Paul L. Pluta, PhD - cbinet.com 2_Paul Pluta_Effect Mgt of PV... · EFFECTIVE MANAGEMENT OF THE...
68
EFFECTIVE MANAGEMENT OF THE PROCESS VALIDATION LIFECYCLE VALIDATION MASTER PLAN DEVELOPMENT Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy 1
Transcript of Paul L. Pluta, PhD - cbinet.com 2_Paul Pluta_Effect Mgt of PV... · EFFECTIVE MANAGEMENT OF THE...
EFFECTIVE MANAGEMENT OF THE
PROCESS VALIDATION LIFECYCLEVALIDATION MASTER PLAN DEVELOPMENT
Paul L. Pluta, PhDJournal of Validation Technology
Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
1
OBJECTIVES
• Comprehensive analysis of he validation function.
• Description of the validation “product”
• Support of the validation “product”
• Design of the Validation Quality System
• Objectives of Validation Quality System
• Quality Attributes of Validation Quality System
• Parameters affecting attributes
• Control of variables affecting quality system performance
• Risk management
• Monitoring performance Continuous improvements
• Documentation in the Validation Master Plan.
VALIDATION: “PRODUCT” and INFRASTRUCTURE
WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?
RISK AND VARIATION
2
OUTLINE• Introduction and definitions
• Defining the validation function
• Validation Master Plan(s)
• Process validations and qualifications
• Lifecycle approach to process validiation
• Other processes and qualified systems
• Department management
• Positives and negatives
• Interactive discussions
PLEASE PARTICIPATE
3
SUMMARY
• Lifecycle approach should be applied to all process validation and
qualifications at site
• QbD approach should be applied to management of the validation
quality system (QSbD)
• Maximize uniformity in validation / qualification approach
• Minimize variation in validation / qualification performance
• Department management infrastructure development
• Risk basis
• Pre-work and post-work
• Document above in the Validation Mater Plan
4
VALIDATION DOCUMENTSValidation Policy
• Policy and corporate templates
VALIDATION MASTER PLAN (VMP) – COMPILATION OR INDIVIDUAL VMP
VALIDATION PROJECT MASTER PLAN
Validation Lifecycle Documents
• Stage 1 documents – Process Design
• Stage 2 documents – Process Qualification
– VALIDATION PLAN
– Validation Protocol(s)
– Engineering Studies
– Others
– Validation Results / Report
• Stage 3 documents – Continued Process Verification
– PQ requirements
– Routine monitoring
• Associated validation and qualification
• Other associated documents
5
IMPORTANCE OF VALIDATION DOCUMENTS
• Validation documents always requested in regulatory audits –especially VMP!
• Validation documentation is retained forever
• Documents reviewed long after people are gone– Documents must “stand alone”
• FDA auditors often focus on documentation – VMP and specific validation documents often requested ahead of audit
• Early documents (Initiation, Plan, Protocol) reviewed when project is in-progress or not completed.
VMP IS KEY DOCUMENT
6
IMPORTANCE OF VALIDATION DOCUMENTS –NEW PROCESS VALIDATION GUIDANCE
FDA Process Validation Guidance has greatly expanded the scope of validation
• Lifecycle approach – documents from development through commercialization. Traditional validation documents (protocol and results) relatively less important
• New expectations for traditional validation documents
Validation organizations should lead sites in transition to lifecycle approach
• Multiple groups at site must now contribute to process validation lifecycle approach
Lifecycle approach being applied to all validation and qualification (equipment, facilities, cleaning, etc.)
7
TERMINOLOGY: PROCESS VALIDATION
Process Validation – Process Qualification -- PPQ
Qualification QualificationEquipment #1 HVAC
UtilitiesEquipment #2 Facilities
ComputersEquipment #3
Analytical methods validation
Cleaning process validation
Packaging process validation
Process is validated
8
UO #1
UO #2
UO #3
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
9
FDA PROCESS VALIDATION GUIDANCEDOCUMENTATION FOCUS
“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.”
10
FDA PROCESS VALIDATION GUIDANCEDOCUMENTATION FOCUS
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.
11
TYPES OF VALIDATION MASTER PLANS
1. Validation Master Plan – site document
2. Validation Master Plan – function document
• Process Validation Master Plan
• Cleaning Validation Master Plan
• Other
3. Validation Project Master Plan – major project management document
4. Validation Plan – Individual validation document (Validation Initiation / Plan)
12
RECOMMENDATION: SITE DICTIONARY
• Validation
• Qualification
• FAT
• SAT
• IQ
• OQ
• PQ
• PV
• PPQ
• VMP
• Validation Project Plan
• Validation Plan
• Others
13
VALIDATION MASTER PLAN –SITE DOCUMENT
• Overview, approach, content, risk analysis
• Chapters
• Major commitments timelines
• Accomplishments
• Document management – Revisions
CRITICAL DOCUMENT
DESCRIPTION OF VALIDATION QUALITY SYSTEM
14
VALIDATION MASTER PLAN –SITE DOCUMENTOVERVIEW, CONTENT, APPROACH, RISK ANALYSIS
Overview: Description of VMP content
Approach: Lifecycle approach to all types of validation / qualification
• Stage 1. Design and development
• Stage 2. Demonstration
• Stage 3. Monitoring and maintenance
Content: Chapter list and chapter content
Risk analysis: Basis for all activities
General procedures applicable to all validation.
15
LIFECYCLE APPROACH RAMIFICATIONS
• Integration of validation with technical support– Product R&D
– Product technical support
– Equipment/facilities/utilities engineering
– Process engineering
– Analytical R&D
– Analytical QA/QC
– Computer systems
– Others
• Integration of validation with QA– Annual Product Reviews
– Stability
– Others
16
VALIDATION MASTER PLAN – SITE DOCUMENTEXAMPLE CHAPTERS
1. Introduction
2. Facilities
3. Utilities
4. Equipment
5. Process
6. Analytical
7. Cleaning
8. Computer systems
9. Others
17
VALIDATION MASTER PLAN – SITE DOCUMENTCHAPTER CONTENT
• Chapter description, approach, content, risk analysis
• Policies
• Procedures
• Commitments (projects, CAPA, others)
• Appendix– Reference list
– List of all products and reference #
– List of all cleaning and reference #
– List of all equipment and reference #
– List of all HVAC and reference #
– List of all utilities and reference #
– Other
18
CHAPTER APPENDIX
• Product or other #
• Product or other name
• Primary validation reference #
• Supplement validation reference #
• Dates
CRITICAL REFERENCE SECTION
19
VALIDATION MASTER PLAN – SITE DOCUMENTMAJOR COMMITMENTS TIMELINES
MAJOR PROJECT LIST
• Validation project #
• Project title
• Major dates
• Responsibility
Benefits / Negatives
• Management tool
• Audit tool -- benefits
• Communication +/-
• Motivational tool
20
VALIDATION MASTER PLAN – SITE DOCUMENTACCOMPLISHMENTS
• List of completed process validations
• List of completed qualifications
• Improvement projects
• Validation Quality System changes
Benefits / Negatives
• Accomplishments list – management tool
• Audit tool -- benefits
• Credibility / communication +/-
• Motivational tool
21
VALIDATION MASTER PLAN – SITE DOCUMENTACCOMPLISHMENTS
DATE # TITLE
1-25-17 xxxx Process Validation Product X
1-25-17 xxxxx Cleaning Validation Product X
_____ _____ _______________________
_____ _____ ________________________
_____ _____ ________________________
_____ _____ ________________________
_____ _____ ________________________
_____ _____ ________________________
22
VALIDATION MASTER PLAN – SITE DOCUMENTDOCUMENT MANAGEMENT -- REVISIONS
DATE TITLE REASON FOR REVISION
1-30-13 4Q 20120Update Completed validations, new equipment
4-30-13 1Q 2013 Update Completed validations, new equipment
7-30-13 2Q 2013 Update Completed validations
10-30-13 3Q 2013 Update Completed validations, new commitments
1-30-14 4Q 2013 Update Completed validations, 2014 goals
4-30-14 1Q 2014 Update Completed validations
7-30-14 2Q 2014 Update Completed validations, new equipment
UPDATE FREQUENCY DEPENDS ON NEED AND WORKLOAD
23
VALIDATION MASTER PLAN –FUNCTION DOCUMENT
• Overview, content, approach, risk analysis
• Policies
• Procedures
• Commitments (projects, CAPA, others)
• Document management – Revisions
• Appendix
– Reference list
24
VMP CHAPTER EXAMPLE – CLEANING VALIDATION
Strategy and approach
• Comprehensive lifecycle approach, Science and technical basis, Risk analysis, Variation identification and control (consistent with site and corporate docs)
Procedures
• List of approved procedures
Supporting information with reference documentation
• Product cleaning matrix
• Equivalent equipment
• Equipment surface area calculations
• Residue calculations
• Technical reports
• Templates
Validation commitments and timelines
• Planned validations
Improvement projects and timelines
• Planned projects
Validation references
• List of all completed cleaning validations, #, date
25
RESPONSIBILITIES OF THE VALIDATION FUNCTION
If products fail specifications, does validation have responsibility?
If re-cleaning is routinely needed, does validation have responsibility?
If equipment fails, does validation have responsibility?
If QA receives an FDA-483 observation, does validation have responsibility for validated items?
Is validation primarily a documentation library?
THE PV GUIDANCE HAS CHANGED THE SCOPE, CONTENT, AND RESPONSIBILITY OF VALIDATION
26
PROCESS VALIDATIONS AND QUALIFICATIONS
Lifecycle approach stages
• Stage 1 -- Key components of QbD for product / process
development
• Stage 2 -- FDA expectations including enhanced
documentation
• Stage 3 – Continued process verification.
Stages summarized:
Understand, demonstrate, monitor and maintain
27
OTHER PROCESSES
• Cleaning, analytical, packaging
• Equipment “processes” – HVAC, water
• Qualified systems -- Equipment, facilities, utilities
• Quality systems.
28
DEPARTMENT MANAGEMENT
Infrastructure supporting lifecycle approach to process validation
• Keys to effective process validation lifecycle
• Risk management
• Apply QbD and lifecycle approach to validation department management
• Minimize internal variation through uniform approach to all validation / qualification.
29
DEFINITIONS AND OBJECTIVES
Quality by Design (QbD)
Validated processes and equipment
Process of validation -- Lifecycle approach to process validation– Stage 1
– Stage 2
– Stage 3
QbD consistency with process validation
-------------------------
FDA Quality Systems
Validation Quality System
QbD / Lifecycle approach to the validation quality system
Risk management applications
30
QUALITY BY DESIGN (QbD)Development Focus
• Target product profile (TPP) and critical quality attributes (CQA)
• Drug substance and excipient properties
• Formulation design and development
• Manufacturing process design and development
• Identification of critical process parameters (CPP) and critical material attributes (CMA)
• Risk assessment and design space
• Scale up, identification of variables, and control strategy
Red = Original QbD
31
VALIDATED PROCESSES AND EQUIPMENT
Process Validation – Process QualificationProcess Performance Qualification (PPQ)
Qualification QualificationEquipment #1 HVAC
UtilitiesEquipment #2 Facilities
ComputersEquipment #3
Analytical methods validation
Cleaning process validation
Packaging process validation
Process is validated
32
Unit Op #1
Unit Op #2
Unit Op #3
PROCESS OF VALIDATION –LIFECYCLE APPROACH TO PROCESS VALIDATION
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 – QbD approach
• Stage 2 – Process Qualification – Demonstrate reproducible manufacturing through conformance lots
• Stage 3 – Continued Process Verification – Routine manufacturing and monitoring of performance.
STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM
33
VALIDATION HISTORY
1978 -- CGMP includes Validation
1987 -- Development -- VALIDATION – Change control
2004 2011 Lifecycle approach
Continuum ---
UNDERSTANDING VALIDATIONMAINTENANCE
34
QbD and PROCESS VALIDATION
QbD provides focus on design and development.
Integration of manufacturing experience throughout lifecycle will results in product and process continuing improvements.
QbD consistent with ICH Q8 and Q11.
Lifecycle approach to process validation integrates QbD principles.
Lifecycle: Design/development –> Performance –> Monitoring/maintenance
Lifecycle approach being applied to other processes, equipment, utilities, quality systems, etc.
35
FDA QUALITY SYSTEMS
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
36
FDA QUALITY SYSTEMS MODELManagement 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 improvement
37
VALIDATION QUALITY SYSTEM
Validation of processes, equipment, facilities, etc. is component of all
quality and manufacturing systems being inspected.
FDA Inspection Approach
– Quality System
– Materials System
– Production system
– Equipment and Facilities System
– Packaging and Labeling System
– Laboratory Controls System
Canada Quality Systems Approach. Inter-relationship of
– Quality Assurance
– GMP
– Quality Control
Validation is a quality system.
Validation mentioned in all FDA inspection systems
Can QbD/lifecycle principles be applied to the validation quality system?
38
DEFINE VALIDATION FUNCTION
• Process validation and qualification
• Supportive infrastructure
• Administration, personnel, etc.
39
VALIDATION QUALITY SYSTEM
Two components:
1. Validated products, processes (manufacturing, cleaning, packaging, etc.), equipment, utilities, facilities, control systems, computer systems, analytical instruments – the “product” of the validation system.
2. The process of accomplishing validation – the infrastructure of the validation function. Protocol strategies, testing approaches, documentation packages, approval committee responsibilities, document library, improvement projects, etc.
40
QbD and VALIDATION QUALITY SYSTEM (QSbD)
Manufacturing Validation QS
Target product profile System objective
Critical quality attributes System attributes
Critical process parameters System parameters
Variation and controls Variation and controls
Risk assessment Risk assessment
Monitoring attributes and process Monitoring metrics
Improvement projects Improvement projects
41
RISK MANAGEMENT
ICH Q9 discusses risk management.
Risk analysis determines everything.
High risk activities must receive most attention.
Risk analysis required for devices.
42
QbD PROCESS VALIDATION
QSbD VALIDATION QUALITYSYSTEM -- LIFECYCLE APPROACH
PRODUCT and PROCESS• Target profile
• Critical quality attributes – product specifications
• Critical process parameters
• Variables and control
• Risk assessment
• Continuous improvement
LIFECYCLE APPROACH
Design/development, PQ, Monitoring Improvements
(Stage 1 Stage 2 Stage 3)**************************************************************************************************************************************************************************************
VALIDATION QUALITY SYSTEM
• Objectives – system and individual process steps
• Attributes
• Parameters
• Variables and control
• Risk assessment
• Improvement projects
LIFECYCLE APPROACH
Design/development, Demonstration, Monitoring Improvements
43
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
44
MANAGEMENT RESPONSIBILITYVALIDATION QUALITY SYSTEM
LIFECYCLE APPROACH
Quality System Design
Is the quality system properly designed to conduct the validation
business process? What about outsourced products, outsourced
processes, outsourced validation/qualification?
Quality System Performance
Does the quality system perform as designed?
Quality System Monitoring and Maintenance
What is done to maintain quality system performance?
RISK AND VARIATION
45
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 for validation personnel
Validation training for associated functions? R&D, Technical support, others
Validation training for document writers?
Adequate number of validation personnel?
Expertise of validation personnel?
Expertise of Validation Approval Committee (VAC)?
VAC responsibilities consistent with expertise?
Technical writers?
Personnel development and training?
Validation facilities?
Facility security?
Document library?
Electronic systems?
Electronic systems to monitor throughput, open documents, errors, etc.?
Monitoring on validated processes? Feedback, e.g., incidence of recleaning?
Monitoring on qualified EFU? Feedback?
46
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
47
VALIDATION QUALITY SYSTEM BUSINESS PROCESS
PROJECT INITIATION, DESIGN, AND DEVELOPMENT BY SITE FUNCTION (STAGE 1)
1. Validation provides information on future needs in support of PQ
2. Validation receives / accesses recommended documents
PROCESS QUALIFICATON (PQ – STAGE 2)
3. Validation initiation – Sources of requests
4. VAC approval
5. Protocol written
6. VAC approval
7. Test results and post-validation recommendations
8. VAC approval
9. Validation administrative closure
10. Document storage
POST VALIDATION (STAGE 3)
11. Post-validation protocol initiation
12. VAC approval
13. Test results
14. VAC approval
15. Validation administrative closure
16. Document storage
17. Monitor validated process, EFU, etc. performance
18. Validation reviews – Deviations, CAPA, etc.
IMPROVEMENT PROJECTS
19. Initiate validation improvement project
20. Complete validation improvement project including implementation
21. Complete validation change project
48
VALIDATION QUALITY SYSTEM BY DESIGNLIFECYCLE APPROACH
INITIATION, DESIGN, AND DEVELOPMENT
1. Objective
2. Attributes and parameters
3. Variation and control of variation
4. Risk analysis
5. Monitoring
PROCESS QUALIFICATION
1. Objective
2. Attributes and parameters
3. Variation and control of variation
4. Risk analysis
5. Monitoring
POST VALIDATION
1. Objective
2. Attributes and parameters
3. Variation and control of variation
4. Risk analysis
5. Monitoring
IMPROVEMENT PROJECTS
1. Objectives
2. Performance and implementation,
49
QbD APPROACH TO VALIDATION QUALITY SYSTEM –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 of variation
– 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 and subsystems
– Review performance of validatd processes, EFU, etc.
50
VALIDATION QSbDINITIATION, DESIGN, AND DEVELOPMENT
Manufacturing Process Validation
1. Objective: Support for Stage 2 PQ
2. Attributes and parameters:
• Formulation / process justification document
• CQA and CPP identification
• Risk analysis document
• Variation and control of variation document
3. Variation: Multiple project teams. Competence and experience
4. Risk: Aseptic processes highest risk. Secondary packaging lowest risk
5. Monitoring:
Improvement Projects
1. Validation training for technical personnel
2. Documentation practices training
3. Document outlines and model documents
ABOVE ANALYSIS FOR SPECIFIC VALIDATION / QUALIFICATION
51
VALIDATION QSbD
PROCESS QUALIFICATION (PQ)
Manufacturing Process Validation1. Objective: PV documentation
2. Attributes and parameters:
– PV Initiation and validation plan, protocol, and results meeting standards
– Documents sections consistent with site procedure
– Documents consistent with FDA PV guidance
– Document quality acceptable
– Acceptable grammar and punctuation
3. Variation:
– Background, experience, and competence of authors
– Validation Approval Committee standards
4. Risk analysis: Testing and acceptance criteria proportionate to risk level
5. Post validation monitoring recommendations consistent practice
Improvement Projects1. Validation training for validation document authors
2. Validation protocol writing training for document authors
3. Document outlines standards and model documents
4. Validation Approval Committee standards and training
ABOVE ANALYSIS FOR SPECIFIC VALIDATION / QUALIFICATION
52
VALIDATION QUALITY SYSTEM -- PROBLEM EXAMPLES
MANUFACTURING EQUIPMENT AND PROCESSES
• Operators did not perceive changes to be changes – inadequate change control
• Everything was “like-for-like” or not significant.
CLEANING VALIDATION
• No technical basis for cleaning
• Operators did whatever needed “to get the job done.”
CLEANING VALIDATION SAMPLING
• Sampling personnel not adequately trained – false negative data
DOCUMENTATION
• Numerous documentation problems such as data recording, original data, back dating, etc.
DOCUMENTATION COMPLIANCE
• Documentation not compliant with corporate requirements or regulatory expectations
DOCUMENTATION GRAMMATICAL
• Documentation poorly written
SAMPLING PROBLEMS
• Sampling personnel not adequately trained
NON-STERILE “CLEAN” PROCESSES
• Sampling personnel not adequately trained in mmicrobiology
LIKE-FOR-LIKE CHANGES
• No testing of correct installation
53
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 Training
Validation Approval Committee Procedure and Responsibilities
Validation Model Documents
Like-for-Like Approval (non-protocol) Process
Microbiology Training
Validation Policy Changes
RECORD CORRECTIVE ACTION PROJECTS IN VMP
54
WHY THE PROBLEM? -- VALIDATION CATEGORIES
Process validations
• Manufacturing
• Cleaning
• Packaging
• Analytical
• Others
Qualifications – IQ, OQ, PQ; ASTM E2500
• Equipment
• Facilities
• Utilities
• Computer systems
• Others
EACH VALIDATION UNIQUE
55
WHY THE PROBLEM? –ORIGINATORS OF VALIDATION / QUALIFICATION PROJECTS
R&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.
56
VALIDATION QUALITY SYSTEM LIFECYCLEQUANTITATIVE MONITORING -- EVALUATION
Performance of validated products, processes, equipment, etc. Do validated processes, EFU, etc. have problems due to validation deficiency, amount of testing, risk evaluation?
External audit observations
Documentation quality
Document throughput. “Open” validation projects – time open
Amendments to validation plan
Amendments and deviations to protocols
Rejected documents
Validation failures
Other document problems
57
OTHER APPLICATIONS
QbD / Lifecycle approach to other quality systems
Documentation in QSMP (equivalent to VMP)
Examples:
Material system – Heparin
Manual cleaning – Methotrexate high risk
Training – “Read and sign” vs. OTJ. Level of training in OTJ.
RISK AND VARIATION
58
POSITIVES AND NEGATIVES
• System performance orientation. Organized and comprehensive focus based on risk to the patient and the organization, strong message to employees and to auditors, “credit” in audits
• Cost effective -- High risk activities emphasized and prioritized
• Difficult to implement, internal audits, transparency, identify deficiencies, make commitments.
59
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 in Stage 1• 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
60
QbD / LIFECYCLE APPROACH NEGATIVES
Difficult • Getting organized is extremely difficult• Problem identification is difficult• Risk analysis is difficult• Gap analysis is difficult• Changes are difficultTransparency• Being open about gaps and deficiencies may have
regulatory and political risksOrganizational commitments• Headcount needed to correct deficiencies
Do the benefits outweigh the negatives?
61
IMPLEMENTATION
1. Identify high risk areas
– Example: Cleaning expertise
– Example: Aseptic processing
2. Senior management discussion – risks to operation
3. Function management discussion – risks to operation
4. Identify receptive individuals in high risk area
5. Training of appropriate individuals
6. Start slowly
7. Communication. Modify strategy as needed to insure success
8. Success is essential
9. Expand effort based on success
10. Expect resistance
62
SUMMARY – 1QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Concepts and Principles
• Quality by Design (QbD)
• Objectives
• Attributes
• Parameters
• Variation and control
• Risk management
• Lifecycle Approach to Process Validation
• Design and development
• Performance
• Monitoring and maintenance
63
SUMMARY – 2QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Validation Quality System function
• “Product” – validated processes, equipment, utilities, computer
systems, etc.
• Infrastructure – Process of conducting validation
Infrastructure lifecycle approach:
1. Design and develop -- Plan
2. Demonstrate performance – Show everything works
3. Monitor – Periodically check
4. Initiate improvement projects a indicated – Fix problems
64
SUMMARY – 3QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Infrastructure – Lifecycle approach and QbD• Objectives -- Goals of each process step?
• Attributes – Successful steps
• Parameters – Factors influencing success
• Variation. Identify sources of variation
• Control of variation -- Training, etc. to minimize variation
• Risk -- management – Prioritize highest risk activities
• Evaluation -- Review performance
Note: Different validation have different problems.
65
SUMMARY – 4QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Review Performance
• Gap analysis: Problem areas
– Initiate corrective action
– Initiate training
– Example projects
– Write model documents
• Quantitative measurements: Throughput, failures,
deviations, etc. These indicate problems with the
validation QS.
Positives and negatives
Implementation difficult
66
INTERCTIVE DISCUSSION
Managing validation is never discussed.
Managing validation is difficult
Implementing improvements is difficult
Does the QSbD approach have merit?
Please your comments, questions, suggestions, and criticisms.
Thank you
67
PAUL L. PLUTA, PhD
Editor-in-Chief• Journal of Validation Technology
• Journal of GXP Compliance
Associate Professor of Biopharmaceutics
• University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Extensive pharmaceutical industry technical and management experience
Contact: [email protected]
68
