Manufacture of medicinal products

✓ Pollution prevention

1. The activity complies with one of the following sets of requirements set out in point 1.1. or 1.2. relating to product substitution. In any case, the activity complies with the requirements set out in point 1.3.1.1. The medicinal product complies with the following requirements set out in points 1.1.1. and 1.1.2.:1.1.1. The medicinal product complies with one of the following requirements:the ingredients that constitute the formulation of the medicinal product are naturally occurring substances such as vitamins, electrolytes, amino acids, peptides, proteins, nucleotides, carbohydrates and lipids and, in line with European Medicines Agency Guideline on the environmental risk assessment of medicinal products for human use (EMA ERA guideline)(20), are generally considered to be degradable in the environment(21);where the ingredients that constitute the formulation of the medicinal product do not comply with the requirements specified in point (a), those ingredients, their key human metabolites and their key transformation products in the environment comply with one of the following: are classified as readily biodegradable based on at least one of the test methods from the OECD Guidelines for the Testing of Chemicals, Test 301 (A-F), Ready Biodegradability(22), in accordance with the pass value for ready biodegradability as defined in that guideline;can be concluded to be mineralised based on a specific Test No. 308: Aerobic and Anaerobic Transformation in Aquatic Sediment Systems (OECD 308)(23) of OECD Guidelines for the Testing of Chemicals(24) compared to persistence criteria as defined in the EMA ERA guideline.1.1.2. The medicinal product qualifies as an appropriate substitute to another medicinal product, within the same therapeutic area or the substance class, that is available in the market or was available during last 5 years and that does not comply with the requirements described in point 1.1.1.Compliance with this requirement is demonstrated through a publicly available analysis verified by an independent third party.1.2. The manufacturer proves that there are no ingredients to produce an alternative medicinal product that qualifies as an appropriate substitute, within the same therapeutic area or the substance class, that comply with the requirements described in point 1.1.1. The activity complies with all the requirements specified in points 1.2.1 to 1.2.6. 1.2.1. The manufacturer performs an analysis that there is no appropriate substitute to the produced medicinal product, publishes the core results of that analysis and demonstrates that they started initiatives to develop that alternative.1.2.2. In line with the EMA ERA guidelines, the PEC/PNEC ratio for the medicinal product obtained in the Environmental Risk Assessment is below 1. 1.2.3. Packaging and distribution systems allow adjusting the sold amount to the required amount by the treatment/s, taking into account the applicable national legislation.1.2.4. Public information, such as leaflets or websites, updated according to the state of the art, is provided about dose and dosing method to minimize the excess of dosed API. 1.2.5. Packaging and distribution systems allow using the most efficient dosing system available according to the state of the art and considering the kind of administration, such as by health care professionals or domestic. The manufacturer publishes the main results of that analysis. 1.2.6. The manufacturer contributes to mitigating the environmental impact of incorrect waste disposal of unused medicinal product, including by providing relevant information to the downstream users on appropriate disposal of unused medicinal product. 1.3. The manufacturing process does not involve the use of substances, whether on their own or in mixtures, that meet the criteria set out in Article 57 of Regulation (EC) 1907/2006 except where it is assessed and documented by the operator that no other suitable alternative substances or technologies are available on the market, and that they are used under controlled conditions(25).2. The activity complies with the following requirements regarding the emission of pollutants: 2.1. Where the activity falls within its scope, the emission limit values shall be lower than the mid-point of the BAT-AEL ranges(26) set out in:the best available techniques (BAT) conclusions for common waste gas management and treatment systems in the chemical sector(27) for emissions to air of new installations (or for existing installations within 4 years of the BATC publication) where relevant conditions apply;the Best Available Techniques Reference Document (BREF) for Manufacture of Organic Fine Chemicals (OFC)(28); for the manufacturing activity under conditions not covered by the BATC mentioned above;the best available techniques (BAT) conclusions for common waste water and waste gas treatment/management systems in the chemical sector(29);the Best Available Techniques Reference Document (BREF) for the Large Volume Inorganic Chemicals – Solids and Others industry(30);the Best Available Techniques Reference Document (BREF) for the manufacture of Large Volume Inorganic Chemicals - Ammonia, Acids and Fertilisers(31);the Best Available Techniques Reference Document (BREF) for the production of speciality inorganic chemicals (SIC) for the manufacturing activity under conditions not covered by the BATC mentioned above (32).Plants within the BAT-AEL range(s) moving to the mid-point ambition do not trigger any significant cross-media impact.Installations that have been granted a derogation in accordance with the procedure set out in Article 15(4) of Directive 2010/75/EU are not considered as fulfilling the technical screening criteria for the period of the derogation.2.2. Where a continuous measurement methodology for a certain pollutant is available, the operator applies Continuous Emission Monitoring Systems (CEMS), Continuous Effluent Quality Monitoring Systems (CEQMS) and other measures ensuring the regular verification of non-deterioration of environment.2.3. The operator applies solvent waste segregation for solvent recovery from concentrated waste streams, where technically applicable. Solvents included in Table 1 of the European Medicines Agency ICH guideline Q3C (R8) on impurities as specified in the guideline for residual solvents(33) are avoided in medicinal products.The maximum solvents loss from total inputs does not exceed a 3% loss. Total volatile organic compound (VOC) recovery efficiency is at least 99%.The operator verifies that no fugitive VOC emission occurs beyond the criteria specified below as to the parts per million volumetric (ppmv) thresholds by carrying out Leak detection and repair (LDAR) campaigns, at least every 3 years. Investments for the use of high integrity equipment are recommended, provided that these are installed in existing plants for cases mentioned under BAT 23b of the best available techniques (BAT) conclusions for common waste gas management and treatment systems in the chemical sector, whereas the pressure threshold is brought to 200 bar. The minimal verification schedule may be reduced in cases where quantification of total VOC emissions from the plant is periodically qualified with tracer correlation (TC) or with optical absorption-based techniques, such as differential absorption light detection and ranging (DIAL) or solar occultation flux (SOX) or other measures of equivalent performance.Diffuse emissions of substances or mixtures classified as CMR1A or 1B from leaky equipment do not exceed a concentration of 100 ppmv(34). The LDAR campaigns have the features described in BAT19 of the best available techniques (BAT) conclusions for common waste gas management and treatment systems in the chemical sector, which include detecting, repairing and maintaining leaks within 30 days of detection and a leak threshold is lower than or equal to 5000 ppmv for substances or mixtures other than those classified as CMR 1A or 1B, which are reviewed and updated for the continuous improvement of the installation. Solvent losses and recovery efficiency of VOC are monitored based on a solvent management plan using a mass balance for verification of compliance, in accordance with Chapter V of Directive 2010/75/EU.2.4. Sewage, refuse, and other waste (including solids, liquids, or gaseous by-products from manufacturing) are disposed of in a safe, timely, and sanitary manner. Containers or pipes for waste material are clearly identified. Analytical data demonstrating the conversion of these substances and their residues to non-hazardous waste materials are available at the facility and kept up to date.