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Best Practice in Biomanufacturing Round Table
AAPS National Biotechnology Conference June 2015 San Francisco
Jason Starkey, Satish Singh, Michael Adler, Karoline Bechtold-Peters, Katie Maass, Pankaj Paranjpe [Pfizer, Roche, MIT, Celgene]
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Best Practice in Biomanufacturing: People
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• Organizer/Moderator: Satish Singh, Pfizer
• Moderator/Presenter: Jason Starkey, Pfizer
• Presenter: Michael Adler, Roche
• Presenter: Karoline Bechtold-Peters, Roche
• Student moderator: Katie Maass, MIT
Best Practice in Biomanufacturing
Agenda
• Introduction (10 min)
• Topics (10 min each x 3)
• Process risk assessment and control strategies-Michael Adler
• PAT solutions-in line/at line and latest developments-Jason Starkey
• Single-use technologies in biologics DP mfg. processes- Karoline Bechtold-Peters
• Q&A (50 min)
Format
• Round Table
• Q&A:
• Please use microphone to ask Questions OR
• Submit Questions using index cards to Katie
• Participate, debate, present alternative point of view!
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BioPharma- New Paradigm
Capacity
Smaller Batch sizes
Smaller Budgets
Increased flexibility
Improved turn around
Multi-product facilities
Product Robustness
Process control
Fast, Flexible, Inexpensive
Adapted from Xcellerex Presentation , 2007. Parrish Galliher
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AAPS NBC Roundtable Discussion
Process Risk Assessment and Control
Strategy
Michael Adler
Process Risk Assessments during Product
Life Cycle
Taken from A-Mab Case Study
Approaches to Control Strategy
Traditional Approach:
Identify potential CQAs
Process development research often conducted one variable at a time
Define an appropriate manufacturing process
Define a control strategy to ensure process performance and product quality
Enhanced Approach:
Identify potential CQAs
Determining the functional relationships that link material attributes and process parameters to CQAs
Multivariate experiments to understand product and process
Use enhanced knowledge to establish a risk based control strategy which can include a proposal for a design space(s) or real-time release testing
Control Strategy not
systematically linked
to understanding of
CQA criticality or
process control
Control Strategy
systematically linked
to understanding of
CQA criticality and
process control
QbD Approach to Control Strategy Design
CQAIdentification
Using RA Tool
Assess Process
Impact/Stability
Impact
Design Attribute Testing
Strategy based on CQA
and Process Impact
Knowledge
Determine CQA
Acceptance
Criterion (CQA-AC)
Overall Control
Strategy
What attributes are
important? What levels?
Does the process control the
CQAs within those levels?
Are they stable?
What needs to be tested?
QbD provides a systematic approach to answer these questions
Critical Quality Attributes Process Control
Control Strategy
Do we have a robust process
& testing strategy?
Doing now what patients need next
Application of PAT in Biologics Manufacturing Jason Starkey Ph.D.
Pfizer, Inc
Focus: PAT in Manufacturing
Expected Outcome
State of the Art
Questions Next Steps
Focus of PAT How can process analytical technologies facilitate the manufacture and development of biological drug substance and drug products?
Move the analytics to the process
Expected Outcome: Where is the value of PAT
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Process
Understanding
Process
Control
State-of-the-Art Technologies • Evolving Technologies
– Optical Sensors and Visual Detection
– Spectroscopy
• Moisture quantitation
• Excipients quantitation
• TDLAS
– Chemometric Models
– On-line UPLC
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Next Steps: What are the most daunting challenges?
• Flexible and Adaptive Manufacturing Capabilities – Analytics and technologies to allow scale and site
transfers – Single use sensors
• Rapid Microbial Methods – Real time endotoxin and bioburden testing
• Real Time Release Capabilities
– Remote and real-time monitoring, at-line and on-line data
– Future capability to replace DS release testing
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Application of single use technologies in
biologics drug product manufacturing
processes
Karoline Bechtold-Peters1,
Christian Matz1, Satish Singh2
1 F. Hoffmann-La Roche
2 Pfizer
What SUTs can be used in DP manufacture?
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Isolators
Storage, mixing and holding bags (2D/2D)
Tubing, needles, surge tanks, assembled whole filling sets
Filters
Liquid Transfer Ports and other ports
Transfer bags
Powder bags
Aseptic connectors
Sampling bags
Covers
Pros and cons (here specifically for material in contact with product)
Advantages
• Less discussion on cross-contamination when dealing with high potent drugs manufacture
• Avoidance of cleaning validation or verification
• No discussion on dedication of equipment or not
• Increased sterility assurance (closed system)
• Reduced burden to qualify/calibrate/store/purchase and use of stainless-steel equipment,
– Saving of maintenance costs
– Saving of CIP/SIP-(re-)validation costs
– Energy savings of WFI and clean steam for CIP/SIP
– Reduction of capital bound as CAPEX
• Higher production flexibility e.g. because various sizes available
• Provision lead times may be no issue (if inventory well managed)
• No metal ion leaching (discolor., oxidation, aggr.)
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Disadvantages
• Discussion on leachables and when to generate/use product-specific data during development (phase-appropriate)
• Difficulty to align within global companies since plethora of disposible items on the market
• Absence of standardization
• Dependency on supplier and his quality systems (changes, consistency of manufacturing process, sterilization)
• Costs on long run ?
• Waste management (volume!)
• Interchangeability discussion
• «Compatibility» (interconnection) of various systems?
• Adsorption/permeation of active or of excipients
• Potential of damage during transportation and handling
Considerations when switching to SUT in DP manufacturing
• DP and DS may be handled here differently, since there is no further purification step after SUT exposure in DP manufacture
• Differentiation between SUT in direct product contact and non-contact material, long-term or short-term contact
• Critical features are e.g.:
– Leachables/extractables
– Endotoxins
– Particulates
– Compatibility with product
– Sterility
• A reasonable and risk-based approach during clinical development may depend on prior knowledge/experience, i.e. a generic rationale (non product –specific) may be adequate during clinical development based on supplier data, surrogate data (e.g. with WFI, WFI plus surfactant) and previous product data
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Doing now what patients need next