An industry database of curated API ecotox data and PNECs

Transcription

1 An industry database of curated API ecotox data and PNECs Presented at the IWA Sweden Conference 2016 on Water and Pharmaceuticals insights and perspectives for health and environment D.J. Caldwell, 12 April 2016

2 Topics for discussion 1. Why we developed the database 2. Temple University Water & Environmental Technology Center 3. Benefits and uses of the database 2

3 Stakeholder Concerns Focus on the Pharmaceutical Supply Chain 1. Mistra Pharma - Swedish research center briefs EU Parliament, recommends including manufacturing losses in drug approval decision (June 2, 2015) 2. Sum of Us Activist group proposes link between antibiotic contamination from Chinese suppliers and antimicrobial resistance. The report, Bad Medicines names several major companies (June 11, 2015) 3. Nordea - The largest Nordic financial services firm expresses concerns with water pollution in India from pharmaceutical suppliers (June 21, 2015) 4. SAICM UNEP declares pharmaceuticals as a new emerging policy issue with focus on developing countries (October, 2015)

4 Time to get clean 164 NATURE VOL OCTOBER 2015 Although drug companies say that they maintain good environmental practices, research shows that drug manufacture is a significant source of pharmaceutical pollution. For example, unpublished data from the US Geological Survey show that concentrations of certain drugs are up to five times higher in the effluents of wastewater-treatment plants that serve drugmanufacturing facilities compared with those that do not. The powerful pharmaceutical and water industries, which fear expensive measures to help to address the problem, have already demonstrated their muscle. Through aggressive lobbying, they managed to derail European efforts to impose legal environmental limits on two drugs in The ICCM agreement should help to change things. With the world s eyes now on this issue, industry groups and lobbyists will find it harder to bend initiatives in their favour. There could be an early test of the resolution: European policymakers plan to publish a strategy to tackle drug pollution in the region s waterways by the end of the year. 4

5 Stakeholder pressures - threats to business model THREAT Denial of marketing authorization / market Re authorization of LOE products / retroactive enforcement of ERA testing Environmental parameters added to GMP requirements [Manufacturing to be included in ERA] It is clear that there is a Global Focus on Manufacturing

6 Eco Pharmaco Stewardship (EPS): a life cycle approach Objective: Providing knowledge and data enabling assessments of sustainability of pharmaceuticals 15 DEC

7 Priority EcoPharmacoStewardship Activities Extension of Scientific Knowledge Base (multi stakeholders) IMI ipie project Developing a high quality eco database Develop effects & exposure prediction models Addressing prioritization methodology for legacy products and R&D Effluent emission control from manufacturing Industry Guidance for effluent control Establish risk based control Give technical guidance Sharing practices Extended Environmental Risk Assessment (eera) Post Authorisation ERA model Provides a framework for ongoing environmental review post launch and a mechanism to follow up on identified risks Not compromising patient access to medicines 7

8 Wastewater Maturity Ladder Caldwell et al Minimum Step 1 Commit & Plan Basic awareness & knowledge *Legal compliance and knowledge about fate and nature of effluent -Fate of effluent known and fully permitted -yearly discharge volume accounted for *Monitoring effluent characteristics and standards *Dedication of assigned persons for WWT *Basic training of WWT responsible persons *Understanding design capacity and performance Step 2 Easy fixes, quick wins, must do s toward prevention and compliance *Communication link WWTP w/production Communication and Planning *Basic spill /calamity procedure -Calamity tank available -External processing *Regular follow-up of WWTP -Influent characterization -Sludge characterization *Redundant critical equipment -pumps, blowers available *WWTP laboratory safe and controlled -General lab safety rules -Regular instrument calibration Advanced Step 3 Assess Risks *Removal efficiency of organics and nutrients evaluated and in line with design -COD, BOD, N, P removal *Rest capacity understood *Spill/Calamity control in place -Awareness -Procedures available/in practice *Advanced training -WWT organizations -Follow-up training -Advanced data interpretation and evaluation *Integration of production planning and WWT capacity/capability *Evaluation of water and pollution balance -Water consumption in production? Rainwater -Sound water and mass balance Step 4 Control Risks *Wastewater acceptance policy -Dedicated acceptance person -Awareness of the impact of new waste streams -Procedures available/in place *Awareness/evaluation of value of microscopic sludge analysis? *Water consumption optimization awareness *Preventative maintenance program *Trending of important parameters and process deviations *Operational WWTP emergency procedure -Back-up power available -Failure alarm system for critical equipment -Personnel available 24/7 High-Level Step 5 Audit/Benchmark Share/implement best practices *Opportunities for improvement identified and evaluated -Audit of production and WW treatment as they relate to each other -Evaluation of water and product use in production to investigate technology efficiency and effectiveness *Have operational efficiencies been benchmarked and improvements evaluated? -Comparison of performance of similar plants in order to optimize -Comparison of operational costs of similar plants in order to optimize Step 6 Integrate & maintain continuous improvement *Process technology reviewed and evaluated for BAT *If direct discharge, is TIE (Toxicity Identification Evaluation) done? -Whole effluent testing (acute/chronic) -Techniques to reduce toxicity tested implemented? *Rational water management -Awareness campaign -Effluent reuse -Rainwater capture/use *Advanced training including microscopic sludge analysis -Microorganism activity level -Floc forming bacteria identification (staining) -Filament identification

9 The Curated Database Constructed from Vestel et al with additional internal data Data Acute effects data for fish, daphnids, green and blue-green algae generated to support ERAs, development, scale-up, manufacturing, and classification and labeling for handling and transport safety Chronic effects data generated to support Environmental Risk Assessments for new drug/medicinal authorization applications Good Laboratory Practice (GLP) and non-glp studies included Sources Unpublished aquatic toxicity data (various pharmaceutical companies) Published aquatic toxicity data Data published on some companies public web sites (e.g., Data published by a national medicinal agency ( Data gaps filled with peer-reviewed literature values, when available, after extensive data review Heavily censored dataset posed significant statistical challenges

10 Therapeutic Class Daphnia Fish Green Algae Blue-Green Algae Acute LC/EC50s Anti-Infective Antineoplastic Antineoplastic (Hormone-like) Cardiovascular Central Nervous System Estrogen & Antiestrogen Gastrointestinal Metabolic Miscellaneous Total Right-Censored, N (%) 24 (29%) 26 (37%) 32 (34%) 6 (33%) Chronic NOECs Anti-Infective Antineoplastic Antineoplastic (Hormone-like) Cardiovascular Central Nervous System Estrogen & Antiestrogen Gastrointestinal Metabolic Miscellaneous Total Right-Censored, N (%) 18 (21%) 26 (36%) 20 (21%) 4 (20%) = 264 = 270

11 Chronic PNECs by Therapeutic Class

12 Summary Analysis of Database The MOA and drug class should be considered as part of an intelligent testing strategy for legacy products Identify which species is likely to be most sensitive and considered for environmental testing A chronic PNEC can be predicted from the acute PNEC for all classes of pharmaceuticals, except endocrine MOA and a few other noted compounds Using the acute data with the appropriate Assessment Factor would be a more conservative approach for risk screening than using the chronic data (i.e., generally lower PNECs) Conservative substitutes for use in ERAs when chronic data are unavailable (except above noted exceptions, including those with an endocrine MOA) The EMA data requirements for ERA of pharmaceuticals are fit for purpose for vast majority of therapeutic categories

13 Temple University Water & Environmental Technology Center US National Science Foundation Industry-University Cooperative Research Center Temple University (Philadelphia), Arizona State University, University of Arizona Industrial members include: Johnson & Johnson, Pfizer, several sanitation districts (i.e., municipal wastewater treatment) Web site: 13

14 Benefits and Uses of the Database Increased transparency on part of industry Supports EcoPharmacoStewardship framework Publicly accessible list of PNECs Can be used as screening PNECs to evaluate local conditions Capacity building for external suppliers Underlying data can be provided to Environment Agencies (NOECs, study type) upon request Prioritization of additional ERA activities Basis for regulatory EQS 14

15 References A Risk Based Tool to Manage Active Pharmaceutical Ingredients in Manufacturing Effluent Caldwell DJ, Mertens B, Kappler K, Senac T, Journel R, Wilson P, Meyerhoff RD, Parke NJ, Mastrocco F, Mattson B, Murray-Smith R, Dolan DG, Straub JO, Wiedemann M, Hartmann A, Finan DS. Environ Toxicol Chem 35: , 2016 (DOI: /etc.3163) Use of Acute and Chronic Ecotoxicity Data in Environmental Risk Assessment of Pharmaceuticals Vestel J, Caldwell DJ, Constantine L, D'Aco VJ, Davidson T, Dolan DG, Millard SP, Murray-Smith R, Parke NJ, Ryan JJ, Straub JO, Wilson P, Environ Toxicol Chem. (DOI: /etc.3260) in press 15