Process Validation Guidance: FDA and Global

Process Validation Guidance: FDA and Global

Process Validation Lifecycle Approach Overview – History and development, FDA commentary, Is the lifecycle approach new?

Lifecycle Approach Stages

• Process Understanding (Process Design)
• Process Demonstration (Process Qualification)
• Maintaining Validation (Continued Process Verification)

Fundamental Concepts

• The “process of process validation”
• Enhanced execution
• Comparison to the traditional approach

Regulatory Guidance : Health Canada, USFDA,EMA

Applications of PV Guidance

• Processes: Manufacturing, cleaning, packaging, analytical, and others
• Equipment, facilities, utilities, others
• Quality Systems

Implementation

•  Implementation is difficult

Objective:

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

Audit questions:

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

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EMA draft guidance•  Global communication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

“It’s only a guidance.”

“Let’s see what happens.”

“It’s only for the USA.”

“We will consider it if we get observations.”

Too costly, no headcount

PROCESS VALIDATION LIFECYCLE APPROACH OVERVIEW

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

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• 2008 – FDA draft guidance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• 2012 – EMA draft guidance

PROCESS VALIDATION LIFECYCLE APPROACH A NEW PARADIGM FOR PHARMA – IS IT NEW?

Health Canada introduced lifecycle phases in 2004.

FDA lifecycle approach (stages) to process validation incorporated concepts of ICH Q8, Q9, Q10, QbD, and PAT – presentations starting in 2005.

Many concepts were previously mentioned in documents issued before 2000.

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

Phases of Validation

Phase 1: Pre-Validation Phase

Phase 2: Process Validation Phase (Process Qualification PhasePhase

Phase 3: Validation Maintenance Phase

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

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

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

CompatibilityICH Q8 PHARMACEUTICAL DEVELOPMENT

Key points

“Information and knowledge gained from development studies and manufacturing experience provide 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 …”

ICH Q8 PHARMACEUTICAL DEVELOPMENT

Key points

• Examination
• Understanding
•  Evaluation
•  Identification
•  Rationale and justification
•  Others
• Discussion in submission

ICH Q8 PHARMACEUTICAL DEVELOPMENT

Implications for Process Validation

•  Process understanding
•  Process development studies are the basis for process validation
•  Continuous process verification is alternative to process validation

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

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

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

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

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

Key points

• Methods of evaluation
• Potential applications – every function, every activity, entire product lifecycle.

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

ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS

Objectives

• Global harmonization of quality systems
• Consistency with ICH Q8 and Q9
• Application throughout the product lifecycle
• Problems addressed
• Inconsistent application
• Inconsistent definitions of common terminology

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

Key points

Quality system application throughout the 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.

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.

Implications for Process Validation

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

ICH Q11 DEVELOPMENT 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

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

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 28

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 parametersDevelopment data serves as the foundation for the manufacturing procedures

Variables are identified in the development phase

Raw materials may vary from 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) 29.

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 30

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 are controlled and monitored

Non-critical parameters not included in the validation

Periodic review of validated systems

Reference: ICH Q7. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. November, 2000.

SUPPORTING DOCUMENTS PROCESS VALIDATION – PRODUCTS / APIA

validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable products.

Proof of validation is obtained through rational experimental design and the ongoing evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase.

Before commercial distribution:

• Product and process development
• Scale-up studies
• Equipment and system qualification
• Conformance batches

Identify and control all critical sources of variability

Advanced 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.

SUPPORTING DOCUMENTS VALIDATION — PHARMACEUTICAL  CGMPS

Cross-Agency workgroup CDER, CBER, ORA, and CVM.“The CPG 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.

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. 35

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.

SUPPORTING DOCUMENTS FDA — QUALITY BY DESIGN (QbD)

• The 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 37

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 38

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

SUPPORTING DOCUMENTS PROCESS ANALYTICAL TECHNOLOGY (PAT)

Processes verified by PAT are not validated

All associated PAT equipment and analytical methods are validated

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 41

LIFECYCLE APPROACH OVERVIEW

• The “process of process validation”
• Process understanding, demonstration, and maintaining the validated state throughout the entire commercial life of the product.
• Comparison to previous approach 42

PROCESS VALIDATION HISTORY

1978

FDA CGMP includes Validation

1987

Development — VALIDATION — Control

2004-2011

Lifecycle approachContinuum of understanding – validation – maintenance

UNDERSTANDING — VALIDATION — MAINTENANCE

Protocol for steam sterilizer and load Pattern