validation boot camp

1

VALIDATION BOOT CAMP LIFECYCLE APPROACH TO

PHARMACEUTICAL VALIDATION – PRINCIPLES, IMPLEMENTATION, AND PRACTICE

Paul L. Pluta, PhD

Journal of Validation Technology Journal of GXP Compliance

University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA

OUTLINE

•  Process Validation Lifecycle Approach Overview •  FDA PV Guidance •  Documentation •  Lifecycle Approach to Cleaning Process Validation •  Lifecycle Approach to Equipment Qualification •  Lifecycle Approach to Validation Quality System •  Implementation Strategy •  Interactive Discussion. Attendees discuss lifecycle

approach to process, other applications, positives/negatives, and impediments to implementation throughout day.

PLEASE PARTICIPATE

2

OBJECTIVES •  Validation lifecycle approach basic understanding

–  Terminology –  Validation and qualification –  History and basis –  Stages and activities

•  Documentation for lifecycle approach –  Comprehensive –  New specific expectations

•  Applications according to lifecycle approach –  Processes, Cleaning, EFU –  Validation quality system –  Other quality systems

•  Implementation strategy

QUESTIONS: DOES THIS MAKE SENSE? HOW DO YOU APPROACH VALIDATION?

3

SCHEDULE 8:15 Registration, welcome and opening remarks

8:30 Part I. Introduction, basis, lifecycle stages 10:00 Break – Specific requests / clarifications

10:30 Part II. Documentation 11:50 Morning assessment

12:00 Lunch – Specific requests / clarifications

1:00 Part III. Applications -- Cleaning, EFU, Quality Systems 2:30 Break – Specific requests / clarifications

3:00 Part IV -- Implementation 3:20 Loose ends, Final Q&A, etc. 3:45 Summary 4:00 End

COMMENTS AND QUESTIONS ANY TIME 4

FILES

#1. Overview and history #2. Documentation #3. Cleaning #4. Equipment #5. Validation Quality System #6. Implementation

5

INTRODUCTION, BASIS, LIFECYCLE STAGES

•  History and Development •  Fundamental Concepts •  Consistency with Medical Devices

IS THE LIFECYCLE APPROACH REALLY NEW?

6

PROCESS VALIDATION LIFECYCLE APPROACH OVERVIEW

2004 – Health Canada guidance 2005 – FDA initial presentations 2007 – ICH Q10 2008 – FDA draft guidance 2009 – ICH Q8(R2) 2009 – Health Canada revision 2011 – FDA guidance issued 2012 – EMA draft guidance

7

HISTORY AND DEVELOPMENT – LIFECYCLE APPROACH

PROCESS VALIDATION LIFECYCLE APPROACH IS IT REALLY NEW?

Health Canada introduces lifecycle phases in 2004. FDA lifecycle approach (stages) to process validation

incorporated concepts of ICH Q8, Q9, Q10, QbD, and PAT – presentations starting 2005.

Many concepts previously mentioned in documents issued before 2000. See slides 8-42.

8

HEALTH CANADA -- VALIDATION GUIDELINES FOR PHARMACEUTICAL DOSAGE FORMS (GUI-0029)

5.0 Phases of Validation Phase 1: Pre-Validation Phase Phase 2: Process Validation Phase (Process Qualification Phase Phase 3: Validation Maintenance Phase

6.0 Interpretation Validation protocol Validation Master Plan Installation and Operational Qualification IQ OQ Re-Qualification Process validation Prospective validation Matrix or family approaches to prospective process validation Concurrent validation Retrospective validation Process Re-Validation Change control

9

ICH Q8 (R2) PHARMACEUTICAL DEVELOPMENT Objectives

Harmonized regulatory submissions (CTD) Principles of Quality by Design (QbD) Consistent with Q9 Risk Management Problems addressed Inconsistency between all regions Inconsistent content Inclusion of development information

10

ICH Q8 PHARMACEUTICAL DEVELOPMENT

Drug product development considerations Components: API and excipients Formulation development Overages Physicochemical and biological properties Manufacturing process development Container-closure systems Microbiological attributes Compatibility

11


Key points “Information and knowledge gained from development

studies and manufacturing experience provides scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.”

“Pharmaceutical development section should describe the knowledge…”

“At a minimum, those aspects of drug substances, excipients, … that are critical to product quality should be determined and control strategies justified.”

“…demonstrate a higher degree of understanding of material attributes, manufacturing processes …”

12

ICH Q8 PHARMACEUTICAL DEVELOPMENT Key points

Examination Understanding Evaluation Identification Rationale and justification Others Discussion in submission

13


Implications for Process Validation Process understanding Process development studies are basis for process validation Continuous process verification is alternate to process validation

14

ICH Q9 QUALITY RISK MANAGEMENT Objectives: •  Effective application of risk management •  Consistent science-based decisions

Incorporate risk management into practice Problems addressed: •  Inconsistent risk-management application •  Common understanding

15

ICH Q9 QUALITY RISK MANAGEMENT Principles of quality risk management •  General process: Initiation, assessment, control,

communication, review •  Methodology •  Integration into industry and regulatory

operations •  Methods and tools •  Potential specific applications

16

ICH Q9 QUALITY RISK MANAGEMENT

•  Initiate risk management process •  Risk assessment •  Risk identification •  Risk analysis •  Risk evaluation •  Risk control •  Risk reduction •  Risk acceptance •  Output •  Risk review

17

ICH Q9 QUALITY RISK MANAGEMENT Risk Management Methods and Tools •  Basic methods: Flow charts, process maps, cause and

effect (fishbone) diagrams

•  FMEA / FMECA •  FTA •  HAACP •  HAZOP •  PHA •  Risk ranking and filtering

18

ICH Q9 QUALITY RISK MANAGEMENT

Applications •  Integrated quality management: Documentation,

training, defects, auditing, periodic review, change control, improvements

•  Regulatory operations •  Development: Process knowledge, PAT development •  Facilities, equipment, utilities: Design, qualification,

cleaning, calibration, PM •  Materials management: Material variation •  Production: Validation, in-process testing •  Laboratory control and stability •  Packaging and labeling

19

ICH Q9 QUALITY RISK MANAGEMENT Key points •  Methods of evaluation •  Potential applications – every function, every

activity, entire product lifecycle

20

ICH Q9 QUALITY RISK MANAGEMENT Implications for Process Validation •  Development: Process knowledge •  Materials: Variation, change control •  Equipment: Qualification, cleaning, calibration,

PM, change control •  Production: Validation, sampling, testing,

change control •  Maintenance / monitoring: Testing

21

ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

Objectives •  Global harmonization of quality systems •  Consistency with ICH Q8 and Q9 •  Application throughout product lifecycle

Problems addressed •  Inconsistent application •  Inconsistent definitions of common terms

22


Overview and definitions Management responsibility: Commitment, policy, planning, resources, communication, review, outsourcing

Continual improvement of performance and quality: Lifecycle stages and elements

Continual improvement of quality system: Management, monitoring, outcomes

23


Key points: •  Quality system application throughout product lifecycle •  Pharmaceutical development •  Technology transfer •  Manufacturing •  Product discontinuation •  Product realization, maintain control, improvements •  Enable by knowledge and risk management •  Management responsibility: Commitment, policy,

planning, resources, communication, review, outsourcing oversight

24


Key points: •  Continual improvement •  Product performance / quality monitoring system •  Control strategy, identify variation, problem feedback,

enhance process understanding •  CAPA system •  Enhance process understanding •  Change management system •  Risk management, evaluation, technical justification •  Management review •  Audits, inspections, changes, CAPA, etc.

25


Implications for Process Validation •  Product performance and monitoring •  CAPA system enhances process understanding •  Change management system •  Process improvements

26

ICH Q11 DEVELOMENT AND MANUFACTURE

OF DRUG SUBSTANCES Consistent with ICH Q8, Q9, and Q10 Lifecycle approach CQA, CPP Design space Control of variables Process validation Risk management

27

QUALITY BY DESIGN (QbD) Quality target product profile (QTTP) Critical quality attributes (CQA), critical material attributes

(CMA) Critical process parameters (CPP) Design space Scale-up and technology transfer Identify input variables Input variable control strategy Continuous improvement Other considerations: PAT, risk analysis

28

SUPPORTING DOCUMENTS PROCESS VALIDATION – 1987 GUIDANCE

Assurance of product quality: Quality parts and materials Adequate product and process design Control of the process

In-Process and end-product testing. Basic principles: Quality, safety, and effectiveness designed and built into the product

Quality cannot be inspected or tested in the product Each process step must be controlled to maximize meeting quality and design specifications.

R&D phase: Product definition and characteristics Equipment and process

Equipment: Installation Qualification Process: Performance Qualification Product (devices only): Performance Qualification

Revalidation. Change control Documentation. Proper maintenance of documentation

Reference: FDA Guideline on General Principles of Process Validation. May, 1987 29

VALIDATION – PHARMACEUTICAL DOSAGE FORMS FDA INSPECTION GUIDELINES

Three phases of the validation process: •  Product development •  Design of the validation protocol •  Demonstration runs (validation) – full scale Process validation Documented evidence •  Consistency •  Predetermined specifications Documented evidence includes experiments, data, and results Product Development Reports Control of the physical characteristics of the excipients Particle size testing of multi-source excipients Critical process parameters Development data serves as the foundation for the manufacturing procedure Variables are identified in the development phase Raw materials may vary lot-to-lot

References: FDA Guides to Inspections. Oral Solid Dosage Forms (January 1994), Topical Drug Products (July 1994), Oral Solutions and Suspensions (August 1994)

30

SUPPORTING DOCUMENTS VALIDATION – MEDICAL DEVICES

Planning the Process Validation Study Installation and Operational Qualification Process Performance Qualification Eliminate controllable causes of variation Product Performance Qualification Evaluate routine production process monitoring data for trends

Process operating in a state of control is determined by analyzing day-to-day process control data and finished device test data for conformance with specifications and for variability.

Reference: FDA Medical Device Quality Systems Manual. January 07, 1997

31

SUPPORTING DOCUMENTS PROCESS VALIDATION – API

Critical parameters / attributes identified during development Qualification of equipment and systems: DQ, IQ, OQ, PQ. Process Validation Program Critical process parameters controlled and monitored Non-critical parameters not included in validation Periodic review of validated systems Reference: ICH Q7. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. November, 2000.

32

SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / API

A validated manufacturing process has a high level of scientific assurance that it will reliably product acceptable product. Proof of validation is obtained through rational experimental design and the ongoing evaluation of data, preferably beginning from the process development phase continuing through the commercial production phase. Reference: FDA Section 490.199. CPG 7132c.08. Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. 2004 revision.

33

SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / API

Before commercial distribution: Product and process development Scale-up studies Equipment and system qualification Conformance batches

Identify and control all critical sources of variability Advance manufacturing control technology may eliminate validation lots.

Reference: FDA Section 490.199. CPG 7132c.08. Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. 2004 revision.

34

SUPPORTING DOCUMENTS VALIDATION -- PHARMACEUTICAL CGMPS

Cross-Agency workgroup CDER, CBER, ORA, and CVM. “The CPG clearly signals that a focus on three full-scale production batches would fail to recognize the complete story on validation.” Reference: FDA. Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach. Final Report, September 2004.

35

SUPPORTING DOCUMENTS PROCESS VALIDATION – MEDICAL DEVICES

Process evaluation – Validation or verification Protocol development Processes well thought out What could go wrong Installation Qualification Operational Qualification “Worst case” testing DOE and screening studies Performance Qualification Process repeatability

Attributes for continuous post-validation monitoring and maintenance Eliminate controllable causes of variation. Maintaining a state of validation – Monitor and control Change control Statistical Methods Risk Analysis Methods

Reference: Global Harmonization Task Force (GHTF) Study Group 3. Quality

Management Systems – Process Validation Guidance. January 2004. 36

SUPPORTING DOCUMENTS VALIDATION – INTERNATIONAL

PIC/S PHARMACEUTICAL INSPECTION CONVENTION A series of experiments should be devised to determine the criticality of process parameters / factors Test processes with starting materials on the extremes of specification Monitoring and in-process controls Reference: PIC/S Recommendations on Validation. July 2004.

37

SUPPORTING DOCUMENTS FDA -- QUALITY BY DESIGN (QbD)

Product is designed to meet patient requirements Process is designed to consistently meet product critical quality attributes Impact of starting materials and process parameters on product quality is understood Critical sources of process variability are identified and controlled Process is continually monitored and updated to assure consistent quality over time Reference: FDA. Chi-wan Chen, ISPE, Japan, June, 2006

38

SUPPORTING DOCUMENTS PROCESS ROBUSTNESS (PQRI)

Robust Process: Able to tolerate expected variability of raw materials, operating conditions, process equipment, environmental conditions, and human factors

Development

Maintenance

Process understanding is key to developing a robust process. Reference: Product Quality Research Institute (PQRI). Pharmaceutical Engineering, November-December, 2006

39

SUPPORTING DOCUMENTS ASTM WK 9935 Standard Guide

Continuous Quality Verification (CQV) A Science and Risk-Based Alternative Approach to Traditional Process Validation of Biopharmaceutical and Pharmaceutical Manufacturing Processes CONTINUOUS QUALITY VERIFICATION Process design / Risk assessment / Process understanding Development phase Scale-up phase Commercialization phase Process capability evaluation Continuous process improvement

40

SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)

Processes verified by PAT are not validated All associated PAT equipment and analytical methods are validated Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004

41

SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)

Process Understanding All critical sources of variability are identified and explained. Variability is managed by the process Product quality attributes can be accurately and reliably predicted over the design space Materials used Process parameters Manufacturing Environmental Other conditions Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004

42

TERMINOLOGY: PROCESS VALIDATION

Process Validation – Process Qualification Process Performance Qualification (PPQ)

Qualification Qualification Equipment #1 HVAC

Utilities Equipment #2 Facilities

Computers Equipment #3

Analytical methods validation Cleaning process validation Packaging process validation

Process is validated

43

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

44

FDA PROCESS VALIDATION GUIDANCE

“Before …commercial distribution to consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process…consistently produce …”

Manufacturers should: •  Understand the sources of variation •  Detect the presence and degree of variation •  Understand the impact of variation on the process and product

attributes •  Control the variation in a manner commensurate with risk to process

and product.”

“…to justify commercial distribution of the product.”

“… use ongoing programs to collect and analyze product and process data … state if control of the process.”

45

FDA PROCESS VALIDATION GUIDANCE

Good project management and good archiving to capture scientific knowledge.

Enhance accessibility of information later in lifecycle. Integrated team approach: Process engineering, industrial

pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance.

Scientific studies throughout the product lifecycle planned, documented, and approved.

Greater control over higher-risk attributes. Reevaluate risks throughout product/process lifecycle. Homogeneity with batch and consistency between batches

are goals of process validation.

46

47

STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING)

1. Building and capturing process knowledge and understanding.

2. Establishing a strategy for process control.

Define commercial-scale process Define unit operations and process parameters Identify and understand sources of variability Identify critical process parameters Studies to understand effects of scale Establish mechanisms to control variability •  Process Analytical Technology Designed experiments Lab scale and pilot scale experiments

PROCESS DESIGN (PROCESS UNDERSTANDING)

Objective API and excipient pharmaceutics Quality attributes Risk analysis Process parameters Design of experiments Design space Normal operating range In-process controls

Product development – key inputs to design stage Variability by different component lots, production operators,

environmental conditions, and measurement systems Use risk analysis tools to screen variables Establish a strategy for process control

48

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 49

50

STAGE 2, PROCESS QUALIFICATION (VALIDATION PERFORMANCE)

1.  Design of a facility and qualification of utilities and equipment 2.  Process performance qualification 3.  PPQ protocol 4.  PPQ protocol execution and report

Confirmation at commercial scale of process design information Qualification of equipment, utilities, facilities Performance qualification Conclusion that process consistently produces quality product. Conformance batches •  All support systems, documents, training, personnel, etc. in place •  Target / nominal operating parameters within design space •  Additional testing •  Decision to “release process” for routine commercial

manufacturing

STAGE 2, PROCESS QUALIFICATION Conformance Lots

Procedures Validation plans Protocols Sampling Testing Results Plan to maintain validation

ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING SYSTEMS MUST BE QUALIFIED.

51

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 52

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

53

54

STAGE 3, CONTINUED PROCESS VERIFICATION (VALIDATION MONITORING AND MAINTENANCE)

Activities to assure process remains in validated state Annual Product Review Trend and assess data Study OOS and OOT (Out of Trend) data Timely monitoring of critical operating and performance

parameters. Monitor product characteristics, materials, facilities,

equipment, and SOP changes Establish process history based on ongoing process

performance Improve process Improve control to detect and reduce variability Change control; evaluate impact of change and test as

necessary

CONTINUED PROCESS VERIFICATION

Monitoring Statistical process control Trend analysis Change control Continuous improvement Revalidation Management review

STATISTICIAN RECOMMENDED BY FDA

55

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

56

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 •  PPQ 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

57

PROCESS VALIDATION HISTORY

1978 CGMP includes Validation 1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

58

VALIDATION PHILOSOPHY

•  Validation is confirmation. •  Acceptable (passing) results are expected.

•  Validation is not – R&D – Final stage of development process – Optimization – Fine-tuning – Debugging

59

SUMMARY Lifecycle Approach to Process Validation •  New document •  Compilation of concepts pre-2000 to current •  Three stages identified

–  Understand –  Demonstrate –  Maintain

•  Comprehensive •  Detailed improvements

QUESTIONS: DOES THIS MAKE SENSE? HOW DO YOU APPROACH VALIDATION?

60

61

SUMMARY WHERE WE ARE -- CURRENT PRACTICE

R&D Validation Commercialization

62

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

63

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

64

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.”

65

SUMMARY PROCESS VALIDATION HISTORY

1978 CGMP includes Validation 1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

66

SUMMARY VALIDATION -- FUTURE

Development Performance Maintenance

Stage 1 à Stage 2 à Stage 3

PAUL L. PLUTA, PhD

Editor-in-Chief Journal of Validation Technology Journal of GXP Compliance Advanstar Communications

Adjunct Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA

Pharmaceutical industry experience

Contact: [email protected]

67

1

VALIDATION BOOT CAMP #2 LIFECYCLE APPROACH TO

PHARMACEUTICAL VALIDATION – PRINCIPLES, IMPLEMENTATION, AND PRACTICE

VALIDATION DOCUMENTATION

Paul L. Pluta, PhD

OUTLINE

•  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

2

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

•  FDA auditors often focus on documentation – validation documents often requested ahead of audit

Above sometimes difficult for technical people

3

SCOPE OF VALIDATION DOCUMENTS

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 documents

Lifecycle approach being applied to all validation and qualification (equipment, facilities, cleaning, etc.)

4

VALIDATION DOCUMENTS -- BASICS •  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

5

PROCESS VALIDATION DOCUMENTS •  Validation policy – Reference PV Guidance approach

–  Corporate templates

•  Validation Master Plan (VMP) – Reference PV Guidance approach •  Stage 1 documents – Process Design •  Stage 2 documents – Process Qualification

–  Validation Request / Plan -- Reference PV Guidance –  Validation Protocol(s) – Reference PV Guidance –  Engineering Studies –  Others –  Validation Results / Report – Reference PV Guidance

•  Stage 3 documents – Continued Process Verification –  PQ requirements –  Routine monitoring – Reference PV Guidance

•  Associated validation and qualification -- Reference PV Guidance •  Other associated documents

6

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

7

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

8

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

9

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

10

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 11

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

12

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

13

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

14

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

15

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

16

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

17

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.


18

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

19

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

20

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

21

VALIDATION PLAN OUTLINE •  Introduction •  Technical information •  Validation strategy and testing •  Validation documentation

–  List of required protocols, reports, procedures, etc. –  Administrative benefit

•  References –  List of reports and scientific references (including Stage 1

reports)


22

VALIDATION PLAN INTRODUCTION •  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

23

VALIDATION PLAN

TECHNICAL INFORMATION •  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 24

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

25

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

26

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)

27

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

28

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

29

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

30

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

31

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 32

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

33

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

34

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

35

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

36

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: _____________ _____________ _____________

37

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 38

VALIDATION PROTOCOL OUTLINE Introduction Unit operations Testing with justification Sampling with justification Sampling and data pages Data treatment Acceptance criteria with justification


39

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

40

VALIDATION PROTOCOL -- PROBLEMS How many lots should be tested?

Consider impact of change. Consider product. Consider process. Consider risk.

ABOVE ADDRESSED IN VALIDATION PLAN

41

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

42

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


43

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

44

VALIDATION RESULTS / REPORT -- PROBLEMS

Protocol requires BME samples for potency. Acceptance criteria: 95-105% B = 95% M = 100% E = 105% All results pass Conclusion?

POST PQ MONITORING?

45

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?

46

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

47

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.”


48

STAGE 3 DOCUMENTS – CONTINUED PROCESS VERIFICATION

POST PQ DOCUMENTS

TYPES OF DOCUMENTS •  Post PQ requirements – work required based on PQ

results •  Ongoing monitoring – routine process monitoring

49

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

50

STAGE 3 DOCUMENT RESPONSIBILITIES ONGOING MONITORING

RESPONSIBILITY Monitoring results (Annual Product Review) QA Change control validation results/reports and monitoring Validation Non-conformances Production Deviations Production Process monitoring (control charts) QA Process changes Production Improvement projects instituted Validation Other changes ----- Record of management review QA

ANNUAL REVIEW NOT GOOD ENOUGH, ESPECIALLY FOR HIGH RISK PROCESSES

51

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.

52

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

53

EQUIPMENT, FACILITIES, UTILTIES, ETC. QUALIFICATION

•  IQ, OQ, PQ •  ASTM E2500 •  Same approach as with processes •  Same philosophy •  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.”

54

ANALYTICAL

•  Analytical methods validated •  Analytical equipment qualified

•  QbD for analytical methods evolving

55

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

56

DOCUMENT OUTLINES / 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

57

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

58

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 59

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

60

PROCESS ANALYTICAL TECHNOLOGY (PAT)

Processes verified by PAT are not validated

All associated PAT equipment are validated

All associated PAT control systems are validated

All new analytical equipment is validated

All new analytical methods are validated “WHEN PAT IS IN PLACE, WILL THERE BE ANY MORE VALIDATION?”

61

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

62

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

63

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

64

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

65

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

66

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

67

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

68

SUMMARY – STAGE 3 DOCUMENTS CONTINUED PROCESS VERIFICATION

•  Specialized post-PQ requirements •  Routine monitoring

– Risk based

69

SUMMARY – ASSOCIATED DOCUMENTS

•  Equipment, facilities, utilities, etc. qualification •  Analytical methods and equipment •  Training records •  Personnel qualification •  Environmental monitoring

70

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

71

PAUL L. PLUTA, PhD





72

1

VALIDATION BOOT CAMP #3

LIFECYCLE APPROACH TO PHARMACEUTICAL VALIDATION –

PRINCIPLES, IMPLEMENTATION, AND PRACTICE

LIFECYCLE APPROACH TO CLEANING VALIDATION

Paul L. Pluta, PhD

MANUAL CLEANING -- Do you really know what is happening?

Q to operator: “Why is there so much foam in the tub?” A: “I put in extra soap because the equipment was really dirty.”

Q to operator: “Why is there powder on the (clean) equipment?” A: “No problem -- We’ll get the residue when we set up.”

Q to operator: “Why don’t you follow the cleaning procedure?” A: “The cleaning procedure really doesn’t work.”

ABOVE NOT ACCEPTABLE – TRAINING NEEDED

2


Q to operator: “Why is there powder on the clean equipment?” A: “It’s clean enough.” Q to QA (equipment inspection person): “Did you approve that the equipment

is clean?” A: “It’s clean enough.” Q to management: “Do you know that your equipment is not clean?” A: “It’s clean enough.”

Q to operator: “You cleaned the gasket with pure soap – this is not the procedure? Also it is dangerous – these are corrosive chemicals.”

A: “That is the only way to get it clean.” Q: “So why don’t you tell someone to change the procedure?” A: “We don’t have time.”


3


Q to management: “Did you finish cleaning the equipment? We are here to swab for cleaning validation.”

A (very proudly): “We cleaned the equipment three times so that we won’t have any problems.”

Q to validation person: “Did you know that the manufacturing people

always clean the equipment multiple times before it is swabbed?” A: “Sure, we knew. Q: “Why didn’t you stop this?” A: “These people are our friends. We have to work with these

people.”


4

OUTLINE Lifecycle Approach Applied to Cleaning Validation Stage 1 Activities •  Cleaning Method Development •  Analytical Method Development •  Site equipment Stage 2 Activities •  Cleaning documentation •  Validation conformance lots Stage 3 Activities •  Maintaining Validation •  Change Control •  Management review

5

OBJECTIVES 1.  Application of lifecycle approach to cleaning

validation 2.  Cleaning lifecycle stage details

•  Process development and understanding •  Process qualification •  Maintaining the validated state

3.  Cleaning validation problems •  Global experiences

6

Lifecycle Approach to Cleaning Validation – Value? Does this make sense?

•  Cleaning is a process

•  Validation lifecycle concepts being applied to equipment, facilities, utilities, computers, etc., by validation and technical experts

•  Who can argue with understanding, performing, and maintaining the validated state?

•  Consistent with QbD and ICH approaches

•  Lifecycle approach (i.e., understanding, performing, maintaining) vs. traditional approach – Which would you rather present to an auditor?

7

WHAT IS THE CLEANING PROCESS? Cleaning Process Performance Qualification (PPQ)

Automated CIP System

Process steps Qualification 1. Residue on equipment Equipment 2. Water procedure Purified Water 3. Cleaning agent procedure Computer / software 4. Water procedure Compressed air 5. Purified Water procedure Conductivity analysis 6. Dry TOC analysis

Equipment is clean -- Process is validated

Process parameters à Quality attributes

8

WHAT IS THE CLEANING PROCESS? Cleaning Process Performance Qualification (PPQ)

Manual Cleaning Process steps Qualification 1. Residue on equipment Personnel 2.  Water rinse Purified Water 3. Scrub with cleaning agent Compressed air 4. Water rinse 5. Scrub 6.  Water rinse 7.  Purified Water rinse 8. Dry

Equipment is clean -- Process is validated

Process parameters à Quality attributes 9

CLEANING VALIDATION OVERVIEW 1990s àpresent

1.  Defined cleaning procedure (SOP) – basis? 2.  Product A batch does not contaminate subsequent

Product B batch 3.  Acceptance limit calculated 4.  Assume uniform contamination of all equipment 5.  Three conformance lots = Validated cleaning procedure 6.  Validated analytical method (original API) 7.  Worst-case matrix approach

One-time event

10

FDA PROCESS VALIDATION GUIDANCE LIFECYCLE APPROACH TRANSITION

APPPLICATION TO CLEANING VALIDATION

Pre Lifecycle

Cleaning development (?) à PQ à change control ________________________

Lifecycle Approach

Development à PQ à Maintenance

EXPANDED SCOPE OF VALIDATION INCREASED SPECIFIC STAGE REQUIREMENTS

11

LIFECYCLE APPROACH TO CLEANING VALIDATION

Scientific and technical approach Design and development

–  Residue + cleaning agent + cleaning procedure à Clean equipment

Performance demonstration Monitoring and maintenance Rationale, responsibility, and accountability Future process improvements

Not the following: –  Standard site method (no basis or rationale) –  Personnel driven (no control) –  “Do whatever it takes” (high variation) –  SOP (no accountability) –  Validation (?) – One-time event.

12

STAGE 1, PROCESS DESIGN (PROCESS UNDERSTANDING) APPLICATION TO CLEANING

FDA Guidance Topics 1. Building and capturing process knowledge and understanding. 2. Establishing a strategy for process control.

Application to Cleaning Understand residue chemistry (solubility, stability) Determine cleaning agent based on residue chemistry Determine cleaning process •  Identify sources of variability •  Establish methods to control variability

–  Process Analytical Technology Rational analytical method and supporting work Characterization of equipment to be cleaned and supporting work Trained sampling personnel

DOCUMENT ALL OF THE ABOVE

13

DEVELOPMENT (STAGE 1) CLEANING PROCESS DEVELOPMENT

•  Physical and chemical properties of the residue is basis for cleaning process

•  Considerations for determination of most difficult-to-clean residue •  Residue solubility and stability in determining worst-case soils •  Residue chemistry critical for analytical method •  Cleaning agent chemistry consistent with residue chemistry •  Cleaning process chemistry and engineering and consistent with

residue and cleaning agent.

RESIDUE CHEMISTRY –  BASIS FOR CLEANING PROGRAM –  BASIS FOR ANALYICAL METHOD

14

RESIDUE PROPERTIES -- BASIS FOR CLEANING PROCESS Case study: Antibiotic suspension containing insoluble API (base)

Original cleaning method: Water, PurW, dry •  No documented cleaning validation for many years •  Unknown peaks on original cleaning validation attempts •  API insoluble

Second method: Alkaline soap wash, water, PurW, dry •  Unknown peaks again •  API insoluble

Final method: Acid wash, alkaline soap wash, water, PurW, dry •  No residues •  Unknown peaks determined to be degradants and flavors. •  API dissolves (acid-base neutralization)

Consider active drug and other residue chemistry in development of cleaning process

15

DETERMINATION OF MOST DIFFICULT TO CLEAN RESIDUE

BASIS FOR CLEANING PROGRAM

Water solubility – USP Tables •  Is this adequate? NO! pH effect – API with ionizable groups? Solubility in cleaning agent? •  Determine solubility at range pH 1-12 •  Understand solubility at pH of cleaning liquid •  Understand solubility in cleaning agent liquid

16

pH SOLUBILITY PROFILE, pH 1-12

Solubility mg/ml

Drug A Drug B

pH 1 7 12

17

RESIDUE SOLUBILITY AND STABILITY FOR DETERMINING WORST-CASE SOILS

Solubility considerations •  Hydrophilic and hydrophobic molecules •  Ionization – Effect of pH •  Effect of temperature •  Surface active molecules •  Liquid and semisolid product vehicle polarity

Stability considerations •  Hydrolysis, oxidation, photolysis, physical changes

What residue is really present? Consider chemistry of residues

18

CLEANING MATRIX Determine Worst-Case Soil

SOLUBILITY (mg / ml) pH 1 Water pH 12 Alkaline

Cleaning Agent Drug A 25 25 25 25

Drug B 15 15 15 15

Drug C 5 5 150 250

Drug D 150 10 10 50

Drug E 125 10 100 250

Consider acid cleaning agent for drugs D and E

19

WORST CASE CLEANING

Determination of worst-case cleaning based on API toxicity, worst-case dose, etc. – Standard calculation

Cleaning procedure may be based on excipients having greatest effect on cleaning – Hydrophilic polymers – Dyes – Hydrophobic vehicles

20

BIOTECH CLEANING CHEMISTRY -- API Protein molecules degrade in alkaline conditions Degradation rate is milder in acidic conditions Degradation rate increases with temperature API residues typically consist of protein fragments and

aggregates Analytical method: Non-specific analysis Reference: Kendrick, Canhuto, and Kreuze. Analysis of

Degradation Products of Biopharmaceutical API Caused by Cleaning Agents and Temperature. Journal of Validation Technology, V15, #3, Summer 2009.

21

BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUM

Medium Composition •  Acids or bases •  Monovalent salts •  Polyvalent salts •  Amino acids •  Proteins (polypeptides) •  Carbohydrates •  Aqueous soluble organics •  Non-aqueous soluble organics

Consider medium composition at end of cycle.

Reference: Azadan and Canhoto. A Scientific Approach to the Selection of Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing. Cleaning and Cleaning Validation, Volume 1. 2011.

22

CLEANING CHEMISTRY MECHANISMS

•  Wetting •  Emulsification •  Dispersion •  Solubility •  Chelation •  Oxidation •  Hydrolysis

23

CLEANING AGENT OPTIONS

•  Water •  Commodity alkalis and acids •  Organic solvents •  Surfactants

–  Anionic –  Cationic –  Amphoteric –  Nonionic

•  Formulated detergents

24

COMPONENTS OF FORMULATED DETERGENTS

•  Surfactants •  Alkalis •  Acids •  Sequestrants / chelants •  Dispersants / anti-redeposition agents •  Corrosion inhibitors •  Oxidizing agents •  Enzymes •  Buffers / builders •  Preservatives

MUST HAVE CONTROL OF CLEANING AGENT HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER

25

CLEANING ENGINEERING Factors affecting cleaning •  Soil residue

–  Soil levels, soil condition, hold times, soil mixing, water quality and residue,

•  Cleaner and parameters (TACT) –  Time, Action, Concentration, Temperature –  Others

•  Surface and equipment design

26

CLEANING PROCESS SOURCES OF VARIATION

•  Cleaning agent preparation – must be exact •  Automated cleaning vs. manual cleaning •  Manual cleaning process variation •  Human physical strength variation •  “Cleaning” between same-product batches in

campaign – residue level build-up •  Campaign length – residue level build-up •  Time to initiate cleaning (dirty hold time) •  Residue chemical and physical changes

27

EQUIPMENT TO BE CLEANED Cleaning-related qualification •  Product-contact materials •  Compatibility with cleaning agents •  Surface areas – need for residue calculations •  Equipment equivalence •  Most-difficult-to-clean locations on equipment -- Highest

risk locations for sampling •  Non-uniform contamination equipment •  Non-uniform contamination sampling locations •  Sampling methods (swab / rinse)

Part of IQ/OQ/PQ for manufacturing equipment

28

PROCEDURE TO DETERMINE SAMPLING LOCATIONS

Specific documented procedure recommended •  Equipment technical evaluation •  Observation of equipment after processing •  Equipment disassembly review •  Cleaning procedure review •  Equipment evaluation review •  Operator interviews

SOP describing above Documentation of above for equipment sampling

29

TIME TO INITIATE CLEANING “DIRTY HOLD TIME”

1. Make Product A 2. Clean 3.  Make Product B How long between end of #1 and start #2? Is residue same? Does residue change? What can happen to the residue? •  Wet and dry processes

•  Chemical changes (hydrolysis, oxidation, etc.)

•  Physical changes

30

CAMPAIGN LENGTH

How many lots in manufacturing campaign before cleaning must be done?

What about “cleaning” between batches? •  Equipment should be visually clean •  Terminology: “Between lot procedure” •  How much residue “build-up?”

DO NOT IDENTIFY AS “BETWEEN LOT CLEANING”

31

MANUAL CLEANING

•  Manual cleaning procedures should be monitored and maintained with increased scrutiny compared to non-manual procedures

•  More frequent training of cleaning personnel •  Increased supervision •  Periodic (annual?) revalidation batches

Manual cleaning is high risk

32

ANALYTICAL METHOD DEVELOPMENT

Early stage 1 (development) analysis – validation not required but must be sound

Validated method when used for Stage 2 cleaning validation and post-validation testing (change control)

All methods and data (including stage 1) subject to

regulatory audit

33


Analytical method must measure actual residue – what residue is actually present on equipment surfaces?

•  Small molecules –  API –  API degraded – specific or non-specific method

•  Biotech molecules –  API degraded – non-specific method

UNDERSTAND RESIDUE CHEMISTRY

34


Cleaning agent residue •  Analytical method to determine residual cleaning

agent. •  Information from cleaning agent vendor

35

ANALYTICAL METHOD DEVELOPMENT Recovery studies Can sampling procedure adequately recover residue

from equipment surfaces? •  Product contact materials •  High % of total surface area •  Obtain representative coupons from equipment

fabricators •  High (e.g., >80%) acceptance criteria •  Factor may be used in calculation

–  Multiple approaches –  Factor every calculation?

All sampled surfaces must have recovery data

36

SAMPLING Sampling methods •  Sampling (swab) critical activity •  Training program •  Trained sampling personnel

–  Demonstrated acceptable performance

•  Documented training and retraining •  Worst case compounds / procedures in training

–  Volatile solvents (importance of rapid technique)

•  Worst case sampling equipment –  Extension poles

•  Retraining considerations –  Who does sampling? Personnel skills

37

SAMPLING TRAINING

Sampling is extremely critical to cleaning validation program

Inadequate sampling = false negative –  Insufficient pressure on surface – Swab solvent evaporation –  Insufficient area sampled

Auditors routinely ask for sampling program training methods and training records

38

STAGE 2, PROCESS QUALIFICATION – (VALIDATION PERFORMANCE)

APPLICATION TO CLEANING 1.  Design of a facility and qualification of utilities and equipment 2.  Process performance qualification 3.  PPQ protocol 4.  PPQ protocol execution and report

Qualification of equipment, utilities, facilities •  Cleaning equipment (CIP) Process Performance Qualification (PPQ) – commercial scale Conclusion that process consistently produces clean equipment Conformance batches •  All support systems, documents, training, personnel, etc. in place •  Target / nominal operating parameters within design space •  Additional testing (swab / rinse) •  Decision to “release cleaning process” for routine commercial use •  Post validation monitoring plan – Based on risk

–  Drug residue properties –  Manual or CIP

39

CLEANING EQUIPMENT

CIP system must be qualified (IQ/OQ/PQ or ASTM E2500)

Riboflavin (or other) coverage testing Temperature controls Flow rates, etc. PAT inline systems

–  Drug disappearance – spectrophotometry, other methods –  Cleaning agent rinse -- conductivity

40

CLEANING PROCEDURE DOCUMENTATION (Cleaning Batch Record)

SOP •  Fill tank half full •  Add half scoop of soap •  Scrub as needed •  Rinse until clean •  Re-scrub and re-rinse if needed

CLEANING PROCEDURE RECORD •  Fill tank with 500 L water. Sign/date __________ •  Add 20.0 kg cleaning agent. Sign/date __________ •  Disassemble Part A. Steps 1,2,3,4,5 •  Scrub for 20 minutes. Sign/date __________ •  Disassemble Part B. Steps 1,2,3,4,5 •  Soak Part B in cleaning liquid for 10 minutes. Sign/date __________ •  Rinse Part A and Part B with 50 L water. Sign/date __________ •  Rinse with 50 L Purified Water. Sign/date __________ •  Dry with compressed air

41

CLEANING PROCEDURE RECORD •  Fill tank with 500 L water. Sign/date __________ •  Add 20.0 kg cleaning agent. Sign/date __________ •  Disassemble Part A. Steps 1,2,3,4,5 •  Scrub for 20 minutes. Sign/date __________ •  Disassemble Part B. Steps 1,2,3,4,5 •  Soak Part B in cleaning liquid for 10 minutes. Sign/date __________ •  Rinse Part A and Part B with 50 L water. Sign/date __________ •  Rinse with 50 L Purified Water. Sign/date __________ •  Dry with compressed air

KEY POINTS Exact concentration of cleaning agent liquid Signature on quantitative steps Grouping non-quantitative steps (e.g., disassembly)

42

VALIDATION REQUEST / PLAN Initiates cleaning validation •  New cleaning validation or change control process

improvements •  Strategy and approach •  Scientific and technical basis •  Specify required protocols and other work to accomplish

validation •  Risk-based •  References: Stage 1 Design / development reports

43

VALIDATION PROTOCOL

Cleaning validation protocols and other work as specified in Validation Plan – Risk based

Include sampling pages indicating worst case sampling locations.

Specify acceptance criteria

44

VALIDATION RESULTS / REPORT

Test results as required in validation protocol. •  Discussion. Consistency with Stage 1

development work. •  Clear statement the cleaning process is (or is

not) validated. •  Recommendations for Stage 3 monitoring and

maintenance. –  Additional limited testing based on data and risk –  Routine monitoring based on risk

45

46

STAGE 3, CONTINUED PROCESS VERIFICATION (VALIDATION MONITORING AND MAINTENANCE)

APPLICATION TO CLEANING Activities to assure process remains in validated state Change control -- evaluate impact of change and validate (test) as

necessary Trend and assess data

–  PAT rinse times –  Conductivity data

Study OOS and OOT (Out of Trend) data Improve process Improve control to detect and reduce variability Cleaning non-conformances and deviations Re-validation – definition: Actual batch or “paper” •  Is re-testing necessary? •  When should re-testing be considered? Periodic Management Review •  Documentation reviewed by management •  Documented review

POST-VALIDATION MONITORING AND MAINTENANCE

1. Stage 2 specific requirements – Additional testing based on actual data – Ex: One location has high (acceptable result)

2. Routine monitoring and maintenance – Risk based

3. Change control program

CHANGE CONTROL MOST IMPORTANT AND DIFFICULT TO ADMINISTER

PERSONNEL MUST RECOGNIZE “CHANGE” 47

POST-VALIDATION MONITORING AND MAINTENANCE

Residue toxicity risk •  Residue that can be visually seen

– Room lighting must be adequate – Provide additional lighting if necessary

•  Residue that cannot be visually seen – Swab after each batch?

CONSIDER PATIENT RISK AND COMPANY RISK

48

CHANGE CONTROL

•  All associated personnel must be aware of change control

•  Change control system developed •  Process improvements expected based on

ongoing experience •  Process improvements should be evaluated by

technical people (i.e., Stage 1) •  Stage 2 PPQ conducted when appropriate

based on Stage 1 technical evaluation.

49

POST-VALIDATION MONITORING

Periodic review of cleaning performance •  Deviations •  Non-conformances (dirty equipment) •  Re-cleaning •  Change control •  Other monitoring (CIP data) •  Product APR data •  Statistical Process Control data treatment •  Management review -- documented

50

CLEANING DOCUMENTATION •  High level documents •  Specific cleaning validation documents

–  Design/Development, performance, monitoring/maintenance

•  Specific cleaning validation support documents (equipment qualifications)

•  Cleaning validation approach documents (Worst case matrix, calculations, sampling locations, etc.)

•  Production documents (Cleaning Procedure Records) –  Production cleaning policies

•  Management review documents •  Associated documents

–  Personnel training in direct and associated areas –  HR records

51

CLEANING DOCUMENTATION High level documents •  Corporate policy •  VMP (Cleaning VMP) Stage 1 documents •  Cleaning process development report •  Analytical method development report •  Supporting equipment documents (materials, surface areas, equivalent equipment,

sampling, etc.) Stage 2 documents •  Validation PPQ request, protocol, results •  Cleaning equipment qualification •  Cleaning procedure record Stage 3 documents •  Change control documents •  Process monitoring •  Management review

CONSISTENT LIFECYCLE STRATEGY AND APPROACH

52

SUMMARY STAGE 1 -- DESIGN AND DEVELOPMENT

INCLUDING COMMON PROBLEMS

Understanding cleaning process •  Residue properties

–  Residue degradation •  Rational cleaning process based on residue •  Scientific and technical cleaning matrix Understand and control sources of variation •  Dirty hold time •  Campaigns Rational analytical method based on residue properties Equipment to be cleaned characterized •  Worst case sampling

53

SUMMARY – EQUIPMENT TO BE CLEANED INCLUDING COMMON PROBLEMS

•  Equipment characterization •  Residue calculations •  Materials of product contact •  Surface areas •  Worst-case areas for sampling based on risk

–  Non-uniform contamination

•  Equivalent equipment

54

SUMMARY – ANALYTICAL INCLUDING COMMON PROBLEMS

Understand residue •  Solubility and stability •  Validated analytical method for actual residue

–  Specific or non-specific analytical methods

•  API and cleaning agent residue

Recovery studies from product contact materials •  API and cleaning agent

Swab / rinse testing on equipment •  Most difficult to clean sampling sites •  Use of auxiliary sampling equipment (extension pole)

Swab / rinse training of sampling personnel

55

SUMMARY STAGE 2 – PERFORMANCE

INCLUDING COMMON PROBLEMS

Cleaning Process Conformance Lots Cleaning equipment qualified Cleaning procedure specified (Not SOP) Cleaning documentation

–  Request –  Protocol –  Results / Report

Manual cleaning – high risk

56

SUMMARY STAGE 3 -- MAINTAINING VALIDATION

Change control -- evaluate impact of change and validate (test) as necessary

Improve process Improve control to detect and reduce

variability Cleaning non-conformances and deviations Periodic Management Review

57

PAUL L. PLUTA, PhD





58

VALIDATION BOOT CAMP #4

LIFECYCLE APPROACH TO PHARMACEUTICAL VALIDATION –

PRINCIPLES, IMPLEMENTATION, AND PRACTICE

EQUIPMENT QUALIFICATION –

LIFECYCLE APPROACH

Paul L. Pluta, PhD

1

OUTLINE

I.  Equipment Qualification – Lifecycle Approach •  Qualification approaches •  Documentation hierarchy •  Document outlines

II.  Documentation problems

2

EQUIPMENT QUALIFICATION – LIFECYCLE APPROACH KEY POINTS SUMMARY

1. Equipment qualification is a vital part of validation. 2. New FDA process validation guidelines has changed expectations

for equipment qualification. 3. Approach equipment qualification by lifecycle approach stages

•  Stage 1. Design / understand •  Stage 2. Demonstrate •  Stage 3. Monitor / maintain.

4. Equipment qualification must not be considered a one-time event. 5. Key validation principles identified -- Confirmation, risk analysis,

documentation, others. 6. Qualification options: IO/OQ/PQ or ASTM E2500. 7. Model documents recommended. 8. Documentation is vital: Consistency, content, good documentation

practices, and document retrieval.

3

INTRODUCTION -- VALIDATION AND QUALIFICATION PROCESS VALIDATION – PROCESS QUALIFICATION

PROCESS PERFORMANCE QUALIFICATION Qualification Qualification Equipment #1 HVAC

Utilities Equipment #2 Facilities


Analytical methods validation Cleaning process validation Packaging process validation

PROCESS IS VALIDATED

ALL SUPPORTING EQUIPMENT, FACILITIES, UTILITIES, CONTROL SYSTEMS, ANALYTICAL, ETC. MUST BE QUALIFIED.

Unit Opera.on

#1 #2 #3

4

FDA PROCESS VALIDATION GUIDANCE 2011

Validation History •  1978 – GMP includes Validation •  1987 – First Validation Guidance

o  Equipment IQ

•  2000 à New approaches / documents / presentations •  2008 – New Process Validation draft guidance

o  Equipment and analytical included

•  2011 – New Process Validation Guidance issued

FDA EXPECTATIONS FOR VALIDATION / QUALIFICATION

CONSIDER POTENTIAL APPLICATION TO EQUIPMENT SAME AUDITORS – PHARMA, DEVICES, PROCESSES, EQUIPMENT

5

Definition FDA – 2011 Definition: Collection and evaluation of data, from the

process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

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 production

1987 VALIDATION -- FOCUS IS PRIMARILY STAGE 2. 2011 VALIDATION -- LIFECYCLE APPROACH

6

Medical Device Validation

Comparison to Pharma

•  Device IQ = Pharma IQ / OQ / PQ •  Device OQ = Product R&D (Stage 1 development) •  Device PQ = Pharma PV

Reference: Device GHTF

7

VALIDATION / QUALIFICATION PRINCIPLES •  Validation is confirmation •  Risk analysis determines everything •  Science and technical basis for design and development •  Lifecycle approach

–  Understand, demonstrate, monitor and maintain

•  Sampling and testing -- rationale and justification •  Pre-approved acceptance criteria •  Data-based judgments •  Documentation of above •  Document retrieval •  Maintain validation continuously •  Change control

APPLICATION TO EQUIPMENT QUALIFICATION

8

VALIDATION IS CONFIRMATION

Successful validation is expected. Do not initiate validation unless success is

expected. Validation is not the final step in development,

installation, optimization, fine-tuning, or other development activities.

Amendments, mistakes, failures scope changes, etc. all have negative implications.

9

RISK MANAGEMENT

Risk defines everything. Test only critical equipment parameters in

validation. Risk level determines level of testing. Test non-critical equipment parameters during

commissioning. Document risk assessment.

10

EQUIPMENT QUALIFICATION APPLICATIONS Lifecycle approach Risk analysis Science and technical basis for design and development Validation confirms equipment design and development Sampling and testing -- rationale and justification – based on risk Pre-approved acceptance criteria Data-based judgments Document everything – Retrieve documents Maintain validation continuously throughout lifecycle -- based on risk •  Preventive maintenance •  Calibration •  Change control

DOES THIS MAKE SENSE?

11

EQUIPMENT QUALIFICATION Qualification approaches •  DQ / IQ / OQ / PQ (IQ for medical devices) •  ASTM E2500

Documentation hierarchy

Document outlines •  Model documents

12

QUALIFICATION APPROACHES DQ / IQ / OQ / PQ

Traditional qualification DQ – Multiple functions and applications

•  Purchasing document •  Equipment design document

Documents may be combined •  IQ, OQ, PQ •  IOQ, PQ •  IOQ

13

DQ / IQ / OQ / PQ CONTENT DQ – Design Qualification •  Equipment description •  Equipment design requirements •  Purchase / design specific requirements

IQ – Installation Qualification •  Components •  Drawings •  Operating manuals •  Product-contact material composition •  Surface area calculations (product contact equipment) •  Calibration •  Preventive maintenance •  Equivalence to other equipment •  Most difficult to clean locations •  Other

OQ – Operation Qualification •  Worst case / range parameter operation

PQ – Performance Qualification •  Integrated parameter operation with representative materials

14

ISPE EQUIPMENT VALIDATION User Requirements PQ Specification Functional Specification OQ Design Specifications IQ

System Build

15 15

EQUIPMENT QUALIFICATION LIFECYCLE 1.  Capital request with design (DQ) 2.  Equipment build 3.  Factory Acceptance Test (FAT) 4.  Site Acceptance Test (SAT) 5.  Commissioning 6.  IQ 7.  OQ 8.  PQ 9.  Preventive Maintenance and Calibration 10.  Change control 11.  Decommissioning

CONSISTENT WITH STAGE APPROACH DOCUMENTATION ON ALL

16 16

EQUIPMENT QUALIFICATION

Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Test and document critical items only. FAT, SAT, and Commissioning Test and document non-critical items.

17

ASTM E2500. Standard Guide for Specifications, Design, and Verification of Pharmaceutical and Biopharmaceutical

Manufacturing Systems and Equipment

•  Design Input •  Design Review •  Risk Mitigation •  Critical Control Parameters Define •  Acceptance Criteria •  Verification Testing •  Performance Testing •  GEP scope and QA scope have clear boundary •  Process, Product Quality and Patient Safety •  Quality by Design, Design Space and Continuous Improvement

18

ASTM E2500

19

ASTM E2500

20

TRADITIONAL QUALIFICATION VS. E2500 Focused objective Comprehensive approach Includes risk analysis Critical parameters Less paperwork

•  Same content

21

DOCUMENTATION HIERARCHY Company policy Validation Master Plan DQ Design and development SAT / FAC Commissioning Validation / Qualification Request / Plan IQ /OQ /PQ Protocol / Results / Report Post Validation Monitoring / Maintenance Change control Associated technical document (e.g., manuals, etc.) Associated documents (e.g., training, HR) Management Review

CONSISTENT LIFECYCLE APPROACH

22

DOCUMENT OUTLINES

Validation Initiation Validation Plan IQ – Protocol and Results OQ – Protocol and Results PQ – Protocol and Results IQ/OQ/PQ Report

23

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


24

QUALIFCATION PLAN OUTLINE Introduction Technical information Qualification strategy and testing Qualification documentation

•  List of required protocols, reports, procedures, etc. •  Administrative benefit

References •  List of reports and scientific references (including Stage 1

reports)


25

PROTOCOL OUTLINE Introduction Equipment Testing with justification Sampling with justification Sampling and data pages Data treatment Acceptance criteria with justification


26

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 / qualified.” Post-validation plan

WRITE DISCUSSION SECTION FIRST – MOST IMPORTANT SECTION


27

QUALIFICATION REPORT

Combined IQ / OQ / PQ results Helpful in audit – total summary “Cut and paste” results and conclusions sections Consistency and completeness important

28

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 •  Validation statement

–  “Results indicate that ______ is validated / qualified.”


29

TEMPLATES vs. MODEL DOCUMENTS

Recommendation: 1. Prepare “perfect” document – make available as

needed 2. Assemble multiple documents from different

applications 3. Upgrade as needed 4. Documents available to technical writers 5. Validation Review Board maintain standards.

30

DOCUMENTATION PROBLEMS

•  Qualification statement: “________ is qualfied.” •  Documentation content

o  Scientific and technical o  Compliance with policies/procedures/regulations

•  Errors, mistakes, and omissions o  Sampling and data pages o  Equipment not ready to be qualified

•  Original data consistency o  Documentation practices – original data o  Missing results o  Retrieval

•  Documentation rules •  Others

31

DOCUMENTATION – THREE SIMPLE RULES

1.  Clear, complete, concise, consistent 2.  “Stand-alone” documents – written for the

reader 3.  Short sentences and simple words

32

SUMMARY

1. Equipment qualification is a vital part of validation. 2. New FDA process validation guidelines has changed expectations for

equipment qualification. 3. Approach equipment qualification by lifecycle approach stages

•  Stage 1. Design / understand •  Stage 2. Demonstrate •  Stage 3. Monitor / maintain.

4. Equipment qualification must not be considered a one-time event. 5. Key validation principles identified -- Confirmation, risk analysis,

documentation, others. 6. Qualification options: IO/OQ/PQ or ASTM E2500 . 7. Documentation is vital: Consistency, content, good documentation

practices, and document retrieval. 8.  Implementation strategies: Management support and document content. 9.  Lifecycle change = Reorientation – Not a significant change.

33

PAUL L. PLUTA, PhD

Editor-‐in-‐Chief Journal of Valida-on Technology Journal of GXP Compliance Advanstar Communica.ons


PharmaceuJcal industry experience


34

VALIDATION BOOT CAMP #5 LIFECYCLE APPROACH TO PROCESS VALIDATION – PRINCIPLES, IMPLEMENTATION, AND PRACTICE

QUALITY BY DESIGN / LIFECYCLE APPROACH to the

VALIDATION QUALITY SYSTEM (Quality System by Design -‐-‐ QSbD)

Paul L. Pluta, PhD

1

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 PARTICIPATE 2

PRESENTATION OBJECTIVES

1. Applica2on of QbD and lifecycle principles to the Valida2on Quality System 2. Design of the Valida2on Quality System 3. Objec2ves of Valida2on Quality System 4. Quality AFributes of Valida2on Quality System 5. Parameters affec2ng aFributes 6. Control of variables affec2ng quality system performance 7. Risk management 8. Monitoring performance à Con2nuous improvements

VALIDATION: VALIDATED “PRODUCT” and INFRASTRUCTURE

AUDIT QUESTIONS WHAT IS YOUR APPROACH TO VALIDATION?

HOW DO YOU MANAGE THE VALIDATION FUNCTION?

3

DEFINITIONS AND OBJECTIVES

Quality by Design (QbD) Validated processes and equipment Process of valida2on -‐-‐ Lifecycle approach to process valida2on

QbD consistency with process valida2on -‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐

Valida2on Quality System QbD / Lifecycle approach to the valida2on quality system

Risk management applica2ons

4

QUALITY BY DESIGN (QbD) Development Focus

•  Target product profile (TPP) and cri2cal quality aFributes (CQA)

•  Drug substance and excipient proper2es •  Formula2on design and development •  Manufacturing process design and development •  Iden2fica2on of cri2cal process parameters (CPP) and cri2cal

material aFributes (CMA) •  Risk assessment and design space •  Scale up, iden2fica2on of variables, and control strategy

Red = Original QbD

5

VALIDATED PROCESSES AND EQUIPMENT Process ValidaRon – Process QualificaRon Process Performance QualificaRon (PPQ)

QualificaRon QualificaRon Equipment #1 HVAC

U2li2es Equipment #2 Facili2es


Analy2cal methods valida2on Cleaning process valida2on Packaging process valida2on

Process is validated

6

Unit Op #1

Unit Op #2

Unit Op #3

PROCESS OF VALIDATION – LIFECYCLE APPROACH TO PROCESS VALIDATION

DefiniRon: Collec2on and evalua2on of data, from the process design stage throughout commercial produc2on, which establishes scien2fic evidence that a process is capable of consistently delivering quality products. Process validaRon involves a series of acRviRes over the lifecycle of the product and process.

Three stages of acRviRes: •  Stage 1 – Process Design – Development and scale-‐up ac2vi2es – QbD approach •  Stage 2 – Process Qualifica2on – Demonstrate reproducible manufacturing

through conformance lots •  Stage 3 – Con2nued Process Verifica2on – Rou2ne manufacturing and monitoring

of performance.

STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM

7

VALIDATION HISTORY

1978 -‐-‐ CGMP includes Valida2on

1987 -‐-‐ Development -‐-‐ VALIDATION – Change control

2004 à 2011 Lifecycle approach Con2nuum -‐-‐-‐ UNDERSTANDING à VALIDATION à MAINTENANCE

8

QbD and PROCESS VALIDATION

QbD provides focus on design and development. Integra2on of manufacturing experience throughout lifecycle

will results in product and process con2nuing improvements. QbD consistent with ICH Q8 and Q11.

Lifecycle approach to process valida2on integrates QbD principles.

Lifecycle: Design/development –> Performance –> Monitoring/maintenance

Lifecycle approach being applied to other processes, equipment, u2li2es, quality systems, etc.

9

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 objec2ve •  Cri2cal quality aFributes – System aFributes •  Cri2cal process parameters – System parameters •  Control of varia2on – Varia2on affec2ng performance •  Risk assessment – Priori2ze according to risk •  Monitoring data à Con2nuous improvements

11

RISK MANAGEMENT

ICH Q9 discusses risk management. Risk analysis determines everything. High risk ac2vi2es must receive most aFen2on. Risk analysis required for devices.

12

VALIDATION FUNCTION “PRODUCT” AND INFRASTRUCTURE

Two components: 1. Validated products, processes (manufacturing, cleaning, packaging, etc.), equipment, u2li2es, facili2es, control systems, computer systems, analy2cal instruments – the “product” of the valida2on func2on.

2. The process of accomplishing valida2on – the infrastructure of the valida2on func2on. Protocols, results, documenta2on packages, approval commiFee, etc.

13

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 à Improvements Stage 1 à Stage 2 à Stage 3

VALIDATION QUALITY SYSTEM •  Objectives •  Quality Attributes •  Parameters •  Variables and control •  Risk assessment •  Continuous improvement

LIFECYCLE APPROACH: Design, Demonstration, Monitoring à Improvements

14

VALIDATION “PRODUCT”

PRODUCT : All validated products, processes (cleaning, packaging, analy2cal, etc.), equipment, facili2es, control systems, computers, etc., including documenta2on.

DocumentaRon affirming performance

PRODUCT/PROCESS LIFECYCLE APPROACH 1.  Design and development – Process understanding 2.  PQ – Process demonstra2on 3.  Con2nuous process verifica2on – Monitoring and

maintenance

15

QUALITY SYSTEM

FDA Defini2on: Formalized business prac2ces that define management responsibili2es for organiza2onal structure processes, procedures, and resources needed to fulfill product/service requirements, customer sa2sfac2on, and con2nual improvement. •  Management responsibili2es •  Resources •  “Manufacturing” •  Evalua2on

16

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 improvement

17

VALIDATION QUALITY SYSTEM LIFECYCLE 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?:

18

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.?

19

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

20

VALIDATION QUALITY SYSTEM BUSINESS PROCESS INFRASTRUCTURE 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. 21

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

ObjecRves –  What are the goals of each process step?

Abributes –  What makes a process step successful?

Parameters –  What factors significantly influence the success of the process step?

VariaRon and control –  What varia2on in performance is expected and how is it controlled?

Risk management –  What are highest risk ac2vi2es? –  Priori2za2on, evalua2on, and review highest level for highest risk

EvaluaRon –  Review performance of valida2on quality system

23

VALIDATION QUALITY SYSTEM VALIDATION CATEGORY

INITIATION DESIGN and DEVELOPMENT

PQ MONITORING MAINTENANCE

OBJECTIVE

QUALITY ATTRIBUTES

PARAMETERS

CONTROL OF VARAITION

RISK

24

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

25

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 26

WHY THE PROBLEM? -‐-‐ VALIDATION CATEGORIES Process valida2ons •  Manufacturing •  Cleaning •  Packaging •  Analy2cal •  Others Qualifica2ons – IQ, OQ, PQ; ASTM E2500 •  Equipment •  Facili2es •  U2li2es •  Computer systems •  Others

EACH VALIDATION UNIQUE

27

WHY THE PROBLEM? – ORIGINATORS OF VALIDATION / QUALIFICATION PROJECTS

R&D Technical Support Process Engineering Facili2es Engineering Maintenance Analy2cal 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.

28

VALIDATION QUALITY SYSTEM LIFECYCLE QUANTITATIVE MONITORING -‐-‐ EVALUATION

PRODUCT Performance of validated products, processes, equipment, etc.

QUALITY SYSTEM Throughput External audit observa2ons •  Documenta2on quality “Open” valida2on projects – 2me open Valida2on failures Protocol amendments Protocol devia2ons Other

29

OTHER APPLICATIONS QbD / Lifecycle approach to other quality systems Documenta2on in QSMP Examples:

Material system – Heparin Manual cleaning – Methotrexate Training – “Read and sign” vs. OTJ

30

QbD / LIFECYCLE APPROACH POSITIVES •  Organized and comprehensive focus based on risk to the pa2ent

and the organiza2on – Based on successful concepts •  System design for each type of valida2on -‐-‐ Gap analysis •  Risk analysis for each type of valida2on •  Cross-‐func2onal systems thinking •  Consistent priori2zed mi2ga2on ac2vi2es across func2ons – based

on risk •  Varia2on iden2fica2on and control strategy •  Con2nuous improvements based on systems monitoring •  Standardized audit expecta2ons and documenta2on •  Organiza2on commitment, transparency, and credibility •  Track organiza2on accomplishments completed •  Strong message to employees •  Strong message to auditors •  Poten2al “credit” in audits for projects completed and new

commitments iden2fied

31

QbD / LIFECYCLE APPROACH NEGATIVES Difficult •  Geqng organized is extremely difficult! •  Risk analysis is difficult •  Gap analysis is difficult •  Changes are difficult Transparency •  Being open about gaps and deficiencies may have regulatory and poli2cal risks

OrganizaRonal commitments •  Headcount needed to correct deficiencies

Do the benefits outweigh the negaRves?

32

SUMMARY 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

33


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

34


Infrastructure – Lifecycle approach and QbD 1. Determine business process

–  Ini2ate valida2on project –  Design and develop items to be validated –  PQ –  Monitor and maintain validated state

2.  QbD for business process –  Objec2ves -‐-‐ Goals of each process step? –  AFributes – Successful steps –  Parameters – Factors influencing success –  Control of varia2on -‐-‐ Expected varia2on in performance

–  Risk -‐-‐ management – Priori2ze highest risk ac2vi2es –  Evalua2on -‐-‐ Review performance

35


Review Performance •  Gap analysis: Problem areas

–  Initiate corrective action –  Example projects

•  Quantitative measurements: Throughput, failures, deviations, etc.

Positives and negatives Implementation difficult

36


AUDIT QUESTIONS: WHAT IS YOUR APPROACH TO VALIDATION? HOW DO YOU MANAGE THE VALIDATION FUNCTION?

1. Product/process/equipment/facili2es/etc: Lifecycle approach –  Design/development (QbD) –  Performance PQ –  Maintenance and monitoring leading to improvments

2. Valida2on Quality System/infrastructure: QbD / lifecycle approach – valida2on business process –  Design of the Quality System –  Objec2ves, AFributes, and Parameters –  Control sources of varia2on –  Risk analysis –  Demonstrate performance –  Evalua2on leading to con2nuous improvements

37

PAUL L. PLUTA, PhD Editor-‐in-‐Chief •  Journal of Valida-on Technology •  Journal of GXP Compliance

VisiRng Clinical Associate Professor •  University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA

Industry experience Contact: [email protected]

38

VALIDATION BOOT CAMP #6 LIFECYCLE APPROACH TO PROCESS VALIDATION – PRINCIPLES, IMPLEMENTATION, AND PRACTICE

IMPLEMENTATION MANUFACTURING PROCESSES

OTHER PROCESSES EQUIPMENT, FACILITIES, UTILITIES VALIDATION QUALITY SYSTEM OTHER QUALITY SYSTEMS

Paul L. Pluta, PhD

1

OUTLINE

1. Status of Implementa6on 2. Posi6ves and Nega6ves 3. Implementa6on Strategy and Approach 4. Impediments to Implementa6on

2

LIFECYCLE APPROACH -- STATUS OF IMPLEMENTATION

OrganizaAons implemenAng lifecycle approach -‐-‐ Reasons •  US FDA guidance •  Health Canada guidance •  EMA draI guidance •  Global communica6on •  ICH Q8, Q11 •  Logical approach – development, performance, and maintenance •  Applica6on to other processes, equipment, facili6es, etc.

OrganizaAons not implemenAng lifecycle approach -‐-‐ Reasons •  “Its only a guidance.” •  “Let’s see what happens.” •  “It’s only for USA.” •  “We will consider it if we get observa6ons.” •  Too costly, no headcount

3

LIFECYCLE APPROACH IMPLEMENTATION

Why implement? •  Guidance documents -‐-‐ Lifecycle approach is the future

•  Lifecycle approach makes sense •  Auditors learning the lifecycle approach

4

LIFECYCLE APPROACH POSITIVES •  Organized and comprehensive focus based on risk to the pa6ent

and the organiza6on – Based on successful concepts •  System design for each type of valida6on -‐-‐ Gap analysis •  Risk analysis for each type of valida6on •  Cross-‐func6onal systems thinking •  Consistent priori6zed mi6ga6on ac6vi6es across func6ons – based

on risk •  Varia6on iden6fica6on and control strategy •  Con6nuous improvements based on systems monitoring •  Standardized audit expecta6ons and documenta6on •  Organiza6on commitment, transparency, and credibility •  Track organiza6on accomplishments completed •  Strong message to employees •  Strong message to auditors •  Poten6al “credit” in audits for projects completed and new

commitments iden6fied

5

LIFECYCLE APPROACH NEGATIVES

Difficult •  Ge_ng organized is extremely difficult! •  Risk analysis is difficult •  Gap analysis is difficult •  Changes are difficult Transparency •  Being open about gaps and deficiencies may have regulatory and poli6cal risks

OrganizaAonal commitments •  Headcount needed to correct deficiencies

6

IMPLEMENTATION 1.  Iden6fy high risk areas

–  Example: Cleaning exper6se –  Example: Asep6c processing

2.  Senior management discussion – risks to opera6on 3.  Func6on management discussion – risks to opera6on 4.  Iden6fy recep6ve individuals in high risk area 5.  Training of appropriate individuals 6.  Start slowly 7.  Communica6on. Modify strategy as needed to insure

success 8.  Expand effort based on success 9.  Expect resistance

7

PRIORITIZATION

•  1. Manufacturing process valida6on •  2. Others

8

IMPLEMENTATION MANUFACTURING PROCESS VALIDATION

•  Plan implementa6on strategy –  Assemble PV Guidance and other references –  Meet with affected groups – R&D, Engineering, Technical Support, QA, others

•  Stage 1 groups •  Stage 3 groups

–  Meet with Valida6on Approval Commihee –  Develop reasonable and deliberate strategy with guaranteed success

•  Upper management input and approval •  General training on valida6on – all including new groups involved in valida6on •  Protocol writer training

–  Expecta6ons for documents

•  Valida6on Approval Commihee responsibili6es –  Science and technical basis –  Compliance with procedures –  Documenta6on quality –  “Surrogate regulatory auditor”

•  Valida6on Approval Commihee training •  Start slowly and build on success

9

IMPLEMENTATION -‐-‐ REALITY

•  Develop reasonable and deliberate strategy •  Assure successful implementaAon •  Do not expect rapid success •  Do not expect agreements and support

10

FINAL Q & A

•  Did we meet objec6ves?

11

PAUL L. PLUTA, PhD Editor-‐in-‐Chief •  Journal of Valida-on Technology •  Journal of GXP Compliance

Associate Professor •  University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA

Industry experience Contact: [email protected]

12

validation boot camp

Health & Medicine

employees

signdate rinse

signdate dry

assure process

establishes

alkaline soap

frequency

technical