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Pharmaceutical Quality by Design Travel Options Keynote @ Patheon QbD 2016

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Emergency: “No-pain No-gain”
Standard: “Plan Do Check & Act”
Pathfinders: B1: “Don’t Use & Don’t Tell”; no more!
B2: Every vertex can be a Tipping Point
G1: Same and Similar
G2: Synthesis & Analysis

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Pharmaceutical Quality by Design Travel Options Keynote @ Patheon QbD 2016

  1. 1. Pharmaceutical Quality by Design: Travel Itineraries Ajaz S. Hussain, Ph.D. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1 Quality by Design Moving to Next Generations September 7th - 8th 2016 Patheon-Greenville Keynote Address
  2. 2. Travel Itineraries Emergency • “No-pain No-gain” Standard • “Plan Do Check & Act” Pathfinders • B1: “Don’t Use & Don’t Tell”; no more! • B2: Every vertex can be a Tipping Point • G1: Same and Similar • G2: Synthesis & Analysis 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 2 Culture of Pharmaceutical Quality
  3. 3. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 3 QbD Travel itineraries: 2015 – 2006-2015…? History: FDA Packages: 2002-2005 Ajaz S. Hussain. FDA ACPS Meeting, 8 May 2002 Pharmaceutical Quality by Design: Review of Progress and Challenges (2012) QbR to QbD to CPV 16 February 2015 Reorganization at FDA; Office of Pharmaceutical Quality CDER/FDA; Emphasis on One Quality Voice . CGMP Alarm bells – ringing again! FDA Draft Guidance: Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry (December 2015)
  4. 4. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 4 QbD Travel Itineraries Emergency Travel Itinerary Continued Process Verification for all commercial products with statistical confidence, effective QMS and CAPA Prevent a Warning Letter Standard Travel Itinerary Confident adoption of PAT, ICH Q8-11 and PV 2011. Emphasis on patient- related failure modes and justification for scale-up and manufacturability (in submissions). Optional comparably protocol for anticipated PAS changes. Pathfinder Option Rapid and/or more confident development with continuous and/or real-time release & (optional) comparability protocol for anticipated changes. First Traditional and Complex Generic with new technology 1 2 3 G1 G2 B1 B2
  5. 5. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 5 Pathfinders “Don’tUse&Don’tTell” nomore! B1 Ray Scherzer ‘s challenge to Pharma: Quality By Design!
  6. 6. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 6 Pathfinders EveryvertexcanbeaTippingPoint! B1 Remembering Einstein’s challenge that we will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today!
  7. 7. G2: A Destination Reached in 2016 Synthesis & Analysis Disputing a 8 year ANDA review! Totality of Evidence The clinical endpoint BE unacceptable - API particle size/shape and manufacturing process control the root cause! FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 7 “.. a first in OGD history” To create a Win-Win-Win! “.. a first in OGD history”
  8. 8. Alarm Bells are Ringing, Again! Generic Drug Scandal Office of Pharmaceutical Science 20th Century to 21st Century Desired State SUPAC to Design Space Rapid Globalization and FDASIA Breaches in Data Integrity Office Pharmaceutical Quality One Quality Voice 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 8 ..a lot going on underneath..
  9. 9. “we can be blind to the obvious, and we are also blind to our blindness.” ― Daniel Kahneman, Thinking, Fast and Slow 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 9 Unaccounted Cognitive Biases & Many reasons to rationalize away dissonance
  10. 10. What is Culture of Pharmaceutical Quality?  We make two products – medicinal product and linked evidence of its quality, safety and efficacy  Both, required by law, to be better than Placebo!  FD&C Act & CGMP regulations – quality cannot be tested into products; it has to be built-in by design! (1987 PV Guidance)  Intention determines the punishment under the law  By Design is by intention to established a Plan-Do-Check-Act Practice 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 10
  11. 11. Integrating Big Ideas Fisher, Shewhart, Deming, Kegan, Kahneman,.. Practicing: Looking Good, Being Good, Doing Good? 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 11 Epistemology essential in human development (Orders of Consciousness) and for overcoming Immunity to Change (Professor Kegan) Our procrustean behavior driven by our cognitive biases and blind spots! [Behavioral Economics, Kahneman & others]
  12. 12. Testing to Document QualityVsQbD Order of Consciousness and approach to SOP’s, education, training experience, supervisory oversight, etc. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 12
  13. 13. Need to reduce variance & skewness in the distributed understanding of pharmaceutical quality & risk to patients 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 13 Elephant in the dark or men with blindfolds on? ExpressPharma16May2016 A 21st Century Fable about Pharmaceutical Quality and Preventing a Clash of Cultures
  14. 14. CPQ: Founded on Quality by Design  We do our best to develop medicines and the evidence needed to satisfy the needs of patients – we develop these products consciously, recognizing that quality cannot be tested into our products .  We know that nothing is perfect and there will be some errors in our design, systems and procedures, or we may make mistakes in following set procedures.  It is normal, easy and rewarding to work within our quality management system, without fear, to detect, correct and to learn from our mistakes.  In doing so we act consciously in the interest of patients – especially when no one else is looking, and we continually improve our quality by design and aim for right first time. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 14
  15. 15. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 15 Framework: Culture of Pharmaceutical Quality (CPQ) Culture – Pharma Quality Quality is Normal Quality is Easy Quality is Rewarding System- QMS Appreciate System Theory of Knowledge Knowledge ofVariation Psychology of Change Practices- GXPs Fear Removed Mastery Awareness Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment Connect to CultureConnect to Practice Quality by Design
  16. 16. ..a lot going on underneath.. FDASIA New Office of Product Quality @ CDER/FDA “One Quality Voice” Will these changes get to the root- cause? 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 16 Latent factors and a globalized supply chain… Variance and skewness of latent factors
  17. 17. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 17 Mentalmodels…. Thinking about “Not of One Mind” to “One Quality Voice” (OPQ/CDER/FDA2016) I believe this is a good model for Confident Quality Assurance. While I was at FDA. After FDA Inspection (e.g.,, Breach in Data Integrity) Current model. Risk of toppling? Risk of toppling?
  18. 18. 6 Observations (Form 483)  Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit  Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed  Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product  The accuracy, specificity, and reproducibility of test methods have not been established . . .  Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .  Laboratory records do not include complete data . . . 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 18 Will the pyramid topple? What will prevent a Warning Letter? December 2013; US Facility
  19. 19. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 19 How to respond to these Observation? 483 Observation # 3 relates to process which delivers products to patients.  Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.  A. Process Validation Protocols for My Head Aches Capsules, 1 mg lack acceptance criteria. For example: In MyPV420 – Process Validation Protocol for My Head Aches Intermediate Delayed-Release Pellets (0.X%) lack acceptance criteria for Blend Uniformity from drums, particle size and Dissolution.  B. There is no data to support the critical process parameter ranges of the My Favorite Fluid Bed Dryer in the current/proposed commercial batch production record A1234 for My Head Aches Intermediate Delayed-Release Pellets for the following:  • Inlet Air Temperature: XX-YY C  • Inlet Air Volume: XXX- YYYY m³/h  • Microclimate Pressure: XX- YYY mbar  • Dynamic Filter Pres. Max.: X-Y bar  • Dynamic filter Pres. Min.: X -Y bar  • Dynamic filter Time: X-YY seconds  • Spray Air Pressure: X-Y bar To be Commercialized & Commercial Products Development or validation reports contain no data supporting identification of critical process parameters and their ranges. Key focus: Process Validation Guidance 2011.
  20. 20. Each observation should be addressed specifically & comprehensively Process capability roadmap a central theme (for all products at the facility) Plus – how are CQA’s linked to PPs; what are CPPs’ and range for controlling? How other observation impact/interact informs the methodology and sequence of work products Process Capability Roadmap  Measurement system capable for all QA’s & PPs?  Is the process stable for all CQA’s?  What can we do to address special causes we will observe?  Are the processes capable?  Plus +++ 483 Observations  Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit  Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed  Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product  The accuracy, specificity, and reproducibility of test methods have not been established . . .  Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .  Laboratory records do not include complete data . . . 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 20
  21. 21. © Light Pharma Process Capability: If you can’t measure it, you can’t improve it Process Capability Roadmap: 1 Has Measurement System capability been verified? STOP! Do not compute Proc. Cap. statistics. Improve the Meas. System. No 2 Is the process stable or unstable via SPC? Yes STOP! Do not compute Proc. Cap. statistics. Investigate special causes. Improve process stability. 3 Is the data normal “enough” via the Normality Test? STOP! Transform data. No 4 Compute Cpk Yes Unstable Stable 0 Challenge Specs! p-value < 0.05 p-value > 0.05 Gage R&R & Calibration SPC Charts Scott Tarpley, UK Arden House 2004 Roadmap to process capability? Challenge specs Measurement system capability for all CQA’s (including dissolution test)? Is the process stable for all CQA’s? What can we do to address special causes we will observe? Are the processes capable? Plus – what is the link between CQA’s & PPs; what are CPPs’ and range for controlling? 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 21 Scott conducted a training program (2004) at FDA for the PAT Team. This slide is from my talk at a USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004.
  22. 22. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 22 Assess impact on CQAs for all process stages and parameters (Science, Product History, Investigations, Complaints) Conduct statistical analyses on all process parameters comparing PV batches and current batches Difference between PV and Current Batches? Identify potential impact of process parameter on CQA Low/High Or Not Applicable Calculate Process Capability for CQA(s) that may be impacted Ppk > 1.3 ? Identify Set-point, Set- point range and Operating Range using existing supporting data Prepare and Approve Process Parameter Summary Report Update Master Batch Record with new ranges YES YES Further evaluation required N/A Low/High NO NO 2 1 3 4 Should we take this path? Initial decision tree: Validation batches Vs Current? To be commercialized vs. products in commerce? Current PPs, set-points, ranges – supporting data? Equipment Qualification Ranges Vs. Process set-points and ranges? Analytical method validation & capability? Data in PD Reports, Validation Reports, SOP’s, BMRs,……? Deviations, Complaints, CAPA? What are the most important questions? What assumptions can we accept/justify? How precise do our answers need to be?
  23. 23. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 23 BMRSOPs Validation Reports CQAs, PPs & CMA’s 30-60 consecutive batches ComplaintsCAPA Database ready for statistical analysis METHADOLOGY [ASTM E2709 & E2281] Manual input Manual input Questions AssumptionsPrecision STATISTICAL METHADOLOGY2 Scientific Impact Assessment (Structured/protocol based FMEA) 3
  24. 24. System wide CAPA Although the other 5 observations posed significant challenge – interconnections; it is a system! An integrated Statistical Assessment & Scientific Impact Analysis provided a way forward System wide implementation - an integrated adoption of PAT, ICH Q8-11 and PV 2011! 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 24
  25. 25. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 25 “No Pain No Gain” the name is justified! 1 2 3 What will you choose (or have already chosen)? “Travel with Family” “No-pain No- gain”
  26. 26. FDA current thinking: Question Based Review, Ppk & CPK Adapted from: “Using process capability to achieve product quality.” March/April 2015. Pharmaceutical Engineering. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 26 Process Capability Roadmap Patient Related Failure Modes
  27. 27. Patient Related Failure Modes & Totality of Evidence How is “clinically relevant evaluation of pharmaceutical equivalence” demonstrated? How will you demonstrate that “fewer risks are managed by BE study alone”? What additional steps are necessary to design a bioequivalence trial to complement equivalence in design and performance? 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 27 Future is upon us!
  28. 28. “No-painNo-gain”: 1 to 2 andthento3 or “Travelwith Family”:2 & 3 Whatwill you choose(or havealreadychosen)? Vertex or Tipping Point? Quality & Assurance  Our knowledge pyramid topples easily because it is an upside down pyramid for several reasons  Need to keep regulatory decisions close to observation or review to maintain objectivity (& thwart corruption)  Market failure and information asymmetry  Prevailing ontological and epistemological gaps Improving the system: One Quality Voice 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 28 US FDA is a large complex organization. How to turn a large ship? How to keep the knowledge pyramid from toppling so frequently? How to improve assurance the system delivers?
  29. 29. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 29 “Tipping point” Summary Review of Regulatory Action for Vertex’s NDA 206038: “Quality-by-Design (QBD) process for the development of the product, manufacturing process, and control strategy. A fully continuous drug product manufacturing process was applied to the manufacture of the product, which is a unique and a new process” “The pharmaceutical industry has been so slow to adopt .., but I think the time is now,” FDA Commissioner Margaret Hamburg said during a tour of Vertex’s new continuous manufacturing line in South Boston. WSJ 9/2/2015 What impact can FDA Commissioners’ comments, made in New England, have in FDA District Offices based in other regions? A unique and new process was utilized in an NDA submission! It also provided for a rapid Quality-by-Design development of product, manufacturing process and control strategy! These two aspects justify the label – Tipping point. Headquarters and Review Centers. Independence of District Offices from Review Centers is an important concept.
  30. 30. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 30 Martin VanTrieste, R. Ph. SVP Quality Amgen PIA Meeting – June 21, 2012 From an FDA Presentation: “FDA’s Evolving Approach to Pharmaceutical Quality” October 21, 2015 One of several ways C” in GGMP Emerges?
  31. 31. 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 31 The outcome from conducting a single USP test cannot be assumed for all the untested units in the batch Implementation of Process Validation 2011 progresses.
  32. 32. Summary Additional roadmap considerations  Target Product Profile (patient related failure modes)  QTPP – RLD CQA Characterization driven (statistical confidence)  ICH Q8 outlines a QbD methodology; don’t forget QbD is also the paradigm  Culture of Pharmaceutical Quality is founded on QbD Paradigm QbD @ Patheon  Quality assured for patients  Synthesis of knowledge by integrating analyses  Effective communication of Why with the clients and regulators  Patheon an important Integrator ; Pathfinder opportunity! 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 32
  33. 33. Thank you! 9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 33  Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Viktor E. Frankl  Between regulatory query and response there is Design Space. In that space is our comparability protocol… will be to arrive where we started and know the place for the first time. T. S. Eliot We shall not cease from exploration, and the end of all our exploring …….

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