Innovation in Medicines PDA: A Global and Manufacturing Association David Tainsh, GSK Keith Pugh, MHRA Joint Regulators/Industry QbD Workshop 28-29 January 2014 London, UK
Introduction Current State We have heard a lot about the challenges and successes of applying QbD Aside from Biopharms which we know are complex, Immediate Release Products are just the tip of the iceberg and we need to be more innovative if we are to be successful in delivering consistent and reliable quality for all products. Future State So before we close this workshop we just wanted to reflect on some of the new challenges facing us, what could be different and to ask how do you see it? 2
Challenges to Innovation Current Levels of Technical Capability Availability of New Skillsets Unwillingness to Deploy New Technology Large Investment in the Current State Perceptions of High Regulatory Hurdles Lack of Process to Manage Complex LCM Changes Lack of an Overall Vision on How to Modernise Pharmaceutical Manufacture 3
Opportunities for Innovation Novel Product Types for QbD More Complex Traditional Medicines Prolonged release Oral, Inhaled DPI, Nanoparticulates Novel products Advanced Therapeutics, Oligonucleotides, Microneedles Novel Methods of Manufacture & Control Continuous Synthetic Biochemistry - Biotransformations Discrete Manufacture & Novel Analytics Others? 4
Continuous Manufacturing: - Enabling Things Batch Can t Do Benefitting - Quality for Patients, - Environment - Business Process Shorter End to End Process Times Faster, Lower Cost Development More Process Understanding Factory Lower Work In Progress Costs Safer More Scale Independent Business Reliable Consistency Volume Flexibility Sustainable & Greener
Synthetic Biochemistry Moving to Microbial Cell Factories Greener, Cleaner, Cheaper - No solvents, fewer reagents - Fewer isolations & by-products - Aqueous based benign waste Biotransformations can be very specific in terms of chirality, position and functional group. Chemoenzymatic Approach Cascade Synthesis Enzyme Enzyme
Liquid Dispensing Technology Platform Industrial scale machine installed to provide Phase 3 and Launch Capability Capacity: 1 million tablets/day, upgradable to 2 million/day 7
Manufacturing - A Paradigm Shift Mfg.. Batch Mfg.. Discrete Units Population of Many Quality assessed by sampling post manufacture Population of One Quality assessed on-line for every tablet 8
Liquid Dispensing Technology with PAT UV / NIR [suspension concentration] 1. Vision system, droplet size 2. Droplet weight 1. Image analysis 2. NIR Chemical Imaging IR or Microwave Drug Solution or Suspension + Placebo Tablets Low Volume (c. 2-20ul) Dispensing Drying On-Line Analysis Chemical Imaging Surface Coating & Printing No Linkage between First and Last Tablet 9
Process Analytical Technologies Video Image of Droplet: What was Delivered NIR Chemical Imaging: Where on the Tablet 10
150 125 100 75 50 25 0 Comparison of Droplet Content Uniformity vs Typical 2mg Tablet Content Uniformity 350 300 250 LSL -3.s +3.s USL 200 150 100 50 0 6.9 4E6 6.9 6E6 6.9 8E6 7E6 7.02E6 7.04E6 7.06E6 7.08E6 7.1E6 7.12E6 7.14E6 7.16E6 7.18E6 7.2E6 7.22E6 7.24E6 7.26E6 7.28E6 7.3E6 7.32E6 7.34E6 7.36E6 Frequency 11 85% Droplet N= 606 PpK =16 115% LSL -3.*S Nominal +3.*S USL Tablet N= 520 PpK =1.4 80 82 84 86 88 90 92 94 96 98 100102104 106 108110112114116 118
100% Vision QC Inspection Control and Testing UV Solution Analysis Reticule Calibration Drop Volume/Dose Content Tunnel Temp. Conditions NIR Dose Position Inspection 100% Vision QC Inspection Incoming core tablet Dosing Drying Coating & Printing Wet Dose Position Inspection Droplet Weight Check Pad Inspection/ Coating Confirmation 12 System monitoring tablet shift register and rejection confirmation
Desired State A Vision to Modernise Pharmaceutical Manufacture Enabling Regulatory Strategy and Process that keeps pace with Innovation Increased Opportunities for Scientific Dialogue around innovative platforms Education and Training to Provide New Skillsets Enhanced scientific and risk based approaches to QbD to match new technologies A Simplified and Streamlined Variations Process 13
Challenges to Innovation Current Levels of Technical Capability Availability of New Skillsets Unwillingness to Deploy New Technology Large Investment in the Current State Perceptions of High Regulatory Hurdles Lack of Process to Manage Complex LCM Changes Lack of an Overall Vision on How to Modernise Pharmaceutical Manufacture 14
Desired State A Vision to Modernise Pharmaceutical Manufacture - Industry driven Enabling Regulatory Strategy and Process that keeps pace with Innovation Facilitate within existing Regulation 15
Desired State Increased Opportunities for Scientific Dialogue around innovative platforms - Scientific Advice (EMA/NCA) - Working Parties e.g. QWP, BWP - PAT team - early interactions recommended Education and Training to Provide New Skillsets - Should also include Regulators 16
Desired State Enhanced scientific and risk based approaches to QbD to match new technologies - Apply and build on existing learning A Simplified and Streamlined Variations Process - EU legislation (Common system since August 2013) - Changes already classified on a risk based basis - Detailed classification guideline 17
Summary - Types of Variations Changes not requiring any prior approval Changes requiring prior approval Design Space No submission required if within an approved design space Type IA Do & tell Type IB (Default) Tell, wait & do Variations Type II Extension Evaluation Procedure adapted to the level of risk
Desired State A Simplified and Streamlined Variations Process - EU - Changes already classified on a risk based basis - Additional flexibility Post Approval Change Management Protocol (PACMP) - justify downgrading in type of required variation - no restrictions to the nature of changes - limit (Type IB) regarding level of downgrading for biopharmaceutical products. - Global challenges - What do you want? 19
Conclusion By No Means a Comprehensive View of the Challenges Facing All of Us or the Possible Solutions But a Stimulus for Further Discussion So How do you See the future Challenges and Opportunities for Innovation? 20