Strategic Implantation of PAT : FDA Perspective

Transcription

1 Strategic Implantation of PAT : FDA Perspective Moheb M. Nasr, Ph.D. CDER, FDA MOHEB.NASR@FDA.HHS.GOV IFPAC 2008 Strategic Implantation of PAT Baltimore, MD January 27, 2008

2 Outline The Desired State - FDA Quality Initiatives Quality by Design (QbD) FDA view of Process Analytical Technology (PAT) How does PAT fit into Quality by Design (QbD)? Where are we with PAT today? FDA progress Industry progress Implementation of PAT What are barriers to expanding the use of PAT in the pharmaceutical industry? 2

3 The Desired State: A Mutual Goal of Industry, Society, and the Regulators A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces highquality drug products without extensive regulatory oversight. Janet Woodcock, M.D. October 5,

4 The Desired State: A Mutual Goal of Industry, Society, and the Regulators Driver Enhanced Quality and Efficiency 4

5 FDA Initiatives: A Quality Timeline Critical Path Initiative 3/04 ONDQA CMC Pilot Program 7/05 21 st Century Initiative Report 9/04 OGD QbR Announced 1/ PAT Guidance 9/04 ICH Q8 Finalized 11/05 ICH Q9 Finalized 11/05 Quality Systems Guidance Finalized 9/06 ICH Q10 (Step 2) 5/ ICH Q8R (Step 2) 11/07

6 Scope of Recent Guidances Product Design Process Design Manufacturing Process Monitoring/ Continuous Verification ICH Q8/Q8(R) - Pharmaceutical Development PAT Guidance ICH Q9 Quality Risk Management FDA Guidance on Quality Systems (9/06)/ ICH Q10 Pharmaceutical Quality Systems

7 Quality by Design (QbD) 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 (ICH Q8(R), step 2) 7

8 Quality by Design

9 QbD Approach (ICH Q8R) Product profile CQAs Risk assessment Design space Control strategy Continual Improvement Target the product profile Determine critical quality attributes (CQAs) Link raw material attributes and process parameters to CQAs and perform risk assessment Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement

10 Quality by Design (QbD) A Systematic Approach to Pharmaceutical Development and Manufacturing Aspects Traditional QbD Pharmaceutical Development Manufacturing Process Process Control Product Specification Control Strategy Lifecycle Management Empirical; typically univariate experiments Fixed In-process testing for go/no-go; offline analysis Primary means of control; based on batch data at time of submission Mainly by intermediate and end product testing Reactive to problems & OOS; post-approval changes needed Systematic; multivariate experiments Adjustable within design space; opportunities for innovation (PAT) PAT tools utilized for feedback and feed forward controls Part of the overall quality control strategy; based on desired product performance (safety and efficacy) Risk-based; controls shifted upstream; reducing product variability; real-time release Continual improvement facilitated

11 FDA s View of Process Analytical Technologies Process Analytical Technology (PAT) a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality PAT Fundamental Tenets Quality cannot be tested into the product; it should be builtin or should be by design PAT Goals Enhance understanding and control of processes 11

12 PAT VS. QbD PAT and QbD share similar goals for pharmaceutical manufacturing Process understanding Process control Risk based decisions PAT tools facilitates the implementation of QbD Some elements of QbD (e.g., dosage form selection, formulation development, design space) can be implemented without implementation of PAT 12

13 PAT Tools PAT tools can be categorized as: Process analyzers Process control tools Multivariate tools for design, data acquisition and analysis Continuous improvement and knowledge management tools PAT is more than just an analyzer! 13

14 Process Analyzers vs. PAT On-line Analyzer (real time measurement data) Store data Evaluate data against criteria Decide Pass/Fail Or Go/No Go Adjust process based upon results Off-line analysis, used to develop process understanding End-product testing True PAT

15 Design Space & PAT Design Space Input Materials Process (or Process Step) Reduced Product Variability Product (or Intermediate) Process Variability Input Process Parameters Monitoring of Parameters or Attributes Process Controls/PAT

16 FDA Progress in PAT Implementation Training 1 st PAT Cadre 15 investigators and reviewers trained 2 nd PAT Cadre 45 investigators and reviewers being trained Pharmaceutical Inspectorate training incorporates fundamentals of PAT Reviewer training multiple sessions on many aspects of PAT 16

17 FDA Progress in PAT Implementation CMC Review experience ONDQA CMC pilot program PAT Tools in all CMC pilots PAT tools used in development In-process controls of manufacturing Process analyzers used for end-product release, including real time release CMC applications outside the pilot Model based feed-forward control PAT for product/batch release Additional implementation for generic and veterinary drugs 17

18 Industry Progress: Examples of PAT Tools in Development In-line laser light scattering analyzer to monitor nucleation during crystallization FTIR and FBRM (Focus Beam Reflectance Measurement) to understand crystal growth and nucleation At-line DSC to monitor crystalline form At-line pressure test to force drug substance degradation At-line particle size distribution monitoring NIR to understand & design blending process 18

19 Industry Progress: Examples of Process Analyzers in Manufacturing Monitoring only: Assay by on-line measurement Identity by on-line measurement On-line particle size monitoring Monitoring and control: Table compression weight check and adjustment Endpoint determination of blending Weight check and adjustment of powder filling operation Adjustment of process parameters based on starting material attributes 19

20 Implementation of PAT Regulators/FDA Challenges Training reviewers and investigators Developing new approaches for review and inspection Integration of review and inspection Communicating expectations to industry International harmonization Industry s apprehension in adopting new approaches and investing in new technologies Industry s apprehension in sharing information with FDA 20

21 Implementation of PAT Industry Challenges Lack of experience in developing and implementing PAT systems Training of scientific, operational and regulatory personnel Fear of change Perceived regulatory risks Investment - more resources needed initially Management support crucial 21

22 Questions to the Audience What is do you see as the major hurdles in implementing PAT? How can the FDA help lower those barriers? 22

23 THANK YOU