QUALITY BY DESIGN / LIFECYCLE APPROACH to the VALIDATION
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QUALITY BY DESIGN / LIFECYCLE APPROACH to the VALIDATION QUALITY SYSTEM (Quality System by Design -- QSbD) Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy 1
Transcript of QUALITY BY DESIGN / LIFECYCLE APPROACH to the VALIDATION
QUALITY BY DESIGN / LIFECYCLE APPROACHto the
VALIDATION QUALITY SYSTEM(Quality System by Design -- QSbD)
Paul L. Pluta, PhD
Journal of Validation Technology
Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
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PRESENTATION OUTLINE
1. Definitions and Objectives
• Quality by Design (QbD)
• Validated Processes and Equipment
• Lifecycle Approach to Validation Performance
2. Lifecycle Approach to Process Validation
3. QbD (QSbD) / Lifecycle Approach to the Validation Quality System
• Design/develop, Demonstrate, Monitor/maintain
• Objectives
• Attributes
• Parameters
• Variation and control
• Risk management
4. Positives and Negatives
5. Implementation
PLEASE PARTICIPATE2
PRESENTATION OBJECTIVES
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
VALIDATION: VALIDATED “PRODUCT” and INFRASTRUCTURE
AUDIT QUESTIONS
WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?
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DEFINITIONS AND OBJECTIVES
Quality by Design (QbD)
Validated processes and equipment
Process of validation -- Lifecycle approach to process validation
QbD consistency with process validation
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Validation Quality System
QbD / Lifecycle approach to the validation quality system
Risk management applications
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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
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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
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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
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VALIDATION HISTORY
1978 -- CGMP includes Validation
1987 -- Development -- VALIDATION – Change control
2004 2011 Lifecycle approach
Continuum ---
UNDERSTANDING VALIDATIONMAINTENANCE
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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.
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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.
Can QbD/lifecycle principles be applied to the validation
quality system?10
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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RISK MANAGEMENT
ICH Q9 discusses risk management.
Risk analysis determines everything.
High risk activities must receive most attention.
Risk analysis required for devices.
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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
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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 improvement17
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?
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.?
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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
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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.22
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
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VALIDATION QUALITY SYSTEM EXAMPLE
INITIATION DESIGN andDEVELOPMENT
PQ MONITORINGMAINTENANCE
OBJECTIVE
QUALITY ATTRIBUTES
PARAMETERS
CONTROL OF VARAITION
RISK
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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.”
CLEANING VALIDATION SAMPLING
• Sampling personnel not adequately trained – false positive 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
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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 Model Documents
Like-for-Like Approval (non-protocol) Process
Microbiology Training
Validation Policy Changes
RECORD CORRECTIVE ACTION PROJECTS IN VMP
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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
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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.
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VALIDATION QUALITY SYSTEM LIFECYCLEQUANTITATIVE MONITORING -- EVALUATION
PRODUCTPerformance of validated products, processes, equipment, etc.
QUALITY SYSTEMThroughput
External audit observations
• Documentation quality
“Open” validation projects – time open
Validation failures
Protocol amendments
Protocol deviations
Other
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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
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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
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QbD / LIFECYCLE APPROACH NEGATIVES
Difficult • Getting organized is extremely 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?
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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. Expand effort based on success
9. Expect resistance
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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
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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
“Product” -- Lifecycle approach:
1. Design and develop to understand
2. Validation PQ
3. Monitor and maintain the validated state
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SUMMARY – 3QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Infrastructure – Lifecycle approach and QbD
1. Determine business process
– Initiate validation project
– Design and develop items to be validated
– PQ
– Monitor and maintain validated state
2. QbD for business process
– Objectives -- Goals of each process step?
– Attributes – Successful steps
– Parameters – Factors influencing success
– Control of variation -- Expected variation in performance
– Risk -- management – Prioritize highest risk activities
– Evaluation -- Review performance
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SUMMARY – 4QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Review Performance
• Gap analysis: Problem areas
– Initiate corrective action
– Example projects
• Quantitative measurements: Throughput, failures,
deviations, etc.
Positives and negatives
Implementation difficult
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SUMMARY – 5QbD (QSbD) / Lifecycle Approach to the Validation Quality System
AUDIT QUESTIONS:WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?
1. Product/process/equipment/facilities/etc: Lifecycle approach
– Design/development (QbD)
– Performance PQ
– Maintenance and monitoring leading to improvments
2. Validation Quality System/infrastructure:
QbD / lifecycle approach – validation business process
– Design of the Quality System
– Objectives, Attributes, and Parameters
– Control sources of variation
– Risk analysis
– Demonstrate performance
– Evaluation leading to continuous improvements
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PAUL L. PLUTA, PhD
Editor-in-Chief
• Journal of Validation Technology
• Journal of GXP Compliance
Visiting Clinical Associate Professor
• University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Contact: [email protected]
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