Published on March 21, 2012
8th World Meeting on Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology 19th to 22nd March 2012, Istanbul, Turkey Pharmaceutical Quality by Design:A Personal Review of Progress and Challenges Ajaz S. Hussain, Ph.D. Current Affiliation: Chief Scientific Officer Philip Morris International R&D, Neuchatel, Switzerland 3/19/2012 Ajaz S. Hussain, Ph.D. 1
Reflections, a decade ago at FDA 3/19/2012 Ajaz S. Hussain, Ph.D. 2
Reflections, a decade ago at FDA OVERALL CYCLE TIMES: QC TESTING TIMES ARE SIGNIFICANT Overall Cycle Time Components 25 20 TIME 1 5 (D ays) 1 0 Pro ce s s Time s QC Te stin g Time s 5 0 A B C D E F PR OC ESS CASE STUD Y MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)•[PPT] Final Report on Process Analytical Technology and ... - FDA•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt•(Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001). 3/19/2012 Ajaz S. Hussain, Ph.D. 3
Reflections, a decade ago at FDA Pharmaceutical Manufacturing: Impact of Exceptions (Detailed Analysis of 2 Products) PERFORMANCE MEASURE VALUE • Average Cycle time 95 days • Std dev(Cycle time) > 100 days • Exceptions increase cycle time by > 50 % • Exceptions increase variability by > 100% • Capacity Utilization of “System” LOW NEED FOR FUNDAMENTAL TECHNOLOGY MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)•[PPT] Final Report on Process Analytical Technology and ... - FDA•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt•(Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001). 3/19/2012 Ajaz S. Hussain, Ph.D. 4
Reflections, a decade ago at FDA Pharma Manufacturing - Unmet Performance Expectations Utilisation levels - 15% or less (but low levels masked). Scrap and rework - we plan for 5-10% (accepted as necessary). Time to effectiveness - takes years (not challenged). Costs of quality - in excess of 20% (thats the way it is). 9•[PPT] Final Report on Process Analytical Technology and ... - FDA•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt•(Source: FDA Science Board Meeting, November 16, 2001). 3/19/2012 Ajaz S. Hussain, Ph.D. 5
Shared vision for the 21st Century Product quality and performance are achieved and assured by design of effective and efficient manufacturing processes Product specifications are based on a mechanistic understanding of how formulation and process factors impact product performance Manufacturers are able to effect continuous improvement and continuous "real time" assurance of quality 3/19/2012 Ajaz S. Hussain, Ph.D. 6
Observing the current trends Recent industry comments suggest an ongoing struggle; for example, “QbD is in its infancy” or “not focused on QbD” State of QbD Implementation: Adoption, Success and Challenges (McKinsey Report, 2011) Negative perceptions - quality related recalls, warning letters, consent decrees, drug shortages, etc. How should we measure progress of this initiative?http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM263468.pdf 3/19/2012 Ajaz S. Hussain, Ph.D. 7
How should we measure progressof this initiative? Number of guidance documents and the numerous conferences on the topic? Industry comments (‘QbD is in its infancy’) or regulatory plans for implementing QbD by 2013? Number of recalls, unresolved OOS investigations, warning letters and the resulting erosion of public trust? QbD has always been the foundation – are there gaps in the initiative that needs to be filled 3/19/2012 Ajaz S. Hussain, Ph.D. 8
Gaps that needs to be filledPrecise vocabulary & communication• QbD is the foundation• Objective is to make science visible‘Initiatives’ and ‘on the ground’ quality• Enhance efforts on effective root-cause investigations• Risk managementPragmatic approach to design-space• Continual improvement• Supporting innovation 3/19/2012 Ajaz S. Hussain, Ph.D. 9
Precise vocabulary &communication The phrase “quality cannot be tested into products, it has to be built in by design” describes the foundation for Process Validation in the pharmaceutical industry In early 2000 an additional focus was placed on this foundational element and the phrase ‘quality by design’ was used for emphasis The objective was to overcome ‘art’ vs. ‘science’ debate and to ‘make science more visible’ and effectively utilized for risk-based decisions 3/19/2012 Ajaz S. Hussain, Ph.D. 10
Design: Art or science? A decade ago, at FDA, we debated the utility of pharmaceutical development information in regulatory decisions; “art (practice) vs. science’ The natural sciences are concerned with how things are...design on the other hand is concerned with how things ought to be Scientific design is based on scientific knowledge but utilizes a mix of both intuitive and non-intuitive design methods Through the application of scientific knowledge in practical tasks, design ‘makes science visible’Cross, Nigel (2001). Designerly ways of knowing: design discipline versus design science. Design Issues, 17(3), pp. 49–55. 3/19/2012 Ajaz S. Hussain, Ph.D. 11
Make science visible Why? To provide assurance of quality, for demonstrating effective risk reduction, and justifying options for efficiency improvements How? Recognizing that ‘uncertainty = risk + opportunity’ and that regulators are open to science- based risk reduction and to create flexibility to facilitate efficiency improvements What? Science and practice of assuring effective quality risk management and efficiency improvement 3/19/2012 Ajaz S. Hussain, Ph.D. 12
Science and practice ofQuality risk reduction Efficiency improvement• Risks such as in 483 • Reducing development, observations & Warning production and regulatory letters, and multiple review cycle times & costs cycles • Timely implementation of• Improving assurance of post-approval changes needed identity, purity, strength, to improve the business potency ‘bottom line’• Justifying acceptable variability • Reducing stress and of critical quality attributes uncertainty associated with• Capability for rapid root-cause regulatory inspections investigations 3/19/2012 Ajaz S. Hussain, Ph.D. 13
Initiatives and ‘on the groundquality’ Currently there are a large number of high profile ‘quality issues’ such as product recalls and warning letters that have attracted publics’ attention While at the same time several companies have significant initiatives related to QbD Is there not a need to balance efforts to also improve assurance of effective quality risk management for current products? 3/19/2012 Ajaz S. Hussain, Ph.D. 14
Enhance the focus on effective qualityrisk management for current products Risks such as in 483 observations & warning letters, and multiple review cycles Justifying acceptable variability of critical quality attributes Capability for rapid and effective problem root-cause investigations 3/19/2012 Ajaz S. Hussain, Ph.D. 15
Capability for effective problemroot-cause investigations Root-cause investigations often conclude with ‘root cause unknown’ How we set specifications can contribute to OOS simply because of inherent variability ( often ‘common cause variability) Discussions in Nov 2001 at the FDA Science Board highlithed a potential weakens in how we currently set specifications Resolution of OOS is often difficult, a reason for warning letter - escalating to a consent decreeOOS: Out of specification Ajaz S. Hussain, Ph.D. 16 3/19/2012
Conflicts in risk management Cognitive: Lack of agreement on causal links Evaluative: Lack of agreement on trade-offs Normative: Lack of agreement on values and fairness Manifest depending on complexity, uncertainty and ambiguity in the problem to be solvedRisk Analysis (2002) 3/19/2012 Ajaz S. Hussain, Ph.D.
Risk management: Simple to ambiguous problems Risk tradeoff analysis and Risk balancing deliberations necessary necessary Scientific risk- • Risk assessment • Risk assessment assessment necessary and balancing necessary necessary Routine operation • Conflict: Cognitive and • Conflict: • Agency staff • Conflict: Cognitive, Cognitive Evaluative • Discourse: Evaluative, • Agency staff & • Agency staff, Normative Internal external external experts • Agency staff, • Simple experts, • Discourse: external Cognitive stakeholders experts, • Complex • Discourse: stakeholders, Reflective public • Uncertain representatives • Discourse:Causal links identified & Low confidence in causal Participatory quantified links • Ambiguous Difficult to identify and Variable interpretation of quantify causal links identical data Risk Analysis (2002) 3/19/2012 Ajaz S. Hussain, Ph.D. 18
Resolving conflicts for effective riskmanagement Cognitive conflict: Improving understanding and acceptance of causal links Evaluative conflict: Improving understanding of uncertainty inherent in the current approach and/or agreement on acceptable level of uncertainty Ideally done by ‘making science visible’ when in good compliance status; after a warning letter focus on options that minimize evaluative conflict 3/19/2012 Ajaz S. Hussain, Ph.D. 19
Making science visible during review phase A decade ago, in the US, pharmaceutical development information was not considered useful for CMC review Currently ICH Q8 has been implemented in the NDA review process and by 2013 will be implemented for ANDAs ICH Q8 introduced the concept of ‘design space’ to facilitate continual improvement; an option to reduce uncertainty and post-approval supplements Pragmatic implementation of ICH Q8 (including design space) is necessaryhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm292533.htm?source=govdelivery 3/19/2012 Ajaz S. Hussain, Ph.D. 20
Pragmatic implementation ofICHQ8 Objective: scientific understanding to identify critical to quality attributes, variability in these attributes; to set controls and specifications Specific information to improve decisions (e.g., risk- based) Design space development – a focus on anticipated or planned efficiency improvements in the post approval phase can be a useful guide Scientific design is based on scientific knowledge but utilizes a mix of both intuitive and non-intuitive design methods 3/19/2012 Ajaz S. Hussain, Ph.D. 21
Regulatory submissions: Pharmaceutics & Pharmaceutical Technology Design thinking (often implicit) Reasoning about uncertainty (blind spot?) Making estimates (implicit) Need to explicitly state the underlying theories and generate testable predictionshttp://www.unusualleading.com/wp-content/uploads/2009/12/HBR-on-Design-Thinking.pdf 3/19/2012 Ajaz S. Hussain, Ph.D. 22
What is scientific and what is not? The U.S. Supreme Court: An Evolved Theory of Science (2000) The theoretical underpinnings of the methods Francis Bacon’s Scientific Method must yield testable predictions by means of which the theory could be falsified Karl Popper’s Falsification Theory Thomas Kuhn’s Paradigm Shifts There should be a known rate of error that can be used in evaluating the results. The methods should preferably be published in a peer-reviewed journal. The methods should be generally accepted within the relevant scientific communityhttp://www.fjc.gov/public/pdf.nsf/lookup/sciman00.pdf/$file/sciman00.pdf 3/19/2012 Ajaz S. Hussain, Ph.D. 23
Quality: Testable predictions?(illustrative) For the selected formulation, plus established raw-material acceptance criteria and control of process equipment, variability in content uniformity is expected to be within X% regardless of manufacturing site (e.g., Chicago vs. Louisiana) Change in the supplier of excipients, using the established acceptance criteria, is expected to have an insignificant impact on shelf-life. The established SOP and training procedures will result in X% deviations in first 1Q 2012 and the rate of deviations will reduce to Y% by end of 4Q 2012. 3/19/2012 Ajaz S. Hussain, Ph.D. 24
Pharmacokinetic/pharmacodynamics modeling • Utilizes theories and methods from physics, mathematics and engineering • Examples • Transform theory from mathematicsPharmacometics • Transport phenomena from (a multidisciplinary field) engineering and physics • Linear systems analysis from engineering systems theory • Control theory from electrical engineering 3/19/2012 Ajaz S. Hussain, Ph.D. 25
Impact of Pharmacometrics on drug approval decisions Pharmacometric analyses are an increasingly important component NDA and BLA submissions to the US FDA (End of Phase II Meetings) During 2000–2008 the number of reviews with an impact on approval and labeling increased significantly Selection of pediatric dosing regimens, approval of regimens that had not been directly studied in clinical trials and provision of evidence of effectiveness to support a single pivotal trial.Clinical Pharmacokinetics (October 2011) 3/19/2012 Ajaz S. Hussain, Ph.D. 26
Concluding remarks A decade ago, at FDA, we debated the utility of pharmaceutical development information in regulatory decisions; “art (practice) vs. science’ Through the application of scientific knowledge in practical tasks, design ‘makes science visible’’ A pragmatic approach based on explicit description of ‘theory’ underpinning assurance of product quality is essential “Without theory, there is no learning.” - William E Deming 3/19/2012 Ajaz S. Hussain, Ph.D. 27
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