Process Validation Guidances: FDA and Global

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PROCESS VALIDATION GUIDANCES FDA AND GLOBAL

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 •  History and development •  Is the lifecycle approach really new? •  FDA commentary Lifecycle Approach Stages •  #1 -- Process Understanding (Process Design) •  #2 -- Process Demonstration (Process Qualification) •  #3 -- Maintaining Validation (Continued Process Verification) Fundamental Concepts •  The “process of process validation” •  Enhanced execution •  Comparison to traditional approach Regulatory Guidances •  Health Canada •  FDA •  EMA Applications of PV Guidance •  Processes: Manufacturing, cleaning, packaging, analytical, others •  Equipment, facilities, utilities, others •  Quality Systems Implementation •  Implementation is difficult

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OBJECTIVES

•  What is the lifecycle approach? •  Is the lifecycle approach new? •  How is it different? •  What are fundamental principles? •  US only or global? •  Is industry accepting this approach? •  Audit questions:

What is your approach to validation? What is your approach to quality systems?

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VALIDATION MANAGER COMMENTARY

Organizations implementing lifecycle approach -- Reasons •  US FDA guidance •  Health Canada guidance •  EMA draft guidance •  Global communication •  ICH Q8, Q11 •  Logical approach – development, performance, and maintenance •  Application to other processes, equipment, facilities, etc.

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

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PROCESS VALIDATION LIFECYCLE APPROACH OVERVIEW

•  History and Development •  Fundamental Concepts •  Consistency with Medical Devices •  Is the lifecycle approach really new?

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HISTORY AND DEVELOPMENT – LIFECYCLE APPROACH

2004 – Health Canada guidance 2005 – FDA initial presentations 2007 – ICH Q10 2008 – FDA draft guidance 2009 – ICH Q8(R2) 2009 – Health Canada revision 2011 – FDA guidance issued 2012 – EMA draft guidance

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PROCESS VALIDATION LIFECYCLE APPROACH A NEW PARADIGM FOR PHARMA –

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 8-41.

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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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•  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 16


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 18


Key points •  Methods of evaluation •  Potential applications – every function,

every activity, entire product lifecycle

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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 20

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 terminology

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•  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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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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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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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)

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

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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

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SUPPORTING DOCUMENTS 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 procedures

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.

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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

LIFECYCLE APPROACH OVERVIEW

•  The “process of process validation” •  Process understanding, demonstration, and

maintaining the validated state throughout entire commercial life of product.

•  Comparison to previous approach

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PROCESS VALIDATION HISTORY 1978 FDA CGMP includes Validation 1987

Development -- VALIDATION -- Control

2004-2011 Lifecycle approach Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

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FDA 2011 PV GUIDANCE – PROCESS VALIDATION REVISITED Paula Katz (FDA) and Cliff Campbell

JGXP Compliance, Vol .16, #4, Fall, 2012

Among other motivating factors, the Agency sought to emphasize process design and maintenance of process control during commercialization. By aligning process validation activities with a lifecycle approach, the 2011 Guidance communicates that process validation is an ongoing program rather than a discrete and isolated activity. Under the 2011 Guidance, process validation is presented as a series of activities that manufacturers carry out over the lifecycle of the product and process. This view of process validation underscores the importance of detecting, understanding, and controlling sources of variability over time in order to consistently produce safe, effective drugs that meet all quality attributes. In turn, the emphasis on understanding and controlling process variability leads to a clarification that the Agency expects manufacturers to employ objective measures and appropriate statistical tools and analysis.

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PROCESS VALIDATION GUIDANCES

•  Health Canada •  FDA •  EMA

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HEALTH CANADA -- VALIDATION GUIDELINES FOR PHARMACEUTICAL DOSAGE FORMS, 2009

Phase 1. Pre-validation phase or qualification phase. Product R&D, pilor studies, scale-up, stability studies, equipment qualification, IQ, OQ, master production documents, others.

Phase 2. Process validation phase or process qualification phase. Verify that all limits of critical process parameters are valid and satisfactory product produced under worst-case conditions.

Phase 3. Validation maintenance phase. Frequent reviews of process-related documents to assure no changes, deviations, or failures, and that SOPs have been followed, including change control No changes that should have results in revalidation.

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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 – Demonstrate reproducible

manufacturing through conformance lots •  Stage 3 – Continued Process Verification – Routine manufacturing

and monitoring of performance.

STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM

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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. 49

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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 52

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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 FDA PV GUIDANCE 55

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 FDA PV GUIDANCE

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

results

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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 (SPC) 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 FDA PV GUIDANCE

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SUMMARY OF FDA GUIDANCE RECOMMENDATIONS

Stage 1: Product Design •  QTPP, development information, identification of CQA, CMA, and CPP •  Identification of sources of variation and control plan •  Experimental studies •  Technology transfer / scale up Stage 2: Process Qualification •  Protocol requirements •  Statistical sampling and acceptance criteria •  Equipment qualification and analytical method validation Stage 3: Continued Process Verification •  Post PQ plan •  APR, batch data, yields, deviations, OOS, non-conformances, etc. •  Incoming material data •  Change control •  Statistical analysis of data / control charting •  Product complaints

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HEALTH CANADA -- VALIDATION MASTER PLAN

•  Company philosophy, intentions and approaches to establish performance adequacy

•  Management agreement •  Meticulous preparation and planning of steps in process •  Structured according to SOP •  List of items to be validated and schedule •  Documentation

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HEALTH CANADA VALIDATION GUIDELINES

Additional sections •  Installation and Operational Qualification •  Requalification •  Process Validation

–  Prospective –  Concurrent –  Retrospective

•  Process Re-Validation – “Periodic review and trend analysis …at scheduled intervals”

•  Change control

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EMA GUIDELINE ON PROCESS VALDIATION Draft March, 2012

•  “…applying enhanced process understanding coupled with risk management tools under an efficient quality system as described by ICH Q8, Q9, and Q10.”

•  Definition •  Continuous process verification (PAT) •  Validation “…not a one-off event.” •  “A lifecycle approach should be applied linking product

and process development, validation of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.”

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•  Traditional process validation – Annex I details

•  Continuous process verification •  Hybrid approach

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Definitions •  Control Strategy •  Continued Process Verification •  Continuous Process Verification •  Critical Process Parameter (CPP) •  Critical Quality Attribute (CQA) •  Design Space •  High Impact Models •  Lifecycle •  Pharmaceutical Quality System (PQS) •  Process Validation

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FUNDAMENTAL CONCEPTS

•  Scientific and technical basis in development (Stage 1)

•  Validation (Stage 2 ) confirms tage 1 development

•  Acceptable (passing) results are expected. •  Validation is not

–  R&D, Final stage of development process –  Optimization, Fine-tuning, or Debugging

•  Monitor and maintain validated state throughout product lifetime (Stage 3).

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FUNDAMENTAL CONCEPTS •  Critical quality attributes (CQA) •  Critical process parameters (CPP) related to CQA •  Identify and control variation •  Statistical applications

–  DOE –  Statistical Process Control (SPC)

•  Rationale and justification – sampling, testing, etc. •  Detailed expectations in guidance

–  Protocol and results –  Monitoring

•  Monitoring and maintenance à Continuous improvements

•  Risk – All decisions based on risk analysis 68

APPLICATIONS OF PV GUIDANCE

•  Processes: Manufacturing, cleaning, packaging, analytical, others

•  Equipment, facilities, utilities, others •  Other new applications •  Quality Systems and compliance

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PROCESSES Manufacturing Packaging Cleaning Analytical Other

ALL PROCESSES MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.

PROCESSES MUST BE CONTINUALLY IMPROVED.

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QUALIFICATION Equipment Facilities Utilities Control systems Computer systems Others

ALL QUALIFIED EQUIPMENT MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.

QUALIFIED EQUIPMENT MUST BE CONTINUALLY IMPROVED.

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EQUIPMENT à PROCESSES

HVAC Systems – Process variable incoming air Water Systems – Process variable incoming water

ALL QUALIFIED EQUIPMENT THAT FUNCTIONS AS PROCESSES MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.

QUALIFIED EQUIPMENT MUST BE CONTINUALLY IMPROVED.

Reference: “The HVAC Process.” Delli Paoli, Alexander. J Validation Technology, Volume 17, #4, Autumn 2011.

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QUALITY SYSTEMS FDA QUALITY SYSTEMS •  Quality system •  Material system •  Production and equipment system •  Laboratory system

ALL QUALITY SYSTEMS MUST BE APPROPRIATELY DESIGNED AND DEVELOPED, DEMONSTRATE PERFORMANCE, AND BE MONITORED AND MAINTAINED.

QUALITY SYSTEMS MUST BE CONTINUALLY IMPROVED.

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IMPLEMENTATION •  MPLEMENTATION VERY DIFFICULT

–  Time –  Cost –  Change

•  Integration of Validation Approval Committee, R&D/technical groups, and QA functions

•  Lifecycle involvement – new to traditional validation •  Technical groups not accustomed to validation •  Post PQ monitoring

–  Prescribed testing based on risk –  Special testing

•  Enhanced PQ and post PQ execution as prescribed in guidance (statistics, etc.)

•  Note direction of global guidances, conferences, meetings

•  Great challenges for validation personnel 74

SUMMARY PROCESS VALIDATION GUIDANCES

Process Validation Guidances have greatly expanded the scope of validation

•  Lifecycle approach – documents from development through commercialization

–  Understanding –  Demonstration –  Monitoring and maintenance

•  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

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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 IMPLEMENTATION AND EFFECTIVE DOCUMENTS CONSISTENT WITH THE ABOVE

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LIFECYCLE APPROACH TO PROCESS VALIDATION

Process Design and Development – Pre-validation work •  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 qualified •  Analytical methods validated •  Confirm commercial process design •  Validation performance

Maintaining the Validated State •  Monitor, collect information, assess •  Maintenance, continuous verification, process improvement •  Change control

•  Validation maintenance

“The process of process validation.” All activities based on risk.

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SUMMARY PROCESS VALIDATION HISTORY

1978 CGMP includes Validation 1987

Development -- VALIDATION -- Control

2004-2011

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

SUMMARY – FUNDAMENTAL CONCEPTS

•  Lifecycle approach •  Scientific and technical basis in development •  Validation is confirmation •  Monitor and maintain •  Management review •  Continuous improvements •  Risk analysis

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SUMMARY – FUNDAMENTAL CONCEPTS

•  CQA and CPP •  Variation – identify and control •  Statistical applications

–  DOE –  Statistical Process Control (SPC)

•  Rationale and justification •  Risk analysis – work appropriate for level of risk

•  Enhanced detailed requirements in guidance –  Protocol and results –  Monitoring

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SUMMARY -- APPLICATIONS

Manufacturing process validation Other processes – cleaning, packaging,

analytical, etc. Equipment, facilities, utilities, computer

systems, etc. Equipment processes – HVAC, water

THERE IS NO ARGUMENT AGAINST DESIGN, DEMONSTRATE, AND MAINTAIN

LIFECYCLE APPROACH INCREASING APPLICATIONS

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SUMMARY FINAL

Lifecycle Approach Status -- 2012: •  Lifecycle approach globally accepted

–  Health Canada 2004 –  FDA 2011 –  EMA draft issued March, 2012

•  Design à Demonstrate à Maintain: No argument •  Approach specifics (QbD, CQA, etc.) accepted and

consistent with ICH and other guidances •  Usage increasing – Application to equipment, facilities,

utilities, computers, quality systems, etc. Stage approach and associated concepts increasing application. UNDERSTANDING à PERFORMANCE à MAINTENANCE

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SUMMARY FINAL -- DID WE MEET OBJECTIVES? •  What is the lifecycle approach? •  Is the lifecycle approach new? •  How is it different? •  What are fundamental principles? •  US only or global? •  Is industry accepting this approach? •  Audit questions:

What is your approach to validation? What is your approach to quality systems? UNDERSTAND – DEMONSTRATE -- MAINTAIN

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PAUL L. PLUTA, PhD

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

Advanstar Communications, USA

Visiting Clinical Associate Professor University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

Extensive pharmaceutical industry experience

Contact: [email protected]

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Health & Medicine

Process Validation Guidances: FDA and Global