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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
6
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
8
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)
9
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
10
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
11
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
12
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
13
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
14
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
15
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?
16
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.
17
Acknowledgements
Occupational Toxicology
Jedd Hillegass
Wendy Luo
Gene Schulze
18
Corporate EHS
Todd Davidson
Janet Gould
David Plutto
Thank You!
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