EFFECTIVE MANAGEMENT OF THE PROCESS VALIDATION LIFECYCLE VALIDATION MASTER PLAN DEVELOPMENT

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

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 Policy VALIDATION DOCUMENTS 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 Equipment #1 Equipment #2 Equipment #3 UO #1 UO #2 UO #3 Qualification HVAC Utilities Facilities Computers Analytical methods validation Cleaning process validation Packaging process validation Process is validated 8

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 GUIDANCE DOCUMENTATION 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 GUIDANCE DOCUMENTATION 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 DOCUMENT OVERVIEW, 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

1. Introduction 2. Facilities 3. Utilities 4. Equipment 5. Process 6. Analytical 7. Cleaning VALIDATION MASTER PLAN SITE DOCUMENT EXAMPLE CHAPTERS 8. Computer systems 9. Others 17

VALIDATION MASTER PLAN SITE DOCUMENT CHAPTER 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 DOCUMENT MAJOR 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 DOCUMENT ACCOMPLISHMENTS 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 DOCUMENT ACCOMPLISHMENTS DATE # TITLE 1-25-17 xxxx Process Validation Product X 1-25-17 xxxxx Cleaning Validation Product X 22

VALIDATION MASTER PLAN SITE DOCUMENT DOCUMENT 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

Strategy and approach VMP CHAPTER EXAMPLE CLEANING VALIDATION 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 Qualification Process Performance Qualification (PPQ) Qualification Equipment #1 Equipment #2 Equipment #3 Unit Op #1 Unit Op #2 Unit Op #3 Qualification HVAC Utilities Facilities Computers Analytical methods validation Cleaning process validation Packaging process validation Process is validated 32

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 VALIDATION MAINTENANCE 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

Management Responsibilities FDA QUALITY SYSTEMS MODEL 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

Two components: VALIDATION QUALITY SYSTEM 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 Target product profile Critical quality attributes Critical process parameters Variation and controls Risk assessment Monitoring attributes and process Improvement projects Validation QS System objective System attributes System parameters Variation and controls Risk assessment Monitoring metrics 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 RESPONSIBILITY VALIDATION 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 DESIGN LIFECYCLE 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

Objectives QbD APPROACH TO VALIDATION QUALITY SYSTEM BUSINESS PROCESS 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 QSbD INITIATION, 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

PROCESS QUALIFICATION (PQ) Manufacturing Process Validation VALIDATION QSbD 1. 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 Projects 1. 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 Training Module VALIDATION QUALITY SYSTEM CORRECTIVE ACTION PROJECTS 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

R&D WHY THE PROBLEM? ORIGINATORS OF VALIDATION / QUALIFICATION PROJECTS 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 LIFECYCLE QUANTITATIVE 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 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? 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 1 QbD (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 2 QbD (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 3 QbD (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 4 QbD (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: paul.pluta@comcast.net 68