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Excipient Knowledge Management Mumbai 12 March 2015 Part 1 & 2

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Why attention to excipient knowledge management (specifically their functionality) is critical to mitigating risks (or to leverage opportunities) posed by the rapidly increasing complexity and uncertainty

Note: Knowledge management in the context of ‘intellectual property’ is not the focus of this talk

Published in: Health & Medicine

Excipient Knowledge Management Mumbai 12 March 2015 Part 1 & 2

  1. 1. [‘Excipient’] Knowledge Management: 2015 & Beyond Ajaz S. Hussain, Ph.D. Insight, Advice & Solutions LLC Maryland, USA Executive Director, the National Institute for Pharmaceutical Technology & Education 3/12/2015 Ajaz S. Hussain, Ph.D. 1
  2. 2. Acknowledgment • Thanks to Arihant Innochem Pvt. Ltd. for inviting me to speak and also for accepting my requests to; (a) expand the program and include other speakers, and (b) inviting faculty members from local schools of pharmacy • For me this is an opportunity to share my insights on excipients and, more importantly, learn something about excipient supplier – Pharma interactions in India • Arihant Innochem Pvt. Ltd. made the travel arrangements for my trip to Mumbai. We have no other business or financial relationship. They did not request to see, nor did I provide, an advance copy of my slides. 3/12/2015 Ajaz S. Hussain, Ph.D. 2
  3. 3. Insights • Why attention to excipient knowledge management (specifically their functionality) is critical to mitigating risks (or to leverage opportunities) posed by the rapidly increasing complexity and uncertainty • Note: Knowledge management in the context of ‘intellectual property’ is not the focus of this talk • In the second talk, end of the day, I plan to discuss how certain management practices can impact effectiveness of knowledge management • Note: Knowledge management is a combination of both IT and human aspects; I intend to focus on ‘human factors’ 3/12/2015 Ajaz S. Hussain, Ph.D. 3
  4. 4. Outline • Declaring my interests, acknowledging experiences contributing to my current thinking • Current hot topics – ‘excipients’, regulatory trends & insights • Why attention to (excipient) knowledge management (specifically physical functionality/performance) is critical 3/12/2015 Ajaz S. Hussain, Ph.D. 4
  5. 5. My interest in [‘excipients’] KM acknowledging experiences contributing to my current thinking • Business decisions • Regulatory research, policy & enforcement • Academic research 3/12/2015 Ajaz S. Hussain, Ph.D. 5
  6. 6. Business decisions • Management responsibilities • VP & Global Head Biopharmaceutical Development @ Sandoz (2005-2009) • Development/regulatory submission: Omnitrope®, Binocrit®, Zarzio®, Generic Enoxaparin & Glatiramer acetate • VP Next Generation Product Assessment & CSO @ Philip Morris International (2009 -2012) • Development/evidence quality/regulatory strategy: Plant based vaccines & assessment of products intended for tobacco harm reduction • President Biotechnology & CSO @ Wockhardt (2012-2013) • Biosimilar and Complex Generic Strategy Improvement • Advisory/Consulting (2013 – currently) • Mitigating risks in development of complex products, Framework for effective compliance & remediation, Strengthening Culture of Quality 3/12/2015 Ajaz S. Hussain, Ph.D. 6
  7. 7. Regulatory research, policy & enforcement support @ US FDA (1995 – 2005) • Research to Policy • SUPAC, BCS, IVIVC, ….Topical Microbicides,…several others • Policy • SUPAC-MR, IVIVC, BCS, …….., PAT, @ ICH FDA Lead (Quality) – “desired state for 21st Century”, ICH Q8 – 10 • Enforcement Support • Expert witness for the prosecution (1995) • Facilitating resolution of difficult WLs linked to shortages 3/12/2015 Ajaz S. Hussain, Ph.D. 7
  8. 8. Knowledge to inform policy improvement 3/12/2015 Ajaz S. Hussain, Ph.D. 8
  9. 9. Physical Attributes: Can be critical for safety, efficacy and quality 3/12/2015 Ajaz S. Hussain, Ph.D. 9 July 15, 2005 FDA Public Health Advisory: Safety Warnings Regarding Use of Fentanyl Transdermal (Skin) Patches.
  10. 10. Also, relevant today: Pattern Recognition 3/12/2015 Ajaz S. Hussain, Ph.D. 10 Preliminary, illustration of a concept. Going forward expect to see regulators utilize state-of –the –art pattern recognition and modeling systems. Effective Regulatory System: Importance of Process Understanding and Quality by Design Ajaz Hussain, Pharmaceutical Quality Forum: 3rd Symposium November 2004, Tokyo, Japan
  11. 11. Academic research University of Cincinnati (1989-1994) • Formulation design • Several projects – oral, topical and transdermal • Example: Elaborating the utility of Transcutol® (Gattefossé) • Computer aided formulation design • Artificial Neural Network based ‘expert systems’ • Example: Prototype for ‘Technical Service Support’ (funding - Aqualon) NIPTE (Currently) • NIPTE’s Excipient Knowledge base • Available since 2007; at http://pharmahub.org/ • The goal of this project is to share information and modeling tools to support pharmaceutical product 3/12/2015 Ajaz S. Hussain, Ph.D. 11
  12. 12. Prototype for ‘Technical Service Support’ 3/12/2015 Ajaz S. Hussain, Ph.D. 12 From a ‘Database’ to a ‘Knowledge base’ • ‘Look-up tables’ to ‘Ability to Predict’ • Ability to predict = generate hypotheses • Ability (simulate) ask questions - what if?
  13. 13. NIPTE * Knowledge Management 3/12/2015 Ajaz S. Hussain, Ph.D. 13
  14. 14. Contact Prof. Hoag @ Univ. Maryland, shoag@rx.umaryland.edu 3/12/2015 Ajaz S. Hussain, Ph.D. 14
  15. 15. NIPTE * Knowledge Management This study was funded by the FDA-sponsored contract “Development of Quality by Design (QbD) Guidance Elements on Design Specifications across Scales with Stability Considerations” (contract number HHSF223200819929C). 3/12/2015 Ajaz S. Hussain, Ph.D. 15
  16. 16. Current hot topics –’excipients’, regulatory trends & insights @ ExcipientFest on 28-29 April 2015 in Washington, Organizational Changes @ CDER/FDA, and Inspectional Trends,…..(Complex Generics,…., Continuous Manufacturing) 3/12/2015 Ajaz S. Hussain, Ph.D. 16
  17. 17. Current experience with ‘Supplier Qualification’? • Recent observations are summarized in this report by ECA Academy (21/01/2015), Areas of attention: • Accuracy and completeness of administrative documentation • Evidence to justify excipient and supplier qualification • Risk-assessment and effective integration within in QMS • Quality agreements • Going forward, I envision a need to emphasize a life- cycle approach (e.g., linking to CAPA, change control) 3/12/2015 Ajaz S. Hussain, Ph.D. 17
  18. 18. FDA’s Inactive Ingredient Database - status? • Substance Registration System (SRS) • Generic listing vs. Specific Grade listing for commonly used excipients – max. precedent levels • Listing of Mixtures? • The UNII code confusing, the National Library of Medicine yet to finalize standards for assigning UNII codes for polymers • Individual Grades vs. Family Data • Legal status of the IID, and FDA communications of changes to the IID • DMF Implications • Impact on ANDAs – ‘Delays’ & ‘Refuse to File Letters’ 3/12/2015 Ajaz S. Hussain, Ph.D. 18
  19. 19. 3/12/2015 Ajaz S. Hussain, Ph.D. 19 Inactive Ingredients’ to ‘Excipients’ to ‘Functionality’ Where are we in this journey?‘ Status of ‘Substances In Regulatory Practice’ Clearly we need a global database with improved precision and accuracy of naming (and coding) to identify, describe, compare and link (to products and AERs) INDs, NDAs, BLAs, CFR’s; Orphan Drug Applications Products that Contain Each Substance Pharmacological Classification Active Moieties, Related Moieties and Salts LADMER Metabolites Metabolic Enzymes, Transporters, and Effects Drug target (therapeutic and other), type of interaction Solubility and Permeability (BCS) Protein Binding Impurities and Related Substance ISO 11238 (ISO IDMP), some challenges Both substances & specified substances Implementation in EU; EMA Task force Global Ingredients Archive System (GInAS)
  20. 20. 3/12/2015 Ajaz S. Hussain, Ph.D. 20 The War Against Fake Medicines, Update on FDASIA- Guidance and Impact on Excipient Suppliers and Users, QbD Sampling Guidelines, The NSF/IPEC/ANSI 363 2014 GMP standards explained, Good Supply Practices – Using Cross Industry Knowledge to Devise Pragmatic Solutions, Impact of Non-harmonized Standards and What is Needed to Achieve Harmonization, Advancements in the Question Based Review approach and various other excipient specific related topics, An Overview of the FDA OGD IID EWG activities, Effective Sourcing and Purchasing of Excipients, Industry Collaboration for Science Based Implementation of Elemental Impurities, Challenges And Opportunities In Developing And Modernizing Public Standards For NF Excipients Monographs For Regulated Drug Products Marketed In The USA, Future Pharma Manufacturing Efficiencies and the Role of Innovative Excipient Technologies. IPEC ExcipientFest 2015 Current Hot Topics @ ExcipientFest on 28-29 April 2015 in Washington
  21. 21. 3/12/2015 Ajaz S. Hussain, Ph.D. 21 The War Against Fake Medicines, Update on FDASIA- Guidance and Impact on Excipient Suppliers and Users, QbD Sampling Guidelines, The NSF/IPEC/ANSI 363 2014 GMP standards explained, Good Supply Practices – Using Cross Industry Knowledge to Devise Pragmatic Solutions, Impact of Non-harmonized Standards and What is Needed to Achieve Harmonization, Advancements in the Question Based Review approach and various other excipient specific related topics, An Overview of the FDA OGD IID EWG activities, Effective Sourcing and Purchasing of Excipients, Industry Collaboration for Science Based Implementation of Elemental Impurities, Challenges And Opportunities In Developing And Modernizing Public Standards For NF Excipients Monographs For Regulated Drug Products Marketed In The USA, Future Pharma Manufacturing Efficiencies and the Role of Innovative Excipient Technologies. IPEC ExcipientFest 2015 Inspectional trends in data integrity (Bangalore, Nov 2014) 22(d) 192 100(a) 160(b) 110(a) 67(b) 68(a) 25(a) 67(a) 100(b) Recurring 483 Observations: Top 10 22(d) 192 100(a) 160(b) 110(a) 67(b) 68(a) 25(a) 67(a) 100(b) Jeff Medwid NIPTE-FDA Conference 13 June 2012 International Society for Pharmaceutical Engineering (ISPE), in conjunction with McKinsey & Co., will release preliminary data and findings from its Quality Metrics Pilot Program at the ISPE Quality Metrics Summit on April 21–22 in Baltimore FDA Launches New Drug Quality Office, With Goal of Improving the Pharmaceutical Industry Posted 13 January 2015By Alexander Gaffney, RAC FDA’s New Pharma Quality Office Will Take a Team Approach: Yu Explains Regulatory Recon: Investigations Find Major Quality Problems at Indian Pharma Companies (3 December 2014) Posted 03 December 2014By Alexander Gaffney, RAC Currently the environment is complex, there is high uncertainty Don’tforgetfunctionality ofexcipientsisimportant!
  22. 22. 3/12/2015 Ajaz S. Hussain, Ph.D. 22 Need for urgent progress: ‘Inactive Ingredients’ to ‘Excipients’ to ‘Functional Excipients’ Importance of assuring quality and controlling variability of excipients, including their ‘functionality’, has long been recognized • Increasing complexity of drugs, their delivery, and failure modes • Patient (e.g., pediatric) relevant failure modes • Simple generics to complex generics & biosimilars Urgent need to address gaps in the FDA’s Inactive Ingredient Database
  23. 23. 3/12/2015 Ajaz S. Hussain, Ph.D. 23 Trends: Lab & Manufacturing “Deletion of Data” “Testing Into Compliance” “BMR manipulation is a slippery slope” “Suggestive of faulty manufacturing process or practices, even if this is not the case” “It is top management’s responsibility to ensure the training program is robust and effective!” Inspectional trends in data integrity (Bangalore, Nov 13 2014 - Nov 14 2014) Growing concern @ some companies “data looks too good to be true”
  24. 24. 3/12/2015 Ajaz S. Hussain, Ph.D. 24 GMP Compliance & Remediation Jeff Medwid NIPTE-FDA Conference 13 June 2012 QbD & QbR: Clarity on Critical Functionality FDA’s New Pharma Quality Office Will Take a Team Approach: Yu Explains Carmelo Rosa, M.S., Psy.D. November 2014 Urgent Need & Opportunity: To align & ensure sound scientific basis of these critical regulatory decisions
  25. 25. FDA CDER OPQ Plans for Surveillance of Pharmaceutical Quality Teresa Mullin, Ph.D. December 2014 3/12/2015 Ajaz S. Hussain, Ph.D. 25
  26. 26. Need for a comprehensive (excipient) knowledge base Teresa Mullin, Ph.D. December 2014 3/12/2015 Ajaz S. Hussain, Ph.D. 26
  27. 27. Why attention to (excipient) knowledge management is critical Specifically for physical attributes, functionality, performance 3/12/2015 Ajaz S. Hussain, Ph.D. 27
  28. 28. 3/12/2015 Ajaz S. Hussain, Ph.D. 28 Today there are several product categories (e.g., controlled release, inhalation products, DPI’s, topical, transdermal, liposomal products, etc.,) which requires an exquisite control of complex physical material and product attributes (functionality) Many of our current measurement systems need improvement We depend on these to ensure control of lot-lot variability Measurement system capability must be confirmed to be able to assess process capability (calibration & Gauge R&R) Life-cycle approach to quality; continued process verification (FDA’s Process Validation, 2011) is a safety net. Supplier & Excipient Qualification & Process Validation
  29. 29. Measurement System Analysis • From ‘calibration’ to ‘Gauge R&R’ Particularly for physical attributes; destructive analysis • Many (including regulators) have not yet understood its importance Gauge R&R well established but not commonly practiced • Measurement system in a state of control; effective CAPA, quality metrics, Culture of Quality With the move towards Statistical Process Control • Demonstrate equivalent in vitro performance; more exacting criteria Development of complex generic products (ER, Injectable, Inhalation, etc.) 3/12/2015 Ajaz S. Hussain, Ph.D. 29
  30. 30. Process Validation (2011), Statistical Confidence, Continued Process Verification… 3/12/2015 Ajaz S. Hussain, Ph.D. 30 http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004 (accessed 6 December 2014)
  31. 31. 3/12/2015 Ajaz S. Hussain, Ph.D. 31 Supplier & Excipient Qualification & CAPA Out of Specification events are difficult to resolve Excipient functionality can be a significant contributing factor Sometimes, reluctantly, have to settle with - “Root cause unknown 600 days* *I have inserted the “600 days’, on the figure – this is based on cases I have seen while at FDA)
  32. 32. 3/12/2015 Ajaz S. Hussain, Ph.D. 32 Prevention of OOS and Effective CAPA needs a focus on critical functional attributes Out of Specification events are difficult to resolve Excipient functionality can be a significant contributing factor Sometimes, reluctantly, have to settle with - “Root cause unknown
  33. 33. Compendial standards and manufacturing 3/12/2015 Ajaz S. Hussain, Ph.D. 33
  34. 34. Practice, Control, Process: Maturity Initial • Unpredictable Managed • Characterized, but reactive Defined • Characterized; proactive Measured & Controlled • In control Optimizing • Focus on improvement 3/12/2015 Ajaz S. Hussain, Ph.D. 34 Capability Maturity Model Integration; Carnegie Mellon University A validated process?
  35. 35. Maturity Level & Assurance of Quality Managed Characterized, but reactive High perceived risk of ‘Cheating by Design’ “Trial Injections” “Testing in to Compliance” Defined Characterized; proactive Lower level of assurance Stopping & Correcting Batch Rejection Measured & Controlled In control Quality by Design Quality Assured Improvement Opportunities 3/12/2015 Ajaz S. Hussain, Ph.D. 35
  36. 36. At the individual level, in QC function– how often does this occur? 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! 3/12/2015 Ajaz S. Hussain, Ph.D. 36 “Testing into compliance” In general – low empowerment is a significant challenge (low perceived behavioral control); plus reasons to rationalize….
  37. 37. Excipient Functionality: Can be critical for safety, efficacy and quality 3/12/2015 Ajaz S. Hussain, Ph.D. 37 July 15, 2005 FDA Public Health Advisory: Safety Warnings Regarding Use of Fentanyl Transdermal (Skin) Patches.
  38. 38. A pattern of failure: Pharmaceutical Equivalence by Design? (2004) 3/12/2015 Ajaz S. Hussain, Ph.D. 38 http://www.nihs.go.jp/drug/PhForum/documents041122/Hussain041122.pdf
  39. 39. An attempt to correct 3/12/2015 Ajaz S. Hussain, Ph.D. 39 http://ipecamericas.org/system/files/KeyNoteEF13May11LawrenceYu(FDA).pdf
  40. 40. Recent challenges 3/12/2015 Ajaz S. Hussain, Ph.D. 40 TheVoiceoftheAmerican PsychiatricAssociationandthe PsychiatricCommunity Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy (OCTOBER 24, 2014) • “most patients” is not the same as“ all patients,” and whether the 24 to 36 normal subjects used in the agency's bioequivalency tests represents the full range of individual variation in the way drugs are absorbed across the pharmaceutical using population is uncertain • Individuals can sometimes be allergic and react differently to whatever substance goes into making up the capsule or the tablet FDA Flags Generic Versions of ADHD Medication (NOVEMBER 14, 2014) • FDA changed the therapeutic equivalence (TE) rating from AB to BX—meaning that the products are still approved and can be prescribed, but are no longer recommended as automatic substitutes
  41. 41. RLD Variability: Can be a block-buster opportunity Focus on ‘control strategy’ • Overcoming CP & IP; provide FDA a submission they need to address CP • Then begin with QTPP; CQA’s, … skip ‘design space’ and focus on ‘control strategy • The entire development team should read the complete package insert of RLD • Discuss to ensure a common understanding • Failure modes & intended use • Pharmaceutical Equivalence • Bioequivalence • Other studies QbD Challenges 3/12/2015 Ajaz S. Hussain, Ph.D. 41 New Regulators are not prepared to handle QbD applications New Misalignment of international regulatory authorities New and Generics R&D incentivized for ‘shots on the goal’; not QbD Generics Lack of belief in business case – ‘Generics are all about file first; figure out later’ Biologics Lack of technology to execute Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
  42. 42. Summary • Excipient functionality can contribute in critical ways to product quality & performance; adequate control is necessary • Our databases, tools, and knowledge are lagging behind the rapidly increasing complexity and uncertainty • Risk to quality and to business is increasing and regulatory transitions pose additional difficulties • Effective knowledge management – IT and Human practices – is critical for organizational ‘bottom-line’ • We all must come together, collaboratively, to address the urgent needs; we owe it to the patients we serve 3/12/2015 Ajaz S. Hussain, Ph.D. 42
  43. 43. Knowledge Management & Culture of Quality Ajaz S. Hussain, Ph.D. Insight, Advice & Solutions LLC Maryland, USA Executive Director, the National Institute for Pharmaceutical Technology & Education 3/12/2015 Ajaz S. Hussain, Ph.D. 43
  44. 44. 3/12/2015 Ajaz S. Hussain, Ph.D. 44 Life-cycle approach needed for knowledge management Investigational Products cGMPs Development Technology Transfer Commercial Manufacturing Discontinuation Management Responsibility Process Performance & Product Quality Monitoring System CAPA, Change Management, Management Review PQS Elements Knowledge Management Quality Risk ManagementEnablers ICH Q10: KM is a systematic approach to acquiring, analyzing, storing and disseminating information related to products, manufacturing processes and components. Based on ICH Q10
  45. 45. “we can be blind to the obvious, and we are also blind to our blindness.” Daniel Kahneman, Thinking, Fast and Slow 3/14/2015 Ajaz@ajazhussain.com 45 http://web.mit.edu/persci/people/adelson/checkershadow_proof.html
  46. 46. 3/12/2015 Ajaz S. Hussain, Ph.D. 46 1938 The Federal Food, Drug, and Cosmetic (FDC) • 1937 Elixir of Sulfanilamide 1962 Kefauver-Harris Drug Amendments • 1962 Thalidomide • 1960 Color Additive Amendment • 1958 Food Additives Amendment; GRAS • 1960 Color Additive Amendment • 1958 Food Additives Amendment; GRAS 1992 Generic Drug Enforcement Act •1989 L-Tryptophan • 1989: Generic Drug Scandal • 1988 Food and Drug Administration Act • 1984 Fines Enhancement Laws; Drug Price Competition and Patent Term Restoration Act 2012 Food and Drug Administration Safety and Innovation Act (FDASIA). • 2007: Heparin Disaster 2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) Drug Quality and Security Act. • 2012: The Deadly Meningitis Outbreak Past 70 years: 1937 – 2007; The diethylene glycol (DEG) narrative
  47. 47. 3/12/2015 Ajaz S. Hussain, Ph.D. 47 0 5 10 15 20 25 30 35 Years DEG: Years since the previous incident 0 50 100 150 200 250 300 350 Number of Reported Deaths 1937:ElixirofSulfanilamide 2007:Tootpastecontamination 0 70 years 0 70 years Frequent reports Mumbai Mumbai Data from Excipient Fest Janeen Skutnik Chair –IPECAmericas 2009 Past 70+ years: DEG contamination or economically motivated adulteration
  48. 48. 3/12/2015 Ajaz S. Hussain, Ph.D. 48 Reported cases underestimate the real tragedy; rapid intervention may not occur ! Epidemic of Pediatric Deaths From Acute Renal Failure Caused by Diethylene Glycol Poisoning. JAMA. 1998;279(15):1175-1180. doi:10.1001/jama.279.15.1175 Month of hospital admission for children with acute renal failure, Haiti October 1995-October 1996. Diethylene glycol poisoning in Gurgaon, India, 1998 Bulletin of the World Health Organization, 2001, 79: 88–95. We report a second episode of poisoning occurring in 1998 in India as a result of children ingesting diethylene glycol; at least 33 children are known to have died. At the beginning of the investigation we never imagined that contaminated medicine was causing acute renal failure in children. A brand of cough expectorant manufactured by a local pharmaceutical company was found by the Central Drugs Laboratory, Calcutta, to contain 17.5% (v/v) diethylene glycol. The district and state drug controller had tested many samples using thin layer chromatography before a sample of medicine tested positive for diethylene glycol at the Central Drugs Laboratory. None of the earlier samples was found to be contaminated.
  49. 49. 3/12/2015 Ajaz S. Hussain, Ph.D. 49 Guidance for Industry Testing of Glycerin for Diethylene Glycol CDER May 2007 Compliance 1. Manufacturers did not perform full identity testing on the glycerin raw material, including tests to quantify the amount of DEG 2. Relied on the certificate of analysis (COA) 3. The origin of the glycerin was not easily apparent from the COA. 4. The COA was often a copy of a COA on the letterhead of the distributor 5. The chain of custody or distribution history of the glycerin was also not readily known USP Glycerin Monograph Type of Posting: Revision Bulletin Posting Date: 04–Feb–2009 Official Date: 01–May–2009 Because of the serious hazards associated with…., and in response to recommendations set forth in the FDA Guidance for Industry, "Testing of Glycerin for Diethylene Glycol" published in May 2007, USP has revised the USP Glycerin monograph.. Because diethylene glycol and ethylene glycol are considered unacceptable toxic substances, the testing of USP Glycerin should demonstrate the absence of these substances. April 2007: FDA request to USP to revise the Glycerin monograph’s IDENTIFICATION section. Revision includes: adding – Identification test B. LIMIT OF DIETHYLENE GLYCOLAND ETHYLENE GLYCOL to detect and quantify DEG/EG in Glycerin. − Is no longer part of the impurity testing, “Limit of DEG and Related Compounds”. − Introduces a capillary gas-chromatographic (GC) method with flame ionization detection (FID). − Limit of NMT 0.10% each for diethylene glycol and ethylene glycol is found. 70+ years to get here; how difficult will it be to change habits such as ‘blind reliance of COA’?
  50. 50. 3/12/2015 Ajaz S. Hussain, Ph.D. 50 Personality and Habitual Frame Biases Myers Brigs: ENTJ (first tested at FDA) S TF Expanded frame, future possibilities objective, ‘cause and effect’ Expanded frame, future possibilities people and relationships. Narrow frame, the present, individuals and relationships. Narrow frame, the present, objective, cause and effect. N Based on Stanford Webinar - How to Overcome the Top 3 MegaBiases in Decision-Making Stanford University’s Strategic Decision and Risk Management certificate program From Mapping a Manager's Brain on Incentives Social influences Relative thinking Uncertainty Complexity
  51. 51. By Design: Intention to act consciously • In the interest of patients, and to continually improve this ability • To provide a healing touch – one life at a time, in what we do, and how we do it. 12/9/2014 Ajaz@ajazhussain.com 51 Consciously Scientific methodology Engineering Design Plan-Do-Check-Act Subconsciously 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) 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
  52. 52. What does it take to come out of the cGMP crisis? Persuasive demonstration of: (1) Ability to face facts (2) Legal & regulatory requirements, 3) Systems approach to quality, 4) Changing behavior & culture What is often missed or is unconvincing is how you will strengthen culture of quality. “Let one who wants to move and convince others, first be convinced and moved themselves.” Thomas Carlyle Signals that question the competence, motivation, and/or integrity of company personnel Do not defend the plainly indefensible; it adds further serious credibility costs 3/14/2015 Ajaz@ajazhussain.com 52
  53. 53. Quality is everyone's responsibility Lack of knowledge... that is the problem. If you do not know how to ask the right question, you discover nothing. If you can't describe what you are doing as a process, you don't know what you're doing. Rational behavior requires theory. Reactive behavior requires only reflex action. Whenever there is fear, you will get wrong figures. 3/14/2015 Ajaz@ajazhussain.com 53 Selected quotes, W. Edwards Deming
  54. 54. 3/14/2015 Ajaz@ajazhussain.com 54 Organization (Policies & Sr. Mgmt.) Technology (Constraints & Controls) Individual (Training & Certification) Team & Supervisor (Soft Defenses) Defenses (Quality Management System) Error Latent अप्रकट conditions Goal conflicts & mixed messages Design flaws Production pressures Fear of error “WE CANNOT CHANGE THE HUMAN CONDITION. BUT…WE CAN CHANGE THE CONDITIONS UNDER WHICH HUMANS WORK” JAMES REASON
  55. 55. Disregard to Malice? 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 55 “….records not completed contemporaneously” “…observed analyst back-date logbooks” “…trial injections…..” “…results failing specifications are retested until acceptable results are obtained….” “…over-writing electronic raw data…..” “…OOS not investigates per XYZ SOP” “…appropriate controls not established….” Each additional observation adds reasons to confirm that this is very likely a system with intentional ‘holes’ in its defenses.
  56. 56. Preconditions Rationalization & Attitude Pressure & Incentive Opportunity – ‘holes in the QMS” 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 56
  57. 57. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 57 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)
  58. 58. Heparin tragedy 2007 and 2008 FDA reports 149 deaths with allergic or hypersensitivity symptoms during that period • Contaminated heparin from China QC Testing • Initial testing failed to detect the contaminant Pharmacovigilence • Signals in the pharmacovigilence systems responded slowly and Eventually, the severity of reactions associated made it likely that the contamination would be detected • too late for those who died or were injured 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 58
  59. 59. Congressman Shimkus: When the drug safety system fails, people get sick. Some die. • Some of these people are already very vulnerable, and proving the cause of harm from impurities, adulteration, and counterfeits can be elusive. It is hard to detect harm • Certainly the companies are obligated to ensure a culture of quality and maintain vigilance as well. This reflects a systems approach to safety. FDA inspectors look for a culture of quality at manufacturing facilities. • FDA policies led to the failure to inspect the Chinese plant. This system approach wasn't at play here. • While it doesn't deny the counterfeit source, tries to say that counterfeits didn't cause the reaction, as if the adulteration itself was no big deal. Is this an acceptable mindset? ………. This brings me to China and its quality culture or lack thereof. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 59 ONE HUNDRED TENTH CONGRESS SECOND SESSION. APRIL 29, 2008. Serial No. 110-109
  60. 60. 21 CFR PART 211: SUBPARTS - Deviations signal gaps in CoQ •GENERAL PROVISIONSA •ORGANIZATION AND PERSONNELB •BUILDINGS AND FACILITIESC •EQUIPMENTD •CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURESE •PRODUCTION AND PROCESS CONTROLSF •PACKAGING AND LABELING CONTROLG •HOLDING AND DISTRIBUTIONH •LABORATORY CONTROLSI 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 60 For example the combination….
  61. 61. The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012) • 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 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 61
  62. 62. CoQ: How? •What are the predictors of CoQ? CoQ Manifests by Design - ‘quality by design’ the foundation •1, 2, 3When do people change their behaviors? •A, B, C, D (any body can dance)What makes a QMS effective? •X, Y, ZWhen proactive compliance occurs? 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 62
  63. 63. Going beyond rules pays.. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 63
  64. 64. Human behavior: Connecting the Dots; With the Right Connectors GXPs – rational behaviors How proactive compliance is achieved? X, Y, Z Quality Management System What makes a QMS reliable? A, B, C, D Culture of Quality Why people change their behavior: 1, 2, 3 Human Behaviors Beyond GXPs Predictors of Culture of Quality Why, What, and How of Culture of Quality? 9/19/2014 © Ajaz S. Hussain | INSIGHT, ADVICE & SOLUTIONS LLC 64
  65. 65. Predictors of CoQ Act consciously in the interest of patients – when no one is looking. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 65 Only four attributes actually predict a culture of quality: Leadership Emphasis Message Credibility Peer Involvement Employee Empower-ment People will change their behavior if they see the new behavior as Normal (1) Rewarding (2) Easy (3)
  66. 66. Dr. W. Edwards Deming’s - “Out of the crisis” 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 66 The journey requires leadership with Profound Knowledge as a guide. • As leaders responsible for system change, top management is most in need of profound knowledge • Quality is often determined in the boardroom. • Problems arise when management reacts to common cause or chance variation as if it were special cause variation • Prediction based in theory provides a foundation for planning a course of action. Plan – Do – Check – Act • The leader serves the people with clear vision and guidance to empower them. To be empowered is to share ownership in the identity • Giving people a certain degree of control over their work fulfills the need for freedom and provides opportunity for taking joy in work
  67. 67. Profound Knowledge as a guide 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 67 Appreciation for a System Theory of Knowledge Knowledge about Variation Human Behavior - Psychology of Change A B C D+
  68. 68. Systems Approach for Error/Deviation Management 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 68 Organization (Policies & Sr. Mgmt.) Technology (Constraints & Controls) Individual (Training & Certification) Team & Supervisor (Soft Defenses) Defenses (Quality Management System) Error Latent अप्रकट conditions Goal conflicts & mixed messages Design flaws Production pressures Fear of error Human error: models and management. J. Reason. BMJ. 320: 768–770 (2000). D+
  69. 69. Culture of Error Management प्रबंधन • Error strain • Covering up Fear of Errors • Anticipation • Risk taking Awareness • Development QbD/RFT • Error detection, Communication • Analyzing errors, Correction Mastery orientation 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 69
  70. 70. Dots & Connections 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 70 CoQ 1 2 3 QMS A B C D GXP Behaviors X Y Z
  71. 71. 3/14/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 71 Culture of Quality Normal Rewarding Easy QMS System Knowledge Variation Behavior Behavior - GXPs Fear Removed Mastery Awareness Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CoQ Connect to GXPs A Framework and a Tool (for gap analysis)

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