Pharmaceutical Manufacturing for New Drugs Current Status and Vision for the Future

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1 Pharmaceutical Manufacturing for New Drugs Current Status and Vision for the Future NIPTE Research Conference on The Future of Pharmaceutical Manufacturing June 18, 2013 Elaine Morefield, Ph.D. Deputy Director, Office of New Drug Quality Assessment CDER/FDA 1

2 Pharmaceutical Manufacturing 2

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4 FDA 21 st Century Initiative (2004) September 2004 Objectives: Encourage the early adoption of new technological advances by the pharmaceutical industry Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches Encourage implementation of risk-based approaches Ensure that regulatory review, compliance, and inspection policies are based on state-ofthe-art pharmaceutical science Enhance the consistency and coordination of FDA's drug quality regulatory programs 4

5 Traditional Drug Product Manufacturing Approaches Batch processing Slow off-line laboratory testing Low equipment efficiency High cycle times 3 batch validation paradigm Avoidance of process monitoring, no testing beyond minimum requirements Avoidance of process changes Reactive changes / CAPA 5

6 Modern Manufacturing Approaches Commonly Used in Other Industries Lean manufacturing Continuous manufacturing Six sigma quality management Green chemistry Advanced analytical methods Real-time process monitoring and control Multivariate statistical process control Proactive changes / continual improvement 6

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8 Quality Related Guidance and Initiatives Initiatives Critical Path Initiative OGD QbR Announced ONDQA CMC Pilot Program 21 st Century Initiative Final Report ICH IWG formed OBP Pilot Program PAT Guidance ICH Q8 Finalized ICH Q9 Finalized Quality Systems Guidance Finalized Guidance/Documents ICH Q11 (Concept Paper) ICH Q10 Finalized ICH Q8(R1) Finalized ICH IWG Q&A s

9 What is Quality by Design (QbD)? Systematic approach to pharmaceutical development and manufacturing Begins with predefined objectives Emphasizes product and process understanding and process control Based on sound science and quality risk management Quality by Design From ICH Q8(R2) 9

10 Pharmaceutical Quality Q8 Q9 Q10 Product & Process Understanding Quality Risk Management Pharmaceutical Quality Systems Quality Culture 10

11 ICH Q8, Q9 and Q10 Working Together over the Product Lifecycle Product Lifecycle Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality Systems 11

12 Pharmaceutical Pharmaceutical Engineering, Engineering, July/Aug July/Aug 2012, 32(4), 2012, (4), 1-10 Survey of 12 companies on their experiences with QbD and their opinions of QbD 12

13 Business Benefits of QbD Improved Product and Process Knowledge and Understanding Improved Development Capability, Speed and Formulation Design Improvement in Product Quality and Product Robustness/ Reproducibility Improved Control Strategy Cost Reduction Benefits Yield Increase Fast and Reliably to Market Increased Process Capability; Reduced Atypicals Reduced Impact of Raw Material Variability Improved Product Stability Improved Scale Up Efficiency/Speed Standardize Ways of Working Engaging Science in Profitable Ways Improvement in Collaboration between Business Units and Enhanced Work Practices The Business Benefits of Quality by Design, T. Kourti and B. Davis, Pharmaceutical Engineering, July/Aug 2012, 32(4),

14 Industry Perspective on The Future of QbD QbD will become the norm The value of QbD principles is clear and will continue to be integrated into the product development processes. QbD is already expanding its scope into new paradigms such as RTRT, continuous quality verification, analytical QbD, lean stability approaches and others. We expect this trend to continue. QbD will continue to grow and become more embedded as it is applied more in production we will get better at it. We will use more prior knowledge and more risk-based approaches. The Business Benefits of Quality by Design, T. Kourti and B. Davis, Pharmaceutical Engineering, July/Aug 2012, 32(4),

15 State of QbD The science and risk based approaches in QbD are being embraced by most innovator pharma companies for development Often, the enhanced knowledge is not used to justify regulatory flexibility in the application Experience has proven to improve product quality, process robustness and operational costs Some other companies starting to adopt QbD, including some generics and biotech companies 15

16 Additional Opportunities Remaining Challenges for QbD Expansion of QbD approaches to more legacy products, generic drugs and biotech products Easing post-approval change reporting requirements through use of risk based assessments Applicable to both newer and older products Developing scientific methodologies to establish clinically relevant specifications Especially for bioavailability Clarifying regulatory expectations for quality systems Including change management and knowledge management International harmonization 16

17 Trends in Applications and Meetings Some application of QbD and PAT concepts into Real Time Release Testing approaches or advanced manufacturing control QbD approaches are being applied to newer areas Analytical methods Container closure Increased interest in RTRT, continuous manufacturing, and biopharmaceutics approaches to QbD 17

18 Patient focus New technologies Control systems Continuous manufacturing 18

19 Linking Process - Product Patient (Quality Target Product Profile)* Process Material Attributes & Process Parameters Product Critical Quality Attributes Patient Clinical Outcome *ICH Q8R Step-2 19

20 What are clinically relevant specifications? Clinically relevant specifications are those specifications that help to assure consistent in vivo performance, as proven by their ability to reject batches with inadequate in vivo performance. 20

21 Importance of Establishing Clinically Relevant Specifications Consistent safety and efficacy profiles for the marketed product relative to those achieved by the clinical trial formulation Delivery of the intended dose to the patient Optimal rate of delivery Optimized drug therapy to the patient 21

22 Clinically Relevant Specifications Challenges Limited number of clinicals during development to provide linking information Limited ability to assess clinical consequences of changes in the manufacturing processes/ formulation Limited availability of in vitro models that can predict in vivo performance 22

23 Increasing Control Sophistication Technology Opportunities Control Systems Fixed operational set points tightly controlled raw materials Known range of allowable operation (Design Space) Real-time monitoring / rapid measurements for end point (go/no go) and release decisions Feed-back controllers Integrated feed-forward and feedback controllers Control to a process signature (single unit operation or plant wide) Traditional Pharmaceutical Manufacturing Quality by Design Approach Current RTRT Approaches Fully Integrated PAT (Univariate) Multivariate Control 23

24 Increasing Control Sophistication Technology Opportunities Control Systems Fixed operational set points tightly controlled raw materials Known range of allowable operation (Design Space) Real-time monitoring / rapid measurements for end point (go/no go) and release decisions Feed-back controllers Integrated feed-forward and feedback controllers Control to a process signature (single unit operation or plant wide) Traditional Pharmaceutical Manufacturing Quality by Design Approach Current RTRT Approaches Fully Integrated PAT (Univariate) Multivariate Control 24

25 Pharmaceutical Quality System Elements Traditional CAPA Reactive Approach Product Performance & Product Quality Monitoring Systems Corrective & Preventive Actions (CAPA) Change Management Systems Management Review Continual Improvement Proactive Approach Product Performance & Product Quality Monitoring Systems Corrective & Preventive Actions (CAPA) Change Management Systems Management Review 25 25

26 Additional Opportunities for Pharmaceutical Manufacturing Regulatory Opportunities: A pathway for risk based assessment to ease post-approval change requirements Clarifying quality systems expectations for change management Increased International harmonization Emerging Technological Opportunities: Multivariate statistical process control (MSPC) Advanced control strategies Continuous manufacturing 26

27 Advanced Pharmaceutical Manufacturing (current state) Raw materials & API dispensing Specifications based on product NIR Monitoring Blend Uniformity Laser Diffraction Particle Size NIR Spectroscopy (At-Line) Identity Assay Dissolution Model - Function of input parameters and in-process measurements Dispensing Blending Sifting Roller compaction Tablet Compression Pan Coating Real time monitoring of intermediates and product, but little adjustable controls 27

28 Regulatory Experience with PAT based In-process Measurements ONDQA has approved the following NDA/sNDA submissions using in-process NIR based spectroscopy measurements: Drying monitoring and end-point detection - 7 Blending monitoring/end-point detection - 9 ONDQA has approved the following NDA/sNDA submissions for RTRT: Online/at-line measurement of tablet content uniformity 6 Models as surrogate for traditional release tests (e.g. dissolution, assay, particle size)

29 Conceptual Example of Control Strategy for RTRT in Continuous Manufacturing Receiving Continuous Granulation Particle Size Distribution Continuous Blending Weight & Hardness Compression On-line Assay Continuous Film Coating Continuous Blending Digital Imaging At-line Chemical Properties Physical Properties Dissolution Model (release) Concentration & Uniformity (Multi-component) 29 Real-time Release Testing

30 Advantages of Continuous Manufacturing Integrated processing with fewer steps Reduced manual handling, increased safety Shorter processing times Lower capital costs, less work-in-progress materials Smaller equipment and facilities Rapid development screening over many conditions Ease of process development Rapid response to change in market demands On-line monitoring and control for increased product quality assurance in real-time Amenable to Real Time Release Testing approaches Potential for reduced cost 30

31 Challenges of Continuous Manufacturing Understanding the dynamic response of the system / amount of backmixing Propagation of disturbances through the system Carryover for changes in raw materials Interactions between unit operations Monitoring and control Sample frequency should be suitable for the system dynamics Challenging to monitor moving streams, probe location(s) 31

32 Process Signatures Crystallization Wet Granulation Many batch processes are path dependent Arriving at the same endpoint does not assure the same quality product Often important physical or chemical attributes are not measured routinely but can affect downstream product performance 32

33 Multivariate Statistical Process Control (MSPC) Multivariate statistical process control (MSPC) simultaneous observes and analyzes multiple parameters in a simplified fashion Can identify some quality issues that univariate analysis might not detect Potential use: Routine monitoring for consistency and identifying atypical operation Part of RTRT approaches Applicable to both new and legacy products 33

34 MSPC Example MSPC of High Shear Granulation MSPC of a Granulation Process 10 5 First Score 0-5 High Shear Wet Granulator Dry Mixing Solution addition Pre-mixing Water addition Rinsing Normal Operation between red lines MSPC flags atypical or previously unseen operation Outliers do not mean a failed batch but trigger investigation Growing examples of saved batches due to MSPC Time Rinsing water addition Kneading SIMCA-P :53:14 Kneading 34

35 Multivariate Model for Predicting Dissolution PROCESS DATA Qualitative Assessment by PCA/MSPC PC2 B3 B1 B2 Calibration Data B4 RAW MATERIAL DATA Manufacturing Data PC1 Quantitative Prediction by PLS Measured Predicted 35

36 How do we get to the Desired State Regulators? Improved efficiency of regulatory oversight Clear manufacturing expectations and consistent consequences Provide additional guidance on manufacturing expectations and quality standards, as needed Differentiate between manufacturers based on quality Degree of regulatory scrutiny more proportional to product and manufacturing risks Develop pharmaceutical manufacturing metrics Provide market rewards for quality? Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages, Woodcock and Wosinska, Clinical Pharmacology and Therapeutics, V. 93(2), Feb 2013 Ease post approval change reporting to support continual improvement Incorporate risk-based approaches into regulatory framework Work toward harmonization and coordination with other regulatory authorities 36

37 Regulatory Experience in Advanced Manufacturing Approaches Multiple companies active in continuous manufacturing for drug product and drug substance At least 8 companies are active in the area At this time, too few NDAs/sNDAs to give statistics Multiple companies using MSPC as part of their process monitoring or RTRT approaches 37

38 Future Opportunities for Advanced Manufacturing Approaches Regulatory Opportunities: Clarifying expectations for verification and change of models used for RTRT and PAT (e.g., NIR models, surrogate models for dissolution) A pathway for risk based assessment to ease postapproval change requirements Increased International harmonization Emerging Technological Opportunities: Multivariate statistical process control (MSPC) Continuous manufacturing Advanced control strategies Complete process / plant-wide integrated process control 38

39 Conclusions Implementation of Quality by Design in the pharmaceutical industry has laid the groundwork for more advanced manufacturing approaches Currently many pharmaceutical companies are developing or have developed approaches for PAT, RTRT, MSPC and/or Continuous Manufacturing ONDQA is willing to discuss advanced manufacturing approaches with applicants prior to submission and as needed during the review process 39

40 Conclusions Recent advances and set-backs in quality have reinforced the importance of: Product and Process Understanding Quality Risk Management Pharmaceutical Quality Systems Quality Culture While significant advances have been made, opportunities remain for further advancement: Regulatory advancements for post approval changes and international harmonization Manufacturing advances in controls and innovative technologies 40

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