1. jwdorpema, leiden, 10-11-20101 GMP for the 21 st Century: GMP

2. jwdorpema, leiden, 10-11-20102 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

3. jwdorpema, leiden, 10-11-20103 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

4. jwdorpema, leiden, 10-11-20104 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?

5. jwdorpema, leiden, 10-11-20105 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 Pharma scores high % defects (rejections, recalls): 2-3 sigma. ICT, medical devices and automotive score 6 sigma. Pharma performance: moderate?

6. jwdorpema, leiden, 10-11-2010 Message: time to change Political issuedLate senator Kennedy Health care inspiredFDA initiative (ICH inspired) Marketing and sales decidedHealth care directed marketing policies Financial controlledProfitability risk management Technical executedQuality by Design (QbD) Clinical fuelledTranslational Medicine Research (TMR) = input Patient directedPersonalized medicine Science guidedMolecular & system biology and nanotechnology innovations to change the making of (bio)pharmaceuticals Process drivenNew business model centred around the redesign of the making of (bio)pharmaceutics i.e. QbD Result: “the faster, cheaper and safer mandate” 6

7. jwdorpema, leiden, 10-11-20107 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

8. jwdorpema, leiden, 10-11-20108 Business Life Cycle

9. jwdorpema, leiden, 10-11-20109 Business Competences

10. jwdorpema, leiden, 10-11-201010 Business Dynamics

11. jwdorpema, leiden, 10-11-201011 Business Dynamics

12. jwdorpema, leiden, 10-11-201012 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

13. 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 “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

14. jwdorpema, leiden, 10-11-201014 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

15. jwdorpema, leiden, 10-11-201015 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

16. jwdorpema, leiden, 10-11-201016 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 Note: this is the general quality principle Meaning: PATIENT is the focal point

17. jwdorpema, leiden, 10-11-201017 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

18. jwdorpema, leiden, 10-11-201018 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

19. jwdorpema, leiden, 10-11-201019 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

20. jwdorpema, leiden, 10-11-201020 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 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

21. jwdorpema, leiden, 10-11-201021 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 CI M CI S 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

22. jwdorpema, leiden, 10-11-201022

23. jwdorpema, leiden, 10-11-201023 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

24. jwdorpema, leiden, 10-11-201024 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