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VALIDATION BOOT CAMPVALIDATION LIFECYCLE MANAGEMENT

PRINCIPLES, POLICY, AND PRACTICE

POTENTIAL APPLICATIONS

Paul L. Pluta, PhD

Journal of Validation Technology

Journal of GXP Compliance

University of Illinois at Chicago (UIC) College of

Pharmacy Chicago, IL, USA

1

OUTLINE and OBJECTIVES

• Provide validation / qualification basic understanding

– General terminology problem

– Specific area problem

– “Fit for use”

• Describe lifecycle approach

– History and basis (1987)

– Lifecycle stages and activities (2005)

• Propose documentation changes based on lifecycle requirements– High level policy documents

– VMP, Protocols, results, etc.

– Post validation

– Associated documents

• Describe evolving applications

– Other processes, cleaning, EFU, qualify systems

– Validation quality system

• Propose implementation approach

– Crisis approach

– Deliberate approach

2

QUESTIONS ANSWERED

• Provide validation / qualification basic understanding

– What is validation? What is qualification? What is the difference? Why so many

problems with consistency and approach?

• Describe lifecycle approach

– What is the lifecycle approach? Why do we need this? Is it new? Is this the end

of validation? What about doing “three lots?”

• Propose documentation changes based on lifecycle approach– What are the effects of the PV guidance on documentation? Are complete revisions

necessary?

• Describe other evolving applications

– Is the lifecycle approach only for manufacturing processes? Does everything

else (cleaning, equipment, computers, etc.) remain as is?

• Propose implementation approach

– How do we implement? Is anyone else doing this? How far along is the rest of

industry? Are people getting “483’s”?

WHAT IS YOUR APPROACH TO VALIDATION?

3

AGENDA

1. Introduction and definitions

2. Historical basis and lifecycle stages

3. Documentation

4. Applications

5. Implementation

6. Summary

4

SUMMARY

• FDA PV lifecycle guidance integrates evolving pharma approaches

– QbD, CQA, CPP, risk, variation, others

• PV scope expanded to include three stages

• Stage 1 design emphasis: Understand product / process

• Stage 2 PQ demonstration stage: Documentation enhancements

• Stage 3 verification: Maintain the validated state improvements

• Applicable to other processes, equipment, quality systems

• Quality systems – business process

• Implementation: Integration of multiple site functions, management

support, and deliberate strategy

• Unified terminology, objectives, and approach to site validation

• Auditor answer: What is your approach to ________ validation?

• Challenges, personal development, and leadership opportunities for

validation personnel.

5

VALIDATION AND QUALIFICATION

VALIDATION. Composed of

• Validation – Process validation: Applicable to

processes – primarily manufacturing processes.

Systems with process variation

• Qualification – Applicable to equipment ,

facilities, utilities, computer systems, etc. No

variation.

• Is packaging equipment or process?

• Is HVAC equipment or process?

• Is WFI equipment or process?

• Quality systems?

6

VALIDATION AND QUALIFICATION

Definition: Processes, equipment, facilities,

utilities, computer systems, analytical methods,

etc. do what they are supposed to do.

Expanded definition:

• Includes design and development

• Includes monitoring and maintenance

Validate or qualify by additional testing

• Processes: Multiple lots

• EFU: Operating limits

7

PROCESS VALIDATION AND QUALIFICTION

Process Validation – Process Qualification

PV – PQ -- PPQ

Qualification Qualification

Equipment #1 HVAC

Utilities

Equipment #2 Facilities

Computers

Equipment #3

Analytical methods validation

Process is validated

8

LIFECYCLE APPROACH TO PROCESS VALIDATION

FDA, 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

9

LIFECYCLE APPROACH TO

PROCESS VALIDATION

• History and development

• Fundamental concepts

• Consistency with medical devices

• Is the lifecycle approach really new?

10

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

2014 – EMA guidance

11

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 1247

12

HEALTH CANADA -- VALIDATION GUIDELINES FOR

PHARMACEUTICAL DOSAGE FORMS (GUI-0029)

5.0 Phases of ValidationPhase 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

13

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

14

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

15


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 …”

16


Key points

Examination

Understanding

Evaluation

Identification

Rationale and justification

Others

Discussion in submission

17


Implications for Process Validation

Process understanding

Process development studies are basis for

process validation

Continuous process verification is

alternate to process validation

18

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

RISK IS EVERYTHING

19


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

20


• Initiate risk management process

• Risk assessment

• Risk identification

• Risk analysis

• Risk evaluation

• Risk control

• Risk reduction

• Risk acceptance

• Output

• Risk review

21


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

22


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

23


Key points

• Methods of evaluation

• Potential applications – every function, every

activity, entire product lifecycle

RISK IS EVERYTHING

24



• Development: Process knowledge

• Materials: Variation, change control

• Equipment: Qualification, cleaning, calibration,

PM, change control

• Production: Validation, sampling, testing,

change control

• Maintenance / monitoring: Testing

25

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

26

ICH Q10


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

27

ICH Q10


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

28

ICH Q10


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.

29

ICH Q10



• Product performance and monitoring

• CAPA system enhances process understanding

• Change management system

• Process improvements

30

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

31

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

32

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

33

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)

34


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

35


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.

36


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.

37


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.

38


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.

39


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.

40


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.

41


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 parameters

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

42


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

43


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

44


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

45


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

46

EMA GUIDELINE ON PROCESS VALIDATION FOR

FINISHED PRODUCTS – INFORMATION AND DATA TO

BE PROVIDED IN REGULATORY SUBMISSIONS (2014)

Process Validation

• Traditional process validation

• Continuous process verification

• Hybrid approach

• Design space verification

• Annex I: Process validation scheme

• Annex II: Standard / non-standard processes

47

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

48

PV GUIDANCE

MANUFACTURING PROCESS VALIDATION

Process Validation (PV) – Process Qualification (PQ)

Process Performance Qualification (PPQ)

Qualification Qualification

Equipment #1 HVAC

Utilities

Equipment #2 Facilities

Computers

Equipment #3

Analytical methods validation

Manufacturing process is validated.

49

UO #1

UO #2

UO #3


“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.”

50


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.

51

52

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

53

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 analysis54

55

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 QUALIFICATIONConformance Lots

Procedures

Validation plans

Protocols

Sampling

Testing

Results

Plan to maintain validation

ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING

SYSTEMS MUST BE QUALIFIED.

56

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

57

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


58

59

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

60

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


61

SUMMARY OF GUIDANCE RECOMMENDATIONS

Stage 1: Product Design

• QTPP, Development information, Identification of CQA, CMA, and CPP

• Identification of sources of variation and control plan

• Experimental studies

• Technology transfer / scale up

Stage 2: Process Qualification

• Protocol requirements

• Statistical sampling and acceptance criteria

• Equipment qualification and analytical method validation

Stage 3: Continued Process Verification

• Post PQ plan

• APR, batch data, yields, deviations, OOS, non-conformances, etc.

• Incoming material data

• Change control

• Statistical analysis of data / control charting

• Product complaints

62

PROCESS VALIDATION HISTORY

1978

CGMP includes Validation

1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach

Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

63

VALIDATION PHILOSOPHY

• Validation is confirmation.

• Acceptable (passing) results are expected.

• Validation is not

– R&D

– Final stage of development process

– Optimization

– Fine-tuning

– Debugging

64

SUMMARY – LIFECYCLE APPROACH

• Three stages of validation

1. Design and development – Understanding

2. PQ – Demonstration

3. Continued process verification – Monitor and maintain

• Emphasis on process understanding – CQA, CPP, CMA,

sources of variation, variation control

• Emphasis on maintaining validated state

– Ongoing improvements expected

• Lifecycle approach integrates original PV, ICH, QbD, and

device concepts into unified approach

• Risk level determined that dictates amount of work.

• Rational decisions and judgments

65

DOCUMENTATION

Key Points

• Documentation involves three stages

• Expectations for Stage 2 expanded

• PV Guidance – Basis for policy

documents, traditional validation

documents, and associated documents

66

DOCUMENTATION

• 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

67

LIFECYCLE APPROACH APPLICATIONS

Can lifecycle approach to applied to other areas?

• Processes

– Cleaning, packaging, analytical, others

• Equipment

– Facilities, utilities, control systems

• Equipment processes

– HVAC, water

• Quality systems

– Basic systems, support systems,

68

CLEANING VALIDATION

Lifecycle approach to cleaning validation

1. Stage 1 – Understanding the cleaning process

Scientific and technical principles

2. Stage 2 – Demonstrating cleaning performance

Traditional cleaning validation PQ

3. Stage 3 – Maintaining the validated state

Monitor and maintain performance

Performance based on risk analysis.

Auditor question: How do you approach cleaning?

69

CLEANING VALIDATION DEFINITION

Validating the Cleaning Process

1. Make Product A

2. Clean equipment

3. Analytical testing for Product A residue

4. Repeat above multiple times

5. If all testing below acceptable level –

CLEANING PROCESS IS VALIDATED

6. Future: Clean equipment -- No testing

70

CLEANING EQUATION

Product A Residue (equipment surface)

+

Cleaning agent

+

Cleaning process parameters (TACT)

Clean equipment surface (for Product B)

71

Lifecycle Approach to Cleaning Validation –

Value? Does this make sense?

• Cleaning is a process

• 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 cleaning approach –

Which would you rather present to an auditor?

72

WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification

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 Analytical

Equipment is clean -- Process is validated

Process parameters Quality attributes

73

WHAT IS THE CLEANING PROCESS?Cleaning Process Performance Qualification

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 Quality attributes74

CLEANING VALIDATION OVERVIEW

1990s present

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

75

LIFECYCLE APPROACH TO CLEANING VALIDATION

Scientific and technical approach

Design and development– Residue + cleaning agent + cleaning procedure Clean equipment

Performance demonstration

Monitoring and maintenance

Rationale, responsibility, and accountability

Risk analysis

Conrol variation

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.

76

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

Validation work related to risk

DOCUMENT ALL OF THE ABOVE

77

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

78

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

79

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

80

pH SOLUBILITY PROFILE, pH 1-12

Solubility

mg/ml

Drug A

Drug B

pH 1 7 12

81

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

82

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

• Equipment differences

83

STAGE 2, PROCESS QUALIFICATION –

(VALIDATION PERFORMANCE)

APPLICATION TO CLEANING1. 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

84

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

85

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)

86

87

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

LIFECYCLE APPROACH

APPLICATION TO PROCESSES

• Cleaning

• Packaging

• Analytical

• HVAC

• WFI

• Others

88

EQUIPMENT QUALIFICATION

Lifecycle approach to equipment qualification

1. Stage 1 – Understanding the equipment

Scientific and technical engineering principles

2. Stage 2 – Demonstrating equipment performance

Equipment qualification

3. Stage 3 – Maintaining the validated state

Monitor and maintain performance, change control

Qualification activities and testing based on risk analysis.

Auditor question: How do you approach equipment qualification?

89

EQUIPMENT QUALIFICATION – LIFECYCLE APPROACH

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 / develop / 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.

90

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?

91


Qualification approaches

• DQ / IQ / OQ / PQ (IQ for medical devices)

• ASTM E2500

Documentation hierarchy

Document outlines

• Model documents

92

QUALIFICATION APPROACHES

DQ / IQ / OQ / PQ

Traditional qualification

DQ – Multiple functions and applications

• Purchasing document

• Equipment design document

• Stage 1 activities

Documents may be combined

• IQ, OQ, PQ -- IOQ

• Stage 2 activities

93

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


• 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

94

ISPE EQUIPMENT VALIDATION

User Requirements PQ

Specification

Functional Specification OQ

Design Specifications IQ

System Build

9595

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

NEED MONITORING/MAINTENANCE REVIEW FOR STAGE 3

9696


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.

97

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

98

LIFECYCLE APPROACH TO EQUIPMENT

SUMMARY

• Stage 1. DQ – Design and development

information

– FAT, SAT, commissioning activities

• Stage 2. IQ/OQ/PQ – Demonstration

• Stage 3. Management review of preventive

maintenance, deviations, calibration, other

records

Includes risk analysis Appropriate testing

Need support of engineering function to

implement Stage 3.99

QUALITY SYSTEMS

Can lifecycle approach be applied to Quality

Systems?

FDA Quality Systems• Quality System

• Materials System

• Production system

• Equipment and Facilities System

• Packaging and Labeling System

• Laboratory Controls System

100

QUALITY SYSTEMS

“Stand-alone” systems supporting major quality

systems

• Validation

• Training

• Stability

• Complaints

• Calibration


• Others

101

VALIDATION QUALITY SYSTEM

1. Application of QbD and lifecycle principles to the Validation Quality

System

2. Design of the Validation Quality System

3. Objectives of Validation Quality System

4. Quality Attributes of Validation Quality System

5. Parameters affecting attributes

6. Control of variables affecting quality system performance

7. Risk management

8. Monitoring performance Continuous improvements

102

QbD and VALIDATION QUALITY SYSTEM

QbD

• Target product profile – System objective

• Critical quality attributes – System attributes

• Critical process parameters – System parameters

• Control of variation – Variation affecting performance

• Risk assessment – Prioritize according to risk

• Monitoring data Continuous improvements

103

VALIDATION FUNCTION

“PRODUCT” AND INFRASTRUCTURE

Two components:

1.Validated products, processes (manufacturing,

cleaning, packaging, etc.), equipment, utilities,

facilities, control systems, computer systems,

analytical instruments – the “product” of the

validation function.

2.The process of accomplishing validation – the

infrastructure of the validation function.

Protocols, results, documentation packages,

approval committee, etc.

104

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 Improvements

Stage 1 Stage 2 Stage 3

VALIDATION QUALITY SYSTEM

• Objectives

• Quality Attributes

• Parameters

• Variables and control

• Risk assessment

• Continuous improvement

LIFECYCLE APPROACH: Design, Demonstration, Monitoring Improvements

105

VALIDATION “PRODUCT”

PRODUCT : All validated products, processes

(cleaning, packaging, analytical, etc.),

equipment, facilities, control systems,

computers, etc., including documentation.

Documentation affirming performance

PRODUCT/PROCESS LIFECYCLE APPROACH

1. Design and development – Process understanding

2. PQ – Process demonstration

3. Continuous process verification – Monitoring and

maintenance

106

QUALITY SYSTEM

FDA Definition: Formalized business practices

that define management responsibilities for

organizational structure processes, procedures,

and resources needed to fulfill product/service

requirements, customer satisfaction, and

continual improvement.

• Management responsibilities

• Resources

• “Manufacturing”

• Evaluation

107

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 improvement108

VALIDATION QUALITY SYSTEMLIFECYCLE 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?

• Attributes

• Parameters

• Variables and control

Quality System Monitoring and Maintenance

What is done to maintain quality system performance?:

109

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.?

110

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

111

VALIDATION QUALITY SYSTEM BUSINESS PROCESSINFRASTRUCTURE 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.

112

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.113

QbD APPROACH TO VALIDATION QUALITY SYSTEM –

SPECIFIC BUSINESS PROCESS

Objectives

– What are the goals of each process step?

Attributes

– What makes a process step successful?

Parameters

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

Variation and control

– What variation in performance is expected and how is it controlled?

Risk management

– What are highest risk activities?

– Prioritization, evaluation, and review highest level for highest risk

Evaluation

– Review performance of validation quality system

114

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.” Procedures not followed.

CLEANING VALIDATION SAMPLING

• Sampling personnel not adequately trained – false negative 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

115

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 Responsibilities

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

116

WHY THE PROBLEM? -- VALIDATION

CATEGORIESProcess validations

• Manufacturing

• Cleaning

• Packaging

• Analytical

• Others

Qualifications – IQ, OQ, PQ; ASTM E2500

• Equipment

• Facilities

• Utilities

• Computer systems

• Others

EACH VALIDATION UNIQUE

117

WHY THE PROBLEM? –

ORIGINATORS OF VALIDATION / QUALIFICATION

PROJECTSR&D

Technical Support

Process Engineering

Facilities Engineering

Maintenance

Analytical 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.

118

VALIDATION QUALITY SYSTEM LIFECYCLE

QUANTITATIVE MONITORING -- EVALUATION

• Throughput

• External audit observations

• Documentation quality

• “Open” validation projects – time open

• Validation failures

• Protocol amendments

• Protocol deviations

• Other

119

OTHER APPLICATIONS

QbD / Lifecycle approach to other quality systems

Documentation in QSMP

Examples:

Material system – Heparin

Manual cleaning – Methotrexate

Training – “Read and sign” vs. OTJ

120

QbD / LIFECYCLE APPROACH POSITIVES

• Organized and comprehensive focus based on risk to the patient and the organization – Based on successful concepts

• System design for each type of validation -- Gap analysis

• Risk analysis for each type of validation

• Cross-functional systems thinking

• Consistent prioritized mitigation activities across functions –based on risk

• Variation identification and control strategy

• Continuous improvements based on systems monitoring

• Standardized audit expectations and documentation

• Organization commitment, transparency, and credibility

• Track organization accomplishments completed

• Strong message to employees

• Strong message to auditors

• Potential “credit” in audits for projects completed and new commitments identified

121

QbD / LIFECYCLE APPROACH

NEGATIVESDifficult

• Getting 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 political risks

Organizational commitments

• Headcount needed to correct deficiencies

Do the benefits outweigh the negatives?

122

VALIDATION QS SUMMARY

• Validation business process

• Quality by Design (QbD) framework

– Objective, CQA, CPP, Variation control,

• Lifecycle approach to validation quality system

– Design

– Demonstrate

– Monitor

• Risk management application to the Validation Quality

System

• Application to other quality systems.

123

IMPLEMENTATION

PV Lifecycle approach is paradigm change

• Entire organization involved in validation

– R&D / Technical support (Stage 1)

• Audit involvement

• Support change control

– QA / Manufacturing (Stage 3)

• How to implement culture change?

124

IMPLEMENTATION

Culture change: Two general approaches

• Crisis approach (Kotter, Harvard)

– Eight-step process

– Respond to crisis or create a crisis

• Slow approach

– Slow success

– No failure

125

IMPLEMENTATION #1

• Plan implementation strategy

– Assemble PV Guidance and other references

– Meet with affected groups – R&D, Engineering, Technical Support, QA, others

– Meet with Validation Approval Committee

– Develop reasonable and deliberate strategy with guaranteed success

• Upper management input

• Upper management approval

• General training on validation – all including new groups involved in

validation

• Protocol writer training

– Expectations for documents

• Validation Approval Committee responsibilities / training

– Science and technical basis

– Compliance with procedures

– Documentation quality

– “Surrogate regulatory auditor”

126

IMPLEMENTATION #2

• Develop model documents– Continually improve / replace model documents

• Pilot projects– Select open-minded people

– Guarantee success

• Build on success with subsequent projects

• General validation training


127

IMPLEMENTATION

Reality

• Resistance to change

• Why are we doing this?

• No time to do work

• No headcount to do work

• No audit observations – why change?

• Do not expect rapid success

• Do not expect agreements and support

128

IMPLEMENTATION SUCCESS

• People utilize old validation plans and reports for new

work

• People refer to old documents

• Validation becomes an organizational resource

• VMP becomes valued site document

• Validation becomes appreciated.

• No internal or external audit observations.

129

SUMMARY

• FDA PV lifecycle guidance integrates evolving pharma

approaches – QbD, CQA, CPP, risk, variation, others

• PV scope expanded to include three stages

– Stage 1 design emphasis: Understand product / process

– Stage 2 PQ demonstration stage: Documentation

enhancements

– Stage 3 verification: Maintain the validated state

improvements

• Applicable to other processes, equipment, quality

systems

• Quality systems – business process

• Implementation: Integration of multiple site functions,

management support, and deliberate strategy

130

SUMMARY

• Unified terminology, objectives, and

approach to site validation

– Understand, demonstrate, maintain

• Auditor answer:

– What is your approach to _____ validation?

• Challenges, personal development, and

leadership opportunities for validation

personnel.

131

132

SUMMARY

WHERE WE ARE -- CURRENT PRACTICE

R&D Validation Commercialization

133

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

134

SUMMARY -- WHERE WE ARE GOING –


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

135


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.”

136

SUMMARY

PROCESS VALIDATION HISTORY

1978

CGMP includes Validation

1987

Development -- VALIDATION -- Control

2008-2011

Lifecycle approach

Continuum of understanding – validation – maintenance

UNDERSTANDING -- VALIDATION -- MAINTENANCE

137

SUMMARY

VALIDATION -- FUTURE

Development Performance Maintenance

Stage 1 Stage 2 Stage 3

SUMMARY – DOCUMENTATION

• Critically important

• Integrate site functions

– R&D / Technical Support / Engineering (Stage 1)

– QA (Stage 3)

• Awareness of responsibility to validation

• Model documents

– Suggested content in outlines

• FDA detailed recommendations in guidance

138

PROCESS VALIDATION DOCUMENTS

• Validation policy – Reference PV Guidance approach

– Corporate and / or site documents

• Validation Master Plan (VMP) – Reference PV Guidance approach

• Validation documents

– Stage 1 documents – Process Design

• Specific documents -- Reference PV Guidance

– Stage 2 documents – Process Qualification (traditional validation)

• 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

139

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

140

SUMMARY -- APPLICATIONS

• Other processes – Cleaning, analytical, packaging, etc.

• Equipment, facilities, utilities, etc.

• Equipment “processes” – HVAC, WFI

• Quality systems

ALL IMPLEMENT STAGE APPROACH:

• Design and understand

• Demonstrate

• Monitor and maintain

141

SUMMARY -- IMPLEMENTATION

• Plan implementation strategy– Develop reasonable and deliberate strategy

– Guarantee success

• Upper management input and approval

• Validation Approval Committee agreement

• Validation Approval Committee responsibilities

• General training on validation – including new groups

involved in validation


• Validation Approval Committee training

• Expect difficulty

142

PAUL L. PLUTA, PhD

Editor-in-Chief

Journal of Validation Technology

Journal of GXP Compliance

Advanstar Communications

Associate Professor of Biopharmaceutics

University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

Pharmaceutical industry experience

Contact: [email protected]

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