HPAPI Process, Scalability & Robustness

Transcription

1 HPAPI Process, Scalability & Robustness Jason Hamm, Ph.D. Director, API Pilot Plants Bristol-Myers Squibb July 14,

2 Agenda 1. Considerations for highly potent compounds 2. Addressing the risk for the scale-up of highly potent compounds 3. Containment approaches within API plants 4. Scaling up processes for highly potent compounds 5. Case studies for example projects 6. Technical transfer to commercial manufacturing 7. Summary 2

3 Considerations associated with the scale-up of HPAPI s What does the operator see? Material Management Warehouse Manufacturing Operations Personnel Maintenance Personnel Waste Management What does the process see? Facility Cleaning Equipment Cleaning Common utility systems Specialized Containment Technology How do we maximize knowledge capture? 3

4 BMS Exposure Guidelines BMS Classification for Drugs, Drug Candidates, Chemical Process Intermediate and Early R&D Materials Band sc Range > to µg/m Pharmacology Class (Examples) Caffeine; chloestrymine; some nonsterioidal antiinfammatory drugs Certain antibiotic classes; some cardiovascular, antiviral, and CNS drugs 10 to <100 Pharmaceutical Intermediates 1 to <10 <1 <0.1 Potent cadiovascular and metabolic compounds; anitvirals; CNS drugs Oncology drugs; androgens, steroid hormones Especially potent compounds Default banding for research compounds is Band 4 4

5 BMS R&D Facilities for Process Development of HPAPI s Laboratories Designed for handling small quantities of high potent API (up to 25 grams) Kilo labs Designed for handling gram to kilogram quantities of high potent API (up to 3-5 kilograms) Pilot Plants Designed for handling multi kilogram quantities of high potent API (>10 kilograms) 5

6 A Typical Process in R&D Facilities Intermediate Solvents Reagents Reaction Reaction endpoint Reaction data Solvents Reagents Solvent Seed Solvent Extraction Distillation Crystallization rich/spent streams Mass Balance Stream attributes (ph, density, etc.) Distillate waste Solvent comp. Solid Product Filtration Drying Mother Liquor & Wash Waste Solid Product ML & wash / Solid Product Solid Product Milling / Solid Product 6

7 Where Are Our Risks? Intermediate Solvents Reagents Reaction Reaction endpoint Reaction data Solvents Reagents Solvent Seed Solvent Extraction Distillation Crystallization rich/spent streams Mass Balance Stream attributes (ph, density, etc.) Distillate waste Solvent comp. Solid Product Filtration Drying Mother Liquor & Wash Waste Solid Product ML & wash / Solid Product Solid Product Milling / Solid Product 7

8 Factors considered when handling HPAPI s 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 equipment / process train Frequency of processing operations and opportunites for exposure 8

9 Containment Approach Tier I Containment within the processing equipment Tier II Containment surrounding equipment (i.e. barrier technology) Tier III Containment within processing environment Tier IV Administrative controls over personnel, equipment, and processing environment 9

10 Manufacturing controls for potent compounds Engineering Controls (Tier I and II) Barrier technology Local exhaust ventilation Powder transfer containment Self-contained equipment Sampling Technology Facility Design (Tier III) HVAC controls Gowning/De-gowning areas Decontamination areas Dust Collection Administrative Controls (Tier IV) Procedures Personnel Training 10

11 BMS High Potent Facility Design Physically separated areas Manufacturing area Gowning/Degowning area Common hallway Controlled HVAC within processing area and adjacent areas Maintain containment within manufacturing area Decontamination Areas Wet/dry showers available if breach of equipment or failure of engineering controls Unidirection traffic flow Materials, equipment, & personnel 11

12 BMS Engineering Controls for Potent Compounds Barrier Technology Hard/softwall isolators Passive/active controls Local ventilation controls Downflow booths Rigid local extraction ventilation Packout booths Powder transfer technology liners Continuous liner Powder transfer containment valves Sampling Process samplers w/ isolators Tray dryer isolator or flexible enclosure 12

13 Risk Reduction for potential operator exposure Risk reduction before and during processing Facility/Equipment specific PHA Baseline for all facilities as part of the Process Safety Management (PSM) program Exposure Management Tool (EM Tool) Process Specific PHA Process unit operations Specialized equipment/procedures Cleaning Waste Movement Job Hazard Analysis Unplanned operations/maintenance In-process swab monitoring and final swab testing 13

14 Chemical Development Operations BMS has been handling highly potent compounds for over 20 years Strong history in the development of Oncology compounds Current high potent facilities designed in early 2000 s Work with Chemical Development team to reduce exposure risks Telescope process steps where possible Minimize/eliminate high risk operations 14