1. PROCESS VALIDATION GUIDANCES
FDA AND GLOBAL
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
• History and development
• Is the lifecycle approach really new?
• FDA commentary
Lifecycle Approach Stages
• #1 -- Process Understanding (Process Design)
• #2 -- Process Demonstration (Process Qualification)
• #3 -- Maintaining Validation (Continued Process Verification)
Fundamental Concepts
• The “process of process validation”
• Enhanced execution
• Comparison to traditional approach
Regulatory Guidances
• Health Canada
• FDA
• EMA
Applications of PV Guidance
• Processes: Manufacturing, cleaning, packaging, analytical, others
• Equipment, facilities, utilities, others
• Quality Systems
Implementation
• Implementation is difficult
2

3. OBJECTIVES
• What is the lifecycle approach?
• Is the lifecycle approach new?
• How is it different?
• What are fundamental principles?
• US only or global?
• Is industry accepting this approach?
• Audit questions:
What is your approach to validation?
What is your approach to quality systems?
3

4. VALIDATION MANAGER COMMENTARY
Organizations implementing lifecycle approach -- Reasons
• US FDA guidance
• Health Canada guidance
• EMA draft guidance
• Global communication
• ICH Q8, Q11
• Logical approach – development, performance, and maintenance
• Application to other processes, equipment, facilities, etc.
Organizations not implementing lifecycle approach -- Reasons
• “Its only a guidance.”
• “Let’s see what happens.”
• “It’s only for USA.”
• “We will consider it if we get observations.”
• Too costly, no headcount
4

5. PROCESS VALIDATION LIFECYCLE APPROACH
OVERVIEW
• History and Development
• Fundamental Concepts
• Consistency with Medical Devices
• Is the lifecycle approach really new?
5

6. HISTORY AND DEVELOPMENT –
LIFECYCLE APPROACH
2004 – Health Canada guidance
2005 – FDA initial presentations
2007 – ICH Q10
2008 – FDA draft guidance
2009 – ICH Q8(R2)
2009 – Health Canada revision
2011 – FDA guidance issued
2012 – EMA draft guidance
6

7. PROCESS VALIDATION LIFECYCLE APPROACH
A NEW PARADIGM FOR PHARMA –
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 8-41.
7

8. 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
8

9. 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
9

10. 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
10

11. 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 …”
11

12. ICH Q8 PHARMACEUTICAL DEVELOPMENT
Key points
• Examination
• Understanding
• Evaluation
• Identification
• Rationale and justification
• Others
Discussion in submission
12

13. 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
13

14. 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
14

15. 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
15

16. 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
16

17. 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
17

18. 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
18

19. ICH Q9 QUALITY RISK MANAGEMENT
Key points
• Methods of evaluation
• Potential applications – every function,
every activity, entire product lifecycle
19

20. 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
20

21. 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 terminology
21

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
22

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
23

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.
24

25. ICH Q10 PHARMACEUTICAL QUALITY SYSTEMS
Implications for Process Validation
• Product performance and monitoring
• CAPA system enhances process understanding
• Change management system
• Process improvements
25

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
26

27. 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
27

28. SUPPORTING DOCUMENTS
PROCESS VALIDATION – 1987 GUIDANCE
Assurance of product quality:
• Quality parts and materials
• Adequate product and process design
• Control of the process
• In-Process and end-product testing.
Basic principles:
• Quality, safety, and effectiveness designed and built into the product
• Quality cannot be inspected or tested in the product
• Each process step must be controlled to maximize meeting quality and design specifications.
R&D phase: Product definition and characteristics
Equipment and process
Equipment: Installation Qualification
Process: Performance Qualification
Product (devices only): Performance Qualification
Revalidation. Change control
Documentation. Proper maintenance of documentation
Reference: FDA Guideline on General Principles of Process Validation. May, 1987
28

29. SUPPORTING DOCUMENTS
VALIDATION – PHARMACEUTICAL DOSAGE FORMS
FDA INSPECTION GUIDELINES
Three phases of the validation process:
• Product development
• Design of the validation protocol
• Demonstration runs (validation) – full scale
Process validation:
• Documented evidence
• Consistency
• Predetermined specifications
Documented evidence includes experiments, data, and results
Product Development Reports
Control of the physical characteristics of the excipients
Particle size testing of multi-source excipients
Critical process parameters
Development data serves as the foundation for the manufacturing procedures
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)
29

30. SUPPORTING DOCUMENTS
VALIDATION – MEDICAL DEVICES
Planning the Process Validation Study
Installation and Operational Qualification
Process Performance Qualification
• Eliminate controllable causes of variation
Product Performance Qualification
• Evaluate routine production process monitoring data for trends
Process operating in a state of control is determined by analyzing
day-to-day process control data and finished device test data
for conformance with specifications and for variability.
Reference: FDA Medical Device Quality Systems Manual. January 07, 1997
30

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.
31

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.
32

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.
33

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.
34

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.
35

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.
36

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
37

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
38

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
39

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
40

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
41

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

43. PROCESS VALIDATION HISTORY
1978
FDA CGMP includes Validation
1987
Development -- VALIDATION -- Control
2004-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
43

44. FDA 2011 PV GUIDANCE – PROCESS VALIDATION REVISITED
Paula Katz (FDA) and Cliff Campbell
JGXP Compliance, Vol .16, #4, Fall, 2012
Among other motivating factors, the Agency sought to emphasize
process design and maintenance of process control during
commercialization. By aligning process validation activities with a
lifecycle approach, the 2011 Guidance communicates that process
validation is an ongoing program rather than a discrete and isolated
activity. Under the 2011 Guidance, process validation is presented
as a series of activities that manufacturers carry out over the
lifecycle of the product and process. This view of process validation
underscores the importance of detecting, understanding, and
controlling sources of variability over time in order to consistently
produce safe, effective drugs that meet all quality attributes. In turn,
the emphasis on understanding and controlling process variability
leads to a clarification that the Agency expects manufacturers to
employ objective measures and appropriate statistical tools and
analysis.
44

45. PROCESS VALIDATION GUIDANCES
• Health Canada
• FDA
• EMA
45

46. HEALTH CANADA -- VALIDATION GUIDELINES FOR
PHARMACEUTICAL DOSAGE FORMS, 2009
Phase 1. Pre-validation phase or qualification phase.
Product R&D, pilor studies, scale-up, stability studies,
equipment qualification, IQ, OQ, master production
documents, others.
Phase 2. Process validation phase or process
qualification phase. Verify that all limits of critical
process parameters are valid and satisfactory product
produced under worst-case conditions.
Phase 3. Validation maintenance phase. Frequent
reviews of process-related documents to assure no
changes, deviations, or failures, and that SOPs have
been followed, including change control No changes
that should have results in revalidation.
46

47. FDA PROCESS VALIDATION GUIDANCE (2011)
Definition: Collection and evaluation of data, from the
process design stage throughout commercial production,
which establishes scientific evidence that a process is
capable of consistently delivering quality products.
Process validation involves a series of activities over the
lifecycle of the product and process.
Three stages of activities:
• Stage 1 – Process Design – Development and scale-up activities
• Stage 2 – Process Qualification – Demonstrate reproducible
manufacturing through conformance lots
• Stage 3 – Continued Process Verification – Routine manufacturing
and monitoring of performance.
STAGE 1 AND STAGE 3 EMPHASIS – NEW PARADIGM
47

48. 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.”
48

49. 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.
49

50. 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
50

51. 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
51

52. 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
52

53. 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
53

54. 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.
54

55. 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 FDA PV GUIDANCE
55

56. 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 FDA PV GUIDANCE
56

57. HEALTH CANADA -- VALIDATION PROTOCOL
Minimum information
• Objective, scope of coverage of the validation study
• Validation team membership, qualifications, and responsibilities
• Type of validation – prospective, concurrent, retrospective, re-validation
• Number and selection of batches
• List of all equipment used. Normal and worst-case operating parameters
• Outcome of IQ and OQ for critical equipment
• Requirements for calibration of all measuring devices
• Critical process parameters and tolerances
• Description of processing steps. Copy of master documents
• Sampling points, stages of sampling, methods of sampling, sampling plans
• Statistical tools for data analysis
• Training requirements for processing operators
• Validated test methods
• Specification for raw and packaging materials and test methods
• Forms and charts for documenting results
• Format for presentation of results, documenting conclusions, and approval of study
results
57

58. 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
58

59. CONTINUED PROCESS VERIFICATION
Monitoring
Statistical process control (SPC)
Trend analysis
Change control
Continuous improvement
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
59

60. CONTINUED PROCESS VERIFICATION
ITEMS TO BE REVIEWED
• Product and process data
• Relevant process trends
• Quality of incoming materials or components
• In-process material
• Finished products
• Defect complaints
• OOS findings
• Deviations
• Yield variations
• Batch records
• Incoming raw material records
• Adverse event reports
• Production operator and quality staff feedback
Above should help identify possible product / process improvements
DETAILS FROM FDA PV GUIDANCE
60

61. SUMMARY OF FDA GUIDANCE RECOMMENDATIONS
Stage 1: Product Design
• QTPP, development information, identification of CQA, CMA, and CPP
• Identification of sources of variation and control plan
• Experimental studies
• Technology transfer / scale up
Stage 2: Process Qualification
• Protocol requirements
• Statistical sampling and acceptance criteria
• Equipment qualification and analytical method validation
Stage 3: Continued Process Verification
• Post PQ plan
• APR, batch data, yields, deviations, OOS, non-conformances, etc.
• Incoming material data
• Change control
• Statistical analysis of data / control charting
• Product complaints
61

62. HEALTH CANADA -- VALIDATION MASTER PLAN
• Company philosophy, intentions and approaches to
establish performance adequacy
• Management agreement
• Meticulous preparation and planning of steps in process
• Structured according to SOP
• List of items to be validated and schedule
• Documentation
62

63. HEALTH CANADA VALIDATION GUIDELINES
Additional sections
• Installation and Operational Qualification
• Requalification
• Process Validation
– Prospective
– Concurrent
– Retrospective
• Process Re-Validation – “Periodic review and
trend analysis …at scheduled intervals”
• Change control
63

64. EMA GUIDELINE ON PROCESS VALDIATION
Draft March, 2012
• “…applying enhanced process understanding coupled
with risk management tools under an efficient quality
system as described by ICH Q8, Q9, and Q10.”
• Definition
• Continuous process verification (PAT)
• Validation “…not a one-off event.”
• “A lifecycle approach should be applied linking product
and process development, validation of the commercial
manufacturing process, and maintenance of the process
in a state of control during routine commercial
production.”
64

65. EMA GUIDELINE ON PROCESS VALDIATION
Draft March, 2012
• Traditional process validation
– Annex I details
• Continuous process verification
• Hybrid approach
65

66. EMA GUIDELINE ON PROCESS VALDIATION
Draft March, 2012
Definitions
• Control Strategy
• Continued Process Verification
• Continuous Process Verification
• Critical Process Parameter (CPP)
• Critical Quality Attribute (CQA)
• Design Space
• High Impact Models
• Lifecycle
• Pharmaceutical Quality System (PQS)
• Process Validation
66

67. FUNDAMENTAL CONCEPTS
• Scientific and technical basis in development
(Stage 1)
• Validation (Stage 2 ) confirms tage 1
development
• Acceptable (passing) results are expected.
• Validation is not
– R&D, Final stage of development process
– Optimization, Fine-tuning, or Debugging
• Monitor and maintain validated state throughout
product lifetime (Stage 3).
67

68. FUNDAMENTAL CONCEPTS
• Critical quality attributes (CQA)
• Critical process parameters (CPP) related to CQA
• Identify and control variation
• Statistical applications
– DOE
– Statistical Process Control (SPC)
• Rationale and justification – sampling, testing, etc.
• Detailed expectations in guidance
– Protocol and results
– Monitoring
• Monitoring and maintenance à Continuous
improvements
• Risk – All decisions based on risk analysis
68

69. APPLICATIONS OF PV GUIDANCE
• Processes: Manufacturing, cleaning,
packaging, analytical, others
• Equipment, facilities, utilities, others
• Other new applications
• Quality Systems and compliance
69

70. PROCESSES
Manufacturing
Packaging
Cleaning
Analytical
Other
ALL PROCESSES MUST BE APPROPRIATELY
DESIGNED AND DEVELOPED, DEMONSTRATE
PERFORMANCE, AND BE MONITORED AND
MAINTAINED.
PROCESSES MUST BE CONTINUALLY IMPROVED.
70

71. QUALIFICATION
Equipment
Facilities
Utilities
Control systems
Computer systems
Others
ALL QUALIFIED EQUIPMENT MUST BE
APPROPRIATELY DESIGNED AND DEVELOPED,
DEMONSTRATE PERFORMANCE, AND BE
MONITORED AND MAINTAINED.
QUALIFIED EQUIPMENT MUST BE CONTINUALLY
IMPROVED.
71

72. EQUIPMENT à PROCESSES
HVAC Systems – Process variable incoming air
Water Systems – Process variable incoming water
ALL QUALIFIED EQUIPMENT THAT FUNCTIONS AS
PROCESSES MUST BE APPROPRIATELY DESIGNED
AND DEVELOPED, DEMONSTRATE PERFORMANCE,
AND BE MONITORED AND MAINTAINED.
QUALIFIED EQUIPMENT MUST BE CONTINUALLY
IMPROVED.
Reference: “The HVAC Process.” Delli Paoli, Alexander. J Validation
Technology, Volume 17, #4, Autumn 2011.
72

73. QUALITY SYSTEMS
FDA QUALITY SYSTEMS
• Quality system
• Material system
• Production and equipment system
• Laboratory system
ALL QUALITY SYSTEMS MUST BE APPROPRIATELY
DESIGNED AND DEVELOPED, DEMONSTRATE
PERFORMANCE, AND BE MONITORED AND
MAINTAINED.
QUALITY SYSTEMS MUST BE CONTINUALLY
IMPROVED.
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74. IMPLEMENTATION
• MPLEMENTATION VERY DIFFICULT
– Time
– Cost
– Change
• Integration of Validation Approval Committee, R&D/technical groups,
and QA functions
• Lifecycle involvement – new to traditional validation
• Technical groups not accustomed to validation
• Post PQ monitoring
– Prescribed testing based on risk
– Special testing
• Enhanced PQ and post PQ execution as prescribed in guidance
(statistics, etc.)
• Note direction of global guidances, conferences, meetings
• Great challenges for validation personnel
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75. SUMMARY
PROCESS VALIDATION GUIDANCES
Process Validation Guidances have greatly expanded the
scope of validation
• Lifecycle approach – documents from development through
commercialization
– Understanding
– Demonstration
– Monitoring and maintenance
• 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
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76. SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D Validation Commercialization
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77. 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
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78. 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 IMPLEMENTATION AND EFFECTIVE DOCUMENTS
CONSISTENT WITH THE ABOVE
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79. LIFECYCLE APPROACH TO PROCESS VALIDATION
Process Design and Development – Pre-validation work
• 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 qualified
• Analytical methods validated
• Confirm commercial process design
• Validation performance
Maintaining the Validated State
• Monitor, collect information, assess
• Maintenance, continuous verification, process improvement
• Change control
• Validation maintenance
“The process of process validation.”
All activities 79
based on risk.

80. SUMMARY
PROCESS VALIDATION HISTORY
1978
CGMP includes Validation
1987
Development -- VALIDATION -- Control
2004-2011
Lifecycle approach
Continuum of understanding – validation – maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
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81. SUMMARY
VALIDATION -- FUTURE
Development Performance Maintenance
Stage 1 à Stage 2 à Stage 3
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82. SUMMARY – FUNDAMENTAL CONCEPTS
• Lifecycle approach
• Scientific and technical basis in development
• Validation is confirmation
• Monitor and maintain
• Management review
• Continuous improvements
• Risk analysis
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83. SUMMARY – FUNDAMENTAL CONCEPTS
• CQA and CPP
• Variation – identify and control
• Statistical applications
– DOE
– Statistical Process Control (SPC)
• Rationale and justification
• Risk analysis – work appropriate for level of risk
• Enhanced detailed requirements in guidance
– Protocol and results
– Monitoring
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84. SUMMARY -- APPLICATIONS
Manufacturing process validation
Other processes – cleaning, packaging,
analytical, etc.
Equipment, facilities, utilities, computer
systems, etc.
Equipment processes – HVAC, water
THERE IS NO ARGUMENT AGAINST DESIGN,
DEMONSTRATE, AND MAINTAIN
LIFECYCLE APPROACH INCREASING APPLICATIONS
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85. SUMMARY FINAL
Lifecycle Approach Status -- 2012:
• Lifecycle approach globally accepted
– Health Canada 2004
– FDA 2011
– EMA draft issued March, 2012
• Design à Demonstrate à Maintain: No argument
• Approach specifics (QbD, CQA, etc.) accepted and
consistent with ICH and other guidances
• Usage increasing – Application to equipment, facilities,
utilities, computers, quality systems, etc. Stage
approach and associated concepts increasing
application.
UNDERSTANDING à PERFORMANCE à MAINTENANCE
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86. SUMMARY FINAL -- DID WE MEET OBJECTIVES?
• What is the lifecycle approach?
• Is the lifecycle approach new?
• How is it different?
• What are fundamental principles?
• US only or global?
• Is industry accepting this approach?
• Audit questions:
What is your approach to validation?
What is your approach to quality systems?
UNDERSTAND – DEMONSTRATE -- MAINTAIN
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87. PAUL L. PLUTA, PhD
Editor-in-Chief
Journal of Validation Technology
Journal of GXP Compliance
Advanstar Communications, USA
Visiting Clinical Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy
Chicago, IL, USA
Extensive pharmaceutical industry experience
Contact: paul.pluta@comcast.net
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