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Pharmaceutical Quality - The Office of

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The keynote address at the Fall meeting of the CPPR Industrial Advisory Board and the Site Directors held yesterday (27 October 2014) at Purdue University. The talk provides a perspective on the recent organizational changes announced by FDA CDER - the Office of Pharmaceutical Quality.

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Pharmaceutical Quality - The Office of

  1. 1. Pharmaceutical Quality: The Office of Ajaz S. Hussain, Ph.D. Executive Director The National Institute for Pharmaceutical Technology & Education Duquesne University Illinois Institute of Technology Purdue University Rutgers University Universidad de Puerto Rico University of Connecticut University of Iowa University of Kansas University of Kentucky University of Maryland University of Michigan University of Minnesota University of Wisconsin 10/27/2014 Ajaz@NIPTE.ORG 1
  2. 2. CDER Creates "Super-Office" to Keep Closer Eye on Drug Quality  “The restructuring will improve the way we deal with global challenges and increasing product complexity, and assure that quality medicines are available to the American public,” Dr. Woodcock added. Genetic Engineering & Biotechnology News, Oct 16, 2014. http://www.genengnews.com/gen-news-highlights/cder-creates-super-office-to-keep-closer-eye-on-drug-quality/81250478/ 10/27/2014 Ajaz@NIPTE.ORG 2
  3. 3. Assurance of pharmaceutical quality poses a challenge Pharmaceuticals exhibit market failures that can have devastating consequences Devastating consequence → intention to change behavior and improve approaches for assuring pharmaceutical quality Lacking effective means to objectively assess & mitigate risks, we accumulate layers of procedures Which increases complexity – it , in and of itself, poses challenges & leads to inefficiencies 10/27/2014 Ajaz@NIPTE.ORG 3
  4. 4. If you change the way you look at things, the things you look at change. Wayne Dyer Attitude towards the behavior Subjective norm Perceived behavioral control Intention Future Behavior usually found to predict behavioral intentions with a high degree of accuracy intentions, in combination with perceived behavioral control, can account for a considerable proportion of variance in behavior. Past Behavior Ajen, I. The theory of planned behavior. ORGANIZATIONAL BEHAVIOR AND HUMAN DECISION PROCESSES 50, 179-211 (1991) http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 4
  5. 5. it only provides unnecessary complexity, since a manufacturing facility’s performance is only as good as the last inspector’s opinion of the GMPs http://www.pharmaceuticalonline.com/doc/cder-s-janet-woodcock-nobody-can-really-tell-me-if-fda-inspections-are-effective-0001 10/27/2014 Ajaz@NIPTE.ORG 5
  6. 6. Presentation Outline: Questions • Assurance of pharmaceutical quality poses a challenge? Why • Complexities? • Global challenges? • Structure of OPQ? What • Improve assurance of quality? • CPPR, NIPTE and other similar collaborative efforts can help? How 10/27/2014 Ajaz@NIPTE.ORG 6
  7. 7. Preconditions to malice or disregard http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 7
  8. 8. Human behavior is predictably irrational In trying to understand how best to regulate “market failure” – Behavioral economics or morality based policies? We ship! When no one is looking! http://www.dilbert.com/ 10/27/2014 Ajaz@NIPTE.ORG 8
  9. 9. Root-cause may be upstream! Satisfy reviewer requirements Throw-over the wall Then just do it … Prone to ‘process entropy’ without FDA Inspections! Commercial Operations Development & Application Pharmacovigilance Inspections – 483, WL,… Marketing,…. Manufacturing Marketing Authorization Pre-Approval Inspection Review Application Development http://www.nike.com/us/en_us/c/justdoit “Throw-over the wall” “Satisfy Reviewer Requirements” http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 9
  10. 10. Chemometric, Pharmacometrics & Econometrics: Three Dimensions of QbD. Ajaz S. Hussain. Swiss Pharma (2012). Business Decisions: Commercial operations, profitability & availability. Periodic Regulatory Inspections Review & Approval Chemometrics Econometrics Three Econometric Papers on Quality Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry. Gopesh Anand, John Gray, and Enno Siemsen. Organization Science. 23:1700-1716 (2012) Regulator Heterogeneity and Endogenous Efforts to Close the Information Asymmetry Gap: Evidence from FDA regulation. Jeffrey T. Macher, John W. Mayo and Jack A. Nickerson. Journal of Law and Economics. 54: 25 – 54 (2011) Quality Risk in Offshore Manufacturing: Evidence from the Pharmaceutical Industry. John Gray, Aleda Roth, and Michael Leiblein. Journal of Operations Management. 29: 737– 752 (2011) How do people really make decisions? Prospect Theory: An Analysis of Decision under Risk. Daniel Kahneman and Amos Tversky Econometrica. 47: 263-291 (1979) The Framing of Decisions and the Psychology of Choice. Amos Tversky and Daniel Kahneman Science. 211, pp. 453-458 (1981) The End of Rational Economics. Dan Ariely. Harvard Business Review, July 2009. http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 10
  11. 11. Complexities & Global Challenges Devastating Consequences Heparin Disaster 2007-2008 Compounding Contamination …2011 and Current Issues Drug Shortages 2007-2012… Currently. Therapeutic In-equivalence Current Issues Data Integrity and Quality Assurance – India, China,.. Current Issue Prophylactic medicine: Poor Adherence or Quality 2003 Six illustrative examples See slide 32 for references. 10/27/2014 Ajaz@NIPTE.ORG 11
  12. 12. Recap • Assurance of pharmaceutical quality poses a challenge? Why • Complexities? • Global challenges? • Structure of OPQ? What • Improve assurance of quality? • CPPR, NIPTE and other similar collaborative efforts can help? How 10/27/2014 Ajaz@NIPTE.ORG 12
  13. 13. Drivers for OPQ: Past Success (?) & Current Challenges FDA’s Pharmaceutical Quality for 21st Century Initiative: Successes  ‘Enabling’ of modern technology (e.g., PAT)  Updates to GMP regulations; revised GMP guidance  Multiple ICH documents:  Pharmaceutical Development and Quality by Design  Quality Risk Management;  Quality Systems  Question-based review  Formation of Pharmaceutical Inspectorate  Risk-based selection of facilities for inspection Current Challenges (Not All-Inclusive or In Order of Priority)  Drug Shortages  State of Quality?  GDUFA Backlog  Internal Process Improvements Needed  Multiple Systems / Databases  Risk Based Quality Assessment Not Fully Realized  Knowledge & Lifecycle Management  Communication / Silos  Innovation is Not Increasing http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf 10/27/2014 Ajaz@NIPTE.ORG 13
  14. 14. OPQ Structure OPQ Immediate Office Office of Programs & Regulatory Operations Office of Policy Office of New Drug Products Office of Lifecycle Drug Products Office of Process and Facilities Office of Surveillance Office of Testing & Research Office of Biotechnology Products http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf 10/27/2014 Ajaz@NIPTE.ORG 14
  15. 15. Highlights Quality intelligence, risk analysis & modeling Organizational excellence, training and development Process & facility (quality & risk) Dosage forms & life-cycle http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf 10/27/2014 Ajaz@NIPTE.ORG 15
  16. 16. Integrative thinking, actions, and tools http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf 10/27/2014 Ajaz@NIPTE.ORG 16
  17. 17. Centralize quality drug review —creating one quality voice by integrating quality review, quality evaluation, and inspection across the product lifecycle Consistent quality standards and risk -based approaches OPQ will establish consistent quality standards and clear expectations for industry Product standards should be captured in clinical quality attributes and clinically - relevant specifications Identifying quality problems, requiring corrective actions where standards are not met, and making enforcement decisions will require close interaction between OC, OPQ, and ORA OPQ will anticipate quality problems before they develop and help prevent drug shortages With better knowledge of product and facility quality, we can help assure better quality drugs that are consistently available http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf 10/27/2014 Ajaz@NIPTE.ORG 17
  18. 18. Recap & Summary • Assurance of pharmaceutical quality poses a challenge? Why • Complexities? • Global challenges? • Structure of OPQ? What • Improve assurance of quality? • CPPR, NIPTE and other similar collaborative efforts help? How 10/27/2014 Ajaz@NIPTE.ORG 18
  19. 19. Past successes?? Why the slow progress? http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final 10/27/2014 Ajaz@NIPTE.ORG 19
  20. 20. Some reasons for the slow progress per McKinsey Report (2011) How will OPQ overcome this? http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final 10/27/2014 Ajaz@NIPTE.ORG 20
  21. 21. Reflecting back 10+ years: Integrated , systems, thinking essential – it is like learning to dance together! What efforts are planned to ensure OPQ will learn to build effective teams.. http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final 10/27/2014 Ajaz@NIPTE.ORG 21
  22. 22. Blind-spots (cognitive biases) Data Integrity and Quality Assurance – India, China,.. Current Issue Prophylactic medicine: Poor Adherence or Quality 2003 More that than a decade ago to the current situation….. 10/27/2014 Ajaz@NIPTE.ORG 22
  23. 23. More U.S. Marines contract Malaria Wednesday, September 10, 2003 Posted: 9:25 AM EDT (1325 GMT) WASHINGTON (CNN) -- Ten more U.S. military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria. More than a decade ago…….  We faced significant challenges in our analysis: Unexpected inter-laboratory differences that highlighted limitation of the current calibration procedure  “We are at a loss to explain the difference between DPA’s and PHI-DO’s initial results. ………………..  We further contend that the Helium sparging does not remove dissolved air as well as the vacuum procedures and therefore could account for the additional 5 or 6% increase in the dissolution results. And finally, for this formulation basket wobble can significantly increase the dissolution values.” DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003 10/27/2014 Ajaz@NIPTE.ORG 23
  24. 24. Today a better understanding; Testing into compliance –why? attitude toward performing the behavior Process validation is done so quality is good; test prone to error “Batch failure means I made a mistake” subjective norm documentation not critical Compendial testing sufficient Indian regulators collect & test samples – no issue there! “Testing into compliance” In general – low empowerment is a significant challenge (low perceived behavioral control); plus reasons to rationalize…. “Throw-over the wall What I am learning via surveys and interviews… http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 24
  25. 25. Process Validation (2011), Statistical Confidence, Continued Process Verification… Quality Metrics,…. Will need us to confront our ‘blind spots’! http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004 10/27/2014 Ajaz@NIPTE.ORG 25
  26. 26. If we are to anticipate quality problems before they develop – it is essential to learn how not to create problems in the first place! http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004 10/27/2014 Ajaz@NIPTE.ORG 26
  27. 27. Recap & Summary • Assurance of pharmaceutical quality poses a challenge? Why • Complexities? • Global challenges? • Structure of OPQ? What • Improve assurance of quality? • CPPR, NIPTE and other similar collaborative efforts can help? How 10/27/2014 Ajaz@NIPTE.ORG 27
  28. 28. Environment that facilitates individuals to guide their behavior to work consciously in the interest of patients and to continually improve this ability. Culture of Quality http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 28
  29. 29. Scientific methodology Engineering Design Plan-Do- Check-Act Consciously Habits (work to get rid of bad ones) Habits (work to cultivate good one) Keystone habits (Safety @ Alcoa; A.L.C.O.A. of data integrity) Subconsciously Consciously ask the right questions in the interest of the patients, describe the accepted assumptions and set the level of precision needed for the answers to the questions posed. Be a good scientist – in the interest of the patients. The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012) http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality 10/27/2014 Ajaz@NIPTE.ORG 29
  30. 30. A useful tool http://www-2.rotman.utoronto.ca/integrativethinking/definition.htm 10/27/2014 Ajaz@NIPTE.ORG 30
  31. 31. A major step taken by FDA – we all must work together to help. We all are regulators! 10/27/2014 Ajaz@NIPTE.ORG 31
  32. 32. Six illustrative examples – references (additional reading)  HOUSE HEARING, 110th CONGRESS -THE HEPARIN DISASTER: CHINESE COUNTERFEITS AND AMERICAN FAILURES. http://www.gpo.gov/fdsys/pkg/CHRG- 110hhrg53183/content-detail.html  Fungal Meningitis Outbreak. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalP roducts/ucm323946.htm  Seeking solutions to “incredibly complex issue” of drug shortages - See more at: http://www.wdde.org/22573-rx-shortages-update#sthash.1Htx532R.dpuf  Drug Shortages. http://www.fda.gov/drugs/drugsafety/drugshortages/  Update: Bupropion Hydrochloride Extended-Release 300 mg Bioequivalence Studies. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/uc m153270.htm  In quality crackdown, US drug regulator finds Indian companies critically ill. US FDA turning stricter to ensure compliance levels and quality of medicines. Sushmi Dey. Business Standard. New Delhi , September 24, 2013. http://www.business-standard. com/article/companies/in-quality-crackdown-us-drug-regulator-finds-indian-companies- critically-ill-113092300890_1.html  More Malaria For Liberia Marines, CBS News September 8, 2003. http://www.cbsnews.com/news/more-malaria-for-liberia-marines/  FDA’s ACPS Meeting October 2005. Achieving and demonstrating “Quality by Design” with respect to drug release/dissolution performance for conventional or immediate release solid oral dosage forms . http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_03-Achieve-Demo-QbD.pdf 10/27/2014 Ajaz@NIPTE.ORG 32

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