HPAPI Process, Scalability &...

HPAPI Process, Scalability & Robustness

Jason Hamm, Ph.D.

Director, API Pilot Plants

Bristol-Myers Squibb

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July 14, 2015

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

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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?

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BMS Exposure Guidelines

BMS Classification for Drugs, Drug Candidates, Chemical Process Intermediate and Early R&D Materials

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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 non-

sterioidal anti-

infammatory

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

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)

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A Typical Process in R&D Facilities

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Reaction

Extraction

Distillation

Crystallization

Filtration

Drying

Milling

Charge Sample

Charge Discharge Sample


Charge

Discharge Sample



• Intermediate •Solvents •Reagents

• Solvents • Reagents

• Solvent

• Seed • Solvent

• Solid Product

• Solid Product

• Reaction endpoint • Reaction data

Discharge • rich/spent streams Sample • Mass Balance • Stream attributes (pH, density, etc.)

Discharge • Distillate waste Sample • Solvent comp.

Discharge • Mother Liquor & Wash Waste • Solid Product Sample • ML & wash

Discharge/Sample • Solid Product


Where Are Our Risks?

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Reaction

Extraction

Distillation

Crystallization

Filtration

Drying

Milling

Charge Sample



Charge

Discharge Sample



• Intermediate •Solvents •Reagents

• Solvents • Reagents

• Solvent

• Seed • Solvent

• Solid Product

• Solid Product

• Reaction endpoint • Reaction data

Discharge • rich/spent streams Sample • Mass Balance • Stream attributes (pH, density, etc.)

Discharge • Distillate waste Sample • Solvent comp.

Discharge • Mother Liquor & Wash Waste • Solid Product Sample • ML & wash



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

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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

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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

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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

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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

• Discharge liners

• Continuous liner

• Powder transfer containment valves

• Sampling

• Process samplers w/ isolators

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Tray dryer isolator or flexible enclosure

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

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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

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HPAPI Process, Scalability &...

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