GLOBAL CHEMICAL REGISTRATIONS: TESTING STRATEGIES AND CMO COMMUNICATION

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1 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

2 2 Background Toxicology Testing: Regulatory Submittal Support 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.

3 Overview 3 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

4 EU REACh 4 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

5 Korea REACh 5 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

6 China REACh Ministry of Environmental Protection (MEP) 6 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

7 Toxicity Studies Tonnage Requirements: 1 - < <100 7 Test OECD Guideline EU Korea China Acute oral toxicity OECD 420 Acute inhalation toxicity OECD 436 one route one route Acute dermal toxicity OECD 402 one route one route In vitro skin corrosion/irritation OECD 435/439 In vitro eye irritation OECD 437 both routes needed both routes needed 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

8 Toxicity Studies (cont.) Tonnage Requirements: 1 - < <100 8 Test In vitro micronucleus study/ In vitro Chrom abs OECD Guideline OECD 473 Mouse Micronucleus test OECD 474 Chromosome aberration OECD 475 EU Korea China 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 Day Repeat Dose OECD 408 one route or OECD 422 Reproduction/Developmental Toxicity Screening Test Combined Repeat Dose Reproduction/Developmental Toxicity Screening Test Toxicokinetic assessment OECD 421 or OECD 422 or OECD 422 or OECD 422 OECD 422 In place of OECD 407/421 In place of OECD 407/421 Recovery phase

9 Eco-Toxicity Studies Tonnage Requirements: 1 - < <100 9 Test Acute Toxicity to Daphnia magna OECD Guideline OECD 202 EU Korea China Acute Toxicity to Fish OECD 203 In China Toxicity to micro-organisms; Activated sludge - OECD 209 Respiration inhibition test Algal Growth Inhibition Test OECD Ready biodegradability OECD 301B In China Hydrolysis as a function of ph Adsorption & Desorption; Soil adsorption coefficient (Koc) OECD 111 OECD 121 OECD 106 OECD 121 or OECD 106 is acceptable 100 OECD 106 Earthworm Acute Toxicity OECD In China (dep) Daphnia Reproductive Test OECD 211 In China (dep) Bioaccumulation OECD 305 In China (dep)

10 Testing Strategy: Data sharing across geographies 10 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 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

11 China MEP Registration: Conducting studies in China 11 Some ecotox studies required to be conducted in China EU/US CROs US Sponsor EU/US CRO Chinese Consulting Firm MEP Approved Lab Timing: 1-2 months to ship material from CRO to China Test Item Final Report Final report 5-9 months from test item receipt Directly contract with MEP Lab: ~4 months total

12 12 China MEP Registration: Timing (Formal Notification 1MT) Overall Time Required: months Varies based on testing required/waived; test item characteristics/availability 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

13 13 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 Needs to be Communicated CRO / Consultant CMO Sponsor Regulatory Body Internal procedures for obtaining data needed for registrations

14 Pros/Cons of Sharing Testing 14 Responsibilities with the CMO CMO Sponsor Registration is the CMOs responsibility Knowledge of MOA of test items 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 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

15 BMS Strategy: Sponsor Controlled Testing 15 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

16 Clear Communication 16 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?

17 Summary 17 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.

18 Acknowledgements 18 Thank You! Occupational Toxicology Jedd Hillegass Wendy Luo Gene Schulze Corporate EHS Todd Davidson Janet Gould David Plutto