CRITICAL DOCUMENTATION REQUIREMENTS FOR VALIDATION. Paul L. Pluta, PhD

Transcription

1 CRITICAL DOCUMENTATION REQUIREMENTS FOR VALIDATION Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA 1

2 PRESENTATION OUTLINE Process Validation General Validation Documents Overview Validation Policy Documents Stage 1 Process Design Documents Stage 2 Process Qualification Documents Validation Requests and Plans Validation Protocols Validation Results and Reports Stage 3 Continued Process Verification Documents Associated Documents Document Outlines / Templates Document Problems Implementation of PV Guidance Recommendations Interactions throughout discussion PARTICIPATION INVITED 2

3 OBJECTIVES 1. Comprehensive and consistent approach to documentation 2. Lifecycle approach principles and key concepts 3. Document details Outlines Examples Problems 4. Implementation 3

4 IMPORTANCE OF VALIDATION DOCUMENTS Validation documents always requested in regulatory audits Documentation is retained forever Documents reviewed long after people are gone Documents must stand alone Early documents (Request, Plan, Protocol) reviewed when project is in-progress or not completed Regulatory auditors often focus on documentation validation documents often requested ahead of audit Above sometimes difficult for technical people 4

5 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) less important 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.) 5

6 TERMINOLOGY: PROCESS VALIDATION Process Validation Process Qualification 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 6

7 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 7

8 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. 8

9 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. 9

10 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 10

11 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 11

12 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 analysis 12

13 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 13

14 STAGE 2, PROCESS QUALIFICATION Conformance Lots Procedures Validation plans Protocols Sampling Testing Results Plan to maintain validation ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING SYSTEMS MUST BE QUALIFIED. 14

15 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 15

16 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 16

17 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 17

18 CONTINUED PROCESS VERIFICATION Monitoring Statistical process control Trend analysis Change control Continuous improvement Revalidation Management review STATISTICIAN RECOMMENDED BY FDA 18

19 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 19

20 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 20

21 PROCESS VALIDATION HISTORY 1978 CGMP includes Validation 1987 Development -- VALIDATION -- Control Lifecycle approach Continuum of understanding validation maintenance UNDERSTANDING -- VALIDATION -- MAINTENANCE 21

22 VALIDATION PHILOSOPHY Validation is confirmation. Acceptable (passing) results are expected. Validation is not R&D Final stage of development process Optimization Fine-tuning Debugging 22

23 VALIDATION DOCUMENTS Written for the reader US vs. Europe Objective: Understanding Clarity much more important than brevity Stand-alone document Potential for review in 10+ years Author / Management not available for explanation Spelling and grammar correct Need good writers Simple sentences Simple words 23

24 PROCESS VALIDATION DOCUMENTS Validation policy Reference lifecycle approach Corporate templates Validation Master Plan (VMP) Reference lifecycle approach Stage 1 documents Process Design Stage 2 documents Process Qualification Validation Request / Plan -- Reference Guidance Validation Protocol(s) Reference Guidance Engineering Studies Others Validation Results / Report Reference Guidance Stage 3 documents Continued Process Verification PQ requirements Routine monitoring Reference lifecycle approach Associated validation and qualification -- Reference lifecycle approach Other associated documents 24

25 VALIDATION POLICY Corporate or company policies High level overview documents Apply to all global manufacturing sites State agreement with local regulatory requirements State agreement with customer regulatory documents Specific corporate requirements Describe general validation approach 25

26 VALIDATION POLICY Describe general validation approach Design and development. Science and technical basis Validation performance Maintain validated state through monitoring, change control, and management review Risk analysis emphasis on highest risk Sampling, testing, acceptance criteria Variation identification and control Continuing improvements GENERAL POLICY WITH KEY POINTS 26

27 VALIDATION MASTER PLAN (VMP) PROGRAM DESCRIPTION AT SITE Comprehensive lifecycle approach based on risk Consistent with general policy MULTI-CHAPTER DOCUMENT Chapter for each major area (may have individual VMP per area) Process Equipment Facilities Analytical Computer Others UPDATED AS NEEDED (Annual, quarterly, monthly) VMP must be current for audits IMPROVEMENT PROJECTS COMMITMENTS AND TIMELINES 27

28 VALIDATION MASTER PLAN (VMP) SITE PROGRAM DESCRIPTION Design and development. Science and technical basis Validation performance Maintain validated state through monitoring, change control, and management review Risk analysis emphasis on high risk activities Variation identification and control Continuing improvements 28

29 VALIDATION MASTER PLAN (VMP) CHAPTER CONTENT Content for processes, cleaning, analytical, etc. Strategy and approach Procedures Supporting information (reference) Ex: Product validation families, Cleaning matrix Validation references Ex: Products, equipment, utilities, etc. document ID Validation commitments and timelines Improvement projects and timelines 29

30 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 references List of all completed cleaning validation Validation commitments and timelines Planned validations Improvement projects and timelines Planned projects 30

31 STAGE 1 DOCUMENTS -- PROCESS DESIGN Technical areas must be aware that their documents are critical to validation throughout the product lifecycle. Direct support of Stage 2 PQ their work is basis of validation R&D technical reports consistent with raw data Rapidly retrieved (within 30 minutes) Accessed throughout product lifecycle Personal support of regulatory audits Stand-alone documents Applies to processes, cleaning, analytical, equipment, facilities, utilities, control systems, others. R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE REQUIREMENTS AND EXPECTATIONS 31

32 STAGE 1 DOCUMENTS POTENTIAL PROBLEMS Reports not available Reports not retrievable Reports incomplete Reports poorly written Reports not approved Personnel not available Original data not available Substandard documentation practices original data No signature / date Data transpositions Data transfer problems Data transfer not verified Inconsistent data Multiple sources of same data inconsistent 32

33 VALIDATION STAGE 2 DOCUMENTS OPTIONS Outlines Templates Model documents RECOMMENDATION 1. Develop outlines for authors get agreements from functional organizations and approval committee 2. Write or collect good documents 3. Documents available to writers 4. Replace (upgrade) as appropriate 33

34 STAGE 2 DOCUMENTS PROCESS QUALIFICATION VALIDATION REQUEST AND VALIDATION PLAN INITIATION OF VALIDATION Request: Statement of recommended validation What? Why needed? Why acceptable? Impact of validation risk analysis Approach to accomplish Validation Plan Approvals Plan: Details of work to accomplish validation Description of strategy and approach References from Stage 1 work supporting validation Approvals MAY BE SINGLE DOCUMENT OR TWO SEPARATE DOCUMENTS 34

35 VALIDATION REQUEST OUTLINE Objective of validation Why needed? Impact of validation Risk analysis Why acceptable? Compliance to internal requirements, policies, engineering standards, etc. Regulatory impact (Prior approval, CBE, CBE30, etc.) Other systems or product impacted Procedure changes or other document changes Notifications to affected groups (internal, external, labs) Validation plan -- Approach to accomplish validation Above applicable to equipment and other qualification HAVE MODEL DOCUMENTS AVAILABLE 35

36 VALIDATION REQUEST -- PROBLEMS Poorly written Inadequate information Prematurely written Written to meet business goals Written to demonstrate future intent Amendments necessary -- changes usually required Validation requests should be submitted for approval only after objective and scope of validation is determined and work details (risk/testing/sampling) determined. Amendments are a planning failure regardless of justification. HAVE MODEL DOCUMENTS AVAILABLE 36

37 VALIDATION REQUEST TERMINOLOGY EXAMPLES Validation request: Process validation of Product A System: New product validation Change impact: High impact. New product validation Reason: New product to be manufactured at site Acceptability: Compliant with policies Regulatory approval Other systems impacted (e.g., cleaning) Procedures approved Notifications (Labs) Justification: See Validation Plan Approvals SIMPLE AND CLEAR 37

38 VALIDATION REQUEST TERMINOLOGY EXAMPLES Validation request: Qualification of 150 cu. ft. blender System: New equipment qualification Change impact: High impact. New equipment and new size at site Reason: New equipment to increase manufacturing efficiency and throughput Acceptability: Compliant with policy Regulatory approval Other systems impacted (e.g., cleaning) Procedures approved Notifications (Labs) Justification: See Validation Plan Approvals SIMPLE AND CLEAR 38

39 VALIDATION REQUEST TERMINOLOGY EXAMPLES Validation request: Change air supply and return ductwork to coincide with Line 1 floor space changes System: HVAC system #3 Change impact: Medium impact. Change to direct product contact support utility Reason: Room configuration change to increase manufacturing efficiency Acceptability: Compliant with policy Regulatory approval not needed Other systems impacted Procedures approved, drawings modified, etc. Notifications Justification: See Validation Plan Approvals SIMPLE AND CLEAR 39

40 Introduction VALIDATION PLAN OUTLINE Technical information Validation strategy and testing -- rationale Validation documentation List of required protocols, reports, procedures, etc. Administrative benefit References List of reports and scientific references (including Stage 1 reports) HAVE MODEL DOCUMENTS AVAILABLE 40

41 INTRODUCTION VALIDATION PLAN Overview describing validation / product / process / equipment / etc. (consistent with request) Requirements to complete validation Conformance to regulations and internal policy Impact of change to maintain the validated state Impact on regulatory submission Impact of change on procedures, drawings, other documents Notifications to other areas internal and external (e.g., environmental agency, internal test labs) impacted by validation 41

42 TECHNICAL INFORMATION VALIDATION PLAN Basic product / process / equipment description Formula Process Specifications Include non-technical description information Technical aspects of validation / qualification Reference to technical reports from Design Stage Total validation approach Experimental studies Past data (retrospective data) Validation protocols Other work New procedures Number of lots related to impact of change and risk WRITTEN FOR THE READER 42

43 VALIDATION PLAN VALIDATION STRATEGY AND TESTING Prospective validation only Types of testing -- general Regulatory specifications Internal controls Process tests Tests and rationale general Address changes based on risk analysis Sampling and rationale general Exceed routine QA testing based on impact and risk analysis Data treatment general Statistical data treatment and confidence limits Acceptance criteria general DETAILS OF ABOVE PROVIDED IN PROTOCOLS 43

44 VALIDATION PLAN VALIDATION DOCUMENTATION Doc # Title Date closed 01 Validation request 02 XXX Dryer Engineering Study 03 XXX Dryer Qualification 04 XXX Process Scale-up Engineering Study 05 XXX Process Validation 06 Update Validation Master Plan Product and Equipment sections 07 XXX Project Summary Report 44

45 VALIDATION PLAN REFERENCES R&D Reports Development and analytical reports Published literature Scientific and technical support to validation plan Report copies should be stored in validation area or readily accessible (within 30 minutes) 45

46 PRODUCT / PROCESS DESIGN INFORMATION Technical reports from R&D Pharmaceutics reports Formulation and process development reports (CQA, CMA, CPP) Technology transfer / Scale-up reports Identification of sources of variation Variation control plans Analytical methods Other technical reports REPORTS SHOULD BE REVIEWED FOR CONSISTENCY BETWEEN GROUPS REPORTS SHOULD BE REFERENCED IN VALIDATION PLAN 46

47 TECHNICAL REPORTS Readily available Consistent across large technical groups Approved by management Linked to original data Observe / store original data Original documentation practices? VALIDATION MUST REVIEW ORIGINAL DATA Rapidly retrievable Consistent with technical report Documentation practices 47

48 VALIDATION PROTOCOLS Execution of the Validation Plan Testing details Sampling details Data sheets Data treatment Acceptance criteria Minimal text repetition from Validation Plan PROTOCOL EASILY WRITTEN IF VALIDATION PLAN IS THOROUGH 48

49 VALIDATION PROTOCOL Objective of validation specific protocol Validation description specific Validation approach Testing and rationale -- specific Sampling and rationale -- specific Data sheets (summary) Data treatment -- specific Acceptance criteria specific All testing must have acceptance criteria No FYI testing in validation VALIDATION IS CONFIRMATION 49

50 VALIDATION PROTOCOL TESTING AND SAMPLING Based on product specifications and testing Exceed routine QA testing based on impact and risk Consider the following: Product for seizures Product for hypertension New product Change in compressing machine Increase compressing machine speed Change in granulation method Change in batch size Risk analysis in above 50

51 VALIDATION PROTOCOL FDA Powder Blends and Finished Dosage Units Stratified Sampling and Assessment Blend sampling. n = 10, Individuals, RSD Tablets. 20 samples, n = 3-7 per location, mean, range, RSD. Application is possible approach for high risk products Supportive of USP Uniformity of Dosage Units on composite / stratified samples Product types: Potency and weight testing 51

52 VALIDATION SAMPLING What is routine QA sampling? Impact of change High impact Medium impact Low impact No impact Risk analysis Related to numerical RPN analysis High risk Medium risk Low risk RISK LEVEL MUST BE ACKNOWLEDGED 52

53 ENGINEERING STUDY Conducted in advance of validation No acceptance criteria Trial run Examples: Manufacturing process without bulk drug (low dose API) Process runs with placebo Categories of Engineering Studies Conduct Engineering Study concurrently with validation? - - Not recommended 53

54 SAMPLING PAGES Designed sheet with space for expected data Data treatment specified Signature and data of person supplying data Highly recommended for Operators or persons not familiar with sampling Data pages consistent with sampling pages Prevents missing data in complex protocols Record sampling and / or testing 54

55 SAMPLING / DATA PAGE EXAMPLE UNIT OPERATION: Tablet compressing, lot # TEST: Content Uniformity (SOP # XX-XXX) SAMPLE: 10 Tables each from beginning, middle, and end of batch Sample #1 by Date Sample #2 by Date Sample #3 by Date TEST RESULTS (Circle P -- Pass or F -- Fail) Sample #1 Sample #2 Sample #3 P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F P / F RECORDED BY: VERIFIED BY: 55

56 PROCESS VALIDATION PROTOCOL (PPQ) FDA GUIDLINE RECOMMENDATIONS 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 Status of analytical method validation Review and approval by appropriate departments and quality unit 56

57 HEALTH CANADA PROTOCOL REQUIREMENTS Minimum information Objective, scope of coverage of the validation study Validation team membership, qualifications, and responsibilities Type of validation prospective, concurrent, retrospective, re-validation Number and selection of batches List of all equipment used. Normal and worst-case operating parameters Outcome of IQ and OQ for critical equipment Requirements for calibration of all measuring devices Critical process parameters and tolerances Description of processing steps. Copy of master documents Sampling points, stages of sampling, methods of sampling, sampling plans Statistical tools for data analysis Training requirements for processing operators Validated test methods Specification for raw and packaging materials and test methods Forms and charts for documenting results Format for presentation of results, documenting conclusions, and approval of study results 57

58 VALIDATION PROTOCOL OUTLINE Introduction Unit operations Testing with justification Sampling with justification Sampling and data pages Data treatment Acceptance criteria with justification HAVE MODEL DOCUMENTS AVAILABLE 58

59 VALIDATION PROTOCOL -- PROBLEMS No plan No basic explanation of validation No statement of strategy and approach No test rationale No sampling rationale Missing samples missing data How to treat data No discussion of results No acceptance criteria rationale No validation statement Poorly written WRITTEN FOR THE READER 59

60 VALIDATION PROTOCOL -- PROBLEMS How many lots should be tested? Consider impact of change. Consider product. Consider process. Consider risk. ABOVE ADDRESSED IN VALIDATION PLAN 60

61 VALIDATION RESULTS Compilation of testing required in protocol Deviations or adverse events Discussion Conclusion WRITE GOOD PLAN PROTOCOL CONSISTENT WITH PLAN RESULTS CONSISTENT WITH PROTOCOL WRITE DISCUSSION FIRST MOST IMPORTANT SECTION 61

62 VALIDATION RESULTS OUTLINE Introduction Data sheets compiled Data treatment Results Deviations, Non-conformances, etc. Discussion Results pass is not sufficient. Validation statement: Results indicate that is validated. Post-validation monitoring plan WRITE DISCUSSION SECTION FIRST MOST IMPORTANT SECTION HAVE MODEL DOCUMENTS AVAILABLE 62

63 VALIDATION RESULTS PROBLEMS Missing data Documentation practices on raw data Raw data and results inconsistent Inadequate or no discussion of results Inadequate or no discussion of amendments or deviations No conclusion statement Poor grammar and composition 63

64 VALIDATION RESULTS / REPORT -- PROBLEMS Protocol requires BME samples for potency. Acceptance criteria: % B = 95% M = 100% E = 105% All results pass Conclusion? POST PQ MONITORING? 64

65 VALIDATION RESULTS / REPORTS -- PROBLEMS Protocol requires BME testing Acceptance Criteria: Not More Than 6.0% Results: B = 2.0% M = 2.1% E = 6.0% All data pass acceptance conclusions. Conclusions? POST PQ MONITORING? 65

66 VALIDATION REPORT Recommended for complex projects Recommended for multiple protocol projects PRIMARY REPORT FOR AUDIT Cut and Paste exercise from multiple documents Best approach to avoid inconsistency 66

67 VALIDATION REPORT FORMAT Introduction Key information from Validation Plan Supporting information Protocol #1 results Cut and paste Protocol #2 results Cut and paste Protocol #3 results Cut and paste Protocol #n results Cut and paste Write transitional narrative Project conclusions (for Validation Plan) Validation statement Results indicate that is validated. HAVE MODEL DOCUMENTS AVAILABLE 67

68 STAGE 3 DOCUMENTS CONTINUED PROCESS VERIFICATION POST PQ DOCUMENTS TYPES OF DOCUMENTS Post PQ requirements work required based on PQ results Example: B = 1.5%, M = 1.8%, E = 6.0% -- all results pass. Ongoing monitoring routine process monitoring 68

69 STAGE 3 DOCUMENT RESONSIBILITIES PQ REQUIREMENTS Requirements specified in PQ results Continued monitoring of critical test results High risk activities Continued monitoring of aberrant values Continued monitoring of statistical (CL) failures 69

70 STAGE 3 DOCUMENT RESPONSIBILITIES ONGOING MONITORING RESPONSIBILITY Monitoring results (Annual Product Review) Change control validation results/reports and monitoring Non-conformances Deviations Process monitoring (control charts) Process changes Improvement projects instituted QA Validation Production Production QA Other changes Record of management review ANNUAL REVIEW NOT GOOD ENOUGH, ESPECIALLY FOR HIGH RISK PROCESSES Production Validation QA 70

71 STAGE 3 DOCUMENTS Regular management review of manufacturing data Data analysis by statistical process control (SPC) principles Review of all associated events, investigations, changes, etc. Record of management review Expanded Annual Product Review, conducted at appropriate intervals based on risk. 71

72 ASSOCIATED VALIDATION AND QUALIFICATION DOCUMENTS Equipment qualification All manufacturing process equipment and associated control systems Example: Drug dispensing qualification (equipment, facilities, HVAC, personnel, etc.) All facilities, utilities, systems, etc. Analytical method validation Analytical equipment qualification ABOVE MENTIONED IN PV GUIDANCE 72

73 IQ, OQ, PQ ASTM E2500 EQUIPMENT, FACILITIES, UTILTIES, ETC. QUALIFICATION Same approach and philosophy as with processes understand, demonstrate, and maintain Confirmation -- Success I expected. Same requirements Same approval Critical tests only Non-critical tests in FAC, SAC, etc. Do as much as possible in commissioning Difference from PV: Do tests only once Validation statement Results indicate that is qualified. 73

74 ANALYTICAL Analytical methods validated Analytical equipment qualified QbD for analytical methods evolving 74

75 OTHER ASSOCIATED DOCUMENTS Training records Operators Approvers Supervisors Personnel qualifications FDA Warning Letter for inconsistent job requirements (HR) and personnel resumes Environmental monitoring history Other 75

76 DOCUMENT OUTLINES vs. TEMPLATES Document templates very difficult Labor intensive Do not fit every situation Suggested approach Document outline of major sections Document outline evolves Model approved documents available Model approved documents improved and are replaced 76

77 VALIDATION DOCUMENT APPROVAL VALIDATION APPROVAL COMMITTEE (VAC) VAC must review documents with perspective of an external regulatory auditor Assure acceptability of technical validation and product quality Assure compliance with regulations, policies, and industry expectations Assure acceptability of documentation. Spelling and grammar VAC IMPORTANT PARTNER WITH VALIDATION 77

78 VALIDATION DOCUMENT APPROVAL Technical validation Scientific and technical principles Consistent approach Supports objective of validation Supports routine manufacturing in type of testing and sampling Support routine manufacturing in duration of sampling and testing Results and discussion support data Correct technical conclusions Equipment testing support entire operating range used in manufacturing 78

79 VALIDATION APPROVAL COMMITTEE Training consistent with area of expertise Specialized training on validation function Emphasize role of internal auditor VALIDATION APPROVAL COMMITTEE IS NOT Training for new personnel Expeditor for engineering documents 79

80 Plan implementation strategy IMPLEMENTATION 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 Science and technical basis Compliance with procedures Documentation quality Surrogate regulatory auditor Validation Approval Committee training 80

81 IMPLEMENTATION -- REALITY Develop reasonable and deliberate strategy Assure successful implementation Do not expect rapid success Do not expect agreements and support Expect complaints and problems OPPORTUNITY FOR VALIDATION LEADERSHIP 81

82 SUMMARY WHERE WE ARE -- CURRENT PRACTICE R&D Validation Commercialization 82

83 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 83

84 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 84

85 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. 85

86 SUMMARY PROCESS VALIDATION HISTORY 1978 CGMP includes Validation 1987 Development -- VALIDATION -- Control Lifecycle approach Continuum of understanding validation maintenance UNDERSTANDING -- VALIDATION -- MAINTENANCE 86

87 SUMMARY VALIDATION -- FUTURE Development Performance Maintenance Stage 1 Stage 2 Stage 3 87

88 SUMMARY COMPREHENSIVE, CONSISTENT, AND EFFECTIVE VALIDATION DOCUMENTS Validation documents consistent with validation guidelines and expectations based on risk Policies and VMP Stage 1 -- Emphasis on development work supporting Stage 2 Technical basis for validation Stage 2 -- Work should consider validation guidance recommendations Plans, protocols, results Stage 3 Emphasis on maintaining validated state through lifecycle Specific needs and routine monitoring Associated documents 88

89 SUMMARY VALIDATION POLICIES Corporate or company policies High level overview documents State agreement with local regulatory requirements and customer regulatory documents Describe general validation approach State key points from Process Validation Guidance Risk-based approach 89

90 SUMMARY VALIDATION MASTER PLAN Program description at site Multi-chapter document Updated as needed (annual, quarterly, monthly) Improvement projects commitments and timelines Consistent with corporate policies State key points from Process Validation Guidance Risk-based approach 90

91 SUMMARY STAGE 1 DOCUMENTS Technical understanding of processes -- basis of validation Reports readily available Accessed throughout product lifecycle Stand-alone documents Applies to processes, cleaning, analytical, equiment, facilities, utilities, control systems, others. R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE REQUIREMENTS 91

92 SUMMARY STAGE 2 DOCUMENTS VALIDATION REQUEST / PLAN Initiates validation Provides basis and details of future work Lists all specific requirements to complete validation Administrative importance Most important document all subsequent documents based on validation plan Risk based 92

93 SUMMARY STAGE 2 DOCUMENTS VALIDATION PROTOCOLS Specific guidance requirements Strategy and approach Impact of change Risk based Testing and sampling rationale Acceptance criteria Statistical data treatment Data sheets Post-validation monitoring plan 93

94 SUMMARY STAGE 2 DOCUMENTS VALIDATION RESULTS / REPORTS Data sheets Discussion of results Evaluate results Additional post-validation testing if necessary Validation statement is validated. Summary report for multiple protocol validation or complex projects Stage 3 Plan included in results document Most important validation document Simple sentences, simple words Written for the reader 94

95 SUMMARY STAGE 3 DOCUMENTS CONTINUED PROCESS VERIFICATION Special post-pq requirements Based on unexpected results Routine monitoring Risk based 95

96 SUMMARY ASSOCIATED DOCUMENTS Equipment, facilities, utilities, etc. qualification Analytical methods and equipment Training records Personnel qualification Environmental monitoring 96

97 SUMMARY OTHER CONSIDERATIONS Follow FDA PV Guidance Use outlines Have model documents available Continually improve model documents Based on guidance requirements Example information to provide expectations for writers and approvers Write most important document sections first Consider problem examples FMEA risk analysis included with validation plan 97

98 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 98

99 SUMMARY -- FINAL 1. Comprehensive and consistent approach to documentation High level documents Stage documents Associated documents 2. Lifecycle approach principles Key concepts and details -- Terminology 3. Documents structures Outlines Examples Problems 4. Implementation Paradigm shift Training 99

100 PAUL L. PLUTA, PhD Editor-in-Chief Journal of Validation Technology Journal of GXP Compliance Advanstar Communications Visiting Clinical Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA Contact: 100