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

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, Bayer Pharma Aktiengesellschaft (hereafter referred to as Bayer Pharma AG), uses 1,2-dichloroethane (EDC) as a solvent in the manufacture of an Active Pharmaceutical Ingredient (API) (Iopromide) that is the key ingredient of an iodine-based X-ray contrast medium (Ultravist®). The manufacture of Iopromide and affiliated use of EDC is restricted to one site, in Bergkamen, Germany.

EDC is used for producing a suspension of the starting material, TAMIP-diacetate; following a two- step reaction, the product, TIP-diamide chloride, is isolated by crystallisation and washed with EDC. Therefore, EDC is essentially used as (a) a process solvent and (b) a washing solvent.

EDC is not present in the final product, Iopromide. In any case, as per exising legislation, the maximum residual solvent in the product is 5 ppm (ICH, 2011).

The vast majority of the EDC circulated in the plant is recycled and only a small percentage needs to be replenished each year. The tonnage of EDC purchased each year is in the 100-1,000 tonnes range ''#B#''''''' ''''''''''''''' '''' '''''''''''. 1.2 Efforts made to identify potential alternatives

EDC has been used as a solvent in the TIP-diamide chloride stage of Iopromide synthesis since commercial manufacture of Iopromide began in 1986. EDC use cannot be eliminated without being substituted by an alternative solvent, when using the existing synthetic route for the API. Bayer Pharma AG have made several attempts to substitute the solvent, which has been a ‘priority substance’ due to its carcinogenicity for a number of years. The research was initiated by Schering AG, a research-centred German pharmaceutical company, which was merged to form the Bayer subsidiary Bayer Schering Pharma AG in 2006. The company was renamed Bayer Pharma AG in 2011. Research into alternatives for EDC in the manufacture of Iopromide also became property of Bayer Pharma AG.

Since 1990, Bayer Pharma AG has made efforts to identify alternatives to EDC within a wide range of different solvent families with a focus on retaining the current route of synthesis (TAMIP-diacetate  TIP-diamide chloride as a one-pot process). Detailed internal (unpublished) reports of the unsuccessful attempts in the form of extensive laboratory testing, made in the period 1990–1996, are available (Kudschus, 1990; Schenk, 1995; Schenk, 1996). In addition, during the preparation of this AoA, Bayer Pharma AG undertook further laboratory tests on additional alternative solvents to evaluate their potential for substituting EDC.

Beyond alternative substances, Bayer Pharma AG is familiar with four alternative synthetic routes to the API, as presented in three different patents, one of which is held by Bayer Pharma AG (originally filed by Schering AG). The identified alternative synthetic routes are not compatible with the existing manufacturing plant, they are much more cost intensive (as they result in low yields and throughputs) and lead to a product with a different impurity profile (i.e. lower quality). As such, Bayer Pharma AG’s focus is on the identification of an alternative solvent that could be successfully implemented within the current synthetic route.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 2 1.3 Assessment of suitability and availability of alternatives for the use applied for

Several solvent families that were considered during Bayer Pharma AG’s R&D work can be screened out without the need for extensive laboratory testing: Table 4-1 explains that solvent families such as alcohols, carboxylic acids, ketones, dipolar aprotic solvents, amines and nitro-compounds would not be sufficiently stable or inert under the reaction conditions of the currently used synthetic route and thus are technically infeasible. On the other hand, solvent families that could offer opportunities for substituting EDC include nitriles, hydrocarbons, halogenated hydrocarbons, esters and ethers.

Within these solvent families that offer a minimum guarantee of process stability, several representative solvents were assessed during Bayer Pharma AG’s R&D work. The following five technical feasibility criteria have been used: (a) inertness to key reagents in the manufacturing process, (b) boiling point, (c) dissolution capabilities, (d) yield and process synchronisation, and (e) recyclability.

The laboratory tests have revealed the following:

 Reaction progress: very few alternatives are capable of delivering both of the two relevant stages in the API manufacturing process, as the conversion rate is typically unacceptably poor and in many cases very poor  Adhesion issues: very few alternatives do not cause adhesion of the intermediate product; some generate solid ‘blocks’ that cannot be stirred, others require very strong stirring and/or higher process temperatures to ensure that the reactions can proceed at an acceptable rate  Quality of final product: no alternative is capable of delivering the final intermediate at the quality required by Bayer Pharma AG and which is stipulated in the hundreds ('#C#'''''') of Marketing Authorisations held for Ultravist®. Even for alternative substances which could deliver (under certain conditions) both reaction steps (for example, acetates), a new impurity re- emerged and the colour of the final product was found to be unacceptable  Yield impacts: no alternative is capable of maintaining the yield that can currently be achieved with EDC. A lower yield results in lower quantities of the API produced and therefore lower sales of the medicinal product and inability to meet market demand. By way of example, in 2014- 2015, the Iopromide plant in Bergkamen worked at 100% capacity in order to fulfil customers’ orders and build up stock.

Overall, there is no known alternative substance that could demonstrate the same combination of technical performance characteristics as EDC.

As far as alternative synthetic routes are concerned, these have not been commercialised and this in itself suggests that their feasibility is poor. In comparison to the existing route, alternative synthetic routes would suffer from gravely reduced yields, recycling and waste generation problems and would also involve a variety of solvents some of which have hazard profiles not (sufficiently) safer than EDC, for example dimethyl formamide (DMF) and dimethyl acetamide (DMA).

In conclusion, no known alternative can demonstrate a minimum of technical feasibility and as such there is currently no known option for the substitution of EDC in the applied for use.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 3 1.4 Actions needed to make alternatives suitable and available

None of the many alternatives that have been considered so far could be improved in terms of their technical feasibility. The shortcomings of the alternative substances largely relate to their physicochemical properties (dissolution parameters affecting reaction rates and yield, boiling point affecting recyclability, etc.) and these cannot be improved. Only additional research into new alternatives or combinations of alternatives could reveal a more feasible option. However, there is no guarantee given the unsuccessful attempts of the distant and more recent past that a positive result will materialise.

This AoA presents a hypothetical plan for the replacement of EDC by an alternative solvent. This is only theoretical and assumes that a feasible candidate could indeed be identified within a reasonable timeframe. The plan includes 6 steps, of which the single most time-consuming would be the variations to the Marketing Authorisations currently held for Ultravist®. Bayer Pharma AG estimates that a minimum of 11.5 years would be required before any yet unknown alternative could be implemented. Such a plant would certainly involve securing a significant volume of Iopromide stockpiles. Furthermore, any feasible candidate which is not listed under the ICH Q3C Guidelines on residual solvents should ideally first be listed therein (as a Class 3 or (at least) 2 solvent) before being used on an industrial scale.

On the other hand, in relation to the economic feasibility of a theoretically technically feasible and available alternative, while changes to operating costs are impossible to predict in the absence of a specific candidate alternative, the following would constitute the main elements of the associated investment cost:

1. Research and development to identify a feasible candidate solvent and to adapt the current synthetic process to the alternative.

2. Engineering work to adapt the production equipment and process to the alternative solvent.

3. Variations to hundreds ('#C#'''''') of Marketing Authorisations that Ultravist® holds in more than 100 ('#C#''''''') countries around the globe.

On the basis of past experience (i.e. the construction of the current plant that uses EDC in 1996, and the manpower needed for undertaking laboratory and desk-based research), the costs of converting to an alternative solvent, irrespective of its identity, could be preliminary estimated as follows.

Table 1-1: Estimated cost of investments for a hypothetical substitution of EDC by an alternative solvent Action – Investment cost Estimated cost Cost range R&D 'All Table 1-1 #D#''''''' '''''''''''''' €1-10 million Plant conversion engineering work ''''''' ''''''''''''' €10-100 million Variations to Marketing Authorisations ''''' ''''''''''''' €1-10 million Total '''''''' '''''''''''' €10-100 million

Importantly, Ultravist® is a legacy product that is successfully marketed on the basis of price on the back of relatively low production costs. It faces strong competition from other similar medicinal products. Therefore, any increase in its production costs (arising from a switch to an alternative) would have severe impacts for Bayer Pharma AG in terms of market share and turnover from sales of Ultravist®. This inability of identifying an alternative that is technically feasible and economically viable supports Bayer Pharma AG’s request for the Authorisation of the continued use of EDC.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 4 2 Analysis of substance function

2.1 Role of the substance

Bayer Pharma AG uses EDC as a solvent in the manufacture of Iopromide (1-N,3-N-bis(2,3- dihydroxypropyl)-2,4,6-triiodo-5-(2-methoxyacetamido)-1-N-methylbenzene-1,3-dicarboxamide). Iopromide is the API in Ultravist®, which is a non-ionic, water-soluble X-ray contrast medium, for intravascular administration (injection). The EDC solvent is used during the production, purification and isolation of the final intermediate of Iopromide.

The structure of Iopromide is shown in Figure 2-1. Iopromide is produced on a scale of thousands of tonnes per year. A total of 5 million EU patients and 15 million non-EU patients use this product.

Figure 2-1: Structure of Iopromide

Iopromide is produced via several synthetic stages, in which EDC is used for the production of the final intermediate, TIP-diamide chloride, the direct precursor of the Iopromide product (see Table 2-1, step 6). TIP-diamide chloride is the first intermediate stage in which impurities are separated effectively by crystallisation (with impurities remaining mainly in the mother liquor), after three intermediate stages in which no significant reduction of impurities by crystallisation occurs (not isolated or isolated with no significant purifying effect at these stages). The purity of the final intermediate, TIP-diamide chloride, defines the quality of the API, Iopromide.

Table 2-1 provides a view of the sequence of reactions leading to the manufacture of Iopromide. This sequence includes the steps that are facilitated by the presence of EDC as a solvent. EDC is present in the step marked in bold letters.

Table 2-1: Overview of entire sequence of reactions/key reagents for the generation of Iopromide # Intermediate / product Acronym Role Relevant reactions 1 'All Table 2-1 #A#''''''''''''''''''''''''''''''' '''''''''''''''''''''' Starting '''''''' '''''''''''''''''''''''''''''' material for API 2 ''''''''''''''''''''''''''''' ''''''''' ''''''''''''''''''''' '''''''''''''' 1st Reaction with ''''''''''''''''''''''''''''''''' '''''' ''''''''''''''''''''''''''''''''''''' '''''''''''''' intermediate ''''''''''' 3 ''''''''''''''''''''''''''''''''' ''''''''' ''''''''''' 2nd Reaction with hydrogen/catalyst ''''''''''''''''''''''' ''''' intermediate '''''''''''''''''''''''''''''''''''' (not isolated) 4 '''''''''''''''''''''''''''''''''''''''''''''' '''''''' '''''''''''' 3rd Reaction with iodine monochloride '''''''''''''''''''''' '''''' intermediate '''''''''''''''''''''''''''''''''''''' 5 '''''''''''''''''''''''''''''''''''''''''''''''''' '''''''' TAMIP- 4th Reaction with '''''''''''''''''' ''''''''''''''''''''' ''''''''''''''''''''''' '''''' '''''''''''''''''' diacetate intermediate '''''''''''''''' '''''''''''''''''''

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 5 Table 2-1: Overview of entire sequence of reactions/key reagents for the generation of Iopromide # Intermediate / product Acronym Role Relevant reactions 6 TIP-diamide chloride (via TIP- TIP-diamide 5th 1st step: reaction with ''''''''''''''''''''''''' diamide) chloride (via intermediate '''''''' ''''''''''''' TIP-diamide) 2nd step: reaction with thionyl chloride 7 Iopromide '''''''' '''''''''''''''''' Iopromide API 1st step: reaction with '''''''''''' '''''''''''''''''''' ''''''' ''''''''''''''''''''''''' '''''''''''''''''''''''' ''''''''''''''''''''' 2nd step: reaction with sodium '''''''''''''''''' hydroxide 3rd step: desalting 4th step: treatment with active carbon 5th step: crystallisation from ethanol

In the presence of EDC, TIP-diamide chloride is produced in a two-stage synthesis, in which the product of the first synthesis stage, TIP-diamide, is not isolated. The two-stage process is shown in Figure 2-2 and can be described as follows:

Figure 2-2: Reactions occurring in the presence of EDC in Bayer Pharma AG’s manufacturing process for Iopromide

1. The starting material, TAMIP-diacetate (4th intermediate in Table 2-1), is suspended in EDC.

2. Methoxyacetyl chloride is added to convert TAMIP-diacetate at 80 °C to TIP-diamide which, as detailed previously, is not isolated. This must pass through a dissolution stage, as otherwise unreacted starting material could proceed onto the next stage and could thus lead to the occurrence of unwanted by-products. In the formation of this first intermediate product, substantial quantities of hydrogen chloride are released.

3. In the second stage, thionyl chloride is added to transform the TIP-diamide intermediate to TIP-diamide chloride. This final intermediate (5th intermediate in Table 2-1), TIP-diamide chloride, forms at ca. 64 °C. To allow complete conversion, the TIP-diamide must stay in solution after having being formed, because otherwise unsolved TIP-diamide would remain unreacted and adversely affect the quality of TIP-diamide chloride. Substantial quantities of hydrogen chloride and sulphur dioxide are released at this stage.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 6 4. On completion of the reaction, the precipitated crystalline TIP-diamide chloride product is isolated from the mother liquor. The product crystals are then freed from by-product containing mother liquor by washing with EDC. The dried TIP-diamide chloride will then be poured into containers and will proceed to the final synthetic manufacturing stages, to produce Iopromide without EDC present after this step. 2.2 Conditions of use and technical feasibility criteria

2.2.1 Overview of the importance of EDC

The formation of TIP-diamide chloride places high demands on the properties of the solvent. Of particular note are the following problems that arise under the existing synthetic route (Kudschus, 1990):

 First stage – TAMIP-diacetate  TIP-diamide: this stage requires an aprotic solvent of medium polarity, which is stable under strongly acidic conditions, and has sufficiently good dissolution properties at the TIP-diamide stage (see Table 2-1), for both the starting compound and for impurities. The last point is of particular significance, because solvents with poor dissolution properties cause the reactant particles to melt on the surface at the required reaction temperatures of 60–80 °C. These particles then adhere to each other.

This adhesion is rapid and strong, and cannot be controlled even on a laboratory scale; consequently, stirrer stoppage and breakage has occurred several times. This behaviour is evidently caused by impurities in TAMIP-diacetate, which cannot be prevented practically without an additional purification step. Even a small change in the quality of TAMIP-diacetate (change of batch) can result in adhesion

 Second stage – TIP-diamide  TIP-diamide chloride: unless solvent-free operation with thionyl chloride (SOCl2) excess is adopted, the solvent required for this stage has to withstand the aggressive conditions of several hours of heating with thionyl chloride (also in the presence of hydrogen chloride and sulphur oxide) and also be capable of absorbing the coloured impurities that form during the reaction, without drastically suppressing the yield of TIP-diamide chloride.

In this context, when assessing potential alternatives, three are the key principles:

 The quality of the API, as defined by purity and the colour of the product, must be maintained. Ultravist® is administered as a contrast medium in substantially higher dosages than most other medicinal products. Therefore, particularly strict requirements apply for the purity of the API (the specification for some impurities (e.g. free aromatic amine, N-chloracetyl-derivate) are about 10 times stricter than for usual pharmaceuticals (e.g. pills))  The manufacturing cost of the API must not unduly increase  The compatibility of the alternative with the operating parameters of the existing process and equipment must be safeguarded.

To establish whether an alternative can accomplish these three principles, it needs to be compared to EDC against a set of relevant technical feasibility criteria. The five relevant criteria are shown Table 2-2 and are discussed overleaf.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 7 Table 2-2: Technical feasibility criteria for alternatives Key principles

h t / i s w s

I e y P c t i A o l I t

i r f P n b p i o

e A

g f y a m t n o i i p p

l t i t a s s m u i

u Criterion has an influence o o x q # Technical feasibility criterion Q C C e e on… 1 Inertness to thionyl chloride and HCl  2 Boiling point  Reaction completeness; …the intermediate substance  conversion (%), adhesion Dissolution Reaction completeness; 3 capacity …the reaction gases, SO and HCl   2 conversion (%) for… …the final intermediate substance   Yield (%) …other substances   Adhesion, colouring Yield of Iopromide synthesis and process 4   synchronisation 5 Recyclability 

2.2.2 Technical feasibility criterion 1: Inertness to thionyl chloride and hydrogen chloride

Importance of the criterion

The solvent must be inert to SOCl2 and HCl, which are very reactive substances, to avoid decomposition.

Technical requirements of the applicant’s process

No measurable decomposition of the solvent is acceptable.

2.2.3 Technical feasibility criterion 2: Boiling point

Importance of the criterion

As the reaction gases are saturated with the solvent at the temperature of the condenser (0-5 °C), the boiling point must be high enough to allow the reaction gases to separate in the reflux condenser during the reaction, without significant loss of solvent. This allows the gases that have formed to escape and facilitates the condensing of solvent vapours. Low boiling point solvents have higher vapour pressure at the condenser temperature; consequently, a larger amount is discharged with the reaction gases. The temperature of the reflux condenser cannot be lower because otherwise sulphur dioxide (having a boiling point: -10 °C) would condense together with EDC and could not be removed.

Technical requirements of the applicant’s process

The boiling point of the solvent should exceed 50 °C.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 8 2.2.4 Technical feasibility criterion 3: Dissolution parameters affecting final product purity

Importance of the criterion

EDC offers a dissolution profile exactly matched to the needs of the chemical synthesis of Iopromide, by ensuring high purity of the final product. The purity, in addition to the avoidance of product adhesion, is a result of the dissolution capabilities of the solvent vis-à-vis the presence of different reagents in the reaction vessel. Table 2-3 summarises the areas where the dissolution of EDC is appropriately high or low depending on the separation and purification needs of the process.

Table 2-3: Dissolution profile for potential alternative solvents Desired Agent to be dissolution Importance of dissolution profile dissolved ability Intermediate High The solvent must have a good dissolution capacity for the starting intermediate substance dissolution product, TAMIP-diacetate, and the intermediate product TIP-diamide. This will ensure high purity of the final intermediate (TIP-diamide chloride) and will help avoid product adhesion and incomplete conversion to the final intermediate (adhesion is caused/favoured by impurities contained in TAMIP-diacetate)

Reaction Low The solvent must have poor dissolution capacity for SO2 and HCl, as these gases SO2 and dissolution substances must be removed from the reaction equilibrium HCl Final Low The solvent must show poor dissolution of the final intermediate to ensure a intermediate dissolution high yield of its production, as this product must be separated from the reaction mixture Sufficient At the same time, the solvent must display sufficient dissolution of the final dissolution intermediate product (TIP-diamide chloride) in order to prevent its early precipitation. The time of spontaneous crystallisation of the product during the reaction phase defines the product quality: premature crystallisation leads to TIP-diamide contamination and thus worsened TIP-diamide chloride product quality Accompanying High The solvent must have good solubility for the accompanying related substances dissolution substances; in particular, colouring impurities must be separated. This will (impurities) further enhance the purity of the final intermediate

Technical requirements of the applicant’s process

No specific requirements (thresholds) for these dissolution properties have been established. The combination of the above parameters must be displayed by any solvent as closely as possible before it can be considered to be a feasible alternative for EDC. The amount of solvent could potentially be changed to compensate for the lack of dissolution capability; however, problems with process synchronisation might then arise. Even if some solvents might be considered to be feasible for the intermediate TIP-diamide chloride, the solvent needs to be able to obtain pure TIP-diamide chloride with a high yield, like EDC does.

2.2.5 Technical feasibility criterion 4: Yield of Iopromide synthesis and process synchronisation

Importance of the criterion

A high yield improves the economics of the synthetic process, even if this refers to only one of the intermediate steps of the overall process.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 9 Yield is highly dependent on maintaining high process synchronisation. As of 2016, Iopromide has been produced in the current production plant in Bergkamen, Germany for 20 years. It is a single- product plant which uses dedicated equipment, i.e. it is used exclusively to produce Iopromide. The overall synthesis consists of a sequence of seven stages, all of which run in parallel without interruption, apart from for maintenance stoppages. Skilful material-flow management ensures that intermediate products are used in the subsequent stage without delay, and no unnecessary, costly transport of product or intermediate storage is required. The production plant utilisation was 100% in 2014.

All equipment has been optimally designed according to the requirements of the synthesis, and dimensioned accordingly to allow for synchronised synthesis. The following parameters are decisive for the dimensioning of each production stage:

 Quantity to be produced at each intermediate stage  Dwell time in the equipment  Space-time yield of each stage (concentration, reaction time).

In short, Iopromide is produced in a highly specialised production unit, which is fine-tuned precisely to the current synthesis, and all stages of synthesis are coordinated in terms of organisation, space and timing. If even one of the intermediate stages was replaced by another less efficient one, then the production capacity of the entire plant would decrease accordingly, as corresponding idle times would arise in the other stages of synthesis (i.e. a bottleneck would occur) and production yield would drop.

Technical requirements of the applicant’s process

From 'All #A#'''''' tonnes of ''''''''''''''''''''''' '''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''' ''''' '''''''''''''''' ''''''''''''''''''' ''''''' '''''''''''''''' '''''''''''''''''''' '''''''''' ''''''''''''' the starting material for Iopromide, Bayer Pharma AG can synthesise a maximum of ''''''''''' tonnes of Iopromide (M.W. 790.9). If it is assumed that there are no losses through the formation of by-products and isolation, the theoretical yield of Iopromide synthesis is '''''''''' tonnes. Thus, the theoretical yield of the present syntheses can be estimated at ''''''''' ''''''' '''''''''' '' ''''''''''' '' ''''''''' '''''''''' ''''' ''''''''''''''''''''

On the other hand, the current yield for conversion of TAMIP-diacetate '''''''''''' '''''''''''' to TIP-diamide chloride ''''''''''''' ''''''''''''' is '''''''' '''' ''''''''''''''''''''' '''' ''''''''''' '''''' '''''''''' '''''''''''''. This means that from ''''''' g of TAMIP-diacetate, Bayer Pharma AG produces 103 g instead of the theoretical '''''''''' g of TIP- diamide chloride.

In the final step, the TIP-diamide chloride is converted to Iopromide with a yield of ''''''''''''''

Any alternative needs to be able to (help) obtain the intermediates and the final API with a yield comparable to that achieved by EDC. Moreover, any alternative substance or, particularly, an alternative synthetic route, must be compatible with the production plant set-up to minimise process disruption, yield/capacity losses and, consequently, increased production costs.

2.2.6 Technical feasibility criterion 5: Recyclability

Importance of the criterion

The solvent must be readily recyclable, as the annual requirement for solvent throughput is in the range of several thousand tonnes. EDC is readily recyclable: stirring with sodium hydroxide solution removes all acidic components (thionyl chloride and methoxy acetic acid chloride) completely and all

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 10 non-volatile components can be separated in a subsequent distillation stage. Its low solubility in water and good stability under slightly alkaline conditions, which, as noted above, is necessary for removing acidic components, makes EDC an easily recyclable solvent. This both reduces costs and supports the sustainability of the manufacturing process.

Technical requirements of the applicant’s process

In 2014, Bayer Pharma AG’s distillation plant supplied the manufacturing plant with '#B#''''''''' tonnes of EDC (recycled + virgin) of which 100-1,000 ('#B#'''''') tonnes were virgin (i.e. solvent purchased to replenish losses) suggesting a recycling rate of 93%. The current recycling rate cannot strictly be used as a threshold of acceptability; a reduction in recycling rate might be possible to tolerate but this would depend on the cost of the alternative solvent and its ability to act as an otherwise technically feasible substitute for EDC. 2.3 Summary of functionality of EDC in the applied for use

Table 2-4 summarises the parameters of EDC use set by Bayer Pharma AG.

Table 2-4: Parameters for EDC use Functional aspect Explanation Tasks performed by the Solvent for the separaration and purification of intermediate products in the substance synthesis of Iopromide, which dissolves the starting material and impurities but not the product, while being resistant to prevailing reaction conditions Physical form of the EDC: liquid; used as ≥99.5% purity product Iopromide: liquid Concentration of the EDC should not be present in the final product, Iopromide. As per exising substance in the product legislation (ICH Q3C Guidelines), the maximum residual solvent in the API is 5 ppm (ICH, 2011) Performance Explanation requirements

No reaction with SOCl2 + Inert against very reactive substances like hydrogen chloride and thionyl chloride HCl Boiling point (84 °C) The boiling point must sufficiently high so that separation of the reaction gases in the reflux condenser is possible during the reaction with no significant loss of solvent Sufficient solubility with This will help avoid product adhesion and incomplete conversion to the final starting intermediate intermediate (adhesion is caused/favoured by impurities contained in TAMIP- TAMIP-diacetate diacetate) Good solubility with not It must have a good dissolution capacity for the not isolated intermediate isolated intermediate product, TIP-diamide TIP-diamide No solubility with Poor dissolution capacity for hydrogen chloride and sulphur dioxide, as these hydrogen chloride and substances must be removed from the reaction equilibrium sulphur dioxide No solubility with the Poor dissolution capacity for TIP-diamide chloride, as this product must be target intermediate TIP- separated from the reaction mixture. However, the dissolution capacity for TIP- diamide chloride diamide chloride must not be too low, as this product must not spontaneously crystallise prematurely (otherwise it leads to the inclusion of the non-isolated intermediate product, TIP-diamide) Good solubility with by- The solvent must have good solubility for the accompanying related substances. products In particular colouring* impurities must be separated

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 11 Table 2-4: Parameters for EDC use Good recycling rate The solvent must be readily recyclable, as the annual requirement for solvent throughput is in the range of several thousand tonnes. At a first step all acidic components have to be completely eliminated (by stirring with NaOH) and at a second step all non-volatile components have to be separated (in a subsequent distillation stage) Other requirements Explanation Industry sector and legal Medicinal Products Directive: The use of EDC in the manufacture of an API falls requirements for within the scope of Regulation (EC) No 726/2004 and Directive 2001/83/EC, technical acceptability relating to medicinal products for human use. that must be met Residual Solvents: EMA (European Medicines Agency) guidance on residual solvents (EMA/CHMP/ICH/82260/2006) contains a specific concentration limit for EDC (class 1 solvent). The ICH guideline Q3C(R5) (ICH, 2011) on impurities: guideline for residual solvents as adopted by the CHMP (EMA/CHMP/ ICH/82260/2006) recognises that if the use of class 1 is unavoidable, then the level should be restricted to ICH limits for class 1 solvents (5 ppm).

See details in Annex 1 * APHA colour index, also known as the Platinum Cobalt (Pt/Co) scale, is a colour standard named by the American Public Health Association and defined by ASTM D1209. It is a colour scale sometimes referred to as a “yellowness index” that is used to assess the quality of liquids that are clear to yellowish in colour

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 12 3 Annual tonnage

3.1 Tonnage band

Confidential annual tonnage (2014): '#B#''''''' tonnes of EDC was purchased.

Annual tonnage band: 100–1000 tonnes per year. 3.2 Trends in the consumption of EDC

'#C#'' ''''''' '''''''''''''' ''''''''''''''''''''''' '''''''''' '''''''''''''' ''''''' '''''''''''''''''' ''' '''''''''''''' ''''''''''''''''' '''' '''''' '''''''''' '''' '''''''''''''''''' '''' ''''' ''''''''''''' '''' ''''''' '''''' '''''''''' '''''''' ''''''' '''''''''''' '''''' '''''''' '''''''' '''''''''''''''''''' '''''''''' '''''''''''''' '''''''''''''''' '''''' ''''''' Bayer Pharma AG estimates that production and sales of Ultravist® would increase '#C#'''' '''''''''''''''''''''''''''' ''''''' ''''''' '''''''''''''' ''''''''' '''''''''' ''''''' '''''''' ''''''''''''' '''''''' ''''''''''' ''''' ''''''''''''''''''''' ''''''''' ''''''''''' ''''''''''''' ''''''''' ''' '''''''''' This will require a proportionate increase in the production volume of Iopromide, which itself will require a proportionate increase in the volume of EDC consumed.

The capacity of the Bergkamen Plant F (building D105) where Iopromide is manufactured is '#A#''''''''''' t/y Iopromide. This is expected to be reached by 2030, after which point volumes of Iopromide manufactured (and used) are assumed to remain stable. This also means that consumption of virgin EDC will remain stable at a maximum of 100-1,000 '#B#'''''''''' t/y and the tonnage of Ultravist® manufactured (and sold) will stabilise at '#A#'''''''''' t/y (these figures are discussed in more detail in Section 2 of the accompanying SEA document).

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 13 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 14 4 Identification of possible alternatives

4.1 List of possible alternatives

EDC has been used as a solvent in the TIP-diamide chloride stage of Iopromide synthesis since commercial manufacture began in 1986. Bayer Pharma AG has made several attempts to substitute the solvent, which has been a ‘priority substance’ due to its carcinogenicity, for a number of years. Bayer Pharma AG’s R&D efforts can be summarised as follows:

 R&D on possible alternative solvents: during Bayer Pharma AG’s R&D work, a wide range of solvent families have been considered in an effort to widen the scope of the research as far as possible. Solvents within some of these families could be readily excluded from detailed consideration as they would not remain sufficiently stable or inert under the Iopromide synthesis reaction conditions due to their fundamental chemical properties. Others, which would theoretically be chemically stable were considered in more detail and subjected to extensive laboratory testing as appropriate.

Table 4-1 (overleaf) provides an overview of the scale of the R&D undertaken by Bayer Pharma AG and the numerous solvent families and representative members considered.

 R&D on possible alternative synthetic routes: apart from alternative solvents, Bayer Pharma AG also considered alternative synthetic routes that might be possible to lead to the formation of Iopromide. Those considered have included:

 Synthetic Route A: based on Patent US 4364921 A (see Example 6 in the patent)  Synthetic Route B: based on Patent US 4364921 A (see Example 7 in the patent)  Synthetic Route C: based on Patent US 4364921 A (see Example 8 in the patent)  Synthetic Route D: based on Patent WO 2009134030 A1.

 Other substitution options: an entirely different alternative would be the substitution of Iopromide by a different X-ray contrast medium. It is acknowledged that all X-ray contrast media containing iodine have the same principle of action: they spread through the bloodstream and the heavy iodine atoms produce a contrast (shadow) when X-ray images are recorded. Nevertheless, an alternative X-ray contrast medium cannot be considered a realistic alternative, because the Iopromide molecule is Bayer Pharma AG’s X-ray contrast medium and Bayer Pharma AG has its own, established, significant, market share '#C#'''''' '''''''''''''''''' ''''''' '''''''' '''' ''''''''''''''. Bayer Pharma AG has invested more than 20 years of production improvements to achieve an optimally synchronised process, generating a product of the highest quality and lowest possible cost for the specific molecule. The abandonment of Iopromide and the start of production of a new X-ray contrast agent would be entirely unrealistic, particularly given that alternative X-ray contrast media available from competitors are already established in the market.

The systematic screening of these alternatives has concluded that no suitable alternative exists that Bayer Pharma AG could adopt in order to substitute EDC. The sections that follow and in particular Annex 2 (Section 9) provide a detailed account of Bayer Pharma AG’s past and present R&D work towards the identification of a feasible alternative for EDC.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 15 Table 4-1: Solvent families considered by Bayer Pharma AG as potential alternatives for EDC Solvent Feasibility Rationale for family feasibility assessment (e.g. undesirable Example members of each family that have been considered family under reactions and stability concerns) # Name EC CAS reaction Number Number conditions Alcohols Infeasible Formation of chloroalkanes and sulphurous acid esters with 1 Methanol 200-659-6 67-56-1 thionyl chloride 2 Ethanol 200-578-6 64-17-5 3 Butanol 200-751-6 71-36-3 Carboxylic Infeasible Formation of acid chlorides; solvent contains the same functional 4 Acetic acid 200-580-7 64-19-7 acids group as starting material so the thionyl chloride would simply react with the solvent rather than the starting material Ketones Infeasible Being aprotic solvents, they are feasible for the reaction conditions 5 Acetone 200-662-2 67-64-1 of the 2nd synthetic stage. However, ketones react with the amine group of the starting materials to form a Schiff base* with TAMIP- 6 Methyl ethyl ketone (MEK) 201-159-0 78-93-3 diacetate (amino group + keto group react); this formation also occurs with MIBK, which is sterically more demanding than acetone or MEK, making all of these solvents infeasible 7 Methyl isobutyl ketone (MIBK) 203-550-1 108-10-1

Nitriles In principle, In principle feasible for the 1st synthetic stage (but acetonitrile 8 Acetonitrile 200-835-2 75-05-8 feasible reacts considerably with thionyl chloride / hydrogen chloride) Dipolar Infeasible Many common polar aprotic solvents react with thionyl chloride. 9 Dimethylformamide (DMF) 200-679-5 68-12-2 aprotic Dimethylsulphoxide (DMSO) reacts with thionyl chloride. DMF 10 Hexamethylphosphoramide 211-653-8 680-31-9 solvents also reacts forming the strongly carcinogenic dimethyl carbamoyl (HMPTA) chloride. Many dipolar aprotic solvents are miscible with water 11 N,N-dimethylacetamide (DMA) 204-826-4 127-19-5 (all of the solvents trialled by Bayer Pharma AG) making the recovery of products very complex 12 Dimethylsulphoxide (DMSO) 200-664-3 67-68-5

Amines Infeasible Violent reaction/salt formation with hydrogen chloride 13 Triethylamine 204-469-4 121-44-8

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 16 Table 4-1: Solvent families considered by Bayer Pharma AG as potential alternatives for EDC Solvent Feasibility Rationale for family feasibility assessment (e.g. undesirable Example members of each family that have been considered family under reactions and stability concerns) # Name EC CAS reaction Number Number conditions Nitro Infeasible Serious process hazards: shock and heat sensitive explosive 14 Nitromethane 200-876-6 75-52-5 compounds properties, e.g. nitromethane (Sax, 1979). Nitrobenzene is the only other nitro compound that is readily available. However, it has a Repr. Cat 1B classification and has a high boiling point (210 15 Nitrobenzene 202-716-0 98-95-3 °C) making it an infeasible and unsuitable solvent

Hydrocarbons In principle, In principle feasible. Alkylated aromatics (e.g. toluene) and 16 Heptane 205-563-8 142-82-5 feasible alkanes, being aprotic solvents, are conditionally feasible for the reaction conditions of the 1st synthetic stage (acylation) and 17 Toluene 203-625-9 108-88-3 nd formation of acid chloride in the 2 stage 18 Cyclohexane 203-806-2 110-82-7

Halogenated In principle, The solvent family EDC belongs to 19 Dichloromethane 200-838-9 75-09-2 hydrocarbons feasible 20 Chloroform 200-663-8 67-66-3 21 1,1,1-Trichloroethane 200-756-3 71-55-6 22 Chlorobenzene 203-628-5 108-90-7 23 1-Chlorobutane 203-696-6 109-69-3 24 Chlorobenzene 203-628-5 108-90-7 25 α,α,α-Trifluorotoluene 202-635-0 98-08-8 26 Fluorobenzene 207-321-7 462-06-6 Esters In principle, In principle feasible, however esters will hydrolyse in strongly 27 Ethyl acetate 205-500-4 141-78-6 feasible acidic or basic aqueous conditions, such as those encountered 28 Butyl acetate 204-658-1 123-86-4 during solvent recovery, making them sub-optimal solvents for the 29 2-ethoxyethyl acetate 203-839-2 111-15-9 second step 30 Diethyl carbonate 203-311-1 105-58-8 31 n-Propyl acetate 203-686-1 109-60-4 32 Isopropyl acetate 203-561-1 108-21-4 33 Ethyl propionate 203-291-4 105-37-3 34 n-Butyl propionate 209-669-5 590-01-2

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 17 Table 4-1: Solvent families considered by Bayer Pharma AG as potential alternatives for EDC Solvent Feasibility Rationale for family feasibility assessment (e.g. undesirable Example members of each family that have been considered family under reactions and stability concerns) # Name EC CAS reaction Number Number conditions Ethers In principle, Cyclic ethers (e.g. THF) are in principle feasible, but are liable to 35 Diethyl ether 200-467-2 60-29-7 feasible decompose (forming chloro alcohols with hydrogen chloride). 36 Di-n-butyl ether 205-575-3 142-96-1 Aliphatic ethers, being quite non-polar solvents, are feasible for 37 Diisopropyl ether 203-560-6 108-20-3 the reaction conditions of both synthetic stages 38 Methyl tert-butyl ether 216-653-1 1634-04-4 39 Tetrahydrofuran (THF) 203-726-8 109-99-9 40 Dioxane 204-661-8 123-91-1 41 Diglyme 203-924-4 111-96-6 42 2-methoxy-2-methylbutane (tert- 213-611-4 994-05-8 Amyl methyl ether (TAME)) 43 2-Methyl-tetrahydrofuran 202-507-4 96-47-9 44 Diisopropyl ether 203-560-6 108-20-3 45 Cyclopentyl methylether 445-090-6 5614-37-9 * A Schiff base is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group. Schiff bases in a broad sense have the general formula R1R2C=NR3, where R is an organic side chain

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 18 4.2 Description of efforts made to identify possible alternative

4.2.1 Research and development on alternative solvents

The R&D work that Bayer Pharma has undertaken on alternative solvents can be distinguished into 2 phases:

1. R&D work that was undertaken before 2014.

2. R&D work that was undertaken in 2014, during the preparation of this Application for Authorisation.

R&D work before 2014

The first phase started in 1990, it was very extensive and the results have been documented in internal research reports which have been used as the basis of the analysis presented in Annex 2 (Section 9) to this AoA. This work looked into the most important solvent families and selected representative solvents from each family to assess. The solvent families considered included those shown in Table 4-1.

The R&D programme involved four steps, the findings of which are described in detail in Annex 2 and are briefly summarised here as follows:

 Step 1 – Stability of solvent families under reaction conditions: this step looked into the stability of solvents under the aggressive (acidic) conditions of the reactions that lead from TAMIP-diacetate to TIP-diamide chloride. Several solvent families were consequently screened out as their members would react under the reaction conditions. These included alcohols, carboxylic acids, ketones, dipolar aprotic solvents, amines, nitro compounds (which also pose hazards), and cyclic ethers. The solvent families retained included nitriles, hydrocarbons, halogenated hydrocarbons, esters and aliphatic ethers

 Step 2 –Testing of individual potential alternative solvents: representatives of the retained solvent families underwent laboratory experiments (see the full list in Table 9-2 of Annex 2) where each alternative was assessed against the technical feasibility criteria described in Section 2.2. Some of the alternative solvents were quickly dismissed as infeasible (for example, dichloromethane and diethyl ether have too low boiling points so they were dismissed without any actual lab testing; dioxane and tert-amyl methyl ether decompose under the reaction conditions). Others required detailed testing, particularly in relation to conversion completeness, adhesion, product quality/colour, yield and recyclability. The full results are given in Table 9-4 of Annex 2. Among all solvents considered, two appeared to be the most promising: toluene and ethyl acetate. Both performed better than the other solvents but also faced important drawbacks:

 Toluene: its performance was crucially dependent on the presence of impurities in the TAMIP-diacetate batches; guaranteeing that TAMIP-diacetate is of very high purity (in order to avoid adhesion problems) would be impossible under industrial scale manufacturing conditions and thus toluene could realistically only deliver too low reaction yields

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 19  Ethyl acetate: ethyl acetate is the solvent that has been assessed in the most detail and has been looked at by Bayer Pharma AG’s researchers for almost 10 years starting in 1986. Its yield might be considered acceptable and it can deliver the partial reactions without product adhesion. However, ethyl acetate faces important technical shortcomings: (a) it results in impurities in TIP-diamide chloride and consequently in impurities, such as dimeric ester or an unknown impurity of the same RT (Retention time) in HPLC, in the Iopromide made from this TIP-diamide chloride, (b) it faces issues with product coloration, and (c) it faces recyclability problems.

 Step 3 – Substitution of EDC by a mixture of solvents: Bayer Pharma AG also examined whether combinations of more than one solvent could be feasible substitutes for EDC. More specifically, Bayer Pharma AG has considered the possibility that each stage (TIP-diamide and TIP-diamide chloride formation) be carried out in their own optimally feasible solvent. To this effect, a dual solvent system, ethyl acetate/toluene, was tested. The tests showed that although product quality might be acceptable, the process became unduly complex and the yield was much poorer compared to EDC

 Step 4 – Substitution of EDC by alternative solvents under a different reaction sequence: another option considered was to avoid the one-pot reaction approach and attempt to prepare TIP-diamide chloride separately. The only solvent considered in principle compatible with the technical requirements of such an approach was 2-ethoxyethyl acetate. However, testing showed that this solvent faced problems with impurities, colour development and posed difficulties in the isolation of TIP-diamide. This option was abandoned as infeasible.

Overall, the testing undertaken before 2014 was not able to identify a feasible alternative solvent or combination of solvents.

R&D work since 2014

The second phase of R&D was undertaken during the preparation of this Application for Authorisation and involved both desk-based analysis and laboratory testing on twelve additional solvents belonging to the halogenated hydrocarbon, ester and ether families, which are considered the most chemically compatible with Bayer Pharma AG’s synthetic route to Iopromide. In addition, ethyl acetate was again tested. The full list of alternative solvents tested is provided in Table 9-5 of Annex 2.

After a first screening of the alternative solvents which eliminated one of them (2-methyl- tetrahydrofuran) on the basis of its reactivity under the reaction conditions, the laboratory testing was undertaken in two batches:

 First test batch: the twelve potential alternative solvents were subjected to scaled-down laboratory experiments to establish whether product formation and isolation would be possible in the two-step chemical reaction leading to the synthesis of TIP-diamide chloride without isolation of the first intermediate (TIP-diamide). Seven out of the twelve alternative solvents failed as the reaction mixture hardened or became sticky under the reaction conditions of Step 1. In the remaining five alternative solvents, the reaction mixture could be stirred under the reaction conditions of Step 1, but no clear solution was formed. For these five solvents, the conversion rate in Step 2 was found to be poor (10–20% formed product) but improved stirring and temperature conditions could perhaps deliver some improvement. The results of this first test batch are shown in Table 9-7 of Annex 2

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 20  Second test batch: the second batch tried to take a step-wise approach to investigating the completeness of the first reaction, then the role of temperature in the second reaction, then the quality/colour of the product, and finally the yield of the reaction in order to establish whether any solvent could perform satisfactorily on the industrial scale. The testing conditions are shown in Section 9.1.2 and the test results are summarised in Table 9-8 of Annex 2. All alternative solvents were eliminated on the basis of poor conversion rate at Step 1 with adhesion (1- chlorobutane, chlorobenzene, α,α,α-trifluorotoluene, fluorobenzene, n-butyl propionate), or without adhesion (diisopropyl ether and cyclopentyl methylether), or poor conversion rate at Step 2 (ethyl acetate and isopropyl acetate) or poor product quality and yield (diethyl carbonate and n-propyl acetate).

4.2.2 Research and development on alternative synthetic routes

Bayer Pharma AG has undertaken extensive literature searches for the identification of alternative synthetic routes to Iopromide that would allow the elimination of the use of EDC. The relevant synthetic routes identified in the literature are summarised in Table 4-2. It should be noted that, Schering AG, identified as the holder of some of the relevant patents, was a research-centred German pharmaceutical company, which was merged to form the Bayer subsidiary Bayer Schering Pharma AG in 2006. The company was renamed Bayer Pharma AG in 2011. Consequently, research into alternatives was also obtained during acquisition and can be considered part of the R&D that Bayer Pharma AG has undertaken in the past.

Table 4-2: Identified alternative synthetic routes for Iopromide which do not require the use of EDC Patent number / Reference Title Synthetic route holder Novel triiodinated isophthalic acid US 4364921 A (Speck, et al., 1982) diamides as non-ionic X-ray contrast Schering AG Synthetic Route A media Example 6 in KR20000061780 Schering AG patent Dong Kook Pharm Co (Gyu, et al., 2000) Process for producing Iopromide Ltd Novel triiodinated isophthalic acid US 4364921 A Synthetic Route B (Speck, et al., 1982) diamides as non-ionic X-ray contrast Schering AG Example 7 in patent media Novel triiodinated isophthalic acid US 4364921 A Synthetic Route C (Speck, et al., 1982) diamides as non-ionic X-ray contrast Schering AG Example 8 in patent media WO 2009134030 A1 (Hwang, et al., Novel process for preparation of Synthetic Route D LG Life Sciences Ltd 2009) Iopromide

Section 9.2 of Annex 2 explains in detail the differences between the synthetic routes proposed in the above patents and the one currently used by Bayer Pharma AG. By way of summary, Table 4-3 (overleaf) presents the key findings of the research undertaken on these alternative routes. Apart from important technical complexities, these are accompanied by poor yields and also introduce risks associated with the potential use of other substances with notable CMR hazard classifications (primarily, dimethyl acetamide (DMA) and dimethyl formamide (DMF)).

The conclusion was that none of the identified and assessed potential alternative synthetic routes could offer an acceptable level of feasibility as a substitute for the currently used EDC-based route and the requirement for a reduction in overall risks might not be possible to meet.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 21 Table 4-3: Technical feasibility, economic feasibility and hazard profile concerns over the identified alternative synthetic routes Economic feasibility issues Route Technical feasibility issues Hazard issues (yield) 44.7% - far lower than what is Problematic recycling. Only a few intermediate steps but currently achieved '#D#'''''''''' but Use of solvents such as A problems with product separation not directly comparable because DMF (Repr. Cat. 1B) from the reaction mixture it is based on late starting and DCM (Carc. Cat. 2) material Late introduction of iodine into the Steric hindrance affecting quality molecule requires aggressive Use of DMA (Repr. Cat. and yield: 41.4% - far lower than B reaction conditions and high risk of 1B) and dioxane (Carc. what is currently achieved formation of by-products that differ Cat. 2) as solvents '#D#''''''''' substantially to known impurities Problematic recycling. Yield of same intermediate is Use of DMA, DMF clearly far worse, 70% vs. C ''#A#'''''''''' '''''''''' ''''''' '''''''''''''' ''''''''''' (Repr. Cat. 1B) and '#D#'''''''' currently for the same DCM (Carc. Cat. 2) as conversion solvents D Improvement over Synthetic Route A with ready separation of symmetric Problematic recycling. diamide, but still problematic 50.7% - far lower than what is Use of DMA (Repr. Cat. efficiency and generation of currently achieved '#D#''''''''''''' 1B) and DCM (Carc. Cat. considerable quantities of iodine- 2) as solvents containing waste

4.2.3 Consultation with the supply chain

Given that EDC is only used as a solvent and does not play a role in the final product, in which EDC is not present, in combination with the fact that Iopromide is used internally by Bayer Pharma AG in the manufacture of the medicinal product, consultation with the supply chain was not deemed necessary for the purposes of the AoA and was not undertaken. 4.3 Screening of identified potential alternatives

The above analysis has explained that for technical reasons (but also, to a lesser extent economic reasons, for example, significant reductions in yield when potential alternatives are used), no feasible alternative for EDC can be identified. Therefore, a screening process in order to transform the master list of potential alternatives into a more manageable shortlist of possible alternatives which can fulfil the technical function of EDC as a minimum is not required. Nevertheless, for completeness and in order to introduce significant additional parameters affecting the availability of potential alternatives (cf. the ICH Q3C(R5) guidelines in respect to the approved residual concentration limits for solvents used in the manufacture of pharmaceutical products), Section 9.3 in Annex 2 provides a detailed screening of the master list of potential alternatives and hereby the conclusions of this screening process are presented:

 All known alternatives perform technically worse than EDC and result in poor yields and product quality. No known alternative can deliver the manufacture of Iopromide under acceptable conditions with satisfactory yield and product quality on an industrial scale. Therefore, none of them can be considered technically feasible. Their poor performance prospects would be combined with the very substantial economic cost of the conversion of Bayer Pharma AG’s plant (more detail is provided in Section 5)

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 22  Some of the identified alternative solvents (DMF, DMA) present no reduction in hazard, relative to EDC, with some of these substances having been prioritised for inclusion in Annex XIV of REACH. In addition, other substances (such as dioxane and dichloromethane) have suspected CMR properties, and their use could only be considered if a minimum level of technical feasibility had been demonstrated; this is not the case. Importantly, if an alternative not listed under the Q3C(R5) guidelines in respect to the approved residual concentration limits were to be selected issues of availability would arise

 Bayer Pharma AG is the only company manufacturing Iopromide, and since 1986, when the production process was established (by Schering AG) no solvent other than EDC has been used or has been proven to work (certainly on an industrial scale). The alternative synthetic routes, which are discussed in published patents (three of the four developed by Schering AG itself), have not found commercial use, due to poor efficiency and use of problematic solvents and reagents.

Overall, despite decades of research and a systematic review of the possibilities for eliminating the use of EDC, none of the identified alternatives can be considered a feasible option. Consequently, no specific alternative can be assessed in Section 5 of this AoA, as no alternative is a realistic option for Bayer Pharma AG’s manufacturing process.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 23 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 24 5 Suitability and availability of possible alternatives

5.1 Introduction

It is worth explaining here why Bayer Pharma AG will aim to develop an alternative solvent rather than an alternative synthetic route. Developing a new synthesis as opposed to replacing only one component of the existing synthesis is clearly more complex; there are however important complicating factors in the case of the use of EDC in the manufacture of Iopromide:

 Developing an alternative synthesis entails greater technical risks and uncertainties: there would be a high risk that the specification of Iopromide would not be met under the new synthesis. Experience shows that reaction conditions on an industrial scale differ from reaction conditions on a lab- and pilot plant scale. The reason for this is the different volume/surface ratio affecting heat transfer, mixing and processes where more than one phase is involved. This can adversely influence quality. If Bayer Pharma AG could not meet the specification under industrial production conditions, the new process would be unsustainable and all prior investment in R&D would be lost. In addition, when adjusting the process on an industrial scale, production might need to stop and sales of the medicinal product would be disrupted. Therefore, there are great uncertainties which would have to be addressed before conversion to the alternative synthetic route could be given the ‘green light’

 Meeting regulatory requirements would be more demanding: as a rule, chemical reactions may lead not only to the formation of the desired product but also to the formation of by- products. These accompany the desired main product and are involved in chemical reactions at subsequent stages, thus the by-product spectrum changes from one stage of synthesis to another. Therefore, the by-product spectrum of the API reflects not only the by-products produced directly in the final stage but also the reaction products of the by-products of previous stages. In other words, the by-product spectrum of the API depends on the entire synthesis, i.e. on the intermediate products involved and the process under which these intermediate products are generated. The currently practised manufacturing process was approved by the regulatory authorities of different countries by the issuing of Marketing Authorisations and any new process developed to substitute the existing one would need to be re-approved. Re- approval is based on the submission of applications for variations of the Marketing Authorisations in which:

 The quality features of the API are maintained in order to minimise the risk of harm from exposure to by-products  Improvements in quality, which have been made in the past as a result of optimisation of the production process, are maintained.

It is therefore imperative that alternative synthetic routes deliver an API which does not show worsened performance in any of quality standards prescribed in the Marketing Authorisations. Conformity with these standards is established through a series of analytical tests; for the manufacture of Iopromide, there are 12 such tests (for example, on the colour and clarity of the solution, the sum of all impurities, and others) each of them accompanied by a threshold which the Iopromide product needs to meet. The tests would essentially aim to establish that (a) no new impurities can be found in the Iopromide product, and (b) none of those which currently occurred are larger than what is achieved by the existing manufacturing process. Failure in the

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 25 tests would lead to rejection due to non-compliance with the specifications in the Marketing Authorisations.

If an alternative synthetic route cannot fulfil the 12 analytical tests, there may be a need for additional purification steps (re-crystallisation) to be introduced at several stages of the synthesis. This would bind equipment capacities, lower production yield and increase production costs

 The cost of implementation would be very high: significant plant changes would be needed, even if some of the existing equipment could be re-used. The only possibility of introducing an alternative synthetic route in Bergkamen without downtime and interruption to the supply of Iopromide would be for Bayer Pharma AG to construct a brand new production plant while simultaneously continuing production of Iopromide in the existing production plant. The cost of setting up the existing plant could give some useful indication of the relevant costs; the existing plant was built ca. 20 years ago and its planning and construction took '#C#'' years. The cost of construction was '#C#'''''''''''''' ''''''''''''' ''''' '''''''''' '''''''''''''. Using past inflation figures1, it can be calculated that, in February 2016 prices, the original cost was equivalent to '#C#'''' ''''''''' ''''''''''''. In addition, significant investments have been made in the last 20 years to meet the demands of modern production of Iopromide (NB. Bayer Pharma AG is able to provide all necessary evidence of these costs). Therefore, the current reasonable estimate is that, to build this plant today, it would cost about '#D#'''''''' '''''''''''''.

In conclusion, for technical, economic and regulatory reasons, developing a new synthetic route would be far less advantageous than identifying an alternative solvent. For this reason, the focus in this Section is on possible alternative substances. 5.2 Technical feasibility

Given the results of the past and present extensive R&D work by Bayer Pharma AG, it would be of limited practical use to reiterate in this Section 5 the aforementioned alternatives’ technical infeasibility. Still, to better inform the ECHA Committees’ and the European Commission’s opinion making and to support Bayer Pharma AG’s argumentation on the lack of feasible alternatives, an analysis of the steps that would be required for making an alternative available and the associated economic costs are detailed below. This analysis would largely apply equally irrespective to the identity of the selected alternative for EDC. 5.3 Economic feasibility

Without having identified a specific possible alternative, a detailed assessment of economic feasibility cannot be provided. The following paragraphs offer a broad overview of the likely magnitude of the costs that would be associated with researching and implementing a yet unknown alternative solvent.

1 Available here: https://www.statbureau.org/en/germany/inflation-calculators?dateBack=1986-1- 1&dateTo=2016-2-1 (accessed on 1 April 2016).

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 26 5.3.1 Estimates of investment costs

R&D costs

Additional R&D will be required. This would apply for both yet unknown alternatives and alternative solvents that have already been tested on a laboratory scale (with demonstrably poor results, as shown earlier). Table 5-1 summarises Bayer Pharma AG’s estimates of the cost of R&D that would be required for any one alternative solvent to substitute EDC before it could reach production maturity. NB. the numbering of steps shown in the table is that in the theoretical substitution plan discussed in Section 5.5.1 below.

Table 5-1: Estimated cost of R&D for the substitution of EDC by an alternative solvent Step Title Description Estimated Estimated duration cost 1 Screening of Desk-based research: involvement of 1 specialist group at 1 year '''''' ''''''''''''' alternatives a cost of 'All Table 5-1 #D#'''' '''''''''''''/year. This includes:  2 FTE* in Process R&D  1 FTE in Analytical Development  1 FTE in Bayer Technology Services 2 Testing Lab-based research: involvement of 1 specialist group at a 1 year ''''' '''''''''''' phase cost of ''''' '''''''''''''/year. This includes:  2 FTE in Process R&D  1 FTE in Analytical Development  1 FTE in Bayer Technology Services 3 Scale-up in Lab-based research: involvement of 1 specialist group at a 1 year ''''' ''''''''''''' the cost of '''''''''''' '''''''''''''/year. This includes: laboratory  2 FTE in Process R&D  1 FTE for scale-up work  1 FTE in Analytical Development  1 FTE in Bayer Technology Services 4 Pilot phase Pilot-scale research: involvement of 1 specialist group at a 1 year '''''''' '''''''''''' (1 kg  100 cost of ''''' ''''''''''''''/year. This includes: kg)  2 FTE in Process R&D  1 FTE in Analytical Development  1 FTE in Bayer Technology Services Upscaling: ''''''''''''''''''' for five intermediates subject to lab- based analysis. Six manufacturing campaigns on a pilot scale will be required at a total cost of '''''''' ''''''''''''' 7 Optimisation This refers to the optimisation of TAMIP-diacetate 1.5 year ''''''''''' of key production, with the aim of improving its quality. These '''''''''''''' process steps could include three steps:  Optimisation of TAMIP-diacetate production over an estimated '''''' '''''''''  Scaling-up over an estimated ''''''' '''''''''  Pilot phase and plant batches over an estimated '''''' '''''''' Lab-based research: for the first two tasks, 1 FTE in Process R&D will be required. For the pilot phase, two manufacturing campaigns would be required at a cost of ''' '' '''''''''''''''''' ''' ''''''''''''''''' Total 5.5 years '''''''' '''''''''''' *FTE means “fulltime equivalent”. For lab assistants this means: 1 lab assistant including supervising chemist, the complete lab, chemicals and energy. In terms of cost, 1 FTE is equivalent to ''''''''''''''''''

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 27 Capital investment costs in modifying the production equipment and process

Under the scenario of the substitution of EDC by an alternative solvent, Bayer Pharma AG could make the working assumption that parts of the plant would need to be gradually replaced, modified and optimised in order to operate with the alternative solvent. Table 5-2 shows theoretical estimates for the likely cost of such an adaptation. Potential additional purification requirements would cause particular difficulties; there is very limited space available for additional equipment to be installed and an extra process step would interfere with the careful co-ordination of the existing steps of the process. This could mean process delays and unavoidably loss of yield and revenues. NB. the numbering of steps shown in the table is that in the theoretical substitution plan discussed in Section 5.5.1 below.

Table 5-2: Estimated duration and cost of engineering work to adapt the existing plant to an alternative solvent Step Title Description Estimated Estimated duration cost 5 Delivery and Modifications: step-by-step replacement and 1 year 'All Table installation of respective reconstruction of production plant 5-2 #D#'''''' new components. Modification of a running plant would '''''''''''' equipment mean a decrease in output with adverse consequences on business continuity. Key new equipment: at least the distillation plant has to be modified to be able to handle the alternative solvent on a large scale. The plant would also potentially need an additional purification step (crystallisation) to meet the Iopromide specification. Cost: because the requirements for modification are not known, the following scenarios can be envisaged:  Very low cost, if the new solvent has about the same properties as EDC  ''''''' '''''''''''' (est.), if some modification is necessary  ''''''' '''''''''''''' of more (est.) for major changes to equipment. It is hereby assumed that the most likely cost would be €25 million. A solvent of very similar properties, if it exists, it would have already been identified. On the other hand, if the engineering costs were too high, Bayer Pharma AG would regard the new solvent as infeasible. The company’s Development Department has also set a requirement that the alternative process will fit into the existing plant. In addition, engineering costs for Solvent Plant are estimated to be up to ''''' '''''''''''' (5) Downtime The manufacture of Iopromide could suffer some Assumed downtime during the installation/replacement of to be minor equipment. As will be discussed below, Bayer Pharma AG would aim to hold a substantial stockpile of Iopromide in order to minimise economic losses from a stoppage of manufacturing activities

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 28 Cost of variations to Marketing Authorisations

X-ray contrast media are high-dosage pharmaceuticals, for which very high purity requirements are demanded, due to the large quantity administered to the human body. Undetected traces of impurities may cause lack of stability and this is the reason that such pharmaceuticals need to pass demanding stability tests. As discussed in Annex 1 (Section 8), the use of a solvent may result in solvent residues remaining in the final pharmaceutical product. A change of solvent would therefore precipitate changes in the residue profile of the pharmaceutical product. This, in practice, means that the safety of the pharmaceutical product needs to be re-assessed and re-established by the relevant authorities in accordance with guidelines issued by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Bayer Pharma AG would need to apply for variations to its existing Marketing Authorisations for Ultravist®.

Being an established, mature product, Ultravist® has national registrations (Marketing Authorisations) only. This means that every country maintains its own dossier. Ultravist® holds hundreds ('#C#''''''') of Marketing Authorisations across more than 100 ('#C#'''''') countries incorporating more than 1,000 ('#C#''''''''') country-concentration-presentation combinations.

As to how many applications for variations need to be filed following the substitution of EDC by an alternative solvent, it is worth noting that every country or region has different requirements regarding the handling of changes to the manufacture or testing of APIs and medicinal products. The level of detail in the registered information and when/how a variation should be filed may differ significantly. The final decision on whether a variation needs to be filed or not is with the countries who know their particular regulatory environment best.

In some countries, several registrations may be active for products with the same API. In some countries all presentations (i.e. designs/packaging forms) of one dose strength are handled under the same Authorisation. In others, there might be two or more active Authorisations because presentations have been added at a later point in time and may have received a new registration number. There are also countries (e.g. France) where every strength/presentation combination receives a separate number. In some countries it will be possible to file one application for variation for all dose strengths and presentations. In others, it might be required to file one for each dose strength or even one per registration. In the EU, it is possible under certain conditions to use a work-sharing procedure where one Member State reviews the variation and all others accept the outcome of this. However, whether a variation is eligible for this kind of procedure depends on the nature of the change.

Table 5-3 (overleaf) summarises Bayer Pharma AG’s estimates of the cost of variations to Marketing Authorisations that would be required if any one alternative solvent substituted EDC. NB. the numbering of steps shown in the table is that in the theoretical substitution plan discussed in Section 5.5.1 below.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 29 Table 5-3: Estimated cost of variations to the Marketing Authorisations of Ultravist® after the substitution of EDC by an alternative solvent Estimated Estimated Step Title Description duration cost 6a Variations of Given the above complexities, and since the identity of >5.5 years '#D#''''''''''''' Marketing the alternative cannot be known, only a rough calculation Authorisatio of the likely cost of variations can be provided, as follows: ns for - '#C#''' Authorisations across '#C#'''' countries means, Ultravist® on average, '#C#'''''' Authorisations per country - It can be assumed that 1 employee needs to spend 1 month (160 hr) on one variation application. The total number of hours needed would therefore be '#C#''''''' ''' '''''''' ''''''' hours - The labour cost for one employee is assumed to be, on average, €'#C#''''/hr. The total labour cost would be ''#C#''''' ''' '''''''' ''' '''''''''''''' - For the total of '#C#''''''' countries, the overall cost could be: ''#C#'''''' ''' '''''''''''''''' ''' ''''''''' ''''''''''''' To allow for economies of scale, overlaps, etc. it is conservatively assumed that the overall costs would be limited to a fraction of the above estimate i.e. '#D#'''''''''''' 6b Plant Generation of plant batches required for variations to batches of Marketing Authorisations. These will come at a real cost TIP-diamide but this will be relatively small compared to the cost of chloride and submission and approval of variations Iopromide 6c Iopromide Section 5.5.1 will explain that during the process of Minor, will stockpile securing variations to Marketing Authorisations, a be ignored build-up stockpile of Iopromide made with the current EDC-based manufacturing method would be required. The required volume would be in the range of '#A#'''''''''''''''''' tonnes. The stockpile would need to be built before the variations are initiated. Stockpile build-up will entail two costs: - Storage costs – the normal stock of Iopromide is '#A#'''''' tonnes (it is now built-up). Bayer Pharma AG can produce '#A#'''''''''''''' t/y for stockpiling, therefore up to '#A#'' years might be needed and additional storage space would need to be found - Deferred profits – Bayer Pharma AG would need to incur the costs of manufacturing the above tonnage of Iopromide (see Table 3-11 in the SEA for a description of the cost) but would not be able sell Ultravist® made with this tonnage of Iopromide and make the associated profit for several years. Both cost elements shown above are assumed to be minor compared to other costs and will not be taken into consideration further (6) Downtime The manufacture of Iopromide could suffer some N/A Minor, will downtime when there is a need to switch between EDC be ignored and the new solvent. The EDC-based process would be required to be used for the duration of stability tests (see description in Section 5.5.1). The availability of a Iopromide stockpile would reduce any adverse impacts from downtime Total >5.5 years '#D#'''''''''''''

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 30 Summary of investment costs

Taking into account the above discussion, a summary of the costs that would be incurred by Bayer Pharma AG if it was decided to substitute EDC by an alternative solvent is shown in Table 5-4.

Table 5-4: Estimated investment costs for a yet unknown alternative solvent Action – Investment cost Estimated cost Range R&D 'All Table 5-4 #D#''''''' '''''''''''''' €1-10 million Plant conversion engineering work '''''''' '''''''''''' €10-100 million Variations to Marketing Authorisations ''''' '''''''''''' €1-10 million Total ''''''' '''''''''''''' €10-100 million

As noted in Section 5.1, an alternative synthetic route could have a substantially higher investment costs compared to what is shown in Table 5-4.

5.3.2 Operating costs and profitability considerations

Given that no specific alternative has been identified as technically feasible, it is not possible to offer any realistic quantitative estimate of the changes to operating costs and profitability following a conversion to an alternative. However, it is useful to consider some important parameters that underpin the profitability of the existing manufacturing process and how this might be affected by the substitution of EDC:

 Common principle of action: all X-ray contrast media containing iodine (Iopamidol, Iomeprol, Iohexol, Iodixanol, Iobitridol and Ioversol) have the same principle of action: the contrast media spread through the bloodstream/body and the heavy iodine atoms that the contrast medium contains produce a contrast (shadow) when X-ray images are recorded. In light of this therapeutical similarity, currently, price and marketing are decisive for market success in such a competitive environment. It is therefore essential that the production cost of Iopromide remains at the levels of the existing production process even after the substitution of EDC.

 Commonalities and differences in molecular structure: all iodine-based X-ray contrast media have a common molecular structure, the one shown in Figure 5-1.

CO-Amine 1

Carboxylic acid N CO-Amine 2 R J Figure 5-1: Generic structure of iodine-based X-ray contrast media

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 31 This common structure includes:

 An aromatic core (isophthalic acid) that is highly iodinated (mostly 3 iodine atoms per aromatic ring) (triiodo isophthalic acid)  Highly hydroxylated side chains to confer high water solubility. Two side chains originate from amines and are connected to carboxylic groups (side chain 1 and 2), one side chain is originated from an carboxylic acid and is connect to the aromatic amine (side chain 3)  Possibly, additional substitution at the aromatic nitrogen (R in Figure 5-1).

For Iopromide, the relevant components are:

 Amine 1: '#A#'''''''''''''''''''''''' '''''''''''''''''''''''' ''''''''''  Amine 2: '#A#'''''''''''''' ''''''''''''''''''''''' ''''''''''''''''''''''''' '''''''''''''''  Carboxylic acid: methoxy acetic acid.

If all side chains are different from each other, it is more difficult to build up the molecule since a larger number of chemical reaction steps are needed. The reason for this is that symmetrical intermediates cannot be used to introduce two groups in one chemical step. Instead, it is necessary to start with a (more expensive) unsymmetrical raw material and to build up any functionality separately. Table 5-5 summarises the differences between Iopromide and the other iodine-based X-ray contrast media. Iopromide is the only asymmetrical molecule in this group.

Table 5-5: Key structural elements of iodine-based X-ray contrast media Contrast Symmetric/ Amine of side chain 1 Amine of side chain 1 Carboxylic acid R at N- medium Asymmetric of side chain 3 atom

Iopromide Asymmetric H2N-CH2-CHOH-CH2OH HNCH3-CH2-CHOH- CH3O-CH2- H Aminopropandiol-2,3 CH2OH COOH Methylaminoproandiol- Methoxy acetic 2,3 acid

Iopamidol Symmetric (HOCH2)2CH-NH2 (HOCH2)2CH-NH2 CH3-CHOH- H 2-Aminoproandiol-1,3 2-Aminoproandiol-1,3 COOH (Serinol) (Serinol) 2-Hydroxy- propionic acid

Iomeprol Symmetric H2N-CH2-CHOH-CH2OH H2N-CH2-CHOH-CH2OH HOCH2-COOH Not H Aminopropandiol-2,3 Aminopropandiol-2,3 Hydroxy acetic acid

Iohexol Symmetric H2N-CH2-CHOH-CH2OH H2N-CH2-CHOH-CH2OH CH3COOH Not H Aminopropandiol-2,3 Aminopropandiol-2,3 Acetic acid

Iodixanol 2 aromatic H2N-CH2-CHOH-CH2OH H2N-CH2-CHOH-CH2OH CH3COOH Not H cores Aminopropandiol-2,3 Aminopropandiol-2,3 Acetic acid Symmetric

Iobitridol Symmetric HNCH3-CH2-CHOH- HNCH3-CH2-CHOH- (HOCH2)2CH- H CH2OH CH2OH COOH Methylaminoproandiol- Methylaminoproandiol- Dihydroxy 2,3 2,3 isobutyric acid

Ioversol Symmetric H2N-CH2-CHOH-CH2OH H2N-CH2-CHOH-CH2OH HOCH2-COOH Not H Aminopropandiol-2,3 Aminopropandiol-2,3 Hydroxy acetic acid

 Production costs are comparatively low: X-ray contrast media are diagnostic pharmaceuticals, which are produced in large quantities, and which as a rule are used in high single doses for medicinal application. Compared with therapeutic drug products, they are relatively inexpensive

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 32 to produce' #C# '''''''''' ''''''''''''''' '''''''' '''''''''''''''''''' ''''''''''''''' ''''''' '''''''''' ''''''''''''''''' '''''''''''' '''''' ''''''''''''''' ''''' '''''''''''''''' ''''' '''''''' '''' '''''''' ''''''''''' '''' ''''''''''''''''''''' ''''''''''''''''''' '''' ''''''' '''''''' ''''' ''''''''''''''''''''''' ''''''''''''''''' ''''''''''''''''''' '''''''''''''''''' ''''''''''''''''''''' ''''''' ''' '''''''''''''' ''''''''''''''''''' '''''''' '''''''' '''''''''''''''''''' '''''''''''''''''''''''' '''''''''''''''''''' '''''''' '''' ''''' '''''''''''''''''' '''''''''''''''''' '''''' ''''''' '''''''''''''''''' '''''''''''''

The implication of the above technical considerations is that '#C#'''''''''''''''''''' '''''''''' ''''' ''''''''''''''''''' '''''' '''''''''''''''' ''''''''''' ''''''''' '''''''''' '''''' ''''''' '''''''''''''''''''''' ''''''''''''''''''' ''''''''' ''''''''''''''''''' ''''''''''''''' ''''''' ''''''''''''' ''''''''''''''''''' ''''''' ''''''''''''''''' '''''''''''' '''''' '''''''' '''''''''''''''''''' '''''' ''''''' ''''''''''''' ''''''''''''' '''''''''''''''' '''' ''''''''''''''''''''' In other words, any alternative for EDC that results in an increase to the production cost of Iopromide, could not be considered as economically feasible as it would harm the competitiveness of Ultravist® in a market where the technology is mature and market price drives market share. 5.4 Reduction of overall risk due to transition to an alternative

Given the lack of a specific possible alternative, a comparison of risks to those from the continued use of EDC cannot be provided here. Nevertheless, Section 9.3.3 in Annex 2 provides a comparison of hazards between EDC and selected potential alternatives that were identified through Bayer Pharma AG’s R&D work. 5.5 Availability

In the absence of a specific possible alternative, a detailed analysis of availability cannot be provided. However, Bayer Pharma AG can provide an in-depth analysis of the steps that would be required to take for an alternative to be identified, researched and implemented on an industrial scale.

5.5.1 Steps required for making an alternative available

Bayer Pharma AG’s Chemical Development, Regulatory and Logistics departments have come together to review the knowledge accumulated over many years of R&D and make the best possible effort to develop a hypothetical plan for the substitution of EDC by another solvent. An alternative solvent, as opposed to an alternative synthetic route, is considered the least infeasible (from a technical and economic perspective) option for altering the manufacturing process of what is now a legacy pharmaceutical product. The plan is described below and estimates that a minimum of 11.5 years would be required before a yet unknown alternative solvent can be used on an industrial scale. Possibilities for overlaps between the different steps will be small; for example, applications for variations to Marketing Authorisations cannot be submitted until the new manufacturing process is operation on an industrial scale.

Step 1: Screening of alternatives

Screening will include both pure solvents and mixtures of solvents. The aim will be to generate a shortlist of possible feasible and suitable alternative solvent systems for further R&D and possibly implementation.

Step 2: Testing phase

Laboratory testing will seek the optimisation of the shortlisted solvents as regards the throughput and yield they are able to achieve. The aim will be to further reduce the length of the shortlist to allow the R&D to focus on the most promising possible alternatives.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 33 Step 3: Scale-up in the laboratory

The research in the laboratory will be scaled-up with a focus on the most promising possible alternative solvents. The aim will be to convert batches of TIP-diamide chloride of good yield and good quality to pure Iopromide (time required per batch: 1 week) and ultimately to select the three most promising solvent systems for the pilot phase.

Step 4: Pilot phase (1 kg  100 kg)

The aim of the pilot phase will be the optimisation of process in the presence of the three possible alternatives and ultimately the comparison of the three solvent systems. This will be completed with the selection of a single candidate solvent system.

Step 5: Plant conversion

New equipment may be needed to accommodate the needs of the selected new solvent. If this is the case delivery times could be up to 1 year.

Step 6: Variations to Marketing Authorisation

As described above, under Economic Feasibility, Bayer Pharma AG would need to apply for variations to its existing Marketing Authorisations for Ultravist®. The time required for the processing of applications for variation by the national authorities can vary between 6 and 18 months. Bayer Pharma AG’s experience is that simultaneous submissions are not possible. Therefore, due to the large number of Marketing Authorisations involved, a significant amount of time would be expended at this step before the placing of Ultravist® on the national markets could resume.

The work on the variation of the existing marketing Authorisations, apart from the write-up and submission of dossiers requesting the variations to the relevant national health authorities, will incorporate additional important activities which might add to the duration and complexity of this step:

 Generation of plant batches of TIP-diamide chloride: some batches will need to be generated with the new solvent and then return to the EDC process. Bayer Pharma AG will have to produce some batches with the new solvent to get “real” samples of Iopromide for stability tests. The results of stability tests will be available within 3 years. In the meantime, Bayer Pharma AG would have to continue producing Iopromide using EDC

 Generation of plant batches of Iopromide: plant batches of pure Iopromide will need to be generated using the new solvent

 Iopromide stock build-up: many countries do not allow imports of pharmaceuticals made according to processes described in obsolete Marketing Authorisation dossiers after the variations are approved. As a result, if the new manufacturing process is approved in one country, Bayer Pharma AG may not be allowed to go back to the old process. Given the large number of Marketing Authorisations involved, the build-up of a stockpile of Iopromide would be unavoidable; the estimated volume required will be '#A#'''''''''''''''''''' tonnes. This range of stockpiled volumes required can be explained as follows: Bayer Pharma AG will have to switch between EDC and the new solvent for about three times during variations to Marketing Authorisation (see note above for the plant batches of TIP-diamide chloride). It is assumed that Bayer Pharma AG will be allowed by the authorities to temporarily go back to EDC although a substitute solvent will be known and applicable. Then a stockpile of only '#A#''''''' tonnes of

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 34 Iopromide will be sufficient. Otherwise, if such permission is not granted, Bayer Pharma AG will have to build-up a stockpile of up to '#A#'''''''''' tonnes of Iopromide. The actual need for stock will also depend on how fast the changeover of the equipment between solvents can be achieved during the variations to Marketing Authorisations stage

Step 7: Optimisation of key process steps:

It is likely that substitution of EDC will be only possible with TAMIP-diacetate of better quality that what can be used at present. Three-sub-steps are envisaged here:

 Optimisation of TAMIP-diacetate production over an estimated 0.5 year  Scaling-up over an estimated 0.5 year  Pilot phase and plant batches over an estimated 0.5 year.

A summary of the above steps and estimates of their duration is provided in Table 5-6.

5.5.2 Other regulatory requirements affecting the availability of alternatives

Apart from the typical considerations of the availability of an alternative in sufficient quantity and quality and the need for an alternative to have been commercially proven, for the use of solvents in pharmaceutical synthesis there is an additional parameter that requires consideration. This is the listing of any solvent in the relevant ICH Q3C Guidelines, as discussed in Annex 1 (Section 8). Section 8.2.2 explains that there are two key implications of the ICH Guidelines on residual solvents in respect of identifying and implementing an alternative to EDC (which is classified as class 1 solvent under the Guidelines):

 An alternative solvent should ideally be classified as class 3 or 2, or else a risk-benefit assessment will be required and levels of residues should be restricted to the prescribed concentration limits

 If a solvent is not listed in the ICH Q3C Guidelines, Bayer Pharma AG would need to supply safety data on this new solvent. Absence of a solvent from the ICH Q3C Guidelines poses a serious and costly obstacle to the timely uptake of the alternative solvent.

It cannot be predicted whether Bayer Pharma AG’s R&D work may identify a suitable candidate substitute solvent which is listed or not in the ICH Q3C Guidelines. If it was assumed that the selected candidate would not be listed in the Guidelines additional time would be required for generating the required information and submitting a request for the listing of the substance. The time that would be required for these activities to complete cannot be estimated; however, it could be assumed that if the need for a new listing was identified at the end of Step 5 in the plan shown in Table 5-6, a request for its listing in the ICH Guidelines would be submitted soon after and would hopefully be granted by the time all variations of marketing Authorisation would be secured.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 35 Table 5-6: Hypothetical substitution plan for EDC Step Title Outcome Estimated Risk analysis duration 1 Screening of A shortlist of possible feasible alternative solvent systems for further R&D 1 year There is no guarantee that a feasible alternatives alternative might be identified 2 Testing phase A shorter shortlist of the most promising alternative solvent systems 1 year Realistic timescale but could be shorter 3 Scale-up in the Selection of select the three most promising solvent systems for the pilot 1 year Realistic timescale but could be shorter laboratory phase 4 Pilot phase Selection of a single candidate solvent system 1 year Realistic timescale but it cannot be (1 kg  100 kg) certain that scaling up will not allow previously unknown or unanticipated technical issues to emerge 5 Delivery and If new equipment will be needed, long delivery times will require approx. 1 1 year Timescale is conservative; significant installation of new year new equipment may not be needed equipment 6a Variations to Submission of applications to health authorities of countries where >5 years Duration of variations is uncertain as Marketing Ultravist® is sold (6-18 months per application) there are too many that need to be Authorisations applied for. 6b Plant batches of Generation of plant batches required for variations to Marketing Such large volumes of Iopromide TIP-diamide Authorisations stockpiles have never been stored in the chloride and past. It is assumed that Bayer Pharma Iopromide AG will be able to build the required 6c Stock-build up Build a stock of '#A#'''''''''''''''''' tonnes Iopromide to ensure the smooth stock during Steps 1-5 above processing of variations to Marketing Authorisations The estimate of 5 years must be considered the lowest minimum required for this step of the plan 7 Optimisation of key Development of ability to produce TAMIP-diacetate of better quality 1.5 year It is unlikely that this work could be process steps undertaken during the variations to marketing Authorisations due to shortages in production and (lab) personnel spare capacity Overall duration >11.5 years

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 36 5.6 Conclusion on suitability and availability of alternatives

Section 4 of this AoA, in conjunction with a detailed account of past and recent R&D work conducted by Bayer Pharma AG (presented in Annex 2, Section 9), has demonstrated the lack of technical feasibility for a wide range of solvent families. It is also clear that the development an alternative synthetic route would be problematic for technical feasibility, economic feasibility, regulatory compliance and risk reduction potential reasons. As a result, Section 5 cannot discuss specific possible alternatives; instead, it examines the practical and economic implications of a hypothetical conversion of Bayer Pharma AG’s Bergkamen plant from EDC to an alternative chemical substance.

A hypothetical substitution plan has been provided. This predicts that at least 11.5 years will be required for the implementation of an alternative solvent. The actual period required will critically depend on the time taken for the identification of potentially feasible alternatives and on the time required for the approval of the variations to the hundreds ('#C#''''''') of Marketing Authorisations currently held by Bayer Pharma for Ultravist® in more than 100 ('#C#'''''') countries around the world. The substitution of EDC will be a complicated and prolonged process which could potentially cause significant disruption to Bayer Pharma AG’s business and could result in the loss of market share and profitability on the national level.

As far as economic feasibility is concerned, out of necessity, the above analysis only focuses on the likely investment costs. These are estimated at between €10 and €100 million '#D#''''''' '''''''''''''' and are expected to be generally similar for any one alternative substance. In terms of changes to operating costs following the conversion to an alternative solvent, these cannot be estimated without the identity and characteristics of a specific selected technically feasible alternative being known. However, in light of the economics of Iopromide manufacture and the very intense competition Ultravist® is facing from a variety of alternative iodine-based X-ray contrast media, any increase in the manufacturing cost of Iopromide would potentially have a very detrimental effect to the competitiveness of Ultravist® and ultimately to Bayer Pharma AG’s market share.

At present, no alternative can demonstrate technical and economic feasibility as a substitute for EDC. It cannot be known if and when a feasible alternative might be identified in the future; nevertheless Bayer Pharma AG will continue its R&D efforts.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 37 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 38 6 Overall conclusions on suitability and availability of possible alternatives

6.1 Background to the use of EDC

Bayer Pharma AG is currently purchasing 100-1000 ('#B#''''''') tonnes per year of EDC for use as a solvent in the manufacture of Iopromide, the API in the X-ray contrast medium Ultravist®. Bayer Pharma AG is the only global manufacturer of Iopromide. Ultravist® is a mature, established medicinal product that is sold in more than 100 countries and is competing for market share in the EU and outside the EU against several other similar products.

The manufacture of Iopromide has been optimised over 20 years with continuous process improvements that have ensured increasingly improved worker conditions in respect of exposure to EDC and progressive cost-optimisation of process parameters in line with Iopromide’s large production scale. The production plant is set up in terms of equipment and capacity for precisely this synthesis and the multi-stage synthesis is synchronised, i.e. all stages run at the same time in specially designed apparatus and the starting material required for each intermediate stage is provided from current production just in time. Therefore, disruption of this fine-tuned process by removing EDC and introducing an alternative solvent (or synthetic route) could potentially have a very detrimental impact on the technical and economic equilibrium of the Bayer Pharma AG’s process. 6.2 Technical feasibility of alternatives

For many years Bayer Pharma AG has investigated the availability of solvents that could feasibly substitute EDC, including alternative synthetic routes. First R&D efforts started in the 1990s but extensive research, including laboratory testing was undertaken as late as in 2014, specifically for the purposes of this Application for Authorisation. A wide range of solvent families have been considered and within them 45 representative family members have been assessed in detail, including them being tested in the laboratory (see Table 4-1). In addition, four alternative synthetic routes for the manufacture of Iopromide has also been considered.

Five key technical feasibility criteria have been established for the assessment of alternative solvents:

 Inertness to key reagents in the manufacturing process (thionyl chloride and HCl)  Boiling point  Dissolution capacity for:

 The starting intermediate substance

 Reaction gases (SO2 and HCl)  The final intermediate substance  Accompanying related substances

 Yield of Iopromide synthesis and process synchronisation  Recyclability.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 39 The results of the desk-based and laboratory-based investigations confirm that none of the identified alternatives can deliver the required technical performance in Bayer Pharma AG’s production process (see summary in Section 4.2 and detailed descriptions in Annex 2). Even though some alternative substances (for instance, acetates) might be considered better performing than others, the laboratory tests have confirmed the serious shortcomings of all candidates in terms of production yield (a significant reduction affecting the effective production capacity of the plant), product quality (impurities causing colouration of the product) and solvent recovery and recyclability.

On the other hand, known alternative synthetic routes face issues of product separation, waste generation and recyclability and are accompanied by far lower yields than the existing route. Given that they would require the presence of solvents such as DMF and DMA (both classified as Repr. Cat. 1B), the alternative synthetic routes cannot be considered realistic options for the substitution of EDC.

Therefore, the overall conclusion is that no known substance or synthetic route could offer a minimum level of technical feasibility as to be considered a realistic possible alternative for EDC in Bayer Pharma AG’s Iopromide manufacturing process. As a result, no alternative could be shortlisted for in-depth analysis in this AoA. 6.3 Economic feasibility of alternatives

In the absence of a specific shortlist of potential alternatives, the assessment of economic feasibility has taken a wider scope and has aimed to demonstrate the types and scale of investment costs that would arise from a switch to either an alternative solvent or an alternative synthetic route.

Three elements of investment cost can be envisaged irrespective of the identity of the selected alternative:

1. Research and development to adapt the current synthetic process to a new solvent (Section 5.1 has explained that developing a new synthetic route would be particularly disadvantageous due to higher technical risks and uncertainties, more demanding regulatory requirements, and high costs of implementation; as a result Bayer Pharma AG’s focus is on alternative solvents).

2. Engineering work to adapt the production equipment and process.

3. Variations to Marketing Authorisations.

Table 5-4 has shown that a minimum of €10-100 million '#D#'''''''' '''''''''''''' would be required for substituting EDC with a yet unknown alternative solvent. Some downtime might be required, during which production of Iopromide would need to be suspended.

Operating cost estimates cannot be provided without selecting a specific alternative to assess and without some detailed R&D work that would allow a basic engineering feasibility analysis to be undertaken, so that a minimum level of understanding of the changes to operating conditions could be established. However, it can be asserted that Ultravist® is facing competition from several alternative iodine-based X-ray contrast media which have the same principle of action and thus can claim therapeutic interchangeability. Therefore, price and marketing efforts are decisive for market success. If production costs increased as a result of converting to an alternative (e.g. through a reduction in production yield), '#D#''' '''''''' '''' '''''''''''''''''''' ''''''''''''' '''''''''''''''''''''''''' '''' '''''''''''''''''''''' '''' ''''

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 40 ''''''''''' '''''''' '''' ''''' ''''''''''''''''''''' '''''''''''''''''' Bayer Pharma AG would experience loss of turnover and market share. 6.4 Risk reduction capabilities of the alternatives

As no alternative can be considered a realistic solution, no alternative has been compared to EDC for risks to human health and the environment; however, a screening for hazards accompanying several of the potential alternatives that have been considered so far is provided in Section 9.3.3 (Annex 2). It is re-iterated that all known alternative synthetic routes would involve the use of at least one solvent that is accompanied by hazard concerns no less severe than EDC. Two substances in particular, dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA), present equivalent concern to EDC and have been proposed for inclusion in REACH Annex XIV. These solvents are relevant to all alternative synthetic routes (A and C for DMF and B, C and D for DMA). Two more substances, dichloromethane and dioxane, are suspected CMRs, (Carc Cat 2). Dichloromethane in particular is currently under investigation by the IARC and has been added to the CoRAP List and therefore, its CLP classification might change in the future. These alternatives would require additional consideration, had the known synthetic routes shown evidence of technical feasibility. 6.5 Availability of alternatives

Since Bayer Pharma AG has been unable to shortlist a single possible alternative, a detailed analysis of availability cannot be provided. However, Bayer Pharma AG has developed a theoretical substitution plan for EDC which could apply if a feasible alternative solvent could be identified in the future. The plant involves 7 steps:

 Step 1: Screening of alternatives  Step 2: Testing phase  Step 3: Scale-up in the laboratory  Step 4: Pilot phase (1 kg  100 kg)  Step 5: Plant conversion  Step 6: Variations to Marketing Authorisation  Step 7: Optimisation of key process steps.

It would also require Bayer Pharma AG to stockpile a significant volume of Iopromide in order for the variations to Marketing Authorisations to be completed without impacting on the operation of the Bergkamen facility. Overall, the duration of the hypothetical substitution plan is a minimum of 11.5 years and potentially longer if the initial research steps are not successful in identifying a feasible candidate of the variations take longer than the optimistic assumptions made earlier in this AoA.

Beyond the time required for implementing a given alternative, a solvent used in pharmaceutical synthesis should ideally be listed in the relevant ICH Q3C Guidelines on residual solvents. If Bayer Parma AG would identify a feasible substitute solvent which would not be listed in the Guidelines, additional time would be required for generating the required information and submitting a request for its listing. The time that would be required for these activities to complete cannot be estimated but it can be assumed that it would be incorporated into the overall implementation timeframe of 11.5 years described above (if Bayer Pharma AG selects a specific solvent, ICH Q3C activities will start so by the end of the variations of Marketing Authorisation phase, the ICH listing will have been completed). It is worth noting that the vast majority of potential alternatives that Bayer Pharma AG has so far considered are not listed in the ICH Q3C Guidelines.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 41 6.6 Overall conclusion

This AoA has demonstrated that there is no known technically feasible alternative for the use of EDC in the manufacture of the final intermediate for and the purification and isolation of Iopromide. Even if an alternative solvent were to be identified in the future (and this could only be after EDC’s Sunset Date in 2017), the period required for converting to any such alternative would be long and the investment costs for conversion would amount to several millions of Euros. As a result, Bayer Pharma AG believes that the continued use of EDC in the applied for use is justified on technical and economic grounds. Failure to obtain an Authorisation would have severe socio-economic impacts, as described in the Socio-economic Assessment that accompanies this AoA. 6.7 Next steps during an Authorisation review period

Very extensive R&D has been undertaken over more than 25 years and the conclusion has been that an alternative that can technically match the performance of EDC cannot be identified. A long list of substances and families of substances have been considered and none of them has been shown to guarantee a minimum level of technical performance and economic feasibility (in terms of yield, purity and recyclability). Therefore, Bayer Pharma AG has well-founded doubts that any feasible alternative could be identified in the future.

Nevertheless, Bayer Pharma AG will not cease their efforts towards the identification of an alternative solvent that could successfully substitute EDC. Bayer Pharma AG will undertake its own research and also keep a watching brief on scientific developments that might point to other potential alternatives as substitutes for EDC. It is aimed that the hypothetical substitution plan described in Section 5.5.1 will be executed if and when a feasible alternative solvent is identified.

In addition to R&D on alternatives, Bayer Pharma AG will also focus on further optimising the use of EDC so that losses and releases are further minimised and, accordingly, worker exposure is reduced to the extent possible. Bayer Pharma AG intends to investigate options for the improvement of the equipment used. A preliminary list of areas where key improvements might be needed is shown in Table 6-1. Several other smaller improvements may be considered with the aim of minimising EDC losses to the extent possible. Further discussion is provided in the Chemical Safety Report where recent improvements are also presented.

Table 6-1: Area of potential engineering improvements to be investigated during the requested review period Area Area of Potential issue Possible improvement Implementation potential timeline improvement Plant F Reactor 841, Leaky valve for filling with Use non-leaky system Early 2017 842 and 843 substance Plant F Reactor 841, Disconnect container at filling Connection with waste Early 2017 842 and 843 operation of reactor air pipe Plant F Reactor 841, Sample taking device for TLC Introduce closed system Early 2017 842 and 843 not completely closed (glove box system) Plant F Dryer Taking samples for Use closed system Early 2017 T141,T142 and determination of residual EDC T143 Plant F Dryer T142 Reusable big bags release EDC Evacuate big bags before Early 2017 vapours use

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 42 Table 6-1: Area of potential engineering improvements to be investigated during the requested review period Area Area of Potential issue Possible improvement Implementation potential timeline improvement Distillation Glass column Old plant. Expensive Construction of a new 2nd quarter 2018 plant and maintenance. Hardly any column and neutralisation flange maintenance possible neutralisation loop loop reactor reactor. dedicated tor The new plant will meet EDC rigorous environmental standards and utilise the latest state of the art technology. The investment costs were calculated at €3.75 million

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 43 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 44 7 List of references

European Commission, undated. Communication from the Commission – Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. [Online] Available at: http://ec.europa.eu/health/files/betterreg/pharmacos/classification_guideline_adopted.pdf [Accessed 2 February 2015].

European Medicines Agency, 2007. Principles to be Applied for the Deletion of Commercially Confidential Information for the Disclosure of EMEA Documents. [Online] Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/ 2009/10/WC500004043.pdf [Accessed 17 March 2015].

Gyu, P. J., Cheol, S. S. & Yeop, L. D., 2000. Process for producing iopromde. South Korea, Patent No. KR20000061780.

Hwang, K. S., Chung, S. M. & Kim, C. K., 2009. Novel process for preparation of iopromide. World, Patent No. WO 2009134030 A1.

ICH, 2011. Impurities: Guideline For Residual Solvents Q3C(R5). [Online] Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_ R5_Step4.pdf [Accessed 13 June 2014].

Kudschus, M., 1990. Revision of Iopromide Synthesis Part 2: Preparation of TIP diamide chloride, Report no.: 17/90, Unpublished, owned by Bayer AG, s.l.: Bayer Ag.

Sax, N. I. ed., 1979. Dangerous Properties of Industrial Materials. Fifth ed. New York: Van Nostrand Reinhold Company Inc.

Schenk, 1995. Pharma Active Substance Production, Bergkamen, Annual Report, 1994, Unpublished, owned by bayer AG, Bergkamen: Bayer Ag.

Schenk, 1996. Annual Report, Pharma Active Substance Production PWP, Unpublished report, owned by Bayer AG, Bergkamen: Bayer AG.

Speck, U., Blaszkiewicz, P., Seidelman, D. & Klieger, E., 1982. Novel triiodinated isophthalic acid diamides as nonionic X-ray contrast media. USA, Patent No. US4364921 A.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 45 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 46 8 Annex 1: Regulatory controls on the use of EDC in the pharmaceutical industry

8.1 Requirements of Marketing Authorisations and their variations

As noted in Table 2-4, the use of EDC in the manufacture of an API falls within the scope of Regulation (EC) No 726/2004 and Directive 2001/83/EC, relating to medicinal products for human use. With this Regulation, the EU develops and improves European procedures for the authorisation, supervision and pharmacovigilance of medicinal products, for human and veterinary use. No medicinal product appearing in the Annex may be placed on the European market without prior authorisation from the EU. Each application for authorisation must be accompanied by the particulars and documents referred to in Directive 2001/83/EC on the community code relating to medicinal products for human use, and by the fee payable to the European Medicines Agency. It should also contain a statement to the effect that clinical trials carried out outside the European Union meet the principles of good clinical practice and the ethical requirements of Directive 2001/20/EC on good clinical practice in the conduct of clinical trials on medicinal products for human use.

The holder of a manufacturing authorisation of a medicinal product referred to in Article 40 of Directive 2001/83/EC is obliged “to comply with the principles and guidelines of Good Manufacturing Practice (GMP)” as laid down by Community Law. Principles and guidelines of good manufacturing practice require impurity testing of pharmaceutical ingredients to ensure that specific threshold limits for residual solvents are met (see discussion below).

The entire manufacturing process for the API (Iopromide) is regulated on the basis of pharmaceutical legislation within the regulatory authorities of all jurisdictions in which the medicinal product (Ultravist®) is marketed. If essential stages of the manufacturing process are changed, then the agreement of all affected regulatory authorities is required. Medicinal authorisations, of which there may be several for the different countries where the relevant drug product is being sold, would be subject to re-assessment following any major change to the manufacturing process; a change in the solvent would fall under this. In accordance with Commission Regulation (EC) No 1234/2008, it can be assumed that the changes to the production process and the final product would be such that a Type II variation of the existing Marketing Authorisation would be required. According to the Regulation, “Major variation of type II means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned” (European Commission, undated). Variations not only require effort and inputs on the part of Bayer Pharma AG and the authorities but also attract fees. It must be noted that market authorisations are required per country, so the total number of authorisations might be particularly large (see Section 0 for more details). In addition, changes to the manufacturing facility would also attract requirements for notifying such changes to the relevant national authorities.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 47 8.2 Regulatory controls on residual solvents

8.2.1 ICH Guidelines

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issues a variety of guidance which pharmaceuticals companies must follow. ICH guidance is of relevance to the use of solvents in synthetic processes and thereby of relevance to EDC, and its potential alternatives too.

One such example of relevant guidance is “Impurities: Guideline For Residual Solvents Q3C(R5)” (ICH, 2011). The objective of this guideline is to recommend acceptable amounts of residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered toxicologically acceptable, for some residual solvents.

Residual solvents in pharmaceuticals are defined in the guideline as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The content of solvents in such products should be evaluated and justified.

Residual solvents assessed in this guideline are listed in its Appendix 1. The residual solvents were evaluated on the potential human health concern and categorised into three classes:

 Class 1 solvents: Solvents to be avoided: Known human carcinogens, strongly suspected human carcinogens and environmental hazards  Class 2 solvents: Solvents to be limited: Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities  Class 3 solvents: Solvents with low toxic potential: Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have a permitted daily exposure (PDE) of 50 mg or more per day.

EDC is categorised in Class 1 due to its toxicity and is accompanied by a concentration limit of 5 ppm. Class 1 solvents should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. However, EDC is used in the final intermediate step only. Iopromide contains no EDC2; therefore, no risk benefit assessment is necessary or has been carried out. Resides of class 2 solvents associated with less severe toxicity should also be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (class 3) should be used where practical.

The guideline suggests that, since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data.

2 No EDC is present in Iopromide because Bayer Pharma AG distils water off Iopromide several times and EDC makes a low boiling azeotrope boiling at 71°C containing 91.8% EDC. If distilled to remove water, the low boiling azeotrope removes all EDC too.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 48 8.2.2 Importance of the regulatory framework to the selection of an alternative extraction solvent

Two are the key implications of the ICH Guidelines on residual solvents in respect of identifying and implementing an alternative to EDC:

 Need to use safer solvents: the choice of an alternative solvent to substitute EDC should be mindful of the requirements of the ICH Guidelines, and should ideally be of Class 2 or 3, unless the choice of a Class 1 substitution can be justified by a risk-benefit assessment and the level can be restricted to the prescribed concentration limits

 Implications of non-listing of a solvent: if a solvent is not listed in the ICH Q3C Guidelines, its use by a pharmaceuticals company is not straightforward. The Guidelines recognise that the solvent lists they contain are not exhaustive and other solvents can be used and later added to the lists. Additionally, recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data become available. However, the application for a Marketing Authorisation (or application for a variation) for a medicinal product that contains residues of a new solvent needs to include safety data on this new solvent. Whilst the safety data may be based on concepts in this guideline, if the medicinal product is made with a new solvent (in this case, a substitute for EDC) and this has a poorly characterised impurity profile then additional testing will be required to establish its safety. This will require significant time, involve considerable cost and a positive outcome would by no means be certain. Therefore, it would be very important that Bayer Pharma AG could select a well-characterised solvent, as this would affect the timeframe and costs of converting to the alternative solvent. Absence of a solvent from the ICH Q3C Guidelines poses a very serious obstacle to the timely uptake of that alternative.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 49 Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 50 9 Annex 2: Research & Development by Bayer Pharma AG

9.1 Research and development on alternative solvents

9.1.1 R&D programmes before 2014

Since 1990, Bayer Pharma AG has taken considerable effort to identify alternatives to EDC, while retaining the current route of synthesis (TAMIP-diacetate  TIP-diamide chloride as a one-pot process). Detailed internal (unpublished) reports of the unsuccessful attempts, made in the period 1990–1996, are available (Kudschus, 1990; Schenk, 1995; Schenk, 1996) and have been used in the preparation of this AoA.

Potential alternative solvents considered

Categorised by functional group, Table 9-1 summarises the alternative solvent families that were considered in the 1990s in R&D work undertaken by Bayer Pharma AG.

Table 9-1: Master list of alternative solvents assessed by Bayer Pharma AG (pre-2014 R&D) Solvent family Example solvents EC Number CAS Number Alcohols Methanol 200-659-6 67-56-1 Ethanol 200-578-6 64-17-5 Butanol 200-751-6 71-36-3 Carboxylic acids Acetic acid 200-580-7 64-19-7 Ketones Acetone 200-662-2 67-64-1 Methyl ethyl ketone (MEK) 201-159-0 78-93-3 Methyl isobutyl ketone (MIBK) 203-550-1 108-10-1 Nitriles Acetonitrile 200-835-2 75-05-8 Dipolar aprotic Dimethylformamide (DMF) 200-679-5 68-12-2 solvents Hexamethylphosphoramide (HMPTA) 211-653-8 680-31-9 N,N-dimethylacetamide (DMA) 204-826-4 127-19-5 Dimethyl sulphoxide (DMSO) 200-664-3 67-68-5 Amines Triethylamine 204-469-4 121-44-8 Nitro Nitromethane 200-876-6 75-52-5 compounds Nitrobenzene 202-716-0 98-95-3 Hydrocarbons Heptane 205-563-8 142-82-5 Toluene 203-625-9 108-88-3 Cyclohexane 203-806-2 110-82-7 Halogenated Dichloromethane 200-838-9 75-09-2 hydrocarbons Chloroform 200-663-8 67-66-3 1,1,1-Trichloroethane 200-756-3 71-55-6 Chlorobenzene 203-628-5 108-90-7 Esters Ethyl acetate 205-500-4 141-78-6 Butyl acetate 204-658-1 123-86-4 2-ethoxyethyl acetate 203-839-2 111-15-9 Ethers Diethyl ether 200-467-2 60-29-7 Di-n-butyl ether 205-575-3 142-96-1 Methyl tert-butyl ether 216-653-1 1634-04-4 Tetrahydrofuran (THF) 203-726-8 109-99-9 Dioxane 204-661-8 123-91-1

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 51 Table 9-1: Master list of alternative solvents assessed by Bayer Pharma AG (pre-2014 R&D) Solvent family Example solvents EC Number CAS Number Diglyme 203-924-4 111-96-6 2-methoxy-2-methylbutane (TAME) 213-611-4 994-05-8

Step 1 – Stability of solvent families under reaction conditions

As discussed in Section 2.1, the first stage of Iopromide synthesis (TAMIP-diacetate  TIP-diamide) requires an aprotic solvent of medium polarity, which is sufficiently stable under strongly acidic conditions and has sufficiently good dissolution properties, for the starting compound and for impurities, or else particles start to melt and adhere.

For the second stage of synthesis (TIP-diamide  TIP-diamide chloride), the solvent has to withstand the aggressive conditions of several hours of heating with thionyl chloride and, in an ideal case, dissolve the coloured impurities. In light of these criterions and using the knowledge accumulated by Bayer Pharma AG, over years of laboratory investigations, the solvent families identified in Table 9-1 can be screened as shown in Table 9-3.

Consequent to this screening step, only a smaller number of solvent families were found to be theoretically feasible in the substitution of EDC, which included: hydrocarbons; halogenated hydrocarbons; esters; and, ethers. Acetonitrile was also found to be conditionally feasible, and was therefore included in further testing by Bayer Pharma AG.

Step 2 – Substitution of EDC by a single alternative solvent – Testing of individual potential alternative solvents

Representatives of the retained solvent families were subject to laboratory experiments in the 1990s. The solvents that were considered for testing included the substances shown in Table 9-2.

Table 9-2: Shortlist of alternative solvents laboratory tested by Bayer Pharma AG (pre-2014 R&D) Example solvents EC Number CAS Number Acetonitrile 200-835-2 75-05-8 Toluene 203-625-9 108-88-3 Cyclohexane 203-806-2 110-82-7 Dichloromethane 200-838-9 75-09-2 Chloroform 200-663-8 67-66-3 1,1,1-Trichloroethane 200-756-3 71-55-6 Chlorobenzene 203-628-5 108-90-7 Ethyl acetate 205-500-4 141-78-6 Butyl acetate 204-658-1 123-86-4 2-ethoxyethyl acetate 203-839-2 111-15-9 Diethyl ether 200-467-2 60-29-7 Di-n-butyl ether 205-575-3 142-96-1 Methyl tert-butyl ether 216-653-1 1634-04-4 Tetrahydrofuran (THF) 203-726-8 109-99-9 Dioxane 204-661-8 123-91-1 Diglyme 203-924-4 111-96-6 2-methoxy-2-methylbutane (tert-Amyl methyl ether (TAME)) 213-611-4 994-05-8

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 52 Table 9-3: Screening of solvent families for stability under the conditions of Bayer Pharma AG’s synthesis (pre-2014 R&D) Screening Relevant original Solvent families Assessment of stability under reaction conditions result sources Alcohols Formation of chloroalkanes and sulphurous acid esters with thionyl chloride Eliminated General chemical Carboxylic acids Formation of acid chlorides; solvent contains the same functional group as starting material so the Eliminated knowledge thionyl chloride would simply react with the solvent rather than the starting material. Ketones Being aprotic solvents, they are feasible for the reaction conditions of the 1st synthetic stage. Eliminated However, ketones react with the amine group of the starting materials to form a Schiff base* with TAMIP-diacetate (amino group + keto group react); this formation also occurs with MIBK, which is sterically more demanding than acetone or MEK, making all of these solvents infeasible Nitriles In principle feasible for the 1st synthetic stage (but acetonitrile reacts considerably with thionyl Retained Kudschus (1990) chloride / hydrogen chloride – see below) Dipolar aprotic Many common polar aprotic solvents react with thionyl chloride. Dimethylsulphoxide (DMSO) reacts Eliminated General chemical solvents with thionyl chloride. DMF also reacts forming the strongly carcinogenic dimethyl carbamoyl chloride knowledge with DMF. Many dipolar aprotic solvents are miscible with water (all of the solvents trialed by Bayer Pharma AG) making the recovery of products very complex Amines Violent reaction/salt formation with hydrogen chloride Eliminated Nitro compounds Serious process hazards: shock and heat sensitive explosive properties, e.g. nitromethane (Sax, 1979). Eliminated Nitrobenzene is the only other nitro compound that is readily available. However, it has a Repr. Cat 1B classification and has a high boiling point (210 °C) making it an infeasible and unattractive solvent Hydrocarbons In principle feasible. Alkylated aromatics (e.g. toluene) and alkanes, being aprotic solvents are Retained Kudschus (1990) conditionally feasible for the reaction conditions of the 1st synthetic stage (acylation) and formation of acid chloride in the second Halogenated In principle, feasible Retained hydrocarbons Esters In principle feasible, however esters will hydrolyse in strongly acidic or basic aqueous conditions, such Retained as those encountered during solvent recovery, making them sub-optimal solvent for the second step Ethers Cyclic ethers (e.g. THF) are in principle feasible, but are liable to decompose (forming chloro alcohols Retained with HCl). Aliphatic ethers, being quite non-polar solvents, are feasible for the reaction conditions of both synthetic stages * A Schiff base is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group. Schiff bases in a broad sense have the general formula R1R2C=NR3, where R is an organic side chain

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 53 The results are summarised in Table 9-4, with additional detail provided in the main text. Cells in grey indicate areas where shortcomings have been identified for the alternative substances under consideration. The criteria used for the screening of the potential alternative solvents are aligned to those described in Section 2.2.

Bayer Pharma AG’s findings in their laboratory tests can be summarised as follows:

Nitriles

Acetonitrile was found feasible for the conversion of TAMIP-diacetate to TIP-diamide and had the fastest reaction rate among the solvents tested in 1990 (the formation of TIP-diamide took 1 hour in reflux) and might be considered feasible for the second synthetic stage (Kudschus, 1990). Having demonstrated a yield of 79% in the laboratory (by comparison the yield currently achieved by using EDC in the conversion of TAMIP-diacetate to TIP-diamide chloride is 91–92%), acetonitrile could be considered superior to several other potential alternative solvents. However, it reacts remarkably with thionyl chloride/hydrogen chloride, so that yields and colour values fluctuate substantially according to reaction conditions (Kudschus, 1990). Particularly the colour values, which are decisive for processing the final intermediate to Iopromide, are always worse than when EDC is used, so that additional purification might be necessary, with corresponding losses of yield (Kudschus, 1990). In theory, purification might be undertaken by extraction via stirring with absolute ethanol at room temperature.

Purification of TIP-diamide chloride by stirring with ethanol would require processing of a very significant tonnage of the product, '#D#'''' ''''''''''' ''''''. This would disturb the synchronisation of the process and increase production costs. It is also doubtful whether such purification could be performed on a large scale, as explained further below.

In addition, acid chlorides normally react with alcohols to form esters. Therefore, although TIP- diamide chloride does not react with ethanol in the laboratory under the reaction conditions used, drying on the industrial scale lasts much longer. Thus, the potential formation of ester cannot be ignored, particularly as a new impurity would be present in iopromide.

Crucial to the manufacturing process, no recycling method is known for this expensive, water- soluble solvent potentially limiting the economic feasibility of the alternative.

Hydrocarbons

Toluene is the only alkyl-substituted aromatic substance that was tested for the conversion of TAMIP-diacetate to TIP-diamide. Toluene could potentially deliver TIP-diamide chloride yields similar to those obtained with EDC; however, its performance is crucially dependent on the presence of impurities in the TAMIP-diacetate batches. Employing the usual TAMIP-diacetate production batches brings the reaction to the limit of adhesion, requiring either (a) continuous analytical data for each TAMIP-diacetate batch that would allow the selection of batches of optimum quality, or (b) very pure TAMIP-diacetate batches, or (c) use toluene in combination with other solvents. The practicalities of these options are described here:

 Analysis of each TAMIP-diacetate batch: it is an unrealistic proposition to have to assess the impurity profile of each TAMIP-diacetate batch and select only the pure ones for further production. This cannot be considered a viable solution to the shortcomings of toluene

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 54 Table 9-4: Second screening of identified potential solvents (pre-2014 R&D) 1 2 3 4 5 6 Inertness to Compati- Potential alternative thionyl Boiling point Conversion Quality/colour value bility solvent Absence of adhesion Yield Recyclability chloride and (°C) completeness (white) with HCl process  EDC  83.6    (92% in   2014)    Complete  Yield varies Poor (if  Acetonitrile  81.6 conversion but  Poor colour, low due to purifica- Not possible reacts with thionyl quality decompos- tion chloride ition needed)  Very poor solubility Not relevant given of starting material poor level of Not  Cyclohexane  80.7   means that the conversion and relevant Poor reaction is not adhesion complete () ()  Only feasible if very Only feasible if very  Yield most  Toluene  110.6  pure intermediate is pure intermediate is Intensely coloured comparabl Poor used used e to EDC Dichloromethane  40 Boiling point too low (<50 °C), not considered further Boiling point marginally above the threshold and poor hazard profile. Chloroform is likely to form phosgene in Chloroform  62 the presence of air. Chloroform is stabilised with alcohols to trap formed phosgene. The reaction conditions are not compatible with alcohols (alcohols react with acid chlorides); not considered further Not relevant given  its poor level of Not  1,1,1-Trichloroethane  74.1 Incomplete   conversion and relevant Poor conversion adhesion    Chlorobenzene  131 -132 ()  Poor colour, low  Poor Poor quality

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 55 Table 9-4: Second screening of identified potential solvents (pre-2014 R&D) 1 2 3 4 5 6 Inertness to Compati- Potential alternative thionyl Boiling point Conversion Quality/colour value bility solvent Absence of adhesion Yield Recyclability chloride and (°C) completeness (white) with HCl process  75% Yield    Ethyl acetate  77.1 / 80.7 ()  after extra Disappointing quality Not possible Poor purificatio n step Ethyl acetate/   Not Not   77.1  cyclohexane (56:44) Very slow reaction Intensely coloured relevant considered Poor      toluene; Poor (if 1st step, ethyl Low quality, 19% lower  ethyl Ethyl acetate/toluene  77.1 / 110.6 nd  purifica- acetate; 2 step, additional than with acetate tion toluene purification needed EDC needed)  Not  Butyl acetate  126  Incomplete conversion and product adhesion; unusable relevant Poor Diethyl ether  34.6 Boiling point too low (<50 °C); very poor dissolution not considered further  Not relevant given Not  Di-n-butyl ether  142-143* Incomplete  the poor conversion  relevant Poor conversion and adhesion  Not relevant given Not  Methyl tert-butyl ether  55.3 Very poor  the poor conversion  relevant Poor dissolution and adhesion   Positive conversion  Not considered due to decomposition Tetrahydrofuran Reacts with 65 results but  Poor quality of the solvent HCl decomposes to 1,4- dichlorobutane  Dioxane would be subject to slow decomposition with formation of 2-(2-chloroethoxy)ethanol which would 100.8 / Dioxane / toluene Reacts with react with Thionyl chloride to bis-(2-chloroethyl)-ether, a suspected carcinogen and acute toxicant; not 110.6 HCl considered further

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 56 Table 9-4: Second screening of identified potential solvents (pre-2014 R&D) 1 2 3 4 5 6 Inertness to Compati- Potential alternative thionyl Boiling point Conversion Quality/colour value bility solvent Absence of adhesion Yield Recyclability chloride and (°C) completeness (white) with HCl process Not relevant given  its poor level of Not  Diglyme  162 Very poor   conversion and relevant Poor dissolution adhesion tert-Amyl methyl ether  87.3 Decomposition (ether cleavage); reaction with methoxyacetyl chloride, not considered further Boiling points have been confirmed at the ECHA Registered Substances database (http://echa.europa.eu/en/information-on-chemicals/registered-substances, accessed on 7 October 2014) * Available at http://www.chemicalbook.com/ChemicalProductProperty_EN_CB2775063.htm (accessed on 7 October 2014)

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 57  Improvement of production parameters of TAMIP-diacetate for improvement of purity: identification of toluene as a theoretically viable EDC substitute, given its ability to reach production yields equivalent to those of EDC, subject to resolving the vital colour issue, led Bayer Pharma AG to undertake extensive optimisation operations. Specifically, for the TAMIP- diacetate synthesis operations internal manufacturing specification K296 was developed, which enabled the production of TAMIP-diacetate with a high level of purity.

Following this, testing with toluene resumed and it was found that, in terms of yield and quality, the TIP-diamide chloride obtained was largely equal to that obtained using EDC. However, the use of toluene would still result in a serious discolouration problem. Crude TIP-diamide chloride precipitates from toluene and is heavily coloured, which is critical in the subsequent iopromide formation (this affects the quality of the final Iopromide product). The colour problem could be solved by subsequently stirring the crude product in absolute ethanol. However, this extraction increases product losses (Kudschus, 1990). As shown above, purification of ethanol at the industrial scale would adversely affect process synchronisation and could result in increased impurities in Iopromide.

Moreover, the use of toluene as a single solvent for the preparation of TIP-diamide chloride ultimately and conclusively failed, as TAMIP-diacetate synthesis could not be carried out on production scale according to internal specification K296. Optimisation operations carried out subsequently (a later specification, K300, was developed) produced TAMIP-diacetate which tended to adhere at the TIP-diamide stage, similarly to the currently ‘normal’ production batches. Toluene was therefore ruled out as a solvent if the current synthetic stage sequence were to be retained. However, it should be mentioned that with the improved TAMIP-diacetate quality (using specification K296), when using EDC (instead of toluene), Bayer Pharma AG could obtain a further increase in yield of 4% and slightly better quality could be achieved without the aforementioned colour problems, in other words EDC was a better solvent than toluene

 Combination of toluene with other solvents: additions of aprotic dipolar solvents (in each case 5% vol. N,N-dimethylacetamide and dimethylethylurea) and relatively small additions of acetonitrile (5, 10, 15% vol.) were also tested, but they too led to adhesion of the batches. Only when larger amounts were added (20 and 25% vol. acetonitrile tested) adhesion was prevented (Kudschus, 1990).

Therefore, toluene would only be very conditionally feasible (with sufficiently pure TAMIP-diacetate) and then only in pure form for the first synthetic stage, but in practice it is a technically infeasible solution.

As far as the other tested hydrocarbon, cyclohexane, is concerned, it is even less polar than toluene and so it does not dissolve the reagents (TAMIP-diacetate or TIP-diamide) through at any time and, therefore, the partial reactions remain incomplete. In addition, it does not have the capacity to keep the accompanying impurities in the mother liquor in solution. Cyclohexane is technically unacceptable as a substitute for EDC in Bayer Pharma AG’s process. Similarly, heptane is non-polar and thus was not tested.

Halogenated hydrocarbons

Several aliphatic halogenated hydrocarbons were excluded from laboratory testing, as they present comparable toxicological and ecological concerns to EDC. Dichloromethane was found to be infeasible as substitute solvent due to its very low boiling point. Similarly, chloroform has a relatively low boiling point (62 °C, still above the threshold of 50 °C) and poor hazard profile (Carc. 2- H351, Repr. 2-H361d, STOT RE 1-H372) so it was not tested, as was also the case for other

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 58 chlorinated aliphatic hydrocarbons which were not seen as viable long-term solutions for the substitution of EDC. Chloroform is also likely to form phosgene in the presence of air. Chloroform is stabilised with alcohols to trap formed phosgene, however, the reaction conditions are not compatible with alcohols (alcohols react with acid chlorides to form esters).

1,1,1-trichlorethane also proved to be infeasible for the conversion of TAMIP-diacetate to TIP- diamide; the dissolution capacity of this solvent is too low and only incomplete conversion to TIP- diamide plus adhesion of the batch have been recorded.

Chlorobenzene was tested as solvent as an example of organic halogenated hydrocarbons and was found to be feasible for the conversion of TAMIP-diacetate to TIP-diamide (Kudschus, 1990). However, the quality and yield of the current process could not be achieved with this solvent.

Esters

In laboratory testing undertaken in 1990, ethyl acetate was found to be feasible for the conversion of TAMIP-diacetate to TIP-diamide (Kudschus, 1990). Indeed, ethyl acetate is the solvent that has been assessed in the most detail; however, experiments carried out in 1986 found that it was not a feasible solvent due to the low yields obtained (Kudschus, 1990). Ethyl acetate was infeasible for the subsequent second synthetic stage leading to the formation of TIP-diamide chloride due to a poor purity profile; the separation of accompanying related substances was found to be insufficient in this solvent. In particular, the colour value, which is critical for the subsequent stage in the production of TIP-diamide chloride, was ca. 10 times higher than acceptable. The coloured product needs to be purified in an additional step (extraction by stirring with absolute ethanol at room temperature) with corresponding losses (Kudschus, 1990). As shown above, purification of ethanol at the industrial scale would adversely affect process synchronisation and could result in increased impurities in Iopromide.

Further attempts were made to produce TIP-diamide chloride in ethyl acetate in the period 1994– 1995 but those again failed to result in acceptable product quality or yield (Schenk, 1995). When TAMIP-diacetate in ethyl acetate is reacted first with methoxyacetyl chloride and then with thionyl chloride, as with the EDC process, the quality of the intermediate deteriorates. In this case, it crystallises from ethyl acetate. The educt3 also precipitates and, subsequently, can no longer be converted completely (Schenk, 1996). Results obtained from Bayer Pharma AG’s research included the following key findings (Schenk, 1995):

 Impurities: 3–4% for the sum of by-products (current quality with EDC: arithmetic mean = 2.3%)  Colour: 1.0 (current quality with EDC: arithmetic mean = 0.16)  “Dimeric ester” in Iopromide: 2% (current quality with EDC: arithmetic mean = 0.05%). This impurity apparently increases when ethyl acetate is used as solvent; however the "dimeric ester" is a by-product of the Iopromide stage and not the TIP stage, so its structural allocation is questionable. Repeated substance isolation and structural allocation did not lead to a different result. This indicates that a new impurity is present at up to 1% when using ethyl acetate instead of EDC4

3 A substance extracted from a mixture, as distinguished from a product.

4 This impurity has the same retardation factor (Rf) by TLC analysis and thus is isolated together with the dimeric ester.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 59  Recyclability: it is difficult to separate ethyl acetate and thionyl chloride – recovery of the solvent is almost impossible. It contains large quantities of thionyl chloride and dissolved hydrogen chloride. In contact with water, hydrolysis of ethyl acetate to ethanol and acetic acid is unavoidable and the solvent recycling process would involve an aqueous wash stage to remove water soluble impurities. Losses occur not only directly due to hydrolysis, as the solubility of ethyl acetate in water is increased considerably by the products of hydrolysis, which results in further losses.

In 1990, the azeotrope ethyl acetate:cyclohexane 56:44% w/w was also found to be feasible for the conversion of TAMIP-diacetate to TIP-diamide (Kudschus, 1990) and it was also possible to successfully carry out the second synthetic step under appropriate conditions. However, the reaction rate with the azeotrope was found to be very slow; the formation of TIP-diamide took 12 hours at 55 °C plus 3-hour reflux (Kudschus, 1990). This is considered unacceptable and, therefore, this mixture was not given further consideration5.

In addition to ethyl acetate, butyl acetate, a solvent with comparatively better recyclability, was tested as a substitute solvent. However, due to its insufficient dissolution properties, complete conversion was not achieved and in some cases product adhesion occurred. Thus, this ester solvent also proved to be completely infeasible. Due to the fundamental disadvantages of the use of esters (insufficient purification effect, problematic recovery), no further tests were carried out with esters in the 1990s, with the exception of 2-ethoxyethyl acetate which was considered under a separate test following an alternative reaction sequence (see discussion below).

Ethers

Only higher boiling, relatively polar ethers were considered. Diethyl ether was found to be infeasible due to its low boiling point, as it is extensively carried over as vapour with the reaction gases. A development report from 1986 (by Schering AG) details the unsuccessful testing of the ethers, methyl tert-butyl ether and diglyme (alongside ethyl acetate, toluene and dichloromethane) – the dissolution capacity of these solvents was too low and they resulted in product adhesion.

Investigatory tests were also carried out with dioxane; however, problems were identified at both stages. Dioxane has such a high dissolution capacity for TIP-diamide chloride that it cannot be isolated from the solvent. Precipitation was successful when toluene was added as anti-solvent; however, it was found that toluene and dioxane could not be separated economically by distillation. In addition, due to hydrogen chloride being present, dioxane would be subject to slow decomposition6 but accelerated under the reaction conditions, with formation of 2-(2- chloroethoxy)ethanol, a chlorinated hydrocarbon which causes significant concern for Bayer Pharma AG. Firstly, the solvent used must not decompose; secondly, 2-(2-chloroethoxy) ethanol would react with thionyl chloride to bis-(2-chloroethyl)-ether (EC No. 203-870-1, CAS No. 111-44-4). This is a double alkylating agent and can possibly connect DNA strands (it is a suspected carcinogen, Carc. 2)7. Additionally this compound resembles mustard gas (which contains sulphur (S) instead of oxygen (O)) and is classified for acute toxicity (Acute Tox. 1, H310). Therefore, no further tests were carried out with the two solvents dioxane/toluene, and dioxane cannot be considered a technically feasible alternative.

5 By comparison, formation of TIP-diamide takes 2 hrs at 85 °C in EDC.

6 See: http://www.masterorganicchemistry.com/reaction-guide/acidic-cleavage-of-ethers-sn2-reaction/

7 See: http://www.usbio.net/item/006245.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 60 Tetrahydrofuran was found to be feasible for the conversion of TAMIP-diacetate to TIP-diamide (Kudschus, 1990); however, it reacts slowly with hydrogen chloride to form 4-chlorobutanol and this reacts further with thionyl chloride to form 1,4-dichlorobutane. This makes the solvent completely infeasible for both synthetic stages (formation of TIP-diamide and TIP-diamide chloride). Therefore, tetrahydrofuran was considered technically infeasible.

On the other hand, tert-amyl methyl ether appears to be subject to ether cleavage8 under the reaction conditions. It was also observed that this solvent reacts with methoxyacetyl chloride and thus, consumes this reaction partner.

Finally, the dissolution capacity of di-n-butyl ether was found to be insufficient. The result is incomplete conversion and in some cases product adhesion. Overall, ethers were ruled out as potential substitute solvents.

Conclusion on the technical feasibility of single potential alternative solvents

None of the alternative solvents considered by Bayer Pharma AG in the 1990s can be considered a promising substitute for EDC. Of all the tested substances, ethyl acetate has been given the most detailed consideration; its yield might be considered acceptable and it can deliver the partial reactions without adhesion. However, ethyl acetate faces important technical shortcomings, resulting in impurities in TIP-diamide chloride and consequently resulting in impurities, such as dimeric ester, in the Iopromide made from this TIP-diamide chloride. There are also issues with colour and recyclability.

Toluene has also been considered as a potential alternative and has been demonstrated to be feasible in the laboratory for both steps when carried out on their own. However, as described previously, the current process involves a one-pot reaction that provides no opportunity for purification of the intermediate TIP-diamide. This means that any impurities are still present when the relatively reactive TIP-diamide chloride is isolated. Given this reactivity, only limited purification is possible and Bayer Pharma AG was not able to purify this material sufficiently without reducing yield to unacceptably low levels

Step 3 – Substitution of EDC by a mixture of solvents

The performance of the two synthetic stages in different solvents would in theory represent a way out of the problems posed from any attempt to reconcile very different requirements (the solvent needs to be both polar and chemically inert) by using a single solvent. Bayer Pharma AG has considered the possibility that each stage (TIP-diamide and TIP-diamide chloride formation) be carried out in their own optimally feasible solvent.

Under this scenario, the simplest possible and most complete substitution would have to be ensured; it would therefore be appropriate for the solvent which is used last to have a significantly higher boiling point, and as far as possible not to form an azeotrope with the one used previously. Nevertheless, the preparation of TIP-diamide chloride would become more complex overall. The process would therefore only be worthwhile if at least yields and product quality similar to the

8 When ethers are treated with strong acid in the presence of a nucleophile, they can be cleaved to give alcohols and alkyl halides.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 61 current ones could be obtained or else a change to the production process would not be worthwhile.

To this effect, Bayer Pharma AG tested a dual solvent system, ethyl acetate/toluene. The two solvents have a boiling point difference of just over 33 °C and do not form an azeotrope. Although different solvent selection would in principle be possible, toluene was selected on the assumption that a combination of pure toluene with very pure TAMIP-diacetate batches could potentially deliver acceptable colour/purity.

Test synthesis using the 2-solvent combination was indeed carried out by Bayer Pharma AG. The following steps were followed (Kudschus, 1990):

1. Preparation of TIP-diamide in ethyl acetate

1. Distillative displacement of ethyl acetate by toluene

2. Formation of TIP-diamide chloride (thionyl chloride and PCl3, phosphorous trichloride) were tested for acid chloride formation

3. Purification of crude TIP-diamide chloride by extraction in absolute ethanol

The product that was obtained corresponds to the quality of that delivered by EDC. However, the yield was found to be 74% based on TAMIP-diacetate (35.8 g TAMIP-diacetate  30.01 g TIP- diamide chloride). If Bayer Pharma AG sets 36.9 g as the target yield (the current yield), 30.01 g is 81.3% of target yield. The ethyl acetate/toluene process eliminates 18.7% of yield. In addition, PCl3 (phosphorous trichloride) proved to be less reactive than thionyl chloride, as the acid chloride did not form until DMF was added as a catalyst, and then substantially more slowly. The yield was a further 9% lower when PCl3 was used (under otherwise identical conditions).

In addition, the process is more complicated: it requires an exchange of solvent, longer reaction time (11 hrs instead of 8 hrs), and extraction with ethanol causing issues due to ester formation, as described earlier.

Conclusion on the technical feasibility of solvent mixtures

Bayer Pharma AG’s testing in the 1990s identified a mixture of ethyl acetate and toluene as a potential solution for the substitution of EDC. However, laboratory testing has revealed that although quality might be acceptable, the yield was poor compared to EDC (ca. 19% lower to the current yield). Given the complexities of switching to a dual solvent system, this reduction in yield and the increased reaction time of the process cannot be justified on technical and economic grounds and, thus, this alternative cannot be given further consideration

Step 4 – Substitution of EDC by alternative solvents under a different reaction sequence

Another theoretical alternative, which might allow Bayer Pharma AG to avoid the use of EDC, involves changing the current stage sequence, in conjunction with separate preparation of TIP- diamide chloride. A possibility would involve the following steps:

TAMIP-monoamide  TAMIP-diacetate  TIP-diamide as a one-pot reaction

Separate preparation of TIP-diamide chloride

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 62 For this to work, it would be important to combine the TAMIP-monoamide to TIP-diamide stages as a one-pot process. The isolated TIP-diamide could in theory then be converted to TIP-diamide chloride in any inert solvent or in the absence of solvent (in excess thionyl chloride as solvent). As a result, the problems described in relation to the use of specific alternative solvents would not apply, as the stages which require a medium-polarity solvent would be isolated from acid chloride preparation (Kudschus, 1990).9

However, this alternative stage sequence has been found to involve a number of new problems, which cannot be sufficiently resolved, particularly from an operational point of view. A particular problem is the removal of the acetic acid which is bound to form in the first partial stage (TAMIP- monoamide + acetic anhydride  TAMIP-diacetate + acetic acid or R-OH + (CH3CO)2O  R-OCOCH3 + CH3COOH), which should be as quantitative as possible. This removal is necessary, as otherwise, the following equilibrium occurs after the addition of methoxyacetyl chloride:

AcOH + MeOCH2COCl AcCl + MeOCH2COOH

The acetyl chloride that forms reacts with TAMIP-diacetate⇌ giving the undesired, so-called N- or triacetate, a maximum content of 1.5% of which is permitted in the TIP-diamide or TIP-diamide chloride intermediates. Therefore, in order to perform the two-stage reaction and to remove acetic acid, a solvent is required (Kudschus, 1990). The solvent must:

 Have sufficiently good dissolution properties for TAMIP-monoamide, TAMIP-diacetate and TIP- diamide, whilst absorbing coloured impurities as far as possible  Have a higher boiling point than acetic acid  Not form azeotropes with acetic acid, as these generally show the maximum boiling point.

The solvent considered best fitting these requirements was assumed to be 2-ethoxyethyl acetate (EC No. 203-839-2, CAS No. 111-15-9). After formation of TAMIP-diacetate, the excess acetic anhydride was decomposed by adding methanol. Acetic acid could then be removed by distillation, however, without a fractionation column the inefficiency of removal may lead to large quantities of solvent being lost. Alternatively, to avoid these large quantities of solvent being lost (after removal of the majority of the acetic acid), the remaining residual acetic acid could be purged by refluxing with a molecular sieve in the vapour phase in the laboratory (Kudschus, 1990). However, removal of residual acetic acid with a molecular sieve was found in testing to result in slightly increased, but tolerable levels of N-acetate impurities in comparison to EDC (from 0.5-0.7%, limit 1.5% in TAMIP- diacetate). This additional step is not practical on production scale, as the handling and removal of solid molecular sieve pellets would require additional equipment and potential manual handling.

Further problems were identified (Kudschus, 1990):

 The insufficient absorption of coloured impurities by 2-ethoxyethyl acetate. This issue could theoretically be solved by adding acetonitrile to the reaction batch (after removal of acetic acid)  The unsatisfactory filterability of the TIP-diamide crystals formed which makes its isolation difficult.

9 For the formation of TIP-diamide, a more polar and for the formation of TIP-diamide chloride a less polar solvent is necessary, and EDC is a good compromise for both steps. Low polarity solvents make TAMIP- diacetate stick together (adhesion), while more polar solvents “purify” in situ.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 63 The maximum laboratory yields obtained were 88% for two stages. Conversion of TIP-diamide to TIP-diamide chloride was not possible, as TIP-diamide was difficult to isolate. Finally, it should be noted that 2-ethoxyethyl acetate has not been registered under REACH yet and is accompanied by a Repr. 1B (H360FD) hazard classification10; therefore, it cannot be considered an alternative eligible for the substitution of EDC.

Conclusion on the technical feasibility of an alternative solvent under a different reaction sequence

The substitution of EDC by 2-ethoxyethyl acetate in combination with a change to the stage sequence has been tested but has not been found to be a feasible option. The removal of acetic acid would imply large solvent losses or, if purging with a molecular sieve were to be used, impurities in the final products might increase, and this would not be practical on production scale. Beyond these issues, the use of 2-ethoxyethyl acetate would result in colour development and difficulties in the isolation of TIP-diamide. These obvious technical shortcomings, coupled with the unfavourable hazard profile of the solvent, render this alternative infeasible and unsuitable. No further consideration is deemed necessary.

9.1.2 R&D programme from 2014 onwards

Identities of potential alternative solvents and initial screening

In the process of preparing this Application for Authorisation, Bayer Pharma AG identified additional solvents that could be considered as substitutes for EDC. Bayer Pharma AG made the positive decision to assess such additional solvents by undertaking desk-based studies and laboratory experiments. Twelve additional solvents belonging to the halogenated hydrocarbon, ester and ether families were identified for assessment, as shown in Table 9-5. In addition, ethyl acetate, the one alternative that the 1990s R&D work had identified as the least infeasible among those tested in the past, was again tested to ensure that adequate consideration has been given to it.

Table 9-5: Master list of alternative solvents assessed by Bayer Pharma AG in 2014 Solvent family Identified potential alternative solvents EC Number CAS Number Halogenated 1-Chlorobutane 203-696-6 109-69-3 hydrocarbons Chlorobenzene 203-628-5 108-90-7 α,α,α-Trifluorotoluene 202-635-0 98-08-8 Fluorobenzene 207-321-7 462-06-6 Esters Diethyl carbonate 203-311-1 105-58-8 Ethyl acetate 205-500-4 141-78-6 n-Propyl acetate 203-686-1 109-60-4 Isopropyl acetate 203-561-1 108-21-4 Ethyl propionate 203-291-4 105-37-3 n-Butyl propionate 209-669-5 590-01-2 Ethers 2-Methyl-tetrahydrofuran 202-507-4 96-47-9 Diisopropyl ether 203-560-6 108-20-3 Cyclopentyl methylether 445-090-6 5614-37-9

10 According to the ECHA C&L Inventory (accessed on 22 October 2014), the harmonised classification of the substance includes Flam. Liq. 3 (H226), Acute Tox. 4 * (H302, H312, H332) and Repr. 1B (H360F).

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 64 Bayer Pharma AG undertook a first screening of the substances for general applicability using the sub-criteria identified earlier:

 Inertness to reaction agents: inertness to thionyl chloride and hydrogen chloride  Boiling point: boiling point must be above 50 °C.

The results are shown in Table 9-6.

Table 9-6: Initial screening of alternative solvents assessed by Bayer Pharma AG in 2014 Identified potential Inertness to thionyl chloride and Boiling point (°C) alternative solvents hydrogen chloride 1-Chlorobutane Acceptable 78.8 Chlorobenzene Acceptable 131-132 α,α,α-Trifluorotoluene Acceptable 102* Fluorobenzene Acceptable 84.5 – 84.9 Diethyl carbonate Acceptable 126 Ethyl acetate Acceptable 77.1 n-Propyl acetate Acceptable 101.5 Isopropyl acetate Acceptable 88.5-89 Ethyl propionate Acceptable 99** n-Butyl propionate Acceptable 145*** 2-Methyl-tetrahydrofuran Unacceptable; it reacts with HCl 78 Diisopropyl ether Acceptable 68.2 Cyclopentyl methylether Acceptable 107 Source: Boiling points have been confirmed at the ECHA Registered Substances database (http://echa.europa.eu/en/information-on-chemicals/registered-substances, accessed on 8 October 2014) * http://www.sigmaaldrich.com/catalog/product/sial/547948?lang=en®ion=GB ** http://www.sigmaaldrich.com/catalog/product/aldrich/112305?lang=en®ion=GB *** http://www.sigmaaldrich.com/catalog/product/aldrich/307378?lang=en®ion=GB

The above table has led to the exclusion of 2-methyl-tetrahydrofuran, as it is not inert in the presence of HCl, thus technically infeasible. Laboratory testing of the remaining 12 potential alternative solvents was undertaken in the period October–December 2014. The key questions that the laboratory testing aimed to address were:

1. Does the product form in these solvents and can it be isolated?

2. Is the yield acceptable?

3. Does the achieved quality warrant further research and development to be undertaken?

The results of this very recent research (undertaken in the second half of 2014) are discussed below.

First test batch – Laboratory testing of product formation and isolation – 12 alternative solvents

As already described, the synthesis of TIP-diamide chloride is a two-step chemical reaction in EDC without isolation of the first intermediate (product of Step 1). The first group test Bayer Pharma AG undertook in the autumn of 2014 was to subject the shortlisted 12 potential alternative solvents to scaled-down laboratory experiments to establish whether product formation and isolation would be possible. For comparison, Bayer Pharma AG also tested EDC under the same conditions.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 65 According to the laboratory results, seven out of the twelve alternative solvents failed as the reaction mixture hardened or became sticky under the reaction conditions of Step 1 (see Table 9-7). With EDC, an easy to stir, clear solution could be obtained.

In the remaining five alternative solvents, the reaction mixture could be stirred under the reaction conditions of Step 1, but no clear solution was formed. For these five solvents, the conversion rate in Step 2 was found to be poor (10–20% formed product) (see Table 9-7). The performance of ethyl acetate, which had been tested in the past, was actually much poorer than originally expected. For EDC, under the same conditions, the measured conversion rate was 98%. It is Bayer Pharma AG’s experience with plant batches that undissolved intermediate does not react in Step 2. If (oversaturated) reaction mixture of Step 1 precipitates, incomplete conversion to TIP-diamide chloride during Step 2 is not possible.

The conclusion of the first test batch was that five alternative substances could be subject to further testing under improved stirring and temperature conditions:

 Diisopropyl ether (repeat with stronger stirrer)  Diethyl carbonate (repeat at higher temperature)  n-Propyl acetate (repeat at higher temperature)  Ethyl acetate (repeat with stronger stirrer).

If this further testing succeeded in producing TIP-diamide chloride, the next concern would be quality.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 66 Table 9-7: First round of laboratory tests in 2014 R&D Stage 2 Identified Stage 1 TIP-diamide  TIP diamide potential TAMIP-diacetate  TIP-diamide Conclusion and route to further chloride alternative testing Mixture ‘stirrability’ solvent Conversion rate Notes Conversion rate (viscosity) EDC – for Can be stirred Clear Baseline 98% (in tests) Baseline comparison Eliminated from testing for Step 2 due to poor Not tested – experiment Not considered feasible or 1-Chlorobutane Mixture became sticky 50% only conversion rate and sticky cancelled realistic mixture Eliminated from testing for Mixture hardened or Not tested – experiment Not considered feasible or Chlorobenzene 95% Step 2 as a new impurity became sticky cancelled realistic was found at 10-20% Eliminated from testing for α,α,α- Mixture hardened or Not tested – experiment Not considered feasible or 50-60% only Step 2 due to poor Trifluorotoluene became sticky cancelled realistic conversion rate Eliminated from testing for Mixture hardened and Step 2 due to poor Note tested – experiment Not considered feasible or Fluorobenzene 80-90% only became sticky conversion rate and sticky cancelled realistic mixture Diethyl Could be stirred with a Included in testing for Step <20% Consider further testing at a Not clear carbonate stronger stirrer 2 (formed product not isolated) higher temperature Included in testing for Step <20% Consider further testing with a Ethyl acetate Could be stirred Not clear 2 (formed product not isolated) stronger stirrer n-Propyl Could be stirred with a Included in testing for Step <20% Consider further testing at a Not clear acetate stronger stirrer 2 (formed product not isolated) higher temperature Isopropyl Could be stirred with a Included in testing for Step <20% Consider further testing with a Not clear acetate stronger stirrer 2 (formed product not isolated) stronger stirrer Ethyl Mixture hardened or Included in testing for Step Solvent completely absorbed by Not considered feasible or >95% propionate became sticky 2 the reaction mixture realistic

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 67 Table 9-7: First round of laboratory tests in 2014 R&D Stage 2 Identified Stage 1 TIP-diamide  TIP diamide potential TAMIP-diacetate  TIP-diamide Conclusion and route to further chloride alternative testing Mixture ‘stirrability’ solvent Conversion rate Notes Conversion rate (viscosity) A hard deposit n-Butyl Mixture hardened or Eliminated from testing for Not tested – experiment Not considered feasible or formed that could propionate became sticky Step 2 due to sticky mixture cancelled realistic not be stirred Diisopropyl ether did not cause formation of a solid block but the reaction Diisopropyl Mixture hardened or Consider further testing with a N/A mixture became too thick to Not tested ether became sticky stronger stirrer be stirred after 2 hours. Thus, it was not possible to test in Step 2 <20% (formed product not At Step 1, a compact solid isolated) A stronger stirrer was mainly formed at the Cyclopentyl At Step 2, 40–50% of the solid Not considered feasible or used but mixture Not clear bottom of the reactor but methylether became a light suspension. This realistic remained hardened the stirrer could move suspension consisted of 20% of above this TIP-diamide chloride

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 68 Second test batch – Laboratory testing of product formation and isolation – alternative solvents at adapted reaction conditions

Although clearly the first batch of tests showed that some of the potential alternatives performed particularly poorly, Bayer Pharma AG undertook further testing under variable test conditions to establish the influence of temperature. The approach taken was as follows:

1. Conduct tests on the completeness of the first reaction step: Reaction with methoxy acetic acid chloride at 85 °C

2. If conversion at Step 1 reaches or exceeds 95%, conduct tests on the second reaction step: Reaction with thionyl chloride at 63 °C

3. If conversion at Step 2 is not satisfactory, increase the temperature and repeat

4. If at a higher temperature, conversion at Step 2 is acceptable, establish quality/colour of product and yield

5. If yield appears to be reasonably high and the alternative seems promising, repeat tests at a standard batch scale.

The results of this iterative process are shown in Table 9-8.

Table 9-8: Second batch of laboratory tests on potential alternative solvents in the 2014 R&D Identified Quality / potential Conversion Absence of colour value Test No. Yield Recovery* alternative (completeness) adhesion (white, 0.11- solvents 0.15) 102% EDC Be2794    based on  mass input  1-Chlorobutane Be2779 Step 1: 50%   conversion   10-20% by- Chlorobenzene Be2778 Step 1: 95%   product at conversion Step 1  α,α,α- Be2791 Step 1: 50-60%   Trifluorotoluene conversion  Fluorobenzene Be2792 Step 1: 80-90%   conversion  Step 1: 95% Be2790 conversion   /? Diethyl Step 2: 10-20% carbonate conversion Mo2021  93°C instead   88%  /? Yellow of 63°C

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 69 Table 9-8: Second batch of laboratory tests on potential alternative solvents in the 2014 R&D Identified Quality / potential Conversion Absence of colour value Test No. Yield Recovery* alternative (completeness) adhesion (white, 0.11- solvents 0.15)  Step 1: >95% conversion Ethyl acetate Mo2020 Suspension   difficult to stir Step 2: 10% conversion  Be2784 Step 1: 10-20%   /? conversion   Step 2: after 13 Mo2018  New impurity, 88%  /? hrs instead of 8 n-Propyl Off-yellow hrs acetate Mo2024 Standard- size batch,    76%  /? 93 °C instead of 68 °C  Step 1: 70% Mo2023 conversion   /? (with magnetic stirrer) Isopropyl  acetate Step 2: 10% conversion Be2787   /? (with a stronger mechanical stirrer)   /  Step 1: >95% Cancelled Ethyl Step 2: solvent during Be2783  /? propionate completely Step 2 absorbed

 n-Butyl Step 1: reaction Mo2022   /? propionate mixture formed a gum  Diisopropyl Mo2019 Step 1: 30-40%   /? ether conversion  Cyclopentyl  /  Be2789 Step 1: 20%  /? methylether Borderline conversion * “?” under recovery means that Bayer Pharma AG has no experience with recovery in the presence of thionyl chloride. Esters and secondary ethers might be hydrolysed

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 70 The following conclusions can be reached which lead to the elimination of several substances from further consideration:

 Elimination on the basis of poor conversion rate at Step 1 and adhesion: several alternatives have very poor conversion rates for reaction Step 1, which result in adhesion of the product; these include 1-chlorobutane, chlorobenzene, α,α,α-trifluorotoluene, fluorobenzene, n-butyl propionate  Elimination on the basis of poor conversion rate at Step 1 without adhesion: some alternatives do not cause product adhesion but still have poor conversion at reaction Step 1, i.e. diisopropyl ether and cyclopentyl methylether  Elimination on the basis of poor conversion rate at Step 2: other alternatives offer acceptable conversion at Step 1 but have very low conversion in Step 2, i.e. ethyl acetate and isopropyl acetate. Ethyl propionate was completely absorbed by the reaction mixture thus conversion rate could not be estimated  Elimination on the basis of poor product quality and yield: diethyl carbonate requires a higher temperature in order to deliver adequate conversion; in addition, the product quality is poor (yellow colour) and the yield is significantly lower than for EDC. n-Propyl acetate also requires a higher temperature but has shown unexpected and insurmountable technical shortcomings:

 Testing with lab-size batches under standard temperature conditions: the reaction time was too long to fit into the synchronised synthesis, thus reducing the production capacity of the plant by ca. 27% thus increasing production costs and preventing Bayer Pharma AG from meeting market demand for Ultravist®  Testing with lab-size batches under elevated temperature conditions: at a higher temperature, the reaction time was acceptable but the yield dropped  Presence of new impurities: under both temperature conditions, a new impurity was found in Iopromide batches made from this TIP-diamide chloride at a concentration of 0.5%. Regulations allow a concentration of only 0.03% of unknown impurities in contrast media. Notably, this unknown impurity was also found in Iopromide batches made from TIP-diamide chloride batches produced in ethyl acetate instead of EDC. Bayer Pharma AG’s experience is that esters of acetic acid and possibly of other carbonic acids lead to formation of a new impurity in TIP-diamide chloride that adversely affects the quality of Iopromide. Furthermore, the new impurity is outside the impurity profile which is described on the Marketing Authorisations of Ultravist®. In addition, the recyclability of n-propyl acetate is still unknown.

Conclusion on the technical feasibility of single potential alternative solvents

The tests that Bayer Pharma AG undertook in October – December 2014 have shown that no alternative of the 12 selected can perform as well as EDC. In most cases, poor conversion and adhesion make the alternatives wholly infeasible. In a few cases, use of the alternative solvent under high stirring and a higher temperature delivered acceptable conversion (n-propyl acetate and diethyl carbonate), however, the quality of the product and the resulting yield were unacceptably poor.

9.1.3 Overall conclusion of Bayer Pharma AG’s R&D programmes

It can be concluded overall that despite Bayer Pharma AG’s systematic efforts, no technically feasible alternative for the specific manufacturing process can be identified. Only few solvents / mixtures of

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 71 solvents have been proved to allow complete conversion to of TAMIP-diacetate to TIP-diamide chloride but nor yield neither quality were within the acceptable range.

Consequently, the conclusion is that none of the identified and assessed potential alternatives could offer an acceptable level of technical (and economic) feasibility as a substitute for EDC. None of these alternatives can be considered further as they lack any feasibility in substituting EDC. 9.2 Research and development on alternative synthetic routes

9.2.1 Alternative Synthetic Route A

Description

According to the 1982 patent filed by Schering AG, Iopromide may be synthesised using the route shown in Example 6 in the patent. This suggests the following route, which is depicted in Figure 9-1.

Figure 9-1: Reaction sequence in the synthesis of iopromide under alternative Synthetic Route A (where J is iodine) (Speck, et al., 1982)

The patent describes the process and achieves the following yields:

 Step 1 – Synthesis of Product (a) from symmetrical acid chloride: 74% yield in DMF. Product precipitated by addition of copious water – a large volume of water is required (a ratio of 1:25 DMF to water, or some 50 mL per g of product obtained) making the recycling of the solvent impossible  Step 2 – reaction with aminopropanediol to form product (b): 74.5% yield in DMF and tributylamine as base. Complex extraction under reduced pressure and precipitated in DCM as anti-solvent. Finally partially purified by hot filtration using ethyl acetate (approx. 25 mL solvent per g of product obtained). Product obtained as a solid (without crystallisation) after removal of

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 72 solvent. This step again requires copious solvent, and as no crystallisation is included, the product may be not be of high purity  Step 3 – reaction with methylaminopropanediol to form Iopromide: 81% yield in DMF and tributylamine as base. Precipitated by copious dichloromethane (DCM) (some 45 mL DCM per g of product obtained). The crude product is then dissolved in water, which is pH adjusted, decolourised using activated charcoal, de-ionised using ion-exchange resins and finally obtained by removal of water under reduced pressure.

Assessment of technical feasibility of the synthetic route

The route described above uses a different starting material to that currently employed by Bayer Pharma AG and the process is not ideally suited to large scale synthesis in a process plant. The reasons for this are described in more detail below.

Issues with product isolation: the use of DMF results in issues with the isolation of solid products. In the laboratory scale examples described in the patent, this is overcome by adding copious amounts of water as an anti-solvent to precipitate the reaction products. On plant scale, this would require vast quantities of water. For each tonne of intermediate product, some 50 m3 of water would be required for the first-step alone, if the process was scaled up using laboratory conditions. Even in the final step, distillation under reduced pressure is used to obtain the final product from an aqueous solution. This step would take a very large amount of energy and, as it does not involve crystallisation, the product crystals are unlikely to have a high level of purity.

Issues with the separation of reaction products: Synthetic Route A goes through only a few intermediate stages, but has the obvious disadvantage that a monoamide (b) has to be produced from the symmetrical diacid chloride (a). The formation of symmetrical diamide is unavoidable and can only be decreased by using a reduced amount of the amine components, as a result of which, in addition to the symmetrical amine, unreacted diacid chloride (a) remains in the reaction mixture.

Separation of the symmetrical diamide and the excess diacid chloride (a) is vital, as the diamide has a very similar structure to that of Iopromide (one methyl group difference) and therefore it is likely that their separation will be difficult. In the further course of synthesis with methylaminopropanediol, the diacid chloride (a) would also result in the formation of a related compound very similar to Iopromide, which would also be very difficult to separate.

Thus, a consequence of the transition through the symmetrical diacid chloride (a) is that the required conversion to monoamide (b) would not be efficient. There is an accumulation of a large quantity of the symmetrical diamide, which cannot be used for further synthesis, and the recycling of the excess diacid chloride (a) is complex. The yield is stated as 74.5%; however, no indication of the purity of the intermediate product is given.

Overall yield of the synthesis: the overall yield of the above reactions is described as 74% × 74.5% × 81% = 44.7% of theoretical. This is reduced with respect to the current yield but it is not directly comparable to the synthesis currently employed (which achieves a '#A#''''''' yield). It does, however, indicate further inefficiencies with the route and would therefore be more wasteful in terms of mass balance, ultimately resulting in increased process costs.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 73 9.2.2 Alternative Synthetic Route B

Description

According to the 1982 patent filed by Schering AG, Iopromide may be synthesised using the pathway defined by Example 7 of the patent. This suggests the following route, depicted in Figure 9-2.

Figure 9-2: Reaction sequence in the synthesis of iopromide under alternative Synthetic Route B (Speck, et al., 1982)

This route has the advantage of starting from the same precursor as the currently employed route; NIPA-MME with six isolated products. However, the route described results in a claimed overall yield of 41.4% without the use of EDC as solvent. This is considerably lower than the '#A#'''''''' obtained by Bayer Pharma AG in the process currently employed.

 Steps 1-3 – synthesis of product (d) from NIPA-MME: this synthesis avoids the use of halogenated solvents for these steps and the intermediate product (d) is obtained in 83.8% × 96% × 92% (over two-steps in-situ) = 73.7% yield.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 74  Step 4 – hydrogenation and iodination of product (d) to obtain product (e): the nitro group is hydrogenated using Raney nickel11 as catalysts to obtain the primary amine and the product is iodinated using NaICl2. Yield 71.3%

 Steps 5-6 – acylation of product (e) followed by removal of acetyl groups to obtain Iopromide, product (f): methoxyacetyl chloride is prepared from methoxy acetic acid using thionyl chloride in dimethyl acetamide (DMA). This is then used to acylate the amine of product (e). The crude product is obtained by removal of solvent under reduced pressure and the acetyl groups hydrolysed (alcohol deprotection) using aqueous ammonia. This results in the formation of acetamide as the by-product. The final product is obtained from an aqueous solution after treatment with ion-exchange resins (Amberlite XAD-4”, as for Alternative Synthetic Route A). The yield resulting from these steps is 78.4%.

Assessment of technical feasibility of the synthetic route

Issues with late iodination: the viability of Synthetic Route B is negatively affected by late iodination, in which a quite complex molecule is subjected to harsh reaction conditions which may involve additional secondary reactions. The relatively low yield of this step of 71.3% supports the premise that a significant number of by-products are formed.

Issues with steric hindrance: due to the steric hindrance of the CH group between the two amide groups, the formation of triiodoaromates is hindered, which results in the impairment of quality and yield.

Issues with acetamide formation: Synthetic Route B also has the disadvantage that acetamide (CH3CONH2) forms in the final removal of protecting groups with ammonia, and due to its toxicity this must be separated completely at great expense.

Overall yield of the synthesis: the overall yield of the above reactions is described as 83.8% × 96% × 92% × 71.3% × 78.4% = 41.4% of theoretical. This is considerably lower than the '#A#''''''' overall that is currently obtained by Bayer Pharma AG from the same starting material, NIPA-MME.

9.2.3 Alternative Synthetic Route C

Description

According to the 1982 patent filed by Schering AG, Iopromide may be synthesised using the route shown in Example 8 in the patent. This suggests the following route, depicted in Figure 9-3. The synthesis is quite similar to the others; however the hydrogenation and iodination steps occur slightly earlier than in Alternative Synthetic Route B, i.e. before the introduction of the methylaminopropanediol component. ''#A#'''''' '''''''''' '''''''''''''''' ''''''''''''''''''' ''''' '''''''''''' ''''''''''''''' ''''''' '''' ''''''''''''''''''' '''' ''''''' '''''''''''''''''''''''' ''''''''''''' '''' '''''''''''''''' ''''' ''' ''''''''''''''''''''''''''''''''' ''''''' ''''''''' '''' '''''''''''''''' '''''' ''' ''''''''''''''''''''''''' '''''''''''''''''' ''''''' '''''''''''''''''' '''' '''''''''''''''''' '''''''''''' '''' '''''' ''''''''''''''' ''''''''''' ''''''' '''''' ''''''''''' ''''' '''' '''''''''''''

 '#A#''''''' ''' ''' '''''''''''''''''''''' ''''' '''''''''''''''''''''''''''''''' '''''' ''''' '''' ''''''' '''''''''''''''' ''''''' '''''''''''''''' ''' '''''''''''''' ''''''' '''' '''''''''''''' '''''''''' '''''''''''''''''''''''''' ''''''''''''''''''''''''''' '''' '''''' ''''''''''''''''''''''' '''''''''' '''''''' '''''''''''''''' '''''''''' ''''' '''''''''''''''''''' '''''''''''''' ''''' ''''''''' ''''''' '''''''''''''' '''''''' ''''''''' '''''''''

11 Raney nickel is a fine-grained solid composed mostly of nickel derived from a nickel-aluminium alloy.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 75  ''''''''' ''' ''' '''''''''''''' '''''''' '''''''''''''''''''''''''' ''''''''''''''' '''' '''''''' ''''''''''''''''''''''' '''''''''''''''' ''''''' '''''''''''''''''''''''''''' '''''''''''''''' '''' ''''''''''''''''' '''' '''''''''' '''' '''''''''''''' ''''''''''' '''''''''''''' '''''''''''''''' ''''''' ''''''''''''''''' ''' ''''''''''''' ''''''' '''' ''''''''''' ''''''''''''''''''''''''' '''''''''' '''''' ''''''''''' '''''''''' ''''''''''''''' '''' '''''''''' '''''''''' ''''''''''''''' ''''''''''''''' ''''''' '''''' ''''''''''''''' '''' '''''''''''''''' ''''' '''''''''''''''''''''' ''''''''''' ''''''''' ''''''' '''''' '''' '''''''' ''''''' ''' '''' '''''''''''''''''''''''' '''''''''''''' ''''''''''''''''' '''''''''''''''''' ''''' ''''''''''''''''''' ''''''''' ''''''''''''''''' '''''''''' ''''''''''''' '''''''''''''''''''''' '''''''''''''' '''''''''''''' ''''''''''' ''''''''''''' '''''''''''''''

Figure 9-3: Reaction sequence in the synthesis of iopromide under alternative Synthetic Route C (Speck, et al., 1982)

Assessment of technical feasibility of the synthetic route

Issues with use of DMA solvent: N,N-dimethylacetamide is used as solvent in the second step. This solvent has issues with recyclability and is also reprotoxic.

Issues with phosphorus pentachloride: phosphorus pentachloride is highly corrosive and toxic, and therefore difficult to handle.

Overall yield of the synthesis: alternative route C converts TAMIP-diacetate into TIP-diamide in 86% × 81% = 70% yield. The current route achieves a '#A#''''''' yield '#A#'''''' ''''''' ''''''''''' '''''''''''''''''''''''''''' ''''''' ''''' '''''' '''''''''''''''''''' '''''''''''''''''''' ''''' '''''''''''''''''''''''''''' ''''''''''''''''''' '''' ''''''''' '''''''''''''''''' ''''''''''' ''''''''''''''''''''' ''''''' ''''''''''' '''''''''''''''' ''''''''' '''''''' '''''''''''''''' '''''''' ''''''''''''''''''' '''''''''''''' '''''''''''''''' '''''''''''' '''''''''' ''''''' '''''' ''''''''''''''''''

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 76 9.2.4 Alternative Synthetic Route D

Description

According to the 2000 patent filed by LG Life Sciences Ltd Iopromide can be synthesised from 5- amino-2,4,6-triiodoisophthalic acid dichloride, which is converted by a sequence of 4 steps to TIP- diamide chloride before conversion to Iopromide (see Figure 9-4).

Figure 9-4: Reaction sequence in the synthesis of Iopromide under alternative Synthetic Route D (Gyu, et al., 2000)

An advantage of this approach in comparison to Alternative synthetic route A is that the starting material is already iodinated; however it shares the issue of a desymmetrisation step that can adversely affect yield:

 Steps 1-2: The methoxyacetyl group is added to the starting material, followed by desymmetrisation by addition of aminopropanediol. The steps of the synthesis are carried out without isolation of the intermediates up to the unacetylated intermediate (Example 1) in a yield of 66.1% in DMA as solvent. In a similar fashion to all of the alternative syntheses described, the intermediate product is isolated using large quantities of DCM

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 77  Step 3 – Acetylation to obtain TIP-diamide chloride (Example 2): The intermediate diol is acetylated using acetic anhydride in a yield of 90.2%.

The synthesis achieves a 66.1% × 90.2% = 59.6% yield of TIP-diamide chloride from 5-amino-2,4,6- triiodoisophthalic acid dichloride.

Assessment of technical feasibility of the synthetic route

Synthetic Route D is based on Synthetic Route A and offers a solution for the difficult separation of the undesirable symmetric diamide. According to the details of the patent, the introduction of the acetate protecting groups permits separation in a simple manner. Nevertheless, the problem of poor efficiency described in Synthetic Route A remains. The symmetric diacid chloride cannot be converted selectively to the monoamide. Considerable quantities of waste materials containing iodine form are generated and are lost for synthesis purposes.

Overall yield of the synthesis: Synthesis D makes use of the same raw materials (building blocks) and the same types of reactions as the current synthetic route. However, the order of the reactions has been changed leading to different intermediates with different properties than the current ones. For example, aminopropandiol is introduced at the very beginning of the current synthesis: ''#A#''''''''''' '’’’’’’’' TAMIP-monoamide '#A#'''''' '''''''' ‘’’’’’’’’’’’’’’’’’''''''''''''''. In synthesis D, aminopropandiol is introduced after iodination (Example 1) with a yield of just 66.1% of theoretical. A comparison of the yields stated in the patent with comparable stages of the Iopromide synthesis currently carried out commercially at Bayer Pharma AG produces Table 9-9. The table confirms that, if the order of reactions were to be changed, Iopromide could be produced without using EDC but the yield would be much lower.

Table 9-9: Comparison of yields of Synthetic Route D and the current Bayer Pharma AG synthetic route Synthetic Route D Current Bayer Pharma AG Functionalisation (% of theoretical) synthetic route (% of theoretical) ''All Table 9-9 #A#''''''''''''''''''''''' '''' '''''''' ''''' '''''''''' '''''''''''''''''''''''''''''''''''' ''''''''''''' '''' '''''''''''''''''''''''' '''' '''''''''''''' ''''''''''''''''''' ''''''''''''' '''''''' '''''' '''''''''''''''''''''''''''''''''''' ''''''''''''''''''' '''' '''''''''''''''''''''' '''' ''''''''''''''''''''''''''''''''''''''''''' '''''''' ''''''''' ''''' ''''''''''''''''''''''' '''''''''''''''''''' '''' ''''''''''''''''''''' ''''''''''''''''''' '''' Total yield of these stages 50.7 '''''''''

Conclusion on the technical feasibility of alternative synthetic routes

Synthetic Route A means that the product has to be isolated from the mixture which forms with such processes, and the remaining by-products need to be purified (diacid chloride) and/or disposed of (di-substituted product). In addition, the yield of Synthetic Route A (44.7%) is clearly far worse than the route currently used by Bayer Pharma AG '#A#'''''''''' (although not directly comparable), thus it may not be considered a realistic, viable alternative technology to the EDC-based route.

The key disadvantage of Synthetic Route B is that the introduction of iodine atoms at a subsequent stage occurs with a complex molecule, in which the positions to be occupied by iodine are impaired spatially by the side chains which are already present in the molecule. As a result of the aggressive reaction conditions which are required (iodination with chlorine iodide), there is a risk that a multitude of by-products will form shortly before the final stage (API), and that these will differ substantially from those which are present in the current iopromide. In addition, the yield of

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 78 Synthetic Route B (41.4%) is clearly far worse than the route currently used by Bayer Pharma AG '#A#''''''''''', thus it may not be considered a realistic, viable alternative technology to the EDC- based route.

Synthetic Route C '#A#'''''''''''' '''''''''''''' ''''''' ''''''''''' '''''''' ''''''''''''''''''''''''''' ''''''''''''''''''''''''' ''''''''''''''' ''''' ''''''''''' '''''''''''''' ''''''''' ''''''''''''' '''''''''''''''''' '''''''''''''''''' the yield of Synthetic Route C '#A#''' '''''''''''''' ''''''' '''''''''' '''''''''''''''''''''''' is clearly far worse (achieving 70% yield) than the route currently used by Bayer Pharma AG ('#A#'''''''' for the same conversion), thus it may not be considered a realistic, viable alternative technology to the EDC-based route.

Synthetic Route D means that the symmetric diacid chloride cannot be converted selectively to the monoamide. The reason for this is the poor selectivity in the reaction of symmetrical diacid chloride with aminopropanediol in Synthetic Route D. In addition, the yield of Synthetic Route D (50.7%), is clearly far worse than the route currently used by Bayer Pharma AG '#A#''''''''''''''' thus it may not be considered a realistic, viable alternative technology to the EDC-based route.

These conclusions are summarised in Table 9-10

Table 9-10: Summary of technical feasibility of alternative synthetic routes Alternative synthetic Technical feasibility issues route  Few intermediate steps only Synthetic Route A  Formation of symmetrical diamide results in unreacted diacid chloride (Speck, et al., 1982; remaining in reaction mixture – difficult separation Hwang, et al., 2009)  Recycling problems  Poor overall yield (44.7%)  Late iodisation and secondary reactions Synthetic Route B  Steric hindrance affecting quality and yield (Speck, et al., 1982)  Poor overall yield (41.4%)  '#D#''''''''''''''' '''''' '''''''''''''''''''''''''''''' ''''''' ''''''''''''''''''''''' '''''''''''''''' Synthetic Route C  Uses hard to recycle solvent, DMA (reprotox) (Speck, et al., 1982)  Poor yield for the same transformation (70%)  Improvement over Synth. Route A with ready separation of symmetric diamide Synthetic Route D  Iodine-containing waste losses (Gyu, et al., 2000)  Uses hard to recycle solvent, DMA (reprotoxic)  Poor overall yield (50.7%)

9.3 Screening of identified potential alternatives

9.3.1 Screening for technical feasibility – Conclusions of past and current assessments

Table 9-11 summarises the findings of the assessment of the technical feasibility of all specific alternatives considered, both substances and synthetic routes. The immediate conclusion is that all alternatives considered are technically infeasible. However, for completeness, a shortlist has been generated for further assessment against market availability criteria with those potential alternatives that can be identified as the ‘least infeasible’. The list includes: ethyl acetate (the most promising of the alternatives tested in the 1990s), n-propyl acetate (the most promising of the alternatives tested in 2014) and synthetic routes A, B, C and D.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 79 Table 9-11: Summary of technical feasibility assessment for all identified alternatives Considered for Investigated solvents EC Number CAS Number Assessment of technical feasibility Conclusion further screening? Methanol 200-659-6 67-56-1 Alcohol: formation of chloroalkanes and sulphurous acid esters with Infeasible  Ethanol 200-578-6 64-17-5 thionyl chloride Infeasible  Butanol 200-751-6 71-36-3 Infeasible  Acetic acid 200-580-7 64-19-7 Carboxylic acid: formation of acid chlorides; solvent contains the Infeasible  same functional group as starting material so the thionyl chloride would simply react with the solvent rather than the starting material Acetone 200-662-2 67-64-1 Ketone: reaction with the amine group of the starting materials to Infeasible  Methyl ethyl ketone (MEK) 201-159-0 78-93-3 form Schiff bases Infeasible  Methyl isobutyl ketone 203-550-1 108-10-1 Infeasible  (MIBK) Acetonitrile 200-835-2 75-05-8 Tested Infeasible  Feasible for 1st synthetic stage. Reacts remarkably with thionyl chloride, so that yields and colour values fluctuate substantially according to reaction conditions; additional purification would be necessary. Yield varies due to decomposition. No recycling method is known Dimethyl formamide (DMF) 200-679-5 68-12-2 Dipolar aprotic solvent: Violent reaction with thionyl chloride. Many Infeasible  Hexamethylphosphoramide 211-653-8 680-31-9 dipolar aprotic solvents are miscible with water (all of the solvents Infeasible  (HMPTA) trialed by Bayer Pharma AG) making the recovery of products very N,N-dimethylacetamide 204-826-4 127-19-5 complex Infeasible  (DMA) Dimethyl sulphoxide (DMSO) 200-664-3 67-68-5 Infeasible  Triethylamine 204-469-4 121-44-8 Amine: violent reaction/salt formation with hydrogen chloride Infeasible  Nitromethane 200-876-6 75-52-5 Nitro compound: unfavourable hazard profile Infeasible  Nitrobenzene 202-716-0 98-95-3 Infeasible  Heptane 205-563-8 142-82-5 Not tested in favour of other alkanes, as it is non-polar Infeasible  Toluene 203-625-9 108-88-3 Tested Infeasible  Feasible for 1st synthetic stage. Affected by impurities in TAMIP- diacetate batches causing adhesion and colouring even if used in combination with other solvents (e.g. acetonitrile). Ultra-pure TAMIP- diacetate batches impossible to produce at industrial scale. Yield was close to EDC

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 80 Table 9-11: Summary of technical feasibility assessment for all identified alternatives Considered for Investigated solvents EC Number CAS Number Assessment of technical feasibility Conclusion further screening? Cyclohexane 203-806-2 110-82-7 Tested Infeasible  Alkane: aprotic solvent, feasible for 1st synthetic stage. Partial reactions remain incomplete. Poor solubility of starting materials. Does not have the capacity to keep the accompanying impurities in the mother liquor in solution Dichloromethane 200-838-9 75-09-2 Boiling point too low (<50 °C) Infeasible  Chloroform 200-663-8 67-66-3 Relatively low boiling point (62 °C) and poor hazard profile Infeasible  1,1,1-Trichloroethane 200-756-3 71-55-6 Tested Infeasible  Infeasible for 1st synthetic stage. Dissolution is too low. Causes adhesion 1-Chlorobutane 203-696-6 109-69-3 Tested (2014) Infeasible  Poor conversion and adhesion. Unusable Chlorobenzene 203-628-5 108-90-7 Tested (2014) Infeasible  Generation of a new impurity (10-20%). Unusable α,α,α-Trifluorotoluene 202-635-0 98-08-8 Tested (2014) Infeasible  Poor conversion and adhesion. Unusable Fluorobenzene 207-321-7 462-06-6 Tested (2014) Infeasible  Poor conversion and adhesion. Unusable Ethyl acetate 205-500-4 141-78-6 Tested Infeasible  Could deliver for both synthetic stages. Substance separation For completeness; this insufficient; colour values very poor; additional purification needed, is the most promising with yield losses. Poor dissolution of impurities. substance from the Poor recyclability as impossible to separate from thionyl chloride. past R&D work and the Combinations with cyclohexane and toluene were unsatisfactory one most thoroughly (poor quality for the former, and process complexities and poor yield assessed so far for the latter) Butyl acetate 204-658-1 123-86-4 Tested Infeasible  Better recyclability than ethyl acetate. Insufficient dissolution properties, no complete conversion was achieved and in some cases product adhesion occurred

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 81 Table 9-11: Summary of technical feasibility assessment for all identified alternatives Considered for Investigated solvents EC Number CAS Number Assessment of technical feasibility Conclusion further screening? 2-ethoxyethyl acetate 203-839-2 111-15-9 Tested Infeasible  Used with alternative reaction sequence. Large losses of solvent during removal of acetic acid. Issues with N-acetate impurities. Colouration issues (possibly solved with addition of acetonitrile (after removal of acetic acid). Unsatisfactory filterability of TIP-diamide, difficult to isolate Diethyl carbonate 203-311-1 105-58-8 Tested (2014) Infeasible  Conversion and adhesion issues resolved at high temperature but yield is poor and product is of very low quality (yellow) n-Propyl acetate 203-686-1 109-60-4 Tested (2014) Infeasible  Conversion and adhesion issues resolved at high temperature but Substance is poor yield is poor and product is of low quality (new impurity and off- compared to EDC but yellow) also the most promising in the 2014 lab tests Isopropyl acetate 203-561-1 108-21-4 Tested (2014) Infeasible  Poor conversion and adhesion. Unusable Ethyl propionate 203-291-4 105-37-3 Tested (2014) Infeasible  Absorbed by the mixture. Unusable n-Butyl propionate 209-669-5 590-01-2 Tested (2014) Infeasible  Created a solid block that could not be stirred. Unusable Diethyl ether 200-467-2 60-29-7 Boiling point too low (<50 °C). Dissolution capacity is too low and Infeasible  results in product adhesion Di-n-butyl ether 205-575-3 142-96-1 Tested Infeasible  Dissolution capacity is too low; incomplete reactions and product adhesion Methyl tert-butyl ether 216-653-1 1634-04-4 Tested Infeasible  Dissolution capacity is too low and results in product adhesion Tetrahydrofuran (THF) 203-726-8 109-99-9 Tested Infeasible  Infeasible for both stages; reacts with HCl slowly to form 4- chlorobutanol and this reacts further with thionyl chloride to form 1,4- dichlorobutane

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 82 Table 9-11: Summary of technical feasibility assessment for all identified alternatives Considered for Investigated solvents EC Number CAS Number Assessment of technical feasibility Conclusion further screening? Dioxane 204-661-8 123-91-1 Tested Infeasible  Feasible for both synthetic stages. Too high dissolution capacity for TIP-diamide chloride that they cannot be isolated. Promising when used with toluene but the two solvents could not be separated economically by distillation (dioxane is water soluble and the Bayer Pharma AG distillation plant could not cope with a dioxane/toluene mixture). In presence of HCl, it is subject to slow decomposition with formation of 2-(2-chloroethoxy)ethanol (CAS No. 628-89-7), which upon reaction with thionyl chloride would give the acutely toxic bis-(2- chloroethyl)-ether. A decomposing solvent such as dioxane cannot be considered a realistic option Diglyme 203-924-4 111-96-6 Tested Infeasible  Dissolution capacity is too low and results in product adhesion 2-methoxy-2-methylbutane 213-611-4 994-05-8 Tested Infeasible  (tert-Amyl methyl ether Subject to ether cleavage under the reaction conditions. Reacts with (TAME)) methoxyacetyl chloride and thus consumes this reaction partner 2-Methyl-tetrahydrofuran 202-507-4 96-47-9 Reacts with HCl Infeasible  Diisopropyl ether 203-560-6 108-20-3 Tested (2014) Infeasible  Created a solid block that could not be stirred. Unusable Cyclopentyl methylether 445-090-6 5614-37-9 Tested (2014) Infeasible  Created a solid block that could not be stirred. Unusable

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 83 Table 9-11: Summary of technical feasibility assessment for all identified alternatives Considered for Investigated solvents EC Number CAS Number Assessment of technical feasibility Conclusion further screening? Alternative synthetic routes Synthetic Route A US 4364921 A  Few intermediate steps only Infeasible  Example 6 in Schering AG Schering AG  Formation of symmetrical diamide results in unreacted diacid For completeness patent (Speck, et al., 1982) chloride remaining in reaction mixture – difficult separation only: process has KR20000061780  Recycling problems been demonstrated in Dong Kook Pharm Co Ltd  Poor yield (44.7%) the lab, but clearly (Gyu, et al., 2000) worse than EDC Synthetic Route B US 4364921 A  Late iodisation and secondary reactions Infeasible  Example 7 in patent Schering AG  Steric hindrance affecting quality and yield For completeness (Speck, et al., 1982)  Poor yield (41.4%) only: process has been demonstrated in the lab, but clearly worse than EDC Synthetic Route C US 4364921 A  Proceeds via TAMIP-diacetate and TIP-diamide chloride Infeasible  Example 8 in patent Schering AG  Poor yield for conversion of TAMIP-diacetate to TIP-diamide For completeness (Speck, et al., 1982) chloride (70%) only: process has  Recycling problems been demonstrated in the lab, but clearly worse than EDC Synthetic Route D WO 2009134030 A1  Improvement over Synth. Route A with ready separation of Infeasible  LG Life Sciences Ltd symmetric diamide For completeness (Hwang, et al., 2009)  Iodine-containing waste losses only: process has  Recycling problems been demonstrated in  Poor yield (50.7%) the lab, but clearly worse than EDC

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 84 9.3.2 Screening for market availability and commercialisation

The second screening step is to assess the availability and commercialisation status of the alternatives in the manufacture of Iopromide. For alternative synthetic routes, Table 9-12 summarises the solvents that have been referred to in the relevant patent documents. The market availability of these solvents is also considered.

Table 9-12: Summary of technical feasibility assessment for all identified alternatives Synthetic Solvents used in relevant patents route A DMF, DCM, ethyl acetate, tributyl amine B Methanol, acetone, dioxane, tributyl amine, acetic acid, DMA

C Acetic acid, methanol, toluene, DCM, petroleum ether, DMA, DMF (also addition of PCl5), tributyl amine D DMA, DCM, acetic acid, triethyl amine

This screening step includes the following considerations:

1. Availability of alternative solvents in the quantity required by Bayer Pharma AG. Table 9-13 looks at the availability of REACH Registrations for each substance. Grey colours indicate problematic areas. Bayer Pharma AG currently (2014) uses 100-1,000 ('#B#'''''') t/y EDC and would need an amount of alternative solvent in a tonnage of a similar order or magnitude.

2. Any alternative solvent should ideally be listed in the ICH Q3C(R5) guidelines in respect to the approved residual concentration limits. If it were not, the solvent would not be considered as immediately available as it would require new testing to establish residual levels and the associated hazards in order to achieve a Guideline listing status. This is also presented in Table 9-13.

3. Any alternative solvent or synthetic route should ideally have been proven at the industrial scale. No alternative meets this criterion. Bayer Pharma AG is the only company globally to produce the specific X-ray contrast medium, Iopromide; therefore, none of the alternatives have ever been placed into commercial use anywhere in the world.

Table 9-13 shows that only a sub-set of the listed alternatives is available on the market and listed in the ICH guidelines, none have been commercially proven. Solvents of poor market availability (tributylamine, dioxane, triethylamine) are involved in one of all four alternative Synthetic Routes.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 85 Table 9-13: Summary of market availability and commercialisation status of all identified alternatives Identified potential CAS Registration status as of 8 ICH Q3(R5) listing Conclusion on EC Number Known commercial use alternative solvents Number October 2014 (limit) availability Alternative solvents from applicant’s R&D Registered Available but Ethyl acetate 205-500-4 141-78-6 100,000 – 1,000,000 t/y Class 3 Not in synthesis of Iopromide commercially Named registrants: 41 unproven Registered Available but n-Propyl acetate 203-686-1 109-60-4 10,000 – 100,000 Class 3 Not in synthesis of Iopromide commercially Named registrants: 5 unproven Solvents/reagents required in alternative synthetic routes Registered Available but Dimethylformamide Class 2 200-679-5 68-12-2 10,000–100,000 t/y commercially (DMF) – Routes: A, C 880 ppm Named registrants: 12 unproven Dichloromethane Registered Available but Class 2 (DCM) – Routes, A, B, 200-838-9 75-09-2 100,000 – 1,000,000 t/y commercially 600 ppm C, D Named registrants: 11 unproven Available but Ethyl acetate – 205-500-4 141-78-6 See above See above commercially Routes: A unproven Relevant synthetic routes have Available but Registered never been used for the Tributylamine – commercially 203-058-7 102-82-9 1,000+ t/y - production of Iopromide due to Routes: A, C unproven and not Named registrants: 3 their low efficiency. In addition, listed by ICH Bayer Pharma AG’s competitors Registered Available but Class 2 do not have the same API Methanol – Routes: B 200-659-6 67-56-1 1,000,000 – 10,000,000 t/y commercially 3,000 ppm Named registrants: >100 unproven Registered Available but Acetone – Routes: B 200-662-2 67-64-1 1,000,000 – 10,000,000 t/y Class 3 commercially Named registrants: 42 unproven Poor market Registered Class 2 availability and Dioxane – Routes: B 204-661-8 123-91-1 100+ t/y 380 ppm commercially Named registrants: 3 unproven

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 86 Table 9-13: Summary of market availability and commercialisation status of all identified alternatives Identified potential CAS Registration status as of 8 ICH Q3(R5) listing Conclusion on EC Number Known commercial use alternative solvents Number October 2014 (limit) availability N,N- Registered Available but dimethylacetamide Class 2 204-826-4 127-19-5 10,000– 100,000 t/y commercially (DMA) – Routes: B, C, 1,090 ppm Named registrants: 13 unproven D Available but Toluene – Routes: C 203-625-9 108-88-3 See above See above commercially unproven Registered Available but Acetic acid – Routes: 200-580-7 64-19-7 1,000,000–10,000,000 t/y Class 3 commercially D Named registrants: >100 unproven Available but Registered Triethylamine – commercially 204-469-4 121-44-8 1,000+ t/y - Routes: D unproven and not Named registrants: 9 listed by ICH Source: Bayer Pharma AG’s data; http://echa.europa.eu/information-on-chemicals/registered-substances (accessed on 8 October 2014); (ICH, 2011)

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 87 9.3.3 Screening for hazard profile

The intrinsic hazard properties of the remaining substances were screened to identify those substances that have critical hazard properties (e.g. CMR properties), which would make them unsuitable alternatives. The following information was retrieved

 Registration status (which, as noted above, also gives a first indication of market availability)  EU Classification (CLP Regulation)  Any other relevant information on SVHC properties i.e. existing restrictions, evaluations of carcinogenicity by other organisations (e.g. IARC) and evidence for endocrine disrupting activity.

To this end, ECHA’s website was consulted and the respective substance searched by CAS Number. Registration status as well as the classification of substances was retrieved from this site. In addition, any information on other REACH-related activities (e.g. listing as SVHC, information on restrictions, authorisation) was followed-up and evaluated regarding its potential consequences for using the substance as an alternative to EDC.

Furthermore, eChemPortal was consulted to check any involvement in other regulatory programmes and existing evaluations (e.g. OECD SIDS reports, US HPVIS, EU Risk Assessment Reports).

Table 9-14 discusses the results for the alternative substances that have been subject to the screening exercise. The following preliminary conclusions may be reached:

 Two substances, dimethyl formamide (DMF) and dimethylacetamide (DMA), present equivalent concern to EDC and have been proposed for inclusion in Annex XIV. Therefore, they were excluded from further investigation. These solvents are relevant to all alternative synthetic routes (A and C for DMF and B, C and D for DMA)

 Two more substances are suspected CMRs, dichloromethane and dioxane (Carc Cat 2). These alternatives would require additional consideration, had they shown evidence of technical feasibility

 Finally, for n-propyl acetate (for which a REACH registration is available but the assessment is largely based on read-across), information is limited. Due to the lack of information, for this alternative it might prove difficult to conclude on whether its use would reduce overall risks in comparison to EDC.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 88 Table 9-14: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status Ethyl acetate 205-500-4 141-78-6 Full Flam. Liq. 2 H225 - No obvious CMR registration Eye Irrit. 2 H319 properties, eligible, 100,000– STOT SE 3 H336 sufficient data for 1,000,000 t/y assessment available n-Propyl 203-686-1 109-60-4 Full Flam. Liq. 2 H225 REACH Registration and C&L data review No obvious CMR acetate registration Eye Irrit. 2 H319 Assessment in registration mainly based on read- properties, but 10,000– STOT SE 3 H336 across limited information, 100,000 t/y OECD SIDS Conclusions assessment in Human health: n-Propyl acetate may present a registration mainly hazard for human health (skin and eye irritation and based on read-across potential reproductive/developmental toxicity at high doses). Environment: n-Propyl acetate may present a hazard for the environment (acute aquatic toxicity values between 1 and 100 mg/L). However, the chemical biodegrades rapidly and exhibits limited potential for bioaccumulation ICH Q3C(R5) Guidelines Class 3 (solvents with low toxic potential solvents which should be limited by GMP or other quality- based requirements) Dimethylform 200-679-5 68-12-2 Full Acute Tox. 4 * H312 REACH Annex XIV (Authorisation) Reprotoxic, amide (DMF) registration Eye Irrit. 2 H319 SVHC Proposal, Toxic to reproduction, Sweden, recommended for 10,000– Acute Tox. 4 * H332 27/08/2012 inclusion in Annex 100,000 t/y Repr. 1B H360D *** Candidate List, 19/12/2012 XIV, not eligible to 5th Recommendation for Prioritisation, 06/02/2014, substitute EDC Proposed latest application date: August 2016 PACT-RMOA Substance List RMOA intention, Italy, 17/01/2014, under development Registry of Intentions Restriction, Italy, 17/01/2014. Placing on the market

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 89 Table 9-14: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status of articles containing DMF in concentration exceeding the level specified in the restriction. PROCs and professional uses (i.e. mixtures of DMF as strippers, paints etc.) where a risk scenario is identified IARC Classification 3 (Not classifiable as to its carcinogenicity to humans), Vol 47, 71 1999 ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 880 ppm Dichlorometh 200-838-9 75-09-2 Fully Carc.2 H351 REACHAnnexXVII(Restrictions) Suspected ane (DCM) registered Paint strippers containing DCM in a carcinogenic 100,000 - concentration equal to or greater than 0,1 % by substance (currently 1,000,000 t/y weight shall not be placed on the market for under review), supply to the general public or to professionals eligible only if there CoRAP List are other strong Italy, Carcinogen/suspected Mutagen/suspected arguments in favour Reprotoxic/suspected sensitiser, high (aggregated) of the substance (e.g. tonnage, new entry technical feasibility) IARC Classification 2A (Probably carcinogenic to humans), Vol 71, 110 In prep ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 600 ppm Tributylamine 203-058-7 102-82-9 Registered Acute Tox. 4 H302 - No obvious CMR 1,000+ t/y Acute Tox. 2 H310 properties, eligible, Skin Irrit. 2 H315 sufficient data for Acute Tox. 1 H330 assessment available Methanol 200-659-6 67-56-1 Fully Flam. Liq. 2 H225 PACT-RMOA Substance List No obvious CMR registered Acute Tox. 3 * H301 RMOA Intention, CMR, Denmark, 10/12/2013, under properties, eligible, 1,000,000 - Acute Tox. 3 * H311 development sufficient data for 10,000,000 t/y Acute Tox. 3 * H331 Restriction proposal assessment available STOT SE 1 H370 ** Poland, 01/08/2014, windshield washer fluids

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 90 Table 9-14: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status CoRAP List Poland, 2012, Human health/suspected CMR; exposure/high exposure for workers and the environment, wide dispersive use, consumer use, on-going OECD SIDS Conclusions Human Health: Methanol exhibits potential hazardous properties for human health (neurological effects, CNS depression, ocular effects, reproductive and developmental effects, and other organ toxicity). Rapid metabolism and excretion is noted depending on the dose. In the US (the Integrated Risk Information System), further work is being performed regarding the use and refinement of pharmacokinetic models for extrapolating animal data to humans. Environment: The chemical is currently of low priority for further work, due to its low hazard profile ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 3,000 ppm Acetone 200-662-2 67-64-1 Fully Flam. Liq. 2 H225 ICH Q3C(R5) Guidelines No obvious CMR registered Eye Irrit. 2 H319 Class 3 (solvents with low toxic potential solvents properties, eligible, 1,000,000 - STOT SE 3 H336 which should be limited by GMP or other quality- sufficient data for 10,000,000 t/y based requirements) assessment available Dioxane 204-661-8 123-91-1 Full Flam. Liq. 2 H225 Regulated under ESR Suspected registration Eye Irrit. 2 H319 Commission Recommendation 2002/575/EC carcinogenic 100+ t/y STOT SE 3 H335 Workers: there is a need for specific measures to substance, eligible Carc. 2 H351 limit the risks because of concerns for (a) defatting only if there are other with subsequent adverse skin effects as a strong arguments in consequence of exposure arising from production, favour of the formulation and use of the substance or the product substance (e.g.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 91 Table 9-14: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status containing the substance, (b) general systemic technical feasibility) toxicity and carcinogenicity as a consequence of dermal exposure arising from the use of the substance in cleaning agents, and (c) general systemic toxicity and carcinogenicity as a consequence of inhalation exposure arising from formulation of the substance Strategy proposed: develop at Community level occupational exposure limit values for the substance IARC Classification 2B (Possibly carcinogenic to humans), Vol. 11, Sup 7, 71 1999 ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 380 ppm N,N- 204-826-4 127-19-5 Fully Acute Tox. 4 * H312 REACH Annex XIV (Authorisation) Reprotoxic, not dimethylaceta registered Acute Tox. 4 * H332 SVHC Proposal, Toxic to reproduction, ECHA, eligible to substitute mide (DMA) 10,000– Repr. 1B H360D *** 29/08/2011 EDC 100,000 t/y Candidate List, 19/12/2011 4th Recommendation for Prioritisation, 17/01/2013, Proposed latest application date: November 2015 ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 1,090 ppm Acetic acid 200-580-7 64-19-7 Fully Flam. Liq. 3 H226 ICH Q3C(R5) Guidelines No obvious CMR registered Skin Corr. 1A H314 Class 3 (solvents with low toxic potential solvents properties, eligible, 1,000,000– which should be limited by GMP or other quality- sufficient data for 10,000,000 t/y based requirements) assessment available Triethylamine 204-469-4 121-44-8 Registered Flam. Liq. 2 H225 OECD SIDS Conclusions No obvious CMR 1,000+ t/y Acute Tox. 4 * H302 Human health: The tertiary amines category properties, eligible, Acute Tox. 4 * H312 members possess properties indicating a hazard for sufficient data for Skin Corr. 1A H314 human health; based on read-across, TEA and DMEA assessment available Acute Tox. 4 * H332 may also cause similar developmental effects by the oral route. Environment: The tertiary amines category

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 92 Table 9-14: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status members possess properties indicating a hazard for the environment (acute aquatic toxicity values between 1 and 100 mg/L). The category members are readily biodegradable and are not expected to bioaccumulate Sources: ECHA Registered Substances database (http://echa.europa.eu/information-on-chemicals/registered-substances, accessed on 22 October 2014) ECHA Classification and Labelling Inventory (http:// http://echa.europa.eu/information-on-chemicals/cl-inventory-database, accessed on 22 October 2014) IACR Cancer Classifications (http://monographs.iarc.fr/ENG/Classification/, accessed on 22 October 2014) ICH Q3C(R5) Guidelines (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf, accessed on 15 December 2015) * Bold letters indicate harmonised classification under the CLP Regulation, normal letters indicate notified classification (joint entry from registration); italics indicate most commonly notified classification only

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 93 9.3.4 Summary of screening process

Finally, Table 9-15 summarises the findings of each step in the screening process and concludes on the overall level of feasibility of each of the shortlisted alternatives as substitutes for EDC and/or the EDC-based synthetic route that Bayer Pharma AG is currently using.

Table 9-15: Conclusion of screening of identified potential alternatives Identified Availability and Conclusion of potential Technical feasibility commercialisation Hazard profile screening alternative status process Alternative solvents from applicant’s R&D No obvious CMR Technically Infeasible Available but properties, eligible, unacceptable; Ethyl acetate Poor quality, poor yield, commercially sufficient data for not a realistic cannot be recycled unproven assessment option Infeasible Technically Conversion and unacceptable; No obvious CMR adhesion issues hazard profile Available but properties, limited resolved at high could be n-Propyl acetate commercially information, assessment in temperature but yield is difficult to unproven registration mainly based poor and product is of establish in full; on read-across low quality (new not a realistic impurity and yellowish) option Solvents required in alternative synthetic routes DMF: Reprotoxic, recommended for inclusion Technically Infeasible Solvents available in Annex XIV unacceptable Synthetic Route Low yield, recycling but synthetic route DCM: Suspected and dependent A problems, separation of is commercially carcinogenic substance on hazardous impurities unproven (currently under review) solvents; Not eligible to substitute not an option EDC DMA: Reprotoxic Dioxane: Suspected Technically Infeasible Solvents available carcinogenic substance unacceptable Low yield and quality Synthetic Route but synthetic route DCM: Suspected and dependent due to steric hindrance, B is commercially carcinogenic substance on hazardous late iodisation and unproven (currently under review) solvents; secondary reactions Not eligible to substitute not an option EDC DMF: Reprotoxic, recommended for inclusion in Annex XIV Technically Solvents available DCM: Suspected unacceptable Infeasible Synthetic Route but synthetic route carcinogenic substance and dependent Low yield, recycling C is commercially (currently under review) on hazardous problems unproven Toluene: Suspected solvents; reprotoxic substance not an option Not eligible to substitute EDC Infeasible DMA: Reprotoxic Technically (better than Synth. Solvents available DCM: Suspected unacceptable Synthetic Route Route A) but synthetic route carcinogenic substance and dependent D Low yield, I-containing is commercially (currently under review) on hazardous waste losses, recycling unproven Not eligible to substitute solvents; problems EDC not an option

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 94 10 Annex 3: Justifications for confidentiality claims

This Annex is available in the complete version of the Analysis of Alternatives.

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 95 Table 10-1: Justifications for confidentiality claims

Reference type Commercial Interest Potential Harm Limitation to Validity of Claim

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft 96