jwdorpema, leiden, 10-11-20101 gmp for the 21 st century: gmp
TRANSCRIPT
jwdorpema, leiden, 10-11-2010 1
GMP for the 21st Century: GMP
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QbD positioned
• QbD concerns the making of medicines• QbD is:
– The new (bio)pharmaceutical quality system– Replaces current GMP rules
– Not longer based on the trial error approach of drug substance and drug product development & production
– Instead it is a systemic, knowlegde and risk based quality methodology
– Complies with the general purpose of product quality: suited for use – Puts the patient in focus
– A quality system customized for (bio)pharmaceutics
QbD: GMP for the 21st Century
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QbD workshop program
• Origin of QbD: why, where, what– Introduction – A-MAB case study– LSH-Biofarmind pilot
• How to apply QbD on biopharmaceutics: – 2 Presentations on the new quality system: how it is implemented– Replaces old GMP rules
• Regulatory consequences– 2 Presentations on regulatory impact– Requirements and demand, communication – Panel discussion: regulatory relief or extra burden– Take home messages
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Time to market is long (> 12J) conservative (blockbuster) strategy
Expensive originator products substitution US 2009 = 66 % generics
Low consumer orientation see next slide
Moderate quality see next slide
Patent cliff pipeline gap
Moderate safety & efficacy phase IV and PMS imposed
Governmental control by GMP and market authorization
deterioration into paper quality terror and technical bureaucracy
Marketing and sales practices transparency lack
3 Crises (2009)
Economic
Microbiologic
Pharmaceutic
QbD: why?
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%Anti depressiva 38Asthma 40Diabetes 43Arthritis 50Alzheimer 70Cancer 75
Avarage % of patients for which a group of drugs is ineffective Cancer: MAB with billions sales/y performs
clinical 5-10% above placebo and show a QOL of 0.5 y.
Note: this is not an exemption, rather common rule
Low consumer directed
Moderate quality
Sigma ppm Defects Yield (%) Cost of Quality (%)2σ 308.537 69,2 25-353σ 66.806 99,3 20-254σ 6210 99,4 12-185σ 233 99,98 4-86σ 3,4 9.999.966 1-3
Pharma scores high % defects (rejections, recalls): 2-3 sigma. ICT , medical devices and automotive score 6 sigma.
Pharma performance: moderate?
jwdorpema, leiden, 10-11-2010
Message: time to change
Political issued Late senator Kennedy
Health care inspired FDA initiative (ICH inspired)
Marketing and sales decided Health care directed marketing policies
Financial controlled Profitability risk management
Technical executed Quality by Design (QbD)
Clinical fuelled Translational Medicine Research (TMR) = input
Patient directed Personalized medicine
Science guided Molecular & system biology and nanotechnology innovations to change the making of (bio)pharmaceuticals
Process driven New business model centred around the redesign of the making of (bio)pharmaceutics i.e. QbD
Result: “the faster, cheaper and safer mandate”
6
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Faster, cheaper and safer mandate
• Western world wages: • the costs in the EU to employ someone are $ 300.000. • In China $ 100.000 ( source: US multinational)
• How to compete than?– Create trade barriers – Change business model: options
– Innovate, perform better and stay ahead (previous slides)– License in R&D– Outsource – Market access strategies– Join them– Become virtual
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Business Life Cycle
Time
Pow
er
Life cycle
START GROWTH MATURE DECAY
© JWD/2004
PHASES
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Business Competences
Time
Pow
er
Life cycle
START GROWTH MATURE DECAY
© JWD/2004
SCIENCE TECHNOLOGY & MARKETING
MARKETING & FINANCAL
LEGAL
PHASES
Business Expertise
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Business Dynamics
Time
Pow
er
Life cycle
START GROWTH MATURE DECAY
© JWD/2004
SCIENCE TECHNOLOGY & MARKETING
MARKETING & FINANCAL
LEGAL
PHASES
Business Expertise
R
5% Cost
Activity
10 -15 %
Dev. Manuf.
15 -20 %
M & F
60 %
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Business Dynamics
Time
Pow
er
Life cycle
START GROWTH MATURE DECAY
© JWD/2004
SCIENCE TECHNOLOGY & MARKETING
MARKETING & FINANCAL
LEGAL
PHASES
Business Expertise
R
5% Cost
Activity
10 -15 %
Dev. Manuf.
15 -20 %
M & F
60 %
EntitiesUn SME Multinationals
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Business Model
• Business model has become uniform & universal: also for sectors such as ict, nanotechnology & mechatronics, automotive ect.
• Features• Like all multinational controlled business the financial strategy is dominant• Earlier vertical integration replaces by horizontal integration• QbD alone is not enough to make the change
• R= 5%• D = max 15%
• Affects the whole (bio)pharma business• Does also affect the biogeneric business• Based on the principle: only profitable business sustains• Dominating issues:
o How to stay in the business of ever growing health care cost?o Comply with the fcs mandate
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QbD position in business model
• Without R&D no innovative products• Do we really need QbD?: the conservative criticism
• “All the billions of dollars poured into research and development in the U.S. wont mean a thing”
• “We must streamline and strengthen the regulatory science” • Areas cited where this is being accomplished include FDA’s
partnership with ICH around Quality by Design (QbD)
New FDA commissioner Margaret Hamburg’s keynote address at Regulatory Affairs Professionals Society annual conference in Philadelphia, September 2009
Conclusion: QbD is the method to innovate (bio)pharma industry
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• DOE (1920s: factorial designs in agriculture)• FMEA (US Military development; combined software available)• Launched through FDA report: “Pharmaceutical cGMPs for the 21st Century (August
2002)”• ICH spin off: perception of reality (“ time to change”)• Implies a strategic change towards the presentation of more scientific knowledge in
submissions• Shortly afterwards FDA issued the guidance document “PAT – a framework for
Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Pat doc. discusses many principles of QbD); finalized in 2004
• PAT plays a pivotal role in the QbD process
Message: systemic product and process development replaces current trial & error approach
QbD origine
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QbD frame (in ICH docs)
Definition QDb: a systemic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management
1. The QbD frame contains concepts and tools - e.g. design space - to practice QbD in a submission file (design space approval)
2. The selection of QbD implies the use of Quality Risk Management (ref.: ICH 9, Quality Risk Management)
3. The connection to a suitable (bio)pharmaceutical quality system offers opportunities to enhance science ad risk based submissions approaches
Ref: Q8 Annex
Message: QbD considers pharmaceutical development
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Pharmaceutical Development
Purpose:
• “to design a quality product such, that the manufacturing of it continuously delivers a drug product suited for is purpose”
Ref: Q8 (R1) June 2009, p2
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Quality by Design (QbD)
Basics: • a systemic (multivariate statistics) development and manufacturing by use
of prior knowledge,• risk assessment guided design and process control,• combined molecular and system biology based diagnostics - therapy
solutions for disease treatment,• through the total life cycle of a product (continuous improvement).
Implications:• Quality back to the roots: product suited for its purpose• Quality is dynamic: continuous improvement• Quality must be build in• Quality means first time right
Message: CONSUMER = PATIENT directed
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QbD: away from the specifications trap
Patient Idea Design Space Control Strategy Risk Assessment Product Life Cycle
Idea Development Preclinical & Licensing Manufacturing M&S Clinical testing
Traditional
QdB
Patient first: the chain is reversed
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QbD: what are the issues?
• Quality itself is not the issue, but pharmaceutical development and manufacturing has to be improved
• Improve how: we need to get it right first time and then continue to improve )
• The problem is (uncontrolled) variability • Varibility is reduced by obtaining increased process and product
understanding leading to first time right performance
• Paradigm change: from regulatory compliance to enhanced product and process understanding
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PWC view: the supply & availability of medicines
Today
2020
Patho-Physiology
Molecule Submission In-Life Development Testing
Development of a molecule only when the company is confident that the mechanism of action works
CIM
CIM
CIS
CIS
Launch
CIM = Confidence in Mechanism (half way Ph II)
CIS = Confidence in Safety (end Ph II)
Ref.: PWC Pharma 2020: The vision, Which path will you take?
Discovery Lead Pre-Clinical Phase I, II Phase III Submission Phase
& Screening Development Evaluation IIIb/IV
Launch
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PWC view & QbD
Approach & Tools
2020
Patho-Physiology
Molecule Submission In-Life Development Testing
Development of a molecule only when the company is confident that the mechanism of action works
CIM
CIS
CIM = Confidence in Mechanism (half way Ph II)CIS = Confidence in Safety (end Ph II)
Ref.: PWC Pharma 2020: The vision
First Time Right
&
Continuous improvement
Develop enabling capabilities
Implementation phase
< 10.209
Ontwikkeling
Onderzoek
Productie
KontroleVerpakking/distributie
Toelating
Vermarkting
Patient
Quality by Design
Translational medicine
Eerste keer meteen goed &
Continue verbetering
Lean en sigma
In life testing
Ontwikkeling en maken van een geneesmiddel: nieuw
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Develop enabling capabilities
Implementation phase
< 10.209Packaging/distribution
Market Authorization
Market Acessand Sales
Patient Research
Development
Production
ControlQuality by Design
Translational Medicine Research
First time right
&
Continuous improvement
Lean &
6 sigma
In life testing
Development & production of biopharmaceutics: new
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QbD: implementation
• Adoption by industry goes slow: why?
• Business must be clear• Planning of the implementation in a way that takes near and long
term returns in account• Quality needs planning (Juran 1992): companies generate much
quality-related waste by redoing work already done
• QbD: an opportunity that brings business benefits for the entire organization
• Basic message is: Control the design and you control the lifecycle
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QbD: what does it bring?
• Time to market reductions: from 12 to 6 years realized by amongst others
• First time right: lean assets management
• Continuous improvement over the total product life cycle (i.e. controlled, patient guided variability)
• Absence of design freeze (no variation issues)
• Less validation burden
• Real time controls (less batch controls)
• Increased price control
• Realistic risk perceptions
• Contributes substantially to realize the better, cheaper and safer mandate