Risk-Based Qualification

ICH, ASTM, and What Makes Sense!

Agenda

• Concepts
• ICH Q9, Quality Risk Management
• ASTM Standard
• Application
Federal Court,
Case NO. 2:02-CV-733 BSJ/
21 October 2005
“The fact that the road chosen by Utah Medical
may be different in degree than that thought to be
appropriate by a regulator, does not mean that it is
wrong, or in violation of the regulations.”
What might a regulator want?

For people to understand the

intent of regulations, and then
implement programs to meet that
intent.
Regulations and Design/
Construction
• US Regulations mention design - YES
• US Regulations mention validation - YES
• US Regulations mention qualification - NO
• EU Regulations mention design - YES
• EU Regulations mention qualification - YES
• EU Regulations mention risk as discriminator -
YES
• ICH Guidelines mention qualification - YES
• ICH Guidelines mention risk as discriminator -
YES
US Regulations
• 210.3, (20) Acceptance Criteria
• 211.22, 810.20(a) (4), Responsibilities of Quality
Unit
• 211.25, 820.25, Personnel Qualifications
• 211.42, 820.40, Facility Design and Construction
Features
• 211.63, 820.60, Equipment Design, Size and
Location
US Regulations

• 211.65 Equipment Construction

• 820.61, Measurement Equipment
• Automatic, mechanical and electronic
equipment
• 820 Subpart F - Production and
Process Control
EU Regulations

• It is a requirement of GMP that

manufacturers identify what validation
work is needed to prove control of the
critical aspects of their particular
operations…A risk based approach
should be used to determine the
scope and extent of validation.
What is Our Typical Approach?

• End goal is approved qualification

protocols
• How many deviations result in field changes vs.
paperwork exercise?
• Rigid structured qualification program to
satisfy regulators, not deliver functioning
manufacturing capacity
• Everything is critical
• If everything is critical, then nothing is critical!
Eight identical HVAC protocols
given to eight different reviewers,
each with different comments
Which is the correct protocol? Are they all
correct? Are none correct? Were any correct
before the comments?
“Unless we do things differently,
nothing will change.”

-A highly paid management

consultant
What We Need to Do Differently
• Content of IQ/OQ/PQ
• Critical items only
• How we determine what is critical
• How we approach start-up/ commissioning/
verification:
• Improve effectiveness
• Execute one set of documents
• Roles and responsibilities
• Dealing with deviations
• Change management
ICH Q9: Quality Risk Management

Solid basis to focus compliance

Key Principles
• The evaluation of risk to quality
• Based on scientific knowledge
• Ultimately link to protection of the patient
• Quality risk management commensurate
with level of risk
• Level of effort
• Formality
• Documentation
QRM Model

Risk Management Tools

Risk Assessment
Risk Communication

Risk Control Risk Reduction

Risk Acceptance

Risk Review
Refocusing Our
Quality and
Compliance
Systems
 Current Practices

Risk Assessment Filter

Additional risk

Risk Control

Risk Management
ASTM Standard

Standard Guide for Specification, Design, and

Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Facilities,
Equipment, and Systems
Standard Contents

• Key concepts
• Specification, design, and verification
process
• Supporting activities
• Implementation approaches
Scope of Standard
• Pharmaceutical and Biopharmaceutical
• Systems and process equipment
• Supporting utilities
• Equipment automation and process control
• Laboratory systems and equipment
• Information systems
• New facilities
• Changes to existing (may be used)
Related Documents

• FDA 21st Century Initiatives

• ICH Q9; also ICH Q8 and Q10
• Other ASTM E55 Standards
Key Concept/ Principle #1

Risk-Based Approach
Key Concept/ Principle #2

Science-Based Approach
Key Concept/ Principle #3

Critical Quality Attributes

Key Concept/ Principle #4

Quality by Design
Key Concept/ Principle #5

Good Engineering Practices

Key Concept/ Principle #6

Subject Matter Experts

Key Concept/ Principle #7

Use of Vendor Documentation

ASTM Process

• Requirements Definition
• Specification and Design
• Verification
• Acceptance and Release
Supporting Activities

• Good Engineering Practice

• Risk Management
• Design Review
• Change Management
Process
Good Engineering Practice
Product
Knowledge

Process Requirements Specification Verification Acceptance

Knowledge and Design and
Release Operation

Regulatory

Company
Quality

Risk Management

Design Review

Change Management

Figure 1 Š The Specification, Design, and Verification Process

Philosophical Changes
• Role of Quality
• Current: quality control of every inspection and
test
• Future: quality assurance focus on that which
affects product quality; focus on a quality
system
• Basis for qualification
• Current: Engineering specifications that are
presumed to be perfect
• Future: Process and product user
requirements and process risk control
mechanisms
• Ability to learn and adjust during start-up
Equipment Suitability

A New Qualification Model

Equipment Suitability

• Demonstrated ability to meet process

requirements
• Demonstrated ability to adequately
control risks to the patient
Major Steps
• Process development -> process understanding ->
process requirements
• Process FMEA -> design development
-> risk control -> design enhancements (iterative
process) + design reviews = Design Qualification
• Critical aspects and acceptance criteria
• Project delivery quality plan
Applying Good Engineering
Practices
• Design process and design reviews
• Specifications to meet requirements
• Specifications to include verification
• Verification approaches
• Fabrication inspections
• Factory acceptance testing
• Construction fabrication quality control
• Site acceptance testing
• Commissioning
• Software engineering practices (GAMP)
Confirming Equipment Suitability
• IQ/OQ/PQ Protocols = critical aspects
• Meet process requirements
• Control risks
• Execution = 1 day
• Review verification documentation
• Confirm critical aspects have been met
• QA approve final report
• Equipment is suitable for its intended use
Process Requirements
Business
Requirements
Risk Management

Quality Plan

Risk Control
Mechanisms Design

Design Qualification

Procure/ Construct

Good Engineering
Practices
FAT/SAT
Commissioning
IQ/OQ/PQ = Equipment Suitability

IQ/OQ/PQ
(Audit/Report)
Release for mfc.
Managing the Process

• Subject Matter Experts

• Determine how to inspect, test
• Judge results
• Adjudicate departures from specification
• Deviations of critical aspects
• QA approval
Managing the Process

• Change management
• Design
• Construction
• Verification
• Change control
• After acceptance of final report
Thoughts

• Risk assessments replace system

and component impact assessments
• Can you qualify a facility if product/
process not yet known?
Future Opportunities

Risk-based quality system

Current Trends
• Global company: ASTM E2500 Initiative
• Company claims to be using E2500 on new
biotech facility
• Biotech expansion on west coast using risk
assessments/ ASTM E2500 (partial)
• Many companies interested
• Few want to be first - “show me where
someone else has received FDA approval”
Risk Management Case Study #1

Process Development/ clinical trial

manufacturing of API
Key Points

• Project description
• Risk assessment
• Reliance on commissioning
• IQ/OQ simple review
• Applied deviation resolution process
to all commissioning items
Risk Management Case Study #2

Aseptic Filling Area

Key Points

• Project description
• Risk assessment approaches
• ISPE impact assessments
• Failure modes analysis
• Hazards analysis
• Risk management plan
 The Risk
Non-value added practices “because the
regulators want it”
“Unless we do things differently,
nothing will change.”
What Have We Changed w/ ASTM
E2500?
• Content of IQ/OQ/PQ
• Critical items only
• How we determine what is critical
• How we approach start-up/ commissioning/
verification:
• Improve effectiveness
• Execute one set of documents
• Roles and responsibilities
• Dealing with deviations
• Change management
Conclusion

• ASTM Standards
• Science based
• International
• Reasonable, logical approach
• Eliminate non-value added activities
and practices
• Do what makes good quality and
business sense
Questions?

Robert E. Chew, PE
President, Commissioning Agents, Inc.
+1 317 710 1530
[email protected]