GLOBAL CHEMICAL REGISTRATIONS:

TESTING STRATEGIES AND CMO

COMMUNICATION

HPAPI Summit

June 21, 2017

Jessica Graham, Ph.D., DABT

Senior Research Investigator, Product Quality

and Occupational Toxicology

Bristol-Myers Squibb

Background Toxicology Testing: Regulatory Submittal Support

2

BMS Occupational Toxicology provides support for

regulatory submittals required for

manufacturing/import/export of key pharmaceutical

intermediates

Require: phys-chem/toxicity/ecotoxicity testing

Routine meetings with international BMS EHS and GMS

(Global manufacturing and Supply) to foster

awareness of compounds in manufacturing and

maintain open communication.

Overview

Brief Overview: International Chemical Registrations

EU REACH, Korea “REACH” and

China MEP Registrations

Testing Strategies for International Registrations

Communication of Registrational Testing Needs

Issues

Process Improvements

3

EU REACh

EU REACh (Registration, Evaluation, Authorisation and

Restriction of Chemicals)

REACh is an EU Regulation and is therefore also national

law in all EU countries (Since 2007)

REACh places greater responsibility on industry to manage

the risks that chemicals may pose to health and the

environment.

Registration generally required for key pharmaceutical

intermediates:

Import

Manufacture

4

Korea REACh

Similar to EU REACh

Came into force Jan. 1, 2015

Korean Labs – Still working to understand testing

requirements

Hesitant to replace in vivo studies with in vitro studies –

unclear if always acceptable

Acceptability of OECD 422 in place of OECD 407 and

OECD 421

Studies performed individually

Box checking vs. Testing strategy

English reports acceptable

5

China REACh

Ministry of Environmental Protection (MEP)

Came into force Oct. 15, 2010 (replaced 2003 regulation)

Similar requirements as EU and Korea

Differences / Challenges:

In vitro options (skin/eye irritation, sensitization, etc.)

CROs (China/US/EU/UK) Hesitant to replace in vivo studies

with in vitro studies – unclear if always acceptable

Report summaries needed in Chinese

Ecotoxicity Testing – Some tests are required to be performed

in China

Level 1: Acute Fish Toxicity, Biodegradation, Earthworm

Regulations are still evolving

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Toxicity Studies 7

Test OECD Guideline EU Korea China

Acute oral toxicity OECD 420

Acute inhalation toxicity OECD 436 one route one route both routes

needed

Acute dermal toxicity OECD 402 one route one route both routes

needed

In vitro skin

corrosion/irritation OECD 435/439

In vitro eye irritation OECD 437

Skin corrosion/irritation OECD 404

Eye corrosion/irritation OECD 405

Skin sensitization OECD 429

Ames test OECD 471

In vitro micronucleus study/

In vitro Chrom abs OECD 473

Tonnage Requirements: ≥1 - <10 ≥10 - <100

Toxicity Studies (cont.)

Test OECD

Guideline EU Korea China

In vitro micronucleus study/

In vitro Chrom abs OECD 473

Mouse Micronucleus test OECD 474

Chromosome aberration OECD 475

Mouse Lymphoma Assay OECD 476 Pending Pending

In vivo comet OECD 489 Pending Pending

28-day Repeated Dose OECD 407 or OECD 422 or OECD 422 one route

or OECD 422

90-Day Repeat Dose OECD 408

Reproduction/Developmental

Toxicity Screening Test OECD 421 or OECD 422 or OECD 422 or OECD 422

Combined Repeat Dose

Reproduction/Developmental

Toxicity Screening Test

OECD 422 In place of

OECD 407/421

In place of

OECD 407/421 Recovery phase

Toxicokinetic assessment

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Tonnage Requirements: ≥1 - <10 ≥10 - <100

Eco-Toxicity Studies

Test OECD

Guideline EU Korea China

Acute Toxicity to Daphnia

magna OECD 202

Acute Toxicity to Fish OECD 203 In China

Toxicity to micro-organisms;

Activated sludge -

Respiration inhibition test

OECD 209 ≥100

Algal Growth Inhibition Test OECD 201

Ready biodegradability OECD 301B In China

Hydrolysis as a function of

pH OECD 111

Adsorption & Desorption;

Soil adsorption coefficient

(Koc)

OECD 121

OECD 106

OECD 121 or

OECD 106 is

acceptable

≥100 OECD 106

Earthworm Acute Toxicity OECD 207 ≥100 In China (dep)

Daphnia Reproductive Test OECD 211 In China (dep)

Bioaccumulation OECD 305 In China (dep)

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Tonnage Requirements: ≥1 - <10 ≥10 - <100

Testing Strategy: Data sharing across geographies

EU and Korea registrations

EU (most member countries), US, Korea: OECD nations

Applicable tests performed in both countries can fulfill requirements for both

registrations

Similar testing requirements

China registrations

China is not an OECD Nation

Acceptability of studies (conducted in China) by EU/Korea – opinions

differ among consultants and CROs

Chinese labs have submitted ecotox studies w/o negative feedback from

EU/Korea

Uncertainty @ whether EU/Korea evaluated the data (<5% evaluated)

Some ecotox studies required to be conducted in China (fish, etc.)

Cannot fully satisfy with EU/other country-based study reports

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China MEP Registration:

Conducting studies in China

Some ecotox studies required to be conducted in China

EU/US CROs

Timing:

1-2 months to ship material from CRO to China

Final report 5-9 months from test item receipt

Directly contract with MEP Lab: ~4 months total

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EU/US

CRO

Chinese

Consulting

Firm

MEP

Approved

Lab

US

Sponsor

Test

Item

Final

Report

China MEP Registration: Timing

(Formal Notification ≥1MT)

Overall Time Required:

Varies based on testing required/waived; test item

characteristics/availability

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Testing

• Contract CRO

• Protocol

• Study

• Final Reports

Dossier Preparation

• Translation of

Report Summaries

to Chinese

• Risk Assessment

Report

• Notification Report

Notification

• Submission of

Notification to

CRC-MEP

• Committee

Review

MEP Decision

• Approved

• Not Approved

8 -11 months 2 months 2 - 3 months 3 – 5 weeks

12 – 18 months

Global Company –

Global Chemical Registrations

Internal and external manufacturers in

numerous countries are typically used

by Big Pharma

The manufacturer in the country is

legally responsible for the

registration

Contract Manufacturing

Organizations (CMOs) CMO may

go off and do testing themselves

which can be problematic if there

is not good communication with the

Sponsor

Registration may be included in

manufacturing costs

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Internal procedures for obtaining

data needed for registrations

Regulatory

Body

CRO /

Consultant

CMO

Sponsor

Needs to be Communicated

Pros/Cons of Sharing Testing

Responsibilities with the CMO

Knowledge of MOA of test items

Knowledge of compound characteristics

Direct communication with CRO

Sponsor has some control/oversite

of study/interpretation

CRO Due Diligence

Animal Welfare Assessment

Quality Assessment

Assessment of data reliability

Sponsor owns reports/data

Knowledge of what is being submitted

to regulatory bodies in other countries

Registration is the CMOs responsibility

Testing at China/Korea CROs generally

less expensive than EU/US labs

Translation of reports is expensive

CMO lacks expertise in monitoring

testing

CMO’s criteria for CRO acceptability?

CMO owns reports/data

Potential issue if switch CMOs or

need to register in another jurisdiction

Sponsor may be unaware of information

in the dossier submitted

Sponsor CMO

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BMS Strategy: Sponsor Controlled Testing

Sponsor should be accountable for testing

Sponsor drives Testing Strategy

Sponsor utilizes CROs

Sponsor engages in data sharing across geographies

Advantages:

Prevent duplication of tests

Knowledge of data submitted in all jurisdictions

Knowledge of upcoming/pending/existing registrations

Knowledge of location and credentials for CRO selected

for testing

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Clear Communication

Interpretation of the regulations

CMO Colleagues

CRO

Consulting Firm preparing the Dossier

Sponsor: Legal

When in doubt, check with your legal department.

Professional experience

What constitutes off-site transportation of a material?

Which compounds need a registration?

Strictly controlled conditions – Pass an Audit?

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Summary

Sponsor should drive the testing strategy and closely communicate with

CMOs or internal manufacturing

CMO supplies information on manufacturing quantities

Sponsor conducts/contracts all required tests

Supplies final reports to CMOs

CMO completes/submits registration

Necessity for transparency across external manufacturing

Newly formed committee and EHS contact for Registrations

Visibility to SRMs (Communicator between Sponsor and CMO)

Enhanced awareness of WW Registrations: Planned, In progress and

Obtained

Importance of communication across various functions and visibility across

the company.

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Acknowledgements

Occupational Toxicology

Jedd Hillegass

Wendy Luo

Gene Schulze

18

Corporate EHS

Todd Davidson

Janet Gould

David Plutto

Thank You!