Upload
lytuyen
View
221
Download
3
Embed Size (px)
Citation preview
“ICH guidelines for the production of biologicals”ICH Q8, Q9, Q10, & Q11 QbD ICH Q7A
Lisa Gonzales- Sr. Regulatory Compliance SpecialistGE Healthcare Life Science- FAST TRAKEmail: [email protected]
2 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Overview
Guidelines- ICH Q8, Q9, Q10 & Q11
Quality by Design (QbD)
Q7A
3 /Rio UFRJ- ICH Guidelines /
August 6, 2009
“Pharmaceutical cGMP for the 21st Century: A Risk-Based Approach” Initiative- Aug. 2002
Integrate quality systems and risk management approaches into existing programsAdopt modern and innovative manufacturing technology Integrate pre-approval review and cGMP programs and achieve more consistent application across agency organization componentsUse existing and emerging science and analysis to ensure that limited resources address important quality issues, especially predicted or identifiable health risksIntended to modernize FDA’s regulation of pharmaceutical quality for veterinary and human drugs and select human biological products such as vaccines
4 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
5 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
6 /Rio UFRJ- ICH Guidelines /
August 6, 2009
ICH Guideline Interface
PRODUCT
LIFECYCLE
Pharmaceutical Development
Q8
Quality RiskManagement
Q9
Pharmaceutical Quality Systems
Q10
Pharmaceutical Development
Technology Transfer
Manufacturing
Enhanced product & process
understanding
Risk management
Robust quality systems
Jeffrey Blumenstein, Pfizer
ConceptPaper
Q11
Harmonize submissions
7 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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)
8 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
9 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
10 /Rio UFRJ- ICH Guidelines /
August 6, 2009
FDA Challenge to Industry
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
The path towards the desired state is unfamiliar to many while the current state provides the comfort of predictability
FDA hopes the pharmaceutical industry will choose to move towards the desired state
Marion Weinreb, “Quality by Design” April 2008
desire
dcurrent
*pharmaceutical development using QbD approach
11 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Approaches to Pharmaceutical Development
Minimal Approach (current)
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
Enhanced (QbD) Approach (desired)
Development • 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
12 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Benefits of the “Enhanced Approach”
• Post- approval CMC regulatory submissions
• Recalls and manufacturing failures
• Uncertainty & Risk
• Costs
• Regulatory burden
• Low value regulatory and/or compliance exercises
• Need for Process Validation
• Documentation
• Regulatory flexibility
• Process understanding “DIRFT”
• Application of technology: e.g., PAT & NIR
• Quality
• Regulatory review criteria
• Scientific/technical literacy among regulators
• Development efficiency
• Global harmonization
Redu
ce
Impr
ove
Marion Weinreb, “Quality by Design” April 2008
13 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 processApplies 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
14 /Rio UFRJ- ICH Guidelines /
August 6, 2009
ICH Q9- Principles Of Quality Risk ManagementRisk- combination of the probability of occurrence of harmand 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 formula-
probable low risk for stability
15 /Rio UFRJ- ICH Guidelines /
August 6, 2009
ICH Q9- Risk Management Process
16 /Rio UFRJ- ICH Guidelines /
August 6, 2009
ICH Q10 Pharmaceutical Quality SystemQ10 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
17 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 2008-John Lepore & James Spavins
18 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
19 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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)
20 /Rio UFRJ- ICH Guidelines /
August 6, 2009
ICH Q11- Development and Manufacture of Drug Substances: Challenges
Biologics vs. Chemical EntitiesDevelopment Approach• Systematic• EnhancedManufacturing• Validation Level of Detail• Enough to be useful• Not so much to be prescriptive
Quality by Design
(QbD)
22 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Definitions
Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property orcharacteristic 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
23 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
24 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 profilingExperimental designProcess mappingRisk assessment Automated process controls
Torbeck and Branning BioPharm Int’l May 2009
Goal: to apply these tools in a structured manner
25 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
26 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 2008-John Lepore & James Spavins
27 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
28 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
29 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Risk Management
• Risk Assessment
• Risk Control
• Risk Communication
• Risk Review
1. What might go wrong?
2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity)?
Risk assessmentSteps
ICH Q9, Quality Risk Management
Types of risk: patient safety, regulatory, business
30 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
31 /Rio UFRJ- ICH Guidelines /
August 6, 2009
“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
32 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 2008-John Lepore & James Spavins
33 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
34 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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”
35 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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, FDAIBC Process Validation for Biologicals, March 2003
36 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Design Space for Biotech ProductsAcceptable Range
Operating Range
Characterization Range
Process characterization
studies
Acceptable variability in Key & Critical
Quality Attributes
(CQAs)
Rathore, Branning, Cecchini (April 2007)
37 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Knowledge BaseProduct-specificProcess-specific
Quality Risks
Quality Life Cycle
Confirm(Control/Predict)
Conformance Lots“Validation Studies”
MonitorPost-Approval
Optimize(Continuous
Improvement Innovation)
Change Control
ProposeDesign- Evaluation (Quality by Design)
Identify(Critical/Key Parameters & Ranges)
DevelopmentStudies Process Characterization(DOE, EOF, robustness)
Patrick Swann, Ph.D. FDA-CDER, Quality by Design for Biopharmaceuticals: Concepts and Implementation.
PDA Workshop May 2007
Risk assessment(FMEA)
38 /Rio UFRJ- ICH Guidelines /
August 6, 2009
PD
RobustnessCharacterization
Process validation
Manufacturing of licensed productProcess U
nderstanding
Design Space
Quality by Design
Risk Assessment
Design Space
39 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
**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
*Adapted from Barry Cherney, Deputy Director, DTP/OBP/CDEROral Presentation, Quality by Design: A Perspective From the
Office of Biotechnology Products, PDA Annual Meeting, April 2006
**BioQuality Feb. 2008: California Separation Science Society- Wash. DC Jan 2008 meeting
40 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 2009International Pharmaceutical Quality May/June 2009
41 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Successful Implementation of QbD
Product meets patient needsProcess consistently meets its CQAsUnderstood 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 timeWill require multi-disciplinary and multi-functional teams working togetherMeet FDA expectationsReduce Cost
ICH Q7A
GMP Guidance for Active Pharmaceutical Ingredients
43 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
44 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
45 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
46 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
47 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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
48 /Rio UFRJ- ICH Guidelines /
August 6, 2009
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 non-
commercial scale equipment
49 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Final notes-1
Know thy process, know thy productRegulatory Emphasis & Lifecycle Validation Thinking• Cost of Quality System failure and not implementing
ICH guidelines through product lifecycleQ7A- default international standard for GMP in the API industry• FDA can’t enforce but is a position of high influenceIPQ predicts Q8, annex, Q9, & Q10 will become an FDA expectation
50 /Rio UFRJ- ICH Guidelines /
August 6, 2009
Final notes-2If your company has:• Good design and control
strategies• Good Risk Management
Practices• Good Quality Systems
Regulatory Quality System
Quality Risk Management
Q9
Pharmaceutical Development
Quality by DesignQ8
Pharmaceutical Quality System
Q10
Decreased:
Regulatory oversight
Submissions for changes/variations
Inspection of Quality Systems
51 /Rio UFRJ- ICH Guidelines /
August 6, 2009
O Fim