Making High Quality Affordable

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Making High Quality Affordable

  1. 1. Fort Aguada; 16th-century Portuguese fort1 Challenge: Make High Quality Medicines Affordable Ajaz S. Hussain, Ph.D., Chief Scientific Officer Ajaz S. Hussain, Ph.D. 4/10/2013
  2. 2. My personal point of view2 Assistant Professor Associate Professor Deputy Director B.Pharm. Ph.D. Interdisciplinary of Pharmacy of Pharmaceutics (tenured) Office of Pharmaceutical Science CSO CSO VP Biopharmaceuticals Ajaz S. Hussain, Ph.D. 4/10/2013
  3. 3. Returning to Pharma, added appreciation for…3 After several years of thinking about how to achieve tobacco harm reduction Predictors of human behavior? Decision- Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6. making in the presence The notion ‘by design’, in the phrase ‘Quality by of risk? Design’, conveys an intention to deliver a product or service with a pre-defined ‘quality’ so as to satisfy intended customers. Behavioral economics Why econometrics? Ajaz S. Hussain, Ph.D. 4/10/2013
  4. 4. Outline4 • Reflecting back to articulation of ‘Vision 2020’ >>> ICH Desired State Background • Focus was on chemometrics and pharmacometrics Topics selected for • Manufacturer “acceptability” increasingly an important driver discussion & why? • Making quality affordable A high level over view of • Maintain high quality - At high rate of capacity utilization my learning: How to … • QbD for complex products - Under high level of uncertainty • Comparable quality (pharmacovigilance) and What should we measure? • Metrics to measure performance of an organization Summary • And closing thoughts Ajaz S. Hussain, Ph.D. 4/10/2013
  5. 5. In 2000 @ FDA – anticipation of changes needed by 20205 PAT Initiative è Pharmaceutical Quality for 21st Centuryè ICH Initiative Real-time and remote inspection was deemed “too radical” (in 2000) www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt Ajaz S. Hussain, Ph.D. 4/10/2013
  6. 6. A simple idea - improved understanding is needed for risk management6 “I can see clearly now” - First Principles Vision 2020 Knowledge based decisions Why? Perspectives on Regulation: Law, MECHANISTIC Desired State Need for regulatory oversight ¤ KNOWLEDGE Discretion, and Bureaucratic How? Behavior (Kagan and Scholz, May 1980) “CAUSAL" KNOWLEDGE n ‘Good citizens’ Vs. {‘political What “Causes” What? citizens, ‘incompetent’, and/or ‘amoral’} CORRELATIVE KNOWLEDGE Current State What Is Correlated to What? ¨ For FDA to be risk-based it needs scientific data & information, DESCRIPTIVE KNOWLEDGE: capability, .. What? http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt Ajaz S. Hussain, Ph.D. 4/10/2013
  7. 7. 21st Century Opportunities7 ¨ “Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based”. ¨ “Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes.” www.fda.gov/ohrms/dockets/ac/04/.../2004-4052S1_01_Hussain.ppt Ajaz S. Hussain, Ph.D. 4/10/2013
  8. 8. Two topics, established fundamentals, a way forward…let me know if you agree, if not, why?8 Manufacturer “acceptability” increasingly an important driver • Who makes the medicines I take? Pride of workmanship is key to delivering manufacturers’ acceptability • I make the medicines you take Making quality affordable • A system which encourages design thinking and continually reduces process entropy Ajaz S. Hussain, Ph.D. 4/10/2013
  9. 9. Example: Pride of workmanship9 • “These disciplined • “The dabbawalas are • “There are many small Interdependence and trust: Management: Motivation: Discipline and Time workers work highly motivated groups and each perpetually and individuals. Their job is group has to be effectively in a city very important. It is a responsible for itself that movement is very big deal in India and for every other difficult due to the if a customer does not group. So there is a extremely high number receive his box on time high interdependence. of residents. They have or even receives a If one team is not received World record wrong box.” working well then the in best time whole procedure is at management.” risk.” Ajaz S. Hussain, Ph.D. http://www.strategicmanagement-sixsigma.com/2011/06/mumbai- 4/10/2013 dabbawalas.html
  10. 10. Example: Pride of workmanship (cont.)10 • “They are very close to • “Three months is the • “A group consists of Close to the customer Small Group Formation Training time the customer. They try training time and a few people with a to satisfy the need of practice test in order supervisor. The team every customer by somebody to be a members share the taking and delivering dabbawala. In revenue. Trust and on time with no contrast big companies respect are the raw mistake.” like Mc Donald’s spend materials that describe less than one day to a group.” train their employees.” http://www.strategicmanagement-sixsigma.com/2011/06/mumbai- Ajaz S. Hussain, Ph.D. dabbawalas.html 4/10/2013
  11. 11. Why is this talk relevant to IPA members?11 Increasing generic Beyond the traditional Beyond the current competition has been an oral dosage forms the Global consensus - the ‘patent cliff’ generic important policy generic drug approval generic model is not companies are looking consideration for several model faces many applicable for towards complex years challenges biotechnology products generics, biosimilars and NCE products Ajaz S. Hussain, Ph.D. 4/10/2013
  12. 12. 12 Who makes the medicines I take? Manufacturer “acceptability” increasingly an important driver Ajaz S. Hussain, Ph.D. 4/10/2013
  13. 13. Today’s challenges13 Increasing complexity and uncertainty • Complex products (e.g., MDI/DPIs, biosimilars) • Evolving regulatory pathways; hence uncertainty • Local to global markets; reducing variability Erosion of public trust • Shortage of injectable products • Falsified and substandard drugs • Other factors Ajaz S. Hussain, Ph.D. 4/10/2013
  14. 14. Public trust is the bed-rock of our industry14 ¨ Perceptions do matter! JAMA, March 5, 2008—Vol 299, No. 9 http://management.fortune.cnn.com/tag/generic-drugs/ Ajaz S. Hussain, Ph.D. 4/10/2013
  15. 15. Continual effort needed to counteract forces that erode public trust15 Ajaz S. Hussain, Ph.D. 4/10/2013
  16. 16. Shortage of injectable products in the US16 • “Cancer drug shortages cause treatment, research Previous week problems” (http://www.oncologynurseadvisor.com/cancer-drug-shortages-cause- treatment-research-problems/article/287359/) news • “Drug shortages spur debate over role of compounding pharmacies” (https://home.modernhealthcare.com) • “Drug shortages at all-time high” (CNN; June 2011) News in 2011 • “New effort to reduce drug shortages a small step” (Business Week; October 2011) Ajaz S. Hussain, Ph.D. 4/10/2013
  17. 17. Today’s challenges.. Not different from challenge a decade ago.... Different companies17 ¨ Reflecting back to 2000 ¤ How is the situation different today? n Then few generic injectable drugs; current injectable shortage predominantly generic manufacturers ¨ Reflecting back to early 1990’s ¤ We were getting beyond the ‘generic drug scandal’ Ajaz S. Hussain, Ph.D. 4/10/2013
  18. 18. Several efforts to understand & correct….18 Economic • “The rapid increase in volume and • “Drug shortages in the technologic US point to a need to Economic and scope … high rate of differentiate analysis of capacity utilization in the al drivers of manufacturers by [generic] industry. At these generic the causes high levels … difficult to reliability.” of drug maintain manufacturing quality sterile • “FDA could support the levels and any disruptions to injectable buyers and payers in their shortages purchase and (ASPE Issue supply – through, for example, drug Briefing October quality problems …..– can reimbursement decisions 2011) lead to cascading and shortages by providing them with persistent shortages.” (J. Woodcock and meaningful [emphasis added] M. Wosinska manufacturing quality (2013)) metrics.” http://aspe.hhs.gov/sp/reports/2011/drugshortages/ib.shtml http://www.nature.com/clpt/journal/v93/n2/abs/clpt2012220a.html Ajaz S. Hussain, Ph.D. 4/10/2013
  19. 19. Global product safety and quality19 “…prepared for a regulatory environment in which product safety and quality know no borders” http://www.fda.gov/downloads/ aboutfda/centersoffices/oc/glob alproductpathway/ucm259845.p df Ajaz S. Hussain, Ph.D. 4/10/2013
  20. 20. Asian middle class: A dominant market by 202020 Indian • 55 billion USD by 2020 (base Pharma case) • Acceptability Growth • Accessibility • Affordability drivers • Epidemiological factors http://online.wsj.com/public/resources/documents/McKinseyPharma http://www.jana.com/blog/the-battle-for-the-emerging-middle-class/ 2020ExecutiveSummary.pdf Ajaz S. Hussain, Ph.D. 4/10/2013
  21. 21. Manufacturer “acceptability”…..21 Historically, in the “Patients are not (The Asian middle Asian context – consumers” – but Increasingly a class) more “Traditional vs. this distinction is concern – “not conscious on where Western” medicine eroding manufactured here” a product is manufactured Ajaz S. Hussain, Ph.D. 4/10/2013
  22. 22. Key points: Established and emerging need to..22 • Maintain high quality Build/maintain • At high rate of capacity utilization public trust • QbD for complex products • Under high level of uncertainty Differentiate • Product safety and quality know no borders manufactures by • Utilize meaningful manufacturing quality metrics reliability Ajaz S. Hussain, Ph.D. 4/10/2013
  23. 23. 23 At high rate of capacity utilization Maintain high quality Ajaz S. Hussain, Ph.D. 4/10/2013
  24. 24. Top FDA 483 citations in 2012 (Drugs)… no significant change in this list since…24 The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. 169 There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to 119 meet any of its specifications] whether or not the batch has been already distributed. There are no written procedures for production and process controls designed to assure that the drug products have the 116 identity, strength, quality, and purity they purport or are represented to possess. Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] 115 [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing 89 processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used 73 in the manufacture, processing, packing or holding of a drug product. Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to 69 a written program designed to assure proper performance. Employees are not given training in [the particular operations they perform as part of their function] [current good 65 manufacturing practices] [written procedures required by current good manufacturing practice regulations]. http://www.fda.gov/ICECI/EnforcementActions/ucm250729.htm Ajaz S. Hussain, Ph.D. 4/10/2013
  25. 25. Econometrics: Important questions25 • How widespread are deviations from SOP? • What factors impact process entropy? • How effective are FDA inspections to decrease process entropy? For example: Modeling • Does offshore production pose an added quality risk relative to of the relationship domestic production? If so, what factors influence the quality between regulators and risk? the firms they regulate • To what extent regulators utilize previously secured information in guiding regulatory (inspection) decisions? • What is the impact of regulator experience and training (along with a host of other controls) on regulatory outcomes? Ajaz S. Hussain, Ph.D. 4/10/2013
  26. 26. Relevant econometric analyses26 Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry Quality risk in offshore manufacturing: Evidence from the Gopesh Anand, pharmaceutical industry John Gray, and Enno Siemsen. Organization John Gray, Aleda Regulator heterogeneity and endogenous efforts to close the Science. Vol. 23, information asymmetry gap: evidence from FDA regulation No. 6, Roth, and Michael November– Leiblein. Journal December 2012, of Operations Management 29 Jeffrey Macher, John Mayo, and Jack Nickerson. Journal of Law and pp. 1700–1716 Economics. Vol. 54, No. 1 (February 2011), pp. 25-54 (2011) 737–752 Ajaz S. Hussain, Ph.D. 4/10/2013
  27. 27. 27 Under high level of uncertainty Achieve QbD for complex products Ajaz S. Hussain, Ph.D. 4/10/2013
  28. 28. A key difference between FDA & EMA28 Ajaz S. Hussain, Ph.D. 4/10/2013
  29. 29. Complex generics and biosimilars29 FDA cGMP Review NDA, Manufacturing Development Inspections BLA, or ANDA QbD approach to Multi-disciplinary; Considered high risk – development of Complexity Increases system wide team inspections analytics, product and ensure appropriate weighting of evidence process Evidence of Validation, state of 483-to-WL-to- pharmaceutical Review evaluation Uncertainty control & rate of Enforcemnt equivalence, similarity, criteria evolving entropy and interchangeability More critical to control Frequency of Expected - different Controlled within lot-lot Variability quality of materials inspections & focus variability of RLD review disciplines & used and final product areas culture Ajaz S. Hussain, Ph.D. 4/10/2013
  30. 30. Woodcock: ‘Paradigm Shift’ in Reviews30 “…companies intending to “..the amount of clinical market Biosimilars must come evidence required by FDA to FDA with an extensive will be related to the amount characterization package, and the quality of analytical comparing theirs with the and functional information reference product.” that is available on any biosimilar product…” Ajaz S. Hussain, Ph.D. DIA/FDA Biosimilars Conference 12 September 2012 4/10/2013
  31. 31. Quality of development and regulatory communication31 Regulators Industry Design Understanding Continuous – Recognize Level of Risk-based real time knowledge understanding People, Prior Experimental Product & Acceptable materials, knowledge – evidence in QMS track process variability machines and similar products development record environment reports Link between Material Specifications & Causal links Monitoring & quality, safety attributes Acceptable controls control system & efficacy critical to variability quality Product use Failure modes Process Intended use Failure modes Process information & likelihood capability & likelihood capability Ajaz S. Hussain, Ph.D. 4/10/2013
  32. 32. ‘Transdisciplinary’ & ‘Design Thinking’32 Transdiciplianry Design Thinking Analytics, mechanisms Not and clinical Target Ability to Multi- a Thing, indications ‘Quality Product measure functional But ‘Interchange- by Profile and review a Way able’ Design’ and explain and (MIT Sloan Management designation QTPP challenge Review, July 2, 2009) ‘Package Insert’ & marketing messages Ajaz S. Hussain, Ph.D. 4/10/2013
  33. 33. QbD Approach: Targeted development33 Sandoz: Thomas Stangler | EAPB SIG Regulatory Aspects for Biopharmaceuticals | October 4th, 2010 Ajaz S. Hussain, Ph.D. 4/10/2013
  34. 34. Organizing for success34 Early investment in analytics and understanding variability in RLD • Inadequate focus on TPP, QTPP (analytics) Common & market research TPP & QTPP in the context of residual pitfalls • Functional check-box uncertainty and • Cut-paste approach Review/challenge culture and decision symptoms to clinical trials ‘gates’ • Rush to clinical Design of clinical trials to address scientific and clinical (market) uncertainty Ajaz S. Hussain, Ph.D. 4/10/2013
  35. 35. 35 Differentiate manufactures by reliability Product safety and quality know no borders Utilize meaningful manufacturing quality metrics Ajaz S. Hussain, Ph.D. 4/10/2013
  36. 36. Product safety and quality know no borders36 ¨ Quality system that can convincingly demonstrate delivery of comparable quality & pharmacovigilance TIME TIME 2 COST 1 Scientific evidence for Select 2? risk-based Optimize quality three? 3 RISK 4 COST QUALITY QUALITY Ajaz S. Hussain, Ph.D. 4/10/2013
  37. 37. Cost, Quality & Risk: Unproductive time37 Product & process quality Regulatory compliance COS Activity - Costs Risk Activity - Cost Risk External failure Complaint investigations, To patient, 483s, WL, seizure,. ….. To patients, impact and RC-investigations, reputation and Recall activities reputation and CAPA business business Internal failure Down-time, impact & RC- To business and OOS investigation report, change - Inability to improve investigations, CAPA quality system regulatory supplements for review or risk to patients? Prevention Improve design of product “Corrective Change control and regulatory CQAs? controls?, and/or process; Quality System, actions” not supplements representative Training,… continual Validation & batch records batches? improvement SOP development/training Focus on documentation & Appraisal Testing and inspection for CQAs?, Batch records, review inadequate system incoming materials and products representative QC release. Document review , audits understanding samples?,…. Ajaz S. Hussain, Ph.D. 4/10/2013
  38. 38. Making high quality affordable38 Consumers, Optimal prescribers Manufactures Drivers “driver and payers behaviors”? Time to market Market access ROI Access to products and Right First Time information Reputation Reliability Ajaz S. Hussain, Ph.D. 4/10/2013
  39. 39. Making high quality affordable39 Purpose Process People Consumers Confidence & satisfaction Regulators Optimal [Benefit/Risk] Professional satisfaction Evidence Rp & financial security Manufacturers Deliver products & Professional satisfaction generate profit Mp & financial rewards Right first time and on-time (identify and eliminate regulatory disharmony in multiple regions that hinders this goal) Ajaz S. Hussain, Ph.D. 4/10/2013
  40. 40. If you don’t measure something, you can’t understand it40 “Measurement is the first step that leads to control and eventually to improvement. If you can’t measure something, you can’t understand it. If you can’t understand it, you can’t control it. If you can’t control it, you can’t improve it.” ― H. James Harrington Ajaz S. Hussain, Ph.D. 4/10/2013
  41. 41. High reliability organization – per Deming41 Org. is a Reduce system that Knowledge variability; interacts Appreciation about statistical with for a system variation process environment control Theory, Mgmt. predict, Theory of Psychology ‘culture’ feedback – Knowledge of people influence the a way to system and learn outcome Ajaz S. Hussain, Ph.D. 4/10/2013
  42. 42. What to measure?42 • The Malcom Baldrige National Quality There are major Award (USA) awards such as • Deming Prize (Japan) Which provide • Alignment and/or relevance to regulatory ‘right first time and on-time’ (review and relevant metrics inspection) need to be factored in Ajaz S. Hussain, Ph.D. 4/10/2013
  43. 43. Summary43 Topics selected for • Manufacturer “acceptability” increasingly an important driver discussion & why? • Making quality affordable A high level over view • Maintain high quality - At high rate of capacity utilization of my learning: How • QbD for complex products - Under high level of uncertainty to … • Ability to provide evidence of comparable global quality What should we (pharmacovigilance) and measure? • Performance metrics per recognized awards – linked to ‘right first time and on time’ (for a high regulatory standard; review & inspection) Ajaz S. Hussain, Ph.D. 4/10/2013
  44. 44. “The essence of communication is intention” Werner Erhard44 ¨ The notion ‘by design’, in the phrase ‘Quality by Design’, conveys an intention to deliver a product or service with a pre-defined ‘quality’ so as to satisfy intended customers. ¤ Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6 http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt Ajaz S. Hussain, Ph.D. 4/10/2013
  45. 45. A quality revolution in India…..45 Deming Prize winners Deming Grand Prize (previously •Since 2000, organizations based in India Japan Quality Medal): 2012 have received 19 prizes while •Tata Steel Limited (India) What steps a Pharma company organizations based in all other countries •Rane (Madras) Ltd. (India) take to achieve this by 2020? combined have received 21 (Thailand 10, Japan 7, USA 1, Singapore 1, China 1 and •Lucas-TV Ltd. (India) Taiwan 1) Ajaz S. Hussain, Ph.D. http://blog.deming.org/2012/10/2012-deming-prize-winners/ 4/10/2013

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