EFPIA Position Paper on REACH. Executive Summary. Position Paper. Draft Final. Author: EFPIA Date: October 2015 Version: Final

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1 Draft Final EFPIA Position Paper on REACH Author: EFPIA Date: October 2015 Version: Final Position Paper Executive Summary An increasing number of substances used in the pharmaceutical manufacturing process are or will be subjected to Authorisation under the REACH regulation. The Authorisation process creates uncertainty over the manufacture and authorisation of medicines in Europe which: 1) may impact the supply of medicines with unintended consequences for public health, and 2) reduces the competitiveness of Europe for pharmaceutical manufacturing. This measure appears disproportionate, considering the objectives of REACH can be achieved under existing legislation. The use of the REACH Authorisation process should be reconsidered in view of the concerns for public health and competitiveness of the EU as a destination for pharmaceutical manufacturing.

2 1. Introduction REACH, the EU regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals, came into force on 1st June One of the objectives of REACH is to determine which substances should be authorised or substituted. Whilst medicinal products and Active Pharmaceutical Ingredients (APIs) are exempted from REACH, other substances (such as processing solvents) used in API manufacturing are not. The European Commission is currently examining whether a number of substances, including processing solvents should be included in the Authorisation process provided for by REACH. When a substance is put on the REACH Authorisation List, companies need to apply to the European Chemical Agency (ECHA) for an Authorisation, so that they can continue using this substance for a limited period of time, whilst researching for substitutions. Consequently, the inclusion of an increased number of substances used in API manufacturing processes within the Authorisation process will have potentially significant consequences for the industry. 2. Impact of REACH on Pharmaceutical Manufacturing An authorisation process, with the objective to eventually substitute the Substances of Very High Concern under REACH, will lead to changes to manufacturing processes for APIs, which in turn may impact the supply, safety and availability of medicines. For example, Triton-X 100 is a substance used for viral clearance of large molecules. This substance is extremely effective and ensures the safety of the product. Alternatives used today or being researched are not nearly as effective in clearing the molecule from viruses, when referring to manufacture of an array of biologics. Banning the use of Triton-X 100 would lead to concerns on safety of the product, the need for further animal testing and perhaps human trials, and changes in marketing authorisations. Issues with the availability of products could not be excluded, especially with regard to substances that are used across the board, since they represent the golden standard in their properties. Therefore, the potential impact on public health stemming from delays, additional safety and efficacy concerns, and potential shortages of medicines should not be discounted. 3. Duplication of existing Community law The pharmaceutical industry supports the objectives of the REACH legislation of ensuring a safe and healthy working environment and to limit a negative environmental impact where possible. The pharmaceutical industry s API manufacturing processes are optimised to handle and control the processing solvents used in the production of medicines. 2

3 EFPIA membership has continuously strived to ensure safe working conditions for employees and high environmental standards by ensuring adherence to EU legislation in this area. The risks associated with the use of substances are already being regulated by Community legislation: the Chemical Agents Directive (98/24/EC) governs occupational exposure limits, while the Water Framework Directive (2000/60/EC) sets environmental quality standards. Consequently, such an expansion of the REACH Authorisation list would be an unnecessary duplication of regulatory control, without any additional benefits. 4. Impact on European competitiveness The authorisation process in itself is uncertain, costly and discourages the competitiveness of the European pharmaceutical sector. To begin with, an Authorisation will only be granted for a limited period of time after which it must be reviewed again by ECHA. Even if an Authorisation is obtained and a substance is substituted, it is possible that the new alternative will soon be subjected to an authorisation and need to be substituted as well. In practical terms, applying for an authorisation is a heavy and costly process that, if required for several molecules, could lead to a reassessment of sourcing and supplying decisions that could have a negative impact on access to medicines. For example, based on the information of 20 EFPIA member companies, one solvent, called DMF, is used in the manufacture of more than 100 commercialised medicines and around 50 pipeline drug products across the industry, including medicines developed for oncology, cardiovascular, rare diseases or dermatology affections. Getting an authorisation for every molecule, legal entity and use of DMF would entail significant regulatory and financial burden. Furthermore, as these substances are not found in the final API and as REACH Authorisation only applies to EU-based manufacturing, this places companies with operations in Europe at a competitive disadvantage. It also creates incentives for companies to relocate operations outside of Europe or not relocate manufacturing sites to Europe. 5. Significant Administrative Burden Finally, substitution, assuming it is technically feasible, is a costly and time-consuming process. It requires additional R&D work to find the substitute, including additional testing and clinical trials to prove efficacy if the new API shows any impurities. In turn, any changes made in the API manufacturing process will impact parts of global Marketing Authorisation dossier assessed and approved by the Drug Regulatory Agencies. One such example shows that direct costs associated with a request for an Authorisation for a single solvent, EDC, reached 300,000/legal entity/use and took two years to complete the process. This does not include costs for complying with the Authorisation, which are 3

4 estimated to reach 11 million, nor the financial impact caused by changes to Marketing Authorisation. For other substances, these costs could double. 6. EFPIA calls for a sector wide exemption from the scope of REACH In light of the above, the pharmaceutical industry believes that expanding the REACH Authorisation List to include processing solvents and other chemicals used in the manufacture of medicines is contrary to the Commission s aim to deliver for high quality, simple legislation and would only duplicate and increase red-tape, and discourage the competitiveness of the European pharmaceutical sector globally. In addition, the rationale to exclude pharmaceutical APIs from the scope of REACH, due to public health, should be considered also in light of these processing solvents that are used in the manufacture of medicines ranging from anything between oncology treatments, antibiotics, Alzheimer s, and cardiovascular therapies. EFPIA therefore calls upon the Commission to provide a sector wide exemption for controlled uses of processing substances used in the manufacture of APIs on the REACH Authorisation List by interpreting the Pharmaceutical exemption to REACH Authorisation provided in REACH Article 2 (5) (a) to include all substances used in the manufacture of the drug product (other than just the API) where it can be shown, on a case by case basis, that the substance: a) has an Occupational Exposure Limit Value (OELV) or Environmental Quality Standard (EQS) i.e. a threshold limit or the substance is an essential nutrient; and b) is used in such a way that limits exposure to the worker and/or the environment as applicable; and c) there is no consumer safety impact; and d) the API is manufactured under Good Manufacturing Practices (GMP) as per the requirements of the Medicinal Products Directive or the Veterinary Medicinal Products Directive and e) the medicinal product containing the API has a valid EU Marketing Authorisation or is being used in clinical trials. 4

5 ANNEX I - Impact on pharmaceutical manufacturing in Europe An increased number of chemicals used in API manufacturing may become subject to Authorisation. If so, the pharmaceutical industry will be able to use these substances for a period of time, during which time they will have to find substitutes. The authorisation process is lengthy, uncertain and expensive: e.g. for EDC, the Application for Authorisation (AfA) took 2 years and cost 300,000 per legal entity and per use. These substances are commonly used across the industry. For example, one solvent, called DMF is used in the manufacture of more than 100 commercialised medicines and around 50 pipeline drug products across the industry. In the future, Pharma use of NMP will increase. NMP, DMAC and DMF are used in the following therapeutic areas and/or diseases: diabetes, cancer, hypertension, blood disorder, lung diseases, allergy, sleep disorder, endometriosis, precocious puberty, neuroendocrine tumours, acromegaly, thyrotrophic adenomas, and digestive fistulae. The table below is data from 20 companies representing approximately 50% of EFPIA membership: COMPANY # of bulk manufacturing sites in the EU 20 EFPIA Members 56 # of sites using TODAY Commercial Products Pipeline Products DMAC NMP DMF DMAC NMP DMF DMAC NMP DMF

6 Annex II Countries and companies impacted by REACH API Manufacture Member State IE DE UK IT ES BE FR AT DK SE NL SI HU 1 Abbvie IE; IT 2 AstraZeneca UK; SE 3 Baxter DE; AT (with Pfizer) 4 Bayer DE; ES 5 BMS IE (x2); 6 Boehringer Ing DE; IT; ES 7 Eli Lilly IE; UK 8 GSK UK; IE; BE 9 Ipsen IE (x2); UK; FR 10 JNJ BE; IE 11 Lundbeck DK; IT 12 Merck KGaA DE; FR; ES; AT 13 MSD IE 14 Novartis IE; UK 15 Novo Nordisk DK 16 Pfizer IE (x3); ES; SE; IT; AT (with Baxter) 17 Roche IE; DE 18 Sanofi FR; DE; IT; HU; BE; UK 19 Servier FR ; ES ; HU 20 UCB IE; BE TOTAL #COMPANIES IN EACH MS EFPIA Brussels Office Leopold Plaza Building Rue du Trône 108 B-1050 Brussels Belgium Tel: + 32 (0) info@efpia.eu