Transcript Quality by Design

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
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Origin of QbD: why, where, what
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How to apply QbD on biopharmaceutics:
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Introduction
A-MAB case study
LSH-Biofarmind pilot
2 Presentations on the new quality system: how it is implemented
Replaces old GMP rules
Regulatory consequences
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2 Presentations on regulatory impact
Requirements and demand, communication
Panel discussion: regulatory relief or extra burden
Take home messages
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QbD: why?
3 Crises (2009)
Economic
Microbiologic
Pharmaceutic
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
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Pharma performance: moderate?
Low consumer directed
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.
%
38
40
43
50
70
75
Anti depressiva
Asthma
Diabetes
Arthritis
Alzheimer
Cancer
Note: this is not an exemption, rather
common rule
Moderate quality
Sigma
2σ
3σ
4σ
5σ
6σ
ppm Defects
308.537
66.806
6210
233
3,4
Yield (%)
69,2
99,3
99,4
99,98
9.999.966
Cost of Quality (%)
25-35
20-25
12-18
4-8
1-3
Pharma scores high % defects (rejections,
recalls): 2-3 sigma. ICT , medical devices
and automotive score 6 sigma.
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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”
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Faster, cheaper and safer mandate
• Western world wages:
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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
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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
GROWTH
MATURE
DECAY
PHASES
Power
START
Life cycle
© JWD/2004
Time
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Business Competences
START
TECHNOLOGY &
MARKETING
MATURE
MARKETING &
FINANCAL
DECAY
LEGAL
PHASES
Business
Expertise
Power
SCIENCE
GROWTH
Life cycle
Time
© JWD/2004
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Business Dynamics
START
GROWTH
TECHNOLOGY &
MARKETING
MARKETING &
FINANCAL
DECAY
LEGAL
PHASES
Business
Expertise
Power
SCIENCE
MATURE
R
5%
Dev.
10 -15 %
Life cycle
Manuf.
15 -20 %
M&F
Activity
60 %
Cost
Time
© JWD/2004
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Business Dynamics
START
GROWTH
SCIENCE
Power
Un
R
5%
MATURE
TECHNOLOGY &
MARKETING
SME
D ev.
10 -15 %
Life cycle
MARKETING &
FINANCAL
DECAY
LEGAL
Multinationals
P H A SES
B usiness
Expertise
Entities
M anuf.
M &F
A ctivity
15 -20 %
60 %
C ost
Time
© JWD/2004
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Business Model
• Business model has become uniform & universal: also for sectors
such as ict, nanotechnology & mechatronics, automotive ect.
• Features
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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
New FDA commissioner Margaret Hamburg’s keynote address at Regulatory Affairs
Professionals Society annual conference in Philadelphia, September 2009
• “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)
Conclusion: QbD is the method to innovate (bio)pharma industry
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QbD origine
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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
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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
Message: QbD considers pharmaceutical development
Ref: Q8 Annex
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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”
Note:
this is the general quality principle
Meaning:
PATIENT is the focal point
Ref: Q8 (R1) June 2009, p2
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Quality by Design (QbD)
Basics:
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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:
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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
Traditional
Idea
Development
Preclinical &
Clinical testing
Licensing
Manufacturing
M&S
Patient first: the chain is reversed
QdB
Patient Idea
Design Space Control Strategy Risk Assessment Product Life Cycle
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QbD: what are the issues?
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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 )
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The problem is (uncontrolled) variability
Varibility is reduced by obtaining increased process and product
understanding leading to first time right performance
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Paradigm change: from regulatory compliance to enhanced product and
process understanding
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PWC view: the supply & availability of medicines
Today
Discovery
Lead
Pre-Clinical
& Screening
Development
Evaluation
Phase I, II
Phase III
Submission
Phase
IIIb/IV
CIM CIS
Launch
2020
PathoPhysiology
Development of a molecule only when the company is confident that the
mechanism of action works
CIM
Molecule
Development
Submission
In-Life
Testing
CIM = Confidence in Mechanism
(half way Ph II)
CIS = Confidence in Safety
(end Ph II)
CIS
Launch
Ref.: PWC Pharma 2020: The vision, Which path will you take?
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PWC view & QbD
Ontwikkeling en maken van een geneesmiddel: nieuw
Approach &
Tools
Quality by Design
< 10.209
Verpakking/
distributie
First Time Right
Kontrole
Develop
Implementation
enabling
phase
capabilities
Eerste keer meteen goed &
Toelating
Productie
&
Lean
en
sigma
Continue verbetering
Continuous
improvement
Ontwikkeling
Vermarkting
In life testing
Translational
medicine
Patient
Onderzoek
2020
Development of a molecule only when the company is
confident that the mechanism of action works
PathoPhysiology
CI
M
Molecule
Development
Ref.: PWC Pharma 2020:
The vision
Submission
In-Life
Testing
CIM = Confidence in
CIS
= Confidence
in Ph II)
Mechanism
(half way
Safety (end Ph II)
CI
S
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Development & production of biopharmaceutics: new
< 10.209
Quality by Design
Packaging/
distribution
Develop
enabling
Market
capabilities
Authorization
Control
Implementation
phase
First time right
Production
Lean &
6 sigma
&
Continuous improvement
Market Acess
and Sales
In life testing
Translational
Medicine Research
Patient
Development
Research
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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?
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Time to market reductions: from 12 to 6 years realized by amongst
others
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First time right: lean assets management
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Continuous improvement over the total product life cycle (i.e. controlled,
patient guided variability)
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Absence of design freeze (no variation issues)
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Less validation burden
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Real time controls (less batch controls)
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Increased price control
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Realistic risk perceptions
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Contributes substantially to realize the better, cheaper and safer
mandate
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