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