Future of Pharmaceutical Quality and the Path to Get There Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research INTERPHEX 2018, April 18, 2018, Javits Center, NYC
FDA s Vision for Pharmaceutical Quality Quality is the underpinning of everything US FDA/CDER does Assures patients have access to safe and effective drug products Over-the-counter Prescription Innovator (Brand) Generic 2
Patients and Caregivers Expect Their Drugs: Are safe, efficacious, and have the correct identity Deliver the same performance as described in the label Perform consistently over their shelf life Are made in a manner that ensures quality Will be available when needed 3
A High Quality Product = 1. A product that reproducibly delivers the therapeutic benefit to the consumer as stated in the label 2. Is free of defects 3. Presents no undeclared risk (e.g., isn t contaminated) 4
FDA s Quality Journey The US FDA quality initiative began more than a decade ago with the 21 st Century Initiative to modernize FDA s regulation of the pharmaceutical quality of drugs. A journey that is still on-going... Vision: A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight. -Dr. Janet Woodcock 5
Class 1 Drug Product Recalls State of Pharm. Quality? Drug Shortage Reasons 14% 8% 6% 2% 4% 35% Quality: Facility Remediation Efforts Quality: Product Manufacturing Issues Discontinuation of Product Raw Materials (API) Shortage Other Component Shortage 31% Increased Demand Loss of Manufacturing Site 6
Product Recall 7
Future of Pharmaceutical Quality A Six Sigma Capable Process is Expected to Have No More than 3.4 Defects per Million Opportunities 8
Consumers and patients deserve six sigma quality products with minimal risks of shortages or recalls Pharma Semicon Sigma 2 σ 3 σ 4 σ 5 σ 6 σ ppm Defects 308,537 66,807 6,210 233 3.4 Yield 69.2% 93.3% 99.4% 99.98% 99.99966% Cost of Quality 25-35% 20-25% 12-18% 4-8% 1-3% 9
Path to Get 6 Sigma Quality Economic Drivers Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational Excellence 10
Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages Woodcock, J; Wocinska, M. Clin. Pharmacol. & Thera. 93:170-176 (2013) The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments... 11 11
Market Observes and Rewards Brand New Drugs 12
Path to Get 6 Sigma Economic Driver Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational Excellence 13
Performance-based Regulation A regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive processes, techniques, or procedures. Performancebased regulation leads to defined results without specific direction regarding how those results are to be obtained At the Nuclear Regulatory Commission, performancebased regulatory actions focus on identifying performance measures that ensure an adequate safety margin and offer incentives to improve safety without formal regulatory intervention by the agency 14 14
Types of Regulations Stages of Organizational Production and Types of Regulation Stage of Production Planning Acting Outputs (both good and bad) Type of Regulation Management- Based Means- Based Performance- Based Pharmaceutical regulation should be designed to improve the performance of individual and organizational behavior in ways that protect and promote public health Coglianese, C., & Lazer, D. (2003) Law & Society Review, 37(4), 691-730. 15 15
Types of Regulations Coglianese, C., & Lazer, D. (2003) Law & Society Review, 37(4), 691-730. 16
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Impact of Machine Learning and Big Data on Regulation Advances in machine learning and big data push regulation to performance-based 18
Path to Get 6 Sigma Economic Driver Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational Excellence 19
Guidance for Industry PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) September 2004 Pharmaceutical CGMPs 20
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Control Strategy Implementation Options Enhanced Approach Level 1 Real - time automatic control + Flexible process parameters to respond to variability in the input material attributes Level 2 Reduced end product testing + Flexible critical material attributes and critical process parameters within design space Traditional Approach Level 3 End product testing + Tightly constrained material attributes and process parameters 22 22
Impact of Active Control Variable Input Fixed Process Variable Output Variable Input PAT Variable Process Uniform Output 23
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Continuous Manufacturing (1) Batch (2) Hybrid (3) End-to-End 25 25
Trends in Continuous Manufacturing Vertex s ORKAMBI (lumacaftor/ivacaftor) 1st NDA approval for using a continuous manufacturing technology for production of the Cystic Fibrosis drug (tablets) (July 2015) J&J Prezista (darunavir) 1st NDA supplement approval for switching from batch manufacturing to continuous manufacturing process for an FDA-approved HIV drug (tablet) (April 2016) Eli Lilly Verzenio (abemaciclib) 2nd NDA approval for using a continuous manufacturing technology for production (September, 2017) Trends Drug substance Drug product Small-molecule and biotechnology products Control strategy utilizing models 26
Industry 4.0: Impact on Pharmaceutical Manufacturing 27
Path to Get 6 Sigma Economic Driver Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational Excellence 28
Quality by Design ICH Q8(R2) Pharmaceutical Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management Quality by Design Tools Prior knowledge Risk assessment Design of experiments (DOE) and data analysis Process analytical technology (PAT) tools 29
Quality by Design: Objectives To achieve meaningful product specifications that are based on clinical performance To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control To increase product development and manufacturing efficiencies To enhance post-approval change management 30
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Relationship of CMA, CPP, and CQA CPPs CMAs Input Materials Pharmaceutical Unit Operation CQAs Output Materials or Product A CQA of an output material may become a CMA if it becomes an input material of another unit operation 32
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Product & Process Understanding STEP 1 Identify all possible material attributes and process parameters STEP 2 Identify high risk attributes or parameters based on risk assessment and scientific knowledge STEP 3 Identify levels or ranges of these high risk attributes or parameters STEP 4 Design and conduct experiments, using DOE when appropriate STEP 5 Analyze the experimental data STEP 6 Develop a control strategy Continuous Improvement 34
QbD Improves Product Quality 35 35
Path to Get 6 Sigma Economic Driver Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational Excellence 36
McKinsey: Flawless: From measuring failures to building quality robustness in pharma There s the challenge of shifting mind-sets across industry that has focused predominantly on compliance rather than on truly knowing the root causes and effects on quality issues 37
Creating a Culture of Quality S. Srinivasan and B. Kurey, Harvard Business Review, 2014 Culture of quality: An environment in which employees not only follow quality guidelines but also consistently see others taking quality-focused actions, hear others talking about quality, and feel quality all around them Four Essentials of Quality Maintaining a leadership emphasis on quality Ensuring message credibility Encouraging peer involvement Increasing employee ownership and empowerment 38
Characteristics of Culture for Quality Clearly visible, engaged and unwavering senior management support for quality Clearly articulated vision and values Active and ongoing engagement with customers to continually identify and address current and evolving needs Clearly stated quality goals Performance expectations for all individuals throughout the company that clearly link to quality goals Appropriate incentives which can favor monetary or recognition-based awards, depending on individual circumstances. 39
Continuous Improvement Leaders must take the lead in quality improvement Investments in quality improvement must be substantial Modern tools for improvement must be put to use Flawless execution, focusing on quality, not compliance/enforcement Communications among industry, patients, and regulators must be open and carefully maintained 40
My Chem. Eng. Ph.D. Research 41
Process Optimization based on Statistics Analysis Y = a 0 + a 1 x 1 + a 2 x 2 + a 3 x 3 + a 4 x 4 + a 5 x 5 + a 6 x 6 + a 7 x 7 + a 8 x 8.+ a 21 x 21 + a 22 x 22 + a 30 x 30 + a 31 x 31 42
Yu et al. The Use of Process Capability to Ensure Product Quality Pharm. Eng. (2015) 43 43
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A Sustained Focus on Quality Risk Management Has Delivered Improvements in Product Quality Comparison of 2013 Performance to 2007 Baseline Activity Indicators Performance Improvement Productivity Improvement PQRI October 2015 2014 Eli Lilly and Company 45
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Conclusion Consumers and patients deserve six sigma quality products with minimal risks of shortages or recalls Market needs to observe and reward Quality Regulatory quality oversight moves to performancebased Regulation Pharm develops and adopts emerging technologies Pharm adopts pharmaceutical Quality by Design Pharm continuous improvement and operational excellence 47