QbD update. Toelichting Pilot beschreven in het BioFarmind Magazine. j.w.dorpema, f.reman & e.c.beuvery, nijmegen, (26-03)

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1 QbD update Toelichting Pilot beschreven in het BioFarmind Magazine 1

2 QbD: what are the issues? Quality itself is not the issue, but pharmaceutical development and manufacturing has to be improved (see our pilot) Improve how: we need to get it right first time and then continue to improve (see our pilot) The problem is (uncontrolled) variability (see our pilot) Varibility is reduced by obtaining increased process and product understanding leading to right first time performance (see our pilot) Paradigm change: from regulatory compliance to enhanced product and process understanding (see our pilot) 2

3 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 3

4 QbD: what s to gain? Improvement of performance Regulatory requirement Cost savings Total product life cycle (later on detailed) Quality cost Sigma ppm Defects Yield (%) Cost of Quality (%) 2σ , σ , σ , σ , σ 3,

5 QbD benefits Process understanding is inversely proportional to risk Increase of process understanding leads to Reduction of process risk Reduction of process variability Yields real time quality assurance (a.o. parametric and real time release) The more assured the quality the lower the risk for consumers Reasons for not doing QbD: To many things to do Don t know what is 5

6 Longer-term business benefits Reduced batch failures, final product testing and batch release costs Low operating costs from fewer failures and deviation investigations Increased predictability of manufacturing output and quality Reduced inventory costs form raw materials, work-inprogress and finished product Faster regulatory approvals of new product applications and process changes Fewer, shorter and less costly regulatory inspections Faster technology transfer between development and manufacturing ( -> shorter time to market) 6

7 Opportunity costs* QbD cost model Total revenue biotech (2002) $ ,00 Number of biotherapeutic drugs : 130 potential revenue per drug/year $ ,69 Number of working days : 250 Opportunity costs per day $ ,23 midpoint process development resource hours ,00 hours Personnel cost p/hour x $225,00 Midpoint development costs $ ,00 Midpoint project time 42,5 months Midpoint project duration in days 850 Cost per day $ ,59 Full cost per day $ ,82 * Opportunity costs: product on the market versus process development days 7

8 Opportunity costs* QbD cost model Verdubbeling R&D inspanning heeft marginaal effect op full cost per day : dus niet snijden, maar investeren in R&D is de boodschap Total revenue biotech (2002) $ ,00 Number of biotherapeutic drugs : 130 potential revenue per drug/year $ ,69 Number of working days : 250 Opportunity costs per day $ ,23 midpoint process development resource hours ,00 hours Personnel cost p/hour x $225,00 Midpoint development costs $ ,00 Midpoint project time 42,5 months Midpoint project duration in days 850 Cost per day $ ,18 Full cost per day $ ,41 * Opportunity costs: product on the market versus process development days 8

9 QbD: momentum Tijdstip: komt op juiste moment, immers gerede twijfel over overheids (pp) business model wetenschapper wordt ondernemer Bij QbD staat de ontwikkeling en productie van geneesmiddelen centraal Kennis zonder kunde leidt tot proces zonder product Implicatie voor de innovatiestrategie: van denk- naar maakindustrie QbD: de hefboom om de innovatie shift naar maakindustrie te stimuleren Realisatie: innovatief gesubsidieerde Biofarmind Pilot (2-3 jaar) 9

10 QbD: hefboom werkelijk nodig? Salarissen: het kost ons $ om iemand in de EU te werk te stellen en $ in China (US multinational) Kunnen wij die strijd aan?: Handelsbelemmeringen opwerpen Voorblijven en beter doen 10

11 QbD: voorblijven en beter doen 1. Potentiele besparingen (Ref.: R. Baker, Bovis Lend*) Actie Besparing (%) Scale up elimineren 4 Later in productie investeren 8-10 Onderbenuttig capaciteit opheffen (30%) 8-10 Verbetering logisitisitek 10 Afval/afkeur vemindering -> besparingen 7 Ruimtebenutting: generic/branded = 1/2? 2. Lean assets management: Toyota Production Systems bij MSD (Ref: Cees Mens*,10% besparingen /jaar v.a bij een volume stijging van 71%) ALLES KOMT SAMEN IN QUALITY by DESIGN * Voordrachten Lean Asset Management in de Frama en Biotech Industrie, ISPE NL, 20 Maart

12 Uitgangspunten Pilot 1 GMP van de 20ste eeuw (kwaliteitsborging op papier) naar GMP van de 21ste eeuw (kwaliteitsborging aan de hand van data); FDA initiatieven in deze. ICH Q8 (Pharmaceutical Development). ICH Q 9 (Quality Risk Management). ICH Q10 (Pharmaceutical Quality Systems). 12

13 Uitgangspunten Pilot 2 Deelname van ongeveer 5-6 bedrijven of onderzoeksinstellingen. Bedrijven of instellingen zijn actief op het gebied van procesontwikkeling of productie. Elk bedrijf brengt een unit operatie van een productieproces in of brengt een procesapparaat in waarmede een unit operatie kan worden uitgevoerd 13

14 Doelstellingen van de Pilot Verbetering procesinzicht (definitie kritische productattributen en kritische procesattributen). Effectief data management. Toepassing van adequate dataverwerkingstools Risicoanalyse waaronder FMEA. Design Space / Control Space /continue procesverbetering. Procesmodellen (relevant voor ondermeer upscaling ). Het vullen van IND- en NDA-dossiers staat centraal 14

15 Sector Inquiry 2008/9: a need for QbD "Individuals and governments want a strong pharmaceuticals sector that delivers better products and value for money. But if innovative products are not being produced, and cheaper generic alternatives to existing products are being delayed, then we need to find out why and, if necessary, take action." Neelie Kroes, European Commissioner for Competition 15