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ANALYSIS of ALTERNATIVES Public Version ANALYSIS OF ALTERNATIVES Public version Legal name of applicant(s): Bayer Pharma Aktiengesellschaft Submitted by: Bayer Pharma Aktiengesellschaft Substance: 1,2-Dichloroethane (EC No. 203-458-1, CAS No. 107-06- 2) Use title: Use as an industrial solvent in the manufacture of the high-grade pure final intermediate of Iopromide, the Active Pharmaceutical Ingredient for the X-ray contrast medium Ultravist® Use number: 1 Copyright ©2016 Bayer Pharma Aktiengesellschaft. This document is the copyright of Bayer Pharma Aktiengesellschaft and is not to be reproduced or copied without its prior authority or permission. Disclaimer This report has been prepared by Risk & Policy Analysts Ltd, with reasonable skill, care and diligence under a contract to the client and in accordance with the terms and provisions of the contract. Risk & Policy Analysts Ltd will accept no responsibility towards the client and third parties in respect of any matters outside the scope of the contract. This report has been prepared for the client and we accept no liability for any loss or damage arising out of the provision of the report to third parties. Any such party relies on the report at their own risk. Note This public version of the Analysis of Alternatives includes some redacted text. The letters indicated within each piece of redacted text correspond to the type of justification for confidentiality claims which is included as Annex 3 (Section 10) in the complete version of the document. Table of contents 1 Summary..............................................................................................................................1 1.1 Applied for use................................................................................................................................2 1.2 Efforts made to identify potential alternatives ..............................................................................2 1.3 Assessment of suitability and availability of alternatives for the use applied for..........................3 1.4 Actions needed to make alternatives suitable and available .........................................................4 2 Analysis of substance function ..............................................................................................5 2.1 Role of the substance......................................................................................................................5 2.2 Conditions of use and technical feasibility criteria.........................................................................7 2.3 Summary of functionality of EDC in the applied for use...............................................................11 3 Annual tonnage.................................................................................................................. 13 3.1 Tonnage band ...............................................................................................................................13 3.2 Trends in the consumption of EDC ...............................................................................................13 4 Identification of possible alternatives.................................................................................. 15 4.1 List of possible alternatives...........................................................................................................15 4.2 Description of efforts made to identify possible alternative........................................................19 4.3 Screening of identified potential alternatives ..............................................................................22 5 Suitability and availability of possible alternatives............................................................... 25 5.1 Introduction ..................................................................................................................................25 5.2 Technical feasibility.......................................................................................................................26 5.3 Economic feasibility ......................................................................................................................26 5.4 Reduction of overall risk due to transition to an alternative........................................................33 5.5 Availability.....................................................................................................................................33 5.6 Conclusion on suitability and availability of alternatives..............................................................37 6 Overall conclusions on suitability and availability of possible alternatives............................ 39 6.1 Background to the use of EDC ......................................................................................................39 6.2 Technical feasibility of alternatives...............................................................................................39 6.3 Economic feasibility of alternatives..............................................................................................40 6.4 Risk reduction capabilities of the alternatives..............................................................................41 6.5 Availability of alternatives ............................................................................................................41 6.6 Overall conclusion.........................................................................................................................42 6.7 Next steps during an Authorisation review period.......................................................................42 7 List of references ................................................................................................................ 45 8 Annex 1: Regulatory controls on the use of EDC in the pharmaceutical industry .................. 47 8.1 Requirements of Marketing Authorisations and their variations.................................................47 8.2 Regulatory controls on residual solvents......................................................................................48 9 Annex 2: Research & Development by Bayer Pharma AG ...................................................51 9.1 Research and development on alternative solvents ....................................................................51 9.2 Research and development on alternative synthetic routes........................................................72 9.3 Screening of identified potential alternatives ..............................................................................79 10 Annex 3: Justifications for confidentiality claims................................................................. 95 1 Summary The Analysis of Alternatives at a glance 1. For nearly 30 years, Bayer Pharma AG has been using EDC as a solvent in the manufacture of Iopromide, the active pharmaceutical ingredient (API) in Ultravist®(a non-ionic, water- soluble iodine-based X-ray contrast medium for intravascular administration), primarily because of its unique dissolution profile. This dissolution profile ensures a high production yield and quality of the final products (essentially, the absence of colouration and avoidance of adhesion). 2. Since 1990, Bayer Pharma AG has undertaken very extensive research towards the identification of a suitable substitute solvent or a feasible alternative synthetic route. More recently, during the preparation of this Application for Authorisation, Bayer Pharma AG undertook additional extensive laboratory tests on a range of potential alternative solvents. 3. The past and recent R&D, which has looked into a wide range of solvent families, has confirmed that all alternatives considered are technically worse than EDC and result in poor yields and product quality, which greatly affects the economics of the manufacturing process. In addition, alternative synthetic routes may use solvents that have hazard profiles which would raise concerns similar to EDC. 4. The implementation of a yet unidentified alternative would require additional R&D, engineering work to adapt the existing production plant and manufacturing process or establish a completely new plant, and variations to a large number of Marketing Authorisations currently held for Ultravist® across more than 100 ('#C#''''') countries. Bayer Pharma AG estimates that substitution of EDC by an alternative solvent would require a minimum of 11.5 years. 5. The costs of converting to any given alternative can provisionally be estimated to rise to tens of millions of Euros. Variations to Marketing Authorisations would be particularly time-consuming, as Ultravist® is an established, mature and popular product and would require applications for variation to the hundreds of national level Marketing Authorisations it currently holds. 6. All iodine-based X-ray contrast media have the same principle of action and, as such, from a therapeutic perspective, they may be considered interchangeable. Price and marketing are decisive for market success. Therefore, if the use of an alternative would result in increased production costs, Ultravist® would become less competitive and its global market share would be eroded. 7. Bayer Pharma AG is planning to continue its search for a technically feasible alternative and will also focus on further optimising the use of EDC, so that EDC losses and worker exposure to the substance continue to decline. Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 1 1.1 Applied for use The applicant,
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