Integrating Toxicological Information Effectively Throughout Organizations. Joel Bercu PhD MPH DABT Director, Gilead Sciences

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1 Integrating Toxicological Information Effectively Throughout Organizations Joel Bercu PhD MPH DABT Director, Gilead Sciences

2 Environmental and Occupational Toxicology Mission Protect patients, employees, and the environment from unintended exposures to chemicals Joel Bercu Alejandra Trejo-Martin Melisa Masuda-Herrera

3 Deliverables / Activities OHCs, OELs, pohcs PDEs for APIs PDEs for impurities QSAR for potentially mutagenic impurities Toxicology support for SDS development Tox Support for Deviations Environmental Risk Assessments Eco Tox Testing Worker Safety Testing (Intermediates and APIs) Toxicology consultation for REACH Leachables and Extractables for devices, product contact, etc. Regulatory submissions and responses Ames testing of intermediates

4 Background Fundamental elements of risk assessment Hazard Assessment Assess exposure Does potential exposure exceed toxicology limit? Risk Assessment Reduce exposure potential

5 Overview of Hazard Evaluation Documents Documentation Purpose Controlled Document? Phase of Development SDS (Safety Data Sheet) formerly labeled MSDS Hazard Communication Yes All phases Preliminary Occupational Health Categorization (pohc) Early (prerfd) OHC decision based on limited data prior to RFD No (data in SDS) Prior to phase I Occupational Health Categorization (OHC) Ranges of acceptable air concentrations for worker safety Yes Phase 1 3 Occupational Exposure Limit (OEL) Permissible Daily Exposure (PDE) Acceptable air concentration for worker safety Acceptable residual API used to support cleaning validation calculations Yes Phase 3 - Marketing Yes After Phase 1

6 Who uses the Hazard Evaluation Documents? Internal Staff CMOs Cleaning Validation EHS Product Development Regulatory 6

7 Development Timeline Data Availability Discovery/ Research CS IND Ph 1 Ph 2a Ph 2b Ph 3 Registration/ Marketed 7 Little to no data available (Target) IND studies - 28 day tox Mutagenicity (Ames) OHC, ppde CS studies - Single dose, 7-day tox - PK Worker Safety studies - Skin irritation (in silico) - Skin sensitization (in silico) Mutagenicity (in silico) pohc, SDS, ppde Environmental tox Phase 1 and 2 clinical studies Developmental/Reproductive tox Worker safety studies - Skin irritation (in vitro) - Eye irritation (in vitro) - Skin sensitization (in vitro) OEL, PDE Update PDE, OEL Environmental Risk Assessment

8 What makes a good product stewardship and occupational toxicology program? Connect with different parts of the organization and introduce the toxicological-based methodology Create high quality, transparent documents that meet current scientific and regulatory guidelines Develop processes for deriving health based limits and comply with those processes Understand business processes and integrate the toxicology with those processes Communicate major changes to key stakeholders 8

9 Example - Integration of PDEs into business processes Issue EMA updates GMPs to require toxicology-based limits for cross-contamination of equipment Business partners currently implement other solutions Process Reviewed guidance and current methodology (EMA, ISPE RiskMapp, RTP 79 (2016) Supp) Talked with business partners, educate, and learn Developed methodology and templates Integrate Developed language in stakeholder processes Established trust Used existing IT solutions to communicate internally, externally, including document updates 9

10 Example Preliminary OHCs Issue No early methodology for classifying the occupational hazards of compounds Can lead to overexposures or unnecessarily controlling exposure Process Benchmarked with other companies and read current literature Talked with business partners, educate, and learn Developed methodology and templates Integrate Built processes into drug development gates Built worker safety testing into drug development gates for intermediates and APIs Built pohcs into SDS development to facilitate hazard communication 10

11 Example Potentially Mutagenic Impurities Issue ICH M7 developed guidance on the identification and control of mutagenic impurities Implementation requires strong adoption from other parts of the organization Process Reviewed guidance document, benchmarked with other companies, read scientific methods Reviewed business processes and how it can be adjusted to comply with ICH M7 Learned about external computational models, testing labs, and developed report templates Integrate Developed cross-functional teams to manage mutagenic impurities in APIs Developed control strategies to mitigate risk Developed storage tools and structural search methodology for impurities 11

12 Outlook The scientific methodology and regulatory expectations are constantly changing Evolution is important to adapt Taking the time to understand the issue, develop crossfunctional processes, and integrate those processes within the company are key There needs to be a mechanism for broad communication to stakeholders 12