“ICH guidelines for the
production of biologicals”
ICH Q8, Q9, Q10, & Q11
QbD
ICH Q7A
Lisa Gonzales- Sr. Regulatory Compliance Specialist
GE Healthcare Life Science- FAST TRAK
Email: Lisa.Gonzales@ge.com
Overview
Guidelines- ICH Q8, Q9, Q10 & Q11
Quality by Design (QbD)
Q7A
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“Pharmaceutical cGMP for the 21st Century:
A Risk-Based Approach” Initiative- Aug. 2002
Integrate quality systems and risk management approaches
into existing programs
Adopt modern and innovative manufacturing technology
Integrate pre-approval review and cGMP programs and achieve
more consistent application across agency organization
components
Use existing and emerging science and analysis to ensure that
limited resources address important quality issues, especially
predicted or identifiable health risks
Intended to modernize FDA’s regulation of pharmaceutical
quality for veterinary and human drugs and select human
biological products such as vaccines
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Risk-Based Approach to Regulate
Pharmaceutical Manufacturing
To keep pace with the many advances in manufacturing
quality management
To enable the Agency to more effectively allocate its
limited regulatory resources
The approach will be applied to the review, compliance,
and inspectional components of FDA regulation
This approach will help the Agency predict where its
inspections are likely to achieve the greatest public
health impact
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International Conference on
Harmonization (ICH)
•
•
•
•
Harmonization process- founded April 1990
US, EU, & Japan
Six Parties (Expert Working Groups- EWGs)
Technical Topics- Safety, Quality, Efficacy,
Multidisciplinary
• 5 step guideline process
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ICH Guideline Interface
P
R
O
D
U
C
T
L
I
F
E
C
Y
C
L
E
Pharmaceutical Quality Risk Pharmaceutical
Development Management Quality Systems
Q10
Q8
Q9
Concept
Paper
Q11
Pharmaceutical
Development
Technology
Transfer
Manufacturing
Enhanced product
& process
understanding
Risk
management
Jeffrey Blumenstein, Pfizer
Robust quality
systems
Harmonize
submissions
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ICH Q8- Pharmaceutical Development
Intended to provide a comprehensive understanding
of the product and manufacturing process for
reviewers and inspectors
Indicates areas where the demonstration of greater
understanding of pharmaceutical and manufacturing
sciences can create a basis for flexible regulatory
approaches
The degree of regulatory flexibility is based on the level
of relevant scientific knowledge provided (not the
volume of data)
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ICH Q8- Pharmaceutical Development
Goal: design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
Information and knowledge gained from development
studies and manufacturing experience provide:
• Scientific understanding to support the
establishment of the design space, specifications,
and manufacturing controls.
• Basis for risk management
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ICH Q8(R1)- Pharmaceutical Development
Revisions 1
Pharmaceutical development should include, the following
elements:
• Defining the target product profile as it relates to Q, S and E
• Identifying critical quality attributes (CQAs) of the drug
product, so that those product characteristics having an
impact on product quality can be studied and controlled
• Determining the quality attributes of the drug substance,
excipients etc. to deliver drug product of the desired quality
• Selecting an appropriate manufacturing process
• Identifying a control strategy
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nt
The path towards the desired state is
unfamiliar to many while the current state
provides the comfort of predictability
rre
cu
At the end of the cGMP initiative, the
pharmaceutical community has arrived at a
crossroad: one path leads towards the
desired state* and the other maintains the
current state
de
si r
ed
FDA Challenge to Industry
FDA hopes the pharmaceutical industry will
choose to move towards the desired state
*pharmaceutical development using QbD approach
Marion Weinreb, “Quality by Design” April 2008
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Approaches to Pharmaceutical Development
Minimal Approach (current)
Enhanced (QbD) Approach (desired)
Development
Development
•
•
Mainly empirical
Developmental research often
conducted one variable at a time
•
•
•
•
Manufacturing Process
•
•
•
Fixed
Validation primarily based on initial
full-scale batches
Focus on optimization and
reproducibility
Systematic, relating mechanistic
understanding of input material
attributes and process parameters to
drug product CQAs
Multivariate experiments to
understand product and process
Establishment of design space
PAT tools utilized
Manufacturing Process
•
•
•
•
Adjustable within design space
Lifecycle approach to validation and,
ideally, continuous process
verification
Focus on control strategy and
robustness
Use of statistical process control
methods
ICH Q8(R1)- Appendix 1
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Benefits of the “Enhanced Approach”
• Post- approval CMC
regulatory submissions
Reduce
• Uncertainty & Risk
Improve
• Recalls and manufacturing
failures
• Regulatory flexibility
• Process understanding
“DIRFT”
• Application of technology:
e.g., PAT & NIR
• Costs
• Quality
• Regulatory burden
• Regulatory review criteria
• Low value regulatory and/or
compliance exercises
• Scientific/technical literacy
among regulators
• Need for Process Validation
• Development efficiency
• Documentation
• Global harmonization
Marion Weinreb, “Quality by Design” April 2008
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ICH Q9- Quality Risk Management
Outlines approaches for producing quality pharmaceutical products
using science and risk management
Intended to provide a practical risk management toolbox implementation
of the pharmaceutical development (Q8) and quality systems (Q10)
• to evolve a more harmonized and flexible quality oversight process
Applies to drug substances, drug products, biological and
biotechnological products
Supports science-based decision making throughout the product lifecycle
• Effective and consistent risk-based decisions
− “Can improve decision making if a quality problem arises”
• Regulatory authorities and industry
− Provides regulators with greater assurance of a company’s ability
to mitigate potential risks
− Impacts direct regulatory oversight- extent and level
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ICH Q9- Principles Of Quality Risk
Management
Risk- combination of the probability of occurrence of harm
and the severity of that harm
Principles:
• The evaluation of the risk to quality should be based on scientific
knowledge and ultimately link to the protection of the patient
• The level of effort, formality, and documentation of the quality
risk management process should be commensurate with the level
of risk
− Aseptic processing- usually high risk
− Stable API with minimal degradation in product formulaprobable low risk for stability
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ICH Q9- Risk Management Process
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ICH Q10 Pharmaceutical Quality
System
Q10 incorporates the concepts behind ICH Q8 “Pharmaceutical
Development” and ICH Q9 “Quality Risk Management” by
providing a model for a pharmaceutical quality system that can
be implemented throughout a product life cycle
Q10 is meant to complement and add to current good
manufacturing practices
The overall goal is to:
• facilitate innovation and continual improvement
• strengthen the link between pharmaceutical development
and manufacturing activities
Angie Drakulich ePT--the Electronic
Newsletter of Pharmaceutical Technology, June 2008
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ICH Q10 Pharmaceutical Quality
System: Objectives
Outlines expectations for the Pharmaceutical Quality Systems
and how they can be applied in the management of the:
• Design space
• Risk assessment
Ensure that quality standards are met over the lifecycle of the
product
• Quality attributes to meet patient needs
• Establish and maintain a state of control
− Process performance and product quality
• Facilitate continual improvement
− Product quality, process improvements, reduce variability,
innovations, enhance quality system
“PQLI Design Space” ISPE May 2008John Lepore & James Spavins
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ICH Q11- Development and Manufacture
of Drug Substances
Concept Paper- Key items
Requirements harmonization
High level technical guidance relevant to the design,
development, and manufacture of drug substances as
part of a total control strategy
Provide guidance for drug substances (Q6A & Q6B)
Identify similarities and differences between biologics
and chemical entities
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ICH Q11- Development and Manufacture
of Drug Substances: Guideline Goals
Harmonize submissions
• What goes into the CTD
• Facilitate regulatory evaluation process
Outline science-based concepts
Offer and recommend approaches for demonstrating process
and product understanding
Address the complexity of different manufacturing process &
products
Address systematic and enhanced approaches (including design
space, control strategies, & real-time release)
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ICH Q11- Development and Manufacture
of Drug Substances: Challenges
Biologics vs. Chemical Entities
Development Approach
• Systematic
• Enhanced
Manufacturing
• Validation
Level of Detail
• Enough to be useful
• Not so much to be prescriptive
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Quality by Design
(QbD)
Definitions
Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the
desired product quality
Critical Process Parameter: A process parameter whose variability has an impact on a critical
quality attribute and therefore should be monitored or controlled to ensure the process
produces the desired quality
Proven Acceptable Range: A characterized range of a process parameter for which operation
within this range, while keeping other parameters constant, will result in producing a material
meeting relevant quality criteria
Quality by Design: A systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding and process control, based on
sound science and quality risk management
Real-time release: The ability to evaluate and ensure the acceptable quality of in-process
and/or final product based on process data, which typically include a valid combination of
assessed material attributes and process controls.
ICH Q8(R1)- Pharmaceutical Development Revisions 1
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Quality by Design is
• Designing and developing a product and associated
manufacturing processes that will be used during product
development to ensure that the product consistently attains
a predefined quality at the end of the manufacturing process
• Quality by design, in conjunction with a quality system,
provides a sound framework for the transfer of product
knowledge and process understanding from drug
development to the commercial manufacturing processes
and for post-development changes and optimization
Guidance for Industry: Quality Systems Approach to Pharmaceutical
Current Good Manufacturing Practice Regulations Sept 2006
QbD is a systematic approach to development
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Quality by Design is
“…products and processes that make them are
designed in advance to meet their product quality
specifications and process control requirements.”
“…is based on solid science, valid statistical tools, and
sound management techniques that have proven their
industrial value for many decades.”
This includes:
Product profiling
Experimental design
Goal: to apply these tools in a structured manner
Process mapping
Risk assessment
Automated process controls
Torbeck and Branning BioPharm Int’l May 2009
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Quality by Design Approach
A systematic evaluation, understanding and refining of the formulation and
manufacturing process, including:
• Identifying, through e.g., prior knowledge, experimentation, and risk
assessment, the material attributes and process parameters that can
have an effect on product CQAs
• Determining the functional relationships that link material attributes and
process parameters to product CQAs
Using the enhanced process understanding in combination with quality risk
management to establish an appropriate control strategy which can, for
example, include a proposal for design space(s) and/or real-time release
As a result, this more systematic approach could facilitate continual
improvement and innovation throughout the product lifecycle (See ICH Q10
Pharmaceutical Quality System).
ICH Q8(R1)- Pharmaceutical Development Revisions 1
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QbD Structure
Establishing the relationship between quality
attributes and clinical performance
Allows more effective dialogue between
industry and regulator during review process*
• Shows the connection between Design Space,
Criticality and Control Strategy
• Reducing change filings snags
*“PQLI Design Space” ISPE May 2008John Lepore & James Spavins
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Regulatory Flexibility: Why?
Facilitate continuous improvement and innovation to improve
quality, efficiency, knowledge, and availability
High level of process understanding and control capability can
further improve our ability to ensure quality on every batch
• compared to a validated process with insufficient
understanding and for which “state of control" is based
primarily on compendial testing
The PAT Guidance
CPG 7132c.08
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Regulatory Flexibility: How?
Quality by design
• Structured product and process development
• Process understanding and control capability
• Design space
Integration of prior knowledge and pharmaceutical development into C, M, C
submission and review
• Present the knowledge gained to provide a more comprehensive
understanding of the product and manufacturing process for reviewers
and inspectors
• Risk based assessment and investigations and knowledge sharing (over a
product’s life cycle)
The PAT Guidance
ICH Q8 (9 &10)
CPG 7132c.08
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Risk Management
Steps
Risk assessment
• Risk Assessment
1. What might go wrong?
• Risk Control
2. What is the likelihood
(probability) it will go wrong?
• Risk Communication
• Risk Review
3. What are the consequences
(severity)?
ICH Q9, Quality Risk Management
Types of risk: patient safety, regulatory, business
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Quality by Design Concept
• Quality cannot be tested into products.
• It has to be built in by design
ICH Q8, Pharmaceutical Development, May 2006
This design incorporates knowledge of the product
and the process to ensure all critical quality
parameters are adequately controlled.
Barry Cherney, Deputy Director, DTP/OBP/CDER, Oral
Presentation, Quality by Design: A Perspective From the Office
of Biotechnology Products, PDA Annual Meeting, April 2006
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“Design Space”
The established range of process parameters
that has been demonstrated to provide
assurance of quality
Working within the design space is not
generally considered as a change of the
approved ranges for process parameters…
Movement out of the design space is considered
to be a change and would normally initiate a
regulatory post-approval change process
ICH Q8, Pharmaceutical Development, May 2006
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Design Space…
“Is linked to criticality through the results of risk
assessment, which differentiates between those
product attributes and process parameters that
are critical to product quality”
Once Critical Quality Attributes and Critical
Process Parameters are identified and
understood, they will need to be controlled
“PQLI Design Space” ISPE May 2008John Lepore & James Spavins
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A Process is well understood when…
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 …
The PAT Guidance
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Process Robustness
• The ability of a process to demonstrate acceptable
quality and performance while tolerating variability
in inputs
• Requires
− Robustness/characterization studies utilizing DoE
− Understanding manufacturing capabilities in
development
• Enables definition of “design space”
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Process Robustness/Characterization
Studies
These studies provide a further understanding of
the relationship between process and product
• identify critical parameters
• identify limits of each parameter
• test to limits
• test to failure, where appropriate
• results not predefined
Adapted from A. Mire-Sluis, Principal Advisor to Director-Product Quality OTTR, CBER, FDA
IBC Process Validation for Biologicals, March 2003
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Design Space for Biotech Products
Characterization Range
Acceptable
variability in
Key & Critical
Quality
Attributes
Acceptable Range
Operating Range
(CQAs)
Process
characterization
studies
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Rathore, Branning, Cecchini (April 2007)Rio UFRJ- ICH
August 6, 2009
Quality Life Cycle
Propose
Design- Evaluation
(Quality by Design)
Identify
(Critical/Key Parameters & Ranges)
Optimize
(Continuous
Improvement
Innovation)
Change Control
Monitor
Post-Approval
Knowledge Base
Product-specific
Process-specific
Quality Risks
Development
Studies
Process Characterization
(DOE, EOF, robustness)
Risk assessment
(FMEA)
Confirm
(Control/Predict)
Conformance Lots
“Validation Studies”
Patrick Swann, Ph.D. FDA-CDER, Quality by Design for
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Biopharmaceuticals: Concepts and Implementation.
Rio UFRJ- ICH Guidelines /
PDA Workshop May 2007
August 6, 2009
Design Space
Process
validation
Design Space
Robustness
Characterization
Quality by Design
Risk Assessment
Process Understanding
Manufacturing of licensed product
PD
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Where are we today?
*Early development: Knowledge for QbD is very limited or nonexistent
Licensed products: Knowledge is often limited for many biotech products
Quality by design is NOT quality by control
Quality by design enables rational design
• e.g., protein engineering
*Adapted from Barry Cherney, Deputy Director, DTP/OBP/CDER
Oral Presentation, Quality by Design: A Perspective From the
Office of Biotechnology Products, PDA Annual Meeting, April 2006
**The QbD approach is still eyed with caution. Many voiced concerns that
they would invest time and resources in a QbD approach and regulators
would still rigidly link specifications to clinical experience.
“We have very little experience with QbD, but we are interested in getting
some.” Steve Kozlowski, MD, CDER, FDA
**BioQuality Feb. 2008: California Separation
Science Society- Wash. DC Jan 2008 meeting
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QbD Case Study- Regulatory Emphasis &
Lifecycle Validation Thinking
A firm recently received an FDA injunction.
Judge’s order: “defendant shall establish and follow scientific
product development and manufacturing process design
procedures…to control all significant variables, including
material attributes and processing parameters, affecting the
process materials and final drug product specifications and
quality attributes. ”
Demonstration of a firm manufacturing multiple products not in
a state of control.
Key is lack of process validation and related issues• Development, science, technology, use of investigations,
handling deviations, etc.
FDA CDER Official ISPE Conference June 2009
International Pharmaceutical Quality May/June 2009
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Successful Implementation of QbD
Product meets patient needs
Process consistently meets its CQAs
Understood impact of formulation components and process parameters on
quality
Identification and control of critical sources of process variability (using PAT)
Process continually monitored and updated to assure consistent quality over
time
Will require multi-disciplinary and multi-functional teams working together
Meet FDA expectations
Reduce Cost
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ICH Q7A
GMP Guidance for Active
Pharmaceutical Ingredients
ICH Q7A Objective
Provide guidance regarding good manufacturing practice (GMP)
for the manufacturing of active pharmaceutical ingredients
(APIs) under an appropriate system for managing quality.
Define manufacturing operations to include:
• Receipt of materials
• Production
• Packaging
• Repackaging
• Labeling and relabeling
• Quality control
• Release
• Storage
• Distribution of APIs and the related controls
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ICH Q7A- Section 18
SPECIFIC GUIDANCE FOR APIs MANUFACTURED
BY CELL CULTURE/FERMENTATION
Covers cell culture, fermentation (CCF), tissue or
animal sources including transgenic animals
Early process steps may be subject to GMP but
are not covered by Q7A (e.g., cell banking)
Vaccines are not included
Should not use as a stand-alone section
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ICH Q7A- Section 18: Cell Culture and
Fermentation
All previous sections apply to CCF but some issues not in
adequate detail
Complexity:
• Inherent heterogeneity
• Full characterization is difficult
• Contamination potential with infectious agents
• Sensitivity to subtle or minor process changes
− Changes in the process, facilities or equipment may lead
to unexpected product quality
• Manufacturing process contributes to product definition
• Process includes facility, equipment, quality of materials
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ICH Q7A- Section 18: Cell Culture and
Fermentation
Doesn’t cover:
• Cell bank creation (ICH Q5D)
• Nature of the organism used in manufacturing or
herd maintenance differences
• Descriptions of different systems (roller bottles,
fermentors, bioreactors, etc.) transfer methods or
monitoring information
• Custom features- inducible or selection systems
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ICH Q7A- Section 18: Cell Culture and
Fermentation
Greater controls
• To prevent (and detect) contamination
− Monitor endotoxin & bioburden for materials and/or process
o Manufacturer defines acceptable limits at each stage
− Design adequate ventilation and exhaust systems
• For biotechnology products than classical fermentation
• For classified environments and EM programs
• Validated reprocessing steps
• Equipment sterilization between batches (cleaning validation section 12.7)
• Water quality (Purified Water or WFI)
• Viral removal/inactivation
− Critical steps should be under validated parameters
− Pre and post inactivation activities clearly defined (SOPs, equipment,
segregation)
− Go to Q5A
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ICH Q7A- Section 19
APIs FOR USE IN CLINICAL TRIALS
Why is there a special section?
• Processes and controls change during
development
• Few batches may be identically produced
• Batches frequently produced in small noncommercial scale equipment
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Final notes-1
Know thy process, know thy product
Regulatory Emphasis & Lifecycle Validation Thinking
• Cost of Quality System failure and not implementing
ICH guidelines through product lifecycle
Q7A- default international standard for GMP in the API
industry
• FDA can’t enforce but is a position of high influence
IPQ predicts Q8, annex, Q9, & Q10 will become an FDA
expectation
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Final notes-2
Regulatory Quality System
Quality Risk
Management
Q9
If your company has:
• Good design and control
strategies
• Good Risk Management
Practices
• Good Quality Systems
Pharmaceutical
Development
Quality by Design
Q8
Pharmaceutical
Quality System
Q10
Decreased:
9
Regulatory oversight
9
Submissions for
changes/variations
9
Inspection of Quality Systems
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O Fim
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