The MIT Consortium on Adventitious Agent Contamination in Biomanufacturing

Michael E. Wiebe, Ph.D.Quantum Consulting

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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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1. To provide a collaborative environment for companies to share their experiences

2. To provide a forum for companies to network, develop collaborations and synergize

3. To identify best industry practices, and to provide opportunities for companies to benchmark

4. To sponsor collaborative research activities and initiatives that promote a better understanding of how to address adventitious agent contamination.

5. To promote the generation and application of new technologies

6. To make public a summary of consortium findings and recommendations.

Consortium Goals

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Consortium Operations & Management

●MIT CAACB Team● Program Director: Dr. Stacy Springs

● Lead Investigators: Michael Wiebe and James Leung

● MIT Faculty Investigator: Anthony J. Sinskey

● MIT Faculty & Staff: As Needed Per Consortium Projects

●Steering Committee● One individual from each member company

●Advisory Board● Kurt Brorson, FDA (CDER)● Marshall Dinowitz, Consultant● Jim Gombold, Charles River Laboratories● Bill Lucas, WuXi AppTec● Ray Nims, Consultant● Carol Marcus-Sekura, Consultant● Anton Steuer, BioReliance● Hannelore Willkommen, Consultant● Ruth Wolff, Consultant

Consortium Operations & Management

●MIT CAACB Team● Program Director: Dr. Stacy Springs

● Lead Investigators: Michael Wiebe and James Leung

● MIT Faculty Investigator: Anthony J. Sinskey

● MIT Faculty & Staff: As Needed Per Consortium Projects

●Steering Committee● One individual from each member company

●Advisory Board● Kurt Brorson, FDA (CDER)● Marshall Dinowitz, Consultant● Jim Gombold, Charles River Laboratories● Bill Lucas, WuXi AppTec● Ray Nims, Consultant● Carol Marcus-Sekura, Consultant● Anton Steuer, BioReliance● Hannelore Willkommen, Consultant● Ruth Wolff, Consultant

Key Components of Consortium

Fee-based Membership

● Full Members● Manufacture Biologics● Steering Committee

representation● Active participants in all

consortium projects including data contribution, results interpretation and report generation

● Associate Members● Do not manufacture Biologics (e.g.

Service Providers & Technology Companies)

● Active participants in projects focusing on technologies and methods assessments & development, roles to be defined

Fee-based Membership

● Full Members● Manufacture Biologics● Steering Committee

representation● Active participants in all

consortium projects including data contribution, results interpretation and report generation

● Associate Members● Do not manufacture Biologics (e.g.

Service Providers & Technology Companies)

● Active participants in projects focusing on technologies and methods assessments & development, roles to be defined

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Consortium Member Companies

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Consortium Activities

Consortium Activities

Purposes Participants

Information Sharing Projects

•To provide company information under NDAs on adventitious agent contamination events, preventive actions and risk mitigation strategies•To identify best practices to prevent adventitious agent contamination from the analysis of consolidated industry data

Member Companies

Sponsor Targeted Research Projects

•To sponsor targeted research projects that lead to better control practices, or new technologies that mitigate risk of adventitious agent contamination

Member Companies

Consortium Workshops & Symposia

•To learn of advances in selected technology areas•To contribute to the understanding of anonymous data collected from CAACB projects•To exchange ideas, experience and knowhow of industry practices

Delegates of Member Companies, Invited MIT faculty

Consortium General Meetings

•To report progress and future plans of CAACB to consortium body•To highlight technology advances and policy changes relevant to mission of CAACB

Delegates of Member Companies, Invited guests

Consortium Sponsored Meetings

•Forum to promote CAACB mission Public

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1. Learning from industry-wide experience and solutions, as compared to only learning from your company’s experience

2. Benchmarking your adventitious agent contamination strategy against best industry practice

3. Networking and establishing collaborations with individuals in other companies, to address similar adventitious agent issues and solutions

4. Learning first-hand how others have addressed adventitious agent contaminations, decontaminated facilities and implemented corrective and preventive actions.

5. 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.

6. Identification of best strategies to obtain regulatory approval for testing and process changes.

7. Sharing best approaches to making risk-based management decisions for implementation of improvements (or corrective actions) to mitigate low risk, high impact events.

8. 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.

Consortium Benefits to Member Companies

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Overview of Inaugural Project

The Collection and Analysis of Virus Contamination Data in Biomanufacturing

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● 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.

Virus Safety Record in Biopharmaceutical Manufacturing

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Virus Cell Year Company Reported By

EHDV CHO 1988 Bioferon GmbH Bioferon GmbH

MMV CHO 1993 Genentech Genentech

MMV CHO 1994 Genentech Genentech

ReovirusHuman

1˚Kidney1999 Abbott Labs FDA

Reovirus CHO ? ? BioReliance

Cache Valley CHO 1999 Amgen / CMO Amgen

Cache Valley CHO 2000 ? BioReliance

Vesivirus 2117 CHO 2003 Boehringer-Ingelheim

Boehringer-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

Virus Contaminations: An Industry-Wide Issue

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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.

Premise of Consortium Inaugural Project

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● Potential Issue For Patient Safety

● Production Shutdown● Product Stock Out● Lost Product And Lost Sales● Expense Of The

Comprehensive Investigation Required

● Delay In Product Approval● Exposes Company To Intense

Regulatory Scrutiny● Changes Public Perception Of

Product Quality

● Requires Development Of Comprehensive Plan For Corrective And Preventive Actions

● Manufacturing Plant Decontamination

● Encourages The Competition ● Complicates Partnerships

And Contractual Agreements● Exposes Company To

Lawsuits● Diverts Focus Of Company

Leadership

Potential Impact of Virus Contaminations

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● 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

● Companies are only really able to learn from their own contamination events.

Virus Contaminations: Company’s Have Learned Primarily From Their Contamination Event(s)

lack of industry wide knowledge

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● 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.

Potential Value of Industry-wide “Lessons Learned” Exercise

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Consortium Information DomainConsortium Information Domain

GeneralMember

(Data Contributor)GeneralMember

(Data Contributor)GeneralMember

(Data Contributor)GeneralMember

(Data Contributor)GeneralMember

(Data Contributor)

Confidential Information Is Protected

Steering Committee

AdvisoryBoard

AdvisoryBoard

Deliverables Available to CAACB Members

MIT CBI/CAACB Team

Project Data

Collection & Coding

Data Management

Data Analysis:Trend & Risk Analysis, etc.

AssociateMember

AssociateMember

AssociateMember

AssociateMember

AssociateMember

AssociateMember

Public ReportsSummary of Findings

Public Presentations Summary of Findings

Preview, ReviewAuthorize by Steering

CommitteeConfidentiality Barrier & Filter

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● 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● Source of Contamination● Process Breach Identification● Frequency of Contamination● Raw Material Treatment & Control System● Process Controls● Methods of Decontamination● Corrective Actions; Restart● Preventive Actions● Lessons Learned● Success of Actions Taken

Initial List of Information to Collect

All data will remain confidential via NDAs between companies and MIT

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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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Project Stage Target Completion

Develop data collection instrument, questionnaire, and process

Complete

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 forum (MIT Team & Industry Member Companies)

2012

Full research report to member companies; to include all methods, data analyses, findings, recommendations

2013

Publication of Research Summary Report: Major findings & recommendations

2013+

Continuous Updates & Expansion of Data: Collection & Analysis

2013+

Project Stages & Proposed Timeline

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● 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

2012 Consortium Workshops

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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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● Consortium Executive DirectorDr. Stacy Springs

email: ssprings@mit.edu

Tel: 1-617-253-3084

● Lead investigators

Dr. Michael Wiebe

email: quantumco@comcast.net

Tel: 1-650-365-7022

Contact Us

Dr. James Leung

email: leungjc@mit.edu

Tel: 1-781-333-8822