Validation Bootcamp
Validation Bootcamp
Validation Bootcamp
LIFECYCLE APPROACH TO
PHARMACEUTICAL VALIDATION
PRINCIPLES, IMPLEMENTATION, AND PRACTICE
Paul L. Pluta, PhD
Journal of Validation Technology
Journal of GXP Compliance
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
OUTLINE
OBJECTIVES
Terminology
Validation and qualification
History and basis
Stages and activities
Implementation strategy
QUESTIONS:
DOES THIS MAKE SENSE?
HOW DO YOU APPROACH VALIDATION?
3
SCHEDULE
8:15
8:30
10:00
10:30
11:50
12:00
1:00
2:30
3:00
3:20
3:45
4:00
Part IV -- Implementation
Loose ends, Final Q&A, etc.
Summary
End
COMMENTS AND QUESTIONS ANY TIME
4
FILES
#1.
#2.
#3.
#4.
#5.
#6.
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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10
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14
15
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17
FMEA / FMECA
FTA
HAACP
HAZOP
PHA
Risk ranking and filtering
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ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Objectives
Global harmonization of quality systems
Consistency with ICH Q8 and Q9
Application throughout product lifecycle
Problems addressed
Inconsistent application
Inconsistent definitions of common terms
22
ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Overview and definitions
Management responsibility: Commitment,
policy, planning, resources, communication,
review, outsourcing
Continual improvement of performance and
quality: Lifecycle stages and elements
Continual improvement of quality system:
Management, monitoring, outcomes
23
ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Key points:
Quality system application throughout product lifecycle
Pharmaceutical development
Technology transfer
Manufacturing
Product discontinuation
Product realization, maintain control, improvements
Enable by knowledge and risk management
Management responsibility: Commitment, policy,
planning, resources, communication, review, outsourcing
oversight
24
ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Key points:
Continual improvement
Product performance / quality monitoring system
Control strategy, identify variation, problem feedback,
enhance process understanding
CAPA system
Enhance process understanding
Change management system
Risk management, evaluation, technical justification
Management review
Audits, inspections, changes, CAPA, etc.
25
ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Implications for Process Validation
Product performance and monitoring
CAPA system enhances process understanding
Change management system
Process improvements
26
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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SUPPORTING DOCUMENTS
PROCESS VALIDATION 1987 GUIDANCE
Assurance of product quality:
Quality parts and materials
Adequate product and process design
Control of the process
In-Process and end-product testing.
Basic principles:
Quality, safety, and effectiveness designed and built into the product
Quality cannot be inspected or tested in the product
Each process step must be controlled to maximize meeting quality and design
specifications.
R&D phase: Product definition and characteristics
Equipment and process
Equipment: Installation Qualification
Process: Performance Qualification
Product (devices only): Performance Qualification
Revalidation. Change control
Documentation. Proper maintenance of documentation
Reference: FDA Guideline on General Principles of Process Validation. May, 1987
29
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
31
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.
32
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.
33
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.
34
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.
35
SUPPORTING DOCUMENTS
PROCESS VALIDATION MEDICAL DEVICES
Process evaluation Validation or verification
Protocol development
Processes well thought out
What could go wrong
Installation Qualification
Operational Qualification
Worst case testing
DOE and screening studies
Performance Qualification
Process repeatability
Attributes for continuous post-validation monitoring and maintenance
Eliminate controllable causes of variation.
Maintaining a state of validation Monitor and control
Change control
Statistical Methods
Risk Analysis Methods
Reference: Global Harmonization Task Force (GHTF) Study Group 3. Quality
Management Systems Process Validation Guidance. January 2004.
36
SUPPORTING DOCUMENTS
VALIDATION INTERNATIONAL
PIC/S PHARMACEUTICAL INSPECTION CONVENTION
A series of experiments should be devised to determine the
criticality of process parameters / factors
Test processes with starting materials on the extremes of
specification
Monitoring and in-process controls
Reference: PIC/S Recommendations on Validation. July
2004.
37
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
38
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
39
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
40
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
41
SUPPORTING DOCUMENTS
PROCESS ANALYTICAL TECHNOLOGY (PAT)
Process Understanding
All critical sources of variability are identified and explained.
Variability is managed by the process
Product quality attributes can be accurately and reliably predicted
over the design space
Materials used
Process parameters
Manufacturing
Environmental
Other conditions
Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance. September
2004
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UO #1
Equipment #2
UO #2
Equipment #3
UO #3
Qualification
HVAC
Utilities
Facilities
Computers
Designed experiments
Lab scale and pilot scale experiments
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Procedures
Validation plans
Protocols
Sampling
Testing
Results
Plan to maintain validation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
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2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
VALIDATION PHILOSOPHY
Validation is confirmation.
Acceptable (passing) results are expected.
Validation is not
R&D
Final stage of development process
Optimization
Fine-tuning
Debugging
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SUMMARY
Lifecycle Approach to Process Validation
New document
Compilation of concepts pre-2000 to current
Three stages identified
Understand
Demonstrate
Maintain
Comprehensive
Detailed improvements
QUESTIONS:
DOES THIS MAKE SENSE?
HOW DO YOU APPROACH VALIDATION?
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SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D
Validation
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Commercialization
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SUMMARY
PROCESS VALIDATION HISTORY
1978
2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
SUMMARY
VALIDATION -- FUTURE
Development
Stage 1
Performance
Stage 2
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Maintenance
Stage 3
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VALIDATION DOCUMENTATION
Paul L. Pluta, PhD
OUTLINE
VALIDATION POLICY
VALIDATION POLICY
Describe general validation approach
Design and development . Science and technical
basis
Validation performance
Maintain validated state through monitoring, change
control, and management review
Risk analysis emphasis on highest risk
Sampling, testing, acceptance criteria
Variation identification and control
Continuing improvements
GENERAL POLICY WITH KEY POINTS
8
Process
Equipment
Facilities
Analytical
Computer
Others
10
Validation references
Ex: Products, equipment, utilities, etc. document ID
Procedures
Templates
Validation references
Planned validations
Planned projects
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RECOMMENDATION
1. Develop outlines for authors get agreements from
functional organizations and approval committee
2. Write or collect good documents
3. Documents available to writers
4. Replace (upgrade) as appropriate
15
What?
Why needed?
Why acceptable?
Impact of validation risk analysis
Approach to accomplish Validation Plan
Approvals
Why acceptable?
17
Prematurely written
Written to meet business goals
Written to demonstrate future intent
Introduction
Technical information
Validation strategy and testing
Validation documentation
References
VALIDATION PLAN
INTRODUCTION
Overview describing validation / product / process /
equipment / etc. (consistent with request)
Requirements to complete validation
23
VALIDATION PLAN
TECHNICAL INFORMATION
Basic product / process / equipment description
Formula
Process
Specifications
Include non-technical description information
Experimental studies
Past data (retrospective data)
Validation protocols
Other work
New procedures
VALIDATION PLAN
VALIDATION STRATEGY AND TESTING
Prospective validation only
Types of testing -- general
Regulatory specifications
Internal controls
Process tests
VALIDATION PLAN
VALIDATION DOCUMENTATION
Doc #
Title
Date closed
01
Validation request
02
03
04
05
06
07
VALIDATION PLAN
REFERENCES
R&D Reports
Development and analytical reports
Published literature
Scientific and technical support to validation plan
Report copies should be stored in validation area
or readily accessible (within 30 minutes)
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TECHNICAL REPORTS
Readily available
Consistent across large technical groups
Approved by management
Linked to original data
Observe / store original data
Original documentation practices?
VALIDATION PROTOCOLS
VALIDATION PROTOCOL
VALIDATION IS CONFIRMATION
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VALIDATION PROTOCOL
TESTING AND SAMPLING
Based on product specifications and testing
Exceed routine QA testing based on impact and risk
Consider the following:
VALIDATION PROTOCOL
FDA Powder Blends and Finished Dosage Units
Stratified Sampling and Assessment
Blend sampling. n = 10, Individuals, RSD
Tablets. 20 samples, n = 3-7 per location, mean,
range, RSD.
Application is possible approach for high risk
products
Supportive of USP Uniformity of Dosage Units on
composite / stratified samples
Product types: Potency and weight testing
33
VALIDATION SAMPLING
What is routine QA sampling?
Impact of change
High impact
Medium impact
Low impact
No impact
ENGINEERING STUDY
Conducted in advance of validation
No acceptance criteria
Trial run
Examples: Manufacturing process without
bulk drug (low dose API)
Process runs with placebo
Categories of Engineering Studies
Conduct Engineering Study concurrently with validation?
-- Not recommended
35
SAMPLING PAGES
Designed sheet with space for expected data
Data treatment specified
Signature and data of person supplying data
Highly recommended for Operators or persons not
familiar with sampling
Data pages consistent with sampling pages
Prevents missing data in complex protocols
Record sampling and / or testing
36
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
Sample #2
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
Sample #3
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
RECORDED BY:
__________
__________
__________
VERIFIED BY:
_____________
_____________
_____________
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Introduction
Unit operations
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance criteria with justification
HAVE MODEL DOCUMENTS AVAILABLE
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VALIDATION RESULTS
42
Missing data
Documentation practices on raw data
Raw data and results inconsistent
Inadequate or no discussion of results
Inadequate or no discussion of amendments or
deviations
No conclusion statement
Poor grammar and composition
44
VALIDATION REPORT
Recommended for complex projects
Recommended for multiple protocol projects
PRIMARY REPORT FOR AUDIT
Cut and Paste exercise from multiple documents
Best approach to avoid inconsistency
47
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 results Cut and paste
Protocol #2 results Cut and paste
Protocol #3 results Cut and paste
Protocol #n results Cut and paste
Write transitional narrative
Project conclusions (for Validation Plan)
Validation statement
Results indicate that ______ is validated.
HAVE MODEL DOCUMENTS AVAILABLE
48
STAGE 3 DOCUMENTS
CONTINUED PROCESS VERIFICATION
POST PQ DOCUMENTS
TYPES OF DOCUMENTS
Post PQ requirements work required based on PQ
results
Ongoing monitoring routine process monitoring
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QA
Validation
Production
Production
QA
Production
Validation
----QA
STAGE 3 DOCUMENTS
Regular management review of manufacturing data
Data analysis by statistical process control (SPC) principles
Review of all associated events, investigations, changes,
etc.
Record of management review
Expanded Annual Product Review, conducted at
appropriate intervals based on risk.
52
IQ, OQ, PQ
ASTM E2500
Same approach as with processes
Same philosophy
Same requirements
Same approval
Critical tests only
Non-critical tests in FAC, SAC, etc.
Do as much as possible in commissioning
Difference from PV: Do tests only once
Validation statement
Results indicate that _____is qualified.
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ANALYTICAL
Analytical methods validated
Analytical equipment qualified
QbD for analytical methods evolving
55
Personnel qualifications
FDA Warning Letter for inconsistent job
requirements (HR) and personnel resumes
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SUMMARY
COMPREHENSIVE, CONSISTENT, AND EFFECTIVE
VALIDATION DOCUMENTS
Validation documents consistent with validation guidelines and
expectations based on risk
Policies and VMP
Stage 1 -- Emphasis on development work supporting Stage 2
Technical basis for validation
Stage 2 -- Work should consider validation guidance recommendations
Plans, protocols, results
Stage 3 Emphasis on maintaining validated state through lifecycle
Specific needs and routine monitoring
Associated documents
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LIFECYCLE APPROACH
TO CLEANING VALIDATION
Paul L. Pluta, PhD
OUTLINE
Lifecycle Approach Applied to Cleaning Validation
Stage 1 Activities
Stage 2 Activities
Cleaning documentation
Validation conformance lots
Stage 3 Activities
Maintaining Validation
Change Control
Management review
OBJECTIVES
1. Application of lifecycle approach to cleaning
validation
2. Cleaning lifecycle stage details
Global experiences
Qualification
Equipment
Purified Water
Computer / software
Compressed air
Conductivity analysis
TOC analysis
Qualification
Personnel
Purified Water
Compressed air
Pre Lifecycle
Cleaning development (?)
PQ change control
________________________
Lifecycle Approach
Development PQ Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
11
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
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.
12
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
14
API insoluble
API insoluble
Final method: Acid wash, alkaline soap wash, water, PurW, dry
No residues
Unknown peaks determined to be degradants and flavors.
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
16
Drug A
Drug B
pH 1
12
17
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
150
250
Drug D
150
10
10
50
Drug E
125
10
100
250
Acids or bases
Monovalent salts
Polyvalent salts
Amino acids
Proteins (polypeptides)
Carbohydrates
Aqueous soluble organics
Non-aqueous soluble organics
Wetting
Emulsification
Dispersion
Solubility
Chelation
Oxidation
Hydrolysis
23
Water
Commodity alkalis and acids
Organic solvents
Surfactants
Anionic
Cationic
Amphoteric
Nonionic
Formulated detergents
24
Surfactants
Alkalis
Acids
Sequestrants / chelants
Dispersants / anti-redeposition agents
Corrosion inhibitors
Oxidizing agents
Enzymes
Buffers / builders
Preservatives
MUST HAVE CONTROL OF CLEANING AGENT
HAVE CONFIDENTIALITY AGREEMENT WITH SUPPLIER
25
CLEANING ENGINEERING
Factors affecting cleaning
Soil residue
Soil levels, soil condition, hold times, soil mixing,
water quality and residue,
26
CLEANING PROCESS
SOURCES OF VARIATION
EQUIPMENT TO BE CLEANED
Cleaning-related qualification
Product-contact materials
Compatibility with cleaning agents
Surface areas need for residue calculations
Equipment equivalence
Most-difficult-to-clean locations on equipment -- Highest
risk locations for sampling
Non-uniform contamination equipment
Non-uniform contamination sampling locations
Sampling methods (swab / rinse)
Part of IQ/OQ/PQ for manufacturing equipment
28
Physical changes
30
CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about cleaning between batches?
Equipment should be visually clean
Terminology: Between lot procedure
How much residue build-up?
DO NOT IDENTIFY AS BETWEEN LOT CLEANING
31
MANUAL CLEANING
Manual cleaning procedures should be
monitored and maintained with increased
scrutiny compared to non-manual procedures
More frequent training of cleaning personnel
Increased supervision
Periodic (annual?) revalidation batches
Manual cleaning is high risk
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33
Biotech molecules
API degraded non-specific method
UNDERSTAND RESIDUE CHEMISTRY
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SAMPLING
Sampling methods
Sampling (swab) critical activity
Training program
Trained sampling personnel
Demonstrated acceptable performance
Retraining considerations
Who does sampling? Personnel skills
37
SAMPLING TRAINING
CLEANING EQUIPMENT
CIP system must be qualified (IQ/OQ/PQ or ASTM
E2500)
Riboflavin (or other) coverage testing
Temperature controls
Flow rates, etc.
PAT inline systems
Drug disappearance spectrophotometry, other methods
Cleaning agent rinse -- conductivity
40
KEY POINTS
Exact concentration of cleaning agent liquid
Signature on quantitative steps
Grouping non-quantitative steps (e.g., disassembly)
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43
VALIDATION PROTOCOL
Cleaning validation protocols and other work
as specified in Validation Plan
Risk based
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CHANGE CONTROL
All associated personnel must be aware of
change control
Change control system developed
Process improvements expected based on
ongoing experience
Process improvements should be evaluated by
technical people (i.e., Stage 1)
Stage 2 PPQ conducted when appropriate
based on Stage 1 technical evaluation.
49
POST-VALIDATION MONITORING
Periodic review of cleaning performance
Deviations
Non-conformances (dirty equipment)
Re-cleaning
Change control
Other monitoring (CIP data)
Product APR data
Statistical Process Control data treatment
Management review -- documented
50
CLEANING DOCUMENTATION
High level documents
Specific cleaning validation documents
Design/Development, performance, monitoring/maintenance
51
CLEANING DOCUMENTATION
High level documents
Corporate policy
VMP (Cleaning VMP)
Stage 1 documents
Cleaning process development report
Analytical method development report
Supporting equipment documents (materials, surface areas, equivalent equipment,
sampling, etc.)
Stage 2 documents
Validation PPQ request, protocol, results
Cleaning equipment qualification
Cleaning procedure record
Stage 3 documents
Change control documents
Process monitoring
Management review
SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS
Understanding cleaning process
Residue properties
Residue degradation
Equipment characterization
Residue calculations
Materials of product contact
Surface areas
Worst-case areas for sampling based on risk
Non-uniform contamination
Equivalent equipment
54
SUMMARY ANALYTICAL
INCLUDING COMMON PROBLEMS
Understand residue
Solubility and stability
Validated analytical method for actual residue
Specific or non-specific analytical methods
SUMMARY
STAGE 2 PERFORMANCE
INCLUDING COMMON PROBLEMS
Cleaning Process Conformance Lots
Cleaning equipment qualified
Cleaning procedure specified (Not SOP)
Cleaning documentation
Request
Protocol
Results / Report
SUMMARY
STAGE 3 -- MAINTAINING VALIDATION
Change control -- evaluate impact of change
and validate (test) as necessary
Improve process
Improve control to detect and reduce
variability
Cleaning non-conformances and deviations
Periodic Management Review
57
VALIDATION
BOOT
CAMP
#4
LIFECYCLE
APPROACH
TO
PHARMACEUTICAL
VALIDATION
PRINCIPLES,
IMPLEMENTATION,
AND
PRACTICE
EQUIPMENT QUALIFICATION
LIFECYCLE APPROACH
Paul L. Pluta, PhD
OUTLINE
I.
II.
Qualification approaches
Documentation hierarchy
Document outlines
Documentation problems
#3
PROCESS IS VALIDATED
ALL SUPPORTING EQUIPMENT, FACILITIES, UTILITIES, CONTROL SYSTEMS,
ANALYTICAL, ETC. MUST BE QUALIFIED.
4
Validation is confirmation
Risk analysis determines everything
Science and technical basis for design and development
Lifecycle approach
Understand, demonstrate, monitor and maintain
VALIDATION IS CONFIRMATION
Successful validation is expected.
Do not initiate validation unless success is
expected.
Validation is not the final step in development,
installation, optimization, fine-tuning, or other
development activities.
Amendments, mistakes, failures scope changes,
etc. all have negative implications.
RISK MANAGEMENT
Risk defines everything.
Test only critical equipment parameters in
validation. Risk level determines level of testing.
Test non-critical equipment parameters during
commissioning.
Document risk assessment.
10
EQUIPMENT QUALIFICATION
Qualification approaches
DQ / IQ / OQ / PQ (IQ for medical devices)
ASTM E2500
Documentation hierarchy
Document outlines
Model documents
12
QUALIFICATION APPROACHES
DQ / IQ / OQ / PQ
Traditional qualification
DQ Multiple functions and applications
Purchasing document
Equipment design document
13
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
Preventive maintenance
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
14
PQ
Functional Specification
OQ
Design Specifications
IQ
System Build
15
15
16
EQUIPMENT QUALIFICATION
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.
17
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
18
ASTM E2500
19
ASTM E2500
20
21
DOCUMENTATION HIERARCHY
Company policy
Validation Master Plan
DQ
Design and development
SAT / FAC
Commissioning
Validation / Qualification Request / Plan
IQ /OQ /PQ Protocol / Results / Report
Post Validation Monitoring / Maintenance
Change control
Associated technical document (e.g., manuals, etc.)
Associated documents (e.g., training, HR)
Management Review
CONSISTENT LIFECYCLE APPROACH
22
DOCUMENT OUTLINES
Validation Initiation
Validation Plan
IQ Protocol and Results
OQ Protocol and Results
PQ Protocol and Results
IQ/OQ/PQ Report
23
Why acceptable?
24
References
PROTOCOL OUTLINE
Introduction
Equipment
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance criteria with justification
HAVE MODEL DOCUMENTS AVAILABLE
26
RESULTS OUTLINE
Introduction
Data sheets compiled
Data treatment
Results
Deviations, Non-conformances, etc.
Discussion
Results pass is not sufficient.
Validation statement:
Results indicate that ___ is validated / qualified.
Post-validation plan
WRITE DISCUSSION SECTION FIRST MOST IMPORTANT SECTION
HAVE MODEL DOCUMENTS AVAILABLE
27
QUALIFICATION REPORT
Combined IQ / OQ / PQ results
Helpful in audit total summary
Cut and paste results and conclusions sections
Consistency and completeness important
28
REPORT FORMAT
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 results Cut and paste
Protocol #2 results Cut and paste
Protocol #3 results Cut and paste
Protocol #n results Cut and paste
Write transitional narrative
Project conclusions
Validation statement
Results indicate that ______ is validated / qualified.
HAVE MODEL DOCUMENTS AVAILABLE
29
30
DOCUMENTATION PROBLEMS
Qualification statement: ________ is qualfied.
Documentation content
o Scientific and technical
o Compliance with policies/procedures/regulations
Documentation rules
Others
31
DOCUMENTATION
THREE SIMPLE RULES
1. Clear, complete, concise, consistent
2. Stand-alone documents written for the
reader
3. Short sentences and simple words
32
SUMMARY
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
33
PAUL
L.
PLUTA,
PhD
Editor-in-Chief
Journal
of
Valida-on
Technology
Journal
of
GXP
Compliance
Advanstar
Communica.ons
Contact: [email protected]
34
PRESENTATION
OUTLINE
1.
2.
3.
4.
5.
Objectives
Attributes
Parameters
Risk management
PLEASE PARTICIPATE
2
PRESENTATION OBJECTIVES
1.
Applica2on
of
QbD
and
lifecycle
principles
to
the
Valida2on
Quality
System
2.
Design
of
the
Valida2on
Quality
System
3.
Objec2ves
of
Valida2on
Quality
System
4.
Quality
AFributes
of
Valida2on
Quality
System
5.
Parameters
aec2ng
aFributes
6.
Control
of
variables
aec2ng
quality
system
performance
7.
Risk
management
8.
Monitoring
performance
Con2nuous
improvements
VALIDATION: VALIDATED PRODUCT and INFRASTRUCTURE
AUDIT QUESTIONS
WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?
Unit
Op
#1
Unit
Op
#2
Unit
Op
#3
QualicaRon
HVAC
U2li2es
Facili2es
Computers
Process
is
validated
PROCESS
OF
VALIDATION
LIFECYCLE
APPROACH
TO
PROCESS
VALIDATION
DeniRon:
Collec2on
and
evalua2on
of
data,
from
the
process
design
stage
throughout
commercial
produc2on,
which
establishes
scien2c
evidence
that
a
process
is
capable
of
consistently
delivering
quality
products.
Process
validaRon
involves
a
series
of
acRviRes
over
the
lifecycle
of
the
product
and
process.
VALIDATION
HISTORY
1978
--
CGMP
includes
Valida2on
Con2nuum
---
UNDERSTANDING
VALIDATION
MAINTENANCE
Quality System
Materials System
Production system
Equipment and Facilities System
Packaging and Labeling System
Laboratory Controls System
11
RISK MANAGEMENT
12
VALIDATION
FUNCTION
PRODUCT
AND
INFRASTRUCTURE
Two
components:
1.Validated
products,
processes
(manufacturing,
cleaning,
packaging,
etc.),
equipment,
u2li2es,
facili2es,
control
systems,
computer
systems,
analy2cal
instruments
the
product
of
the
valida2on
func2on.
2.The
process
of
accomplishing
valida2on
the
infrastructure
of
the
valida2on
func2on.
Protocols,
results,
documenta2on
packages,
approval
commiFee,
etc.
13
Objectives
Quality Attributes
Parameters
Variables and control
Risk assessment
Continuous improvement
VALIDATION
PRODUCT
PRODUCT
:
All
validated
products,
processes
(cleaning,
packaging,
analy2cal,
etc.),
equipment,
facili2es,
control
systems,
computers,
etc.,
including
documenta2on.
DocumentaRon
arming
performance
QUALITY
SYSTEM
FDA
Deni2on:
Formalized
business
prac2ces
that
dene
management
responsibili2es
for
organiza2onal
structure
processes,
procedures,
and
resources
needed
to
fulll
product/service
requirements,
customer
sa2sfac2on,
and
con2nual
improvement.
Management
responsibili2es
Resources
Manufacturing
Evalua2on
16
Promote improvement
17
18
Risk management
Highest risk activities prioritized
20
Risk analysis
Documentation
Abributes
What
makes
a
process
step
successful?
Parameters
What
factors
signicantly
inuence
the
success
of
the
process
step?
Risk
management
What
are
highest
risk
ac2vi2es?
Priori2za2on,
evalua2on,
and
review
highest
level
for
highest
risk
EvaluaRon
Review
performance
of
valida2on
quality
system
23
DESIGN
and
DEVELOPMENT
PQ
MONITORING
MAINTENANCE
OBJECTIVE
QUALITY
ATTRIBUTES
PARAMETERS
CONTROL
OF
VARAITION
RISK
24
QUALITY
SYSTEM
Throughput
External
audit
observa2ons
Documenta2on
quality
Open
valida2on
projects
2me
open
Valida2on
failures
Protocol
amendments
Protocol
devia2ons
Other
29
OTHER
APPLICATIONS
QbD
/
Lifecycle
approach
to
other
quality
systems
Documenta2on
in
QSMP
Examples:
Material
system
Heparin
Manual
cleaning
Methotrexate
Training
Read
and
sign
vs.
OTJ
30
SUMMARY
QbD (QSbD) / Lifecycle Approach to the Validation Quality System
Concepts and Principles
Objectives
Attributes
Parameters
Risk management
Performance
33
SUMMARY
34
SUMMARY
35
SUMMARY
Review Performance
Gap analysis: Problem areas
36
SUMMARY
37
38
IMPLEMENTATION
MANUFACTURING
PROCESSES
OTHER
PROCESSES
EQUIPMENT,
FACILITIES,
UTILITIES
VALIDATION
QUALITY
SYSTEM
OTHER
QUALITY
SYSTEMS
Paul
L.
Pluta,
PhD
OUTLINE
1.
Status
of
Implementa6on
2.
Posi6ves
and
Nega6ves
3.
Implementa6on
Strategy
and
Approach
4.
Impediments
to
Implementa6on
Why
implement?
Guidance
documents
--
Lifecycle
approach
is
the
future
Lifecycle
approach
makes
sense
Auditors
learning
the
lifecycle
approach
IMPLEMENTATION
1. Iden6fy
high
risk
areas
2.
3.
4.
5.
6.
7.
PRIORITIZATION
1.
Manufacturing
process
valida6on
2.
Others
IMPLEMENTATION
MANUFACTURING
PROCESS
VALIDATION
Stage
1
groups
Stage
3
groups
IMPLEMENTATION -- REALITY
10
FINAL
Q
&
A
Did
we
meet
objec6ves?
11
12