The MIT Consortium on Adventitious Agent Contamination in Biomanufacturing aims to identify best practices for preventing contamination of biomanufacturing processes. The Consortium will provide a collaborative environment for member companies to share experiences and develop solutions. Initial projects include collecting and analyzing industry virus contamination data in a confidential manner to determine risk factors and mitigation strategies. The goal is to advance practices for ensuring product safety and quality.

1. The MIT Consortium on Adventitious Agent
Contamination in Biomanufacturing
Michael E. Wiebe, Ph.D.
Quantum Consulting

2. Purpose of the Consortium
To combine the knowledge, experience and
resources of companies that manufacture, or
support the manufacture of biopharmaceuticals
or vaccines, to identify best practices and
technologies that control and mitigate the risk of
contamination of biomanufacturing processes by
adventitious agents.
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3. Consortium Goals
● To provide a collaborative environment for companies to
share their experiences
● To provide a forum for companies to network, develop
collaborations and synergize
● To identify best industry practices, and to provide
opportunities for companies to benchmark
● To sponsor collaborative research activities and
initiatives that promote a better understanding of how to
address adventitious agent contamination.
● To promote the generation and application of new
technologies
● To make public a summary of consortium findings and
recommendations.
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4. Key Components of Consortium
Consortium Operations & Management Fee-based Membership
●MIT CAACB Team ● Full Members
● Program Director: Dr. Stacy Springs ● Manufacture Biologics
● Lead Investigators: Michael Wiebe and James
Leung
● Steering Committee
representation
● MIT Faculty Investigator: Anthony J. Sinskey
● MIT Faculty & Staff: As Needed Per Consortium
● Active participants in all
Projects consortium projects including data
contribution, results interpretation
●Steering Committee and report generation
● One individual from each member company
●Advisory
● Associate Members
Board
● Kurt Brorson, FDA (CDER)
● Do not manufacture Biologics (e.g.
● Marshall Dinowitz, Consultant Service Providers & Technology
● Jim Gombold, Charles River Laboratories Companies)
● Bill Lucas, WuXi AppTec ● Active participants in projects
● Ray Nims, Consultant focusing on technologies and
Carol Marcus-Sekura, Consultant
●
methods assessments &
● Anton Steuer, BioReliance
development, roles to be defined
● Hannelore Willkommen, Consultant
● Ruth Wolff, Consultant
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5. Consortium Member Companies
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6. Consortium Activities
Consortium Activities Purposes Participants
•To provide company information under NDAs on
adventitious agent contamination events, preventive
Information Sharing actions and risk mitigation strategies
Member Companies
Projects •To identify best practices to prevent adventitious agent
contamination from the analysis of consolidated industry
data
•To sponsor targeted research projects that lead to
Sponsor Targeted Member Companies
better control practices, or new technologies that
Research Projects
mitigate risk of adventitious agent contamination
•To learn of advances in selected technology areas
•To contribute to the understanding of anonymous data Delegates of Member
Consortium Workshops
collected from CAACB projects Companies, Invited
& Symposia
•To exchange ideas, experience and knowhow of MIT faculty
industry practices
•To report progress and future plans of CAACB to
Delegates of Member
Consortium General consortium body
Companies, Invited
Meetings •To highlight technology advances and policy changes
guests
relevant to mission of CAACB
Consortium Sponsored
•Forum to promote CAACB mission Public
Meetings
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7. Consortium Benefits to Member Companies
● Learning from industry-wide experience and solutions, as compared to only
learning from your company’s experience
● Benchmarking your adventitious agent contamination strategy against best industry
practice
● Networking and establishing collaborations with individuals in other companies, to
address similar adventitious agent issues and solutions
● Learning first-hand how others have addressed adventitious agent contaminations,
decontaminated facilities and implemented corrective and preventive actions.
● Learning of cutting edge technologies that can be applied to virus testing and
contamination risk reduction, and providing guidance to technology providers as to
when new technology applications are ready for implementation.
● Identification of best strategies to obtain regulatory approval for testing and
process changes.
● Sharing best approaches to making risk-based management decisions for
implementation of improvements (or corrective actions) to mitigate low risk, high
impact events.
● Promotion of higher industry standards through consortium recommendations to
implement scientifically reasonable and beneficial testing and process
improvements, without being compelled to implement low value and potentially
burdensome changes.
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8. Overview of Inaugural Project
The Collection and Analysis of Virus
Contamination Data in Biomanufacturing
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9. Virus Safety Record
in Biopharmaceutical Manufacturing
● No rDNA derived product has been shown to transmit a viral safety
problem in 25+ years of biopharmaceutical manufacturing.
● This can largely be attributed to lessons learned from the past history of
biologics manufacturing, and the implementation of a comprehensive
multifaceted approach to prevention and control.
● Master Cell Bank testing
● Raw material testing & source control
● Closed manufacturing systems; Unidirectional flow
● Identification of viruses that replicate in the engineered cell substrate
● Lot by lot virus testing
● Downstream processes for virus clearance; Separation or pre- and post-
virus clearance steps
● However, we know that adventitious viruses have contaminated cell
culture biomanufacturing operations.
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10. Virus Contaminations: An Industry-Wide Issue
Virus Cell Year Company Reported By
EHDV CHO 1988 Bioferon GmbH Bioferon GmbH
MMV CHO 1993 Genentech Genentech
MMV CHO 1994 Genentech Genentech
Reovirus Human 1˚Kidney 1999 Abbott Labs FDA
Reovirus CHO ? ? BioReliance
Cache Valley CHO 1999 Amgen / CMO Amgen
Cache Valley CHO 2000 ? BioReliance
Vesivirus 2117 CHO 2003 Boehringer- Boehringer-
Ingelheim Ingelheim
Cache Valley CHO 2003 ? BioReliance
Cache Valley CHO 2004 ? BioReliance
Hu Adenovirus HEK 293 ? Eli Lilly Eli Lilly
MMV CHO 2006 Amgen Amgen
Vesivirus 2117 CHO 2008 Genzyme, Belgium Genzyme
Vesivirus 2117 CHO 2008 Genzyme, USA Genzyme
Vesivirus 2117 CHO 2009 Genzyme, USA Genzyme
MMV CHO 2009 Merrimack Merrimack
PCV-1 Vero 2010 GlaxoSmithKline GlaxoSmithKline
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11. Premise of Consortium Inaugural Project
The confidential collection of industry-
wide viral contamination data and a
subsequent risk analysis assessment would
be a highly valuable “lessons learned”
exercise for industry, and could guide
companies in best practices to mitigate the
risks that lead to these events.
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12. Potential Impact of Virus Contaminations
● Potential Issue For Patient ● Requires Development Of
Safety Comprehensive Plan For
● Production Shutdown Corrective And Preventive
Actions
● Product Stock Out ● Manufacturing Plant
● Lost Product And Lost Sales Decontamination
● Expense Of The ● Encourages The Competition
Comprehensive Investigation
Required ● Complicates Partnerships
And Contractual Agreements
● Delay In Product Approval ● Exposes Company To
● Exposes Company To Intense Lawsuits
Regulatory Scrutiny ● Diverts Focus Of Company
● Changes Public Perception Of Leadership
Product Quality
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13. Virus Contaminations: Company’s Have Learned
Primarily From Their Contamination Event(s)
● Many companies have not publically disclosed virus contamination
events
● No obligation to disclose unless the contamination results in a “material
change” to the business
● Motivated by concerns for negative publicity.
● This is well known in the industry.
● Some companies do not notify regulatory authorities
● Companies that have disclosed rarely describe the event in sufficient
detail to be of significant value
lack of industry wide knowledge
● Companies are only really able to learn from their own contamination
events.
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14. Potential Value of Industry-wide
“Lessons Learned” Exercise
● Identification Of Industry Risks
● Which viruses have contaminated operations?
● What virus sources have been identified?
● What are the most likely process breaches?
● Which cell lines are most likely to be contaminated?
● Do some process designs have higher risk? (batch vs. perfusion)
● Identification of effective barriers
● Is there value in raw material testing?
● Has the elimination of animal derived raw materials lowered the
frequency of virus contamination?
● How effective are procedures used to inactivate virus in cell culture
media before use?
● Is there value in using molecular virus detection methods for in-process
testing?
● Shared information could save industry millions of dollars
and prevent a potential patient safety catastrophe.
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15. Confidential Information Is Protected
Consortium Information Domain
General
Steering Advisory
Member
General Committee Board
(Data Contributor)
Member
General
(Data Contributor)
Member
General
(Data Contributor)
Member
General
(Data Contributor)
Member
(Data Contributor) Deliverables Available to
CAACB Members
MIT CBI/CAACB Team
Project Data Management
Data
Collection Data Analysis:
& Coding Trend & Risk
Analysis, etc.
Associate
Member
Associate
Preview, Review
Member
Associate Authorize by Steering
Member
Associate Confidentiality Committee
Member
Associate Barrier & Filter
Member
Associate
Member
Public Reports Public Presentations
Summary of Findings Summary of Findings
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16. Initial List of Information to Collect
● Virus Identification
● Method of Virus Detection & Identification
● Experience with False Positive Tests
● Investigation Organization & Management
● Communication with Regulatory Authorities; others
● Cell Line Contaminated
● Extent of Contamination All data will remain
● Source of Contamination confidential via NDAs
● Process Breach Identification between companies
● Frequency of Contamination
● Raw Material Treatment & Control System
and MIT
● Process Controls
● Methods of Decontamination
● Corrective Actions; Restart
● Preventive Actions
● Lessons Learned
● Success of Actions Taken
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17. Project Goals
1. Collect and analyze consortium member virus
contamination data (if experienced by member)
2. Compile processed data into a searchable
database with access for members while
maintaining confidentiality
3. Uncover any new risk factors for contamination
4. Determine best industry practice to mitigate risk
5. Identify technology gaps for further R&D
6. Publish summary of key findings from the project
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18. Project Stages & Proposed Timeline
Project Stage Target Completion
Develop data collection instrument, questionnaire, and Complete
process
Raw data collection from participating members & partners In Progress
Anonymous data pooling, annotated and collated 2012
Preliminary report to member companies 2012
Analysis of processed data; Interpretation from CAACB 2012
forum (MIT Team & Industry Member Companies)
Full research report to member companies; to include all 2013
methods, data analyses, findings, recommendations
Publication of Research Summary Report: Major findings & 2013+
recommendations
Continuous Updates & Expansion of Data: Collection & 2013+
Analysis
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19. 2012 Consortium Workshops
● Media Treatment Workshop
● Sharing of experience with HTST, UV-C, nanofiltration and other methods of
virus inactivation or removal
● Where – MIT, Cambridge, MA
● When – June 21 & 22, 2012
● Open to Consortium member company participants and invited speakers
● Virus Contamination Project Workshop
● Currently in planning phase
● To present early draft of collected data; to solicit input on data interpretation
● When – Q4, 2012
● Open to Consortium member data contributors
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20. How to Join
● Written information to be sent for review and
discussion with colleagues and management
● Teleconference and/or company visit with
Consortium Staff
● Consortium agreement and membership fee
● Company representatives to steering committee
determined
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21. Contact Us
● Consortium Executive Director
Dr. Stacy Springs
email: ssprings@mit.edu
Tel: 1-617-253-3084
● Lead investigators
Dr. Michael Wiebe Dr. James Leung
email: quantumco@comcast.net email: leungjc@mit.edu
Tel: 1-650-365-7022 Tel: 1-781-333-8822
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