This full day presentation gives an overview of the process validation lifecycle approach, the FDA PV Guidance, the lifecycle approach to cleaning validation, equipment qualification, and validation quality systems.

1. VALIDATION BOOT CAMP
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
1

2. OUTLINE
• Process Validation Lifecycle Approach Overview
• FDA PV Guidance
• Documentation
• Lifecycle Approach to Cleaning Process Validation
• Lifecycle Approach to Equipment Qualification
• Lifecycle Approach to Validation Quality System
• Implementation Strategy
• Interactive Discussion. Attendees discuss lifecycle
approach to process, other applications, positives/
negatives, and impediments to implementation
throughout day.
PLEASE PARTICIPATE
2

3. OBJECTIVES
• Validation lifecycle approach basic understanding
– Terminology
– Validation and qualification
– History and basis
– Stages and activities
• Documentation for lifecycle approach
– Comprehensive
– New specific expectations
• Applications according to lifecycle approach
– Processes, Cleaning, EFU
– Validation quality system
– Other quality systems
• Implementation strategy
QUESTIONS:
DOES THIS MAKE SENSE?
HOW DO YOU APPROACH VALIDATION?
3

4. SCHEDULE
8:15 Registration, welcome and opening remarks
8:30 Part I. Introduction, basis, lifecycle stages
10:00 Break – Specific requests / clarifications
10:30 Part II. Documentation
11:50 Morning assessment
12:00 Lunch – Specific requests / clarifications
1:00 Part III. Applications -- Cleaning, EFU, Quality Systems
2:30 Break – Specific requests / clarifications
3:00 Part IV -- Implementation
3:20 Loose ends, Final Q&A, etc.
3:45 Summary
4:00 End
COMMENTS AND QUESTIONS ANY TIME
4

5. FILES
#1. Overview and history
#2. Documentation
#3. Cleaning
#4. Equipment
#5. Validation Quality System
#6. Implementation
5

6. INTRODUCTION, BASIS, LIFECYCLE STAGES
• History and Development
• Fundamental Concepts
• Consistency with Medical Devices
IS THE LIFECYCLE APPROACH REALLY NEW?
6

7. 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2008 – FDA draft guidance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 issued
2012 – EMA draft guidance
7

8. 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 8-42.
8

9. HEALTH CANADA -- VALIDATION GUIDELINES FOR
PHARMACEUTICAL DOSAGE FORMS (GUI-0029)
5.0 Phases of Validation
Phase 1: Pre-Validation Phase
Phase 2: Process Validation Phase (Process Qualification Phase
Phase 3: Validation Maintenance Phase
6.0 Interpretation
Validation protocol
Validation Master Plan
Installation and Operational Qualification
IQ
OQ
Re-Qualification
Process validation
Prospective validation
Matrix or family approaches to prospective process validation
Concurrent validation
Retrospective validation
Process Re-Validation
Change control
9

10. 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
10

11. 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
11

12. ICH Q8 PHARMACEUTICAL DEVELOPMENT
Key points
“Information and knowledge gained from development
studies and manufacturing experience provides scientific
understanding to support the establishment of the design
space, specifications, and manufacturing controls.”
“Pharmaceutical development section should describe the
knowledge…”
“At a minimum, those aspects of drug substances,
excipients, … that are critical to product quality should be
determined and control strategies justified.”
“…demonstrate a higher degree of understanding of
material attributes, manufacturing processes …”
12

13. ICH Q8 PHARMACEUTICAL DEVELOPMENT
Key points
Examination
Understanding
Evaluation
Identification
Rationale and justification
Others
Discussion in submission
13

14. ICH Q8 PHARMACEUTICAL DEVELOPMENT
Implications for Process Validation
Process understanding
Process development studies are basis for
process validation
Continuous process verification is
alternate to process validation
14

15. 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
15

16. ICH Q9 QUALITY RISK MANAGEMENT
Principles of quality risk management
• General process: Initiation, assessment, control,
communication, review
• Methodology
• Integration into industry and regulatory
operations
• Methods and tools
• Potential specific applications
16

17. ICH Q9 QUALITY RISK MANAGEMENT
• Initiate risk management process
• Risk assessment
• Risk identification
• Risk analysis
• Risk evaluation
• Risk control
• Risk reduction
• Risk acceptance
• Output
• Risk review
17

18. ICH Q9 QUALITY RISK MANAGEMENT
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
18

19. ICH Q9 QUALITY RISK MANAGEMENT
Applications
• Integrated quality management: Documentation,
training, defects, auditing, periodic review, change
control, improvements
• Regulatory operations
• Development: Process knowledge, PAT development
• Facilities, equipment, utilities: Design, qualification,
cleaning, calibration, PM
• Materials management: Material variation
• Production: Validation, in-process testing
• Laboratory control and stability
• Packaging and labeling
19

20. ICH Q9 QUALITY RISK MANAGEMENT
Key points
• Methods of evaluation
• Potential applications – every function, every
activity, entire product lifecycle
20

21. ICH Q9 QUALITY RISK MANAGEMENT
Implications for Process Validation
• Development: Process knowledge
• Materials: Variation, change control
• Equipment: Qualification, cleaning, calibration,
PM, change control
• Production: Validation, sampling, testing,
change control
• Maintenance / monitoring: Testing
21

22. 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

23. 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

24. 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

25. 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

26. ICH Q10
PHARMACEUTICAL QUALITY SYSTEMS
Implications for Process Validation
• Product performance and monitoring
• CAPA system enhances process understanding
• Change management system
• Process improvements
26

27. 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
27

28. 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
28

29. 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

30. 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)
30

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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
42

43. TERMINOLOGY: PROCESS VALIDATION
Process Validation – Process Qualification
Process Performance Qualification (PPQ)
Qualification Qualification
Equipment #1 HVAC
UO #1
Utilities
Equipment #2 Facilities
UO #2
Computers
Equipment #3
UO #3
Analytical methods validation
Cleaning process validation
Packaging process validation
Process is validated
43

44. 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
44

45. FDA PROCESS VALIDATION GUIDANCE
“Before …commercial distribution to consumers, a manufacturer
should have gained a high degree of assurance in the performance
of the manufacturing process…consistently produce …”
Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and product
attributes
• Control the variation in a manner commensurate with risk to process
and product.”
“…to justify commercial distribution of the product.”
“… use ongoing programs to collect and analyze product and process
data … state if control of the process.”
45

46. FDA PROCESS VALIDATION GUIDANCE
Good project management and good archiving to capture
scientific knowledge.
Enhance accessibility of information later in lifecycle.
Integrated team approach: Process engineering, industrial
pharmacy, analytical chemistry, microbiology, statistics,
manufacturing, and quality assurance.
Scientific studies throughout the product lifecycle planned,
documented, and approved.
Greater control over higher-risk attributes.
Reevaluate risks throughout product/process lifecycle.
Homogeneity with batch and consistency between batches
are goals of process validation.
46

47. 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
47

48. 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
48

49. QUALITY BY DESIGN (QbD)
1. Quality target product profile (QTTP)
2. Critical quality attributes (CQA), critical material
attributes (CMA)
3. Critical process parameters (CPP)
4. Design space
5. Scale-up and technology transfer
6. Identify input variables
7. Input variable control strategy
8. Continuous improvement
Other considerations: PAT, Risk analysis
49

50. 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
50

51. STAGE 2, PROCESS QUALIFICATION
Conformance Lots
Procedures
Validation plans
Protocols
Sampling
Testing
Results
Plan to maintain validation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
51

52. 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
52

53. PERFORMANCE QUALIFICATION APPROACH
“The PPQ lots should be manufacturer under normal conditions by
personnel expected to routinely perform each step of each unit
operation in the process. Normal operating conditions should cover
the utility systems (air handling and water purification), material,
personnel environment, and manufacturing procedures.”
PQ report:
• Discuss all aspects of protocol
• Summarize and analyze data as specified in protocol
• Evaluate unexpected observations and additional data
• Summarize and discuss non-conformances
• Describe corrective actions or changes
• Clear conclusions
• Approval by appropriate departments and quality unit
DETAILS FROM PV GUIDANCE
53

54. 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
54

55. CONTINUED PROCESS VERIFICATION
Monitoring
Statistical process control
Trend analysis
Change control
Continuous improvement
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
55

56. CONTINUED PROCESS VERIFICATION
ITEMS TO BE REVIEWED
• Product and process data
• Relevant process trends
• Quality of incoming materials or components
• In-process material
• Finished products
• Defect complaints
• OOS findings
• Deviations
• Yield variations
• Batch records
• Incoming raw material records
• Adverse event reports
• Production operator and quality staff feedback
Above should help identify possible product / process improvements
DETAILS FROM PV GUIDANCE
56

57. 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
• PPQ 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
57

58. PROCESS VALIDATION HISTORY
1978
CGMP includes Validation
1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
58

59. VALIDATION PHILOSOPHY
• Validation is confirmation.
• Acceptable (passing) results are expected.
• Validation is not
– R&D
– Final stage of development process
– Optimization
– Fine-tuning
– Debugging
59

60. 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?
60

61. SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D Validation Commercialization
61

62. 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
62

63. SUMMARY -- WHERE WE ARE GOING –
LIFECYCLE APPROACH TO PROCESS VALIDATION
Lifecycle approach:
• Validation is never completed
• Validation is always ongoing
Objectives:
• Scientific and technical process
• Demonstrate process works as intended
• Process must remain in control throughout lifecycle
EFFECTIVE DOCUMENTS CONSISTENT WITH THE ABOVE
63

64. LIFECYCLE APPROACH TO PROCESS VALIDATION
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.”
64

65. SUMMARY
PROCESS VALIDATION HISTORY
1978
CGMP includes Validation
1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
65

66. SUMMARY
VALIDATION -- FUTURE
Development Performance Maintenance
Stage 1 à Stage 2 à Stage 3
66

67. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: paul.pluta@comcast.net
67

68. VALIDATION BOOT CAMP #2
LIFECYCLE APPROACH TO
PHARMACEUTICAL VALIDATION –
PRINCIPLES, IMPLEMENTATION, AND PRACTICE
VALIDATION DOCUMENTATION
Paul L. Pluta, PhD
1

69. OUTLINE
• Validation Documents Overview
• Validation Policy Documents
• Stage 1 Process Design Documents
• Stage 2 Process Qualification Documents
– Validation Requests and Plans
– Validation Protocols
– Validation Results and Reports
• Stage 3 Continued Process Verification Documents
• Associated Documents
• Document Outlines / Templates
• Document Problems
2

70. IMPORTANCE OF VALIDATION DOCUMENTS
• Validation documents always requested in regulatory
audits
• Documentation is retained forever
• Documents reviewed long after people are gone
– Documents must “stand alone”
• Early documents (Request, Plan, Protocol) reviewed
when project is in-progress or not completed
• FDA auditors often focus on documentation – validation
documents often requested ahead of audit
Above sometimes difficult for technical people
3

71. SCOPE OF VALIDATION DOCUMENTS
FDA Process Validation Guidance has greatly expanded
the scope of validation
• Lifecycle approach – documents from development through
commercialization
• Traditional validation documents (protocol and results) less
important
Validation organizations should lead sites in transition to
lifecycle approach
• Multiple groups at site must now contribute to process validation
lifecycle approach documents
Lifecycle approach being applied to all validation and
qualification (equipment, facilities, cleaning, etc.)
4

72. VALIDATION DOCUMENTS -- BASICS
• Written for the reader – US vs. Europe
• Objective: Understanding
• Clarity much more important than brevity
• Stand-alone document
• Potential for review in 10+ years
• Author / Management not available for explanation
• Spelling and grammar correct
– Need good writers
– Simple sentences
– Simple words
5

73. PROCESS VALIDATION DOCUMENTS
• 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
6

74. VALIDATION POLICY
• Corporate or company policies
• High level overview documents
• Apply to all global manufacturing sites
• State agreement with local regulatory
requirements
• State agreement with customer regulatory
documents
• Specific corporate requirements
• Describe general validation approach
7

75. 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

76. VALIDATION MASTER PLAN (VMP)
PROGRAM DESCRIPTION AT SITE
• Comprehensive lifecycle approach based on risk
• Consistent with general policy
MULTI-CHAPTER DOCUMENT
• Chapter for each major area (may have individual VMP per area)
– Process
– Equipment
– Facilities
– Analytical
– Computer
– Others
UPDATED AS NEEDED (Annual, quarterly, monthly)
• VMP must be current for audits
IMPROVEMENT PROJECTS COMMITMENTS AND TIMELINES
9

77. VALIDATION MASTER PLAN (VMP)
SITE PROGRAM DESCRIPTION
• Design and development . Science and technical basis
• Validation performance
• Maintain validated state through monitoring, change
control, and management review
• Risk analysis – emphasis on high risk activities
• Variation identification and control
• Continuing improvements
10

78. VALIDATION MASTER PLAN (VMP)
CHAPTER CONTENT
Content for processes, cleaning, analytical, etc.
• Strategy and approach
• Procedures
• Supporting information (reference)
– Ex: Product validation families, Cleaning matrix
• Validation references
– Ex: Products, equipment, utilities, etc. document ID
• Validation commitments and timelines
• Improvement projects and timelines
11

79. VMP CHAPTER EXAMPLE – CLEANING VALIDATION
Strategy and approach
• Comprehensive lifecycle approach, Science and technical basis, Risk analysis,
Variation identification and control (consistent with site and corporate docs)
Procedures
• List of approved procedures
Supporting information with reference documentation
• Product cleaning matrix
• Equivalent equipment
• Equipment surface area calculations
• Residue calculations
• Technical reports
• Templates
Validation references
• List of all completed cleaning validation
Validation commitments and timelines
• Planned validations
Improvement projects and timelines
• Planned projects
12

80. STAGE 1 DOCUMENTS -- PROCESS DESIGN
Technical areas must be aware that their documents are critical to
validation throughout the product lifecycle.
• Direct support of Stage 2 PQ – their work is basis of validation
• R&D technical reports consistent with raw data
• Rapidly retrieved (within 30 minutes)
• Accessed throughout product lifecycle
• Personal support of regulatory audits
• Stand-alone documents
• Applies to processes, cleaning, analytical, equipment, facilities,
utilities, control systems, others.
R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE
REQUIREMENTS AND EXPECTATIONS
13

81. STAGE 1 DOCUMENTS – POTENTIAL PROBLEMS
• Reports not available
• Reports not retrievable
• Reports incomplete
• Reports poorly written
• Reports not approved
• Personnel not available
• Original data not available
• Substandard documentation practices – original data
• No signature / date
• Data transpositions
• Data transfer problems
• Data transfer not verified
• Inconsistent data
• Multiple sources of same data inconsistent
14

82. VALIDATION STAGE 2 DOCUMENTS
OPTIONS
• Outlines
• Templates
• Model documents
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

83. STAGE 2 DOCUMENTS – PROCESS QUALIFICATION
VALIDATION REQUEST AND VALIDATION PLAN
INITIATION OF VALIDATION
Request: Statement of recommended validation
• What?
• Why needed?
• Why acceptable?
• Impact of validation – risk analysis
• Approach to accomplish – Validation Plan
• Approvals
Plan: Details of work to accomplish validation
• Description of strategy and approach
• References from Stage 1 work supporting validation
• Approvals
MAY BE SINGLE DOCUMENT OR TWO SEPARATE DOCUMENTS
16

84. VALIDATION REQUEST OUTLINE
• Objective of validation
• Why needed?
• Impact of validation
– Risk analysis
• Why acceptable?
– Compliance to internal requirements, policies, engineering standards, etc.
– Regulatory impact (Prior approval, CBE, CBE30, etc.)
– Other systems or product impacted
– Procedure changes or other document changes
– Notifications to affected groups (internal, external, labs)
• Validation plan -- Approach to accomplish validation
Above applicable to equipment and other qualification
HAVE MODEL DOCUMENTS AVAILABLE
17

85. VALIDATION REQUEST -- PROBLEMS
• Poorly written
– Inadequate information
• Prematurely written
– Written to meet business goals
– Written to demonstrate future intent
• Amendments necessary -- changes usually required
Validation requests should be submitted for approval only
after objective and scope of validation is determined and
work details (risk/testing/sampling) determined.
Amendments are a planning failure regardless of
justification.
HAVE MODEL DOCUMENTS AVAILABLE
18

86. VALIDATION REQUEST TERMINOLOGY EXAMPLES
Validation request:
Process validation of Product A
System: New product validation
Change impact: High impact. New product validation
Reason: New product to be manufactured at site
Acceptability:
• Compliant with policies
• Regulatory approval
• Other systems impacted (e.g., cleaning)
• Procedures approved
• Notifications (Labs)
Justification: See Validation Plan
Approvals
SIMPLE AND CLEAR
19

87. VALIDATION REQUEST TERMINOLOGY EXAMPLES
Validation request:
Qualification of 150 cu. ft. blender
System: New equipment qualification
Change impact: High impact. New equipment and new size at site
Reason: New equipment to increase manufacturing efficiency and
throughput
Acceptability:
• Compliant with policy
• Regulatory approval
• Other systems impacted (e.g., cleaning)
• Procedures approved
• Notifications (Labs)
Justification: See Validation Plan
Approvals
SIMPLE AND CLEAR
20

88. VALIDATION REQUEST TERMINOLOGY EXAMPLES
Validation request:
Change air supply and return ductwork to coincide with Line 1 floor space
changes
System: HVAC system #3
Change impact: Medium impact. Change to direct product contact support
utility
Reason: Room configuration change to increase manufacturing efficiency
Acceptability:
• Compliant with policy
• Regulatory approval not needed
• Other systems impacted
• Procedures approved, drawings modified, etc.
• Notifications
Justification: See Validation Plan
Approvals
SIMPLE AND CLEAR
21

89. VALIDATION PLAN OUTLINE
• Introduction
• Technical information
• Validation strategy and testing
• Validation documentation
– List of required protocols, reports, procedures, etc.
– Administrative benefit
• References
– List of reports and scientific references (including Stage 1
reports)
HAVE MODEL DOCUMENTS AVAILABLE
22

90. VALIDATION PLAN
INTRODUCTION
• Overview describing validation / product / process /
equipment / etc. (consistent with request)
• Requirements to complete validation
– Conformance to regulations and internal policy
– Impact of change to maintain the validated state
– Impact on regulatory submission
– Impact of change on procedures, drawings, other documents
– Notifications to other areas internal and external (e.g.,
environmental agency, internal test labs) impacted by validation
23

91. VALIDATION PLAN
TECHNICAL INFORMATION
• Basic product / process / equipment description
– Formula
– Process
– Specifications
– Include non-technical description information
• Technical aspects of validation / qualification
• Reference to technical reports from Design Stage
• Total validation approach
– Experimental studies
– Past data (retrospective data)
– Validation protocols
– Other work
– New procedures
• Number of lots – related to impact of change and risk
WRITTEN FOR THE READER
24

92. VALIDATION PLAN
VALIDATION STRATEGY AND TESTING
• Prospective validation only
• Types of testing -- general
– Regulatory specifications
– Internal controls
– Process tests
• Tests and rationale – general
– Address changes – based on risk analysis
• Sampling and rationale – general
– Exceed routine QA testing – based on impact and risk analysis
• Data treatment – general
– Statistical data treatment and confidence limits
• Acceptance criteria – general
DETAILS OF ABOVE PROVIDED IN PROTOCOLS
25

93. VALIDATION PLAN
VALIDATION DOCUMENTATION
Doc # Title Date closed
01 Validation request
02 XXX Dryer Engineering Study
03 XXX Dryer Qualification
04 XXX Process Scale-up Engineering Study
05 XXX Process Validation
06 Update Validation Master Plan – Product and
Equipment sections
07 XXX Project Summary Report
26

94. 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)
27

95. PRODUCT / PROCESS DESIGN INFORMATION
• Technical reports from R&D
• Pharmaceutics reports
• Formulation and process development reports (CQA, CMA, CPP)
• Technology transfer / Scale-up reports
• Identification of sources of variation
• Variation control plans
• Analytical methods
• Other technical reports
REPORTS SHOULD BE REVIEWED FOR CONSISTENCY BETWEEN
GROUPS
REPORTS SHOULD BE REFERENCED IN VALIDATION PLAN
28

96. TECHNICAL REPORTS
• Readily available
• Consistent across large technical groups
• Approved by management
• Linked to original data
– Observe / store original data
– Original documentation practices?
VALIDATION MUST REVIEW ORIGINAL DATA
• Rapidly retrievable
• Consistent with technical report
• Documentation practices
29

97. VALIDATION PROTOCOLS
• Execution of the Validation Plan
• Testing details
• Sampling details
• Data sheets
• Data treatment
• Acceptance criteria
• Minimal text repetition from Validation Plan
PROTOCOL EASILY WRITTEN IF
VALIDATION PLAN IS THOROUGH
30

98. VALIDATION PROTOCOL
• Objective of validation – specific protocol
• Validation description – specific
• Validation approach
• Testing and rationale -- specific
• Sampling and rationale -- specific
• Data sheets (summary)
• Data treatment -- specific
• Acceptance criteria – specific
– All testing must have acceptance criteria
– No FYI testing in validation
VALIDATION IS CONFIRMATION
31

99. VALIDATION PROTOCOL
TESTING AND SAMPLING
• Based on product specifications and testing
• Exceed routine QA testing based on impact and risk
Consider the following:
• Product for seizures
• Product for hypertension
• New product
• Change in compressing machine
• Increase compressing machine speed
• Change in granulation method
• Change in batch size
Risk analysis in above
32

100. 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

101. VALIDATION SAMPLING
What is routine QA sampling?
Impact of change
• High impact
• Medium impact
• Low impact
• No impact
Risk analysis – Related to numerical RPN analysis
• High risk
• Medium risk
• Low risk
RISK LEVEL MUST BE ACKNOWLEDGED
34

102. 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

103. 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

104. SAMPLING / DATA PAGE EXAMPLE
UNIT OPERATION: Tablet compressing, lot # ________________
TEST: Content Uniformity (SOP # XX-XXX)
SAMPLE: 10 Tables each from beginning, middle, and end of batch
Sample #1 by _________ Date _________
Sample #2 by _________ Date _________
Sample #3 by _________ Date _________
TEST RESULTS (Circle P -- Pass or F -- Fail)
Sample #1 Sample #2 Sample #3
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
_____ P/F _____ P/F _____ P/F
RECORDED BY:
__________ __________ __________
VERIFIED BY:
_____________ _____________ _____________
37

105. PROCESS VALIDATION PROTOCOL (PPQ)
FDA GUIDLINE RECOMMENDATIONS
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
• Status of analytical method validation
• Review and approval by appropriate departments and quality unit
38

106. VALIDATION PROTOCOL OUTLINE
Introduction
Unit operations
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance criteria with justification
HAVE MODEL DOCUMENTS AVAILABLE
39

107. VALIDATION PROTOCOL -- PROBLEMS
No plan
No basic explanation of validation
No statement of strategy and approach
No test rationale
No sampling rationale
Missing samples – missing data
How to treat data
No discussion of results
No acceptance criteria rationale
No validation statement
Poorly written
WRITTEN FOR THE READER
40

108. VALIDATION PROTOCOL -- PROBLEMS
How many lots should be tested?
Consider impact of change.
Consider product.
Consider process.
Consider risk.
ABOVE ADDRESSED IN VALIDATION PLAN
41

109. VALIDATION RESULTS
• Compilation of testing required in protocol
• Deviations or adverse events
• Discussion
• Conclusion
WRITE GOOD PLAN
PROTOCOL CONSISTENT WITH PLAN
RESULTS CONSISTENT WITH PROTOCOL
WRITE DISCUSSION FIRST – MOST IMPORTANT SECTION
42

110. VALIDATION 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.”
Post-validation monitoring plan
WRITE DISCUSSION SECTION FIRST – MOST IMPORTANT SECTION
HAVE MODEL DOCUMENTS AVAILABLE
43

111. VALIDATION RESULTS PROBLEMS
• 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

112. VALIDATION RESULTS / REPORT -- PROBLEMS
Protocol requires BME samples for potency.
Acceptance criteria: 95-105%
B = 95%
M = 100%
E = 105%
All results pass
Conclusion?
POST PQ MONITORING?
45

113. VALIDATION RESULTS / REPORTS -- PROBLEMS
Protocol requires BME testing
Acceptance Criteria: Not More Than 6.0%
Results:
B = 2.0%
M = 2.1%
E = 6.0%
All data pass acceptance conclusions.
Conclusions?
POST PQ MONITORING?
46

114. 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

115. VALIDATION 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 (for Validation Plan)
• Validation statement
– “Results indicate that ______ is validated.”
HAVE MODEL DOCUMENTS AVAILABLE
48

116. 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
49

117. STAGE 3 DOCUMENT RESONSIBILITIES
PQ REQUIREMENTS
Requirements specified in PQ results
• Continued monitoring of critical test results
– High risk activities
• Continued monitoring of aberrant values
• Continued monitoring of statistical (CL) failures
50

118. 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
51

119. 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

120. ASSOCIATED VALIDATION AND
QUALIFICATION DOCUMENTS
Equipment qualification
• All manufacturing process equipment and
associated control systems
• Example: Drug dispensing qualification
(equipment, facilities, HVAC, personnel, etc.)
• All facilities, utilities, systems, etc.
Analytical method validation
• Analytical equipment qualification
ABOVE MENTIONED IN PV GUIDANCE
53

121. EQUIPMENT, FACILITIES, UTILTIES, ETC.
QUALIFICATION
• 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.”
54

122. ANALYTICAL
• Analytical methods validated
• Analytical equipment qualified
• QbD for analytical methods evolving
55

123. OTHER ASSOCIATED DOCUMENTS
Training records
• Operators
• Approvers
• Supervisors
Personnel qualifications
• FDA Warning Letter for inconsistent job
requirements (HR) and personnel resumes
Environmental monitoring history
Other
56

124. DOCUMENT OUTLINES / TEMPLATES
Document templates very difficult
• Labor intensive
• Do not fit every situation
Suggested approach
• Document outline of major sections
• Document outline evolves
• Model approved documents available
• Model approved documents improved and are
replaced
57

125. 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
58

126. VALIDATION DOCUMENT APPROVAL
Technical validation
• Scientific and technical principles
• Consistent approach
• Supports objective of validation
• Supports routine manufacturing in type of testing and
sampling
• Support routine manufacturing in duration of sampling
and testing
• Results and discussion support data
• Correct technical conclusions
• Equipment testing support entire operating range used in
manufacturing
59

127. VALIDATION APPROVAL COMMITTEE
• Training consistent with area of expertise
• Specialized training on validation function
• Emphasize role of internal auditor
VALIDATION APPROVAL COMMITTEE
IS NOT
Training for new personnel
Expeditor for engineering documents
60

128. PROCESS ANALYTICAL TECHNOLOGY (PAT)
Processes verified by PAT are not validated
All associated PAT equipment are validated
All associated PAT control systems are validated
All new analytical equipment is validated
All new analytical methods are validated
“WHEN PAT IS IN PLACE, WILL THERE BE ANY MORE VALIDATION?”
61

129. 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
62

130. SUMMARY – VALIDATION POLICIES
• Corporate or company policies
• High level overview documents
• State agreement with local regulatory
requirements and customer regulatory
documents
• Describe general validation approach
• State key points from Process Validation
Guidance
• Risk-based approach
63

131. SUMMARY – VALIDATION MASTER PLAN
• Program description at site
• Multi-chapter document
• Updated as needed (annual, quarterly, monthly)
• Improvement projects commitments and
timelines
• Consistent with corporate policies
• State key points from Process Validation
Guidance
• Risk-based approach
64

132. SUMMARY – STAGE 1 DOCUMENTS
• Technical understanding of processes -- basis of
validation
• Reports readily available
• Accessed throughout product lifecycle
• Stand-alone documents
• Applies to processes, cleaning, analytical, equiment,
facilities, utilities, control systems, others.
R&D / TECHNICAL AREAS NOT ACCUSTOMED TO THESE
REQUIREMENTS
65

133. SUMMARY – STAGE 2 DOCUMENTS
VALIDATION REQUEST / PLAN
• Initiates validation
• Provides basis and details of future work
• Lists all specific requirements to complete
validation
• Administrative importance
• Most important document – all subsequent
documents based on validation plan
• Risk based
66

134. SUMMARY – STAGE 2 DOCUMENTS
VALIDATION PROTOCOLS
• Specific guidance requirements
• Strategy and approach
• Impact of change
• Risk based
• Testing and sampling rationale
• Acceptance criteria
• Statistical data treatment
• Data sheets
• Post-validation monitoring plan
67

135. SUMMARY – STAGE 2 DOCUMENTS
VALIDATION RESULTS / REPORTS
• Data sheets
• Discussion of results – Evaluate results
– Additional post-validation testing if necessary
• Validation statement – “___ is validated.”
• Summary report for multiple protocol validation
or complex projects
• Stage 3 Plan included in results document
• Most important validation document
• Simple sentences, simple words
• Written for the reader
68

136. SUMMARY – STAGE 3 DOCUMENTS
CONTINUED PROCESS VERIFICATION
• Specialized post-PQ requirements
• Routine monitoring
– Risk based
69

137. SUMMARY – ASSOCIATED DOCUMENTS
• Equipment, facilities, utilities, etc. qualification
• Analytical methods and equipment
• Training records
• Personnel qualification
• Environmental monitoring
70

138. SUMMARY – OTHER CONSIDERATIONS
• Follow FDA PV Guidance
• Use outlines
• Have model documents available
• Continually improve model documents
– Based on guidance requirements
– Example information to provide expectations for writers and
approvers
– Write most important document sections first
• Consider problem examples
• FMEA risk analysis included with validation plan
71

139. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: paul.pluta@comcast.net
72

140. VALIDATION BOOT CAMP #3
LIFECYCLE APPROACH TO
PHARMACEUTICAL VALIDATION –
PRINCIPLES, IMPLEMENTATION, AND PRACTICE
LIFECYCLE APPROACH
TO CLEANING VALIDATION
Paul L. Pluta, PhD
1

141. MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there so much foam in the tub?”
A: “I put in extra soap because the equipment was really dirty.”
Q to operator: “Why is there powder on the (clean) equipment?”
A: “No problem -- We’ll get the residue when we set up.”
Q to operator: “Why don’t you follow the cleaning procedure?”
A: “The cleaning procedure really doesn’t work.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
2

142. MANUAL CLEANING -- Do you really know what is happening?
Q to operator: “Why is there powder on the clean equipment?”
A: “It’s clean enough.”
Q to QA (equipment inspection person): “Did you approve that the equipment
is clean?”
A: “It’s clean enough.”
Q to management: “Do you know that your equipment is not clean?”
A: “It’s clean enough.”
Q to operator: “You cleaned the gasket with pure soap – this is not the
procedure? Also it is dangerous – these are corrosive chemicals.”
A: “That is the only way to get it clean.”
Q: “So why don’t you tell someone to change the procedure?”
A: “We don’t have time.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
3

143. MANUAL CLEANING -- Do you really know what is happening?
Q to management: “Did you finish cleaning the equipment? We are
here to swab for cleaning validation.”
A (very proudly): “We cleaned the equipment three times so that we
won’t have any problems.”
Q to validation person: “Did you know that the manufacturing people
always clean the equipment multiple times before it is swabbed?”
A: “Sure, we knew.
Q: “Why didn’t you stop this?”
A: “These people are our friends. We have to work with these
people.”
ABOVE NOT ACCEPTABLE – TRAINING NEEDED
4

144. OUTLINE
Lifecycle Approach Applied to Cleaning Validation
Stage 1 Activities
• Cleaning Method Development
• Analytical Method Development
• Site equipment
Stage 2 Activities
• Cleaning documentation
• Validation conformance lots
Stage 3 Activities
• Maintaining Validation
• Change Control
• Management review
5

145. OBJECTIVES
1. Application of lifecycle approach to cleaning
validation
2. Cleaning lifecycle stage details
• Process development and understanding
• Process qualification
• Maintaining the validated state
3. Cleaning validation problems
• Global experiences
6

146. Lifecycle Approach to Cleaning Validation –
Value? Does this make sense?
• Cleaning is a process
• Validation lifecycle concepts being applied to equipment,
facilities, utilities, computers, etc., by validation and
technical experts
• 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 approach – Which would
you rather present to an auditor?
7

147. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
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 TOC analysis
Equipment is clean -- Process is validated
Process parameters à Quality attributes
8

148. WHAT IS THE CLEANING PROCESS?
Cleaning Process Performance Qualification (PPQ)
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 à Quality attributes
9

149. CLEANING VALIDATION OVERVIEW
1990s à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
10

150. FDA PROCESS VALIDATION GUIDANCE
LIFECYCLE APPROACH TRANSITION
APPPLICATION TO CLEANING VALIDATION
Pre Lifecycle
Cleaning development (?) à PQ à change control
________________________
Lifecycle Approach
Development à PQ à Maintenance
EXPANDED SCOPE OF VALIDATION
INCREASED SPECIFIC STAGE REQUIREMENTS
11

151. LIFECYCLE APPROACH TO CLEANING VALIDATION
Scientific and technical approach
Design and development
– Residue + cleaning agent + cleaning procedure à Clean equipment
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

152. 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
DOCUMENT ALL OF THE ABOVE
13

153. 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

154. 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
15

155. 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

156. pH SOLUBILITY PROFILE, pH 1-12
Solubility
mg/ml
Drug A
Drug B
pH 1 7 12
17

157. RESIDUE SOLUBILITY AND STABILITY FOR
DETERMINING WORST-CASE SOILS
Solubility considerations
• Hydrophilic and hydrophobic molecules
• Ionization – Effect of pH
• Effect of temperature
• Surface active molecules
• Liquid and semisolid product vehicle polarity
Stability considerations
• Hydrolysis, oxidation, photolysis, physical changes
What residue is really present?
Consider chemistry of residues
18

158. 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
19

159. WORST CASE CLEANING
Determination of worst-case cleaning based
on API toxicity, worst-case dose, etc.
– Standard calculation
Cleaning procedure may be based on
excipients having greatest effect on
cleaning
– Hydrophilic polymers
– Dyes
– Hydrophobic vehicles
20

160. BIOTECH CLEANING CHEMISTRY -- API
Protein molecules degrade in alkaline conditions
Degradation rate is milder in acidic conditions
Degradation rate increases with temperature
API residues typically consist of protein fragments and
aggregates
Analytical method: Non-specific analysis
Reference: Kendrick, Canhuto, and Kreuze. Analysis of
Degradation Products of Biopharmaceutical API Caused
by Cleaning Agents and Temperature. Journal of
Validation Technology, V15, #3, Summer 2009.
21

161. BIOTECH CLEANING CHEMISTRY – GROWTH MEDIUM
Medium Composition
• Acids or bases
• Monovalent salts
• Polyvalent salts
• Amino acids
• Proteins (polypeptides)
• Carbohydrates
• Aqueous soluble organics
• Non-aqueous soluble organics
Consider medium composition at end of cycle.
Reference: Azadan and Canhoto. A Scientific Approach to the Selection of
Cleaning Validation Worst-Case Soils for Biopharmaceutical manufacturing.
Cleaning and Cleaning Validation, Volume 1. 2011.
22

162. CLEANING CHEMISTRY MECHANISMS
• Wetting
• Emulsification
• Dispersion
• Solubility
• Chelation
• Oxidation
• Hydrolysis
23

163. CLEANING AGENT OPTIONS
• Water
• Commodity alkalis and acids
• Organic solvents
• Surfactants
– Anionic
– Cationic
– Amphoteric
– Nonionic
• Formulated detergents
24

164. COMPONENTS OF FORMULATED DETERGENTS
• 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

165. CLEANING ENGINEERING
Factors affecting cleaning
• Soil residue
– Soil levels, soil condition, hold times, soil mixing,
water quality and residue,
• Cleaner and parameters (TACT)
– Time, Action, Concentration, Temperature
– Others
• Surface and equipment design
26

166. 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
27

167. 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

168. PROCEDURE TO DETERMINE SAMPLING
LOCATIONS
Specific documented procedure recommended
• Equipment technical evaluation
• Observation of equipment after processing
• Equipment disassembly review
• Cleaning procedure review
• Equipment evaluation review
• Operator interviews
SOP describing above
Documentation of above for equipment sampling
29

169. TIME TO INITIATE CLEANING
“DIRTY HOLD TIME”
1. Make Product A
2. Clean
3. Make Product B
How long between end of #1 and start #2?
Is residue same? Does residue change?
What can happen to the residue?
• Wet and dry processes
• Chemical changes (hydrolysis, oxidation, etc.)
• Physical changes
30

170. 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

171. 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
32

172. ANALYTICAL METHOD DEVELOPMENT
Early stage 1 (development) analysis –
validation not required but must be sound
Validated method when used for Stage 2
cleaning validation and post-validation
testing (change control)
All methods and data (including stage 1) subject to
regulatory audit
33

173. ANALYTICAL METHOD DEVELOPMENT
Analytical method must measure actual residue –
what residue is actually present on equipment
surfaces?
• Small molecules
– API
– API degraded – specific or non-specific method
• Biotech molecules
– API degraded – non-specific method
UNDERSTAND RESIDUE CHEMISTRY
34

174. ANALYTICAL METHOD DEVELOPMENT
Cleaning agent residue
• Analytical method to determine residual cleaning
agent.
• Information from cleaning agent vendor
35

175. ANALYTICAL METHOD DEVELOPMENT
Recovery studies
Can sampling procedure adequately recover residue
from equipment surfaces?
• Product contact materials
• High % of total surface area
• Obtain representative coupons from equipment
fabricators
• High (e.g., >80%) acceptance criteria
• Factor may be used in calculation
– Multiple approaches
– Factor every calculation?
All sampled surfaces must have recovery data
36

176. SAMPLING
Sampling methods
• Sampling (swab) critical activity
• Training program
• Trained sampling personnel
– Demonstrated acceptable performance
• Documented training and retraining
• Worst case compounds / procedures in training
– Volatile solvents (importance of rapid technique)
• Worst case sampling equipment
– Extension poles
• Retraining considerations
– Who does sampling? Personnel skills
37

177. SAMPLING TRAINING
Sampling is extremely critical to cleaning
validation program
Inadequate sampling = false negative
– Insufficient pressure on surface
– Swab solvent evaporation
– Insufficient area sampled
Auditors routinely ask for sampling program training
methods and training records
38

178. STAGE 2, PROCESS QUALIFICATION –
(VALIDATION PERFORMANCE)
APPLICATION TO CLEANING
1. 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
39

179. 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

180. 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
41

181. 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)
42

182. VALIDATION REQUEST / PLAN
Initiates cleaning validation
• New cleaning validation or change control process
improvements
• Strategy and approach
• Scientific and technical basis
• Specify required protocols and other work to accomplish
validation
• Risk-based
• References: Stage 1 Design / development reports
43

183. VALIDATION PROTOCOL
Cleaning validation protocols and other work
as specified in Validation Plan
– Risk based
Include sampling pages indicating worst
case sampling locations.
Specify acceptance criteria
44

184. VALIDATION RESULTS / REPORT
Test results as required in validation protocol.
• Discussion. Consistency with Stage 1
development work.
• Clear statement the cleaning process is (or is
not) validated.
• Recommendations for Stage 3 monitoring and
maintenance.
– Additional limited testing based on data and risk
– Routine monitoring based on risk
45

185. 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
46

186. POST-VALIDATION MONITORING AND MAINTENANCE
1. Stage 2 specific requirements
– Additional testing based on actual data
– Ex: One location has high (acceptable result)
2. Routine monitoring and maintenance
– Risk based
3. Change control program
CHANGE CONTROL MOST IMPORTANT AND
DIFFICULT TO ADMINISTER
PERSONNEL MUST RECOGNIZE “CHANGE”
47

187. POST-VALIDATION MONITORING AND MAINTENANCE
Residue toxicity risk
• Residue that can be visually seen
– Room lighting must be adequate
– Provide additional lighting if necessary
• Residue that cannot be visually seen
– Swab after each batch?
CONSIDER PATIENT RISK AND COMPANY RISK
48

188. 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

189. 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

190. CLEANING DOCUMENTATION
• High level documents
• Specific cleaning validation documents
– Design/Development, performance, monitoring/maintenance
• Specific cleaning validation support documents (equipment
qualifications)
• Cleaning validation approach documents (Worst case matrix,
calculations, sampling locations, etc.)
• Production documents (Cleaning Procedure Records)
– Production cleaning policies
• Management review documents
• Associated documents
– Personnel training in direct and associated areas
– HR records
51

191. 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
CONSISTENT LIFECYCLE STRATEGY AND APPROACH
52

192. SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
INCLUDING COMMON PROBLEMS
Understanding cleaning process
• Residue properties
– Residue degradation
• Rational cleaning process based on residue
• Scientific and technical cleaning matrix
Understand and control sources of variation
• Dirty hold time
• Campaigns
Rational analytical method based on residue properties
Equipment to be cleaned characterized
• Worst case sampling
53

193. SUMMARY – EQUIPMENT TO BE CLEANED
INCLUDING COMMON PROBLEMS
• Equipment characterization
• Residue calculations
• Materials of product contact
• Surface areas
• Worst-case areas for sampling based on risk
– Non-uniform contamination
• Equivalent equipment
54

194. SUMMARY – ANALYTICAL
INCLUDING COMMON PROBLEMS
Understand residue
• Solubility and stability
• Validated analytical method for actual residue
– Specific or non-specific analytical methods
• API and cleaning agent residue
Recovery studies from product contact materials
• API and cleaning agent
Swab / rinse testing on equipment
• Most difficult to clean sampling sites
• Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling personnel
55

195. 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
Manual cleaning – high risk
56

196. 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

197. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications
Adjunct Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Pharmaceutical industry experience
Contact: paul.pluta@comcast.net
58

198.
VALIDATION
BOOT
CAMP
#4
LIFECYCLE
APPROACH
TO
PHARMACEUTICAL
VALIDATION
–
PRINCIPLES,
IMPLEMENTATION,
AND
PRACTICE
EQUIPMENT QUALIFICATION –
LIFECYCLE APPROACH
Paul L. Pluta, PhD
1

199. OUTLINE
I. Equipment Qualification – Lifecycle Approach
• Qualification approaches
• Documentation hierarchy
• Document outlines
II. Documentation problems
2