1 Biogen | Confidential and Proprietary

Raw Material Scale-up for Clinical

Manufacturing

Date July 16th, 2015

Dave Kolwyck

2 Biogen | Confidential and Proprietary

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

3 Biogen | Confidential and Proprietary

“Ideal” Raw Material Scale-up

Development

Clinical

Commercial

4 Biogen | Confidential and Proprietary

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

5 Biogen | Confidential and Proprietary

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

6 Biogen | Confidential and Proprietary

Raw material attributes that can result in

process variation during scale-up

7 Biogen | Confidential and Proprietary

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

8 Biogen | Confidential and Proprietary

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

9 Biogen | Confidential and Proprietary

• 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

13 Biogen | Confidential and Proprietary

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

14 Biogen | Confidential and Proprietary

Does it really matter?

Yes!

Biotechnology and Bioengineering, Vol 96, Issue 3, 25 Aug 2006

15 Biogen | Confidential and Proprietary

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

17 Biogen | Confidential and Proprietary

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.

?

18 Biogen | Confidential and Proprietary

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?

19 Biogen | Confidential and Proprietary

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

20 Biogen | Confidential and Proprietary

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

Questions?

7/27/2015