1 Biogen | Confidential and Proprietary
Raw Material Scale-up for Clinical
Manufacturing
Date July 16th, 2015
Dave Kolwyck
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Outline • Raw Material Scale-up during clinical development
• Critical Attributes for Raw Material Scale Up
• Critical Attributes during Supplier Manufacturing Process Scale-up
• Closing thoughts
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“Ideal” Raw Material Scale-up
Development
Clinical
Commercial
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Mid-Stage (PHII-PHIII) Commercial Early Stage (Pre-
Clinical/PH1)
Typical Raw Material Demand Profile
Clinical Molecule Development
Dem
and Q
uantity
Non-GMP
Pilot GMP /
Semi-GMP
Rapid Scale-up!
“The Lull”
cGMP Ramp Up
and Steady
State Demand
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Process Variation
Variation with Operational Scale
• Raw Variability
May correlate to the use of a specific sub-supplier or manufacturing process
Impact can be consistent or inconsistent/random
Raw Material Variation
Total Variation
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Raw material attributes that can result in
process variation during scale-up
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Physical Attributes
• The majority of raw material performance issues encountered have been related to previously
unknown shifts in physical attributes.
• Impurities profile differences potentially greatest contributor of media performance differences
• Consistency of the supply chain and source is important for some critical raw materials.
7
• Endo/Exo-toxin
• Bioburden
• Media hold duration and temp.
Adventitious Agents
• Particle size distribution
• Flowability
• Dissolution rate
Crystalline Structure
• Trace metals
• Line clearance in multi-use facility
• Extraneous Matter
Impurities
• Dissolution
• Performance for application
• Filterability
Mol. Wt. Profile
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N-2 N-1 N
Media A
Chem. 1
Supplier A
Supplier B
Chem. 2 Supplier C
Genealogical Patterns of Variation Inter-Supplier: Differences between suppliers
Intra-Supplier: Difference between lots from the same supplier
Inter-Site: Same supplier different sites
Intra-Site/Inter-line: Single supplier site but different production lines
Intra-Site/Intra-line: Supplier controls and starting raw materials
Basic Genealogy Tree
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• Multiple distribution nodes and sub-manufacturing sites
• Increase in demand can disrupt the supply chain network for some specialty raw materials
Supply chain maps can be complex
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Sub-supplier Changes
• As demand increases for a complex mixture of components, the sub-suppliers may change due to
increases in demand or upgrades in Quality / Grade of raw material.
• Example: Many salts such as MgCl2 are either mined or bi-products of other industries depending on
demand and potentially re-crystalized depending on purity/grade requirements.
Zr Production with
MgCl2 bi-product
11 Biogen | Confidential and Proprietary
How predictive is the pilot process?
• Some processes are not easily scalable in a linear manner
Example: Depth filtration and Plate and Frame filtration as they require a specific ratio of filtrate vol.,
flow rate and filter matrix to maintain a consistent charge potential.
Zeta Potential
Ask for large scale lots or demonstrate scaling for your process
12 Biogen | Confidential and Proprietary
Pilot Scale Production Process • Media and some chemicals can milled in several ways and that can impact particle size distribution
and critical performance attributes such as the dissolution profile.
Hammer Mill Ball Mill Pin Mill
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Scale up model should include all
manufacturing steps
• This includes:
Adventitious agent reduction
Filtration membrane type and surface to volume ratios
Final packaging and humidity protection
• Scale-up for post-manufacturing processing
• May reveal unintended scaling impact
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Does it really matter?
Yes!
Biotechnology and Bioengineering, Vol 96, Issue 3, 25 Aug 2006
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Questions to consider for your DS
supply chain Raw Material Risk Assessment for Scale-up
Who are your stakeholders?
7/27/2015
Clinical
Program Mgt.
Technical Mgt.
Org. Com.
PM Support
Operations
Production
Issues
Tech Dev.
Process and RM
Characterization
Planning and
Sourcing
Inventory Mgt.
Legal Agreements
RM Forecasts
Quality
RM Release
Investigations
Supplier Quality
VCNs
Suppliers
Raw Material
Knowledge/Data
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How does my future demand compare to
the overall supplier capacity?
If future demand exceeds or is a majority portion of supplier capacity then changes in
the supplier manufacturing process are more likely to keep up with demand.
?
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Particularly for some amino acids and sugars animal sources are often used at large
scale for animal feed supplementation (low cost drivers) and this should be
monitored to maintain animal component free production status.
Are there multiple manufacturing modes
for the raw material or sources of starting
material?
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A different source for a new grade can have an impact to the impurity profile which
may impact the manufacturing process.
Is the GMP grade the same as non-GMP
grade with more tests and controls or is
it a different manufacturing process?
Non-cGMP
cGMP
cGMP
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Raw Material Characterization during
Clinical Development
Define CQA’s of Raw Materials
Determine RM Attribute Ranges
Define CPP’s of Process
Define CPP’s and CQA relationship
Set Raw Material Specs/Limits
• Defining critical quality attributes of raw materials is continuous through process characterization
• Requires multiple raw material lots to determine normal “range” of variation
• Attributes of raw materials can change as a function of manufacturing scale
Quality
Technical
Development Manufacturing
Sciences
Materials
Procurement
Raw Materials
Governance
Team
Raw Materials Governance Team
Cross Functional Raw Materials Strategy Governance
Global Materials
Management
Governance Scope: Drug Substance Chemicals
Media/Biologics
Resin
Filters
Bags/Consumables
Tubing/Assemblies
Excipients
Label & Pack
22 Biogen | Confidential and Proprietary
Acknowledgements • Robin Hyde-Deruyscher
• Rashmi Kshirsagar
• Doug Osborne
• Robert Posgai
• Terrance Dobrowsky
• Greg Stromberg
• Erik Hughes
• Sarah Yuan
• Eliana Clark