[
Validation Learning Center.
Paul L. Pluta, Coordinator
Maintaining the
Validated State
Paul L. Pluta, David W. Vincent, David E. Jones, and Timothy J. Fields
“Validation Learning Center” addresses basic topics in
validation and qualification. “Maintaining the Validated
State” is the fourth paper in a series specifically addressing current expectations for validated processes. The
first installment, “Expectations for Validated Processes,”
was published in Volume 14, Number 2 (Winter 2008) of
this journal. “Process Understanding—Manufacturing
Processes” was published in Volume 14, Number 3
(Spring 2008). “Process Performance—Conformance
Lots” was published in Volume 14, Number 4 (Summer
2008). Comments, questions, and suggestions for
future discussion topics are invited and most welcome. Contact column coordinator Paul Pluta at paul.
[email protected] or journal coordinating editor Susan
Haigney at [email protected].
EXECUTIVE SUMMARY
Recent articles and discussions have emphasized
the expectations for a comprehensive and integrated
approach to the validation of manufacturing processes—the lifecycle approach to process validation. This
approach comprises process understanding derived
from laboratory studies and process development
history, commercial scale manufacturing at target
process parameter values (i.e., conformance batches),
and maintenance of the validated state through ongoing monitoring of process performance.
After formulation and process development, validation performance in conformance lots, and release of
the manufacturing process for commercial manufacturing, organizations must implement appropriate
systems to monitor and maintain the validated state
of the manufacturing process. Validated processes
must be continually maintained and monitored to
guarantee the release of quality product as intended
For more Author
information,
go to ivthome.
com/bios
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in the product design. Qualification of associated
manufacturing equipment and systems must also be
continually maintained.
The validation strategy and systems adopted by an
organization is fundamental to the success of both the
validation program and to maintaining the validated
state. Key supporting factors that demonstrate the
organizational strategy, approach, and responsibilities include the following:
• Embracing the lifecycle approach to process
validation
• Collaboration of key functions in the organization
• Development of quality systems
• Allocation of adequate resources
• Support by management
• Risk analysis of product and associated processes.
Risk management enables appropriate focus on
areas of review, levels of testing, impact of change, frequency of review, and use of resources—literally every
aspect of process review and maintenance should be
appropriately based on risk analysis.
Once the manufacturing process is validated by
the successful manufacture of conformance lots and
the validated process is released for routine commercial scale manufacturing, the firm must then implement appropriate activities to assure that the process
remains in a state of control. These activities include
the following:
• Trend and assessment data using statistical
methods
• Monitoring of key manufacturing data
• E stablishment of process history, change control
of formulation, process, equipment, etc. associated with the product
• Periodic evaluation of monitoring data.
[
ABOUT THE AUTHOR
Paul Pluta, Ph.D., is coordinator of “Validation Learning Center” and has more than 30 years pharmaceutical industry
experience. He can be reached at [email protected]. David Vincent iis CEO of Validation Technologies, Inc. David
Jones is an independent consultant. Tim Fields is president of Drumbeat Dimensions, Inc.
of
Validation T echnology [Autumn 2008]
iv thome.com
Paul L. Pluta, Coordinator
All of these activities rely on organizational beliefs
and strategy. Further, without appropriate quality
systems, organization resources, and ongoing management support, successful maintenance of the validated
state will be highly unlikely. Risk analysis of product
and associated processes should be used to prioritize
efforts and thus make most efficient use of personnel
and resources.
All work associated with maintaining the validated
state of processes must be documented. Although
terminology may differ and cause communication
problems, the intent of all validation programs is the
same. All validated processes must contain the same
elements including maintaining the validated state
throughout the entire product lifecycle.
INTRODUCTION
This focus of the “Validation Learning Center” is to
provide a summary of information on maintaining
validated processes. Maintenance of the validated
state is the final phase in the lifecycle approach to
process validation. This phase is based on information
obtained during formulation and process development,
and includes the process experience obtained from the
validation conformance lots. Validated processes must
be continually monitored and maintained during the
entire commercial life of the product.
Validated processes must be maintained and monitored to ensure the release of quality product as intended in the product design. Qualification of associated
manufacturing equipment and systems must also be
continually maintained. Ongoing process monitoring
and review of product performance data at appropriate
frequency are necessary to assure continued acceptable performance and control of the validated process.
Process monitoring typically reveals opportunities for
improving the process, improving control strategies,
reduction of variation, and product improvements.
OVERVIEW OF MAINTAINING THE
VALIDATED STATE
After the successful manufacture of conformance lots
and the approval of the validated manufacturing process for routine commercial manufacturing, attention
should then be focused on the appropriate strategies,
collaboration, infrastructure, resources, and management oversight to enable an organization to appropriately maintain the validated state. Maintaining
validated processes comprises the continuing demonstration of controlled process performance through
monitoring, review, change control, and associated
activities. Validation is never truly finished. The activities merely change from the performance phase to the
maintenance phase. Without the maintenance phase,
the collective body of industry evidence tells us that
the validated state will be lost through erosion and
lack of proactive steps.
Maintaining the validated state requires basic
understanding and acceptance of validation principles
throughout the organization. These include embracing the lifecycle approach to process validation and its
associated ramifications. There must be a collaborative
effort of the various organizational functions related
to manufacturing for successful maintenance of the
validated state. Functions affected include manufacturing operations, technical function, quality/approval
function, and validation group. The organization
must adopt and implement modern quality systems
concepts which support maintaining of the validated
state. There must be adequate resources to support
these quality systems. Management responsibilities
are significant to enable and support all of the above.
All validation maintenance activities should be prioritized and performed based on risk analyses of product
and process.
Specific activities to maintain the validated state
include: Timely process data monitoring and analysis; statistical process control; corrective and preventive action (CAPA); change management and control;
management review, and other associated activities.
Process improvements should be facilitated by means
of the above.
Qualification of associated manufacturing equipment and systems must in parallel be continually
maintained. Activities associated with maintaining
the qualified status of equipment include preventive
maintenance programs, calibration programs; monitoring, review, and evaluation of equipment and systems
based on risk analysis.
This discussion of maintaining the validated state
addresses the supporting organizational framework
and specific maintenance activities as follows:
• Key factors supporting maintenance of the validated state. These include a lifecycle approach to
process validation, collaboration of various organizational functions, quality systems concepts,
resource allocation, management responsibilities, and appropriate risk analyses of product and
processes.
• Activities for maintaining the validated state. These
include process data monitoring and analysis using
statistical methods, including critical operating
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Validation Learning Center.
and performance parameters, product characteristics, materials, other changes, and CAPA incidents;
establishing process history, including measure of
process variability and process performance over
time; change management and control of formulation, processes, procedures, and quality attributes;
and periodic evaluation to determine if new studies
or conformance batches are needed.
Supporting Reference Presentations and
Documents
The expectations for maintenance of the validated state
and the activities required for assurance that the process remains in a state of control are clearly expressed
in “Lifecycle Approach Process Validation” (1,2) and
“Benefits of a Pharmaceutical Quality System” (3).
Activities described include trending and assessment
of data, and monitoring critical operating and performance parameters, product performance characteristics, personnel training, and problem investigations.
Establishing process history over time should suggest
process improvements and enhanced control strategies.
Change control and periodic assessment of process
and test data should be used to decide if and when
new validation or other development work needs to
be initiated. This is in contrast to prior approaches
which may have specified re-validation activities on
time rather than event-based premises.
The September 2006 US Food and Drug Administration’s Quality Systems Approach to Pharmaceutical
CGMP Regulations (4) clearly states, “An important
purpose of implementing a quality systems approach
is to enable a manufacturer to more efficiently and
effectively validate, perform, and monitor operations
and insure that the controls are scientifically sound and
appropriate.” Further, “Although initial commercial
batches can provide evidence to support the validity and consistency of the process, the entire product
life cycle should be addressed by the establishment of
continual improvement mechanisms in the quality
system. Thus, in accordance with the quality systems
approach, process validation is not a one-time event,
but an activity that continues through a products life.”
This document discusses trend analysis, CAPA, change
control, and other quality systems programs.
The International Conference on Harmonisation’s
(ICH) Q10 Pharmaceutical Quality System (5) similarly
discusses continual improvements of process performance and product quality. Four elements discussed
include the following:
• Process performance and product quality moni32
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toring system. This includes risk management
techniques, data management and statistical tools,
analysis of parameters and attributes to verify
continuing controlled operations, reduction and
control of sources of variation, feedback of product
quality from internal and external sources, and
enhanced process understanding.
• C APA system. Application of CAPA principles
should be based on risk analysis. CAPA systems
enhance product and process understanding and
enable further improvements.
• Change management system. Improvement initiatives must be supported by a change management
system to evaluate, test, approve, and implement
changes. Quality risk management should be part
of change management.
• Management review of process performance and
product quality. Management reviews should
include results of regulatory and other inspections, periodic quality reviews including customer
complaints, product/process performance, and
follow-up from previous reviews. Management
reviews should stimulate appropriate action such
as product/process improvements, resource realignment, and dissemination of knowledge.
These activities should be conducted during all lifecycle stages. In the manufacturing stage, these activities maintain a state of control, facilitate continual
improvement, and expand the body of knowledge
about product and manufacturing processes.
The September 2004 FDA Pharmaceutical cGMPs for
the 21st Century—A Risk-Based Approach Final Report
2004 (6) summarizes all activities to enhance and
modernize regulation or pharmaceutical manufacturing and quality initiatives. Included is discussion
of quality systems and process validation activities.
Ongoing evaluation of data, achieving and maintaining a state of control as stated in the FDA Compliance
Policy Guide (7) is mentioned. The guide states, “The
document (CPG) clearly signals that a focus on three
full-scale production batches would fail to recognize
the complete story on validation.”
In addition to discussing the general quality risk
management process and risk management methods
and tools, ICH Q9 Quality Risk Management (8) discusses
example applications of risk analysis throughout essentially every function in pharmaceutical manufacturing.
Applications of risk assessment to areas associated with
maintaining the validated state include assessment of
quality defects, frequency and scope of audits; selection, evaluation, and interpretation of periodic review
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Paul L. Pluta, Coordinator
data; interpretation of monitoring data, support of
appropriateness of revalidation; evaluation of change
impact of to product, equipment, facilities, etc., and
many other applications.
Recent medical device documents are consistent
with a comprehensive approach to process validation.
The Global Harmonization Task Force (GHTF) Study
Group 3. Quality Management Systems—Process Validation
Guidance (9) describes activities conducted post validation to maintain the product/process. For example,
“Maintaining a state of validation” by monitoring and
controls that include: trend analysis; changes in processes and/or product; and continued state of control of
potential input variation such as raw materials. Tools
described include statistical methods, process capability, control charts, design of experiments, risk analysis,
and other concepts.
The ICH Q7 Good Manufacturing Practice Guide for
Active Pharmaceutical Ingredients (10) also discusses
activities conducted post validation. Specifically, it
states that critical parameters/attributes should be
identified during development, and these critical process parameters should be controlled and monitored.
Non-critical parameters should not be included in
validation. There should be periodic review of validated systems.
The 1997 FDA Medical Device Quality Systems Manual
(11) further emphasizes activities to be conducted post
validation. It states, “Process and product data should
be analyzed to determine what the normal range of
variation is for the process output. Knowing what is the
normal variation of the output is crucial in determining
whether a process is operating is a state of control and
is capable of consistently producing the specified output. Process and product data should also be analyzed
to identify any variation due to controllable causes.
Appropriate measures should be taken to eliminate
controllable causes of variation …Whether the process is operating is a state of control is determined by
analyzing day-to-day process control data and finished
device test data for conformance with specifications
and for variability.”
The 1997 Guide to Inspections of Medical Device Manufacturers (12) states, “It is important to remember
that the manufacturer needs to maintain a validated
state. Any change to the process, including changes
in procedures, equipment, personnel, etc. needs to
be evaluated to determine the extent of revalidation
necessary to assure the manufacturer that they still
have a validated process.”
The 1987 FDA Guideline on General Principles of Process
Validation (13) includes mention of the following post
validation considerations: “...quality assurance system
in place which requires revalidation whenever there
are changes in packaging, formulation, equipment,
or processes which could impact product effectiveness or product characteristics, and whenever there
are changes in product characteristics.” “The quality
assurance procedures should establish the circumstances under which revalidation is required. These
may be based upon equipment, process, and product
performance observed during the initial validation
challenge studies.”
FACTORS SUPPORTING MAINTENANCE
OF THE VALIDATED STATE
The validation strategy and supporting functional
systems infrastructure of the organization are fundamental to the success of the validation program and
to maintaining the validated state. Specific supportive
factors include the following:
• Lifecycle approach to process validation
• Functional group collaboration—roles and
responsibilities
• Quality systems development and implementation
• Adequate resources
• Management responsibilities
• R isk analysis of product and associated
processes.
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. See previous articles (14,15,16) in this
series for an overview and discussion of individual
phases of the lifecycle approach to process validation.
With respect to maintaining the validated state, there
must be an ongoing focus on manufacturing process
performance through established systems in the organization. Implementation of a lifecycle approach to
process validation includes a comprehensive and integrated approach to manufacturing processes rather than
a focus only on the specific (usually three) validation
batches. Process validation is never completed but is
continually ongoing.
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Validation Learning Center.
Functional Group Collaboration—Roles
and Responsibilities
The successful maintenance of the validated state phase
of the validation lifecycle requires a collaborative effort
of all groups associated with the validation. While
there may be organizational differences in group titles
or membership in the respective functions, four organizational functions are identified to maintain the
validated state. These include the technical function,
performance (manufacturing) function, approval/quality function, and validation function. These groups
should have the same overall objective: To successfully maintain the validated state of all manufacturing
processes. Each function must execute their respective
responsibilities and must also understand and respect
the roles, perspectives, and responsibilities of the other
groups for the collaboration to be successful.
Technical Group Function
The technical group is responsible for technical
aspects of the process validation including understanding the process to be validated. The technical
function is most knowledgeable of the process and
performs the technical work supportive to validation,
subsequent routine manufacturing, and maintenance
of the validated state. The technical function must
know what is required for validation and should conduct their development work with future validation
and subsequent commercial manufacturing in mind.
All development reports and other fundamental formula/process information is supportive of validation
and is considered part of validation documentation.
This work establishes the standards for product and
process performance against which ongoing process
monitoring will be compared.
The technical group includes authors of validation
documentation and ongoing validation maintenance/
monitoring documentation. Validation maintenance
documents must be acceptable to the approval function. Validation maintenance documents must meet
validation requirements as required by the validation
function. Documentation must be written so that all of
the groups will be satisfied with the data presentation,
review, analysis, recommendations, and other actions.
Data analyses must include statistical methods.
The technical group and authors of validation documents must focus on the following three objectives:
• Technical content. Work must demonstrate that
ongoing manufacturing is consistent with the
product/process design and remains in control.
Discussion should be consistent with technical
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data developed during development in the process
understanding phase. There should be a systematic
and consistent approach to maintenance, monitoring, and review activities.
• Compliance with regulations, policies, and procedures. The validation must be compliant with
company policies and standards, approaches stated
in the validation master plan, and with regulatory
requirements and industry standards for maintaining the validated state.
• Document quality. Documents should adequately
evaluate whether the validated process remains in
control. Discussion 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. Documentation must be grammatically correct. Documents
demonstrating the maintenance of the validated
state must “stand alone” (i.e., provide adequate
information without additional explanation).
Performance Group Function
The performance function executes the manufacturing batch record. Their activity is critical to process
performance and dosage form quality attributes. The
performance group should contribute to maintenance
of the validated state by ongoing awareness of expected
process performance. As experience is obtained in
commercial manufacturing, opportunities to improve
processes, reduce variation, and maximize efficiency
will become apparent. Subtle changes in raw material
properties, process performance, equipment operations, and other unexpected observations should be
reported to management for evaluation. The performance group represents an important defense against
potential process variations and problems. The experience and observations of the performance group are
invaluable resources for investigations of aberrant or
non-conforming results.
Approval/Quality Group Function
The approval group comprises a multidisciplinary group
including the quality assurance department and other
appropriate site representatives. Representatives of the
technical group, performance group, and validation
group often participate in approval of document evaluating the maintenance of the validated state. Other
appropriate representatives (e.g., regulatory affairs)
may be asked to participate in review discussions. The
approval group approves all validation maintenance
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Paul L. Pluta, Coordinator
documents such as annual product reviews, change
control documents, management reviews, and other
monitoring 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). The approval group 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 group must be aware of
expectations for validated processes, and must review
documents with the eye of an FDA or other regulatory
agency auditor.
Validation Group Function
The validation group is responsible for maintaining
validation standards as required by the organization,
regulatory agencies, and industry practice. Validation
of process changes or associated equipment changes
are an important responsibility of the validation function, and are critical to maintaining the validated state.
The validation group should be part of the approval
function for validation maintenance documentation.
Validation documents must then be managed to be
quickly and easily accessible. Validation documents
demonstrating maintenance of the validated state are
very likely to be requested for regulatory audits.
Quality Systems Development and
Implementation
The organization must embrace, develop, and implement generally accepted concepts of modern quality
systems (4). These quality systems are continually
used in maintaining the validated state of validated
manufacturing processes. In brief, these include the
following:
• Quality. The organization must be committed
to manufacture quality products, i.e., products
that meet design criteria and product specifications. The approach to manufacture of quality
products should be comprehensive (i.e., starting
with product design and development and continuing throughout the product lifecycle). Quality
should be built into the product, not tested into
the product.
• Quality by design and product development. Products and processes must be designed and developed
according to scientific and technical principles
as espoused in the FDA quality by design (QbD)
initiative. This initiative is consistent with FDA
expectations for the lifecycle approach to process
validation. Process understanding is the basis for
validation performance as demonstrated in conformance lots. Thereafter, the information learned
during product development serves throughout
the entire product lifecycle.
• Quality risk management. Quality risk management should be pervasive in the organization.
Quality risk management enables appropriate
prioritization and emphasis on organizational
activities, processes, quality attributes (i.e., literally
everything associated with product and manufacturing processes).
• C APA. CAPA is a well-known quality concept
addressing the investigation, understanding, and
correction of problem situations. Actions to prevent recurrence are also performed. The product
history of CAPA occurrences must be reviewed as
part of monitoring and maintaining the validated
state.
• Change control. Change control is another wellknown quality concept that addresses management
of changes in the organization. Change control
is relevant to product formulation and manufacturing process (e.g., all associated equipment,
facilities, utilities, and control systems), cleaning
processes, analytical methods, and so on—literally
everything impacting the formulation/process that
has been validated.
• The quality unit. The quality unit comprises organizational activities conducted by the respective
quality control (QC) and quality assurance (QA)
functions in the organization. The current good
manufacturing practice (CGMP) regulations specifically assign the quality unit the authority to
create, monitor, and implement a quality system.
Other responsibilities of the quality unit include
in-process control during manufacturing, compliance with procedures, approving and rejecting
materials and products, and reviewing production
records and investigating discrepancies. The quality unit is a key part of the review and approval
function for maintaining the validated state.
• Six-system inspection model. This model describes
the FDA approach to conducting inspections. The
six systems are the quality system and five manufacturing systems including production, facilities
and equipment, laboratory controls, materials, and
packaging and labeling. These systems form an
integrated unit that help organizations remain in a
state of control. There are validation aspects in all
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Validation Learning Center.
of the quality systems in the six-system inspection
model and these must be continually maintained
in the validated state.
Adequate Resources
Assuming commitment of the organization to maintain
the validated state of manufacturing processes and an
adequate infrastructure of quality systems, there must
be adequate resources to enable maintenance of the
validated state. In brief, these include the following:
• General staffing. There must be adequate staffing of functions to perform activities to maintain
the validated state. These activities are generally
performed by individuals along with their other
organizational responsibilities.
• Qualified personnel. The personnel involved in
validation maintenance activities must be qualified for their respective functions. There must be
adequate scientific and technical expertise available in the organization, product knowledge,
process knowledge, risk assessment capabilities,
data analysis skills with supporting computer
systems, and other appropriate quality systems
knowledge. Continuing education is critical to
assure that personnel maintain competence in the
respective functions.
• Facilities and equipment. The organization must
have adequate facilities and equipment to accomplish necessary activities. Workspace for people
and storage space for work documents and files
are basic requirements. Computer systems for data
retrieval and analysis are essential for validation
maintenance activities.
• Outsourcing and control. Outsourced manufacturing operations must be monitored and maintained
to the same level as those done in house.
Management Responsibilities
The responsibilities of management in support of quality systems have been clearly identified in several quality systems papers (4,5). These same responsibilities
extend to maintenance of the validated state of manufacturing processes. In brief, these include:
• Providing leadership. Management must be committed to the lifecycle approach to process validation, and must understand the requirements of the
lifecycle approach and maintaining the validated
state. Just as maintaining the validated state of manufacturing processes is a long-term commitment,
management’s commitment to the activities that
support this maintenance must also be long term.
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• Structuring the organization. The organization
must be appropriately designed, structured, and
monitored to facilitate performance of maintenance activities. The respective organizational
units must clearly know their responsibilities
regarding validation maintenance.
• Building the system to meet requirements. There
must be appropriate procedures to support maintaining validation. Timely and effective communications must be ensured. For example, changes
to manufacturing equipment should be reviewed
by knowledgeable personnel to determine the
impact on validated processes. Procedures for
planned changes and emergency changes must
be considered.
• Establishing policies, objectives, and plans. These
provide the operational structure for maintaining
validated processes.
• Committing resources. Structure, systems, policies,
objectives, and plans must be adequately supported
with financial and personnel resources.
• Reviewing the system. The above components must
be periodically reviewed to guarantee ongoing
effectiveness. Resource review should be especially
critical when production increases, new shifts are
added, or other organizational changes occur.
• Advocating continual improvement. Management
support of improvement efforts is critical for continuing organizational success.
Risk Analysis of Product and Associated
Processes
The organization must employ risk analysis to enable
appropriate focus on areas of review, levels of testing, impact of change, frequency of review, use of
resources—literally every aspect of process review and
maintenance should be appropriately based on risk
analysis. ICH Q9 (8) provides a comprehensive list
of risk management applications for various activities associated with pharmaceutical manufacturing
including validation. Regarding validation, ICH Q9
recommends quality risk management to determine
the extent of follow-up activities such as sampling,
monitoring, and revalidation. Other risk management
applications related to maintaining the validated state
include quality defects evaluation, periodic review
evaluation and interpretation, change management,
various development activities, equipment/facilities/
utilities qualification, cleaning, calibration, preventive
maintenance, and so on.
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Paul L. Pluta, Coordinator
ACTIVITIES FOR MAINTAINING THE
VALIDATED STATE
After the manufacturing process is validated by successful manufacture of conformance lots and the validated process is released for routine commercial scale
manufacturing, activities to continually assure that
the process remains in a state of control are initiated.
The following are three primary activities to maintain
the validated state:
• Trend and assess data using statistical methods.
Data to be evaluated include key manufacturing
data, including critical operating and performance
parameters, product characteristics, personnel
training, material and other changes, and CAPA
incidents. A process history, including measure of
process variability and process performance over
time should be developed.
• Change control of formulation, processes, procedures, quality attributes. etc.
• Periodic evaluation to determine if new studies or
conformance batches are needed.
All of these activities rely completely on the organizational beliefs and strategy discussed previously in
this article. Further, without various quality systems,
organization resources, and ongoing management support, successful maintenance of the validated state will
not be possible. Risk analysis of product and associated
processes should be used to prioritize efforts and thus
make most efficient use of personnel and resources.
Trend and Assess Data
The review and evaluation of manufacturing data
is critically important to maintaining the validated
state. Data reviewed is required annually per 21 CFR
211.180(e) to determine the need for changes in drug
product specifications or manufacturing and control
procedures. However, this frequency of review should
be considered a minimum requirement. Data review
should be based on risk analysis of product and process.
Modern software and laboratory information management systems enable literally instantaneous review and
graphical analysis of test results. Statistical analysis
of data should be performed whenever possible. Out
of specification (OOS) data and out-of-trend (OOT)
data should be investigated. The impact of product
and process changes over time can be easily evaluated
using graphical representations.
•D
ata for evaluation. Manufacturing process data
and product quality attribute data are the primary
measures of process performance. In addition to
actual manufacturing process data, all associated
manufacturing and product data and information
should be monitored and evaluated. These include
monitoring of critical operating and performance
parameters, production yields, number and type of
process deviations and non-conformances, packaging performance data, product stability data, and
customer complaints. Monitoring product stability
performance after process changes or deviations
is especially critical since these changes may have
been made without benefit of prior stability testing. Review of customer complaints is another
important source of product information; customer
complaints often occur on product lots with no
discernable manufacturing problems. Occurrences
of material changes should be identified and evaluated. Material changes, such as sourcing lower cost
materials from alternate vendors, may introduce
variation into manufacturing processes. Stability
testing of lots with new vendor materials should
be reviewed. The effect of facility and equipment
changes on product/process data should be noted.
Changes in business such as increased product
demand that can require increased/new personnel, additional operating shifts, and additional
demands on equipment should also be evaluated
for potential impact on processes. The effect of
batch record changes, SOP changes, changes in
employee training, and other changes may all
affect product and process performance.
•E
stablish process history. Process variability for
commercial scale manufacturing is usually not well
known when a new product is introduced. Exceptions may occur if the new product is very similar
to another currently manufactured product (e.g.,
low dosage strength products containing similar
formulation and manufacturing process). However, extensive production experience at product
introduction is not common. Process data are
accumulated through small-scale development
trails and scale-up batches. Depending on the
product, there may be relatively few full-scale
batches at the time of process validation conformance lots. Monitoring process performance of
post-validation lots with data analysis facilitates
good baseline understanding of process capability
useful for future comparative analysis, evaluation
of changes and improvements, and other applications. These data are useful for comparison of
performance to other products. Process monitoring reveals opportunities for improving the process. Also, opportunities for improving the control
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Validation Learning Center.
strategy to better detect input variation as well as
reduce process output variation should result from
process monitoring.
Change Management and Control
A comprehensive change control system is extremely
important in maintaining the validated state of product, manufacturing processes, and all associated equipment/facilities/utilities. FD&C Act Section 506A(b)
and 21 CFR 211.100(a) and 21 CFR 211.180(e) clearly
require attention to process changes. Change control management should be implemented at all levels
throughout the organization. Formulation, process,
and equipment changes at high levels are usually well
communicated and appropriately evaluated. Less visible changes, such as subtle changes at the operator or
mechanic level, may be overlooked or thought to be
inconsequential. The organization should develop
systems to guarantee communication of all changes.
Evaluation of impact and risk can then be initiated by
responsible and competent personnel. Original process validation documents should be reviewed when
making changes. These original documents are fundamental for assessing the potential impact on the
process/equipment/facilities, etc. Too often, changes
are implemented without concurrent review of the
original validation when the original documentation
provides the basis for the change.
A pervasive change management system may eliminate scheduled revalidation of certain processes, again
based on risk analysis.
Periodic Evaluation
All data assessment and change control must be periodically reviewed. Periodic evaluation of manufacturing data is required at least annually per 21 CFR
211.180(e). However, this should be considered a
minimum requirement. The frequency and extent of
periodic reviews should be based on product/process
risk management considerations. Most critical products and/or most critical attributes should be more
frequently reviewed until a reliable process history
is demonstrated. Thereafter, periodic reviews can be
adjusted accordingly. Modern software and data analysis systems enable literally instantaneous evaluation
of manufacturing data. These systems enable timely
response to developing trends, rather than delaying
evaluation and investigation to a designated time
interval. The number and frequency of other changes
should also be reviewed and evaluated. For example,
multiple process changes, equipment changes, or vari38
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of
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able production yield data may indicate process issues
despite acceptable quality attribute data. Periodic
revalidation should not be required if the organization has an adequate change control system. Per FDA
(1), the term “re-validation” is not being used in the
future revised Process Validation Guidance.
DOCUMENTATION
All work associated with process validation must be
documented. This includes development studies to
demonstrate process understanding, design of experiments to determine critical process parameters, design
space, and normal operating ranges; process parameter
optimization, validation and qualification protocols;
and ongoing process monitoring and maintenance of
the validated state. Summary documents are recommended when multiple documents must be integrated
by the reader. Documentation must be written for
the reader. 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 on to new
careers inside or outside of the company. All associated documents must be readily retrievable since they
are highly likely to be requested for review by auditors.
Document storage in an easily accessible centralized
location is recommended.
TERMINOLOGY
The terminology associated with the various phases of
validation has had minor variations over the years and
will likely continue to evolve. The 1987 FDA Validation Guidance describes installation and operational
qualification, process performance qualification,
and product performance qualification. Products
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 terms process
design, process qualification, and commercialization
for the three phases of validation. The actual performance of validation within the process qualification
phase is termed “performance qualification,” and the
lots manufactured are called “conformance batches.”
The GHTF Process Validation Guidance for medical
devices describes three phases of process validation
as “Installation Qualification” for addressing equipment, “Operational Qualification” for equipment and
product including manufacturing at worst-case condiiv thome.com
Paul L. Pluta, Coordinator
tions, and “Performance Qualification” for product
under normal operating conditions., This document
discusses “Maintaining a validated state” after validation is completed.
While the variety of terminology used may cause difficulties in communicating, the intent of all validation
programs is the same: Process understanding, validation performance including conformance batches, and
maintenance of the validated state as described in this
article. 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 of robustness, repeatability, and reliability of validated process.
CONCLUSIONS
Commentary on the expectations for validated processes
has been published for more than 20 years. The various activities and expectations discussed in many published documents have not described how they should
be integrated. More recent guidelines and presentations
indicated that process validation must comprise activities
beginning in product/process development and continue
throughout the product lifecycle. Validation performance,
as demonstrated by conformance lots (usually three lots),
provides a “snapshot in time,” one of many pictures in the
complete story on validation. Evidence that the validated
state of a manufacturing process is being maintained is a
critical component of validation. Activities that support
the maintaining of validation should be comprehensive,
integrated, and ongoing throughout the entire product/process lifecycle. Process validation is a process that is never
completed because the maintenance of the validated state
must be continuously ongoing.
Organizational focus on maintaining the validated
state of manufacturing processes is critical to the lifecycle
approach to process validation. Primary activities in maintaining the validated state include: Manufacturing data
analysis and evaluation; change management and change
control; and a thorough and documented periodic review
of production/process data. Successfully maintaining the
validated state of manufacturing processes requires a strategic plan and tactical infrastructure. Key factors supporting
maintenance of the validated state include organizational
acceptance of the lifecycle approach to process validation,
collaboration of various organizational functions, development and implementation of quality systems concepts,
appropriate and adequate allocation of resources, management support of this program, and appropriate risk analyses
of product and processes to prioritize activities.
REFERENCES
1.McNally, Grace E., “Lifecycle Approach Process Validation,” GMP by the Sea, Cambridge, MD, August 26, 2008.
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.FDA, Quality Systems Approach to Pharmaceutical CGMP
Regulations, September 2006.
5.ICH, Q10 Pharmaceutical Quality System, May 9, 2007.
6.FDA, Pharmaceutical cGMPs for the 21st Century—A RiskBased Approach, September 2004.
7. FDA, Compliance Policy Guide 7132c.08, Section 490.100,
“Process Validation Requirements for Drug Products and
Active Pharmaceutical Ingredients Subject to Pre-Market
Approval.”
8.ICH, Q9 Quality Risk Management, November 9, 2005.
9.GHTF Study Group 3. Quality Management Systems—Process
Validation Guidance, Edition 2, January 2004.
10.ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, November 10, 2000.
11.FDA, Medical Device Quality Systems Manual, January
1997.
12.FDA, Guide to Inspections of Medical Device Manufacturers,
Process Validation—21 CFR 820.75, December 9, 1997.
13.FDA, Guideline of General Principles of Process Validation, May
1987.
14.Pluta, P.L., John M. Hyde, and Miguel Montalvo, “Validation Learning Center: Expectations for Validated Processes,” Journal of Validation Technology, Volume 14, No. 2,
Winter 2008.
15.Pluta, P.L. and Richard Poska, “Validation Learning Center: Process Understanding—Manufacturing Processes.”
Journal of Validation Technology, Volume 14, No. 3, Spring
2008.
16.Pluta, P.L., David W. Vincent, David E. Jones, and Timothy J. Fields, “Validation Learning Center: Process Performance—Conformance Lots,” Journal of Validation Technology, Volume 14, No. 4, Summer 2008. JVT
ARTICLE ACRONYM LISTING
CAPACorrective Action and Preventative Action
FDAUS Food and Drug Administration
GHTFGlobal Harmonization Task Force
ICHInternational Conference on Harmonisation
OOSOut of Specification
OOTOut of Trend
QAQuality Assurance
QbDQuality by Design
QCQuality Control
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