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For QbD, What Should a Small Company Do and Why?
James Blackwell, Ph.D. MBASenior Consultant
BioProcess Technology Consultants, Inc.BioProcess International Conference
Raleigh, NCOctober 12-16th, 2009
From Clone to Commercial®
OverviewSmall company example‐ a CMC view
QbD versus the minimalist approach
Does QbD have a value proposition for small companies?
• Regulatory and quality
• Development and business
Considerations for implementation
Summary and concluding thoughts
Key references
Talk focuses on development (Design) through the Phase 3 process
Small Company Example-A CMC View
From Clone to Commercial®
A small company definition and perspectiveSmall company definition for discussion purposes
• One whose resources are almost entirely devoted to development of new therapeutics and has not commercialized a product
• Capabilities (some may be out‐sourced) include filing an IND; involvement with Phase 1 and 2 manufacturing; development of a Phase 3 process
Company is resource limited and very eager to meet POC and clinical milestones ASAP
Hard to see “down the road” beyond 2 years
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QbD view for many:
• An unnecessary burden
• A “big company” initiative that gives larger companies a competitive advantage
• Design Space will require resources beyond company’s capabilities
• It’s greatest value is “pleasing” regulatory authorities
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Main thesis
For small companies, the pros and net benefits to implementing QbD outweighs the cons
The key is to keep it simple and appropriate to needs
QbD versus the Minimalist Approach
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ICH Q8 compares QbD with the minimalist approach
The minimalist approach described in ICH Q8(R1) Pharmaceutical Development is typical of small companies and provides a good contrast with QbD
• ICH Q11 Development and Manufacture of Drug Substancesconsensus document not expected earlier than Q1 2010
Should have many commonalities and have no inconsistencies with ICH Q8
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Desired QbD State*
preventative; continual improvementreactive; post-approval changes needed
Lifecycle management
risk-based; controls shifted upstreammainly by intermediate and end product testing
Control strategy
part of overall quality control strategy; based on desired performance and supportive data
primary means of quality control; based on batch data
Product specification
PAT utilized for feedback and feed forward in real time
in-process testing for go/no-go; offline analysis
Process control
Design Space flexibility; continuous verification within design space; focus on control strategy and SPC
locked down; validation on 3 batches; focus on reproducibility
Manufacturing process
more science based; systematic; multivariate experiments; focus on unit operation outputs; Design Space; PAT
empirical; typically univariate experiments
Development/Design
Desired QbD StateCurrent StateAspect
**Adapted from ICH Q8(R1)Adapted from ICH Q8(R1)
Does QbD have a Value Proposition for Small Companies?
From Clone to Commercial®
Our industry needs to change
"The pharmaceutical industry has a little secret: Even as it invents futuristic new drugs,
its manufacturing techniques (still) lag(s) far behind those of potato‐chip and laundry‐soap makers." WSJ Sept. 3, 2003
[emphasis mine]
And I would also add development techniques
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QFD- A precursor to QbDQuality Function Deployment (QFD)
A “method to transform user demands into design quality, to deploy the functions forming quality, and to deploy methods for achieving the design quality into subsystems…, and ultimately to specific elements of the manufacturing process.” *
• Core principles of QbD are seen in this definition and most of its methods and techniques can be used for QbD
• QFD (QbD) is the only comprehensive quality system aimed specifically at satisfying the customer (i.e., patient) throughout the development and business process
Dr. Yoji Akao originally developed QFD in Japan in 1966 and it has been used very successfully for decades to improve product quality, cuts costs, and speed development*Akao, Y. "Development History of Quality Function Deployment“. The Customer Driven Approach to Quality Planning and Deployment. Minato, Tokyo 107 Japan: Asian Productivity Organization. pp. 339.
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Proven success in other industriesSemi‐conductor, software, and medical device industries offer the best lessons and case studies for our industry
• QFD techniques have been used to increase agility, cost control, speed to market, and quality (LEAN)
• All things important to a small company developing biologics
Our industry can learn much from them
• E.g., FDA’s Draft Guidance for Industry: Process Validation General Principles and Practices references Quality Management Systems – Process Validation, edition 2* for medical devices
*http://www.ghtf.org/documents/sg3/sg3‐final.html
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Overall, modern QFD can provide insights into how QbD can provide a framework for integration of various innovative quality methods into the development process
I believe there are significant opportunities for modern qualitytechniques to be used in conjunction with QbD to greatly enhance development efficiencies
Modern QFD is tailored to identify the
minimum QFD (or QbD) effort required with the
optimum tools and sequence
Development efficiencies can be greatly improved
From Clone to Commercial®Moheb NasrMoheb Nasr
From Clone to Commercial®
Regulatory and qualityFDA's 1987 "Guideline on General Principles of Process Validation“ was and is “voluntary”, but almost all of its concepts were quickly incorporated into the vast majority of process validations being performed
Likewise, when the FDA’s product lifecycle concept guidance on process validation (based largely on QbD concepts) is finalized (~November 2009), it is also likely to find general applicability and acceptance
Failure to adopt approaches “encouraged” by regulatory authorities will represent increasing regulatory risk with time and for particular development programs
Reducing regulatory risk adds significant program value by speeding time to clinic and market by preventing avoidable regulatory delays
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An effective quality risk management is a proactive means to identify and control potential quality issues during development and manufacturing
Quality risk management can facilitate better and more informed decisions; provide regulators with greater assurance and benefit the extent of direct regulatory oversight
KM within the quality system helps produce higher value knowledge and documents that are organized and easier to retrieve years later
KM supports lean development and the product life‐cycle
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Development and businessFull value of QbD is realized when business objectives and processes are incorporated and modern quality methods are incorporated
• E.g., Titer must by > 3 g/L and overall yield > 75% for commercial product to be cost competitive
Increased program value (and value to a potential partner) by “porting” into their systems by de‐risking, aiding tech transfer, and easing regulatory concerns
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Patient focus and long term view driven by Target Product and Process Profile, risk analysis, and DOE: 1) sharpen near term thinking and helps prioritize efforts; 2) limit unnecessary changes; and 3) help focus the team and reduces sub‐optimization
Change control makes for better decision making as a result of cross functional input
Better understanding of risks aligns resources and helps avoid costly mistakes later
Considerations for Implementation
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Quality systemsFrom a product lifecycle viewpoint, biggest impact of QbD will be to development‐ (Design phase)
Process Qualification (previously know as validation) becomes almost an afterthought
Pillars to QbD implementation
• Change control
• Knowledge management
• Risk management
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Implementation priorities
Implementation
1. First priority‐ QbD implementation with focus on regulatory requirements
• Update quality system with the essential QbD elements of ICH and new guidance from FDA on process validation
2. In order to gain full benefit, a longer term priority‐ integrate QbD system and approach with other quality and business methods as time and resources allow, e.g., QFD processes and methods
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Implementing QbDIndustry consensus on application of QbD doe not exist for all aspects of process development
• This should not be an excuse for not starting down that path now
• The majority of the requirements and basis for implementation have been worked out since the FDA’s “21st
Century Initiative” was launched in 2004 and are covered in ICH guidances other publications
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Science and Technological Innovation
ICH Q8(R1)
“The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science‐based submissions and their regulatory evaluation. “[emphasis mine]
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Implementation considerationsImplementation of QbD does not mean experimentalexploration of all potential process variables, and their interactions and impact, on all potential critical quality attributes and product variants in order to establish a Design Space
• In fact, you don’t need a Design Space at all*
A number of things can be done to focus efforts and use development efforts efficiently
1. Development effort should be proportional to stage of clinical development and business need
• E.g., FIH study may not need the most productive clone possible. All CQA will not be known at this stage but many important ones will (e.g., DP sterility)
*ICH Quality Implementation Working Group on Q8, Q9 and Q10 Questions & Answers
June 10, 2009
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2. Fully exploit previous literature and scientific rationale
3. Judicious use of screening experiments, fractional factorial design, risk analysis to set stage for full multivariate experimentation based on desired operational flexibility and fundamental process characterization
4. Exploit scale‐down and HTS experimental techniques
• E.g., minibioreactors; PreDictor™ (GE Healthcare) 64 well plates for chromatography studies
From Clone to Commercial®
5. Selective development of the Design Space‐ it may not be necessary or prudent to have a Design Space for every unit operation
• A combination of proven acceptable ranges (PARs) developed from univariate experimentation is not a design space
6. Use of platform (or very well characterized and robust) technologies (e.g., Protein A for monoclonal antibody capture)
7. Use of modern quality and lean practices to drive efficiencies and manage the development process
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Very Good Very Good Quality Quality SystemSystem
≠≠ Large and Large and Complex Complex
OneOne!!
KISS
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QbD adjustments to the quality system
Overall lifecycle approach to process validation and QbD needs to be described in the Quality Manual
Key aspects of quality system affected in development phase
• Management review and responsibilities
• Change control
• Quality system enablers: knowledge management and quality risk management
Key documents: ICH Q8(R1), Q9, Q10, and forthcoming Q11 and new FDA guidance on process validation
From Clone to Commercial®
Change control system
Focus on change control management directed on areas of QbD that can affect product quality
• Justification for and changes to CQA, CMA, CPP, and TPP and their risk analyses
• Quality and technical documents
• Movement within or changes to the Design Space
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Knowledge managementProcess validation definition: “Establishing documented evidencewhich provides a high degree of assurance that a specific process will consistently produce a product meeting its pre‐determined specifications and quality attributes” ‐ FDA Guideline, 1987
Given a lifecycle view of process validation and QbD, KM during development is vitally important
Development knowledge supports filings and is discoverable during audits
• It will be used by regulators to understand the basis for the manufacturing process and control strategy, including the rationale for selection of critical process parameters and critical quality attributes; and for the Design Space
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Needs linkage to management review
Single most important aspect for small companies is to write andarchive technical reports that document experiments and conclusions
• Incorporate risk analyses and rationale for CQA, CMA, and CPP, and appropriate attributes of TPP
• Needs QA data review and sign‐off, document control, and safe archiving
• Lab notebooks need appropriate controls and archiving
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Quality risk managementICH Q9 suggests tools and methodology, it does not dictate a specific approach
One possible approach is to reference ICH Q9 and state that QRM will be used to support selection of CQA, CMA, CPP, TPP and thecontrol strategy; and state that this will be documented in appropriate technical reports and other QA documentation
• The quality system should describe how to document the quality risk management process that is defined, deployed and reviewed for these purposes, and could include:
Problem and/or risk question, including pertinent assumptions identifying the potential for risk
Background information and/ or data on the potential hazard harm or human health impact relevant to the risk assessment
Risk analysis leader and other involved resources
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Barriers to QbD implementationLack of understanding of present and future value of QbD
For a small company, adapting the company culture is not a huge barrier, but
• Upper management buy‐in and support is needed for success
Lack of understanding of cost and resources needed for implementation and fear that cost and resources needed is prohibitive
Summary and Concluding Thoughts
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Cost and Benefit of QbD (Small Company)
Initiate QbDEfforts
QbD FullyRealized
QbD Implementation Progress
Dev
elop
men
t and
Man
ufac
turin
g C
osts
Current State
Desired State
•Quality by testing & inspection•Empirical•Reactive•Not lean
•Quality by design development•Efficient development efforts
•Faster to clinic and commercial•Proactive
•Lean
Increased Resources(e.g., development costs, organizational planning) Decreased Resources
(e.g., development costs, organizational planning)
From Clone to Commercial®
QbD and improved business processes are not out of reach for small companies
QbD can add value to a small company if the will power exists
• The key is to implement it efficiently and cost effectively
• KISS
QbD has significant value, even if a Design Space is not developed and filed
• At a minimum, use a science and risk based development approach
• If a Design Space is desired, keep the resource requirements focused and limited, as appropriate
Don’t worry that “all the details haven’t been worked out”‐rather, get started
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Change control, KM, and QRM should focus on CQA, CMA, and CPP, and appropriate attributes of TPP
Adopt and drive modern quality and business methods to speed time to market; improve quality; and lower costs
• Study precedents set in other industries
• These methods and tools are not difficult to use and everyone does not need to be “Black” and “Green” belts
• Swarm around and focus on the CQA, CMA, CPP, and TPP
Keep quality system flexible and allow for both minimal and QbD approaches
If using a CMO, make sure they are capable and willing to support your needs and quality system
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Key referencesICH, Q8(R1), Q9, Q10 and Q11 (soon)
FDA’s Draft Guidance for Industry Process Validation: General Principles and Practices
FDA’s Draft Guidance for Industry: Process Validation General Principles and Practices references Quality Management Systems – Process Validation, edition 2
Rathore A, Winkle H. Quality by Design for Biopharmaceuticals. Nat Biotechnol. 2009 Jan;27(1):26‐34.
ReVelle Jack, et al. The QFD Handbook
Driscoll C. Building Agility into Pharma and Biopharma‐ Learning lessons from other industries. Contract Pharma. 2009 Sep.
QFD case studies and lessons: http://www.qfdi.org/books/proceedings.htm
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Thanks
Sheila Magil, Senior Consultant, BioProcess Technology Consultants
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My contact information
James Blackwell, Ph.D., M.B.A
BioProcess Technology Consultants, Inc.
289 Great Road, Acton, MA
Ph: 978‐266‐9112