Quality by Design (QbD)

Transcription

1 Evaluating the Critical Quality attributes & Critical Process Parameters-A Case Study-Tablets GMP International Workshop February 20/21, 2008 Mumbai, India Mukund Yelvigi Director, Therapeutic Area Management, Pre-Clinical Development Wyeth Research, New York 1 Quality by Design (QbD) Key Drivers ICH Q8 Guidance (Design Space) ICH Q9 Guide on Quality Risk Management ICH Q10 Pharmaceutical Quality Systems Use of Comparability Protocols as a viable regulatory pathway CMC Pilot Program: Discussions with FDA FDA s Final Guidance on PAT (September 2004) EU PAT Initiative (Openness to parametric release) USP PAT Initiative (Expand the use of PAT in USP-NF) 2 1

2 The New Quality Paradigm Evolving Regulatory Framework Product Life Cycle Product Design Process Design Scale-up & Transfer Commercial Manufacture Product Deletion ICH Q8/Q8(R) - Pharmaceutical Development PAT Guidance ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality Systems 3 What is Quality by Design? Product and process characteristics are scientifically designed to meet patient needs and performance requirements Critical quality attributes are defined and controlled Impact of variables is defined Raw materials Process Equipment Personnel Product specifications are tied to fit for use and not empiric ally derived from batch analysis Quality Risk Management framework 4 2

3 ICH Q8 Pharmaceutical Development Emphasises building quality into product by design Describes good practices for pharmaceutical development Suggests contents for 3.2.P.2 Pharmaceutical Development in CTD format Opportunity to present knowledge from application of science and quality risk management during development of product and manufacturing process Content of 3.2.P.2 to be updated during product lifecycle Provides comprehensive understanding of product for reviewers and inspectors Introduces concepts of Design Space Regulatory Flexibility Predicated on level of knowledge provided Links to Quality Risk Management (ICH Q9) 5 ICH Q9: Principles of Quality Risk Management The evaluation of risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk 6 3

4 Tablet Case Study-Where To Start Dosage Form Considerations Extended Release vs. Immediate? Clinical Considerations Established IVIVc Drug Product Attributes Low Dose? Drug Substance Attributes Stable Polymorph, hygroscopic? 7 DEFINITIONS Design Space Goal is to Established through Clinical Relevance Control Space Process Capability/Manufacturing Experience (Subset of Design Space) Control Strategy Change Control Continuous Improvement Regulatory Considerations 8 4

5 Case Study- Critical Quality Attributes/Parameters Critical Quality Attributes Purity Potency Bioavailability Critical Process Parameters - Critical To Quality Attributes (API, DP properties that can affect CQA s) - Key Process Variables 9 Case History Extended Release Tablet Dosage Form Biopharmaceutical Properties relatively high dose highly water soluble salt high permeability Formulation strategy ER formulation for once-a-day dosing Polymer matrix tablet Densification roller compaction 10 5

6 Quality Risk Assessment Tools (QRA) FMEA: Risk scores based on probability, severity, and detectability Risk Prioritization Matrix Quality Function Deployment Fish bone or Ishikawa diagram Pareto Chart 11 Risk Prioritization Matrix Process and Formulation Inputs QUALITY ATTRIBUTES WEIGHTED AVERAGE Polymer CONCENTRATION BLEND TIME LUBE TIME API PARTICLE SIZE PRE- COMPRESSION FORCE COMPRESSING FORCE MACHINE SPEED FEEDER SPEED POROSITYOF RIBBON/ ROLL GAP EXCIPIENT PARTICLE SIZE PSD OF INTRA- GRANULAR BLEND REGULATORY MANUFACTURING DISSOLUTION ASSAY/ POTENCY UNIFORMITY HARDNESS THICKNESS FLOW APPEARANCE STABILITY YIELD TOTALS PERCENT IMPORTANCE

7 Tablet Hardness Basic risk facilitation methods Blending Raw Material Compression Tooling Cam selection Surface Discharge rate Fill Weight Feed frame setting Mg. Stea TALC Fill Vol. Order of ddn. Material addition Feeder speed Storage Blend time Discharge Blend rpm HPMC API Press speed force Gap Pre & Post Compression Hardness of Tablet (Friability) Transport Material Transfer Moisture Humidity Environmental Temp. PSD er Compaction Porosity (den) Ribbon strength Cause Effect Diagram for Tablet Hardness 13 ELEMENTS OF A SUCCESSFUL QbD PROGRAM Robust Product Formulation & Materials Process Equipment 14 7

8 Process and Control Parameters Process Parameter Attributes Raw Material Attributes Bin Blend er Compaction Bin Blend Compression Film Coating Polymer Blending time/end point force gap speed Feed screw rate Milling conditions Blend time/end point Compression force Press speed Feeder speed Pan Speed EEF Concentration, Viscosity, Particle size Blend Uniformity Ribbon Attributes Porosity Granule Attributes psd Blend Uniformity Tablet Attributes hardness Appearance, Tablet weight gain Clinical relevance 15 Critical & Non Critical Parameters Control Space/Design Space (Example) Table 3.1-6: er Compaction Unit Operation Critical / Non- Critical Parameter Control Space Design Space Key Attributes er Compaction - Gap - Force Critical Critical Next slide Next slide -Feed Screw Speed Non-Critical Not Applicable Not Applicable a Speed Non-Critical Milling -Pre-granulator -Fine Screen granulator Non-Critical Non-Critical Adjust rpm to maintain throughput Adjust rpm to maintain throughput Particle Size Distribution Tablet Hardness Dissolution a. Controlled by Gap 16 8

9 Quality by Design - Tablet Development Scale-up Parameters for er Compaction Pilot-scale (design space) Manufacturing scale (predicted design space) 2.2 mm gap Scale up 52.11% 3.8 mm gap 52.11% 1.8 mm mer Poly 40% force 45 bar 65 bar 3.0 mm 55 bar force 65 bar mer Poly 40% Polymer conc % Gap mm force bar Polymer conc % Gap mm force bar 17 Quality by Design - Tablet Development Confirmation of Design Space at Mfg Scale 4.0 mm 3.8 mm 3.8 mm 3.6 mm Failed batch Good batch gap 3.4 mm 70 bar 52.1% 3.0 mm 3.2 mm 55 bar force 2.8 mm 65 bar Polymer 40.0% 18 9

10 Control/Design Space Critical Process Parameters Critical Process Parameters (CPP) identified using a risk analysis investigated extensively using a DOE. Design Space Established on the basis of the DOE and experience during manufacture of clinical/registration batches In certain cases where response of critical quality attribute studied/investigated was insignificant, extrapolation was used to expand/establish design space Control Space Subset of design space established on the basis of process capability, prior knowledge Intent is to stay within the control space during commercial manufacturing 19 Control/Design Space Non-Critical Process Parameters Non-Critical Process Parameters those identified as low risk which lead to low probability of product failure Design Space Established on the basis of range studies (in some cases DOE s) and manufacturing experience at various scales Control Space Subset of design space established on the basis of process capability, prior knowledge Intent is to stay within the control space during commercial manufacturing 20 10

11 Control strategy - Critical Process Parameters Polymer Single point dissolution within control space Dissolution profile when Polymer outside control space but within design space is used Gap and Force Single point dissolution within control space Dissolution profile when roll gap and roll force are outside control space but within design space is used Impact of product being manufactured outside control space and within design space will be assessed through the Event Report Forms If control space is revised based on experience during manufacturing, will manage the change through the plant change control system and notify the agency via the annual report 21 Closing Statement Future of pharmaceutical development The time to implement is now Thank You 22 11