Use of Disposable Technologies
to Maximize Utilization of an
Existing Manufacturing Facility
Michael C. Hausladen, Ph.D.
Bristol-Myers Squibb Technical Operations
2011 CNY Biotechnology Symposium
02 Jun 11
1
Background
• Facing industry-wide pressure from patent
expiry
• Commercialize new biologics – “help patients
prevail over serious diseases”
• Bristol-Myers Squibb has established clinical
and commercial biologics manufacturing
• Focus – how we are combining our existing
stainless steel infrastructure with disposables
to do more
2
Challenges
The GOOD problem: BMS has an extensive
biologics pipeline in development

Transfer multiple clinical molecules per year

Maintain a short Technical Transfer timeline
 Keep supply off the critical path to approval

Maximize utilization of available assets to minimize
outsourcing
 More lots from the same facility
 Maintain concurrent manufacturing with clinical/launch
and commercial products
 New processes introduced to an existing facility with
minimal capital investment
3
Strategy to Meet Challenges
•
Technical Transfer
•
Established Technical Transfer Methodology – Phased approach
•
The right people – get the experts together:
•
•
•
Process + Facility + Quality + Support Functions
Minimize facility modifications required from product to product
•
Platform processes
•
Disposables to fill process – facility/equipment gaps
Maximize Utilization of Assets through:
•
Minimizing product changeover time
•
Increase the cadence
•
“Dispose” of low-value activities
4
Technical Transfer
5
Tech Transfer Strategy – Phased Approach
Phase 1: Screen candidate process for manufacturability and
fit in an existing site
Phase 2: Develop process flow and identify gaps
•
Utilize disposable technology to fill facility – process gaps
•
Conduct lab and pilot scale experiments demonstrate facility –
process gap solutions
•
Schedule pilot scale runs to demonstrate consistency of the
modified manufacturing process
Phase 3: Detailed implementation and GMP documentation
•
Quickly implement facility reconfiguration using disposables to
meet process requirements
Manufacture
6
Phase I Process: Overview
• Purpose: Perform analysis to determine high level productivity and
cost to initiate technical transfer of a target molecule to a site.
Technical Transfer Report
Process Description
Analytical Testing Plan
MSDS(s)
Process Yield
Initial Cadence
Process Volume Analysis
Buffer and Media Analysis
Cycle Assessment
High Level Gap Analysis
7
Phase I: Example
Step
Affinity
IEX
MMC
UF/DF
VF
UF II
Column Loading (g/Lresin)
Filter Loading (L/m2)
35
30
25
3500
300
150
Proposed Flowrate (L/min)
25
25
15
5
5
5
Load Volume (L)
4000
390
1100
1600
800
850
Pool Volume (L)
350
1050
1600
800
850
750
Pool Concentration (g/L)
14
5
3
7
4.9
5.0
Cycles
2
5.00
1
4.75
2
4.00
1
3.95
1
3.90
1
3.85
Step Output (kg)
• Ensure that the volumes and throughput requirements are
supported by existing equipment
• Unit Operations and process sequence
• Regulatory requirements (viral segregation)
8
Phase II Process - Overview
• Purpose: Determine the scope of work and schedule required for
implementation of new process into manufacturing.
Phase 1 Deliverables
Demand Forecast
Analytical Needs
Proposed Schedule
Existing Documents
MSDS
Process Scale
Schedule/Cadence
Process Flow Diagram
Expected Process Results
Raw Material Forecast
Capital Process Initiation
Process Gap Analysis
9
Potential Process – Facility Gaps
Addition of a “new” unit operation

Filtration: membrane, depth, TFF
Existing unit operation is under/over sized

Vessel/piping is too large and has a large
holdup volume
– Insufficient volume in process vessels
– Yield
– Mixing, temperature control

Process vessels too small
10
Phase II: Process – Example Gap Analysis
1. Create a specific process flow diagram through the facility
2. Include specific vessels, buffers, transfer lines, filters
3. Identify equipment/Process gaps
•
Utilize disposables to fill gap
11
Using Disposables to Enhance
Existing Facility Capabilities
Marry the flexibility of disposables with the utility of stainless
• Disposables offer a low cost ability to modify process flows and
minimize impact to existing CIP and SIP validation.
•
Reduce costs
•
Reduce implementation and operational time
•
Minimize validation by leverage existing vendor package
•
Eliminate common CIP and SIP challenges associated with product
change over, filter housing and Ultra Filtration
• Stainless offers the ability to leverage platform process flows
and maintain previous validation efforts.
12
Unit Operations Available in Disposables
Mixing/Batching
•
Media preparation
•
Buffer preparation
•
Process steps
•
Viral inactivation,
flocculation,
precipitation, refolding
Filtration
•
•
•
•
•
•
Mammalian
Microbial
Yeast
Inoculum Expansion
Centrifugation
•
Clarification, Viral, Final Fill
Tangential Flow Filtration
•
Concentration, Diafiltration,
Clarification
Chromatography
•
Bioreactor
•
Normal Filtration
•
•
Disposable product contact
flow path
Columns
Membrane Chromatography
Instrumentation
•
Pressure, temperature, flow,
conductivity, pH, DO, OD
Clarification
13
Resolving Facility Fit Gaps with
Disposable Technologies
Photos are examples of products on the market and do not constitute BMS’s endorsement of a particular vendor or product
14
Disposables and Automation/Control
Trend toward increasing capabilities

Automation of unit operations
– Chromatography
– TFF

Temperature control

Pre-assembled flow paths
– Disposable instrumentation
Photos are examples of products on the market and do not constitute BMS’s endorsement of a particular vendor or product
15
Phase III Process - Introduction
• Purpose: Implement technical transfer for manufacture
Phase 2 Deliverables
Gap closure strategy
Facility Fit Checklists
Facility Fit Report
Bill of Materials
Training Materials
Analytical Plan
Change Control
Capital Implementation
New/Modified Documents
Buffer Layout
Gap Closure Reports
16
Phase 2
Phase 1 – Evaluation to bring in molecule
Phase III Deliverable Schedule
Phase 3
17
Maximize Utilization of Assets
18
Maximizing the Utilization of Existing Assets
•
Minimizing product changeover time
•
More lots in less time
•
Trends in utilization of disposables
•
Utilize where it makes sense
19
Advantages and Challenges of Disposables
Advantages

No
cleaning/steaming

Fast setup

Limited validation

Speed to implement

Flexibility in
configuration

Cost
Disadvantages

High flow rates

Reliability of flow
path

Disposal volume,
storage

Frequent changes to
products

Cost
20
Utilizing Disposables for an Existing Facility
Quick to Utilize
Disposables
Slower to Adopt/Utilize
Disposables

Inoculum Expansion

Media Preparation

Depth Filtration

Bioreactors

Membrane
Chromatography

Centrifugation

Buffer Preparation

Column Chromatography
(and Skids)

Tangential Filtration Skids

Established commercial
products

Viral Filtration

Membrane Filtration

Tangential Filtration
Membranes

Drug Substance Fill and
Storage (including frozen)

Clinical products
21
Conclusions
1. Disposables can be utilized to fill the gap between a new
process and an existing facility
A.
Reduces time for technical transfer
B.
Reduces cost of technical transfer
2. Disposables have advantages and disadvantages
3. Utilize disposables to increase operational efficiency and
minimize cleaning/change over time
4. Disposables are introduced into existing facilities where it
makes sense
22