Environmental Assessment of Pharmaceutical Products - a deliverable of NPS 7.2 - For more info: www.ansvarsblogg.se

Environmental Assessment of Pharmaceutical Products - a deliverable of NPS 7.2 - For more info: www.ansvarsblogg.se LIF, Oct 9, 2013

Pharmaceuticals in the Environment (PiE) 2 WWTP 1 3 How do pharmaceutical substances end up in the environment?

Background to Swedish initiatives and activities within the PiE area 1. Excretion of pharmaceutical substances and metabolites from patients Intense discussions since 2003/2004 2. Releases of pharmaceutical substances from manufacturing operations Several reports from Swedish researcher Joakim Larsson (University of Gothenburg) on releases from the WWTP in Patancheru, India (from 2007 and onwards) 3. Unused medicines Have been addressed by LIF and stakeholders in several nation-wide campaigns since the 1990 s NOT regarded a significant contributor to pharmaceuticals in the environment in Sweden. The issue is under good control

1. Excretion of pharmaceutical substances and metabolites from patients Frogs, fish and pharmaceuticals a troubling brew Prozac, other drugs detected in streams and their inhabitants By Marsha Walton CNN Friday, November 14, 2003 Posted: 9:14 AM EST (1414 GMT) Two tapdpoles after 57 days of development in the lab. The one on the right, which has yet to sprout limbs, was exposed to fluoxetine, also known as Prozac. (CNN) -- A number of aquatic and amphibian species are being exposed to small amounts of everything from Prozac to perfume to birth control pills that make their way into U.S. rivers and streams. And scientists now have evidence that this "cocktail" of pharmaceuticals, in high enough quantities, can lead to problems that may be serious enough to prevent wildlife from reproducing. It's not yet clear how the buildup over time could affect the species. In 2002, 80 percent of streams sampled by the U.S. Geological Survey showed evidence of drugs, hormones, steroids and personal care products such as soaps and perfumes. The U.S.G.S. tested 139 rivers in 30 states. Pharmaceutical substances are also found in Swedish water bodies, at very low concentrations Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients 2004/2005: LIF s initiative to develop a system for environmental information on pharmaceutical substances to be introduced on www.fass.se Swedish Task Force Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Distinguish Between Hazard and Risk Hazard The inherent capacity to cause harm. Risk The probability to cause harm. Without exposure, the hazard does not pose a risk. Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Environmental studies to determine hazard Is the substance accumulated in organisms? Is it degraded? Is it toxic? Answers the question on HAZARD the ability of the substance to cause harm

Environmental risk Assessment Fate of the substance? How much ends up in the environment? 1. Excretion of pharmaceutical substances and metabolites from patients To calculate risk, exposure data is needed in addition to hazard: A HAZARD does not pose a RISK, if there is not a potential EXPOSURE Exposure could be measured, occurrence in the environment estimated, e.g. by sales volumes estimated, exposure assessment models Läkemedelsindustriföreningen, LIF 2013-10-22

Basic Principle Used in ERA/EA 1. Excretion of pharmaceutical substances and metabolites from patients Predicted concentration of the substance in the environment is related to the toxicity to organisms living there. Predicted Environmental Concentration Predicted No Effect Concentration PEC / PNEC Läkemedelsindustriföreningen, LIF 2013-10-22

Calculation of PEC Predicted Environmental Concentration 1. Excretion of pharmaceutical substances and metabolites from patients Quantity on market Excretion and metabolism in man - Provided by IMS PEC Fate during sewage treatment - Does it degrade or adsorb to sludge? Urine Faeces Parent compound Metabolites (pharmacological activity) Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Calculation of PNEC Predicted No Effect Concentration Ecotoxicity to fish Ecotoxicity to Daphnia PNEC Ecotoxicity to algae Assessment factors The most sensitive species is used. Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Is there an Environmental Risk? EU model - Based on the PEC/PNEC ratio PEC/PNEC < 1 No significant risk identified, no risk management action needed PEC/PNEC 1 Potential risk identified, precautionary and safety measures may be required, e.g: Restricted clinical use, e.g. hospitals only Product labelling E.g. return the unused medicine to the pharmacy

Environmental Risk according to www.fass.se PEC/PNEC 0.1 Use of *name of the substance* has been considered to result in insignificant environmental risk 0.1 < PEC/PNEC 1 Use of *name of the substance* has been considered to result in low environmental risk 1 < PEC/PNEC 10 Use of *name of the substance* has been considered to result in moderate environmental risk PEC/PNEC > 10 Use of *name of the substance* has been considered to result in high environmental risk No or not enough data: 1. Excretion of pharmaceutical substances and metabolites from patients Risk of environmental impact of *name of the substance* cannot be excluded, since no ecotoxicity data are available Risk of environmental impact of *name of the substance* cannot be excluded, since there is not sufficient ecotoxicity data available Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Degradation and bioaccumulation according to www.fass.se Degradation: *Name of the substance* is degraded in the environment or *Name of the substance* is slowly degraded in the environment or *Name of the substance* is potentially persistent Bioaccumulation: *Name of the substance* has low potential for bioaccumulation or *Name of the substance* has high potential for bioaccumulation If the pharmaceutical fulfills the criteria for PBT (Persistent, Bioaccumulative and Toxic) and/or vpvb (very Persistent and very Bioaccumulative), the following phrase should be added: According to the established EU criteria, the compound should be regarded as a PBT/vPvB substance. Läkemedelsindustriföreningen, LIF 2013-10-22

1. Excretion of pharmaceutical substances and metabolites from patients Swedish Environmental Classification of Pharmaceutical Substances - SUMMARY Almost 90% have been considered to have insignificant impact, only a few have a high risk for environmental impact Roughly 80% have a low potential for bioaccumulation More than 90% of the substances are slowly degraded or potentially persistent in the environment

2. Releases of pharmaceutical substances from manufacturing operations Treatment plant in Patancheru receiving process water from ~90 bulk drug industries 99 % of them are suppliers for generic pharmaceutical companies opyright: Cecilia de Pedro

2. Releases of pharmaceutical substances from manufacturing operations River Iskavagu Discharges in Manjira river, tributary of Godavari river, major waterway in central India Manjiera drinking resourse for 1/3 of Hyderabads population, 2 million people opyright: Cecilia de Pedro

2. Releases of pharmaceutical substances from manufacturing operations Treated effluent contains extremely high levels of pharmaceuticals Active ingredient Type of drug Range (μg/l) Ciprofloxacin antibiotic-fluoroquinolone 28,000-31,000 Losartan angiotensin II receptor antagonist 2,400-2,500 Cetirizine H 1 -receptor antagonist 1,300-1,400 71 products with an API from this list, manufactured in a factory using this WWTP, are present on the Swedish market Metoprolol b 1 -adrenoreceptor antagonist 800-950 Enrofloxacin antibiotic-fluoroquinolone (veterinary use) 780-900 Citalopram serotonin reuptake inhibitor 770-840 Norfloxacin antibiotic-fluoroquinolone 390-420 Lomefloxacin antibiotic-fluoroquinolone 150-300 Enoxacin antibiotic-fluoroquinolone Larsson, D.G.J., Fick, J., Transparency throughout the production chain a way to reduce 150-300 pollution from the manufacturing of pharmaceuticals?, Regulatory Toxicology and Pharmacology (2009), Ofloxacin antibiotic-fluoroquinolone doi:10.1016/j.yrtph.2009.01.008 150-160 Ranitidin H 2 -receptor antagonist 90-160 Based on LC-MS/MS, ESI+, 3-point standard addition, no preconcentration of samples

Swedish National Pharmaceutical Strategy (NPS) Reduce effects on the environment from pharmaceuticals, locally and globally: Action Plan 2011 7.1. Investigate if the environmental aspects should be considered when decisions on subsidy for a pharmaceutical are decided (Lead: Ministry of Health): Review of possibilities to within the context of the national reimbursement system - increasingly take environmental considerations. 7.2. Encourage voluntary control of emissions from pharmaceutical factories (Lead: LIF): Introduction of a voluntary environmental assessment of pharmaceutical products. 7.3. Investigate what further measures can be taken at national level to reduce wastage of medicines or in other ways limit the environmental impact of use of pharmaceuticals (Lead: Swedish MPA): Investigation of the causes of wastage and propose measures to reduce wastage of medicines. Implementation of joint information efforts to encourage patients to return leftover medicines. 7.4. Promote the possibilities for environment considerations during production and use of medicines (Lead: Cabinet Office): The Government on June 9, 2011 took the decision (M 2010:04) to give Miljömålsberedningen the additional task of developing a strategy for Sweden's work in the EU as well as internationally for a non-toxic environment. The strategy should also encompass the impact of pharmaceuticals on the environment.

De viktigaste resultaten från Sofias delbetänkande NEJ till miljöhänsyn vid subventionsbeslut för nya läkemedel JA till miljöhänsyn imom ramen för det generiska utbytet Miljöbedömningsmodellen (NLS 7.2) ska användas för att differentiera mellan produkter med samma API Miljökriterier: Utgångspunkt bör vara livscykelperspektiv, miljöpåverkan från produktion bör ingå. LV är beslutande instans. Bör om möjligt kopplas till internationella standarder Egendeklaration och/eller tredjepartscertifiering Diskussioner om socialt ansvarstagande är helt utelämnat i betänkandet Miljöpremie: TLV ges i uppdrag att utreda vidare Samhälls- eller konsumentbetald (betänkandet rekommenderar samhällsbetald) Storlek på premie Pilotförsök under 2 år (sedan 6 månaders utvärdering) Systemet avvecklas när/om EU-gemensamt initiativ tas

Utgångspunkt bör vara livscykelperspektiv, miljöpåverkan från produktion bör ingå Packaging Distribution Manufacturing Use Delivery End of life Raw Materials Recycling

Environmental Assessment Model for Pharmaceutical Products Diskussioner genomförda i LIF:s miljökommitté våren 2012 Fortsatta diskussioner inom ramen för rundabordssamtalen under hösten 2012/våren 2013 Diskussioner med läkemedelsbolagens globala miljöexperter under våren 2013 LIF:s förslag till miljöbedömningsmodell inskickad till Socialdepartementet 30 juni 2013

Environmental Assessment Model for Pharmaceutical Products (slide 1 out of 3) Effective Management of API Residue Arising from the Manufacturing Process Step 1: The question would be asked; Can you confirm that the predicted concentrations of the API in the receiving environment outside your manufacturing site(s), or those of your supplier(s), present no significant risk to the environment for this compound? (Yes/No) If Yes, then proceed to Step 2. Step 2 : Please provide the following information to support your statement; Country of primary API manufacture Country of secondary manufacture (formulation) Name and location of supplier General overview of manufacturing process and mitigation controls (including details of any wastewater treatment or other handling of process waste, e.g. if incinerated) General overview of emission scenario, load estimates, wastewater volumes, dilution factors etc Details of the PEC calculation Summary of the PEC/PNEC

Environmental Assessment Model for Pharmaceutical Products (slide 2 out of 3) Materiality Analysis, Carbon Foot Print and other Environmental Resource Measures Associated with the Manufacture of APIs and Pharmaceutical Products Basic Entry: This would use the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) Tool for Eco-Footprinting APIs,or a tool/model similar to it. Applicants should enter the chemistry for all steps from commonly available starting materials and should not just be the chemistry that is run in house The tool gives a materials only carbon foot print. Applicants should calculate the Green House Gas impact of the energy to run both their facility and their supplier s facilities. This should be calculated using the Green House Gas Protocol Product Life Cycle Assessment and Reporting Standard The GCIPR Tool also gives a number of other outpoints including solvent usage, water usage, reagent usage and process mass intensity (PMI). The applicant should include all of these data. Applicants should include data over time to demonstrate improvement wherever possible.

Environmental Assessment Model for Pharmaceutical Products (slide 3 out of 3) Materiality Analysis, Carbon Foot Print and other Environmental Resource Measures Associated with the Manufacture of APIs and Pharmaceutical Products (cont.) Standard Entry: The applicant should submit all of the data for the basic entry but in addition should provide carbon footprint data for both primary and secondary packaging materials as used in the Swedish market. The applicant should refer to the packaging section 4.5.7 of the NHS Sector Guidance. Enhanced Entry: The applicant should submit all of the data for the Basic and Standard entries, solvent usage, water usage, reagent usage, process mass efficiency and packaging components however the applicant should now calculate the carbon footprint of both the API and the product including formulation, packaging and distribution to the Swedish patient. Details for such an entry using existing ISO standards and the NHS Green House Gas Accounting Sector Guidance for Pharmaceutical and Medical Devices will need to be developed. LIF believes that the Basic Entry level is appropriate for at least the pilot phase of the environmental incentive scheme. The evaluation of the pilots will identify whether or not the chosen approach drives reduced environmental impact and awards improvement and transparency.

Miljöbedömningsmodellen och dess relation till andra initiativ inom läkemedel och hållbarhetsområdet Tre källor till relevant hållbarhetsinformation tillgänglig för det offentliga och/eller allmänhet inom läkemedelsområdet: Om enskilda läkemedelssubstanser: Miljöklassificeringen av substanser på www.fass.se (publikt tillgängligt) Om tillverkningens miljöpåverkan från olika läkemedelsprodukter: I dokument framtagna enligt den bedömningsmodell som vi nu diskuterar (hos LV/TLV och förslagsvis på någon publikt tillgänglig website eller motsvarande) Om socialt ansvarstagande: Inom ramen för det arbete som drivs av Pauline Göthberg för alla landsting och regioner utvecklas Uppföljningsportalen.se, en portal där bolagens sociala ansvarstagande i leverantörskedjan redovisas (tillgängligt för landsting/regioner, i övrigt återstår att se hur information kan spridas)

Miljöklassificering av läkemedelssubstanser på Fass.se Uppföljningsportalen.se Uppföljningsportal för socialt ansvarstagande inom offentlig upphandling Miljöbedömningsmodell för läkemedelsprodukter Utsläpp av API från tillverkning Utsläpp av API från substanstillverkande fabrik: PEC eller MEC / PNEC < 1 Övriga miljöaspekter Basic Entry - Chemistry and Carbon Footprint for all steps from commonly available starting materials - Green House Gas impact of the energy to run both their facility and their supplier s facilities. - Solvent usage, water usage, reagent usage and process mass intensity (PMI). - Inclusion of data over time to demonstrate improvement wherever possible

Kommande steg Fortsatta diskussioner med svenska intressenter och internationella experter LIF levererade förslag 30 juni till Socialdepartementet: Miljöbedömningsmodell Gröna ekonomiska incitament, exempelvis En samhällsbetald miljöpremie vid prisjämförelser för val av månadens vara Möjlighet för patient att betala mellanskillnad upp till en grön produkt Prisminskning till 40% istället för 35% vid patentutgång för grönt läkemedel Organisation för administration av miljöbedömning LV kommer att spela en central roll i den framtida processen LIF avvaktar med framtagande och lansering av e-utbildning till dess att LV har fastställt miljöbedömningsmodell i enlighet med Läkemedels och apoteksutredningens delbetänkande TLV ska enligt Läkemedels och apoteksutredningens delbetänkande Designa systemet för miljöhänsyn inom läkemedelsförmånen (1 år) Genomföra pilottester av systemet i utvalda produktgrupper (2 år) Utvärdera piloterna (6 månader)