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VALIDATION BOOT CAMPVALIDATION LIFECYCLE MANAGEMENT
PRINCIPLES, POLICY, AND PRACTICE
POTENTIAL APPLICATIONS
Paul L. Pluta, PhD
Journal of Validation Technology
Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of
Pharmacy Chicago, IL, USA
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OUTLINE and OBJECTIVES
• Provide validation / qualification basic understanding
– General terminology problem
– Specific area problem
– “Fit for use”
• Describe lifecycle approach
– History and basis (1987)
– Lifecycle stages and activities (2005)
• Propose documentation changes based on lifecycle requirements– High level policy documents
– VMP, Protocols, results, etc.
– Post validation
– Associated documents
• Describe evolving applications
– Other processes, cleaning, EFU, qualify systems
– Validation quality system
• Propose implementation approach
– Crisis approach
– Deliberate approach
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QUESTIONS ANSWERED
• Provide validation / qualification basic understanding
– What is validation? What is qualification? What is the difference? Why so many
problems with consistency and approach?
• Describe lifecycle approach
– What is the lifecycle approach? Why do we need this? Is it new? Is this the end
of validation? What about doing “three lots?”
• Propose documentation changes based on lifecycle approach– What are the effects of the PV guidance on documentation? Are complete revisions
necessary?
• Describe other evolving applications
– Is the lifecycle approach only for manufacturing processes? Does everything
else (cleaning, equipment, computers, etc.) remain as is?
• Propose implementation approach
– How do we implement? Is anyone else doing this? How far along is the rest of
industry? Are people getting “483’s”?
WHAT IS YOUR APPROACH TO VALIDATION?
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AGENDA
1. Introduction and definitions
2. Historical basis and lifecycle stages
3. Documentation
4. Applications
5. Implementation
6. Summary
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SUMMARY
• FDA PV lifecycle guidance integrates evolving pharma approaches
– QbD, CQA, CPP, risk, variation, others
• PV scope expanded to include three stages
• Stage 1 design emphasis: Understand product / process
• Stage 2 PQ demonstration stage: Documentation enhancements
• Stage 3 verification: Maintain the validated state improvements
• Applicable to other processes, equipment, quality systems
• Quality systems – business process
• Implementation: Integration of multiple site functions, management
support, and deliberate strategy
• Unified terminology, objectives, and approach to site validation
• Auditor answer: What is your approach to ________ validation?
• Challenges, personal development, and leadership opportunities for
validation personnel.
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VALIDATION AND QUALIFICATION
VALIDATION. Composed of
• Validation – Process validation: Applicable to
processes – primarily manufacturing processes.
Systems with process variation
• Qualification – Applicable to equipment ,
facilities, utilities, computer systems, etc. No
variation.
• Is packaging equipment or process?
• Is HVAC equipment or process?
• Is WFI equipment or process?
• Quality systems?
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VALIDATION AND QUALIFICATION
Definition: Processes, equipment, facilities,
utilities, computer systems, analytical methods,
etc. do what they are supposed to do.
Expanded definition:
• Includes design and development
• Includes monitoring and maintenance
Validate or qualify by additional testing
• Processes: Multiple lots
• EFU: Operating limits
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PROCESS VALIDATION AND QUALIFICTION
Process Validation – Process Qualification
PV – PQ -- PPQ
Qualification Qualification
Equipment #1 HVAC
Utilities
Equipment #2 Facilities
Computers
Equipment #3
Analytical methods validation
Process is validated
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LIFECYCLE APPROACH TO PROCESS VALIDATION
FDA, 2011
Definition: Collection and evaluation of data, from the process design
stage throughout commercial production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. Process validation involves a series of
activities over the lifecycle of the product and process.
Three stages of activities:
• Stage 1 – Process Design – Development and scale-up activities
• Stage 2 – Process Qualification – Reproducible manufacturing
• Stage 3 – Continued Process Verification – Routine manufacturing
STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM
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LIFECYCLE APPROACH TO
PROCESS VALIDATION
• History and development
• Fundamental concepts
• Consistency with medical devices
• Is the lifecycle approach really new?
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PROCESS VALIDATION LIFECYCLE APPROACH
OVERVIEW
2004 – Health Canada guidance
2005 – FDA initial presentations
2007 – ICH Q10
2008 – FDA draft guidance
2009 – ICH Q8(R2)
2009 – Health Canada revision
2011 – FDA guidance
2014 – EMA guidance
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HISTORY AND DEVELOPMENT –
LIFECYCLE APPROACH
PROCESS VALIDATION LIFECYCLE APPROACH
IS IT REALLY NEW?
Health Canada introduces lifecycle phases in 2004.
FDA lifecycle approach (stages) to process validation
incorporated concepts of ICH Q8, Q9, Q10, QbD, and
PAT – presentations starting 2005.
Many concepts previously mentioned in documents issued
before 2000.
See slides 1247
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HEALTH CANADA -- VALIDATION GUIDELINES FOR
PHARMACEUTICAL DOSAGE FORMS (GUI-0029)
5.0 Phases of ValidationPhase 1: Pre-Validation Phase
Phase 2: Process Validation Phase (Process Qualification Phase
Phase 3: Validation Maintenance Phase
6.0 Interpretation
Validation protocol
Validation Master Plan
Installation and Operational Qualification
IQ
OQ
Re-Qualification
Process validation
Prospective validation
Matrix or family approaches to prospective process validation
Concurrent validation
Retrospective validation
Process Re-Validation
Change control
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ICH Q8 (R2) PHARMACEUTICAL DEVELOPMENT
Objectives
Harmonized regulatory submissions (CTD)
Principles of Quality by Design (QbD)
Consistent with Q9 Risk Management
Problems addressed
Inconsistency between all regions
Inconsistent content
Inclusion of development information
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ICH Q8 PHARMACEUTICAL DEVELOPMENT
Drug product development considerations
Components: API and excipients
Formulation development
Overages
Physicochemical and biological properties
Manufacturing process development
Container-closure systems
Microbiological attributes
Compatibility
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ICH Q8 PHARMACEUTICAL DEVELOPMENT
Key points
“Information and knowledge gained from development
studies and manufacturing experience provides scientific
understanding to support the establishment of the design
space, specifications, and manufacturing controls.”
“Pharmaceutical development section should describe the
knowledge…”
“At a minimum, those aspects of drug substances,
excipients, … that are critical to product quality should
be determined and control strategies justified.”
“…demonstrate a higher degree of understanding of
material attributes, manufacturing processes …”
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ICH Q8 PHARMACEUTICAL DEVELOPMENT
Key points
Examination
Understanding
Evaluation
Identification
Rationale and justification
Others
Discussion in submission
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ICH Q8 PHARMACEUTICAL DEVELOPMENT
Implications for Process Validation
Process understanding
Process development studies are basis for
process validation
Continuous process verification is
alternate to process validation
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ICH Q9 QUALITY RISK MANAGEMENT
Objectives:
• Effective application of risk management
• Consistent science-based decisions
Incorporate risk management into practice
Problems addressed:
• Inconsistent risk-management application
• Common understanding
RISK IS EVERYTHING
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ICH Q9 QUALITY RISK MANAGEMENT
Principles of quality risk management
• General process: Initiation, assessment, control,
communication, review
• Methodology
• Integration into industry and regulatory
operations
• Methods and tools
• Potential specific applications
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ICH Q9 QUALITY RISK MANAGEMENT
• Initiate risk management process
• Risk assessment
• Risk identification
• Risk analysis
• Risk evaluation
• Risk control
• Risk reduction
• Risk acceptance
• Output
• Risk review
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ICH Q9 QUALITY RISK MANAGEMENT
Risk Management Methods and Tools
• Basic methods: Flow charts, process maps, cause and
effect (fishbone) diagrams
• FMEA / FMECA
• FTA
• HAACP
• HAZOP
• PHA
• Risk ranking and filtering
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ICH Q9 QUALITY RISK MANAGEMENT
Applications
• Integrated quality management: Documentation,
training, defects, auditing, periodic review, change
control, improvements
• Regulatory operations
• Development: Process knowledge, PAT development
• Facilities, equipment, utilities: Design, qualification,
cleaning, calibration, PM
• Materials management: Material variation
• Production: Validation, in-process testing
• Laboratory control and stability
• Packaging and labeling
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ICH Q9 QUALITY RISK MANAGEMENT
Key points
• Methods of evaluation
• Potential applications – every function, every
activity, entire product lifecycle
RISK IS EVERYTHING
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ICH Q9 QUALITY RISK MANAGEMENT
Implications for Process Validation
• Development: Process knowledge
• Materials: Variation, change control
• Equipment: Qualification, cleaning, calibration,
PM, change control
• Production: Validation, sampling, testing,
change control
• Maintenance / monitoring: Testing
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Objectives
• Global harmonization of quality systems
• Consistency with ICH Q8 and Q9
• Application throughout product lifecycle
Problems addressed
• Inconsistent application
• Inconsistent definitions of common terms
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Overview and definitions
Management responsibility: Commitment,
policy, planning, resources, communication,
review, outsourcing
Continual improvement of performance and
quality: Lifecycle stages and elements
Continual improvement of quality system:
Management, monitoring, outcomes
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Key points:
• Quality system application throughout product lifecycle
• Pharmaceutical development
• Technology transfer
• Manufacturing
• Product discontinuation
• Product realization, maintain control, improvements
• Enable by knowledge and risk management
• Management responsibility: Commitment, policy,
planning, resources, communication, review, outsourcing
oversight
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Key points:
• Continual improvement
• Product performance / quality monitoring system
• Control strategy, identify variation, problem feedback,
enhance process understanding
• CAPA system
• Enhance process understanding
• Change management system
• Risk management, evaluation, technical justification
• Management review
• Audits, inspections, changes, CAPA, etc.
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Implications for Process Validation
• Product performance and monitoring
• CAPA system enhances process understanding
• Change management system
• Process improvements
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ICH Q11
DEVELOMENT AND MANUFACTURE
OF DRUG SUBSTANCES
Consistent with ICH Q8, Q9, and Q10
Lifecycle approach
CQA, CPP
Design space
Control of variables
Process validation
Risk management
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QUALITY BY DESIGN (QbD)
Quality target product profile (QTTP)
Critical quality attributes (CQA), critical material attributes
(CMA)
Critical process parameters (CPP)
Design space
Scale-up and technology transfer
Identify input variables
Input variable control strategy
Continuous improvement
Other considerations: PAT, risk analysis
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SUPPORTING DOCUMENTS
PROCESS VALIDATION – 1987 GUIDANCE
Assurance of product quality:
Quality parts and materials
Adequate product and process design
Control of the process
In-Process and end-product testing.
Basic principles:
Quality, safety, and effectiveness designed and built into the product
Quality cannot be inspected or tested in the product
Each process step must be controlled to maximize meeting quality and design
specifications.
R&D phase: Product definition and characteristics
Equipment and process
Equipment: Installation Qualification
Process: Performance Qualification
Product (devices only): Performance Qualification
Revalidation. Change control
Documentation. Proper maintenance of documentation
Reference: FDA Guideline on General Principles of Process Validation. May, 1987
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VALIDATION – PHARMACEUTICAL DOSAGE FORMS
FDA INSPECTION GUIDELINES
Three phases of the validation process:
• Product development
• Design of the validation protocol
• Demonstration runs (validation) – full scale
Process validation
Documented evidence
• Consistency
• Predetermined specifications
Documented evidence includes experiments, data, and results
Product Development Reports
Control of the physical characteristics of the excipients
Particle size testing of multi-source excipients
Critical process parameters
Development data serves as the foundation for the manufacturing procedure
Variables are identified in the development phase
Raw materials may vary lot-to-lot
References: FDA Guides to Inspections. Oral Solid Dosage Forms (January 1994), Topical Drug
Products (July 1994), Oral Solutions and Suspensions (August 1994)
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SUPPORTING DOCUMENTS
VALIDATION – MEDICAL DEVICES
Planning the Process Validation Study
Installation and Operational Qualification
Process Performance Qualification
Eliminate controllable causes of variation
Product Performance Qualification
Evaluate routine production process monitoring data for trends
Process operating in 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.
Reference: FDA Medical Device Quality Systems Manual. January
07, 1997
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SUPPORTING DOCUMENTS
PROCESS VALIDATION – API
Critical parameters / attributes identified during
development
Qualification of equipment and systems: DQ, IQ, OQ, PQ.
Process Validation Program
Critical process parameters controlled and monitored
Non-critical parameters not included in validation
Periodic review of validated systems
Reference: ICH Q7. Good Manufacturing Practice Guide
for Active Pharmaceutical Ingredients. November, 2000.
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SUPPORTING DOCUMENTS
PROCESS VALIDATION – PRODUCTS / API
A validated manufacturing process has a high level of
scientific assurance that it will reliably product acceptable
product.
Proof of validation is obtained through rational experimental
design and the ongoing evaluation of data, preferably
beginning from the process development phase continuing
through the commercial production phase.
Reference: FDA Section 490.199. CPG 7132c.08.
Process Validation Requirements for Drug Products and
Active Pharmaceutical Ingredients Subject to Pre-Market
Approval. 2004 revision.
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SUPPORTING DOCUMENTS
PROCESS VALIDATION – PRODUCTS / API
Before commercial distribution:
Product and process development
Scale-up studies
Equipment and system qualification
Conformance batches
Identify and control all critical sources of variability
Advance manufacturing control technology may
eliminate validation lots.
Reference: FDA Section 490.199. CPG 7132c.08.
Process Validation Requirements for Drug Products and
Active Pharmaceutical Ingredients Subject to Pre-Market
Approval. 2004 revision.
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SUPPORTING DOCUMENTS
VALIDATION -- PHARMACEUTICAL CGMPS
Cross-Agency workgroup CDER, CBER, ORA, and CVM.
“The CPG clearly signals that a focus on three full-scale
production batches would fail to recognize the complete
story on validation.”
Reference: FDA. Pharmaceutical CGMPs for the 21st
Century – A Risk-Based Approach. Final Report,
September 2004.
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SUPPORTING DOCUMENTS
PROCESS VALIDATION – MEDICAL DEVICES
Process evaluation – Validation or verification
Protocol development
Processes well thought out
What could go wrong
Installation Qualification
Operational Qualification
“Worst case” testing
DOE and screening studies
Performance Qualification
Process repeatability
Attributes for continuous post-validation monitoring and maintenance
Eliminate controllable causes of variation.
Maintaining a state of validation – Monitor and control
Change control
Statistical Methods
Risk Analysis Methods
Reference: Global Harmonization Task Force (GHTF) Study Group 3. Quality
Management Systems – Process Validation Guidance. January 2004.
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SUPPORTING DOCUMENTS
VALIDATION – INTERNATIONAL
PIC/S PHARMACEUTICAL INSPECTION CONVENTION
A series of experiments should be devised to determine the
criticality of process parameters / factors
Test processes with starting materials on the extremes of
specification
Monitoring and in-process controls
Reference: PIC/S Recommendations on Validation. July
2004.
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SUPPORTING DOCUMENTS
FDA -- QUALITY BY DESIGN (QbD)
Product is designed to meet patient requirements
Process is designed to consistently meet product critical
quality attributes
Impact of starting materials and process parameters on
product quality is understood – Critical parameters
Critical sources of process variability are identified and
controlled
Process is continually monitored and updated to assure
consistent quality over time
Reference: FDA. Chi-wan Chen, ISPE, Japan, June,
2006
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SUPPORTING DOCUMENTS
PROCESS ROBUSTNESS (PQRI)
Robust Process: Able to tolerate expected variability of
raw materials, operating conditions, process equipment,
environmental conditions, and human factors
Development
Maintenance
Process understanding is key to developing a robust
process.
Reference: Product Quality Research Institute (PQRI).
Pharmaceutical Engineering, November-December, 2006
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SUPPORTING DOCUMENTS
ASTM WK 9935 Standard Guide
Continuous Quality Verification (CQV)
A Science and Risk-Based Alternative Approach to
Traditional Process Validation of Biopharmaceutical
and Pharmaceutical Manufacturing Processes
CONTINUOUS QUALITY VERIFICATION
Process design / Risk assessment / Process
understanding
Development phase
Scale-up phase
Commercialization phase
Process capability evaluation
Continuous process improvement
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SUPPORTING DOCUMENTS
PROCESS ANALYTICAL TECHNOLOGY (PAT)
Processes verified by PAT are not validated
All associated PAT equipment and analytical methods are
validated
Reference: FDA. PAT -- A Framework for Innovative
Pharmaceutical Development, Manufacturing, and Quality
Assurance. September 2004
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SUPPORTING DOCUMENTS
PROCESS ANALYTICAL TECHNOLOGY (PAT)
Process Understanding
All critical sources of variability are identified and explained.
Variability is managed by the process
Product quality attributes can be accurately and reliably predicted
over the design space
Materials used
Process parameters
Manufacturing
Environmental
Other conditions
Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance. September
2004
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EMA GUIDELINE ON PROCESS VALIDATION FOR
FINISHED PRODUCTS – INFORMATION AND DATA TO
BE PROVIDED IN REGULATORY SUBMISSIONS (2014)
Process Validation
• Traditional process validation
• Continuous process verification
• Hybrid approach
• Design space verification
• Annex I: Process validation scheme
• Annex II: Standard / non-standard processes
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FDA PROCESS VALIDATION GUIDANCE
2011
Definition: Collection and evaluation of data, from the process design
stage throughout commercial production, which establishes
scientific evidence that a process is capable of consistently
delivering quality products. Process validation involves a series of
activities over the lifecycle of the product and process.
Three stages of activities:
• Stage 1 – Process Design – Development and scale-up activities
• Stage 2 – Process Qualification – Reproducible manufacturing
• Stage 3 – Continued Process Verification – Routine manufacturing
STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM
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PV GUIDANCE
MANUFACTURING PROCESS VALIDATION
Process Validation (PV) – Process Qualification (PQ)
Process Performance Qualification (PPQ)
Qualification Qualification
Equipment #1 HVAC
Utilities
Equipment #2 Facilities
Computers
Equipment #3
Analytical methods validation
Manufacturing process is validated.
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UO #1
UO #2
UO #3
FDA PROCESS VALIDATION GUIDANCE
“Before …commercial distribution to consumers, a manufacturer should
have gained a high degree of assurance in the performance of the manufacturing process…consistently produce …”
Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and product
attributes
• Control the variation in a manner commensurate with risk to process
and product.”
“…to justify commercial distribution of the product.”
“… use ongoing programs to collect and analyze product and process
data … state if control of the process.”
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FDA PROCESS VALIDATION GUIDANCE
Good project management and good archiving to capture
scientific knowledge.
Enhance accessibility of information later in lifecycle.
Integrated team approach: Process engineering, industrial
pharmacy, analytical chemistry, microbiology, statistics,
manufacturing, and quality assurance.
Scientific studies throughout the product lifecycle planned,
documented, and approved.
Greater control over higher-risk attributes.
Reevaluate risks throughout product/process lifecycle.
Homogeneity with batch and consistency between batches
are goals of process validation.
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STAGE 1, PROCESS DESIGN
(PROCESS UNDERSTANDING)
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.
Define commercial-scale process
Define unit operations and process parameters
Identify and understand sources of variability
Identify critical process parameters
Studies to understand effects of scale
Establish mechanisms to control variability• Process Analytical Technology
Designed experiments
Lab scale and pilot scale experiments
PROCESS DESIGN (PROCESS UNDERSTANDING)
Objective
API and excipient pharmaceutics
Quality attributes
Risk analysis
Process parameters
Design of experiments
Design space
Normal operating range
In-process controls
Product development – key inputs to design stage
Variability by different component lots, production operators,
environmental conditions, and measurement systems
Use risk analysis tools to screen variables
Establish a strategy for process control
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QUALITY BY DESIGN (QbD)
1. Quality target product profile (QTTP)
2. Critical quality attributes (CQA), critical material
attributes (CMA)
3. Critical process parameters (CPP)
4. Design space
5. Scale-up and technology transfer
6. Identify input variables
7. Input variable control strategy
8. Continuous improvement
Other considerations: PAT, Risk analysis54
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STAGE 2, PROCESS QUALIFICATION
(VALIDATION PERFORMANCE)
1. Design of a facility and qualification of utilities and equipment
2. Process performance qualification
3. PPQ protocol
4. PPQ protocol execution and report
Confirmation at commercial scale of process design information
Qualification of equipment, utilities, facilities
Performance qualification
Conclusion that process consistently produces quality product.
Conformance batches
• All support systems, documents, training, personnel, etc. in place
• Target / nominal operating parameters within design space
• Additional testing
• Decision to “release process” for routine commercial manufacturing
STAGE 2, PROCESS QUALIFICATIONConformance Lots
Procedures
Validation plans
Protocols
Sampling
Testing
Results
Plan to maintain validation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
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PERFORMANCE QUALIFICATION APPROACH
Higher level of sampling, testing, and scrutiny of process performance.
Protocol should address:
• Operating parameters, processing limits, and raw material inputs
• Data to be collected and how evaluated
• Test to be performed and acceptance criteria
• Sampling plan – sampling points, number of samples, frequency
• Statistical methods used
• Statistical confidence levels
• Provisions to address deviations and non-conformances
• Facility, utility, and equipment qualification
• Personnel training
• Status of analytical method validation
• Review and approval by appropriate departments and quality unit
DETAILS FROM PV GUIDANCE
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PERFORMANCE QUALIFICATION APPROACH
“The PPQ lots should be manufacturer under normal conditions by
personnel expected to routinely perform each step of each unit
operation in the process. Normal operating conditions should cover
the utility systems (air handling and water purification), material,
personnel environment, and manufacturing procedures.”
PQ report:
• Discuss all aspects of protocol
• Summarize and analyze data as specified in protocol
• Evaluate unexpected observations and additional data
• Summarize and discuss non-conformances
• Describe corrective actions or changes
• Clear conclusions
• Approval by appropriate departments and quality unit
DETAILS FROM PV GUIDANCE
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STAGE 3, CONTINUED PROCESS VERIFICATION
(VALIDATION MONITORING AND MAINTENANCE)
Activities to assure process remains in validated state
Annual Product Review
Trend and assess data
Study OOS and OOT (Out of Trend) data
Timely monitoring of critical operating and performance parameters.
Monitor product characteristics, materials, facilities, equipment, and SOP changes
Establish process history based on ongoing process performance
Improve process
Improve control to detect and reduce variability
Change control; evaluate impact of change and test as necessary
CONTINUED PROCESS VERIFICATION
Monitoring
Statistical process control
Trend analysis
Change control
Continuous improvement
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
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CONTINUED PROCESS VERIFICATION
ITEMS TO BE REVIEWED
• Product and process data
• Relevant process trends
• Quality of incoming materials or components
• In-process material
• Finished products
• Defect complaints
• OOS findings
• Deviations
• Yield variations
• Batch records
• Incoming raw material records
• Adverse event reports
• Production operator and quality staff feedback
Above should help identify possible product / process improvements
DETAILS FROM PV GUIDANCE
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SUMMARY OF GUIDANCE RECOMMENDATIONS
Stage 1: Product Design
• QTPP, Development information, Identification of CQA, CMA, and CPP
• Identification of sources of variation and control plan
• Experimental studies
• Technology transfer / scale up
Stage 2: Process Qualification
• Protocol requirements
• Statistical sampling and acceptance criteria
• Equipment qualification and analytical method validation
Stage 3: Continued Process Verification
• Post PQ plan
• APR, batch data, yields, deviations, OOS, non-conformances, etc.
• Incoming material data
• Change control
• Statistical analysis of data / control charting
• Product complaints
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PROCESS VALIDATION HISTORY
1978
CGMP includes Validation
1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
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VALIDATION PHILOSOPHY
• Validation is confirmation.
• Acceptable (passing) results are expected.
• Validation is not
– R&D
– Final stage of development process
– Optimization
– Fine-tuning
– Debugging
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SUMMARY – LIFECYCLE APPROACH
• Three stages of validation
1. Design and development – Understanding
2. PQ – Demonstration
3. Continued process verification – Monitor and maintain
• Emphasis on process understanding – CQA, CPP, CMA,
sources of variation, variation control
• Emphasis on maintaining validated state
– Ongoing improvements expected
• Lifecycle approach integrates original PV, ICH, QbD, and
device concepts into unified approach
• Risk level determined that dictates amount of work.
• Rational decisions and judgments
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DOCUMENTATION
Key Points
• Documentation involves three stages
• Expectations for Stage 2 expanded
• PV Guidance – Basis for policy
documents, traditional validation
documents, and associated documents
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DOCUMENTATION
• Validation policy – Reference PV Guidance approach– Corporate templates
• Validation Master Plan (VMP) – Reference PV Guidance approach
• Stage 1 documents – Process Design
• Stage 2 documents – Process Qualification
– Validation Request / Plan -- Reference PV Guidance
– Validation Protocol(s) – Reference PV Guidance
– Engineering Studies
– Others
– Validation Results / Report – Reference PV Guidance
• Stage 3 documents – Continued Process Verification
– PQ requirements
– Routine monitoring – Reference PV Guidance
• Associated validation and qualification -- Reference PV Guidance
• Other associated documents
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LIFECYCLE APPROACH APPLICATIONS
Can lifecycle approach to applied to other areas?
• Processes
– Cleaning, packaging, analytical, others
• Equipment
– Facilities, utilities, control systems
• Equipment processes
– HVAC, water
• Quality systems
– Basic systems, support systems,
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CLEANING VALIDATION
Lifecycle approach to cleaning validation
1. Stage 1 – Understanding the cleaning process
Scientific and technical principles
2. Stage 2 – Demonstrating cleaning performance
Traditional cleaning validation PQ
3. Stage 3 – Maintaining the validated state
Monitor and maintain performance
Performance based on risk analysis.
Auditor question: How do you approach cleaning?
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CLEANING VALIDATION DEFINITION
Validating the Cleaning Process
1. Make Product A
2. Clean equipment
3. Analytical testing for Product A residue
4. Repeat above multiple times
5. If all testing below acceptable level –
CLEANING PROCESS IS VALIDATED
6. Future: Clean equipment -- No testing
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CLEANING EQUATION
Product A Residue (equipment surface)
+
Cleaning agent
+
Cleaning process parameters (TACT)
Clean equipment surface (for Product B)
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Lifecycle Approach to Cleaning Validation –
Value? Does this make sense?
• Cleaning is a process
• Who can argue with understanding, performing, and
maintaining the validated state?
• Consistent with QbD and ICH approaches
Lifecycle approach (i.e., understanding, performing,
maintaining) vs. traditional cleaning approach –
Which would you rather present to an auditor?
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WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification
Automated CIP System
Process steps Qualification
1. Residue on equipment Equipment
2. Water procedure Purified Water
3. Cleaning agent procedure Computer / software
4. Water procedure Compressed air
5. Purified Water procedure Conductivity analysis
6. Dry Analytical
Equipment is clean -- Process is validated
Process parameters Quality attributes
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WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification
Manual Cleaning
Process steps Qualification
1. Residue on equipment Personnel
2. Water rinse Purified Water
3. Scrub with cleaning agent Compressed air
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8. Dry
Equipment is clean -- Process is validated
Process parameters Quality attributes74
CLEANING VALIDATION OVERVIEW
1990s present
1. Defined cleaning procedure (SOP) – basis?
2. Product A batch does not contaminate subsequent
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5. Three conformance lots = Validated cleaning procedure
6. Validated analytical method (original API)
7. Worst-case matrix approach
One-time event
75
LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development– Residue + cleaning agent + cleaning procedure Clean equipment
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
Risk analysis
Conrol variation
Future process improvements
Not the following:
– Standard site method (no basis or rationale)
– Personnel driven (no control)
– “Do whatever it takes” (high variation)
– SOP (no accountability)
– Validation (?) – One-time event.
76
STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)
APPLICATION TO CLEANING
FDA Guidance Topics
1. Building and capturing process knowledge and understanding.
2. Establishing a strategy for process control.
Application to Cleaning
Understand residue chemistry (solubility, stability)
Determine cleaning agent based on residue chemistry
Determine cleaning process
• Identify sources of variability
• Establish methods to control variability
– Process Analytical Technology
Rational analytical method and supporting work
Characterization of equipment to be cleaned and supporting work
Trained sampling personnel
Validation work related to risk
DOCUMENT ALL OF THE ABOVE
77
DEVELOPMENT (STAGE 1)
CLEANING PROCESS DEVELOPMENT
• Physical and chemical properties of the residue is basis for cleaning
process
• Considerations for determination of most difficult-to-clean residue
• Residue solubility and stability in determining worst-case soils
• Residue chemistry critical for analytical method
• Cleaning agent chemistry consistent with residue chemistry
• Cleaning process chemistry and engineering and consistent with
residue and cleaning agent.
RESIDUE CHEMISTRY
– BASIS FOR CLEANING PROGRAM
– BASIS FOR ANALYICAL METHOD
78
RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS
Case study: Antibiotic suspension containing insoluble API (base)
Original cleaning method: Water, PurW, dry
• No documented cleaning validation for many years
• Unknown peaks on original cleaning validation attempts
• API insoluble
Second method: Alkaline soap wash, water, PurW, dry
• Unknown peaks again
• API insoluble
Final method: Acid wash, alkaline soap wash, water, PurW, dry
• No residues
• Unknown peaks determined to be degradants and flavors.
• API dissolves (acid-base neutralization)
Consider active drug and other residue chemistry in development
of cleaning process
79
DETERMINATION OF
MOST DIFFICULT TO CLEAN RESIDUE
BASIS FOR CLEANING PROGRAM
Water solubility – USP Tables
• Is this adequate? NO!
pH effect – API with ionizable groups?
Solubility in cleaning agent?
• Determine solubility at range pH 1-12
• Understand solubility at pH of cleaning liquid
• Understand solubility in cleaning agent liquid
80
CLEANING MATRIX
Determine Worst-Case Soil
SOLUBILITY (mg / ml)
pH 1 Water pH 12 Alkaline
Cleaning Agent
Drug A 25 25 25 25
Drug B 15 15 15 15
Drug C 5 5 150 250
Drug D 150 10 10 50
Drug E 125 10 100 250
Consider acid cleaning agent for drugs D and E
82
CLEANING PROCESS
SOURCES OF VARIATION
• Cleaning agent preparation – must be exact
• Automated cleaning vs. manual cleaning
• Manual cleaning process variation
• Human physical strength variation
• “Cleaning” between same-product batches in campaign
– residue level build-up
• Campaign length – residue level build-up
• Time to initiate cleaning (dirty hold time)
• Residue chemical and physical changes
• Equipment differences
83
STAGE 2, PROCESS QUALIFICATION –
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING1. Design of a facility and qualification of utilities and equipment
2. Process performance qualification
3. PPQ protocol
4. PPQ protocol execution and report
Qualification of equipment, utilities, facilities
• Cleaning equipment (CIP)
Process Performance Qualification (PPQ) – commercial scale
Conclusion that process consistently produces clean equipment
Conformance batches
• All support systems, documents, training, personnel, etc. in place
• Target / nominal operating parameters within design space
• Additional testing (swab / rinse)
• Decision to “release cleaning process” for routine commercial use
• Post validation monitoring plan – Based on risk
– Drug residue properties
– Manual or CIP
84
CLEANING PROCEDURE DOCUMENTATION
(Cleaning Batch Record)
SOP
• Fill tank half full
• Add half scoop of soap
• Scrub as needed
• Rinse until clean
• Re-scrub and re-rinse if needed
CLEANING PROCEDURE RECORD
• Fill tank with 500 L water. Sign/date __________
• Add 20.0 kg cleaning agent. Sign/date __________
• Disassemble Part A. Steps 1,2,3,4,5
• Scrub for 20 minutes. Sign/date __________
• Disassemble Part B. Steps 1,2,3,4,5
• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
• Rinse Part A and Part B with 50 L water. Sign/date __________
• Rinse with 50 L Purified Water. Sign/date __________
• Dry with compressed air
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CLEANING PROCEDURE RECORD
• Fill tank with 500 L water. Sign/date __________
• Add 20.0 kg cleaning agent. Sign/date __________
• Disassemble Part A. Steps 1,2,3,4,5
• Scrub for 20 minutes. Sign/date __________
• Disassemble Part B. Steps 1,2,3,4,5
• Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
• Rinse Part A and Part B with 50 L water. Sign/date __________
• Rinse with 50 L Purified Water. Sign/date __________
• Dry with compressed air
KEY POINTS
Exact concentration of cleaning agent liquid
Signature on quantitative steps
Grouping non-quantitative steps (e.g., disassembly)
86
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STAGE 3, CONTINUED PROCESS VERIFICATION
(VALIDATION MONITORING AND MAINTENANCE)
APPLICATION TO CLEANING
Activities to assure process remains in validated state
Change control -- evaluate impact of change and validate (test) as necessary
Trend and assess data– PAT rinse times
– Conductivity data
Study OOS and OOT (Out of Trend) data
Improve process
Improve control to detect and reduce variability
Cleaning non-conformances and deviations
Re-validation – definition: Actual batch or “paper”
• Is re-testing necessary?
• When should re-testing be considered?
Periodic Management Review
• Documentation reviewed by management
• Documented review
LIFECYCLE APPROACH
APPLICATION TO PROCESSES
• Cleaning
• Packaging
• Analytical
• HVAC
• WFI
• Others
88
EQUIPMENT QUALIFICATION
Lifecycle approach to equipment qualification
1. Stage 1 – Understanding the equipment
Scientific and technical engineering principles
2. Stage 2 – Demonstrating equipment performance
Equipment qualification
3. Stage 3 – Maintaining the validated state
Monitor and maintain performance, change control
Qualification activities and testing based on risk analysis.
Auditor question: How do you approach equipment qualification?
89
EQUIPMENT QUALIFICATION – LIFECYCLE APPROACH
1. Equipment qualification is a vital part of validation.
2. New FDA process validation guidelines has changed expectations
for equipment qualification.
3. Approach equipment qualification by lifecycle approach stages
• Stage 1. Design / develop / understand
• Stage 2. Demonstrate
• Stage 3. Monitor / maintain.
4. Equipment qualification must not be considered a one-time event.
5. Key validation principles identified -- Confirmation, risk analysis,
documentation, others.
6. Qualification options: IO/OQ/PQ or ASTM E2500.
7. Model documents recommended.
8. Documentation is vital: Consistency, content, good documentation
practices, and document retrieval.
90
EQUIPMENT QUALIFICATION APPLICATIONS
Lifecycle approach
Risk analysis
Science and technical basis for design and development
Validation confirms equipment design and development
Sampling and testing -- rationale and justification – based on risk
Pre-approved acceptance criteria
Data-based judgments
Document everything – Retrieve documents
Maintain validation continuously throughout lifecycle -- based on risk
• Preventive maintenance
• Calibration
• Change control
DOES THIS MAKE SENSE?
91
EQUIPMENT QUALIFICATION
Qualification approaches
• DQ / IQ / OQ / PQ (IQ for medical devices)
• ASTM E2500
Documentation hierarchy
Document outlines
• Model documents
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QUALIFICATION APPROACHES
DQ / IQ / OQ / PQ
Traditional qualification
DQ – Multiple functions and applications
• Purchasing document
• Equipment design document
• Stage 1 activities
Documents may be combined
• IQ, OQ, PQ -- IOQ
• Stage 2 activities
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DQ / IQ / OQ / PQ CONTENT
DQ – Design Qualification
• Equipment description
• Equipment design requirements
• Purchase / design specific requirements
IQ – Installation Qualification
• Components
• Drawings
• Operating manuals
• Product-contact material composition
• Surface area calculations (product contact equipment)
• Calibration
• Preventive maintenance
• Equivalence to other equipment
• Most difficult to clean locations
• Other
OQ – Operation Qualification
• Worst case / range parameter operation
PQ – Performance Qualification
• Integrated parameter operation with representative materials
94
ISPE EQUIPMENT VALIDATION
User Requirements PQ
Specification
Functional Specification OQ
Design Specifications IQ
System Build
9595
EQUIPMENT QUALIFICATION LIFECYCLE
1. Capital request with design (DQ)
2. Equipment build
3. Factory Acceptance Test (FAT)
4. Site Acceptance Test (SAT)
5. Commissioning
6. IQ
7. OQ
8. PQ
9. Preventive Maintenance and Calibration
10. Change control
11. Decommissioning
CONSISTENT WITH STAGE APPROACH
NEED MONITORING/MAINTENANCE REVIEW FOR STAGE 3
9696
EQUIPMENT QUALIFICATION
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Test and document critical items only.
FAT, SAT, and Commissioning
Test and document non-critical items.
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ASTM E2500. Standard Guide for Specifications, Design, and
Verification of Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment
• Design Input
• Design Review
• Risk Mitigation
• Critical Control Parameters Define
• Acceptance Criteria
• Verification Testing
• Performance Testing
• GEP scope and QA scope have clear boundary
• Process, Product Quality and Patient Safety
• Quality by Design, Design Space and Continuous Improvement
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LIFECYCLE APPROACH TO EQUIPMENT
SUMMARY
• Stage 1. DQ – Design and development
information
– FAT, SAT, commissioning activities
• Stage 2. IQ/OQ/PQ – Demonstration
• Stage 3. Management review of preventive
maintenance, deviations, calibration, other
records
Includes risk analysis Appropriate testing
Need support of engineering function to
implement Stage 3.99
QUALITY SYSTEMS
Can lifecycle approach be applied to Quality
Systems?
FDA Quality Systems• Quality System
• Materials System
• Production system
• Equipment and Facilities System
• Packaging and Labeling System
• Laboratory Controls System
100
QUALITY SYSTEMS
“Stand-alone” systems supporting major quality
systems
• Validation
• Training
• Stability
• Complaints
• Calibration
• Preventive maintenance
• Others
101
VALIDATION QUALITY SYSTEM
1. Application of QbD and lifecycle principles to the Validation Quality
System
2. Design of the Validation Quality System
3. Objectives of Validation Quality System
4. Quality Attributes of Validation Quality System
5. Parameters affecting attributes
6. Control of variables affecting quality system performance
7. Risk management
8. Monitoring performance Continuous improvements
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QbD and VALIDATION QUALITY SYSTEM
QbD
• Target product profile – System objective
• Critical quality attributes – System attributes
• Critical process parameters – System parameters
• Control of variation – Variation affecting performance
• Risk assessment – Prioritize according to risk
• Monitoring data Continuous improvements
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VALIDATION FUNCTION
“PRODUCT” AND INFRASTRUCTURE
Two components:
1.Validated products, processes (manufacturing,
cleaning, packaging, etc.), equipment, utilities,
facilities, control systems, computer systems,
analytical instruments – the “product” of the
validation function.
2.The process of accomplishing validation – the
infrastructure of the validation function.
Protocols, results, documentation packages,
approval committee, etc.
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QbD PROCESS VALIDATION
QSbD VALIDATION QUALITYSYSTEM
LIFECYCLE APPROACH
PRODUCT and PROCESS• Target profile: Tablet, immediate release, rapid dissolution, bioavailability
• Critical quality attributes: Content uniformity, dissolution, moisture
• Critical process parameters: Granulation, drying, blending parameters
• Variables and control: API particle size, PAT processing
• Risk assessment: Emphasis on high risk materials and processes
• Continuous improvement: Based on review of product / process experiences
LIFECYCLE APPROACH: Design/development, PQ, Monitoring Improvements
Stage 1 Stage 2 Stage 3
VALIDATION QUALITY SYSTEM
• Objectives
• Quality Attributes
• Parameters
• Variables and control
• Risk assessment
• Continuous improvement
LIFECYCLE APPROACH: Design, Demonstration, Monitoring Improvements
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VALIDATION “PRODUCT”
PRODUCT : All validated products, processes
(cleaning, packaging, analytical, etc.),
equipment, facilities, control systems,
computers, etc., including documentation.
Documentation affirming performance
PRODUCT/PROCESS LIFECYCLE APPROACH
1. Design and development – Process understanding
2. PQ – Process demonstration
3. Continuous process verification – Monitoring and
maintenance
106
QUALITY SYSTEM
FDA Definition: Formalized business practices
that define management responsibilities for
organizational structure processes, procedures,
and resources needed to fulfill product/service
requirements, customer satisfaction, and
continual improvement.
• Management responsibilities
• Resources
• “Manufacturing”
• Evaluation
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FDA QUALITY SYSTEMS MODEL
Management Responsibilities
1. Provide leadership
2. Structure the organization
3. Build your quality system to meet requirements
4. Establish policies, objectives, and plans
5. Review the system
Resources
1. General arrangements
2. Personnel development
3. Facilities and equipment
4. Control outsourced operations
Manufacturing
1. Design, develop, and document product and processes
2. Examine inputs
3. Perform and monitor operations
4. Address non-conformities
Evaluation activities
1. Analyze data for trends
2. Conduct internal audits
3. Quality risk management
4. Corrective action
5. Preventive action
6. Promote improvement108
VALIDATION QUALITY SYSTEMLIFECYCLE APPROACH
Quality System Design
Is the quality system properly designed to conduct the validation
business process? Outsourced products, outsourced processes,
outsourced validation/qualification?
Quality System Performance
Does the quality system perform as designed?
• Attributes
• Parameters
• Variables and control
Quality System Monitoring and Maintenance
What is done to maintain quality system performance?:
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QUALITY SYSTEM QUESTIONS
Procedures for all validation quality system activities -- Manufacturing processes,
cleaning processes, analytical processes, equipment qualifications, other
qualifications, computer systems, and other categories of validation/qualification?
Model documents for above categories of activities regarding validation initiation,
validation plans, protocols, results, and reports?
Validation documents templates?
Validation training?
Validation document preparation training?
Adequate number of validation personnel?
Expertise of validation personnel?
Expertise of Validation Approval Committee?
Responsibilities consistent with expertise?
Technical writers?
Personnel development and training?
Facilities?
Facility security?
Document library?
Electronic systems?
Electronic systems to monitor throughout, open documents, errors, etc.?
110
QbD and VALIDATION QUALITY SYSTEM
Objectives
• Validation business process performance excellence
Validation quality system attributes
• Business process performance attributes
Validation quality system parameters
• Business process performance
Variation and control
• Business system procedures and training
Risk management
• Highest risk activities prioritized
Validation quality system improvement
• Improvements based on evaluation activities
111
VALIDATION QUALITY SYSTEM BUSINESS PROCESSINFRASTRUCTURE SUPPORTING “PRODUCT”
1. Initiation. Site functions initiate new validations and qualifications or changes to
validated systems.
• New product / processes, equipment, facilities, utilities, other
• Origin: R&D, Technical Support, Operations, Quality, Maintenance
2. Design / Development. Functions design / develop new systems or changes
3. PQ. Validation documentation written/monitored by validation group
• Different requirements for different validation / qualification
• Risk analysis
• Different plans, protocols, results, reports
• Documentation
• Approval by Validation Approval Committee
• Documentation storage and retrieval
4. Verification/Evaluation. Appropriate post-validation lifecycle maintenance, monitoring,
and review
• Product process data (APR), Non-conformances and deviations; complaints,
changes, others. Management review
• Validation infrastructure. Gaps, throughput, open packages, etc.
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VALIDATION BUSINESS PROCESS -- DETAILS
INITIATION
1. Initiating group obtains site project approvals if necessary.
2. Project risk assessment
3. Interactions with validation group to identify requirements (critical attributes, critical parameters,
other recommendations, etc.)
4. Initiate validation documentation if necessary.
DESIGN/DEVELOPMENT
1. Technical work performed if necessary.
2. Technical documentation completed.
3. Technical documentation approved.
PQ
1. Initiate validation plan. Validation Plan consistent with technical support work and risk assessment.
2. Approve validation plan.
3. Initiate validation protocol.
4. Approval validation protocol
5. Execute validation protocol.
6. Initiate validation results report.
7. Validation report recommends post-validation monitoring
8. Approve validation results report.
EVALUATION
1. Initiate post-validation monitoring as required.
2. Review post-validation monitoring as required.
3. Management review of post-validation monitoring as required.113
QbD APPROACH TO VALIDATION QUALITY SYSTEM –
SPECIFIC BUSINESS PROCESS
Objectives
– What are the goals of each process step?
Attributes
– What makes a process step successful?
Parameters
– What factors significantly influence the success of the process step?
Variation and control
– What variation in performance is expected and how is it controlled?
Risk management
– What are highest risk activities?
– Prioritization, evaluation, and review highest level for highest risk
Evaluation
– Review performance of validation quality system
114
VALIDATION QUALITY SYSTEM -- PROBLEM EXAMPLES
MANUFACTURING EQUIPMENT AND PROCESSES
• Operators did not perceive changes to be changes – inadequate change control
CLEANING VALIDATION
• Operators did whatever needed “to get the job done.” Procedures not followed.
CLEANING VALIDATION SAMPLING
• Sampling personnel not adequately trained – false negative data
DOCUMENTATION
• Numerous documentation practices problems such as data recording, original data,
back dating, etc.
DOCUMENTATION COMPLIANCE
• Documentation not compliant with corporate requirements
DOCUMENTATION GRAMMATICAL
• Documentation poorly written
POWDER BLEND UNIFORMITY TESTING
• Sampling personnel not adequately trained
NON-STERILE “CLEAN” PROCESSES
• Sampling personnel not adequately trained
LIKE-FOR-LIKE CHANGES
• No testing of correct installation
115
VALIDATION QUALITY SYSTEM –
CORRECTIVE ACTION PROJECTS
Validation Training Module
Validation Protocol Writer Training
Cleaning Validation Training
Cleaning Visual Inspection Training
Documentation Practices Training
Validation Approval Committee Responsibilities
Validation Approval Committee Training
Validation Model Documents
Like-for-Like Approval (non-protocol) Process
Microbiology Training
Validation Policy Changes
RECORD CORRECTIVE ACTION PROJECTS IN VMP
116
WHY THE PROBLEM? -- VALIDATION
CATEGORIESProcess validations
• Manufacturing
• Cleaning
• Packaging
• Analytical
• Others
Qualifications – IQ, OQ, PQ; ASTM E2500
• Equipment
• Facilities
• Utilities
• Computer systems
• Others
EACH VALIDATION UNIQUE
117
WHY THE PROBLEM? –
ORIGINATORS OF VALIDATION / QUALIFICATION
PROJECTSR&D
Technical Support
Process Engineering
Facilities Engineering
Maintenance
Analytical R&D
QA/QC
Other
EACH GROUP UNIQUE. EACH WITH SPECIFIC EXPERTISE.
EACH WITH SPECIFIC LANGUAGE AND TERMINOLOGY.
ALL ABOVE GROUPS MUST UNDERSTAND VALIDATION
OBJECTIVES.
118
VALIDATION QUALITY SYSTEM LIFECYCLE
QUANTITATIVE MONITORING -- EVALUATION
• Throughput
• External audit observations
• Documentation quality
• “Open” validation projects – time open
• Validation failures
• Protocol amendments
• Protocol deviations
• Other
119
OTHER APPLICATIONS
QbD / Lifecycle approach to other quality systems
Documentation in QSMP
Examples:
Material system – Heparin
Manual cleaning – Methotrexate
Training – “Read and sign” vs. OTJ
120
QbD / LIFECYCLE APPROACH POSITIVES
• Organized and comprehensive focus based on risk to the patient and the organization – Based on successful concepts
• System design for each type of validation -- Gap analysis
• Risk analysis for each type of validation
• Cross-functional systems thinking
• Consistent prioritized mitigation activities across functions –based on risk
• Variation identification and control strategy
• Continuous improvements based on systems monitoring
• Standardized audit expectations and documentation
• Organization commitment, transparency, and credibility
• Track organization accomplishments completed
• Strong message to employees
• Strong message to auditors
• Potential “credit” in audits for projects completed and new commitments identified
121
QbD / LIFECYCLE APPROACH
NEGATIVESDifficult
• Getting organized is extremely difficult!
• Risk analysis is difficult
• Gap analysis is difficult
• Changes are difficult
Transparency
• Being open about gaps and deficiencies may have regulatory and political risks
Organizational commitments
• Headcount needed to correct deficiencies
Do the benefits outweigh the negatives?
122
VALIDATION QS SUMMARY
• Validation business process
• Quality by Design (QbD) framework
– Objective, CQA, CPP, Variation control,
• Lifecycle approach to validation quality system
– Design
– Demonstrate
– Monitor
• Risk management application to the Validation Quality
System
• Application to other quality systems.
123
IMPLEMENTATION
PV Lifecycle approach is paradigm change
• Entire organization involved in validation
– R&D / Technical support (Stage 1)
• Audit involvement
• Support change control
– QA / Manufacturing (Stage 3)
• How to implement culture change?
124
IMPLEMENTATION
Culture change: Two general approaches
• Crisis approach (Kotter, Harvard)
– Eight-step process
– Respond to crisis or create a crisis
• Slow approach
– Slow success
– No failure
125
IMPLEMENTATION #1
• Plan implementation strategy
– Assemble PV Guidance and other references
– Meet with affected groups – R&D, Engineering, Technical Support, QA, others
– Meet with Validation Approval Committee
– Develop reasonable and deliberate strategy with guaranteed success
• Upper management input
• Upper management approval
• General training on validation – all including new groups involved in
validation
• Protocol writer training
– Expectations for documents
• Validation Approval Committee responsibilities / training
– Science and technical basis
– Compliance with procedures
– Documentation quality
– “Surrogate regulatory auditor”
126
IMPLEMENTATION #2
• Develop model documents– Continually improve / replace model documents
• Pilot projects– Select open-minded people
– Guarantee success
• Build on success with subsequent projects
• General validation training
• Protocol writer training
127
IMPLEMENTATION
Reality
• Resistance to change
• Why are we doing this?
• No time to do work
• No headcount to do work
• No audit observations – why change?
• Do not expect rapid success
• Do not expect agreements and support
128
IMPLEMENTATION SUCCESS
• People utilize old validation plans and reports for new
work
• People refer to old documents
• Validation becomes an organizational resource
• VMP becomes valued site document
• Validation becomes appreciated.
• No internal or external audit observations.
129
SUMMARY
• FDA PV lifecycle guidance integrates evolving pharma
approaches – QbD, CQA, CPP, risk, variation, others
• PV scope expanded to include three stages
– Stage 1 design emphasis: Understand product / process
– Stage 2 PQ demonstration stage: Documentation
enhancements
– Stage 3 verification: Maintain the validated state
improvements
• Applicable to other processes, equipment, quality
systems
• Quality systems – business process
• Implementation: Integration of multiple site functions,
management support, and deliberate strategy
130
SUMMARY
• Unified terminology, objectives, and
approach to site validation
– Understand, demonstrate, maintain
• Auditor answer:
– What is your approach to _____ validation?
• Challenges, personal development, and
leadership opportunities for validation
personnel.
131
133
SUMMARY -- VALIDATION – CURRENT PRACTICE
Emphasis on repeatability (3x)
One-time effort
Documentation important
Last step in development
“Hope we can pass validation”
Required for product release to market
Key regulations:
• 1987 Process Validation Guidance
• 1990’s Pharma Inspection Guidelines
• 1997 Medical Device Quality Systems Manual
134
SUMMARY -- WHERE WE ARE GOING –
LIFECYCLE APPROACH TO PROCESS VALIDATION
Lifecycle approach:
• Validation is never completed
• Validation is always ongoing
Objectives:
• Scientific and technical process
• Demonstrate process works as intended
• Process must remain in control throughout lifecycle
EFFECTIVE DOCUMENTS CONSISTENT WITH THE ABOVE
135
LIFECYCLE APPROACH TO PROCESS VALIDATION
Process Design
• Studies to establish process
• Identify critical process parameters
• Identify sources of variation
• Consider range of variation possible in processes
• Process understanding
Process Qualification
• Equipment, facilities, and utilities
• Confirm commercial process design
• Validation performance
Continued process verification
• Monitor, collect information, assess
• Maintenance, continuous verification, process improvement
• Change control
• Validation maintenance
“The process of process validation.”
136
SUMMARY
PROCESS VALIDATION HISTORY
1978
CGMP includes Validation
1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
SUMMARY – DOCUMENTATION
• Critically important
• Integrate site functions
– R&D / Technical Support / Engineering (Stage 1)
– QA (Stage 3)
• Awareness of responsibility to validation
• Model documents
– Suggested content in outlines
• FDA detailed recommendations in guidance
138
PROCESS VALIDATION DOCUMENTS
• Validation policy – Reference PV Guidance approach
– Corporate and / or site documents
• Validation Master Plan (VMP) – Reference PV Guidance approach
• Validation documents
– Stage 1 documents – Process Design
• Specific documents -- Reference PV Guidance
– Stage 2 documents – Process Qualification (traditional validation)
• Validation Request / Plan -- Reference PV Guidance
• Validation Protocol(s) – Reference PV Guidance
• Engineering Studies
• Others
• Validation Results / Report – Reference PV Guidance
– Stage 3 documents – Continued Process Verification
• PQ requirements
• Routine monitoring – Reference PV Guidance
• Associated validation and qualification -- Reference PV Guidance
• Other associated documents
139
STAGE 3 DOCUMENT RESPONSIBILITIES
ONGOING MONITORING
RESPONSIBILITY
Monitoring results (Annual Product Review) QA
Change control validation results/reports and monitoring Validation
Non-conformances Production
Deviations Production
Process monitoring (control charts) QA
Process changes Production
Improvement projects instituted Validation
Other changes -----
Record of management review QA
ANNUAL REVIEW NOT GOOD ENOUGH,
ESPECIALLY FOR HIGH RISK PROCESSES
140
SUMMARY -- APPLICATIONS
• Other processes – Cleaning, analytical, packaging, etc.
• Equipment, facilities, utilities, etc.
• Equipment “processes” – HVAC, WFI
• Quality systems
ALL IMPLEMENT STAGE APPROACH:
• Design and understand
• Demonstrate
• Monitor and maintain
141
SUMMARY -- IMPLEMENTATION
• Plan implementation strategy– Develop reasonable and deliberate strategy
– Guarantee success
• Upper management input and approval
• Validation Approval Committee agreement
• Validation Approval Committee responsibilities
• General training on validation – including new groups
involved in validation
• Protocol writer training
• Validation Approval Committee training
• Expect difficulty
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PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Associate Professor of Biopharmaceutics
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: [email protected]
143