Validation boot camp 1

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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

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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?

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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

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INTRODUCTION, BASIS, LIFECYCLE STAGES

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

IS THE LIFECYCLE APPROACH REALLY NEW?

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2004 – Health Canada guidance 2005 – FDA initial presentations 2007 – ICH Q10 2008 – FDA draft guidance 2009 – ICH Q8(R2) 2009 – Health Canada revision 2011 – FDA guidance issued 2012 – EMA draft guidance

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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.

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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

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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

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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

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ICH Q8 PHARMACEUTICAL DEVELOPMENT

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 …”

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ICH Q8 PHARMACEUTICAL DEVELOPMENT Key points

Examination Understanding Evaluation Identification Rationale and justification Others Discussion in submission

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ICH Q8 PHARMACEUTICAL DEVELOPMENT

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

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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

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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

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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

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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

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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

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

activity, entire product lifecycle

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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

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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

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ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

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

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ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

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

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ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

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.

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ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

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

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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

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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

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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)

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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

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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.

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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.

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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.

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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.

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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.

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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

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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

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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

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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

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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

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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

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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

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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.”

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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.

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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

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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

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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.

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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

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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

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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

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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

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PROCESS VALIDATION HISTORY

1978 CGMP includes Validation 1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

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VALIDATION PHILOSOPHY

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

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

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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?

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SUMMARY WHERE WE ARE -- CURRENT PRACTICE

R&D Validation Commercialization

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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

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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

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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.”

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SUMMARY PROCESS VALIDATION HISTORY

1978 CGMP includes Validation 1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

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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: paul.pluta@comcast.net

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