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QbR to QbD to CPV 16 February 2015

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Question Based Development to Quality by Design to Continued Process Verification

Does your QbD program delivery confidence in CQA’s?

Does it reduce the risk of development failure?

Does it provide a process which is stable and ‘in control’?

Does it reduce risk of GMP noncompliance?

Are we asking the right question and at the right time?

Published in: Health & Medicine
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QbR to QbD to CPV 16 February 2015

  1. 1. Question Based Development to Quality by Design to Continued Process Verification Ajaz S. Hussain, Ph.D. Insight Advice & Solutions LLC National Institute for Pharmaceutical Technology & Education 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 1
  2. 2. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 2 Does your QbD program delivery confidence in CQA’s? Does it reduce the risk of development failure? Does it provide a process which is stable and ‘in control’? Does it reduce risk of GMP noncompliance?
  3. 3. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 3 Continuous Process Verification: An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8) Continuous Quality Verification (CQV) is described as an approach to process validation where manufacturing process (or supporting utility system) performance is continuously monitored, evaluated and adjusted as necessary”. (ASTM E2537-08) Continued Process Verification - a stage (Stage 3) of the Process Lifecycle, after Performance Qualification (FDA Process Validation 2011)
  4. 4. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 4 Stage 3 ― Continued Process Verification (FDA) ..continual assurance that the process remains in a state of control (the validated state) during commercial manufacture…PV Guidance 2011 An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.
  5. 5. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 5 21 CFR 211.180 “Firm must review, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures”
  6. 6. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 6 21 CFR 211.110a “Control procedures shall be established to monitor the output and to 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”
  7. 7. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 7 21 CFR 211.110a & 21 CFR 211.180 Expected trend in (2015?): 2016-18?
  8. 8. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 8 High risk at foreign facilities; Quality Unit ineffective  Breaches in assurance of data integrity; “Data too good to be true“ Effectiveness of CAPA and Complaint Resolution Sporadic & heterogeneous enforcement of CPV & Statistical Confidence [Pharmaceutical Equivalence challenges and high profile generic recalls ] Current Concerns 2015  CPV & Statistical Confidence – the “C“ in GMP  Ppk & Cpk linked to CAPA; Facility risk classification  Question based Review improved and integrated with Process Validation & CPV  “In Control“ the Engineering Perspective  Starting to realize the ‘Vision 2020’- “I can see clearly now” Continual Improvement a reality; CAPA is not continual improvement  “And so gradually over the next couple of years or so I think purchasers will become aware that they need to pay for reliability – just like we would do with a car." Dr. Janet Woodcock, Director Center for Drug Evaluation and Research, FDA (June 2013) 2016-18 2018-2020 OPQ Successful Pressureof Shortages Metrics&Risk Based GADUFA Challenges @ OGD OPQ Maturing Culture of Quality QbD QbR CPV Quality Metrics
  9. 9. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 9 Culture of Quality QbD QbR CPV Quality Metrics Are we asking the right question and at the right time?
  10. 10. Culture of Quality QbD QbR CPV Quality Metrics 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 10 Are we asking the right question and at the right time? Effective Date: 11/18/2014
  11. 11. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 11 CDER OPS MAPP 5015.10 (Selected Questions 14-17) • 14. What is the rationale for selecting this manufacturing process for the drug product? • 15. What is the potential risk of each process step to impact the drug product CQAs and how is the risk level justified? • 16. For each of the potentially high risk manufacturing unit operations: • a) What input material attributes and process parameters were selected for study and what are the justifications for the selection? • b) What process development studies were conducted? Provide a summary table listing batch size, process parameter ranges, equipment type and estimated use of capacity. • c) What process parameters and material attributes were identified as critical and how do they impact the drug product CQAs? • d) How were the process parameters adjusted across lab, pilot/registration and commercial scale? What are the justifications for any changes? • 17. If applicable, what online/at-line/in-line monitoring technologies are proposed for routine commercial production that allows for real-time process monitoring and control? Provide a summary of how each technology was developed.
  12. 12. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 12 http://www.raps.org/Regulatory-Focus/News/2015/01/13/21061/FDA-Launches-New-Drug-Quality-Office-With-Goal-of-Improving-the-Pharmaceutical-Industry/
  13. 13. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 13 Using Process Capability To Ensure Pharmaceutical Product Quality by Lawrence X. Yu, Daniel Y. Peng, Robert Lionberger, Alex Viehmann and Karthik Iyer This article introduces the definition and calculation of process capability, illustrates their use in the pharmaceutical industry, and describes the relationship of process capability with production batch failure rate. The use of process capability in product development, process scale up and qualification, and commercial production is also described.
  14. 14. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 14 Product & Process Design Process scale-up & Qualification Commercial Manufacturing Get the CQA’s right Ensure your process is well understood! Control (CMAs + CPPs) → CQA in Control Common & Special Causes, Control Strategy. Initial Ppk reasonable. Sable process on scale-up and in Operations. Why? Process Qualification Protocol with Confidence. What? Process Qualified with Confidence. How? Process “in control”; Cpk/Ppk monitoring & trending; reduced (traditional) testing. Process “not in control”; statistically meaningful testing; effective CAPA – identify and eliminate ‘special causes’; improve control strategy
  15. 15. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 15
  16. 16. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 16 This journey began decades ago….. Useful information on http://www.slideshare.net/a2zpharmsci
  17. 17. “And like the heroes of the French Revolution, we look to a future that will bring us everything or nothing, depending on the public trust”  The Nation Needs a Comprehensive Pharmaceutical Engineering Education and Research System  “A recent re-examination by the US Food and Drug Administration of the current pharmaceutical quality decision-making system raised fundamental questions about its efficiency and its continuing effectiveness to address the increasing complexity of pharmaceutical systems.”  “….low success rate for identifying the root cause of deviations and out-of-specification observations as well as the predominant focus on end-product testing—often based on an inadequate statistical consideration of inherent variability and static process conditions— which, some argue, evolved to facilitate regulatory document expectations for “process validation.” VIEWPOINT 2005 Pharmaceutical Technology SEPTEMBER 2005 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 17
  18. 18. “Generics is all about file first and figure out later” State of QbD Implementation Report to FDA June 2010, Ted Fuhr, Mckinsey& Company “It would also mean the FDA had no power to deny tentative approval to an application that clearly could never win final approval - an applicant could state in its ANDA that it planned to manufacture a generic drug in an outhouse behind the applicant's house using a child's chemistry set.“ U.S. District Judge Beryl Howell (March 11, 2015) 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 18 Generics need to be defended
  19. 19. Rationalization & Attitude Pressure & Incentive Opportunity – ‘holes in the QMS” “The key to good decision‐making is not knowledge, it is understanding. We are swimming in the former. We are desperately lacking in the latter” ‐ Malcolm Gladwell 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 19
  20. 20. Do these questions continue to linger in Company X? What is pharmaceutical quality? Compendial testing sufficient? Process validation – representative of commercial manufacturing? Any deviation from cGMP means the product is ‘adulterated’? 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 20
  21. 21. Practice, Control, Process: Maturity Initial • Unpredictable Managed • Characterized, but reactive Defined • Characterized; proactive Measured & Controlled • In control Optimizing • Focus on improvement 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 21 Capability Maturity Model Integration; Carnegie Mellon University A validated process?
  22. 22. Maturity Level & Assurance of Quality Managed Characterized, but reactive High 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 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 22
  23. 23. Risk of unintended or intended normative support for ‘testing into compliance’? 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 Documents not critical; Compendial testing sufficient Local regulators collect & test samples – no issue there! 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 23 “Testing into compliance”
  24. 24.  Systems thinking: System is the product of interacting parts; improving the parts taken separately will not improve the system CEO & Sr. Management Culture of Quality Managers & Leaders Effective QMS GXP Compliance All Employees Quality is Easy 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 24
  25. 25. 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 25 What will it take to ensure that your QbD program delivers (a) confidence in the CQA’s? (b) provides a ‘stable’ and ‘in control’ process? (c) reduces the risk of development failure? (d) reduce risk of GMP noncompliance?
  26. 26. To remain true to ‘first do no harm’ we, the legitimate pharmaceutical community, have inherited, and accepted, a culture of quality that demands that our intention, our awareness and our skills deliver ‘quality by design’ with continued vigilance to detect, correct and to prevent errors that have caused, or have the potential to cause, harm to the patients we serve. We also recognize the limitations of our pharmacovigilance. We must more clearly recognize that CAPA is not ‘continual improvement’ and that we must strengthen our culture of quality to deliver continual improvement in our ability to assure quality, reduce costs and enhance confidence in what we do. Ajaz S. Hussain, Ph.D., Mumbai, 24 March 2015 VIEWPOINT 2015 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 26
  27. 27. 9. Into a blind darkness they enter who follow after the Ignorance, they as if into a greater darkness who devote themselves to the Knowledge alone. 10. Other, verily, it is said, is that which comes by the Knowledge, other that which comes by the Ignorance; this is the lore we have received from the wise who revealed That to our understanding. 11. He who knows That as both in one, the Knowledge and the Ignorance, by the Ignorance crosses beyond death and by the Knowledge enjoys Immortality Isha Upanishad: Knowledge and Ignorance, Verses 9 – 11 VIDYA AND AVIDYA VOLUME 17 THE COMPLETE WORKS OF SRI AUROBINDO (2003) The problem of reductionism: - it works for small, not for big steps - it misses the whole - it misses the meaning - in the end, it undercuts itself. Systems approach…… Note. I have take a different point of view from that of Dharm P. S. Bhawuk, Science of Culture and Culture of Science: Worldview and Choice of Conceptual Models & Methodology. The Social Engineer. Vol. 11, No. 2, July, 2008. Practicing to improve (awareness of) our intentions is our wisdom tradition, and is reflected in our laws, in US, India and around the globe… 4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 27

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