GMP for the 21 st Century: GMP

1. GMP for the 21st Century: GMP jwdorpema, leiden, 10-11-2010

2. 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 jwdorpema, leiden, 10-11-2010

3. 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 jwdorpema, leiden, 10-11-2010

4. QbD: why? jwdorpema, leiden, 10-11-2010

5. Pharma performance: moderate? Low consumer directed 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 Moderate quality Pharma scores high % defects (rejections, recalls): 2-3 sigma. ICT , medical devices and automotive score 6 sigma. jwdorpema, leiden, 10-11-2010

6. Message: time to change Result: “the faster, cheaper and safer mandate” jwdorpema, leiden, 10-11-2010

7. 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 jwdorpema, leiden, 10-11-2010

8. Business Life Cycle jwdorpema, leiden, 10-11-2010

9. Business Competences jwdorpema, leiden, 10-11-2010

10. Business Dynamics jwdorpema, leiden, 10-11-2010

11. Business Dynamics jwdorpema, leiden, 10-11-2010

12. 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: • How to stay in the business of ever growing health care cost? • Comply with the fcs mandate jwdorpema, leiden, 10-11-2010

13. 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 jwdorpema, leiden, 10-11-2010

14. QbD origine • 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 jwdorpema, leiden, 10-11-2010

15. 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 • The QbD frame contains concepts and tools - e.g. design space - to practice QbD in a submission file (design space approval) • The selection of QbD implies the use of Quality Risk Management (ref.: ICH 9, Quality Risk Management) • The connection to a suitable (bio)pharmaceutical quality system offers opportunities to enhance science ad risk based submissions approaches QbD frame (in ICH docs) Message: QbD considers pharmaceutical development Ref: Q8 Annex jwdorpema, leiden, 10-11-2010

16. Purpose: • “to design a quality product such, that the manufacturing of it continuously deliversa drug product suited for is purpose” • Ref: Q8 (R1) June 2009, p2 Pharmaceutical Development jwdorpema, leiden, 10-11-2010

17. 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 jwdorpema, leiden, 10-11-2010

18. QbD: away from the specifications trap Traditional Idea Development Preclinical & Licensing Manufacturing M&S Clinical testing Patient first: the chain is reversed QdB Patient Idea Design SpaceControl StrategyRisk AssessmentProduct Life Cycle jwdorpema, leiden, 10-11-2010

19. 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 timeright performance • Paradigm change: from regulatory compliance to enhanced product and process understanding jwdorpema, leiden, 10-11-2010

20. PWC view: the supply & availability of medicines Today Discovery Lead Pre-ClinicalPhase I, II Phase III Submission Phase & Screening Development Evaluation IIIb/IV Launch CIM CIS 2020 Development of a molecule only when the company is confident that the mechanism of action works Patho- Physiology Molecule Submission In-Life Development Testing CIM 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? jwdorpema, leiden, 10-11-2010

21. PWC view & QbD Approach & Tools First Time Right & Continuous improvement 2020 Development of a molecule only when the company is confident that the mechanism of action works Patho- Physiology Molecule Submission In-Life Development Testing CIM CIM = Confidence in Mechanism (half way Ph II) CIS = Confidence in Safety (end Ph II) CIS Ref.: PWC Pharma 2020: The vision jwdorpema, leiden, 10-11-2010

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23. 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 jwdorpema, leiden, 10-11-2010

24. 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 QbD: what does it bring? jwdorpema, leiden, 10-11-2010