Boot Camp for FDA CMC/GMP Initiatives

1. Boot Camp for FDA CMC/GMP Initiatives
for Biotech and Specialty Pharma
Design Space InPharmatics LLC
Edward A. Narke
PDA Annual Conference
March 14­17, 2010 – Orlando
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2. Company Information
Design Space InPharmatics (DSI) is a consulting firm
providing integrated CMC drug development and CMC
Regulatory services to emerging pharmaceutical and
biotechnology companies
DSI provides support for its customers from the initial
phases of development through successful
manufacturing and Regulatory approval
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3. Objectives of the Presentation
Provide a perspective of the Quality‐by‐Design
application for the start‐up to midsize sponsor
Provide a perspective on how CTD Module 3 might be
constructed in parallel with milestone target planning
during Phase development
Improve alignment with Regulatory expectations,
place greater emphasis on sharing critical scientific
information essential to regulatory decision making,
and help enhance the efficiency of the Regulatory
process
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4. Outline of the Presentation
Drivers for QbD
Why it‘s worth the Effort ‐ Providing Business
Benefits
Incentives and Barriers
Examples of how it can work
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5. Drivers
Drivers for Quality by Design
Prompted by ICH 1, 2
> “Assurance of product quality is derived from careful attention to a number of
factors including selection of quality parts and materials, adequate product and
process design, control of the process, and in‐process and end‐product testing.”
> “Due to the complexity of today’s medical products, routine end‐product testing
alone often is not sufficient to assure product quality for several reasons.”
More efficient change control assessment; fewer amendments,
reduced testing, easier problem solving, less production
downtime, fewer failed batches etc.
Empirical approach, anecdotal (disconnected) data still
acceptable today, however QbD is the future – so be prepared!
1. ICH Q8, Q9 Q10
2. Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
Assurance
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6. Drivers
QbD
Introduced into the CMC review process in 2004 as a result of
the pharmaceutical current Good Manufacturing Practice (cGMP)
for the 21st Century Initiative
Expectations outlined in PAT Guidance and ICHQ8, Q9 and Q10
Proposed implementation comprised of 5 key steps
> Identification of Product Attributes of significant importance to
safety/efficacy
> Quality Target Product Profile (TPPP)
> Critical Quality Attributes (CQAs)
> Design of the Process to deliver these attributes
> A Robust Control Strategy to ensure consistent Process Performance
> Validation and Regulatory Filing of the Process
> Demonstrating the effect of the Control Strategy
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7. Drivers
QbD
Familiar Foundation for these activities include:
> Risk Assessment
> Raw material management
> Use of Statistical Approaches
> PAT etc.
Several Case Studies have already been published
highlighting benefits
> Yu, L.X. et al. (2004) Applications of process analytical technology to crystallization process. Adv. Drug Deliv. Rev.
56, 349–369
> Gnoth, S. et al. (2007) Process analytical technology (PAT): batch‐to‐batch reproducibility of fermentation
processes by robust process operational design and control. J. Biotechnol. 132, 180–186
> Nail, S.L. and Searles, J.A. (2008) Elements of quality by design in development and scale‐up of freeze‐dried
parenterals. BioPharm Int. 21 (1), 44–53
> Harms, J. et al. (2008) Defining design space for biotech products: case study of Pichia pastoris fermentation.
Biotechnol. Prog. 24, 655–662
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8. Why?
Why it‘s worth the effort
QbD goal: Use resources in the most efficient manner by
producing a better quality data package which will provide
flexibility throughout the API/product life cycle
> Collect the right data, not necessarily more data*
> Data that is information rich, building product knowledge
> Avoid checkbox mentality*
> Get the most mileage from experiments throughout
development. E.g.., use early data/knowledge base to guide
DoE – requires initial hard data as input
> Easier to respond to questions from the Agency
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9. Why?
Why it is worth the effort?
QbD provides a chance to develop new ideas and
opportunities to explore new options to meet
regulatory requirements and operational
flexibility
> Gain experience for future Agency expectations
> Still collecting data, but in a different manner
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10. Incentives and Barriers
Incentives and Barriers
Caveats:
> Extra effort, DoE in development (Increased $ spent
initially during development to define design space =
potential returns)
‐ Gain Savings depends on project, timing – not guaranteed!
‐ Payoff may be delayed until post approval
‐ Why does it make good business sense to start a QbD effort when 90%
of the candidates fail to make it to market?
> Internal fear within companies to push the boundaries /
fear of failure and resistance to change – especially near
filing time.
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11. Incentives and Barriers
Incentives and Barriers
Critical Role of Start­ups and First­Product Companies
Business Perspective
> Provide a new pipeline for New Products
> Return a profit to stakeholders
Regulatory Perspective
> Address recent initiatives and expectations moving forward
‐ Quality by design (QbD) continues to receive much attention.
‐ Although several QbD concepts are being practiced, continued
dialogue and partnership between the industry and its
regulators will be the key to successful QbD realization
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12. Incentives and Barriers
Incentives and Barriers
The Facts
“The degree of sponsor experience with FDA regulations and
procedures is generally of importance. Large US­based
companies have the highest first­cycle approval rate, at
approximately twice the rate of small biotechnology
companies with no prior FDA approvals.
The underlying drivers seem to be lack of personnel with US
regulatory experience and suboptimal­internal regulatory
processes’”(1)
1. Independent Evaluation of FDA's First Cycle Review Performance ­ Retrospective Analysis Final Report, Booz, Allen, Hamilton.
FDA (January 2006).
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13. Incentives and Barriers
Incentives and Barriers
Shortfall of Start­ups and First­
Product Companies
Management in these companies
encounter the constant pressure of
> Raising funds
CMC Clin/Nonclinical
> Building a creative and effective
team
CMC Regulatory Clinical Research
> Keeping ahead of the competition
Quality
Pharm/Tox
Assurance
Focus is on ensuring a viable and
effective clinical development CMC Operations Medical Affairs
strategy to keep the product moving
forward
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14. Incentives and Barriers
Incentives and Barriers
Consequences of Shortfalls
In many instances
> Few resources are available to
devote to the challenge of
developing a viable and effective
long­term CMC regulatory strategy CMC Clin/Nonclinical
Lack of focus in this area, coupled
with frequent lack of CMC regulatory
compliance experience can be a
formula for disaster
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15. Incentives and Barriers
Barriers
Challenges (in the new economy)
> Little control on knowledge base for late stage in‐
licensed, acquired compounds
‐ Gaps exist between FIH and POC
> Late changes in process, methods etc. that limit the
utility of previous data
> When using Contract Manufacturing
‐ Gaps occur between vendors
‐ Lack of sharing the knowledge between sponsor and CMO
‐ Limited resources do not allow for scientific understanding
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16. Incentives and Barriers
Incentives
Motivation for Business Benefit
> Better scientific understanding, easier decisions, (less
data and samples to manage?)
> Need commitment and better understanding of the
benefits to build momentum (QbD is extra work during
development, streamlining will be a challenge)
> When using Contract Manufacturing
‐ Create an environment of knowledge sharing
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17. How it might Work
Example of how it might work
Milestone planning
QbD Blueprint
Development Phases
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18. How it might Work
Example of how it might work
Milestone planning – Everyone has a Target
QbD Blueprint
Development Phases
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19. Milestone Planning
CMC‘s Role in the Development Process
Early Dev POC Post‐
Discovery Pre‐IND Registration
(Phase 1/2) (Phase 2/3) Approval
DISCOVERY NEW CHEMICAL ENTITY PRODUCT DEVELOPMENT
PRECLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW
Lead Identification Synthesis & Purification
Lead Optimization Manufacturing Formulation/Process Optimization
Identify Candidate Phase 1
Synthesis & Characterization Phase 2
Screening and
Planning Phase 3
Definition Phase
Pre­Formulation Accelerated Development/Review
Treatment IND
Animal Testing Parallel Track
Short­Term
Long­Term
Institutional Review
Boards
Assays for Therapeutic Efficacy
2 ­ 5 years 1 ­ 3 years 8 ­ 15 years
IND submitted
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20. Milestone Planning
You Must Have a Target!
IND submitted NDA submitted
Early Dev POC Post‐
Discovery Pre‐IND Registration
(Phase 1/2) (Phase 2/3) Approval
Continuous
What is
What? correlated
Improvement
Confirmation
to What? Phase =
Product
Optimize Phase = Knowledge
Building •Process
Optimization
Robustness
•Design‐space
•API Alternate Route defined
Scouting •Validation via QbD
•To‐Be Marketed, •Optimization within
Design Phase = Formulation Design filied ranges
Building the •Site Transfer •Post‐launch support
Basics •QbD/PAT •Life Cycle Strategy
•API Route scouting
•IVIVC And How?
•API Impurity What
Identification
•API Solid Form causes
Selection
•Initial Risk What?
Assessment
•Tox Formulation
•FIH Formulation
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21. Milestone Planning
Management of Targets in the CTD
Management of Knowledge in Module 3
> Provide interwoven experimental evidence that supports a
more systematic approach to product development.
> Emphasize critical knowledge, analysis and assessment
Start with standardized templates
> Provides framework for most CMC dossier projects
> Ensures proper implementation of regulatory strategy in dossier filings
‐ Enhances quality and reduces risks in CMC dossier projects
> Helps achieve on‐time delivery of NDA/MAA CMC investigational and
marketing application filings
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22. Milestone Planning
Manage Knowledge in Module 3
Compliance Data
API and Product general Justification of Specification
properties Methods
Control of starting materials Validation of methods
and Excipients
Analytical development history
Control of reagents, solvents,
auxiliary materials Typical batch data
Control of intermediates Reference standards
Elucidation of API structure Stability
List of impurities
Specifications
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23. Milestone Planning
Manage Knowledge in Module 3
Continuous Conformance Data
Use CTD Module 3: P2, S26 and S45, P55 as the primary
review documents
Present to regulators all they need to know to make an
approval decision
Present a compelling description and critique of the Quality
component in the CTD to make it information and knowledge
rich
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24. Milestone Planning
Manage Knowledge in Module 3
P.2.1 Components of the Drug Product
> Which physical chemical characteristics of the drug substance affect drug product development,
manufacture, or performance?
> What evidence supports compatibility between excipients and the excipients and the drug
substance?
P.2.2 Drug Product
> What attributes should the drug product possess?
> How was the drug product designed to have these attributes?
> What (if any) were alternative formulations or mechanisms that have been investigated?
> How were the excipients and their grades selected?
> How was the final formulation optimized?
> What are the design space for critical parameters and attributes, and how justified?
P.2.3 Manufacturing Process Development
> Why was the manufacturing process described in P.3 selected for this drug product?
> How are the manufacturing steps (unit operations) related to the drug product quality?
> How were the critical process parameters identified, monitored, and/or controlled?
> What is the scale­up experience with the unit operations in this process?
> What are the design space for critical parameters and attributes, and how can they be
justified?
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25. Milestone Planning
Manage Knowledge in Module 3
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26. Blueprint
Blueprint for how it can work
Milestone planning
QbD Blueprint – Creating the Data
> Build Quality Target Product Profile
> Identify CQAs
> Characterize Design Space
> Identify Control Strategy
> Validation the Process
> File the Data
Development Phases
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27. Blueprint
Blueprint for QbD – An Overview
QbD Blueprint
Build Quality Target Product
Profile (QTPP)
Identify Critical Quality
Attributes (CQAs)
Characterize Design Space
Identify Control Strategy
Validate the Process
File the Data!
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28. QTPP
Build Quality Target Product Profile (QTPP)
QbD Blueprint
What would need to be achieved to ensure that quality
affecting safety and efficacy is realized?
QTPP
Start at the End and work backwards!
Key Questions
Conditions/Features Build a ‘‘prospective” summary of the quality characteristics
Dosage form and route of administration strength(s)
Basis/Considerations
Therapeutic moiety release or delivery
Milestone/Result ‐
Further Actions
Pharmacokinetic characteristics (e.g. dissolution and
CQAs bioavailability) appropriate to the dosage form
Quality criteria (e.g. sterility and purity)
Design Space
Control Strategy QTPP should be established as soon as product has been
identified as a viable candidate for commercialization and
Validation should be revisited at key stages of development
Forms the basis of design for the product
File the Data
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29. CQAs
Identify Critical Quality Attributes (CQAs)
QbD Blueprint
QTPP Desired attributes of a successful Product include?
What are the relevant CQAs?
CQAs
Key Questions CQA identification can be performed using risk‐based analysis, in
accordance with the ICH Q9 guidance
Conditions/Features Risk assessment should account for design of the molecule (hot
spots); engineering studies, non‐clinical studies, clinical studies with
Basis/ Considerations the product and/or other platform products; and published
literature
Milestone/Result ‐
Further Actions Attributes known to impact safety and efficacy (such as dissolution,
sterility, solubility or aggregate species) rank high in criticality
Design Space To have no impact on safety and efficacy (such as qualified
impurities) rank low in criticality
Control Strategy
Validation The Critical Attributes used to guide the product and process
development!
File the Data Along with QTPP, forms the basis of Design for the product!
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30. Design Space
Design and Characterize
QbD Blueprint
Characterizing the Product Design Space
QTPP
Once CQAs have been identified, the concept of design
CQAs space can be extended to product quality
This product design space should be documented in the
Design Space regulatory filing in the form of in‐process and release
specifications that define the acceptable variability in
CQAs
Considerations Characterizing the Process Design Space
Process characterization studies can be used to define the
Control Strategy
acceptable variability in process parameters
The approach for defining a process design space has been
Validation discussed often in the literature e.g. risk analysis, design
of experiments (DOE), linkage of the inputs versus the
File the Data
critical attributes
The acceptable ranges for a process should be
documented in the regulatory filing.
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31. Control Strategy
Identify Control Strategy
QbD Blueprint What assures process performance and product quality?
QTPP What are the controls, derived product and process
understanding that assures process and product quality?
CQAs
Design Space IPC testing
Raw material controls
Control Strategy Specifications
Product characterization
Key Questions Container closure system
Stability studies
Basis/Considerations Validation
Comparability studies
Conditions/Features
Will depend of the criticality of the quality attribute and
Milestone/Result ‐ capability of the process and analytical methods
Further Actions
Validation
Using an active control strategy allows manufacturing controls
File the Data to be altered (within the design) to remove or reduce the
variability caused by process inputs
QC moved Upstream!
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32. Validation
Validation of Process and Control Strategy
QbD Blueprint
QTPP
Control strategy defined and the product and process design
CQAs spaces are established
Design Space Validation to demonstrate that the process will deliver a product
of acceptable quality if operated within the design space
Control Strategy
Regulatory filing is then compiled, to include Knowledge
Linkages
Process Validation
Acceptable ranges for all key and critical operating
parameters that define the designed process space, in
Conditions/Features
addition to the more restricted operating space (NOR,
PAR) typically described today
Milestone/Result ‐
Further Actions
File the Data
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33. Reg Filing
Regulatory Submission
QbD Blueprint Internal quality system of the manufacturer needs to provide
adequate oversight during QbD implementation to any changes
QTPP occurring that do not have to pass through regulatory review
CQAs
and approval
Does your Knowledge have linkages?
Design Space What does the Agency say?
Control Strategy
Process Validation
and Filing Can process improvement during the product life cycle in
Regulatory Filing terms of process consistency and throughput be approved
with reduced submissions?
Key Questions
Basis/Considerations
With a design space developed and approved under the QbD
Conditions/Features paradigm, process changes within this design space will not
require further review or approval?
Milestone/Result ‐ Any changes to the design space itself need to be characterized,
Further Actions validated and approved by the regulatory authorities prior to
implementation
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34. Reg Filing
Examples of a Linkages
Cross reference between CTD section P2 (Pharm. Development)
and relevant sections in S (Drug Substance) and in P (Drug
Product)
‐ S 1.3 Properties of the active substance
‐ S.2 Manufacture
‐ S 3.1 Studies on Polymorphism (experimental data)
‐ S 4.1 Specifications relating to control of physical forms
‐ S.4.3 Analytical methods used
‐ S 4.5 Justification of Specifications
‐ P 2: Influence of the polymorphic forms on product characteristics – dissolution,
stability
‐ P 5.1 Product Specifications
‐ P 5.6 Justification of Specifications
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35. Blueprint
QbD – Collecting the Data
Key question: How and when to invest in process science
and process characterization to really get
to know the manufacturing process and its
outcome
Basics: This investment should be made wisely
understanding the science does not come cheap
Marginal conditions: ‐ Seek out regulatory authority advice
‐ It’s not about a company believing that it
knows more about its process and
product than the regulatory authority
‐ It’s about involving the regulatory authority
as a team player
Milestones: ‐ A reality check for your CMC regulatory
compliance strategy at any transition
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36. Development Phases ‐ Overview
A Target for each Milestone
Milestone planning
QbD Blueprint
Development Phase
> Pre‐IND
> Initiating Phase 1
> Early Clin Dev
> Clinical Transition from Phase 2 to Phase 3
> POC to Registration
> Continuous Improvement
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37. Development Phases ‐ Overview
Development Phases ‐ Overview
Development Phases
Pre‐IND
Initiating Phase 1
Early Clin Dev
Transition from Ph 2 to Ph 3
POC to Registration
Continuous Improvement
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38. Milestone Planning
Critical Role of Integrated Planning
Not in the Guidances
Applies to Small Molecules, Biotech and Vaccines
Most Traditional approach:
> Design Phase ‐ Initiating Phase 1 clinical trials
> Optimize Phase ‐ Clinical transition from Phase 2 to Phase 3
> Confirm Phase ‐ Submission of the marketing application
Everyone has a Target!
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39. Development Phases ‐ Overview
The Development Process
Early Dev POC Post‐
Discovery Pre‐IND Registration
(Phase 1/2) (Phase 2/3) Approval
Trials, Scale-up
non-GMP/GMP
•CMC
•API Characterization
•API Route and Scale‐
up
•Toxicology/FIH
Formulation
•Definition of QTPP
Optimize Continuous
•ID CQAs Phase •Process Optimization Improvement
•Design Space
•Methods •QbD
Development Planning and Implementation
Validation • Life‐Cycle
•TechTransfer/
•Stability Program
Definition Phase•Risk Assessment •Additional Supply
management.
•To‐Be marketed Chain etc.
Formulation Design
Confirmation
Design Phase •Process Design
•Control Strategy Phase
•Clin •IVIVC
•TPP •ID CQAs
•Transfer to
•Preclin Operations
•Proof of Concept
•Tox
•DDI
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40. Pre‐IND
Pre‐IND Phase
Development Phases
•Are you ready to File the IND?
Pre­IND •Have you defined the Quality Target Product Profile?
Key Questions
Conditions/Features •API Characterization
Basis/Considerations •API Route and Scale up
Milestone/Result ‐ •Toxicology/FIH Formulation Design
Further Actions
•Methods Development
Initiating Phase 1
•Initial Stability Program
Early Clin Dev
Transition Ph2 to Ph3 Items that affect safety and that can trigger a clinical hold can be
determined/ruled out via the QTPP and identifiaction of the
POC to Registration critical attributes!
Continuous Improve
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41. Phase 1
Initiating Phase 1
Development Phases How Much? How Controlled? How Tight?
Pre‐IND
Modifications to the method of preparation of the new drug substance and
Initiating Phase 1 dosage form, and even changes in the dosage form itself, are likely as the
investigation progresses.
Key Questions Emphasis in an initial Phase 1 CMC submission should, therefore, be placed on
providing information that will allow evaluation of the safety of subjects in the
proposed study
Conditions/Features The identification of a safety concern or insufficient data to make an evaluation
of safety is the only basis for a clinical hold
Basis/ Considerations
Milestone/Result ‐ Products do not lend themselves readily to questions of "how much?", "how
controlled?" and "how tight?" at Phase 1
Further Actions
An effective quality risk management assessment does not simply list all of the
CMC challenges for a product at Phase 1, but prioritizes what the sponsor
Early Clin Dev absolutely needs to do or identify at this early stage of drug development to
address these challenges ...(CQAs?)
Transition Ph2 to Ph3
At Phase I, it is too early to think "test method validation" (instead, think
POC to Registration "suitable for use and scientifically sound") or "manufacturing consistency"
(instead, think "manufacturing control") or "product maximum shelf life"
Cont‘ Improvement (instead, think "stable for the duration of the planned study")
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42. Phase 1/2
Early Clinical Development
The manufacturing process is critical to ensure the correct
Development Phases composition, Quality, and Safety of the product
Pre‐IND
It becomes more critical to carefully control and record process
Initiating Phase 1 development in conjunction with the appropriate testing to
reproduce a comparable Phase 2 investigational drug
Early Clin Dev
Appropriate equipment and controls should be in place in
manufacturing to ensure that unit operations with safety‐related
Considerations functions (e.g., viral clearance, virus/toxin attenuation.
Transition Ph2 to Ph3
sterilization) perform their function with a high degree of
assurance. Specific IPC testing may also serve to complement
these functions and can eliminate testing down the chain
POC to Registration
Cont‘ Improvement When evaluating the manufacturing process for early Phase 1&2
investigational drugs, it is of particular importance to begin to
evaluate the process and scale you will need to be at the
confirmation stage
Best time to define Design Space is before you are
locked into a ‘process’ for pivotal studies.
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43. Phase 2 to 3
Transition from Phase 2 to Phase 3
Development Phases Are manufacturing decisions scientifically based on
enhanced knowledge of product performance over a wider
Pre‐IND range of material attributes, processing options and
process?
Iniatiating Phase 1
Quality by Chance (QbC), is a very risky option
Early Clin Dev This investment in QbD should be made wisely
Understanding the science does not come cheap
Transition Ph 2 to Ph 3 Be selective in how limited time, resources and money are invested
Goal is to increase the level of manufacturing process knowledge and
Key Questions understanding, not just to generate volumes of scientific data
Basis/Considerations
Want to avoid CMC regulatory compliance delays? Seek out Agency advice.
Regulatory authorities do not expect a company to agree with them in every
Conditions/Features instance, but they do expect thoughtful consideration and a scientifically justified
response.
Milestone/Result ‐
Further Actions
An effective regulatory compliance strategy is critical at this stage to ensure
POC to Registration All chemistry, manufacturing and controls (CMC) activities necessary for
eventual market approval are being planned
Continuous Improve Any identified CMC impediment should be discussed with the
regulatory agency
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44. Phase 3 to Registration
POC to Registration
Development Phases
Pre‐IND
Provide enough information to permit the regulatory authority
Initiating Phase 1 to determine
Whether the process used in manufacturing the drug and
Early Clin Dev the controls used to maintain its quality are appropriate
and adequate
Transition Ph2 to Ph3
POC to Registration
Utilize the knowledge
Conditions/Features
Milestone/Result ‐
Further Actions
Continuous Improvement
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45. Lifecycle Management
Continuous Improvement
Development Phases As the expanded body of manufacturing knowledge occurs
with the contract partner, management should ensure that
Pre‐IND
continual process improvement is evaluated and given an
Initiating Phase 1 appropriate response
Facilitate continual improvement: the ICH Q10 mandate for
Early Clinical Dev management
Avoid slippage of current Good Manufacturing Practice
Transition Ph2 to Ph3 (cGMP) compliance
POC to Registration
Are you capable to building adequate commercial
Cont‘ Improvement inventories?
How does market expansion opportunities affect Supply
Key Questions Chain?
Basis/Considerations
The people involved, their competency, training, and
Conditions/Features cooperation, are the key element to the success or failure of
managing a process and product
Milestone/Result ‐
Further Actions
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46. Summary
Develop strategies for a QbD approach
> These quality initiatives should not be a “one size fits all“ approach to
development
Put together alignment, guide transition and build
a value chain
> Strive for seamless Transition and Knowledge Transfer from early
Development to launch and beyond
> There will always be questions but they should be managed based on the
level of risk to quality
Enablers – ICH guidance’s Q8, Q9 and Q10 (and
soon Q11)
> Implementation will take time and experience as well as Open
Communication
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47. Acknowledgements
Anthony Durning
David Urquhart
Daniel Torok
Suzan Aschmies
Hedley Rees
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48. Thank you …
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