Validation Bootcamp

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
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
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
SCHEDULE
8:15
Registration, welcome and opening remarks
8:30
10:00
Part I. Introduction, basis, lifecycle stages

Break Specific requests / clarifications
10:30
11:50
Part II. Documentation

Morning assessment
12:00
Lunch Specific requests / clarifications
1:00
2:30
Part III. Applications -- Cleaning, EFU, Quality Systems

Break Specific requests / clarifications
3:00
3:20
3:45
4:00
Part IV -- Implementation
Loose ends, Final Q&A, etc.
Summary
End
COMMENTS AND QUESTIONS ANY TIME
4
FILES
#1.
#2.
#3.
#4.
#5.
#6.
Overview and history

Documentation
Cleaning
Equipment
Validation Quality System
Implementation
INTRODUCTION, BASIS, LIFECYCLE STAGES
History and Development

Fundamental Concepts
Consistency with Medical Devices
IS THE LIFECYCLE APPROACH REALLY NEW?
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2008 FDA draft guidance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2012 EMA draft guidance
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.
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
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
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

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

Key points
Examination
Understanding
Evaluation
Identification
Rationale and justification
Others
Discussion in submission
13
Implications for Process Validation

Process understanding
Process development studies are basis for
process validation
Continuous process verification is
alternate to process validation
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
15

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
Initiate risk management process

Risk assessment
Risk identification
Risk analysis
Risk evaluation
Risk control
Risk reduction
Risk acceptance
Output
Risk review
17

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

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

Key points
Methods of evaluation
Potential applications every function, every
activity, entire product lifecycle
20

Development: Process knowledge
Materials: Variation, change control
Equipment: Qualification, cleaning, calibration,
PM, change control
Production: Validation, sampling, testing,
change control
Maintenance / monitoring: Testing
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 terms
22
ICH Q10
Overview and definitions
Management responsibility: Commitment,
policy, planning, resources, communication,
review, outsourcing
Continual improvement of performance and
quality: Lifecycle stages and elements
Continual improvement of quality system:
Management, monitoring, outcomes
23
ICH Q10
Key points:
Quality system application throughout product lifecycle
Pharmaceutical development
Technology transfer
Manufacturing
Product discontinuation
Product realization, maintain control, improvements
Enable by knowledge and risk management
Management responsibility: Commitment, policy,
planning, resources, communication, review, outsourcing
oversight
24
ICH Q10
Key points:
Continual improvement
Product performance / quality monitoring system
Control strategy, identify variation, problem feedback,
enhance process understanding
CAPA system
Enhance process understanding
Change management system
Risk management, evaluation, technical justification
Management review
Audits, inspections, changes, CAPA, etc.
25
ICH Q10
Product performance and monitoring
CAPA system enhances process understanding
Change management system
Process improvements
26
ICH Q11
DEVELOMENT AND MANUFACTURE
OF DRUG SUBSTANCES
Consistent with ICH Q8, Q9, and Q10
Lifecycle approach
CQA, CPP
Design space
Control of variables
Process validation
Risk management
27
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
TERMINOLOGY: PROCESS VALIDATION

Process Validation Process Qualification
Process Performance Qualification (PPQ)
Qualification
Equipment #1
UO #1
Equipment #2
UO #2
Equipment #3
UO #3
Analytical methods validation

Cleaning process validation
Packaging process validation
Process is validated
43
Qualification
HVAC
Utilities
Facilities
Computers
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
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 processconsistently 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

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
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
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

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
STAGE 2, PROCESS QUALIFICATION

(VALIDATION PERFORMANCE)
1.
2.
3.
4.
Design of a facility and qualification of utilities and equipment

Process performance qualification
PPQ protocol
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

Conformance Lots
Procedures
Validation plans
Protocols
Sampling
Testing
Results
Plan to maintain validation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
51
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
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
53
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
CONTINUED PROCESS VERIFICATION

Monitoring
Statistical process control
Trend analysis
Change control
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
55

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
56
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
PROCESS VALIDATION HISTORY

1978
CGMP includes Validation

1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE

58
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
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:
HOW DO YOU APPROACH VALIDATION?
60
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D
Validation
61
Commercialization
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
1990s Pharma Inspection Guidelines
1997 Medical Device Quality Systems Manual
62
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

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
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
SUMMARY
VALIDATION -- FUTURE
Development
Stage 1
Performance
Stage 2
66
Maintenance
Stage 3
PAUL L. PLUTA, PhD

Editor-in-Chief
Advanstar Communications
Adjunct Associate Professor

Chicago, IL, USA
Pharmaceutical industry experience

Contact: paul.pluta@comcast.net
67
VALIDATION BOOT CAMP #2

VALIDATION DOCUMENTATION
Paul L. Pluta, PhD
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
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
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
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
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
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
VALIDATION POLICY
Design and development . Science and technical
basis
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
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

SITE PROGRAM DESCRIPTION
Design and development . Science and technical basis
Maintain validated state through monitoring, change
control, and management review
Risk analysis emphasis on high risk activities
Variation identification and control
Continuing improvements
10

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
VMP CHAPTER EXAMPLE CLEANING VALIDATION

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
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
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
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
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
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
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.
18
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

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)
Approvals
SIMPLE AND CLEAR
20

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
Approvals
SIMPLE AND CLEAR
21
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)

22
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
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
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
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
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
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
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
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
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
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
VALIDATION PROTOCOL
FDA Powder Blends and Finished Dosage Units
Stratified Sampling and Assessment
Blend sampling. n = 10, Individuals, RSD
Tablets. 20 samples, n = 3-7 per location, mean,
range, RSD.
Application is possible approach for high risk
products
Supportive of USP Uniformity of Dosage Units on
composite / stratified samples
Product types: Potency and weight testing
33
VALIDATION SAMPLING
What is routine QA sampling?
Impact of change
High impact
Medium impact
Low impact
No impact
Risk analysis Related to numerical RPN analysis

High risk
Medium risk
Low risk
RISK LEVEL MUST BE ACKNOWLEDGED
34
ENGINEERING STUDY
Conducted in advance of validation
No acceptance criteria
Trial run
Examples: Manufacturing process without
bulk drug (low dose API)
Process runs with placebo
Categories of Engineering Studies
Conduct Engineering Study concurrently with validation?
-- Not recommended
35
SAMPLING PAGES
Designed sheet with space for expected data
Data treatment specified
Signature and data of person supplying data
Highly recommended for Operators or persons not
familiar with sampling
Data pages consistent with sampling pages
Prevents missing data in complex protocols
Record sampling and / or testing
36
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
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
Sample #2
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
Sample #3
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
P/F
RECORDED BY:
__________
__________
__________
VERIFIED BY:
_____________
_____________
_____________
37
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
VALIDATION PROTOCOL OUTLINE
Introduction
Unit operations
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance criteria with justification
39
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
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
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
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
43
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
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
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
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
VALIDATION REPORT FORMAT
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 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.
48
STAGE 3 DOCUMENTS
POST PQ DOCUMENTS
TYPES OF DOCUMENTS
Post PQ requirements work required based on PQ
results
Ongoing monitoring routine process monitoring
49
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
STAGE 3 DOCUMENT RESPONSIBILITIES

ONGOING MONITORING
RESPONSIBILITY
Monitoring results (Annual Product Review)
Change control validation results/reports and monitoring
Non-conformances
Deviations
Process monitoring (control charts)
Process changes
Improvement projects instituted
Other changes
Record of management review
ANNUAL REVIEW NOT GOOD ENOUGH,
ESPECIALLY FOR HIGH RISK PROCESSES
51
QA
Validation
Production
Production
QA
Production
Validation
----QA
STAGE 3 DOCUMENTS
Regular management review of manufacturing data
Data analysis by statistical process control (SPC) principles
Review of all associated events, investigations, changes,
etc.
Record of management review
Expanded Annual Product Review, conducted at
appropriate intervals based on risk.
52
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
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
Results indicate that _____is qualified.
54
ANALYTICAL
Analytical methods validated
Analytical equipment qualified
QbD for analytical methods evolving
55
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
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
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
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
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

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
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
SUMMARY VALIDATION POLICIES

Corporate or company policies
High level overview documents
State agreement with local regulatory
requirements and customer regulatory
documents
State key points from Process Validation
Guidance
Risk-based approach
63
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
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

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

VALIDATION PROTOCOLS
Specific guidance requirements

Impact of change
Risk based
Testing and sampling rationale
Acceptance criteria
Statistical data treatment
Data sheets
Post-validation monitoring plan
67

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

Specialized post-PQ requirements

Routine monitoring
Risk based
69
SUMMARY ASSOCIATED DOCUMENTS
Equipment, facilities, utilities, etc. qualification

Analytical methods and equipment
Training records
Personnel qualification
Environmental monitoring
70
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
PAUL L. PLUTA, PhD

Editor-in-Chief

Chicago, IL, USA

72

LIFECYCLE APPROACH
TO CLEANING VALIDATION
Paul L. Pluta, PhD
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 -- Well get the residue when we set up.
Q to operator: Why dont you follow the cleaning procedure?
A: The cleaning procedure really doesnt work.
ABOVE NOT ACCEPTABLE TRAINING NEEDED

Q to operator: Why is there powder on the clean equipment?
A: Its clean enough.
Q to QA (equipment inspection person): Did you approve that the equipment
is clean?
Q to management: Do you know that your equipment is not clean?
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 dont you tell someone to change the procedure?
A: We dont have time.

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
wont 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 didnt you stop this?
A: These people are our friends. We have to work with these
people.
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
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
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
WHAT IS THE CLEANING PROCESS?

Cleaning Process Performance Qualification (PPQ)
Automated CIP System
Process steps
1. Residue on equipment
2. Water procedure
3. Cleaning agent procedure
4. Water procedure
5. Purified Water procedure
6. Dry
Qualification
Equipment
Purified Water
Computer / software
Compressed air
Conductivity analysis
TOC analysis
Equipment is clean -- Process is validated
Process parameters Quality attributes

8
WHAT IS THE CLEANING PROCESS?

Cleaning Process Performance Qualification (PPQ)
Manual Cleaning
Process steps
1. Residue on equipment
2. Water rinse
3. Scrub with cleaning agent
4. Water rinse
5. Scrub
6. Water rinse
7. Purified Water rinse
8. Dry
Qualification
Personnel
Purified Water
Compressed air
Equipment is clean -- Process is validated

Process parameters Quality attributes
9
CLEANING VALIDATION OVERVIEW

1990s present
1. Defined cleaning procedure (SOP) basis?
2. Product A batch does not contaminate subsequent
Product B batch
3. Acceptance limit calculated
4. Assume uniform contamination of all equipment
5. Three conformance lots = Validated cleaning procedure
6. Validated analytical method (original API)
7. Worst-case matrix approach
One-time event
10

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

Scientific and technical approach
Design and development
Residue + cleaning agent + cleaning procedure Clean equipment
Performance demonstration
Monitoring and maintenance
Rationale, responsibility, and accountability
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
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
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
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
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
pH SOLUBILITY PROFILE, pH 1-12

Solubility
mg/ml
Drug A
Drug B
pH 1
12
17
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
CLEANING MATRIX
Determine Worst-Case Soil
SOLUBILITY (mg / ml)
pH 1
Water
pH 12
Alkaline
Cleaning Agent
Drug A
25
25
25
25
Drug B
15
15
15
15
Drug C
150
250
Drug D
150
10
10
50
Drug E
125
10
100
250
Consider acid cleaning agent for drugs D and E

19
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
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
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
CLEANING CHEMISTRY MECHANISMS
Wetting
Emulsification
Dispersion
Solubility
Chelation
Oxidation
Hydrolysis
23
CLEANING AGENT OPTIONS
Water
Commodity alkalis and acids
Organic solvents
Surfactants
Anionic
Cationic
Amphoteric
Nonionic
Formulated detergents
24
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
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
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
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
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
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
CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about cleaning between batches?
Equipment should be visually clean
Terminology: Between lot procedure
How much residue build-up?
DO NOT IDENTIFY AS BETWEEN LOT CLEANING
31
MANUAL CLEANING
Manual cleaning procedures should be
monitored and maintained with increased
scrutiny compared to non-manual procedures
More frequent training of cleaning personnel
Increased supervision
Periodic (annual?) revalidation batches
Manual cleaning is high risk
32
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

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

Cleaning agent residue
Analytical method to determine residual cleaning
agent.
Information from cleaning agent vendor
35

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
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
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

(VALIDATION PERFORMANCE)
1.
2.
3.
4.
Design of a facility and qualification of utilities and equipment

Process performance qualification
PPQ protocol
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
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
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
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
VALIDATION REQUEST / PLAN

Initiates cleaning validation
New cleaning validation or change control process
improvements
Scientific and technical basis
Specify required protocols and other work to accomplish
validation
Risk-based
References: Stage 1 Design / development reports
43
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
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
STAGE 3, CONTINUED PROCESS VERIFICATION

(VALIDATION MONITORING AND MAINTENANCE)
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
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
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
CHANGE CONTROL
All associated personnel must be aware of
change control
Change control system developed
Process improvements expected based on
ongoing experience
Process improvements should be evaluated by
technical people (i.e., Stage 1)
Stage 2 PPQ conducted when appropriate
based on Stage 1 technical evaluation.
49
POST-VALIDATION MONITORING
Periodic review of cleaning performance
Deviations
Non-conformances (dirty equipment)
Re-cleaning
Change control
Other monitoring (CIP data)
Product APR data
Statistical Process Control data treatment
Management review -- documented
50
CLEANING DOCUMENTATION
High level documents
Specific cleaning validation documents
Design/Development, performance, monitoring/maintenance
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
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
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
SUMMARY EQUIPMENT TO BE CLEANED

Equipment characterization
Residue calculations
Materials of product contact
Surface areas
Worst-case areas for sampling based on risk
Non-uniform contamination
Equivalent equipment
54
SUMMARY ANALYTICAL
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
SUMMARY
STAGE 2 PERFORMANCE
Cleaning Process Conformance Lots
Cleaning equipment qualified
Cleaning procedure specified (Not SOP)
Cleaning documentation
Request
Protocol
Results / Report
Manual cleaning high risk

56
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
PAUL L. PLUTA, PhD

Editor-in-Chief

Chicago, IL, USA

58

EQUIPMENT QUALIFICATION
LIFECYCLE APPROACH
Paul L. Pluta, PhD
OUTLINE
I.
Equipment Qualification Lifecycle Approach
II.
Qualification approaches
Documentation hierarchy
Document outlines
Documentation problems
EQUIPMENT QUALIFICATION LIFECYCLE APPROACH

KEY POINTS SUMMARY
1. Equipment qualification is a vital part of validation.
2. New FDA process validation guidelines has changed expectations
for equipment qualification.
3. Approach equipment qualification by lifecycle approach stages
Stage 1. Design / understand

Stage 2. Demonstrate
Stage 3. Monitor / maintain.
4. Equipment qualification must not be considered a one-time event.

5. Key validation principles identified -- Confirmation, risk analysis,
documentation, others.
6. Qualification options: IO/OQ/PQ or ASTM E2500.
7. Model documents recommended.
8. Documentation is vital: Consistency, content, good documentation
practices, and document retrieval.
3
INTRODUCTION -- VALIDATION AND QUALIFICATION

PROCESS VALIDATION PROCESS QUALIFICATION
PROCESS PERFORMANCE QUALIFICATION
Qualification
Qualification
Unit
Equipment #1
HVAC
Opera.on
#1
Utilities

Equipment #2
Facilities

#2
Computers

Equipment #3

Analytical methods validation

Cleaning process validation
Packaging process validation
#3

PROCESS IS VALIDATED
ALL SUPPORTING EQUIPMENT, FACILITIES, UTILITIES, CONTROL SYSTEMS,
ANALYTICAL, ETC. MUST BE QUALIFIED.
4
FDA PROCESS VALIDATION GUIDANCE 2011

Validation History
1978 GMP includes Validation
1987 First Validation Guidance
o Equipment IQ
2000 New approaches / documents / presentations

2008 New Process Validation draft guidance
o Equipment and analytical included
2011 New Process Validation Guidance issued

FDA EXPECTATIONS FOR VALIDATION / QUALIFICATION
CONSIDER POTENTIAL APPLICATION TO EQUIPMENT
SAME AUDITORS PHARMA, DEVICES, PROCESSES, EQUIPMENT
Definition FDA 2011

Definition: Collection and evaluation of data, from the
process design stage throughout production, which
establishes scientific evidence that a process is capable
of consistently delivering quality products.
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 production
1987 VALIDATION -- FOCUS IS PRIMARILY STAGE 2.
2011 VALIDATION -- LIFECYCLE APPROACH
Medical Device Validation

Comparison to Pharma
Device IQ = Pharma IQ / OQ / PQ
Device OQ = Product R&D (Stage 1 development)
Device PQ = Pharma PV
Reference: Device GHTF
VALIDATION / QUALIFICATION PRINCIPLES
Validation is confirmation
Risk analysis determines everything
Science and technical basis for design and development
Lifecycle approach
Understand, demonstrate, monitor and maintain
Sampling and testing -- rationale and justification

Pre-approved acceptance criteria
Data-based judgments
Documentation of above
Document retrieval
Maintain validation continuously
Change control
APPLICATION TO EQUIPMENT QUALIFICATION

8
VALIDATION IS CONFIRMATION
Successful validation is expected.
Do not initiate validation unless success is
expected.
Validation is not the final step in development,
installation, optimization, fine-tuning, or other
development activities.
Amendments, mistakes, failures scope changes,
etc. all have negative implications.
RISK MANAGEMENT
Risk defines everything.
Test only critical equipment parameters in
validation. Risk level determines level of testing.
Test non-critical equipment parameters during
commissioning.
Document risk assessment.
10
EQUIPMENT QUALIFICATION APPLICATIONS

Lifecycle approach
Risk analysis
Science and technical basis for design and development
Validation confirms equipment design and development
Sampling and testing -- rationale and justification based on risk
Pre-approved acceptance criteria
Data-based judgments
Document everything Retrieve documents
Maintain validation continuously throughout lifecycle -- based on risk
Preventive maintenance
Calibration
Change control
11
Qualification approaches
DQ / IQ / OQ / PQ (IQ for medical devices)
ASTM E2500
Documentation hierarchy
Document outlines
Model documents
12
QUALIFICATION APPROACHES
DQ / IQ / OQ / PQ
Traditional qualification
DQ Multiple functions and applications
Purchasing document
Equipment design document
Documents may be combined

IQ, OQ, PQ
IOQ, PQ
IOQ
13
DQ / IQ / OQ / PQ CONTENT
DQ Design Qualification
Equipment description
Equipment design requirements
Purchase / design specific requirements
IQ Installation Qualification
Components
Drawings
Operating manuals
Product-contact material composition
Surface area calculations (product contact equipment)
Calibration
Preventive maintenance
Equivalence to other equipment
Most difficult to clean locations
Other
OQ Operation Qualification
Worst case / range parameter operation
PQ Performance Qualification
Integrated parameter operation with representative materials
14
ISPE EQUIPMENT VALIDATION

User Requirements
Specification
PQ
Functional Specification
OQ
Design Specifications
IQ
System Build
15
15
EQUIPMENT QUALIFICATION LIFECYCLE

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Capital request with design (DQ)

Equipment build
Factory Acceptance Test (FAT)
Site Acceptance Test (SAT)
Commissioning
IQ
OQ
PQ
Preventive Maintenance and Calibration
Change control
Decommissioning
CONSISTENT WITH STAGE APPROACH
DOCUMENTATION ON ALL
16
16
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Test and document critical items only.
FAT, SAT, and Commissioning
Test and document non-critical items.
17
ASTM E2500. Standard Guide for Specifications, Design, and

Verification of Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment
Design Input
Design Review
Risk Mitigation
Critical Control Parameters Define
Acceptance Criteria
Verification Testing
Performance Testing
GEP scope and QA scope have clear boundary
Process, Product Quality and Patient Safety
Quality by Design, Design Space and Continuous Improvement
18
ASTM E2500
19
ASTM E2500
20
TRADITIONAL QUALIFICATION VS. E2500

Focused objective
Comprehensive approach
Includes risk analysis
Critical parameters
Less paperwork
Same content
21
DOCUMENTATION HIERARCHY
Company policy
Validation Master Plan
DQ
SAT / FAC
Commissioning
Validation / Qualification Request / Plan
IQ /OQ /PQ Protocol / Results / Report
Post Validation Monitoring / Maintenance
Change control
Associated technical document (e.g., manuals, etc.)
Associated documents (e.g., training, HR)
Management Review
CONSISTENT LIFECYCLE APPROACH
22
DOCUMENT OUTLINES
Validation Initiation
Validation Plan
IQ Protocol and Results
OQ Protocol and Results
PQ Protocol and Results
IQ/OQ/PQ Report
23
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
24
QUALIFCATION PLAN OUTLINE

Introduction
Technical information
Qualification strategy and testing
Qualification documentation
List of required protocols, reports, procedures, etc.

Administrative benefit
References
List of reports and scientific references (including Stage 1

reports)

25
PROTOCOL OUTLINE
Introduction
Equipment
Testing with justification
Sampling with justification
Sampling and data pages
Data treatment
Acceptance criteria with justification
26
RESULTS OUTLINE
Introduction
Data sheets compiled
Data treatment
Results
Deviations, Non-conformances, etc.
Discussion
Results pass is not sufficient.
Validation statement:
Results indicate that ___ is validated / qualified.
Post-validation plan
WRITE DISCUSSION SECTION FIRST MOST IMPORTANT SECTION
27
QUALIFICATION REPORT
Combined IQ / OQ / PQ results
Helpful in audit total summary
Cut and paste results and conclusions sections
Consistency and completeness important
28
REPORT FORMAT
Introduction
Key information from Validation Plan
Supporting information
Protocol #n results Cut and paste
Write transitional narrative
Project conclusions
Results indicate that ______ is validated / qualified.
29
TEMPLATES vs. MODEL DOCUMENTS

Recommendation:
1.Prepare perfect document make available as
needed
2.Assemble multiple documents from different
applications
3.Upgrade as needed
4.Documents available to technical writers
5.Validation Review Board maintain standards.
30
DOCUMENTATION PROBLEMS
Qualification statement: ________ is qualfied.
Documentation content
o Scientific and technical
o Compliance with policies/procedures/regulations
Errors, mistakes, and omissions

o Sampling and data pages
o Equipment not ready to be qualified
Original data consistency

o Documentation practices original data
o Missing results
o Retrieval
Documentation rules
Others
31
DOCUMENTATION
THREE SIMPLE RULES
1. Clear, complete, concise, consistent
2. Stand-alone documents written for the
reader
3. Short sentences and simple words
32
SUMMARY
1. Equipment qualification is a vital part of validation.
2. New FDA process validation guidelines has changed expectations for
equipment qualification.
3. Approach equipment qualification by lifecycle approach stages
Stage 1. Design / understand

Stage 2. Demonstrate
Stage 3. Monitor / maintain.
4. Equipment qualification must not be considered a one-time event.

5. Key validation principles identified -- Confirmation, risk analysis,
documentation, others.
6. Qualification options: IO/OQ/PQ or ASTM E2500 .
7. Documentation is vital: Consistency, content, good documentation
practices, and document retrieval.
8. Implementation strategies: Management support and document content.
9. Lifecycle change = Reorientation Not a significant change.
33

PAUL L. PLUTA, PhD

Editor-in-Chief
Journal of Valida-on Technology
Advanstar Communica.ons


Chicago, IL, USA

PharmaceuJcal industry experience

34

QUALITY BY DESIGN / LIFECYCLE APPROACH

to the
VALIDATION QUALITY SYSTEM
(Quality System by Design -- QSbD)

Paul L. Pluta, PhD
PRESENTATION OUTLINE
1.
Definitions and Objectives
2.
3.

QbD (QSbD) / Lifecycle Approach to the Validation Quality System
4.
5.
Quality by Design (QbD)

Validated Processes and Equipment
Lifecycle Approach to Validation Performance
Design/develop, Demonstrate, Monitor/maintain
Objectives
Attributes
Parameters
Variation and control
Risk management
Positives and Negatives

Implementation
PLEASE PARTICIPATE
2
PRESENTATION OBJECTIVES
1. Applica2on of QbD and lifecycle principles to the Valida2on Quality System
2. Design of the Valida2on Quality System
3. Objec2ves of Valida2on Quality System
4. Quality AFributes of Valida2on Quality System
5. Parameters aec2ng aFributes
6. Control of variables aec2ng quality system performance
7. Risk management
8. Monitoring performance Con2nuous improvements
VALIDATION: VALIDATED PRODUCT and INFRASTRUCTURE
AUDIT QUESTIONS
WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?
DEFINITIONS AND OBJECTIVES

Validated processes and equipment
Process of valida2on -- Lifecycle approach to process
valida2on
QbD consistency with process valida2on
-------------------------
Valida2on Quality System
QbD / Lifecycle approach to the valida2on quality
system
Risk management applica2ons

Development Focus
Target product prole (TPP) and cri2cal quality aFributes
(CQA)
Drug substance and excipient proper2es
Formula2on design and development
Manufacturing process design and development
Iden2ca2on of cri2cal process parameters (CPP) and cri2cal
material aFributes (CMA)
Risk assessment and design space
Scale up, iden2ca2on of variables, and control strategy

Red = Original QbD

VALIDATED PROCESSES AND EQUIPMENT

QualicaRon

Equipment #1

Equipment #2

Equipment #3
Process ValidaRon Process QualicaRon

Process Performance QualicaRon (PPQ)
Unit Op
#1

Unit Op
#2

Unit Op
#3

Analy2cal methods valida2on

Cleaning process valida2on
Packaging process valida2on
QualicaRon

HVAC

U2li2es

Facili2es

Computers

Process is validated

PROCESS OF VALIDATION
DeniRon: Collec2on and evalua2on of data, from the process design stage
throughout commercial produc2on, which establishes scien2c evidence
that a process is capable of consistently delivering quality products.
Process validaRon involves a series of acRviRes over the lifecycle of the
product and process.

Three stages of acRviRes:
Stage 1 Process Design Development and scale-up ac2vi2es QbD approach

Stage 2 Process Qualica2on Demonstrate reproducible manufacturing
through conformance lots
Stage 3 Con2nued Process Verica2on Rou2ne manufacturing and monitoring
of performance.
STAGE 1 AND STAGE 3 EMPHASIS NEW PARADIGM
VALIDATION HISTORY
1978 -- CGMP includes Valida2on

1987 -- Development -- VALIDATION Change control

2004 2011 Lifecycle approach
Con2nuum ---
UNDERSTANDING VALIDATION MAINTENANCE

QbD and PROCESS VALIDATION

QbD provides focus on design and development.
Integra2on of manufacturing experience throughout lifecycle
will results in product and process con2nuing improvements.
QbD consistent with ICH Q8 and Q11.

Lifecycle approach to process valida2on integrates QbD

principles.
Lifecycle: Design/development > Performance > Monitoring/
maintenance

Lifecycle approach being applied to other processes, equipment,

u2li2es, quality systems, etc.

Validation of processes, equipment, facilities, etc. is component of all
quality and manufacturing systems being inspected.
FDA Inspection Approach
Quality System
Materials System
Production system
Equipment and Facilities System
Packaging and Labeling System
Laboratory Controls System
Canada Quality Systems Approach. Inter-relationship of

Quality Assurance
GMP
Quality Control
Validation is a quality system.

Can QbD/lifecycle principles be applied to the validation
quality system?
10
QbD and VALIDATION QUALITY SYSTEM

QbD
Target product prole System objec2ve

Cri2cal quality aFributes System aFributes
Cri2cal process parameters System parameters
Control of varia2on Varia2on aec2ng performance
Risk assessment Priori2ze according to risk
Monitoring data Con2nuous improvements
11
RISK MANAGEMENT
ICH Q9 discusses risk management.

Risk analysis determines everything.
High risk ac2vi2es must receive most aFen2on.
Risk analysis required for devices.

12
VALIDATION FUNCTION
PRODUCT AND INFRASTRUCTURE
Two components:
1.Validated products, processes (manufacturing,
cleaning, packaging, etc.), equipment, u2li2es,
facili2es, control systems, computer systems,
analy2cal instruments the product of the
valida2on func2on.
2.The process of accomplishing valida2on the
infrastructure of the valida2on func2on. Protocols,
results, documenta2on packages, approval
commiFee, etc.
13
QbD PROCESS VALIDATION

QSbD VALIDATION QUALITYSYSTEM
LIFECYCLE APPROACH
PRODUCT and PROCESS
Target profile: Tablet, immediate release, rapid dissolution, bioavailability

Critical quality attributes: Content uniformity, dissolution, moisture
Critical process parameters: Granulation, drying, blending parameters
Variables and control: API particle size, PAT processing
Risk assessment: Emphasis on high risk materials and processes
Continuous improvement: Based on review of product / process experiences
LIFECYCLE APPROACH: Design/development, PQ, Monitoring Improvements

Stage 1 Stage 2 Stage 3
Objectives
Quality Attributes
Parameters
Variables and control
Risk assessment
LIFECYCLE APPROACH: Design, Demonstration, Monitoring Improvements

14
VALIDATION PRODUCT
PRODUCT : All validated products, processes (cleaning,
packaging, analy2cal, etc.), equipment, facili2es,
control systems, computers, etc., including
documenta2on.
DocumentaRon arming performance

PRODUCT/PROCESS LIFECYCLE APPROACH

1. Design and development Process understanding
2. PQ Process demonstra2on
3. Con2nuous process verica2on Monitoring and
maintenance
15
QUALITY SYSTEM
FDA Deni2on: Formalized business prac2ces that
dene management responsibili2es for
organiza2onal structure processes, procedures, and
resources needed to fulll product/service
requirements, customer sa2sfac2on, and con2nual
improvement.
Management responsibili2es
Resources
Manufacturing
Evalua2on
16
FDA QUALITY SYSTEMS MODEL

Management Responsibilities
1.
Provide leadership
2.
Structure the organization
3.
Build your quality system to meet requirements
4.
Establish policies, objectives, and plans
5.
Review the system
Resources
1.
General arrangements
2.
Personnel development
3.
Facilities and equipment
4.
Control outsourced operations
Manufacturing
1.
Design, develop, and document product and processes
2.
Examine inputs
3.
Perform and monitor operations
4.
Address non-conformities
Evaluation activities
1.
Analyze data for trends
2.
Conduct internal audits
3.
Quality risk management
4.
Corrective action
5.
Preventive action
6.
Promote improvement
17

LIFECYCLE APPROACH
Quality System Design

Is the quality system properly designed to conduct the
validation business process? Outsourced products,
outsourced processes, outsourced validation/
qualification?
Quality System Performance

Does the quality system perform as designed?
Quality System Monitoring and Maintenance

What is done to maintain quality system performance?:
18
QUALITY SYSTEM QUESTIONS

Procedures for all validation quality system activities -- Manufacturing processes,
cleaning processes, analytical processes, equipment qualifications, other
qualifications, computer systems, and other categories of validation/qualification?
Model documents for above categories of activities regarding validation initiation,
validation plans, protocols, results, and reports?
Validation documents templates?
Validation training?
Validation document preparation training?
Adequate number of validation personnel?
Expertise of validation personnel?
Expertise of Validation Approval Committee?
Responsibilities consistent with expertise?
Technical writers?
Personnel development and training?
Facilities?
Facility security?
Document library?
Electronic systems?
Electronic systems to monitor throughout, open documents, errors, etc.?
19
QbD and VALIDATION QUALITY SYSTEM

Objectives
Validation business process performance excellence
Validation quality system attributes

Business process performance attributes
Validation quality system parameters

Business process performance

Business system procedures and training
Risk management
Highest risk activities prioritized
Validation quality system improvement

Improvements based on evaluation activities

20
VALIDATION QUALITY SYSTEM BUSINESS PROCESS

INFRASTRUCTURE SUPPORTING PRODUCT
1. Initiation. Site functions initiate new validations and qualifications or changes to

validated systems.
New product / processes, equipment, facilities, utilities, other
Origin: R&D, Technical Support, Operations, Quality, Maintenance

2. Design / Development. Functions design / develop new systems or changes
3. PQ. Validation documentation written/monitored by validation group
Different requirements for different validation / qualification
Risk analysis
Different plans, protocols, results, reports
Documentation
Approval by Validation Approval Committee
Documentation storage and retrieval

4. Verification/Evaluation. Appropriate post-validation lifecycle maintenance, monitoring,
and review
Product process data (APR), Non-conformances and deviations; complaints,

changes, others. Management review
Validation infrastructure. Gaps, throughput, open packages, etc.

21
VALIDATION BUSINESS PROCESS -- DETAILS

INITIATION
1. Initiating group obtains site project approvals if necessary.
2. Project risk assessment
3. Interactions with validation group to identify requirements (critical attributes, critical parameters,
other recommendations, etc.)
4. Initiate validation documentation if necessary.
DESIGN/DEVELOPMENT
1. Technical work performed if necessary.
2. Technical documentation completed.
3. Technical documentation approved.
PQ
1. Initiate validation plan. Validation Plan consistent with technical support work and risk assessment.
2. Approve validation plan.
3. Initiate validation protocol.
4. Approval validation protocol
5. Execute validation protocol.
6. Initiate validation results report.
7. Validation report recommends post-validation monitoring
8. Approve validation results report.
EVALUATION
1. Initiate post-validation monitoring as required.
2. Review post-validation monitoring as required.
3. Management review of post-validation monitoring as required.
22
QbD APPROACH TO VALIDATION QUALITY SYSTEM

SPECIFIC BUSINESS PROCESS
ObjecRves
What are the goals of each process step?
Abributes
What makes a process step successful?
Parameters
What factors signicantly inuence the success of the process step?
VariaRon and control

What varia2on in performance is expected and how is it controlled?
Risk management
What are highest risk ac2vi2es?
Priori2za2on, evalua2on, and review highest level for highest risk
EvaluaRon
Review performance of valida2on quality system
23

VALIDATION CATEGORY
INITIATION
DESIGN and
DEVELOPMENT
PQ
MONITORING
MAINTENANCE
OBJECTIVE
QUALITY
ATTRIBUTES
PARAMETERS
CONTROL OF
VARAITION
RISK
24
VALIDATION QUALITY SYSTEM -- PROBLEM EXAMPLES

MANUFACTURING EQUIPMENT AND PROCESSES
Operators did not perceive changes to be changes inadequate change control
CLEANING VALIDATION
Operators did whatever needed to get the job done.
CLEANING VALIDATION SAMPLING
Sampling personnel not adequately trained false positive data
DOCUMENTATION
Numerous documentation practices problems such as data recording, original data,
back dating, etc.
DOCUMENTATION COMPLIANCE
Documentation not compliant with corporate requirements
DOCUMENTATION GRAMMATICAL
Documentation poorly written
POWDER BLEND UNIFORMITY TESTING
Sampling personnel not adequately trained
NON-STERILE CLEAN PROCESSES
Sampling personnel not adequately trained
LIKE-FOR-LIKE CHANGES
No testing of correct installation
25

CORRECTIVE ACTION PROJECTS
Validation Training Module
Validation Protocol Writer Training
Cleaning Validation Training
Cleaning Visual Inspection Training
Documentation Practices Training
Validation Approval Committee Training
Validation Model Documents
Like-for-Like Approval (non-protocol) Process
Microbiology Training
Validation Policy Changes
RECORD CORRECTIVE ACTION PROJECTS IN VMP
26
WHY THE PROBLEM? -- VALIDATION CATEGORIES

Process valida2ons
Manufacturing
Cleaning
Packaging
Analy2cal
Others
Qualica2ons IQ, OQ, PQ; ASTM E2500
Equipment
Facili2es
U2li2es
Computer systems
Others
EACH VALIDATION UNIQUE

27
WHY THE PROBLEM?

ORIGINATORS OF VALIDATION / QUALIFICATION PROJECTS
R&D
Technical Support
Process Engineering
Facili2es Engineering
Maintenance
Analy2cal R&D
QA/QC
Other

EACH GROUP UNIQUE. EACH WITH SPECIFIC EXPERTISE.

EACH WITH SPECIFIC LANGUAGE AND TERMINOLOGY.
ALL ABOVE GROUPS MUST UNDERSTAND VALIDATION OBJECTIVES.
28
VALIDATION QUALITY SYSTEM LIFECYCLE

QUANTITATIVE MONITORING -- EVALUATION
PRODUCT
Performance of validated products, processes, equipment, etc.
QUALITY SYSTEM
Throughput
External audit observa2ons
Documenta2on quality
Open valida2on projects 2me open
Valida2on failures
Protocol amendments
Protocol devia2ons
Other
29
OTHER APPLICATIONS
QbD / Lifecycle approach to other quality systems
Documenta2on in QSMP

Examples:
Material system Heparin
Manual cleaning Methotrexate
Training Read and sign vs. OTJ
30
QbD / LIFECYCLE APPROACH POSITIVES

Organized and comprehensive focus based on risk to the pa2ent
and the organiza2on Based on successful concepts
System design for each type of valida2on -- Gap analysis
Risk analysis for each type of valida2on
Cross-func2onal systems thinking
Consistent priori2zed mi2ga2on ac2vi2es across func2ons based
on risk
Varia2on iden2ca2on and control strategy
Con2nuous improvements based on systems monitoring
Standardized audit expecta2ons and documenta2on
Organiza2on commitment, transparency, and credibility
Track organiza2on accomplishments completed
Strong message to employees
Strong message to auditors
Poten2al credit in audits for projects completed and new
commitments iden2ed

31
QbD / LIFECYCLE APPROACH NEGATIVES

Dicult
Geqng organized is extremely dicult!
Risk analysis is dicult
Gap analysis is dicult
Changes are dicult
Transparency
Being open about gaps and deciencies may have
regulatory and poli2cal risks
OrganizaRonal commitments
Headcount needed to correct deciencies

Do the benets outweigh the negaRves?

32
SUMMARY
Concepts and Principles
Objectives
Attributes
Parameters
Risk management
Performance
Monitoring and maintenance
33
SUMMARY

Validation Quality System function
Product validated processes, equipment, utilities, computer

systems, etc.
Infrastructure Process of conducting validation

Product -- Lifecycle approach:
1. Design and develop to understand
2. Validation PQ
3. Monitor and maintain the validated state

34
SUMMARY

Infrastructure Lifecycle approach and QbD
1. Determine business process
Ini2ate valida2on project

Design and develop items to be validated
PQ
Monitor and maintain validated state
2. QbD for business process
Objec2ves -- Goals of each process step?

AFributes Successful steps
Parameters Factors inuencing success
Control of varia2on -- Expected varia2on in performance
Risk -- management Priori2ze highest risk ac2vi2es
Evalua2on -- Review performance
35
SUMMARY
Review Performance
Gap analysis: Problem areas
Initiate corrective action

Example projects
Quantitative measurements: Throughput, failures,

deviations, etc.
Positives and negatives

Implementation difficult
36
SUMMARY

AUDIT QUESTIONS:
WHAT IS YOUR APPROACH TO VALIDATION?
HOW DO YOU MANAGE THE VALIDATION FUNCTION?

1. Product/process/equipment/facili2es/etc: Lifecycle approach

Design/development (QbD)
Performance PQ
Maintenance and monitoring leading to improvments
2. Valida2on Quality System/infrastructure:

QbD / lifecycle approach valida2on business process
Design of the Quality System
Objec2ves, AFributes, and Parameters
Control sources of varia2on
Risk analysis
Demonstrate performance
Evalua2on leading to con2nuous improvements

37
PAUL L. PLUTA, PhD

Editor-in-Chief
VisiRng Clinical Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Industry experience

38

IMPLEMENTATION
MANUFACTURING PROCESSES
OTHER PROCESSES
EQUIPMENT, FACILITIES, UTILITIES
OTHER QUALITY SYSTEMS

Paul L. Pluta, PhD
OUTLINE
1. Status of Implementa6on
2. Posi6ves and Nega6ves
3. Implementa6on Strategy and Approach
4. Impediments to Implementa6on

LIFECYCLE APPROACH -- STATUS OF IMPLEMENTATION

OrganizaAons implemenAng lifecycle approach -- Reasons
US FDA guidance
Health Canada guidance
EMA draI guidance
Global communica6on
ICH Q8, Q11
Logical approach development, performance, and maintenance
Applica6on to other processes, equipment, facili6es, etc.
OrganizaAons not implemenAng lifecycle approach -- Reasons
Its only a guidance.
Lets see what happens.
Its only for USA.
We will consider it if we get observa6ons.
Too costly, no headcount
LIFECYCLE APPROACH IMPLEMENTATION
Why implement?
Guidance documents -- Lifecycle approach is the
future
Lifecycle approach makes sense
Auditors learning the lifecycle approach
LIFECYCLE APPROACH POSITIVES

Organized and comprehensive focus based on risk to the pa6ent
and the organiza6on Based on successful concepts
System design for each type of valida6on -- Gap analysis
Risk analysis for each type of valida6on
Cross-func6onal systems thinking
Consistent priori6zed mi6ga6on ac6vi6es across func6ons based
on risk
Varia6on iden6ca6on and control strategy
Con6nuous improvements based on systems monitoring
Standardized audit expecta6ons and documenta6on
Organiza6on commitment, transparency, and credibility
Track organiza6on accomplishments completed
Strong message to employees
Strong message to auditors
Poten6al credit in audits for projects completed and new
commitments iden6ed

5
LIFECYCLE APPROACH NEGATIVES

Dicult
Ge_ng organized is extremely dicult!
Risk analysis is dicult
Gap analysis is dicult
Changes are dicult
Transparency
Being open about gaps and deciencies may have
regulatory and poli6cal risks
OrganizaAonal commitments
Headcount needed to correct deciencies

IMPLEMENTATION
1. Iden6fy high risk areas
Example: Cleaning exper6se

Example: Asep6c processing
2.
3.
4.
5.
6.
7.
Senior management discussion risks to opera6on

Func6on management discussion risks to opera6on
Iden6fy recep6ve individuals in high risk area
Training of appropriate individuals
Start slowly
Communica6on. Modify strategy as needed to insure
success
8. Expand eort based on success
9. Expect resistance
7
PRIORITIZATION
1. Manufacturing process valida6on
2. Others
IMPLEMENTATION
MANUFACTURING PROCESS VALIDATION
Plan implementa6on strategy

Assemble PV Guidance and other references
Meet with aected groups R&D, Engineering, Technical Support, QA, others
Stage 1 groups
Stage 3 groups
Meet with Valida6on Approval Commihee

Develop reasonable and deliberate strategy with guaranteed success
Upper management input and approval

General training on valida6on all including new groups involved in valida6on
Protocol writer training
Expecta6ons for documents
Valida6on Approval Commihee responsibili6es
Science and technical basis

Compliance with procedures
Documenta6on quality
Surrogate regulatory auditor
Valida6on Approval Commihee training

Start slowly and build on success
9
IMPLEMENTATION -- REALITY
Develop reasonable and deliberate strategy

Assure successful implementaAon
Do not expect rapid success
Do not expect agreements and support
10
FINAL Q & A
Did we meet objec6ves?
11
PAUL L. PLUTA, PhD

Editor-in-Chief
Associate Professor
University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Industry experience

12

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VALIDATION BOOT CAMP

Process Validation Lifecycle Approach Overview

Validation lifecycle approach basic understanding

Documentation for lifecycle approach

Applications according to lifecycle approach

Registration, welcome and opening remarks

Part I. Introduction, basis, lifecycle stages

Part II. Documentation

Lunch Specific requests / clarifications

Part III. Applications -- Cleaning, EFU, Quality Systems

Overview and history

INTRODUCTION, BASIS, LIFECYCLE STAGES

History and Development

PROCESS VALIDATION LIFECYCLE APPROACH

HISTORY AND DEVELOPMENT

HEALTH CANADA -- VALIDATION GUIDELINES FOR

ICH Q8 (R2) PHARMACEUTICAL DEVELOPMENT

ICH Q8 PHARMACEUTICAL DEVELOPMENT

ICH Q8 PHARMACEUTICAL DEVELOPMENT

ICH Q8 PHARMACEUTICAL DEVELOPMENT

ICH Q8 PHARMACEUTICAL DEVELOPMENT

Implications for Process Validation

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

Initiate risk management process

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

ICH Q9 QUALITY RISK MANAGEMENT

QUALITY BY DESIGN (QbD)

VALIDATION PHARMACEUTICAL DOSAGE FORMS

TERMINOLOGY: PROCESS VALIDATION

Analytical methods validation

FDA PROCESS VALIDATION GUIDANCE (2011)

FDA PROCESS VALIDATION GUIDANCE

FDA PROCESS VALIDATION GUIDANCE

STAGE 1, PROCESS DESIGN

PROCESS DESIGN (PROCESS UNDERSTANDING)

QUALITY BY DESIGN (QbD)

STAGE 2, PROCESS QUALIFICATION

Design of a facility and qualification of utilities and equipment

Confirmation at commercial scale of process design information

STAGE 2, PROCESS QUALIFICATION

PERFORMANCE QUALIFICATION APPROACH

PERFORMANCE QUALIFICATION APPROACH

STAGE 3, CONTINUED PROCESS VERIFICATION

Activities to assure process remains in validated state

CONTINUED PROCESS VERIFICATION

CONTINUED PROCESS VERIFICATION

SUMMARY OF GUIDANCE RECOMMENDATIONS

PROCESS VALIDATION HISTORY

CGMP includes Validation

UNDERSTANDING -- VALIDATION -- MAINTENANCE

SUMMARY -- VALIDATION CURRENT PRACTICE

SUMMARY -- WHERE WE ARE GOING

LIFECYCLE APPROACH TO PROCESS VALIDATION

The process of process validation.

CGMP includes Validation

UNDERSTANDING -- VALIDATION -- MAINTENANCE

PAUL L. PLUTA, PhD

Adjunct Associate Professor

Pharmaceutical industry experience