that comply with expectations
for validation, i.e., technically sound, compliant
with policies, and well written. Documents must
be logical, provide appropriate rationale, and be
defendable. They must also be acceptable regarding style, appearance, grammar, punctuation, and
other non-technical considerations. The approval
function serves as an internal auditor regarding review of the documents. If an approved document
is later criticized by a regulatory auditor, the approval function has failed in its responsibility. The
approval function must be aware of expectations
for validated processes, and must review documents with the eye of an FDA or other regulatory
agency auditor.
• Validation function. The validation function
group is responsible for maintaining validation
standards as required by the company, regulatory
agencies, and industry practice. Validation documents must then be managed to be accessible and
quickly and easily retrieved as needed for audits
and other reviews.
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PRE-PROCESS PERFORMANCE DOCUMENTS
The pre-performance documents are documents that
support and are specific to the process to be validated.
Included in this category are all documents supporting the process understanding phase of the validation
lifecycle (9). These include pharmaceutics reports,
technical development reports, engineering reports,
method development reports, laboratory studies, and
other documents supportive to process understanding. All technical supporting documents must be organized in a logical manner that best represents the
information gained by the work. Application of the
data, and especially data affecting specific process parameters, should be discussed. There should be statistical treatment of data and discussion of process robustness.
Product and process quality
attributes/specifications should be discussed. Information provided in development reports is the basis
for process performance, process parameters, quality
attributes, and ongoing monitoring. A final report discussing this information is highly desirable, will be a
continuing resource supporting the product and
process, and will very likely be referenced throughout
the entire product lifecycle.
This discussion of validation process performance
addresses specific documents relevant to the process
performance phase of the validation lifecycle. These
include the VMP, the validation plan for the specific
validation, and the validation protocol including sampling, testing, and acceptance criteria. These validation documents provide overview information and
specific information for the validation to be conducted.
The manufacturing batch record provides documentation of the detailed process and process parameters
to be validated.
Validation Master Plan
The VMP is a key support document for validation information and strategy for the entire manufacturing site.
In brief, the VMP provides general and specific information describing the validation program for the site.
It contains overview information relevant to all validation/qualification. The VMP can be a detailed and comprehensive plan that includes all of the site validation
activities or can be divided into separate parts. For example, there may be a cleaning validation master plan,
computer system master plan, etc. The VMP is one of
the most requested documents in regulatory audits. Examples of typical information found in the site VMP include the following (not an all-inclusive list):
• Site validation/qualification general philosophy
and approach
• Site facility description including floor plan
• Qualification general approach for site equipment,
HVAC, and utilities including references to associated validation/qualification
• Process validation general approach and products
manufactured including references to associated
validation documentation
• Cleaning validation general approach and including references to associated validation documentation
• Analytical methods including references to associated validation documentation
• Schedule of future planned validation/qualification to be conducted.
The information in the VMP is fundamental to all
specific validation/qualification conducted at the site
and provides the basis for individual validation process
performance. Regarding process validation, the VMP
provides the general approach to process validation
conducted at the manufacturing site. The general strategy and approach provided in the VMP may be referenced in specific protocols and does not need to be
repeated. The VMP should generally discuss the lifecycle approach to process validation as the validation
approach embraced at the site. All validation conducted at the site must be consistent with the general
strategy and approach defined in the VMP. In short,
the VMP is a road map to a successful validation lifecycle approach.
Validation Plan for Specific Process Validation
The validation plan for the specific process validation
to be executed describes the overall requirements to
accomplish the specific validation. This document
will be the first document to describe the specific validation to be performed. The following describes a
general format for a validation plan for a specific
process validation. Five categories of information are
proposed including introduction, technical considerations for the specific validation and information
demonstrating process understanding, validation approach and strategy, validation documentation requirements, and references and supporting documents. The information provided in the validation
plan summarizes and specifies work to be done to
complete the validation and thus provides a framework for the specific validation.
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• Introduction. The introduction includes the description of the manufacturing process to be validated
and the reason to initiate the validation; for example:
“Initial process validation of product X; product X is a
new product to be manufactured at this manufacturing site;” or for a process change to be validated, for
example, “Change in drying temperature for drying
process of product Y; this temperature will optimize
the product Y drying process.”
A discussion of the validation or the change is then
provided, including the evaluation of the change
(major, minor, etc. depending on the site change classification system and risk analysis method) and the
requirements to accomplish the change. For example, a validation protocol requiring successful manufacturing of three lots may be required. Other requirements to complete may include procedure changes,
regulatory notification, VMP update, new training
modules, and other documentation changes. Discussion of product release considerations (e.g., all conformance lots will not be released to the market until
the final validation approval is complete) should also
be discussed in this section. After reading this section, there should be a good understanding of the objective of the validation and all requirements (e.g.,
technical, procedures, documentation, etc.) to complete the validation.
• Technical information. This section should provide technical considerations and information supporting the validation to be conducted, thus demonstrating the process understanding phase of the lifecycle
approach to process validation. The total information
discussed in this section should indicate that the process
to be validated has been completely developed and is
ready for the confirmatory activities of validation. Technical information provided may include textbook information, experimental work, manufacturing experience, and other information. Product description,
product indications, manufacturing process, and other
supplementary information are helpful to the reader
in understanding the validation. Information provided
in this section should indicate that the process or proposed change is ready for validation, and that the validation is expected to be successful. Technical reference documents supporting the validation may be
attached to the validation plan or may be referenced.
• Validation general approach and strategy. The
general strategy and approach to the validation is briefly
described. This must be consistent with the validation
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general strategy and approach described in the site
VMP. This section describes the general strategy and
approach for the total process validation, which may
include new equipment qualification, experimental
trials, and the final process performance runs. All
process validations should be prospective validation.
In general, consideration of critical quality attributes
and critical process parameters, support of regulatory
specifications, support of internal controls and inprocess tests, and other technical process tests comprise the validation strategy and approach to confirm
the validated process. The general approach to sampling and acceptance criteria are also described.
• Validation documentation. This section describes
all validation documents to be prepared to complete
the specific validation. Numbering for tracking of documents may be assigned at this time. Experimental
studies, qualifications of new equipment needed for
the process validation, protocols, and associated documents for the validation are specified. Supporting
technical documents may also be specified in this section. When a validation plan describes a complex project requiring multiple equipment and process validation protocols, a validation summary report may be
specified as a requirement to complete the validation
project. Specifying a requirement to write a summary
report at this stage is useful; if not specified at this stage,
the report will likely never be completed.
This section is also helpful to clerical non-technical
personnel who are assisting in the compilation of validation documents and maintaining validation files.
The clerical personnel will know the documents required to “close” the validation because they are clearly
specified in this section.
• References and supporting documents. Documents referenced in the validation plan are cited. These
may include R&D studies, literature citations, other
documents referenced in the technical section, previous relevant process validations, and so on.
Validation Protocol
The validation protocol for the specific process validation to be executed describes the specific requirements
to accomplish the validation. The following describe
the key sections of a validation protocol: Protocol objective, validation strategy and approach, manufacturing information, validation testing and rationale, validation sampling and rationale, and acceptance criteria:
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• Protocol objective. This section describes the
manufacturing process to be validated and the reason
for the validation.
• Validation strategy and approach. The specific
strategy and approach applicable to the specific protocol is briefly described. This must be consistent with
the general strategy and approach described in the validation plan and the VMP. The process validation
should be prospective. Consideration of critical quality attributes and critical process parameters, support
of regulatory specifications, support of internal controls and in-process tests, and other technical process
tests comprise the validation strategy and approach to
process validation. The specific approach to sampling
and acceptance criteria are described for this process
validation, again consistent with general discussion in
the validation plan and the VMP.
• Manufacturing information. This section provides specific product/process information, including
the product description and patient use, detailed formulation and manufacturing process, critical process
parameters, and critical quality attributes. This information is especially helpful to external auditors and
others not familiar with the product/process being validated.
• Validation testing and rationale. This section
provides specific details of the tests to be conducted
to accomplish the validation. The rationale for the
choice of tests must be discussed. Tests to be conducted
should be related to critical quality attributes of the
product and process.
• Validation sampling and rationale. This section
provides specific details of the sampling to be conducted to accomplish the validation. The rationale for
the sampling must be discussed.
• Acceptance criteria. This section provides the acceptance criteria for the testing and sampling described
above. All testing should have acceptance criteria. “For
information only” or “Report results” are not appropriate for validation protocols. Acceptance criteria
should be based on process development data and be
scientifically justified.
rationale in protocols and acceptance criteria, specifically,
“As opposed to general problems … a more specific problem that we see is a lack of scientific rationale in the protocols and acceptance criteria. At least there is a lack of
documentation of such rationale, which is what we’re expecting to see. We want the process to be there, that you've
come up with a scientific study, a protocol—this is what
you're attempting to show, and this is why, and this is how
it going to be evaluated, and then just simply executing that.
That’s documentation of the scientific rationale. Oftentimes they have it; they just haven't documented it. I’ve always maintained that if you have a good process of developing protocol, you're going to develop good protocols. In
a good process, that means coming from a logical scientific
standpoint, looking at it as a scientific study, and the whole
idea that this is our objective, and this is how we're going
to show it and evaluate it. Take that protocol and subject
it to internal peer review. Make sure enough people with
varied expertise can look at that and say, ‘Yes, this is a valid
study,’ and then simply execute it. Then, with all those
pieces up front, hopefully the execution goes well, and years
later, when we look at that particular study or validation,
it's clear to everyone what was done, what the objective was,
how it was met, and it's a good complete package” (10).
• Data recording templates. Templates for recording future manufacturing parameters, in-process test
data, analytical laboratory data, and other data are recommended for inclusion in the protocol. These should
be approved by the validation approval function. When
validation results are reviewed post process performance, a consistent and logical presentation of data will
be desirable for internal review as well as for future review by external auditors.
Manufacturing Batch Record
The manufacturing batch record contains all relevant
information for product manufacturing. This includes
the quantitative formulation, manufacturing equipment, individual process steps, process parameters for
process steps, signature/date to record performance,
other CGMP requirements, safety information, and
other detailed manufacturing information. This document provides the detailed process to be validated.
A published (2000) interview with an FDA investigator indicated that one of the most important deficiencies in process validation is the lack of scientific
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Validation Learning Center.
MANUFACTURING
BATCHES
CONFORMANCE
Manufacturing conformance batches include the actual product batches to be manufactured and associated testing. Considerations and activities conducted
prior to manufacturing and testing are critical to successful process performance. These include communication of the impending process performance to all
affected groups to ensure adequate preparation for validation. All equipment, facilities, utilities, and associated control system must be qualified and ready for
use (i.e., all must have current operating procedures)
and have calibration and preventive maintenance
within scheduled time requirements. Specific training
of operators and other personnel on new processes or
process changes must be conducted as necessary. After
these considerations have been addressed, conformance
lot manufacturing may be initiated.
Communication
All affected groups must be aware of the impending
conformance lots. Groups affected include technical
support, manufacturing including manufacturing operators, quality assurance and quality control, laboratory analysts, and others as needed. Most relevant are
groups who are directly participating in the validation
(i.e., production operators). However, other associated groups more remote to manufacturing must also
be aware of the validation. For example, laboratory
analysts who will test samples from the conformance
lots must confirm that a changed formula/process will
not impact testing methods.
Preparation for process validation
Preparation for process validation includes very specific activities that may be easily overlooked. These include procedures for equipment operation, qualification of associated equipment, facilities, and systems,
preventive maintenance, calibration, personnel training, and consideration of variables apart from process
parameters specified in the manufacturing instructions.
The following describe these activities in detail:
• Procedures. Although the manufacturing batch
record is the primary document describing the process
validation, there are procedures describing equipment
operation, facility control, utility operation, etc. that
support manufacturing. These procedures must be correct and consistent with the manufacturing batch
record. Procedures must be correct and current in order
to manufacture correctly. Procedures may be in the
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process of being changed; there must be no confusion
which procedure or part of procedure is to be performed. Conformance lots must not be initiated if
supporting procedures are not current and correct.
• Qualification of associated equipment, utilities,
facilities, and systems. All equipment, utilities, facilities, and associated systems must be qualified prior
to use in process validation. Qualified ranges of operational parameters should be checked for consistency
with the manufacturing process to be validated. For
example, if a granulation drying process is being
changed to dry at a higher temperature, the drying
equipment must be qualified to operate at that higher
temperature. Also, calibration may need to be changed
to reflect the higher operating temperature. All test
methods including in-process testing must be validated
before being used in test conformance lots.
• Preventive maintenance and calibration. All
equipment, utilities, facilities, and associated systems
must be appropriately maintained through the preventive maintenance program and the calibration program. Conformance lots must not be initiated if preventive maintenance and calibration is not current.
• Personnel training. Personnel training must be
correct and current before initiation of validation. New
training may be required for the process validation.
Conformance lots must not be initiated if personnel
training is not correct and current.
• Process variables. Use of multiple lots or multiple sources of active pharmaceutical ingredients (API)
and of key formulation excipients is desirable in process
validation. Use of multiple manufacturing operators
is desirable in process validation. These practices
demonstrate the robustness of the process. If all active drugs and excipients used in the three conformance
lots were from their respective same bulk lots, manufacturing repeatability would not truly be demonstrated.
If only one manufacturing operator made all conformance batches, manufacturing repeatability would not
truly be demonstrated.
Conformance Batch Manufacturing
Manufacturing of conformance batches using the specific process to be validated may be initiated after completion of all preparatory activities described previously. If all activities are carefully accomplished,
conformance batch manufacturing will be successful.
ivthome.com
Validation Learning Center.
POST-PROCESS PERFORMANCE
DOCUMENTS
The post-process performance documents either contain or summarize process performance data and provide discussion and conclusions. After manufacturing
of the conformance lots, the executed manufacturing
batch records and test results are utilized to develop
the validation results report. This document summarizes and discusses the conformance lots. A final summary report may be necessary for complex validation
projects. A plan for maintaining the validated state
should be discussed in the final validation report.
Executed Manufacturing Batch Record
The executed manufacturing batch record documents
the process that was validated and is thus a key document for the process performance phase. It should be
stored appropriately and be readily retrievable as needed
for audits. These records may need to be accessed many
years after they had been executed. Manufacturing operator compliance with requirements for data entry,
signature/date, data correction, handwriting legibility,
and other documentation standards are especially important for conformance lot batch records.
Conformance Lots Test Results
Data from the manufacturing batch records, in-process
quality control tests, and analytical laboratory tests
are compiled in the conformance lots test results document. Data presentation in previously-designed and
approved templates (see protocol section) is recommended. Statistical treatment of data is required if
appropriate. Non-statistical evaluation of data for
trends and aberrations must be considered. For example, if acceptance criteria for potency determination of conformance lots are 90-110%, and data were
91%, 100%, and 109%, would we be satisfied that all
results passed acceptance criteria? Good judgment in
data analysis is critical, as opposed to review solely vs.
acceptance criteria.
All results must be evaluated, thoroughly discussed,
and appropriate conclusions stated. Simply stating
“Results pass” is not adequate. Results must be discussed so that they are understandable to the reader.
Also, we do not know whom the reader may be, background, expertise, experience, and when the review will
occur. Clarity in discussing results is much more important than brevity. A final concluding statement after
thorough discussion of results such as “Based on the
results of testing in this protocol, the manufacturing
process for Product X is validated” is recommended.
Validation Performance Final Report
A final report summarizing the entire validation performance may be desirable for complex process validations. For example, a process validation comprising
multiple preliminary studies prior to validation, requalification of multiple equipment to include a new
range of operating conditions, and finally, process validation of multiple conformance lots would be most
easily explained in a summary document discussing
all validations, qualifications, and experimental work
conducted. Consider the effort required for an auditor to review a complex project without the benefit of
a summary report. Although summary reports are an
“extra” document and extra work, they are well worth
the effort.
Amendments and Mistakes
Amendments are changes to validation documents.
Amendments to validation plans and protocols are legitimately possible. For example, a project scope may
change requiring a protocol change. Amendments,
however, have a negative connotation. Even legitimate
amendments imply that something unexpected has
happened—contrary to good project management and
to the confirmatory nature of validation. Development
work on projects should be completed and successful
before validation plans and protocols are approved.
Many amendments are avoidable such as amendments
resulting from insufficient planning or insufficient preliminary work. These types of amendments must be
avoided. Mistakes may occur in executing manufacturing batch records or in executing validation protocols. Mistakes (non-conformances) must also be
avoided. If mistakes happen, operators must immediately consult their supervisors and the validation
function must also be consulted. Clear and explicit
explanations regarding what caused the mistake must
be clearly written. Mistakes will happen and must be
carefully investigated and explained. Amendments
and mistakes must be evaluated to determine whether
they impact the intent of the validation. Additional
conformance batches may need to be manufactured if
an amendment or mistake negated the true objective
of the validation.
Plan for Maintaining the Validated State
The final process validation report must include the
plan to maintain the validated state. It is well understood that completion of the validation performance
phase of the lifecycle approach does not complete validation (11). The FDA Pharmaceutical cGMPs for the
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Validation Learning Center.
21st Century – A Risk-Based Approach, Final Report—
2004, states, “The (CPG) document stresses the importance of rational experimental design and ongoing
evaluation of data. The document also notes that
achieving and maintaining a state of control for a
process begins at the process development phase and
continues throughout the commercial phase of a product’s life-cycle” (12).
Maintaining the validated state will be discussed in
the Autumn 2008 ”Validation Learning Center.”
DOCUMENTATION
All work associated with validation performance must
be documented. This includes all process validation
documents, manufacturing batch records of conformance lots, test results, test data, and qualification of
associated equipment and systems. Documentation
must be clearly written for reader understanding. Clarity is much preferred over brevity. Documentation
must stand alone (i.e., be understandable without additional explanation). In many cases, documents are
reviewed literally years after they are written and long
after authors have moved to new areas in the company
or have left the company. All associated documents
(e.g., process understanding documents that are supportive to validation performance) must be readily retrievable. Copies of experimental studies conducted
by R&D personnel should be stored with validation
documents so as to be readily available for validation
audits. Document storage in an easily-accessible and
centralized location is recommended.
Validation documentation must be written using
correct grammar, spelling, and punctuation.
TERMINOLOGY
The terminology associated with process performance
and other areas of validation has had minor variations
over the years and will likely continue to evolve. The
1987 FDA Validation Guidance (7) described “Installation and Operational Qualification,” “Process Performance Qualification,” and “Product Performance
Qualification.” Product lots manufactured in validation have been termed “demonstration lots,” “conformance lots,” and “validation lots” in various documents over the years.
The most recent FDA presentations addressing the
lifecycle approach to validation have used the term
“Process Qualification” to describe process performance, and the lots manufactured are called “conformance lots.” It also refers to “Qualification of equip70
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ment, utilities, and facilities” supporting Performance
Qualification, (i.e., process performance is called “Performance Qualification”).
The GHTF Process Validation Guidance (5) for medical devices describes three phases of process validation as “Installation Qualification” for addressing
equipment, “Operational Qualification” for equipment and product including manufacturing at worstcase conditions, and “Performance Qualification” for
product under normal operating conditions.
While the variety of terminology used may cause
difficulties in communicating, the intent of all validation programs is the same: There must be process
performance by conformance lots to demonstrate
process understanding; thereafter, the validated state
must be maintained. Validation programs addressing these phases of the product/process lifecycle, no
matter what specific terminology is used or how categorized in documentation, will meet the expectations
for validated process.
CONCLUSIONS
The process performance phase of the lifecycle approach to process validation is an extremely important phase. This phase demonstrates the success of the
process understanding phase as conducted in development. Success in process performance is the basis
for judgment to “release the process” for future commercial manufacturing and introduction of product
into the marketplace. Data and results from conformance lots are the starting data for the continuing monitoring of product performance for maintaining the
validated state.
Regulatory guidelines and presentations specify the
requirement to demonstrate process performance and
associated equipment qualification. The specific details to accomplish process performance are less well
defined. The discussion and comments of this paper
incorporate process understanding information into
the validation performance phase of the validation
lifecycle. A plan to maintain the validated state is recommended for inclusion in the final validation report. This approach to process performance thus integrates all phases of the validation lifecycle approach
to process validation.
REFERENCES
1. Pluta, Paul L, John M. Hyde, and Miguel Montalvo. “Expectations for Validated Processes,” Journal of Validation
Technology, Volume 14, #2, Winter 2008.
ivthome.com
Validation Learning Center.
2. McNally, Grace E., Lifecycle Approach Process Validation,
GMP by the Sea, Cambridge, MD, August 29, 2007.
3. Famulare, Joseph, Benefits of a Pharmaceutical Quality System, PDA / FDA Joint Conference, Bethesda, MD, November 2, 2007.
4. Pharmaceutical Inspection Convention, Pharmaceutical
Inspection Co-Operation Scheme (PIC/S), “Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation,
Cleaning Validation,” July 1 2004.
5. GHTF Study Group 3, Quality Management Systems—
Process Validation Guidance, Edition 2, January 2004.
6. FDA, Compliance Policy Guide 7132c.08, Section 490.100,
“Process Validation Requirements for Drug Products and
Active Pharmaceutical Ingredients Subject to Pre-Market
Approval.”
7. FDA, Guideline of General Principles of Process Validation,
May 1987.
8. FDA, Guide to Inspections of Oral Solid Dosage Forms,
“Pre/Post Approval Issues for Development and Validation,” January 1994.
9. Pluta, Paul L. and Richard Poska, “Expectations for Process
Validation—Process Understanding,” Journal of Validation
Technology, Volume 14, No. 3, Spring 2008.
10. Evans, Kristen, and Vincent, D., “Critical Factors Which
Affect Conducting Effective Process Validation: One FDA
Investigator’s View,” Journal of Validation Technology, Volume 6, No. 2, February 2000.
11. Lanese, Jerry, “Three Times Is Not Even The Beginning—
2008 update,” Journal Validation Technology, Volume 14,
No. 2, Winter 2008.
12. FDA, Pharmaceutical cGMPs for the 21st Century—A RiskBased Approach, Final Report, September 2004. JVT
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