ISIA /JAACT Meeting Rosemary J Verstegeen Ph.D.

November 2016

Thank you! JAACT

and

NICHEREI BIOSCIENCES INC

• What is ISIA ? • A brief history of serum use • ISIA product characterization programs

– Standardization – Traceability – Origin testing – Risk mitigation

• Regulatory efforts

Agenda

• International Association of serum producers, suppliers and customers, founded in 2006

• Members supply more than 90% of all animal serum used globally

• Members are also major suppliers of other animal derived products

• Protein, Antibodies, Enzymes, etc. – Expanded mandate includes all animal derived products

• Currently 57 members – All major suppliers – Several large end-user companies

International Serum Industry Association

ISIA Global Membership

ISIA Mission

• ETHICS - ISIA shall establish, promote and assure compliance

with uncompromised standards of excellence

and ethics in the business practices of the

global animal serum and animal derived

products supply industry.

• SAFETY AND SAFE USE - Primary focus will be on safety and safe use of serum and animal derived products through proper origin traceability, truth in labeling, and appropriate standardization and oversight.

• EDUCATION - Work to educate stakeholders on the scientific

foundation of the safe use of serum and animal

derived products.

Members

Bovine Derived Products

• Animal serum is used extensively in » Life science research

» Production of human and animal vaccines

» Production of biopharmaceuticals

» Production of diagnostic products

• Total liters of FBS is in excess of 700,000 per annum – Liters of other serum are in vastly in excess of this number

• The Biotechnology industry is a multibillion dollar business affecting healthcare worldwide relying extensively on serum and animal derived products as essential raw materials

Industry Background

• Fetal bovine serum (FBS) has had an impressive

historical validation after more than 65 years of safe use

– Salk Vaccine in the early1950 • No thing else has the same broad spectrum cell growth promoting capabilities • FBS is still the media additive of choice for use in basic research applications

The demise of FBS has been predicted

since the early 1960s

A Brief History

• Over time, concerns have arisen over utilization of animal derived materials in healthcare related manufacturing – Guidance from major regulatory bodies against their

use any time in the last 20 years • Considerable efforts have been made to avoid the

use of animal derived materials with some success – Variability exists in what works for what

• Anyone developing a new process will try to avoid using serum and animal derived materials – But it doesn’t always work

Where are we now?

80% used in industrial applications

Serum Use by Geography

• What are the alternatives – “defined” – “serum-free” – “chemically defined”

• Lack of clarity on what these terms mean

– “Serum free” may actually contain serum fractions – Chemicals may be produced using animal derived

components • How far down the chain needs to be “animal

free” – How do you audit for that? – Issues with plant materials?

• Plant and animal

Concerns

• By-product of the meat industry – All serum comes from animals deemed fit for human consumption

by competent government authorities

– Fetuses come from dams deemed fit for human consumption • These materials do NOT become part of the food chain!!

– Material from many animals is pooled • Possible viral contamination

• Biotechnology companies prefer serum from certain geographies based on disease prevalence and rigorous infrastructure – FMD, BSE and other infectious agents

– NZ, Australia and USA preferred

Serum Sourcing

Serum Countries of Origin

• Some things still work best with serum • Primary cells • Some Cells producing extensively modified proteins • Legacy Products (cost to switch) • Products that need to happen quickly

• Demand for serum and other animal derived components continues to increase,

suggesting that they are not going away

So ….how do we use these materials safely and

effectively?

However….

ISIA Programs impacting

Product Characterization

in October 2015

• Standardization of definitions – Minimize customer confusion – Just revised

• Standardization of testing

– USP collaboration • Chapters <1024> and <90> • Fetal bovine serum standard

– Under revision

Product Characterization

• Current Critical Programs –Traceability –Origin testing –Gamma Irradiation

Product Characterization

Traceability An important risk mitigation program

Why the program works!

• Independent Audit

• Covers all transactions

• in the company

– Not just those for a specific customer

• Focuses on each handoff

– What came in at what price ?

– What went out at what price ?

• Certification not available for purchase

Scope of Traceability

• What happened to the product every step of the way from the abattoir to the customer

• Not just Origin

• Paperwork for exportation

• What kind of serum is it ?

– Blending of serum types and origins

– Serum alternatives

• Has it been treated

• Does it comply with all ISIA requirements

Certification is granted for three years No historic claims

Traceability Certified Companies

• Life Science Production

• Moregate Biotech

• Newman Biotech Australia

• Proliant Health & Biologicals

• River City Biologicals

• Rocky Mountain Biologicals

• VWR/Seradigm

• SeraTec LLC

• Serum Technologies

• Vacca Biologics LLC

• Abattoir Basics Company

• Animal Technologies Inc.

• Atlas Biologicals

• Axenia Biologix

• BioArra

• Biomin Biotechnologia

• Boval BioSolutions

• By Productos S.A. de C.V.

• Central Biomedia Inc

• GE Healthcare

• Gibco Thermo Fisher Scientific

70% of companies that have been members for more than 2 years

are certified or in the certification process

Status

• Increasing awareness and acceptance of program

– Australian government

• Ongoing effort to keep current through program revisions

• Testing methods under

investigation as addition

to the program

Origin Testing An important risk mitigation program

Geographic Origin

There have been hints!

• In 1997 we became

aware that strontium

isotopes might provide an indication of geography of origin………..

• In 2013 we became aware that heavy water isotopes were being used to determine geographic origin for other materials

Isotopic Testing

• In 2014 we heard about – How the heavy isotope technology

works and that the technology was valid • Origin of hamburgers in the USA!!

• We designed a pilot study to investigate heavy isotopes with samples from known geographic origin

• We also identified another testing method using trace elements and set up another another pilot study

Why are we interested?

87Sr/86Sr

The application of stable

isotope and trace

element analysis can

distinguish

materials that are

chemically identical.

2H/1H

18O/16O

13C/12C

15N/14N

Pilot Study Stable Isotopes

USA and

Mexico not

separated

Pilot Study Trace Elements

USA and Mexico

separated!!

Current Comparison

• Further analysis confirms better

resolution using trace elements

• Current results give 99%

certainty for geographies tested with

more than150 samples tested so far

• We are working to define an industry

data base and develop a program to

identify geographic origin

Current Status

• After considerable investigation and discussion

• We are also monitoring for other technologies to determine origin and age of source

• Antibody based methods

We are in the process of finalizing

an agreement to develop an

industry wide trace element data

base

Future of Traceability

• Combination of testing and paperwork audit will strengthen the program

– Continued focus by ISIA

• Increased focus from customers and regulators will also strengthen the program

Gamma Irradiation An important risk mitigation program

Gamma Irradiation Task Force

• A proposal was made in October 2015 at a meeting with US regulators to allow FBS irradiated outside the USA to be imported

• All parties knew there was a need to understand this subject better

• ISIA volunteered to work on this project

• Several months were spent recruiting experts – First meeting January 2016

©2016 ISIA Confidential & Proprietary

What is the concern?

• Many customers, suppliers and others do not fully understand gamma irradiation

• Although not perfect, ISIA recommends Gamma Irradiation as THE method of choice for post manufacturing treatment of serum

• “Suppliers are secretive”

• “There don’t seem to be any rules

about how the process is validated”

• “Gamma kills all viruses”

• “All the big suppliers have their own

irradiation facilities”

Task Force Participants

Participant Affiliation Representing

Sue Brown TCS Biosciences Supplier

Bart Croonenborghs Sterigenics Irradiator

James Dunster Moregate BioTech Supplier

Debbie Elms Thermofisher Scientific Supplier

Randy Fitzgerald Proliant Supplier

Greg Hansen GE Healthcare/HyClone Supplier

Karl Hemmerich Ageless Processing Technologies End-users

Huw Hughes Zoetis End-users

Robert J. Klostermann Merial End-users

Ray Nims RMC Pharmaceutical Solutions End-users

Mark Plavsic Torque End-users

Andy Pratt GE Healthcare End User

Mara Senescu STERIS Irradiator

Pierre Leonard GSK End User

Martell Winters Nelson labs End User

Marc Wintgens Excellencia End user

©2016 ISIA Confidential & Proprietary

Approach

• It was agreed that

– We would not wait until this was perfect or totally complete to begin publishing

• Or it might never happen…...

– The task would be broken up into several parts

– These parts would stand alone and be published as ready

• FDA requested that this be freely available!

– We might turn this work into a standard eventually

©2016 ISIA Confidential & Proprietary

Areas of Focus

The task is currently broken into 6 parts with different experts taking the lead

FOCUS LEAD STATUS

Introduction to Gamma Irradiation and Serum

RJV and Karl Hemmerich Published

Effect of Gamma Irradiation on viruses

Mark Plavsic and Ray Nims Punlished

Dose mapping and validation Andy Pratt and Bart Croonenborghs

Will be published today!!

Effect of gamma irradiation on polymers

Karl Hemmerich and others Almost final

Product Maintenance through the process

Sue Brown and Mara Senescu Outline complete

What does all this mean? TBD Waiting for solid drafts of first 5

©2016 ISIA Confidential & Proprietary

Publication

All articles will

be published in

BioProcessing

Journal in open access

Links to Published Papers

©2016 ISIA Confidential & Proprietary

Gamma Irradiation of Animal Serum : An Introduction http://www.biotechnoblog.net/XTQ53/J152-Versteegen-HTML/J152-Versteegen-HTML.html

Gamma Irradiation of Animal Serum : Validation of Efficacy for Pathogen

Reduction and Assessment of impacts on Serum Performance http://www.biotechnoblog.net/XTQ53/J152-Plavsic-HTML/J152-Plavsic-HTML.html

Gamma Irradiation of Frozen Animal Serum : Dose Mapping for Irradiation

Process Validation Coming today

What else do we do?

• The blood derived products industry is considerably more complex than expected by non-participants

• ISIA is committed to the simplification and global harmonization of appropriate regulation

• ISIA believes that education should precede regulation

• Failure to educate has led to complexity and impracticality of regulations

Community Relations Philosophy

• November 2006 - ISIA begins our outreach and educate program • First meetings with SANCO, DEFRA and others

• Over time ISIA has become an active and credible partner, working as a single point resource with regulatory agencies and associations worldwide:

• Working to strengthen the understanding of the use of serum and blood derived products

• Helping to clarify safety related issues

• A source for information that is not always openly available or simple

– Guidance Document

• Dramatically expanded network • Associations

• Member States

• World Bodies

• Regulators

Community Relations

Thank You!

Looking forward to better

understanding your needs!

Contact me at

rjv@serumindustry.org

Join us May 3 and 4th 2017 in

Hong Kong for the

12th Annual ISIA Meeting

Information available at

www.serumindustry.org

Download this presentation from

www.nichirei.co.jp

Thank You!