The Evolution of Upstream Processing: Mitigating Risk through Single Use

& Cell Culture Technologies

Joshua Hays – Upstream Technology Director MilliporeSigma

26.April.2016 - Interphex, NYC

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What is Risk?

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Some food for thought…

Average upstream biomanufacturing process comprises up to 70% of the overall cost ($$ and time) of each batch

Cell culture media (production & seed train)

Support structure (buffer & media prep)

Labor (assuming a typical 14-day mAb process)

Many other process specific factors

Upstream Virus Contamination in Biopharma

Source: Case Studies of Microbial Contamination in Biologic Product Manufacturing Suvarna, K., Lolas, A., Hughes, P., Friedman, R. Biotechnology Manufacturing Team, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drug Evaluation and Research, Food and Drug Administration

“Genzyme expects a fine of $175 Million

…$100-300 million in lost sales.”

– Pollack, Andrew. “Genzyme Drug Shortage Leaves Users Feeling Betrayed.” The New York Times, April 15, 2010.

Genentech 1993

“…two contaminations …No definitive source

identified.” – Garnick, R.L. “Raw Materials as a Source of Contamination in Large-Scale Cell Culture.” Dev Biol Stand. 1998; 93:21-9.

Genzyme 2009 GSK 2010

“Vaccine Contamination Sparks Fears.”

– Alazraki, Melly. “GlaxoSmithKline’s

Rotavirus Vaccine Suspended for Pig Virus

Contamination.” InvestorCenter, May 23,

2010.

Upstream processing is at particular risk for virus contamination

Multiple sources of potential adventitious virus exist within the mfg. process

High profile contaminations have risen awareness for upstream virus safety

Virus contamination is a business risk, because of the cost and disruption of contamination events

Cost of Contamination – Two “Cost Buckets”

Lost Raw Materials

Investigation

Cleaning

Production Shut Down

Re-Validation

Additional Regulatory Audits

Product Recall

Lost Market Share

Legal Liabilities

Brand Damage

Internal Contaminated product never leaves facility

External Contaminated product reaches patients

Let’s quantify just that lost revenue piece…..

$ 1,000,000,000

Jonathan D. Rockoff, The Wall Street Journal, “Drug Manufacturing Mending After Questions of Quality”, June 11, 2010

http://online.wsj.com/news/articles/SB10001424052748703627704575298872338013864

Yes, that’s Billion with a ‘B’

So…. How do I reduce my risk??

With a holistic evaluation of your process

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Cell Line Engineering

Targets to Reduce MVM Uptake and Propagation

Create a CHO parental cell line (CHOZN® background) that is resistant to (or cannot propagate) an MVM infection

Target receptor Target viral replication pathways

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HTST Dedicated Media Viral Filtration

Component Pre-Treatment

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Single-Use: Systems, Sterile Connectors and Sterile Filtration

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EHS/Operational Considerations

Compacted Cell Culture Media

Powder delivery solutions

Hygroscopic chemical storage

Improved, stronger films

True Redundancy in cGMP Manufacturing Capability

St. Louis, MO NA Site – Liquid Only

SAFC Distribution Sites Only

Lenexa, KS NA Site – DPM Only

Harmonized Supply Chain Management Program

Harmonized Quality Systems

Harmonized Milling Technology

True Redundant Supply – Reduced Risk Irvine, Scotland

EU Site – DPM & Liquid

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Cell Culture PD Viral Inactivation Cell Culture Clarification Affinity Chrom

Viral Clearance Ultrafiltration Sterile Filtration Final Formulation

Polishing Chrom

Purification Chrom

Buffers and CIP Solutions Cell Culture Media Specialty Chemicals Key:

Think Big Picture and Entire Bioprocess, not individual steps

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Thank you Questions?