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CRITICAL COMPONENTS –

CLEANING VALIDATION MASTER PLAN

Paul L. Pluta, PhD

Journal of Validation Technology and Journal of GXP Compliance

University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

OUTLINE

• Definitions – Cleaning Validation Master Plan (CVMP) and

Validation Master Plan (VMP)

• Lifecycle approach applied to cleaning validation -- Comparison to

prior approach

– Process Understanding – Scientific and technical aspects supporting cleaning

process

– Process Demonstration – Enhanced execution

– Maintaining Validation – Periodic monitoring

• Application to Cleaning Validation Master Plan

• Application to individual cleaning validation.

• Cleaning validation problems -- 2015

• Changing the cleaning culture

• Other applications of the PV Guidance – Processes, EFU, hybrid

systems (water/HVAC), Quality Systems

PARTICIPATION AND COMMENTS INVITED

CLEANING VALIDATION MASTER PLAN (CVMP)

DEFINITION

Three possible definitions:

• Program: High level comprehensive document

describing site cleaning validation program.o Stand alone or part of VMP

o Document importance

• Multifunction Project: Comprehensive document

describing complete cleaning validation project (e.g.,

utility, equipment, product).

• Product Cleaning Validation: Individual product cleaning

validation .

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IMPORTANCE OF VALIDATION

DOCUMENTS AND VMP / CVMP

• Validation documents always requested in regulatory

audits – especiallyVMP!

• Validation documentation is retained forever

• Documents reviewed long after people are gone

– Documents must “stand alone”

• FDA auditors often focus on documentation – VMP and

specific validation documents often requested ahead of

audit

• Early documents (Initiation, Plan, Protocol) reviewed

when project is in-progress or not completed

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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 – Reproducible manufacturing

• Stage 3 – Continued Process Verification – Routine manufacturing

STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM

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FDA PROCESS VALIDATION GUIDANCE

DOCUMENTATION FOCUS

“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.”

NOTE KEY WORDS

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FDA PROCESS VALIDATION GUIDANCE

DOCUMENTATION FOCUS

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.

NOTE KEY WORDS

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LIFECYCLE APPROACH TO PROCESS VALIDATION

RAMIFICATIONS

FDA Process Validation Guidance has greatly expanded

the scope of validation

• Lifecycle approach – documents from development through

commercialization. Traditional validation documents (protocol and

results) relatively less important

• New expectations for traditional validation documents

Multiple groups at site must now contribute and interact to

maintain process validation lifecycle approach

Lifecycle approach being applied to all validation and

qualification (equipment, facilities, utilities, etc.)

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VALIDATION TRANSITION

1987:

R&D VALIDATION Change control

2011:

STAGE 1 VALIDATION STAGE 3

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LIFECYCLE APPROACH

CLEANING PROCESS VALIDATION

• Stage 1: Process Understanding – Scientific

and technical aspects supporting cleaning

process – must be documented

• Stage 2: Process Demonstration – Enhanced

execution and documentation

• Stage 3: Maintaining Validation – Periodic

monitoring and maintenance.

NEW APPROACH CONSISTENT WITH PV GUIDANCE

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CLEANING PROCESS “VALIDATION” –

CURRENT APPROACH

• Same method for all products + operator effort

• No basis for cleaning process

• Buy cheapest soap available

• Trial and error among all site methods

• Operator discretion

• “Do whatever it takes”

• SOP – no details, no accountability

• Minimal supporting documentation

• Others

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CLEANING VALIDATION ACTIVITIES

Cleaning procedures – detergents and processes

o Equipment #1, Equipment #2, Equipment n

• Sampling locations for each equipment

• Sampling methods (swab, rinse)

• Analytical methods (specific, non-specific, detergent)

• Acceptance criteria

• Validation initiation and plan

• Validation protocol

o Dirty hold time

• Validation results

• Validation monitoring and maintenance

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CLEANING VALIDATION SUPPORTING ACTIVITIES

STAGE 1 – DESIGN AND DEVELOPMENT

Cleaning method development

• Cleaning detergent justification based on residue

• Cleaning process development

Specific residue toxicology

Equipment surface area calculations

Equipment sampling methods justification

Equipment sampling locations justification

Sampling training

Residue calculations justification

Equivalent equipment

Clean hold time

Analytical methods development / sensitivity

Material recovery studies

DISCUSS IN VALIDATION PLAN

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CLEANING VALIDATION MASTER PLANCleaning method development approach

• Stage requirements

• Procedures for above

Product cleaning matrix and justification

Equipment surface area calculation method

Equivalent equipment approach and justification and equipment listing

Sampling methods approach and justification

Equipment sampling methods and locations justification

Sampling training

Residue toxicology and calculations approach and justification

Clean hold time approach and justification

Analytical methods development approach

Recovery studies approach

Other

ABOVE ALL APPROVED DOCUMENTS THROUGH

VALIDATION APPROVAL COMMITTEE

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CLEANING VALIDATION LIBRARY

APPENDIX 1

PRODUCT NAME VALIDATION # DATE

2275 Drug A Tablets, 50 mg 2009-12-3 3-1-2010

3389 Drug B Tablets, 250 and 500 mg 2011-3-6 9-1-2011

4455 Drug C Tablets, 0.1 mg 2011-3-9 10-1-2011

5721 Drug D Tablets, 0.5 mg 2012-5-1 9-1-2012

5833 Drug E Tablets, 50 mg 2010-3-7 7-1-2010

6692 Drug A CR Tablets,100 mg 2012-4-1 9-1-2012

7971 Drug A CR Tablets, 200 mg 2012-4-2 9-1-2012

8903 Drug F Tablets, 10 mg 2015-5-3 10-1-2015

9955 Drug G Tablets, 25 mg 2015-6-4 10-2-2015

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CLEANING VALIDATION PROJECTS

APPENDIX 2

+/- of above: “Dirty laundry”

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# NAME MILESTONE

2015-1 Equipment #A99 Sampling Locations 11-1-15

2015-2 Product D Cleaning Validation 1-1-16

2015-3 Product E Cleaning Validation 2-1-16

2015-4 Detergent X Replacement 7-6-16

2015-5 Product J Dirty Hold Time Extension 9-1-16


CLEANING VALIDATION COMPLETED PROJECTS

APPENDIX 3

# NAME COMPLETED

2014-1 Equipment 98 Sampling locations 3-1-15

2014-2 Product A Cleaning Validation 6-1-16

2014-3 Product B Cleaning Validation 8-1-16

2014-4 Detergent M replacement 9-6-16

2014-5 Product L Dirty hold time extension 10-1-16

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Strategy and approach

• Comprehensive lifecycle approach, Science and technical basis, Risk analysis,

Variation identification and control (consistent with site and corporate docs)

• Stage 1, 2, 3 strategy and approach

Procedures

• List of approved procedures

Supporting information with reference documents including justifications

• Product cleaning matrix

• Equivalent equipment

• Equipment surface area calculations

• Residue calculations

• Technical reports

• Templates

Validation references

• List of all completed cleaning validations, #, date

Validation commitments, improvement projects, and timelines

• Planned projects

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CONTINUITY OF VALIDATION DOCUMENTS

Cleaning Validation Policy

• Policy and corporate templates

CLEANING VALIDATION MASTER PLAN (CVMP)

• Approach and justification with procedures – Stages 1, 2, 3.

• Stage 1 general supporting documents

• Cleaning validation library

• Appendices

CLEANING VALIDATION

• Stage 1 specific validation supporting documents

• Stage 2 documents – Process Performance Qualification

– Validation Initiation / Plan

– Validation Protocol(s)

– Engineering Studies

– Others

– Validation Results / Report

• Stage 3 documents plan – Continued Process Verification

– PQ requirements

– Routine monitoring

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CLEANING VALIDATION MASTER PLAN –

DOCUMENT REVISIONS

DATE TITLE REASON FOR REVISION

10-30-`13 3Q 2013 Update Completed validations, new

commitments

1-30-14 4Q 2013 Update Completed validations, 2014

goals

4-30-14 1Q 2014 Update Completed validations

7-30-14 2Q 2014 Update Completed validations, new

equipment

10-30-14 3Q 2014 Update Completed validation, new goals

1-30-15 4Q 2015 Update Completed validations, 2015

goals

4-30-15 1Q 2015 Update Completed validations, new

equipment

7-30-15 2Q 2015 Update Completed validations

UPDATE FREQUENCY DEPENDS ON NEED AND WORKLOAD

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CLEANING VALIDATION PROBLEMS -- 2015

PRODUCT PROBLEMS

• Residue chemistry as basis for cleaning

• Solubility in worst-case residue determination

• Cleanability in worst case residue determination

EQUIPMENT-RELATED PROBLEMS

• Non-uniform contamination transfer

• Most difficult-to-clean locations

CLEANING PROCESS PROBLEMS

• Manual cleaning qualification

• Cleaning procedure documentation

• Dirty hold time (time to initiate cleaning)

LABORATORY PROBLEMS

• Residue stability in cleaning residue analysis

• Residue recovery studies

• Swab sampling technique, reliability, and training

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AUDIT QUESTIONS

• Is residue chemistry considered in developing cleaning procedure?

• Is pH-solubility profile considered in worst-case matrix analysis?

• Is residue “cleanability” considered in worst-case residue

determination?

• Is non-uniform contamination considered in residue calculations?

• Are most difficult-to-clean equipment locations proceduralized?

• Are manual cleaning personnel qualified and requalified?

• Are cleaning procedures quantitative and documented?

• Are dirty hold times controlled?

• Is residue stability considered in cleaning residue analytical?

• Have analytical recovery studies been conducted? On

representative materials?

• Are swab sampling personnel trained / qualified?

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CHANGING THE CLEANING CULTURE

Cleaning is a process --

Same as a manufacturing process.

Same expectations including accountability.

Equipment surfaces with residue

Cleaning process

Clean surface

“WE DO WHATEVER IT TAKES TO GET THE JOB DONE.”

Cleaning documentation = Manufacturing documentation

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VALIDATION DOCUMENT APPROVAL

VALIDATION APPROVAL COMMITTEE (VAC)

VAC must review documents with perspective of an

external regulatory auditor

• Assure acceptability of technical validation and product

quality

• Assure compliance with regulations, policies, and

industry expectations

• Assure acceptability of documentation.

– Spelling and grammar

VAC IMPORTANT PARTNER WITH VALIDATION

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PV GUIDANCE – OTHER APPLICATIONS

• Processes: Packaging, analytical, other

processes

• Equipment, utilities, facilities, controls

• Hybrid systems (water/HVAC)

• Quality systems

Benefit: All validations have same approach.

Design/Develop Demonstrate Monitor/Maintain

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SUMMARY

• Cleaning Validation Master Plan (CVMP) – Key document

• Apply PV lifecycle approach to cleaning validation

– Stage 1: Design / develop

– Stage 2: Demonstrate

– Stage 3: Monitor / maintain

• CVMP content

– Strategy and approach with procedures

– General supportive information applicable to all CV – Stage 1 information

– Completed cleaning validations

– Improvement projects with timeline commitments

– Completed improvement projects

• CV content

– Specific product cleaning information• Stages 1, 2, 3 specific information

– Associated analytical and equipment qualification

• CVMP revisions as needed (quarterly?)

• Culture, problems, Validation Approval Committee, applications

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PAUL L. PLUTA, PhD

Editor-in-Chief

Journal of Validation Technology

Journal of GXP Compliance

UBM Advanstar Communications

Associate Professor of Biopharmaceutics

University of Illinois at Chicago (UIC) College of Pharmacy

Chicago, IL, USA

Contact: [email protected]

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