Key Strategic Considerations in the Early Development and Manufacture of Potent Compounds Melanie Miller Head of API Operations, Pharmaceutical Development Bristol-Myers Squibb June 22, 2016 1 Agenda Introduction to Containment Philosophy at BMS Exposure Control Band Approach Mitigating Exposure Risk for Highly Potent Compounds Case Study – Phase 1 API Delivery Summary 2 Scope of API Operations: Discovery to Launch Early development Full development, launch, LCM Commercial Manufacture Formulation Development Analytical Development & Testing a Clinical Manufacturing & Supply CMC documentation, GMP & Operations Support 3 Commercial Support API Synthesis Development Tech Transfer Discovery Support Discovery Strategies to Deliver API Triage Route and Process Route Selection Process Optimization IND Toxicology/Phase 1 Phase 1 reload/Phase 2a Phase 2b/Phase 3 Goal Expedient delivery of chemical intermediates and API to enable rapid progression of projects Goal Integrate process knowledge deliverables with API deliveries within a costeffective global network to ensure on-time/on-quality deliveries Goal Integrated development model where every campaign has duel objective (process knowledge and API delivery). Strategy • Use ‘rapid entry’ suppliers with agility to ensure early delivery • Limited capacity for placement of Band 5 and/or complex chemistries Leverage risk-based process development and containment strategies to achieve agility and speed to patient. Strategy • Build external supply chain for intermediates •Leverage key partners and BMS capacity for advanced intermediates and API • Expedient and sustainable deliveries of API Strategy • Package of knowledge to deliver into the commercial plant (advanced intermediates and API) • Starting to develop external commercial supply chain • Use of a common supplier base for late stage development into early commercial It Begins with the Exposure Control Band Assignment Need to be “right” ECB dictates the containment, handling controls, practices and PPE Can increase cost and time Can decrease flexibility in manufacturing Balanced with: Protection of workers 5 BMS Exposure Guidelines BMS Classification for Drugs, Drug Candidates, Intermediate and Early R&D Materials Band 1 2 3 4 5 5 sc Range µg/m3 >1000 100 to 1000 10 to <100 1 to <10 <1 <0.1 Pharmacology Class (Examples) Caffeine; chloestrymine; some nonsterioidal antiinfammatory drugs Certain antibiotic classes; some cardiovascular, antiviral, and CNS drugs Pharmaceutical Intermediates Potent cadiovascular and metabolic compounds; anitvirals; CNS drugs Oncology drugs; androgens, steroid hormones Especially potent compounds Default banding for research compounds is Band 4 6 Approach for 1-10µg/m3 Compounds • Tier I • Containment within the processing equipment • Closed operations whenever possible • Tier II • Containment surrounding equipment (i.e. barrier technology) • Hard walled and soft walled barriers provide flexibility • Tier III • Containment within processing environment (e.g., HVAC) • Tier IV • Administrative controls over personnel, equipment, and processing environment 7 Flexible Barrier Technology Increases Speed and Agility • Flexibility of equipment train design (e.g., JIT chromatography set up) • ‘Design once, use often’ economics – variable cost • Increases speed of product changeovers - disposable • Example – Isolation equipment train Glove Box Flexible Barrier Remove Contaminated Filters Yes Yes Clean Isolation Equip Yes No - Disposable Swab Sample(s) / Visual Inspection Yes N/A Sample Analysis Yes N/A 8 BMS R&D Facilities for Handling HP Compounds • Laboratories • Designed for handling small quantities of highly potent compounds (up to 25 grams) • Kilo Labs • Designed for handling gram to kilogram quantities of highly potent compounds (up to 35 kilograms) • Pilot Plants (Multi-purpose) • Designed for handling multi kilogram quantities of API and intermediates (>10 kilograms) • Temporary measures applied to extend to HPs • Electronic batch records and data collection are standard – no paper 9 Reducing the Risk of Operator Exposure – Before, During and After Processing •Facility/Equipment specific PHA • Baseline performed for all facilities as part of the Process Safety Management program •Process Specific PHA • Process unit operations • Specialized equipment/procedures • Cleaning • Waste Movement •Process Chemistry Safety Review (Basis of Design) •Job Hazard Analysis • Unplanned operations/maintenance •In-process swab monitoring and final swab testing 10 Considerations for Process Basis of Design • Quantity of API or intermediate being handled • Form or state of the product (i.e. liquids, solid) • Energy introduced by the process (i.e. milling, transfers) • Duration of the individual processing steps • Level of containment around the process equipment train • Frequency of processing operations and opportunities for exposure 11 A Typical Process in R&D Facilities • Intermediate •Solvents •Reagents • Solvents • Reagents • Solvent • Seed • Solvent Charge Reaction Sample Charge Extraction Discharge Sample Charge Distillation Discharge Sample Charge Crystallization • Reaction endpoint • Reaction data Discharge • rich/spent streams Sample • Mass Balance • Stream attributes (pH, density, etc.) Discharge • Distillate waste Sample • Solvent comp. Filtration Discharge Sample Discharge • Mother Liquor & Wash Waste • Solid Product Sample • ML & wash • Solid Product Charge Drying Discharge Sample Discharge/Sample • Solid Product • Solid Product Charge Milling Discharge Sample Discharge/Sample • Solid Product 12 Where Are the Risks? • Intermediate •Solvents •Reagents • Solvents • Reagents • Solvent • Seed • Solvent Charge Reaction Sample Charge Extraction Discharge Sample Charge Distillation Discharge Sample Charge Crystallization • Reaction endpoint • Reaction data Discharge • rich/spent streams Sample • Mass Balance • Stream attributes (pH, density, etc.) Discharge • Distillate waste Sample • Solvent comp. Filtration Discharge Sample Discharge • Mother Liquor & Wash Waste • Solid Product Sample • ML & wash • Solid Product Charge Drying Discharge Sample Discharge/Sample • Solid Product • Solid Product Charge Milling Discharge Sample Discharge/Sample • Solid Product 13 Application of Containment Technology at BMS Unit Operation Operations Containment Technology Reaction Charging • Split butterfly valve w/ bags or bottles Sampling • Process samplers on all reactors Extraction Discharging • Rigid local ventilation arms or downflow booths Chromatography Input/sample/output • • Crystallization Charging (seeds) • Split butterfly valve w/bags or bottles Filtration Discharging • Rigid local ventilation arms or downflow booths Drying Charging • Split butterfly valve w/ bags or bottles • Same equipment as filtration (i.e. filter dryer) • In-series equipment (i.e. centrifuge w/peeler and conical dryer) Discharging (product) Milling Charging/discharging Hard wall/soft wall barrier Closed sampling systems with on-line analysis where possible • Packout booth w/ discharge liners • Hard wall/soft wall barrier • Hard wall/soft wall barrier • Packout booth w/ discharge liners 14 Early Development vs. Late Development OR Fit for Purpose vs. Process Robustness • • • • • Development studies for potent compounds are often performed on a small scale (5 to 50g) Target areas of highest risk to quality and safety and defer if non-essential for early delivery Process design may have low throughput (e.g., chromatography vs. crystallization) Milling vs. sophisticated particle size engineering Modeling tools may assist in evaluation of scale-dependent parameters 15 Case Study – Phase 1 API Delivery • API assigned ECB 5SC (<0.1 µg/m3) • Projected Drug Dose: up to 5 mg/kg every 3 weeks • Expedient chemistry to deliver supplies for IND Tox and Phase 1 studies • Demand = 30 grams and 200 grams in separate deliveries • Multiple batches executed across various HP laboratories and plants • Deliver process and data • Several steps after the likely regulatory starting material were assigned ECB 5 • Delivery timeline was compressed 16 Potential Safety/Quality Risks • 1st scale-up of laboratory process • Limited process knowledge • Handling of potent powders and solutions in the laboratory and kilolab • Purification of API process stream required using preparative chromatography • 20cm column was necessary to maximize throughput • Containment of chromatography pumping skid was necessary • Potential for spraying and leaking hazards due to high operating pressure • Chromatography column unpacking/cleaning posed high risk for operator exposure • Product isolated via rotary evaporator • Cycle time was suboptimal (~1 week for 40 g API) • Introduction of potential solvent derived impurities 17 Engineering and Administrative Controls • All powders were handled in hard walled isolators • Cleaning methods were used for spills and decontamination • No deactivation solution available • Chromatography performed in Pilot Plant • Utilize 2000 L vessels • Pre-packed column purchased for chromatography • Soft walled flexible enclosure designed and purchased for chromatography pumping skid 18 Implementation of Chromatography in Plant • Utilized multi-tier equipment and facility engineering controls • All connections between vessels were flanged to prevent leaks • Personal protective equipment • Supplied breathing air protection • Process compatible protective suits • Multiple layers of gloves • Contamination zones determined based on potential for contamination • Facility monitoring via surface swabs to determine effectiveness of controls (engineering/administrative) • Deactivation solution utilized for cleaning • Personnel training - process and equipment 19 Outcomes Campaign goals were met Risk mitigation strategies were successful – no incidents of operator exposure API deliveries on time to support initiation of toxicology and Phase 1 clinical studies. 20 Summary • A multi-tiered approach to containment decreases the risk of operator exposure during scale up • Effective early development approaches target critical-to-quality aspects with respect for risks inherent to manufacture of HP compounds • Successful manufacturing of highly potent compounds requires diligence and risk mitigation before, during, and after processing 21 Acknowledgements Jason Hamm – Head of Plants, API Operations Michael Cassidy – Head of Small Scale Operations, API Operations Janet Gould – Global Environmental Health, Safety, and Sustainability API Operations operating staff for everything that they do to deliver new medicines to patients 22 Thank You Questions? 23
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