ISPE Boston Chapter Webinar: ISPE Baseline Guide Volume 5, 2nd Edition

ISPE Boston Chapter
Webinar
ISPE Baseline Guide
Volume 5, 2nd Edition
Chip Bennett
Assistant Director, Global C&Q
CAI
Webinar
05 March 2020
Chip Bennett, PMP
Assistant Director, Global C&Q, CAI
> CQV Program Development Lead SME
> QRM SME
Pharma/CQV since 2000
Contact:
> [email protected]
> (636) 236-1776
A Project Manager and Senior Validation Engineer, Chip is a PMI® Certified Project Management Professional
(PMP) with 20 years of experience in the pharmaceutical and regulated non-pharmaceutical industries and with
expertise in risk-based verification, aseptic manufacturing, cleaning validation, quality systems, and owner project
management. Chip is responsible for developing and implementing Quality Risk Management (QRM) based
Commissioning and Qualification programs and projects, with a focus on assessing and training clients regarding
development, implementation, and transition to risk-based approaches.
Connecting Pharmaceutical Knowledge ispe.org 2

Agenda
ISPE Baseline Guide Volume 5, 1st Edition

 Industry and Regulatory Drivers
 QRM Shortcomings
The Path to ISPE Baseline Guide Volume 5, 2nd Edition
 Business Drivers
 QRM as Regulatory Driver and Industry Focus
Differences Between 1st and 2nd Editions
 QRM Incorporation and Other Benefits
 Defined/Retired Terms and Activities
 Integrated C&Q Process and Deliverables
 Risk Assessment and Supporting Processes
Applying QRM to C&Q Processes
Benefits and Opportunities
Q&A

Before We Begin…
Caveats:
I am not a CoP steering committee member or an author/contributor to
the Guide
This is not, and does not replace, the official CoP Presentation
About This Presentation:
More than just the content of the revised Guide
Historical context and evolution
Practical implementation based on project experience

ISPE Baseline Guide
Volume 5, 1st Ed
Where were we in 2001?
ISPE Baseline Guide Volume 5, 1st Ed
Drivers for 1st Edition:
Industry Drivers
 V-Model delivery cost, schedule, Design Qualify
effectiveness – duplicated effort
 Inconsistent C&Q terminology User
Requirements
Performance
Qualification
 Inconsistent interpretation of
Functional Operational
CGMP requirements Design Qulification
Regulatory Drivers Specification
Detailed Installation
 Alignment with industry regarding Design Specification Qualification
C&Q expectations
 Consistent C&Q terminology and Build
approach FAT
SAT /
 Focus effort on product quality, risk Commissioning
Connecting Pharmaceutical Knowledge ispe.org

ISPE Baseline Guide Volume 5, 1st Ed
Challenges Implementing 1st Edition:
QRM Not Incorporated
 PPK (CQAs/CPPs) not
understood/documented
 Risk to product quality not identified,
assessed, or controlled
 Testing not commensurate with risk
Siloed Roles and Responsibilities
 Engineering and Quality roles and
responsibilities overlap and contradict
Inefficient Approach
 Prescriptive testing strategy
 “Test everything” mentality
 Engineering and Qualification: non-
value-added testing redundancy

Business Drivers
The path to ISPE Baseline
Guide Volume 5, 2nd Ed.
ISPE Baseline Guide Volume 5, 2nd Ed
Industry Drivers: Desired Start-Up Experience: Speed to Market
Start-Up Time
Efficiency (%)
Efficiency (%)
Goal
0
Problems Time
Problems
NORMAL

Industry Drivers: Desired Start-Up Experience: Speed to Market
Start-Up Time Start-Up Time

Efficiency (%)
Efficiency (%)
Goal
0 0
Problems Time Time
Problems
Problems
Problems
NORMAL DESIRED

Regulatory Drivers:
QRM
Regulatory Drivers: QRM
2001:
 ISPE, Baseline Guide Vol 5, 1st Ed: Commissioning and Qualification [C&Q Approach]
2004:
 ICH Q8, Pharmaceutical Development (revised 2008) [CQA, CPP, QbD]
 FDA, Pharmaceutical Development for the 21st Century – A Risk-Based Approach
2005:
 ISPE, White Paper: Risk-Based Qualification for the 21st Century [RBV Principles]
 ICH Q9, Quality Risk Management [QRM]
2007:
 ASTM E2500, Spec, Design, and Ver. of Pharma/Biopharma Mfg. Sys and Equip (rev. 2013, 2019) [RBV
Process]
2011:
 ICH Q10, Pharmaceutical Quality System [Control Strategy]
2011:
 FDA, Guidance for Industry – Process Validation: General Principles and Practices
 ISPE, Guide: Science and Risk Based Approach for the Delivery of Facilities, Systems, and Equipment
 ISPE, Good Practice Guide 10: Applied Risk Management for Commissioning and Qualification
2015:
 EudraLex, Volume 4, Annex 15: EU Guidelines for GMPs for Medicinal Products for Human and Veterinary
Use
2019:
 ISPE, Baseline Guide Vol 5, 2nd Ed: Commissioning and Qualification [QRM-Based Integrated C&Q]

Regulatory Drivers: QRM
US FDA Report (2004):

Pharmaceutical Development for the 21st Century – A Risk-Based Approach
 Innovation, QRM/Quality Systems, Risk-Based Approaches, Critical
Areas, State of the Art Science
US FDA Guidance for Industry (2011):

Process Validation: General Principles and Practices
 QRM/Quality Systems, Risk-Based Decisions, Criticality as a Continuum,
Control Commensurate with Risk, Less Reliance on Terminology
EU EudraLex, Volume 4, Annex 15 (2015):

EU Guidelines for GMPs for Medicinal Products for Human and Veterinary Use
 Control of Critical Aspects, QRM Approach, Risk Assessment
Basis/Justification for Qualification/Validation

QRM: Industry Focus
Industry Focus: QRM
2001:
2004:
2005:
2007:
Process]
2011:
2011:
2015:
Use
2019:

Industry Focus: QRM
CQV Benchmarking

Industry Focus: QRM

Industry Focus: QRM
2001:
2004:
2005:
2007:
Process]
2011:
2011:
2015:
Use
2019:

Baseline Guide Volume
5:
1st Ed vs 2nd Ed
What has changed?
Benefits
QRM Incorporation
Science- and Risk-Based Approach
Focus on Quality by Design (QbD)
Incorporates Industry Standards
Other Benefits
Consistent, Compliant Approach
Efficient Approach
Risk-Based Lifecycle Approach

Defined, Retired Terms
Defined: Retired:
 Commissioning  Indirect Impact
 Qualification  Component Criticality Assessment
 Commissioning and Qualification (C&Q)  V-Model
 Validation  Enhanced Documentation
 Verification  Enhanced Commissioning
 Enhanced Design Review
 Leveraging

Defined Terms
A well-planned, documented, and managed, engineering approach to the start-up and turnover
Commissioning of facilities, systems, utilities, and equipment to the end user that results in a safe and functional
environment that meets established design requirements and stakeholder expectations.
Qualification
For the purpose of this guide, a process to demonstrate and document that the critical
manufacturing facilities, systems, utilities, and equipment are suitable for the intended purpose.
Commissioning For the purposes of this Guide, the term Commissioning and Qualification (C&Q) is used to
and Qualification describe the process for establishing that facilities, systems, utilities, and equipment are
(C&Q) suitable for their intended purpose.
Establishing documented evidence which provides a high degree of assurance that a specific
Validation process will consistently produce a product meeting its predetermined specifications and quality
attributes (FDA Process Validation Guidance, 1987)
Verification
An activity that is performed within the C&Q process to document that the manufacturing
facilities, systems, utilities, and equipment are suitable for the intended purpose.
Design functions or features of an engineered system that are necessary to consistently

Critical Design manufacture products with the desired quality… CDEs are identified and documented based on
Element (CDE) technical understanding of the product CQAs, process CPPs, and equipment
design/automation. CDEs are verified through C&Q.

Defined, Retired Terms
Defined: Retired:
 Commissioning  Indirect Impact
 Qualification  Component Criticality Assessment
 Commissioning and Qualification (C&Q)  V-Model
 Validation  Enhanced Documentation
 Verification  Enhanced Commissioning
 Enhanced Design Review
 Leveraging

Integrated C&Q Process
Figure 1.1: Science and Risk-Based C&Q Process Map

Integrated C&Q – Roles and Responsibilities
Engineering
 Role: system delivery
 Focus: system fitness for use
 Responsibility: verification (testing and documentation)
Quality
 Role: product quality
 Focus: PPK, risk control strategy, system design, and verification
 Responsibility: oversight (approval)

QRM-Based C&Q: Roles and Responsibilities

QRM-Based C&Q: Roles and Responsibilities

Quality Risk
Management
Introduction and
application to C&Q
Processes
ICH Q9: QRM Process

QRM as a Holistic Lifecycle Process
Process Development Define Product/Process Knowledge (PPK): CQA, CPP
Risk Assessment Identify Risks to Product Quality
Risk Control Identify Critical Aspects (CAs) to Mitigate Identified Risks
Risk Review Design Review: Identify CDEs / Risk Control Strategy
Design Qualification: Design of Risk Controls (CAs/CDEs)

Quality by Design (QbD) Acceptably Mitigates Risk
C&Q Strategy Verify CAs/CDEs, Testing Rigor Commensurate w/Risk
Periodic Review/Revalidation, Continuous Improvement,

Risk Review Change Management, Deviation/CAPA Management

Applying QRM Concepts to C&Q
Critical Quality Attribute (CQA):
Applies to the product.
Origin: Product and Process Knowledge (PPK) Risk to Product Quality = failure to meet CQA
Critical Process Parameter (CPP):

Applies to the process.
Origin: Product and Process Knowledge (PPK) and Risk Assessment
Process Risk = failure to maintain CPP
(RA)
Critical Aspect (CA):

Applies to a process system (equipment, utility, facility).
Risk Control Strategy = CAs collectively mitigate
Origin: Risk Assessment (RA)
unacceptable risk to product quality
Critical Design Element (CDE):

Applies to a process system design element (component, process control, alarm, etc.).
Verification Strategy = CDEs tested to verify
Origin: Critical Aspects (CA) and System Design Definition
installation/operation fit for intended use

Relationship Between CQA, CPP, CA, and CDE
Step Mixing
Process
System Tank, Agitator
CQAs Potency
PPK Mixing Speed
CPPs
Mixing Time
Risk Failure Failure to control Mixing Speed. CQA impact: Incorrect Potency
Assessment Modes Failure to control Mixing Time. CQA impact: Incorrect Potency
Control, Monitoring, and Alarming of Mixing Speed
CAs
Control, Monitoring, and Alarming of Mixing Time
Risk Control
Agitator Speed Controller, Agitator Speed Indicator, Agitator Speed Alarm Sensor
CDEs
Timer, Time Indicator, Time Alarm Sensor

Applying QRM to C&Q Process Deliverables
RTM
Traceability
URS RA DR DQ CQP C&Q ARR
Specification & Acceptance &

Requirements Design Verification Release

RTM
Traceability


Step WFI Generation, Distribution, and Storage

Process
System WFI Storage Tank
CQAs Water Meets Specifications for WFI, USP

PPK Product Contact Surfaces Non-Additive, Non-Reactive, Non-Absorptive
CPPs Drainability
Cleanability

Explicitly define/specify
CQAs, CPPs
Type URs based on

product quality impact

RTM
Traceability



Process

CPPs Drainability
Cleanability
Additive/reactive/absorptive MOC. CQA impact: Chemical (TOC/Cond/pH Failure)
Risk Failure
Not Drainable. CQA impact: Microbial (Bioburden/Endotoxin) Failure
Assessment Modes
Not Cleanable. CQA impact: Chemical/Microbial Failure
Design of Materials of Construction
CAs Hygienic Vessel Design
Design and Control of Cleaning/Coverage
Risk Control

CQAs, CPPsRisk Mitigation: Design Controls, Process Risks to CQAs:

are inputsAlarms, Procedural Controls Failure to Control CPPs

RTM
Traceability


URS -> Risk

Assessment
Risk Controls (CAs) trace to CQAs,

CPPs

RTM
Traceability



Process

CPPs Drainability
Cleanability
Additive/reactive/absorptive MOC. CQA impact: Chemical (TOC/Cond/pH Failure)
Risk Failure
Not Drainable. CQA impact: Microbial (Bioburden/Endotoxin) Failure
Assessment Modes
Not Cleanable. CQA impact: Chemical/Microbial Failure
Design of Materials of Construction
CAs Hygienic Vessel Design
Design and Control of Cleaning/Coverage
Risk Control
316L Stainless Steel Vessel
CDEs Conical Vessel Bottom
Spray Ball, Control and Monitoring of CIP Supply Flow

URS -> Design Review
CDEs trace to CQAs,

CPPs

RTM
Traceability


Design of CDEs
Design Satisfied Quality URs
Satisfies CAs
QbD: Verifies that CQA/CPP based risk controls
Risk
have been incorporated into the design
Control
QbD: Verifies that Critical Aspects acceptably Strategy
mitigate risk to product quality (CAs,
CDEs)
Identified

RTM
Traceability


RTM
Traceability


RTM
Traceability


URS -> Verification Testing
Verification testing traces to CQAs, CPPs and meets specification

RTM
Traceability


System
Installation andSatisfies
Operation of CDEs are fit for intended use
Critical
System Meets Specification for Quality URs
Aspects
(CA)

Benefits/Opportunities
Benefits and opportunities
from ISPE Baseline Guide
Volume 5, 2nd Ed.
Benefits of Changes to C&Q Processes
Process Historical Approach Apply New Approach Benefit

Qualification process Efficient use of
Qualification protocols at project Good
integrated into engineering resources and
C&Q Testing end with testing redundant to Engineering
project without non-value- reduced pressure on
engineering lifecycle Practices
added redundant testing project schedule
Qualification testing based on Testing considers controls, Focuses qualification
Quality Risk
Requirements equipment specifications and detection mechanisms, and efforts on defined
Management
capabilities all quality systems critical aspects
Design review applied
Systematic Design review well-directed Enables appropriate
inconsistently with
Design Design with defined Quality and defendable
unstructured Quality
Review involvement Quality oversight
involvement
Changes are not well- Engineering All changes are effectively Prevents the need to
Change
controlled until a system is Change managed throughout the perform redundant
Management
qualified and released for use Management engineering project testing at project end

Applying QRM Through the System Lifecycle
Process Development Define Product/Process Knowledge (PPK): CQA, CPP
Risk Assessment Identify Risks to Product Quality
Risk Control Identify Critical Aspects (CAs) to Mitigate Identified Risks
Risk Review Design Review: Identify CDEs / Risk Control Strategy
Design Qualification: Design of Risk Controls (CAs/CDEs)

Quality by Design (QbD) Acceptably Mitigates Risk
C&Q Strategy Verify CAs/CDEs, Testing Rigor Commensurate w/Risk
Periodic Review/Revalidation, Continuous Improvement,

Risk Review Change Management, Deviation/CAPA Management

Discussion
Questions?
For further information, please contact
Mr. Chip Bennett
at [email protected]
Chip Bennett
Assistant Director, Global C&Q
CAI
[email protected]
Supporting Processes
Supporting processes and
enablers for the QRM-
based integrated C&Q
process
System Risk Assessment

Central to Integrated C&Q Approach:
 Defines risk to product quality
 Identifies Risk Controls
 Determines instrument/alarm criticality
 Links verification activities to process and product quality controls
 Provides rationale for C&Q strategy
Benefits of System Risk Assessment:
 Provides focal point for Design Review and Design Qualification
 Defines control strategy for process risks, focuses Quality on product
quality/CDEs
 Provides a focus for C&Q to ensure controls are in place and tested
 Established traceability from Qualification Summary to lifecycle activities
and verification

Supporting Processes: System Classification

High-level first pass to identify systems with direct product quality impact
Based on system boundaries for integrated testing
Same yes-no question methodology, updated questions
Q1 Does the system contain CAs/CDEs or perform functions that serve to meet one or more process requirements (CQAs) including
CPPs?
Q2 Does the system have direct contact with the product or process stream and does such contact have the potential to impact the
final product quality or pose a risk to the patient?
Q3 Does the system provide an excipient or produce an ingredient or solvent (e.g., WFI) and could the quality (and compliance with
the required specifications thereof) of this substance impact the final product quality or pose a risk to the patient?.
Q4 Is the system used in cleaning, sanitizing, or sterilizing, and could malfunction of the system result in failure to adequately clean,
sanitize, or sterilize such that a risk to the patient would result?
Q5 Is the system used in cleaning, sanitizing, or sterilizing, and could malfunction of the system result in failure to adequately clean,
sanitize, or sterilize such that a risk to the patient would result?
Q6 Does the system use, produce, process, or store data used to accept or reject product, CPPs, or electronic records subject to 21
CFR Part 11 [20] and EU GMP Vol. 4, Annex 11 [21] or the local equivalent?
Q7 Does the system provide container closure or product protection, the failure of which would pose a risk to the patient or
degradation of product quality?.
Q8 Does the system provide product identification information (e.g., lot number, expiration date, counterfeit prevention features)
without independent verification or is the system used to verify this information?

Supporting Processes: Good Engineering Practice (GEP)

Design Review:
 Ensures design meets URS
 Identifies CDEs that satisfy Critical Aspects
 Supports implementation of Quality by Design (QbD) principles
 Culminates in DQ


Engineering Change Management:
 System lifecycle process: Design through Operation to End of Life
 Following final design acceptance, subsequent changes evaluated for
quality impact
 CQA, CPP, CA, CDE
 Project ECM through C&Q
 After system acceptance and release:
 Site ECM
 Quality Change Control if quality impact


Engineering Quality Process:
 Documented activities during system lifecycle stages:
 Design/Procurement: Vendor/Supplier Management
 Implementation: Construction Quality, Commissioning, Handover
 Operations: Asset Management, Calibration, Maintenance
 Supporting systems throughout system lifecycle:
 Document/Drawing Control
 Issue/Punchlist Management
 Engineering Good Documentation Practice (GDP)

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ISPE Boston Chapter

> CQV Program Development Lead SME

> QRM SME

Pharma/CQV since 2000

> (636) 236-1776

Connecting Pharmaceutical Knowledge ispe.org 2

ISPE Baseline Guide Volume 5, 1st Edition

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Start-Up Time Start-Up Time

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US FDA Report (2004):

US FDA Guidance for Industry (2011):

EU EudraLex, Volume 4, Annex 15 (2015):

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Design functions or features of an engineered system that are necessary to consistently

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Figure 1.1: Science and Risk-Based C&Q Process Map

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Process Development Define Product/Process Knowledge (PPK): CQA, CPP

Risk Assessment Identify Risks to Product Quality

Risk Control Identify Critical Aspects (CAs) to Mitigate Identified Risks

Risk Review Design Review: Identify CDEs / Risk Control Strategy

Design Qualification: Design of Risk Controls (CAs/CDEs)

C&Q Strategy Verify CAs/CDEs, Testing Rigor Commensurate w/Risk

Periodic Review/Revalidation, Continuous Improvement,

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Critical Process Parameter (CPP):

Critical Aspect (CA):

Critical Design Element (CDE):

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URS RA DR DQ CQP C&Q ARR

Specification & Acceptance &

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URS RA DR DQ CQP C&Q ARR

Specification & Acceptance &

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Step WFI Generation, Distribution, and Storage

CQAs Water Meets Specifications for WFI, USP

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Type URs based on