Draft Revision of FDA Guidance on
Process Validation
Chris Ames
Director Global Validation
Catalent Pharma Solutions
June 17, 2009
Interesting/Key Points
The following are some interesting aspects in the Guidance
• FDA has emphasized the statutory support for this Guideline
• Emphasis on the Use of Statistics with statutory support
• Emphasis on Process Understanding
• Process Validation is not a single activity but life cycle
• No insight into expected sample sizes, replicates, or any
specifics regarding expectations for validation studies.
• Expects objective scientific data supporting products /
processes relying upon sound statistics, but no statistical
methods are identified
• Special Section devoted to Concurrent Validation
• Retrospective Validation not mentioned.
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Old Definitions
The following are the previous definitions used by FDA:
“Providing Documented Evidence That a Specific Process Will
Consistently Produce a Product Meeting Its Pre-determined
Specifications and Quality Attributes”
— Guideline of General Principles of Process Validation - May 1987
“A Validated Manufacturing Process has a high level of scientific
assurance that it will reliably produce acceptable product.”
— Compliance Policy Guide 7132c.08 – Sec 490.100
Process Validation Requirements for Drug Products and Active
Pharmaceutical Ingredients Subject to Pre-Market Approval -March 2004
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“New Definition”
The draft Guidance has a new definition of Process Validation:
“For purposes of this guidance, process validation is defined as
the collection and evaluation of data, from the process
design stage throughout production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. Process validation involves a
series of activities taking place over the lifecycle of the
product and process.”
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Process Understanding
Process Knowledge is KEY to Process Validation
• “A successful validation program depends upon information
and knowledge from product and process development. This
knowledge and understanding is the basis for establishing an
approach to control that is appropriate for the manufacturing
process.”
• “Manufacturers should:
— understand the sources of variation
— detect the presence and degree of variation
— understand the impact of variation on the process and ultimately on
product attributes
— control the variation in a manner commensurate with the risk it
represents to the process and product.”
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Process Understanding
Process Knowledge is KEY to Process Validation
• “Focusing on qualification efforts without understanding the
manufacturing process may not lead to adequate assurance
of quality.”
• Team Approach
— Process engineering
— Industrial pharmacy
— Analytical chemistry
— Microbiology
— Statistics
— Manufacturing
— Quality Assurance
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Life Cycle Approach
Process Validation is not a single activity
• “The assurance should be obtained from objective
information and data from laboratory-, pilot-, and/or
commercial scale studies. Information and data should
demonstrate that the commercial manufacturing process is
capable of consistently producing acceptable quality products
within commercial manufacturing conditions, including those
conditions that pose a high risk of process failure.”
• “After establishing and confirming the process,
manufacturers must maintain the process in a state of
control over the life of the process, even as materials,
equipment, production environment, personnel, and
manufacturing procedures change.”
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Stages of Validation
The following are the Stages of Process Validation is Proposing
• Stage 1 – Process Design: The commercial process is defined
during this stage based on knowledge gained through
development and scale-up activities.
• Stage 2 – Process Qualification: During this stage, the
process design is confirmed as being capable of reproducible
commercial manufacturing.
• Stage 3 – Continued Process Verification: Ongoing assurance
is gained during routine production that the process remains
in a state of control.
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Stage 1 - Process Design
“Building and Capturing Process Knowledge and Understanding”
• “Process design is the activity of defining the commercial
manufacturing process that will be reflected in the master
production and control records.”
• “The goal of this stage is to design a process suitable for
routine commercial manufacturing that can consistently
deliver a product that meets its critical quality attributes.”
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Stage 1 - Process Design
General Expectation
• Not all process design experiments must be under GMP
• They MUST be scientifically sound and well documented.
• “Decisions and justification of the controls should be
sufficiently documented and internally reviewed to verify and
preserve their value for use later in the lifecycle of the
process and product.”
• “It is not a regulatory expectation that the process be
developed and tested until it fails, but rather that a process
be controlled within commercial manufacturing conditions,
including those combinations of conditions posing a high risk
of process failure.”
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Stage 1 - Process Design
Design of Experiments
• “Design of Experiment (DOE) studies can help develop
process knowledge by revealing relationships, including
multifactorial interactions, between the variable inputs (e.g.,
component characteristics or processing parameters) and the
resulting outputs (e.g., in-process material, intermediates, or
the final product).”
• “Risk analysis tools can be used to screen potential variables
for DOE studies to minimize the total number of experiments
conducted while maximizing knowledge gained.”
• Included references to modeling the process.
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Stage 1 - Process Design
Process Control Strategy
• “Process knowledge and understanding is the basis for
establishing an approach to process control for each unit
operation and the process overall.”
• “Process controls address variability to assure quality of the
product. Controls.”
• “These controls are included in the master production and
control records.”
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Stage 2 - Process Qualification
Two Components
• Equipment and Facility Qualification
• Performance Qualification (formerly validation)
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Stage 2 - Process Qualification
Equipment and Facility Qualification
• “Activities undertaken to demonstrate that utilities and
pieces of equipment are suitable for their intended use and
perform properly is referred to in this guidance as
qualification.”
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Stage 2 - Process Qualification
Equipment Qualification
• Life-cycle approach – Also Part of Stage 3
• Emphasis on design
— “Proper design of a manufacturing facility is required under 21 CFR
part 211, subpart C, of the CGMP regulations on Buildings and
Facilities.”
• Use of Risk Based Verification (ASTM E2500)
• Selection of utilities and equipment based upon specified use
— Materials
— Operating principles
— Performance characteristics
• Not a large emphasis in Guidance
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Stage 2 - Process Qualification
Qualification Versus Verification
• Language similar to ASTM E2500
• Broad interpretation (facility, utilities, and equipment)
• Risk based to establish priorities and level of effort and
documentation but no specific reference to
— Critical vs. non-critical
— Direct impact vs. non-direct impact
• Significant flexibility implied
— Use of term “verify”
— The term “plans” used in the Equipment Qualification section and the
term “protocols” is used in the Performance Qualification
— But Quality Unit must approve
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Stage 2 - Process Qualification
Verification Challenges
• Challenge equipment/systems
— Under load for time expected to run
— Include performance of interventions, stoppages, and start-ups
• Quality oversight and approval
— Required
— Focus
• Timing of qualification activities explicitly part of plan
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Stage 2 - Process Qualification
Performance Qualification Overview
• Needs to be completed prior to commercial distribution
• Pre-approved protocol
• PAT implementation may need a different approach
• Previous studies (i.e., development) may apply
• Number of replicates
— Three batch rule no longer applicable
— How many batches will be enough?
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Stage 2 - Process Qualification
Performance Qualification Expectations
• Pre-approved protocol
• Commercial scale in the plant
• Plant operators/conditions
• Target parameters
• Pre-commercial distribution
• Enhanced sampling plan
• Enhanced testing
• May employ lab, and pilot studies in support
• Objective measure: use statistics
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Stage 2 - Process Qualification
Performance Qualification Challenges
• How many batches/runs?
• Application of statistics
— Allowable intra-batch variability
— Allowable inter-batch variability
— Statistical significance????
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Stage 3 – Continued Process Verification
The following are the facets emphasized in the Guidance
• Goal is to continually assure the process remains in a
state of control
• Use statistics / statistical review
• Use Data Review to
— Ensure Process is not drifting out of control
— Identify need for Process improvement
• Include
— Enhanced sampling until variability can be assessed
— Review of maintenance of facility, utilities and equipment
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Stage 3 – Continued Process Verification
Ensure product quality
• Process design and development identifies SIGNIFICANT
sources of variability but not all
• Likely to identify new sources of variability during production
• May Suggest ways to improve and/or optimize process
— Operating conditions (ranges and set points)
— Process controls
— Component characteristics
— In-process material characteristics
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Stage 3 – Continued Process Verification
On-going Monitoring
• Detect departure from process design
• Evaluate to determine if action/changes are required
• Program should include
— Collection and analysis of product and PROCESS data
— Statistical trending and analysis by trained personnel
— Procedure driven
— Assess Intra- and Inter- batch variability
— Continued monitoring and/or sampling at Qualification stage level
— Recommend use of quantitative, statistical tools
— Periodic assessment of data identifying qualification status of
facility, utilities and equipment
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Stage 3 – Continued Process Verification
Operator Error tracking
• Measure training program effectiveness
• Identify performance issues
• Potential improvements
— Batch records
— Procedural
— Process
Periodic Quality Unit and Operations Review meetings
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Stage 3 – Continued Process Verification
Variations can be identified through:
• Timely assessment of
— Defect complaints
— OOS findings
— Process deviation reports
— Yield variations
— Adverse event reports
• Operator and Quality Unit Staff feedback
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Concurrent Release
Expectations
• “FDA expects that concurrent release will be used rarely.”
• “When warranted and used, concurrent release should be
accompanied by a system for careful oversight of the
distributed batch to facilitate rapid customer feedback.”
• “…which should be coordinated with the Agency.”
• “We recommend that each batch in a concurrent release
program also undergo stability testing and that this test data
be promptly evaluated to ensure rapid detection and
correction of any problems.”
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Documentation
Documentation at each stage
• “…essential for effective communication in complex, lengthy,
and multidisciplinary projects.”
• “…important so that knowledge gained about a product and
process is accessible and comprehensible to others involved
in each stage of the lifecycle.”
• “The degree and type of documentation required by CGMP is
greatest during stage 2, process qualification, and stage 3,
continued process verification.”
• “CGMP documents for commercial manufacturing (i.e., the
initial commercial master batch production and control record
(21 CFR 211.186) and supporting procedures) are key
outputs of stage 1, process design.”
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Analytical Methodology
Interesting that it was felt it needed to be included
• “Process knowledge is dependent on accurate and precise
measuring techniques that are used to test and examine the
quality of drug components, in-process materials, and
finished products.”
• “While validated analytical methods are not required during
product- and process-development activities, methods
should be scientifically sound (e.g., specific, sensitive, and
accurate), suitable, and reliable for the specified purpose.”
• Analytical methods supporting clinical supply production,
particularly stage 2 and 3 studies, must follow appropriate
CGMPs in parts 210 and 211.”
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PAT
Several places within the draft there is reference that PAT
• Manufacturing systems of this type can provide a higher
degree of process control.
• But they may need different process qualification approach:
— “The process design stage and the process qualification stage should
have as a focus the measurement and control loop.”
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Implementation Challenges
The challenges to implement this new draft are:
• Balancing European requirements for 3 validation batches
with the requirements in the draft
• Deciding when we have sufficiently assessed sources of
variability to allow distribution
— “Each manufacturer should judge whether it has gained sufficient
understanding to provide a high degree of assurance in its
manufacturing process to justify commercial distribution of the
product.”
• Data collection and analysis of process and product data
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Questions
???
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