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 thehigh-grade pure final intermediate of Iopromide, theActive Pharmaceutical Ingredient for the X-ray contrastmedium Ultravist®

Use number: 1

Copyright

©2016 Bayer Pharma Aktiengesellschaft. This document is the copyright of Bayer Pharma Aktiengesellschaft and is not to

be reproduced or copied without its prior authority or permission.

Disclaimer

This report has been prepared by Risk & Policy Analysts Ltd, with reasonable skill, care and diligenceunder 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 ofany matters outside the scope of the contract. This report has been prepared for the client and weaccept 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 indicatedwithin each piece of redacted text correspond to the type of justification for confidentiality claimswhich 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

Use number: 1 Legal name of applicant(s): Bayer Pharma Aktiengesellschaft1

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 manufactureof Iopromide, the active pharmaceutical ingredient (API) in Ultravist®(a non-ionic, water-soluble iodine-based X-ray contrast medium for intravascular administration), primarilybecause of its unique dissolution profile. This dissolution profile ensures a high productionyield and quality of the final products (essentially, the absence of colouration andavoidance of adhesion).

2. Since 1990, Bayer Pharma AG has undertaken very extensive research towards theidentification of a suitable substitute solvent or a feasible alternative synthetic route.More recently, during the preparation of this Application for Authorisation, Bayer PharmaAG undertook additional extensive laboratory tests on a range of potential alternativesolvents.

3. The past and recent R&D, which has looked into a wide range of solvent families, hasconfirmed that all alternatives considered are technically worse than EDC and result inpoor yields and product quality, which greatly affects the economics of the manufacturingprocess. In addition, alternative synthetic routes may use solvents that have hazardprofiles 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 orestablish a completely new plant, and variations to a large number of MarketingAuthorisations currently held for Ultravist® across more than 100 ('#C#''''') countries.Bayer Pharma AG estimates that substitution of EDC by an alternative solvent wouldrequire a minimum of 11.5 years.

5. The costs of converting to any given alternative can provisionally be estimated to rise totens of millions of Euros. Variations to Marketing Authorisations would be particularlytime-consuming, as Ultravist® is an established, mature and popular product and wouldrequire applications for variation to the hundreds of national level MarketingAuthorisations it currently holds.

6. All iodine-based X-ray contrast media have the same principle of action and, as such, froma therapeutic perspective, they may be considered interchangeable. Price and marketingare decisive for market success. Therefore, if the use of an alternative would result inincreased production costs, Ultravist® would become less competitive and its globalmarket share would be eroded.

7. Bayer Pharma AG is planning to continue its search for a technically feasible alternativeand will also focus on further optimising the use of EDC, so that EDC losses and workerexposure to the substance continue to decline.


1.1 Applied for use

The applicant, Bayer Pharma Aktiengesellschaft (hereafter referred to as Bayer Pharma AG), uses1,2-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, themaximum 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 tobe 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 sincecommercial manufacture of Iopromide began in 1986. EDC use cannot be eliminated without beingsubstituted by an alternative solvent, when using the existing synthetic route for the API. BayerPharma AG have made several attempts to substitute the solvent, which has been a ‘prioritysubstance’ due to its carcinogenicity for a number of years. The research was initiated by ScheringAG, a research-centred German pharmaceutical company, which was merged to form the Bayersubsidiary Bayer Schering Pharma AG in 2006. The company was renamed Bayer Pharma AG in2011. Research into alternatives for EDC in the manufacture of Iopromide also became property ofBayer Pharma AG.

Since 1990, Bayer Pharma AG has made efforts to identify alternatives to EDC within a wide range ofdifferent 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 theunsuccessful 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 ofthis AoA, Bayer Pharma AG undertook further laboratory tests on additional alternative solvents toevaluate their potential for substituting EDC.

Beyond alternative substances, Bayer Pharma AG is familiar with four alternative synthetic routes tothe API, as presented in three different patents, one of which is held by Bayer Pharma AG (originallyfiled by Schering AG). The identified alternative synthetic routes are not compatible with theexisting manufacturing plant, they are much more cost intensive (as they result in low yields andthroughputs) 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 successfullyimplemented within the current synthetic route.


1.3 Assessment of suitability and availability of alternatives forthe use applied for

Several solvent families that were considered during Bayer Pharma AG’s R&D work can be screenedout without the need for extensive laboratory testing: Table 4-1 explains that solvent families suchas alcohols, carboxylic acids, ketones, dipolar aprotic solvents, amines and nitro-compounds wouldnot be sufficiently stable or inert under the reaction conditions of the currently used synthetic routeand thus are technically infeasible. On the other hand, solvent families that could offeropportunities for substituting EDC include nitriles, hydrocarbons, halogenated hydrocarbons, estersand ethers.

Within these solvent families that offer a minimum guarantee of process stability, severalrepresentative solvents were assessed during Bayer Pharma AG’s R&D work. The following fivetechnical feasibility criteria have been used: (a) inertness to key reagents in the manufacturingprocess, (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 relevantstages in the API manufacturing process, as the conversion rate is typically unacceptably poorand 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/orhigher 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 thequality required by Bayer Pharma AG and which is stipulated in the hundreds ('#C#'''''') ofMarketing Authorisations held for Ultravist®. Even for alternative substances which coulddeliver (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 achievedwith EDC. A lower yield results in lower quantities of the API produced and therefore lower salesof 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 oftechnical performance characteristics as EDC.

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

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


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 theirtechnical feasibility. The shortcomings of the alternative substances largely relate to theirphysicochemical properties (dissolution parameters affecting reaction rates and yield, boiling pointaffecting recyclability, etc.) and these cannot be improved. Only additional research into newalternatives or combinations of alternatives could reveal a more feasible option. However, there isno guarantee given the unsuccessful attempts of the distant and more recent past that a positiveresult will materialise.

This AoA presents a hypothetical plan for the replacement of EDC by an alternative solvent. This isonly theoretical and assumes that a feasible candidate could indeed be identified within areasonable timeframe. The plan includes 6 steps, of which the single most time-consuming wouldbe the variations to the Marketing Authorisations currently held for Ultravist®. Bayer Pharma AGestimates that a minimum of 11.5 years would be required before any yet unknown alternativecould be implemented. Such a plant would certainly involve securing a significant volume ofIopromide stockpiles. Furthermore, any feasible candidate which is not listed under the ICH Q3CGuidelines on residual solvents should ideally first be listed therein (as a Class 3 or (at least) 2solvent) before being used on an industrial scale.

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

1. Research and development to identify a feasible candidate solvent and to adapt the currentsynthetic 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 morethan 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, andthe manpower needed for undertaking laboratory and desk-based research), the costs of convertingto 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 theback of relatively low production costs. It faces strong competition from other similar medicinalproducts. 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 salesof Ultravist®. This inability of identifying an alternative that is technically feasible and economicallyviable supports Bayer Pharma AG’s request for the Authorisation of the continued use of EDC.


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, forintravascular administration (injection). The EDC solvent is used during the production, purificationand 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 oftonnes 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 thefinal intermediate, TIP-diamide chloride, the direct precursor of the Iopromide product (see Table2-1, step 6). TIP-diamide chloride is the first intermediate stage in which impurities are separatedeffectively by crystallisation (with impurities remaining mainly in the mother liquor), after threeintermediate stages in which no significant reduction of impurities by crystallisation occurs (notisolated or isolated with no significant purifying effect at these stages). The purity of the finalintermediate, 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 ispresent 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#''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''''

'''''''''''''''''''''' Startingmaterial forAPI

2 ''''''''''''''''''''''''''''' ''''''''' ''''''''''''''''''''''''''' '''''''''''''''''''''''''''''''''''''

''''''''''''''''''''''''''''

1st

intermediateReaction with ''''''''''''''''''''''''''''''''''''''''''''

3 ''''''''''''''''''''''''''''''''' '''''''''''''''''''''''''''''''' '''''''''''''''''''''''''''''''''''''''''

''''''''''' 2nd

intermediate(not isolated)

Reaction with hydrogen/catalyst

4 '''''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''''''''''''''''''

'''''''''''' 3rd

intermediateReaction with iodine monochloride

5 '''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''''' '''''' '''''''''''''''''''''''''''''''''' '''''''''''''''''''

TAMIP-diacetate

4th

intermediateReaction with '''''''''''''''''' '''''''''''''''''''''


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-diamide)

TIP-diamidechloride (viaTIP-diamide)

5th

intermediate1

ststep: reaction with '''''''''''''''''''''''''

'''''''' '''''''''''''2

ndstep: reaction with thionyl

chloride

7 Iopromide '''''''' ''''''''''''''''''''''''''''''''''''''

Iopromide''''''''''''''''''''''''''''''''''''''''''''''

API 1st

step: reaction with ''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''2

ndstep: reaction with sodium

hydroxide3

rdstep: desalting

4th

step: treatment with activecarbon5

thstep: crystallisation from ethanol

In the presence of EDC, TIP-diamide chloride is produced in a two-stage synthesis, in which theproduct of the first synthesis stage, TIP-diamide, is not isolated. The two-stage process is shown inFigure 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 forIopromide

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, asotherwise unreacted starting material could proceed onto the next stage and could thuslead to the occurrence of unwanted by-products. In the formation of this first intermediateproduct, substantial quantities of hydrogen chloride are released.

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


4. On completion of the reaction, the precipitated crystalline TIP-diamide chloride product isisolated from the mother liquor. The product crystals are then freed from by-productcontaining mother liquor by washing with EDC. The dried TIP-diamide chloride will then bepoured into containers and will proceed to the final synthetic manufacturing stages, toproduce 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. Ofparticular 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 mediumpolarity, which is stable under strongly acidic conditions, and has sufficiently good dissolutionproperties at the TIP-diamide stage (see Table 2-1), for both the starting compound and forimpurities. The last point is of particular significance, because solvents with poor dissolutionproperties cause the reactant particles to melt on the surface at the required reactiontemperatures 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 isevidently caused by impurities in TAMIP-diacetate, which cannot be prevented practicallywithout 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 thionylchloride (SOCl2) excess is adopted, the solvent required for this stage has to withstand theaggressive conditions of several hours of heating with thionyl chloride (also in the presence ofhydrogen chloride and sulphur oxide) and also be capable of absorbing the coloured impuritiesthat 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 othermedicinal 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) areabout 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 comparedto EDC against a set of relevant technical feasibility criteria. The five relevant criteria are shownTable 2-2 and are discussed overleaf.


Table 2-2: Technical feasibility criteria for alternatives

# Technical feasibility criterion

Key principles

Criterion has an influenceon…Q

ual

ity

of

AP

I

Co

sto

fA

PI

Co

mp

atib

ility

wit

h

exi

stin

gp

roce

ss/

eq

uip

me

nt

1 Inertness to thionyl chloride and HCl

2 Boiling point

3Dissolutioncapacityfor…

…the intermediate substance Reaction completeness;conversion (%), adhesion

…the reaction gases, SO2 and HCl Reaction completeness;conversion (%)

…the final intermediate substance Yield (%)

…other substances Adhesion, colouring

4Yield of Iopromide synthesis and processsynchronisation

5 Recyclability

2.2.2 Technical feasibility criterion 1: Inertness to thionyl chloride andhydrogen chloride

Importance of the criterion

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

Technical requirements of the applicant’s process

No measurable decomposition of the solvent is acceptable.

2.2.3 Technical feasibility criterion 2: Boiling point


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 refluxcondenser during the reaction, without significant loss of solvent. This allows the gases that haveformed to escape and facilitates the condensing of solvent vapours. Low boiling point solvents havehigher vapour pressure at the condenser temperature; consequently, a larger amount is dischargedwith the reaction gases. The temperature of the reflux condenser cannot be lower becauseotherwise sulphur dioxide (having a boiling point: -10 °C) would condense together with EDC andcould not be removed.


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


2.2.4 Technical feasibility criterion 3: Dissolution parameters affecting finalproduct purity


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 productadhesion, is a result of the dissolution capabilities of the solvent vis-à-vis the presence of differentreagents in the reaction vessel. Table 2-3 summarises the areas where the dissolution of EDC isappropriately high or low depending on the separation and purification needs of the process.

Table 2-3: Dissolution profile for potential alternative solvents

Agent to bedissolved

Desireddissolutionability

Importance of dissolution profile

Intermediatesubstance

Highdissolution

The solvent must have a good dissolution capacity for the starting intermediateproduct, TAMIP-diacetate, and the intermediate product TIP-diamide. This willensure high purity of the final intermediate (TIP-diamide chloride) and will helpavoid product adhesion and incomplete conversion to the final intermediate(adhesion is caused/favoured by impurities contained in TAMIP-diacetate)

Reactiongases SO2 andHCl

Lowdissolution

The solvent must have poor dissolution capacity for SO2 and HCl, as thesesubstances must be removed from the reaction equilibrium

Finalintermediate

Lowdissolution

The solvent must show poor dissolution of the final intermediate to ensure ahigh yield of its production, as this product must be separated from thereaction mixture

Sufficientdissolution

At the same time, the solvent must display sufficient dissolution of the finalintermediate product (TIP-diamide chloride) in order to prevent its earlyprecipitation. The time of spontaneous crystallisation of the product during thereaction phase defines the product quality: premature crystallisation leads toTIP-diamide contamination and thus worsened TIP-diamide chloride productquality

Accompanyingsubstances(impurities)

Highdissolution

The solvent must have good solubility for the accompanying relatedsubstances; in particular, colouring impurities must be separated. This willfurther enhance the purity of the final intermediate


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

2.2.5 Technical feasibility criterion 4: Yield of Iopromide synthesis andprocess synchronisation


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


Yield is highly dependent on maintaining high process synchronisation. As of 2016, Iopromide hasbeen 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. Theoverall synthesis consists of a sequence of seven stages, all of which run in parallel withoutinterruption, apart from for maintenance stoppages. Skilful material-flow management ensures thatintermediate products are used in the subsequent stage without delay, and no unnecessary, costlytransport 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, anddimensioned accordingly to allow for synchronised synthesis. The following parameters are decisivefor 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 preciselyto the current synthesis, and all stages of synthesis are coordinated in terms of organisation, spaceand timing. If even one of the intermediate stages was replaced by another less efficient one, thenthe production capacity of the entire plant would decrease accordingly, as corresponding idle timeswould arise in the other stages of synthesis (i.e. a bottleneck would occur) and production yieldwould drop.


From 'All #A#'''''' tonnes of ''''''''''''''''''''''' '''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''' ''''' '''''''''''''''' ''''''''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''' '''''''''' ''''''''''''' the starting material for Iopromide, Bayer Pharma AG cansynthesise a maximum of ''''''''''' tonnes of Iopromide (M.W. 790.9). If it is assumed that there are nolosses through the formation of by-products and isolation, the theoretical yield of Iopromidesynthesis 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-diamidechloride ''''''''''''' ''''''''''''' is '''''''' '''' ''''''''''''''''''''' '''' ''''''''''' '''''' '''''''''' '''''''''''''. This means that from ''''''' gof 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 yieldcomparable to that achieved by EDC. Moreover, any alternative substance or, particularly, analternative synthetic route, must be compatible with the production plant set-up to minimiseprocess disruption, yield/capacity losses and, consequently, increased production costs.

2.2.6 Technical feasibility criterion 5: Recyclability


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


non-volatile components can be separated in a subsequent distillation stage. Its low solubility inwater and good stability under slightly alkaline conditions, which, as noted above, is necessary forremoving acidic components, makes EDC an easily recyclable solvent. This both reduces costs andsupports the sustainability of the manufacturing process.


In 2014, Bayer Pharma AG’s distillation plant supplied the manufacturing plant with '#B#''''''''' tonnesof EDC (recycled + virgin) of which 100-1,000 ('#B#'''''') tonnes were virgin (i.e. solvent purchased toreplenish losses) suggesting a recycling rate of 93%. The current recycling rate cannot strictly beused as a threshold of acceptability; a reduction in recycling rate might be possible to tolerate butthis would depend on the cost of the alternative solvent and its ability to act as an otherwisetechnically 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 thesubstance

Solvent for the separaration and purification of intermediate products in thesynthesis of Iopromide, which dissolves the starting material and impurities butnot the product, while being resistant to prevailing reaction conditions

Physical form of theproduct

EDC: liquid; used as ≥99.5% purity Iopromide: liquid

Concentration of thesubstance in the product

EDC should not be present in the final product, Iopromide. As per exisinglegislation (ICH Q3C Guidelines), the maximum residual solvent in the API is 5ppm (ICH, 2011)

Performancerequirements

Explanation

No reaction with SOCl2 +HCl

Inert against very reactive substances like hydrogen chloride and thionyl chloride

Boiling point (84 °C) The boiling point must sufficiently high so that separation of the reaction gases inthe reflux condenser is possible during the reaction with no significant loss ofsolvent

Sufficient solubility withstarting intermediateTAMIP-diacetate

This will help avoid product adhesion and incomplete conversion to the finalintermediate (adhesion is caused/favoured by impurities contained in TAMIP-diacetate)

Good solubility with notisolated intermediateTIP-diamide

It must have a good dissolution capacity for the not isolated intermediateproduct, TIP-diamide

No solubility withhydrogen chloride andsulphur dioxide

Poor dissolution capacity for hydrogen chloride and sulphur dioxide, as thesesubstances must be removed from the reaction equilibrium

No solubility with thetarget intermediate TIP-diamide chloride

Poor dissolution capacity for TIP-diamide chloride, as this product must beseparated from the reaction mixture. However, the dissolution capacity for TIP-diamide chloride must not be too low, as this product must not spontaneouslycrystallise prematurely (otherwise it leads to the inclusion of the non-isolatedintermediate product, TIP-diamide)

Good solubility with by-products

The solvent must have good solubility for the accompanying related substances.In particular colouring* impurities must be separated


Table 2-4: Parameters for EDC use

Good recycling rate The solvent must be readily recyclable, as the annual requirement for solventthroughput is in the range of several thousand tonnes. At a first step all acidiccomponents have to be completely eliminated (by stirring with NaOH) and at asecond step all non-volatile components have to be separated (in a subsequentdistillation stage)

Other requirements Explanation

Industry sector and legalrequirements fortechnical acceptabilitythat must be met

Medicinal Products Directive: The use of EDC in the manufacture of an API fallswithin the scope of Regulation (EC) No 726/2004 and Directive 2001/83/EC,relating to medicinal products for human use.Residual Solvents: EMA (European Medicines Agency) guidance on residualsolvents (EMA/CHMP/ICH/82260/2006) contains a specific concentration limit forEDC (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 thelevel 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 theAmerican Public Health Association and defined by ASTM D1209. It is a colour scale sometimes referred to asa “yellowness index” that is used to assess the quality of liquids that are clear to yellowish in colour


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 ofIopromide, 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 ofIopromide manufactured (and used) are assumed to remain stable. This also means thatconsumption of virgin EDC will remain stable at a maximum of 100-1,000 '#B#'''''''''' t/y and thetonnage of Ultravist® manufactured (and sold) will stabilise at '#A#'''''''''' t/y (these figures arediscussed in more detail in Section 2 of the accompanying SEA document).



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 sincecommercial manufacture began in 1986. Bayer Pharma AG has made several attempts to substitutethe 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 ofsolvent families have been considered in an effort to widen the scope of the research as far aspossible. Solvents within some of these families could be readily excluded from detailedconsideration as they would not remain sufficiently stable or inert under the Iopromidesynthesis reaction conditions due to their fundamental chemical properties. Others, whichwould theoretically be chemically stable were considered in more detail and subjected toextensive laboratory testing as appropriate.

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

R&D on possible alternative synthetic routes: apart from alternative solvents, Bayer PharmaAG also considered alternative synthetic routes that might be possible to lead to the formationof 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 ofIopromide by a different X-ray contrast medium. It is acknowledged that all X-ray contrastmedia containing iodine have the same principle of action: they spread through the bloodstreamand 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 PharmaAG has its own, established, significant, market share '#C#'''''' '''''''''''''''''' ''''''' '''''''' '''' ''''''''''''''.Bayer Pharma AG has invested more than 20 years of production improvements to achieve anoptimally synchronised process, generating a product of the highest quality and lowest possiblecost for the specific molecule. The abandonment of Iopromide and the start of production of anew X-ray contrast agent would be entirely unrealistic, particularly given that alternative X-raycontrast media available from competitors are already established in the market.

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


Table 4-1: Solvent families considered by Bayer Pharma AG as potential alternatives for EDC

Solventfamily

Feasibilityunderreactionconditions

Rationale for family feasibility assessment (e.g. undesirablereactions and stability concerns)

Example members of each family that have been considered

# Name ECNumber

CASNumber

Alcohols Infeasible Formation of chloroalkanes and sulphurous acid esters withthionyl chloride

1 Methanol 200-659-6 67-56-1

2 Ethanol 200-578-6 64-17-5

3 Butanol 200-751-6 71-36-3

Carboxylicacids

Infeasible Formation of acid chlorides; solvent contains the same functionalgroup as starting material so the thionyl chloride would simplyreact with the solvent rather than the starting material

4 Acetic acid 200-580-7 64-19-7

Ketones Infeasible Being aprotic solvents, they are feasible for the reaction conditionsof the 2

ndsynthetic stage. 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 alsooccurs with MIBK, which is sterically more demanding thanacetone or MEK, making all of these solvents infeasible

5 Acetone 200-662-2 67-64-1

6 Methyl ethyl ketone (MEK) 201-159-0 78-93-3

7 Methyl isobutyl ketone (MIBK) 203-550-1 108-10-1

Nitriles In principle,feasible

In principle feasible for the 1st

synthetic stage (but acetonitrilereacts considerably with thionyl chloride / hydrogen chloride)

8 Acetonitrile 200-835-2 75-05-8

Dipolaraproticsolvents

Infeasible Many common polar aprotic solvents react with thionyl chloride.Dimethylsulphoxide (DMSO) reacts with thionyl chloride. DMFalso reacts forming the strongly carcinogenic dimethyl carbamoylchloride. Many dipolar aprotic solvents are miscible with water(all of the solvents trialled by Bayer Pharma AG) making therecovery of products very complex

9 Dimethylformamide (DMF) 200-679-5 68-12-2

10 Hexamethylphosphoramide(HMPTA)

211-653-8 680-31-9

11 N,N-dimethylacetamide (DMA) 204-826-4 127-19-5

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



Solventfamily




# Name ECNumber

CASNumber

Nitrocompounds

Infeasible Serious process hazards: shock and heat sensitive explosiveproperties, e.g. nitromethane (Sax, 1979). Nitrobenzene is theonly other nitro compound that is readily available. However, ithas a Repr. Cat 1B classification and has a high boiling point (210°C) making it an infeasible and unsuitable solvent

14 Nitromethane 200-876-6 75-52-5

15 Nitrobenzene 202-716-0 98-95-3

Hydrocarbons In principle,feasible

In principle feasible. Alkylated aromatics (e.g. toluene) andalkanes, being aprotic solvents, are conditionally feasible for thereaction conditions of the 1

stsynthetic stage (acylation) and

formation of acid chloride in the 2nd

stage

16 Heptane 205-563-8 142-82-5

17 Toluene 203-625-9 108-88-3

18 Cyclohexane 203-806-2 110-82-7

Halogenatedhydrocarbons

In principle,feasible

The solvent family EDC belongs to 19 Dichloromethane 200-838-9 75-09-2

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,feasible

In principle feasible, however esters will hydrolyse in stronglyacidic or basic aqueous conditions, such as those encounteredduring solvent recovery, making them sub-optimal solvents for thesecond step

27 Ethyl acetate 205-500-4 141-78-6

28 Butyl acetate 204-658-1 123-86-4

29 2-ethoxyethyl acetate 203-839-2 111-15-9

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



Solventfamily




# Name ECNumber

CASNumber

Ethers In principle,feasible

Cyclic ethers (e.g. THF) are in principle feasible, but are liable todecompose (forming chloro alcohols with hydrogen chloride).Aliphatic ethers, being quite non-polar solvents, are feasible forthe reaction conditions of both synthetic stages

35 Diethyl ether 200-467-2 60-29-7

36 Di-n-butyl ether 205-575-3 142-96-1

37 Diisopropyl ether 203-560-6 108-20-3

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-Amyl methyl ether (TAME))

213-611-4 994-05-8

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 basesin a broad sense have the general formula R

1R

2C=NR

3, where R is an organic side chain


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 2phases:

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

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

R&D work before 2014

The first phase started in 1990, it was very extensive and the results have been documented ininternal 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 selectedrepresentative solvents from each family to assess. The solvent families considered included thoseshown in Table 4-1.

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

Step 1 – Stability of solvent families under reaction conditions: this step looked into thestability of solvents under the aggressive (acidic) conditions of the reactions that lead fromTAMIP-diacetate to TIP-diamide chloride. Several solvent families were consequently screenedout as their members would react under the reaction conditions. These included alcohols,carboxylic acids, ketones, dipolar aprotic solvents, amines, nitro compounds (which also posehazards), 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 retainedsolvent 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 Section2.2. 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 withoutany actual lab testing; dioxane and tert-amyl methyl ether decompose under the reactionconditions). Others required detailed testing, particularly in relation to conversioncompleteness, adhesion, product quality/colour, yield and recyclability. The full results are givenin Table 9-4 of Annex 2. Among all solvents considered, two appeared to be the mostpromising: toluene and ethyl acetate. Both performed better than the other solvents but alsofaced important drawbacks:

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


Ethyl acetate: ethyl acetate is the solvent that has been assessed in the most detail andhas been looked at by Bayer Pharma AG’s researchers for almost 10 years starting in1986. Its yield might be considered acceptable and it can deliver the partial reactionswithout product adhesion. However, ethyl acetate faces important technicalshortcomings: (a) it results in impurities in TIP-diamide chloride and consequently inimpurities, such as dimeric ester or an unknown impurity of the same RT (Retentiontime) in HPLC, in the Iopromide made from this TIP-diamide chloride, (b) it faces issueswith product coloration, and (c) it faces recyclability problems.

Step 3 – Substitution of EDC by a mixture of solvents: Bayer Pharma AG also examined whethercombinations 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-diamidechloride formation) be carried out in their own optimally feasible solvent. To this effect, a dualsolvent system, ethyl acetate/toluene, was tested. The tests showed that although productquality might be acceptable, the process became unduly complex and the yield was much poorercompared 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 prepareTIP-diamide chloride separately. The only solvent considered in principle compatible with thetechnical requirements of such an approach was 2-ethoxyethyl acetate. However, testingshowed that this solvent faced problems with impurities, colour development and poseddifficulties 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 orcombination of solvents.

R&D work since 2014

The second phase of R&D was undertaken during the preparation of this Application forAuthorisation and involved both desk-based analysis and laboratory testing on twelve additionalsolvents belonging to the halogenated hydrocarbon, ester and ether families, which are consideredthe 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 ofAnnex 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 testingwas undertaken in two batches:

First test batch: the twelve potential alternative solvents were subjected to scaled-downlaboratory experiments to establish whether product formation and isolation would be possiblein the two-step chemical reaction leading to the synthesis of TIP-diamide chloride withoutisolation of the first intermediate (TIP-diamide). Seven out of the twelve alternative solventsfailed as the reaction mixture hardened or became sticky under the reaction conditions of Step1. In the remaining five alternative solvents, the reaction mixture could be stirred under thereaction conditions of Step 1, but no clear solution was formed. For these five solvents, theconversion rate in Step 2 was found to be poor (10–20% formed product) but improved stirringand temperature conditions could perhaps deliver some improvement. The results of this firsttest batch are shown in Table 9-7 of Annex 2


Second test batch: the second batch tried to take a step-wise approach to investigating thecompleteness of the first reaction, then the role of temperature in the second reaction, then thequality/colour of the product, and finally the yield of the reaction in order to establish whetherany solvent could perform satisfactorily on the industrial scale. The testing conditions are shownin Section 9.1.2 and the test results are summarised in Table 9-8 of Annex 2. All alternativesolvents 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 atStep 2 (ethyl acetate and isopropyl acetate) or poor product quality and yield (diethyl carbonateand 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 alternativesynthetic routes to Iopromide that would allow the elimination of the use of EDC. The relevantsynthetic 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-centredGerman pharmaceutical company, which was merged to form the Bayer subsidiary Bayer ScheringPharma AG in 2006. The company was renamed Bayer Pharma AG in 2011. Consequently, researchinto alternatives was also obtained during acquisition and can be considered part of the R&D thatBayer 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 /holder

Reference Title Synthetic route

US 4364921 ASchering AG

(Speck, et al., 1982)Novel triiodinated isophthalic aciddiamides as non-ionic X-ray contrastmedia

Synthetic Route AExample 6 in

Schering AG patentKR20000061780Dong Kook Pharm CoLtd

(Gyu, et al., 2000) Process for producing Iopromide



Synthetic Route BExample 7 in patent



Synthetic Route CExample 8 in patent

WO 2009134030 A1LG Life Sciences Ltd

(Hwang, et al.,2009)

Novel process for preparation ofIopromide

Synthetic Route D

Section 9.2 of Annex 2 explains in detail the differences between the synthetic routes proposed inthe 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. Apartfrom important technical complexities, these are accompanied by poor yields and also introducerisks 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 routescould offer an acceptable level of feasibility as a substitute for the currently used EDC-based routeand the requirement for a reduction in overall risks might not be possible to meet.


Table 4-3: Technical feasibility, economic feasibility and hazard profile concerns over the identifiedalternative synthetic routes

Route Technical feasibility issuesEconomic feasibility issues

(yield)Hazard issues

AOnly a few intermediate steps butproblems with product separation

from the reaction mixture

44.7% - far lower than what iscurrently achieved '#D#'''''''''' butnot directly comparable because

it is based on late startingmaterial

Problematic recycling.Use of solvents such as

DMF (Repr. Cat. 1B)and DCM (Carc. Cat. 2)

B

Late introduction of iodine into themolecule requires aggressive

reaction conditions and high risk offormation of by-products that differ

substantially to known impurities

Steric hindrance affecting qualityand yield: 41.4% - far lower than

what is currently achieved'#D#'''''''''

Use of DMA (Repr. Cat.1B) and dioxane (Carc.

Cat. 2) as solvents

C ''#A#'''''''''' '''''''''' ''''''' '''''''''''''' '''''''''''

Yield of same intermediate isclearly far worse, 70% vs.

'#D#'''''''' currently for the sameconversion

Problematic recycling.Use of DMA, DMF

(Repr. Cat. 1B) andDCM (Carc. Cat. 2) as

solvents

D Improvement over Synthetic Route Awith ready separation of symmetric

diamide, but still problematicefficiency and generation of

considerable quantities of iodine-containing waste

50.7% - far lower than what iscurrently achieved '#D#'''''''''''''

Problematic recycling.Use of DMA (Repr. Cat.1B) and DCM (Carc. Cat.

2) as solvents

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 isnot present, in combination with the fact that Iopromide is used internally by Bayer Pharma AG inthe manufacture of the medicinal product, consultation with the supply chain was not deemednecessary 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 economicreasons, for example, significant reductions in yield when potential alternatives are used), nofeasible alternative for EDC can be identified. Therefore, a screening process in order to transformthe master list of potential alternatives into a more manageable shortlist of possible alternativeswhich can fulfil the technical function of EDC as a minimum is not required. Nevertheless, forcompleteness and in order to introduce significant additional parameters affecting the availability ofpotential alternatives (cf. the ICH Q3C(R5) guidelines in respect to the approved residualconcentration limits for solvents used in the manufacture of pharmaceutical products), Section 9.3in Annex 2 provides a detailed screening of the master list of potential alternatives and hereby theconclusions of this screening process are presented:

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


Some of the identified alternative solvents (DMF, DMA) present no reduction in hazard, relativeto EDC, with some of these substances having been prioritised for inclusion in Annex XIV ofREACH. In addition, other substances (such as dioxane and dichloromethane) have suspectedCMR properties, and their use could only be considered if a minimum level of technical feasibilityhad been demonstrated; this is not the case. Importantly, if an alternative not listed under theQ3C(R5) guidelines in respect to the approved residual concentration limits were to be selectedissues of availability would arise

Bayer Pharma AG is the only company manufacturing Iopromide, and since 1986, when theproduction process was established (by Schering AG) no solvent other than EDC has been usedor 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 andreagents.

Overall, despite decades of research and a systematic review of the possibilities for eliminating theuse 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 realisticoption for Bayer Pharma AG’s manufacturing process.



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 ratherthan an alternative synthetic route. Developing a new synthesis as opposed to replacing only onecomponent of the existing synthesis is clearly more complex; there are however importantcomplicating factors in the case of the use of EDC in the manufacture of Iopromide:

Developing an alternative synthesis entails greater technical risks and uncertainties: therewould be a high risk that the specification of Iopromide would not be met under the newsynthesis. Experience shows that reaction conditions on an industrial scale differ from reactionconditions on a lab- and pilot plant scale. The reason for this is the different volume/surfaceratio affecting heat transfer, mixing and processes where more than one phase is involved. Thiscan adversely influence quality. If Bayer Pharma AG could not meet the specification underindustrial production conditions, the new process would be unsustainable and all priorinvestment 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 tothe alternative synthetic route could be given the ‘green light’

Meeting regulatory requirements would be more demanding: as a rule, chemical reactionsmay 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 atsubsequent stages, thus the by-product spectrum changes from one stage of synthesis toanother. Therefore, the by-product spectrum of the API reflects not only the by-productsproduced directly in the final stage but also the reaction products of the by-products of previousstages. 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 intermediateproducts are generated. The currently practised manufacturing process was approved by theregulatory authorities of different countries by the issuing of Marketing Authorisations and anynew 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 MarketingAuthorisations in which:

The quality features of the API are maintained in order to minimise the risk of harmfrom exposure to by-products

Improvements in quality, which have been made in the past as a result of optimisationof the production process, are maintained.

It is therefore imperative that alternative synthetic routes deliver an API which does not showworsened performance in any of quality standards prescribed in the Marketing Authorisations.Conformity with these standards is established through a series of analytical tests; for themanufacture of Iopromide, there are 12 such tests (for example, on the colour and clarity of thesolution, the sum of all impurities, and others) each of them accompanied by a threshold whichthe Iopromide product needs to meet. The tests would essentially aim to establish that (a) nonew impurities can be found in the Iopromide product, and (b) none of those which currentlyoccurred are larger than what is achieved by the existing manufacturing process. Failure in the


tests would lead to rejection due to non-compliance with the specifications in the MarketingAuthorisations.

If an alternative synthetic route cannot fulfil the 12 analytical tests, there may be a need foradditional purification steps (re-crystallisation) to be introduced at several stages of thesynthesis. This would bind equipment capacities, lower production yield and increaseproduction 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 analternative synthetic route in Bergkamen without downtime and interruption to the supply ofIopromide would be for Bayer Pharma AG to construct a brand new production plant whilesimultaneously continuing production of Iopromide in the existing production plant. The cost ofsetting up the existing plant could give some useful indication of the relevant costs; the existingplant was built ca. 20 years ago and its planning and construction took '#C#'' years. The cost ofconstruction was '#C#'''''''''''''' ''''''''''''' ''''' '''''''''' '''''''''''''. Using past inflation figures1, it can becalculated 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 ofmodern production of Iopromide (NB. Bayer Pharma AG is able to provide all necessary evidenceof these costs). Therefore, the current reasonable estimate is that, to build this plant today, itwould cost about '#D#'''''''' '''''''''''''.

In conclusion, for technical, economic and regulatory reasons, developing a new synthetic routewould be far less advantageous than identifying an alternative solvent. For this reason, the focus inthis 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 oflimited practical use to reiterate in this Section 5 the aforementioned alternatives’ technicalinfeasibility. Still, to better inform the ECHA Committees’ and the European Commission’s opinionmaking and to support Bayer Pharma AG’s argumentation on the lack of feasible alternatives, ananalysis of the steps that would be required for making an alternative available and the associatedeconomic costs are detailed below. This analysis would largely apply equally irrespective to theidentity of the selected alternative for EDC.

5.3 Economic feasibility

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

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


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 alternativesolvents that have already been tested on a laboratory scale (with demonstrably poor results, asshown earlier). Table 5-1 summarises Bayer Pharma AG’s estimates of the cost of R&D that wouldbe required for any one alternative solvent to substitute EDC before it could reach productionmaturity. NB. the numbering of steps shown in the table is that in the theoretical substitution plandiscussed 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 Estimatedduration

Estimatedcost

1 Screening ofalternatives

Desk-based research: involvement of 1 specialist group ata 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

1 year '''''' '''''''''''''

2 Testingphase

Lab-based research: involvement of 1 specialist group at acost of ''''' '''''''''''''/year. This includes:

2 FTE in Process R&D



1 year ''''' ''''''''''''

3 Scale-up inthelaboratory

Lab-based research: involvement of 1 specialist group at acost of '''''''''''' '''''''''''''/year. This includes:


1 FTE for scale-up work



1 year ''''' '''''''''''''

4 Pilot phase(1 kg 100kg)

Pilot-scale research: involvement of 1 specialist group at acost of ''''' ''''''''''''''/year. This includes:



1 FTE in Bayer Technology ServicesUpscaling: ''''''''''''''''''' for five intermediates subject to lab-based analysis. Six manufacturing campaigns on a pilotscale will be required at a total cost of '''''''' '''''''''''''

1 year '''''''' ''''''''''''

7 Optimisationof keyprocess steps

This refers to the optimisation of TAMIP-diacetateproduction, with the aim of improving its quality. Thesecould include three steps:

Optimisation of TAMIP-diacetate production over anestimated '''''' '''''''''

Scaling-up over an estimated ''''''' '''''''''

Pilot phase and plant batches over an estimated ''''''''''''''

Lab-based research: for the first two tasks, 1 FTE inProcess R&D will be required. For the pilot phase, twomanufacturing campaigns would be required at a cost of ''''' '''''''''''''''''' ''' '''''''''''''''''

1.5 year '''''''''''''''''''''''''

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 ''''''''''''''''''


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 couldmake the working assumption that parts of the plant would need to be gradually replaced, modifiedand optimised in order to operate with the alternative solvent. Table 5-2 shows theoreticalestimates for the likely cost of such an adaptation. Potential additional purification requirementswould cause particular difficulties; there is very limited space available for additional equipment tobe installed and an extra process step would interfere with the careful co-ordination of the existingsteps 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 discussedin Section 5.5.1 below.

Table 5-2: Estimated duration and cost of engineering work to adapt the existing plant to an alternativesolvent

Step Title Description Estimatedduration

Estimatedcost

5 Delivery andinstallation ofnewequipment

Modifications: step-by-step replacement andrespective reconstruction of production plantcomponents. Modification of a running plant wouldmean a decrease in output with adverse consequenceson business continuity.Key new equipment: at least the distillation plant hasto be modified to be able to handle the alternativesolvent on a large scale. The plant would alsopotentially need an additional purification step(crystallisation) to meet the Iopromide specification.Cost: because the requirements for modification arenot known, the following scenarios can be envisaged:

Very low cost, if the new solvent has about thesame properties as EDC

''''''' '''''''''''' (est.), if some modification is necessary

''''''' '''''''''''''' of more (est.) for major changes toequipment.

It is hereby assumed that the most likely cost would be€25 million. A solvent of very similar properties, if itexists, it would have already been identified. On theother hand, if the engineering costs were too high,Bayer Pharma AG would regard the new solvent asinfeasible. The company’s Development Departmenthas also set a requirement that the alternative processwill fit into the existing plant.In addition, engineering costs for Solvent Plant areestimated to be up to ''''' ''''''''''''

1 year 'All Table5-2 #D#''''''

''''''''''''

(5) Downtime The manufacture of Iopromide could suffer somedowntime during the installation/replacement ofequipment. As will be discussed below, Bayer PharmaAG would aim to hold a substantial stockpile ofIopromide in order to minimise economic losses from astoppage of manufacturing activities

Assumedto be minor


Cost of variations to Marketing Authorisations

X-ray contrast media are high-dosage pharmaceuticals, for which very high purity requirements aredemanded, due to the large quantity administered to the human body. Undetected traces ofimpurities may cause lack of stability and this is the reason that such pharmaceuticals need to passdemanding stability tests. As discussed in Annex 1 (Section 8), the use of a solvent may result insolvent residues remaining in the final pharmaceutical product. A change of solvent would thereforeprecipitate changes in the residue profile of the pharmaceutical product. This, in practice, meansthat the safety of the pharmaceutical product needs to be re-assessed and re-established by therelevant authorities in accordance with guidelines issued by the International Conference onHarmonisation 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 forUltravist®.

Being an established, mature product, Ultravist® has national registrations (MarketingAuthorisations) only. This means that every country maintains its own dossier. Ultravist® holdshundreds ('#C#''''''') of Marketing Authorisations across more than 100 ('#C#'''''') countriesincorporating 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 analternative solvent, it is worth noting that every country or region has different requirementsregarding 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 differsignificantly. The final decision on whether a variation needs to be filed or not is with the countrieswho know their particular regulatory environment best.

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

Table 5-3 (overleaf) summarises Bayer Pharma AG’s estimates of the cost of variations to MarketingAuthorisations that would be required if any one alternative solvent substituted EDC. NB. thenumbering of steps shown in the table is that in the theoretical substitution plan discussed in Section5.5.1 below.


Table 5-3: Estimated cost of variations to the Marketing Authorisations of Ultravist® after the substitutionof EDC by an alternative solvent

Step Title DescriptionEstimatedduration

Estimatedcost

6a Variations ofMarketingAuthorisations forUltravist®

Given the above complexities, and since the identity ofthe alternative cannot be known, only a rough calculationof the likely cost of variations can be provided, as follows:- '#C#''' Authorisations across '#C#'''' countries means,

on average, '#C#'''''' Authorisations per country- It can be assumed that 1 employee needs to spend 1

month (160 hr) on one variation application. Thetotal 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 wouldbe ''#C#''''' ''' '''''''' ''' ''''''''''''''

- For the total of '#C#''''''' countries, the overall costcould be: ''#C#'''''' ''' '''''''''''''''' ''' ''''''''' '''''''''''''

To allow for economies of scale, overlaps, etc. it isconservatively assumed that the overall costs would belimited to a fraction of the above estimate i.e. '#D#''''''''''''

>5.5 years '#D#'''''''''''''

6b Plantbatches ofTIP-diamidechloride andIopromide

Generation of plant batches required for variations toMarketing Authorisations. These will come at a real costbut this will be relatively small compared to the cost ofsubmission and approval of variations

6c Iopromidestockpilebuild-up

Section 5.5.1 will explain that during the process ofsecuring variations to Marketing Authorisations, astockpile of Iopromide made with the current EDC-basedmanufacturing method would be required. The requiredvolume would be in the range of '#A#'''''''''''''''''' tonnes.The stockpile would need to be built before the variationsare 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 AGcan produce '#A#'''''''''''''' t/y for stockpiling, thereforeup to '#A#'' years might be needed and additionalstorage space would need to be found

- Deferred profits – Bayer Pharma AG would need toincur the costs of manufacturing the above tonnageof Iopromide (see Table 3-11 in the SEA for adescription of the cost) but would not be able sellUltravist® made with this tonnage of Iopromide andmake the associated profit for several years.

Both cost elements shown above are assumed to beminor compared to other costs and will not be taken intoconsideration further

Minor, willbe ignored

(6) Downtime The manufacture of Iopromide could suffer somedowntime when there is a need to switch between EDCand the new solvent. The EDC-based process would berequired to be used for the duration of stability tests (seedescription in Section 5.5.1). The availability of aIopromide stockpile would reduce any adverse impactsfrom downtime

N/A Minor, willbe ignored

Total >5.5 years '#D#'''''''''''''


Summary of investment costs

Taking into account the above discussion, a summary of the costs that would be incurred by BayerPharma 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 investmentcosts 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 offerany realistic quantitative estimate of the changes to operating costs and profitability following aconversion to an alternative. However, it is useful to consider some important parameters thatunderpin the profitability of the existing manufacturing process and how this might be affected bythe 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 mediaspread through the bloodstream/body and the heavy iodine atoms that the contrast mediumcontains produce a contrast (shadow) when X-ray images are recorded. In light of thistherapeutical similarity, currently, price and marketing are decisive for market success in such acompetitive environment. It is therefore essential that the production cost of Iopromideremains 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 mediahave a common molecular structure, the one shown in Figure 5-1.

N

R

JJ

J

CO-Amine 1

CO-Amine 2

Carboxylic acid

Figure 5-1: Generic structure of iodine-based X-ray contrast media


This common structure includes:

An aromatic core (isophthalic acid) that is highly iodinated (mostly 3 iodine atoms peraromatic ring) (triiodo isophthalic acid)

Highly hydroxylated side chains to confer high water solubility. Two side chainsoriginate from amines and are connected to carboxylic groups (side chain 1 and 2), oneside 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 alarger number of chemical reaction steps are needed. The reason for this is that symmetricalintermediates cannot be used to introduce two groups in one chemical step. Instead, it isnecessary to start with a (more expensive) unsymmetrical raw material and to build up anyfunctionality separately. Table 5-5 summarises the differences between Iopromide and theother iodine-based X-ray contrast media. Iopromide is the only asymmetrical molecule in thisgroup.

Table 5-5: Key structural elements of iodine-based X-ray contrast media

Contrastmedium

Symmetric/Asymmetric

Amine of side chain 1 Amine of side chain 1 Carboxylic acidof side chain 3

R at N-atom

Iopromide Asymmetric H2N-CH2-CHOH-CH2OHAminopropandiol-2,3

HNCH3-CH2-CHOH-CH2OH

Methylaminoproandiol-2,3

CH3O-CH2-COOH

Methoxy aceticacid

H

Iopamidol Symmetric (HOCH2)2CH-NH2

2-Aminoproandiol-1,3(Serinol)

(HOCH2)2CH-NH2

2-Aminoproandiol-1,3(Serinol)

CH3-CHOH-COOH

2-Hydroxy-propionic acid

H

Iomeprol Symmetric H2N-CH2-CHOH-CH2OHAminopropandiol-2,3

H2N-CH2-CHOH-CH2OHAminopropandiol-2,3

HOCH2-COOHHydroxy acetic

acid

Not H

Iohexol Symmetric H2N-CH2-CHOH-CH2OHAminopropandiol-2,3


CH3COOHAcetic acid

Not H

Iodixanol 2 aromaticcores

Symmetric



CH3COOHAcetic acid

Not H

Iobitridol Symmetric HNCH3-CH2-CHOH-CH2OH


HNCH3-CH2-CHOH-CH2OH


(HOCH2)2CH-COOH

Dihydroxyisobutyric acid

H

Ioversol Symmetric H2N-CH2-CHOH-CH2OHAminopropandiol-2,3


HOCH2-COOHHydroxy acetic

acid

Not H

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 formedicinal application. Compared with therapeutic drug products, they are relatively inexpensive


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 ofIopromide, could not be considered as economically feasible as it would harm the competitivenessof 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 continueduse of EDC cannot be provided here. Nevertheless, Section 9.3.3 in Annex 2 provides a comparisonof hazards between EDC and selected potential alternatives that were identified through BayerPharma AG’s R&D work.

5.5 Availability

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

5.5.1 Steps required for making an alternative available

Bayer Pharma AG’s Chemical Development, Regulatory and Logistics departments have cometogether to review the knowledge accumulated over many years of R&D and make the best possibleeffort to develop a hypothetical plan for the substitution of EDC by another solvent. An alternativesolvent, as opposed to an alternative synthetic route, is considered the least infeasible (from atechnical and economic perspective) option for altering the manufacturing process of what is now alegacy pharmaceutical product. The plan is described below and estimates that a minimum of 11.5years 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 forvariations to Marketing Authorisations cannot be submitted until the new manufacturing process isoperation 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 ashortlist of possible feasible and suitable alternative solvent systems for further R&D and possiblyimplementation.

Step 2: Testing phase

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


Step 3: Scale-up in the laboratory

The research in the laboratory will be scaled-up with a focus on the most promising possiblealternative solvents. The aim will be to convert batches of TIP-diamide chloride of good yield andgood quality to pure Iopromide (time required per batch: 1 week) and ultimately to select the threemost 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 possiblealternatives and ultimately the comparison of the three solvent systems. This will be completedwith 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 isthe 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 variationsto its existing Marketing Authorisations for Ultravist®. The time required for the processing ofapplications for variation by the national authorities can vary between 6 and 18 months. BayerPharma AG’s experience is that simultaneous submissions are not possible. Therefore, due to thelarge number of Marketing Authorisations involved, a significant amount of time would be expendedat 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 andsubmission of dossiers requesting the variations to the relevant national health authorities, willincorporate additional important activities which might add to the duration and complexity of thisstep:

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

Generation of plant batches of Iopromide: plant batches of pure Iopromide will need to begenerated using the new solvent

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


Iopromide will be sufficient. Otherwise, if such permission is not granted, Bayer Pharma AG willhave to build-up a stockpile of up to '#A#'''''''''' tonnes of Iopromide. The actual need for stockwill also depend on how fast the changeover of the equipment between solvents can beachieved 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 thatwhat 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 andquality and the need for an alternative to have been commercially proven, for the use of solvents inpharmaceutical synthesis there is an additional parameter that requires consideration. This is thelisting of any solvent in the relevant ICH Q3C Guidelines, as discussed in Annex 1 (Section 8). Section8.2.2 explains that there are two key implications of the ICH Guidelines on residual solvents inrespect of identifying and implementing an alternative to EDC (which is classified as class 1 solventunder the Guidelines):

An alternative solvent should ideally be classified as class 3 or 2, or else a risk-benefitassessment will be required and levels of residues should be restricted to the prescribedconcentration limits

If a solvent is not listed in the ICH Q3C Guidelines, Bayer Pharma AG would need to supply safetydata on this new solvent. Absence of a solvent from the ICH Q3C Guidelines poses a serious andcostly 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 candidatesubstitute solvent which is listed or not in the ICH Q3C Guidelines. If it was assumed that theselected candidate would not be listed in the Guidelines additional time would be required forgenerating the required information and submitting a request for the listing of the substance. Thetime that would be required for these activities to complete cannot be estimated; however, it couldbe assumed that if the need for a new listing was identified at the end of Step 5 in the plan shown inTable 5-6, a request for its listing in the ICH Guidelines would be submitted soon after and wouldhopefully be granted by the time all variations of marketing Authorisation would be secured.


Table 5-6: Hypothetical substitution plan for EDC

Step Title Outcome Estimatedduration

Risk analysis

1 Screening ofalternatives

A shortlist of possible feasible alternative solvent systems for further R&D 1 year There is no guarantee that a feasiblealternative 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 thelaboratory

Selection of select the three most promising solvent systems for the pilotphase

1 year Realistic timescale but could be shorter

4 Pilot phase(1 kg 100 kg)

Selection of a single candidate solvent system 1 year Realistic timescale but it cannot becertain that scaling up will not allow

previously unknown or unanticipatedtechnical issues to emerge

5 Delivery andinstallation of newequipment

If new equipment will be needed, long delivery times will require approx. 1year

1 year Timescale is conservative; significantnew equipment may not be needed

6a Variations toMarketingAuthorisations

Submission of applications to health authorities of countries whereUltravist® is sold (6-18 months per application)

>5 years Duration of variations is uncertain asthere are too many that need to be

applied for.Such large volumes of Iopromide

stockpiles have never been stored in thepast. It is assumed that Bayer PharmaAG will be able to build the required

stock during Steps 1-5 aboveThe estimate of 5 years must beconsidered the lowest minimumrequired for this step of the plan

6b Plant batches ofTIP-diamidechloride andIopromide

Generation of plant batches required for variations to MarketingAuthorisations

6c Stock-build up Build a stock of '#A#'''''''''''''''''' tonnes Iopromide to ensure the smoothprocessing of variations to Marketing Authorisations

7 Optimisation of keyprocess steps

Development of ability to produce TAMIP-diacetate of better quality 1.5 year It is unlikely that this work could beundertaken during the variations to

marketing Authorisations due toshortages in production and (lab)

personnel spare capacity

Overall duration >11.5 years


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 conductedby Bayer Pharma AG (presented in Annex 2, Section 9), has demonstrated the lack of technicalfeasibility for a wide range of solvent families. It is also clear that the development an alternativesynthetic route would be problematic for technical feasibility, economic feasibility, regulatorycompliance and risk reduction potential reasons. As a result, Section 5 cannot discuss specificpossible alternatives; instead, it examines the practical and economic implications of a hypotheticalconversion 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 berequired for the implementation of an alternative solvent. The actual period required will criticallydepend on the time taken for the identification of potentially feasible alternatives and on the timerequired for the approval of the variations to the hundreds ('#C#''''''') of Marketing Authorisationscurrently held by Bayer Pharma for Ultravist® in more than 100 ('#C#'''''') countries around theworld. The substitution of EDC will be a complicated and prolonged process which could potentiallycause significant disruption to Bayer Pharma AG’s business and could result in the loss of marketshare and profitability on the national level.

As far as economic feasibility is concerned, out of necessity, the above analysis only focuses on thelikely investment costs. These are estimated at between €10 and €100 million '#D#''''''' '''''''''''''' andare expected to be generally similar for any one alternative substance. In terms of changes tooperating costs following the conversion to an alternative solvent, these cannot be estimatedwithout the identity and characteristics of a specific selected technically feasible alternative beingknown. However, in light of the economics of Iopromide manufacture and the very intensecompetition Ultravist® is facing from a variety of alternative iodine-based X-ray contrast media, anyincrease in the manufacturing cost of Iopromide would potentially have a very detrimental effect tothe 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 forEDC. 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.



6 Overall conclusions on suitability and availability ofpossible 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 asolvent in the manufacture of Iopromide, the API in the X-ray contrast medium Ultravist®. BayerPharma AG is the only global manufacturer of Iopromide. Ultravist® is a mature, establishedmedicinal product that is sold in more than 100 countries and is competing for market share in theEU and outside the EU against several other similar products.

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

6.2 Technical feasibility of alternatives

For many years Bayer Pharma AG has investigated the availability of solvents that could feasiblysubstitute EDC, including alternative synthetic routes. First R&D efforts started in the 1990s butextensive research, including laboratory testing was undertaken as late as in 2014, specifically forthe purposes of this Application for Authorisation. A wide range of solvent families have beenconsidered 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 syntheticroutes for the manufacture of Iopromide has also been considered.

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

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.


The results of the desk-based and laboratory-based investigations confirm that none of theidentified alternatives can deliver the required technical performance in Bayer Pharma AG’sproduction process (see summary in Section 4.2 and detailed descriptions in Annex 2). Even thoughsome alternative substances (for instance, acetates) might be considered better performing thanothers, the laboratory tests have confirmed the serious shortcomings of all candidates in terms ofproduction yield (a significant reduction affecting the effective production capacity of the plant),product quality (impurities causing colouration of the product) and solvent recovery andrecyclability.

On the other hand, known alternative synthetic routes face issues of product separation, wastegeneration and recyclability and are accompanied by far lower yields than the existing route. Giventhat 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 ofEDC.

Therefore, the overall conclusion is that no known substance or synthetic route could offer aminimum level of technical feasibility as to be considered a realistic possible alternative for EDC inBayer Pharma AG’s Iopromide manufacturing process. As a result, no alternative could beshortlisted 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 feasibilityhas taken a wider scope and has aimed to demonstrate the types and scale of investment costs thatwould 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 (Section5.1 has explained that developing a new synthetic route would be particularlydisadvantageous due to higher technical risks and uncertainties, more demanding regulatoryrequirements, and high costs of implementation; as a result Bayer Pharma AG’s focus is onalternative 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 forsubstituting EDC with a yet unknown alternative solvent. Some downtime might be required, duringwhich production of Iopromide would need to be suspended.

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


''''''''''' '''''''' '''' ''''' ''''''''''''''''''''' '''''''''''''''''' Bayer Pharma AG would experience loss of turnover andmarket 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 forrisks to human health and the environment; however, a screening for hazards accompanying severalof 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 onesolvent that is accompanied by hazard concerns no less severe than EDC. Two substances inparticular, dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA), present equivalentconcern to EDC and have been proposed for inclusion in REACH Annex XIV. These solvents arerelevant to all alternative synthetic routes (A and C for DMF and B, C and D for DMA). Two moresubstances, dichloromethane and dioxane, are suspected CMRs, (Carc Cat 2). Dichloromethane inparticular is currently under investigation by the IARC and has been added to the CoRAP List andtherefore, its CLP classification might change in the future. These alternatives would requireadditional 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 analysisof availability cannot be provided. However, Bayer Pharma AG has developed a theoreticalsubstitution plan for EDC which could apply if a feasible alternative solvent could be identified in thefuture. 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 thevariations to Marketing Authorisations to be completed without impacting on the operation of theBergkamen facility. Overall, the duration of the hypothetical substitution plan is a minimum of 11.5years and potentially longer if the initial research steps are not successful in identifying a feasiblecandidate 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 pharmaceuticalsynthesis should ideally be listed in the relevant ICH Q3C Guidelines on residual solvents. If BayerParma 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 requestfor its listing. The time that would be required for these activities to complete cannot be estimatedbut it can be assumed that it would be incorporated into the overall implementation timeframe of11.5 years described above (if Bayer Pharma AG selects a specific solvent, ICH Q3C activities will startso by the end of the variations of Marketing Authorisation phase, the ICH listing will have beencompleted). It is worth noting that the vast majority of potential alternatives that Bayer Pharma AGhas so far considered are not listed in the ICH Q3C Guidelines.


6.6 Overall conclusion

This AoA has demonstrated that there is no known technically feasible alternative for the use of EDCin 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’sSunset Date in 2017), the period required for converting to any such alternative would be long andthe investment costs for conversion would amount to several millions of Euros. As a result, BayerPharma AG believes that the continued use of EDC in the applied for use is justified on technical andeconomic 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 thatan alternative that can technically match the performance of EDC cannot be identified. A long list ofsubstances and families of substances have been considered and none of them has been shown toguarantee 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 feasiblealternative could be identified in the future.

Nevertheless, Bayer Pharma AG will not cease their efforts towards the identification of analternative solvent that could successfully substitute EDC. Bayer Pharma AG will undertake its ownresearch and also keep a watching brief on scientific developments that might point to otherpotential alternatives as substitutes for EDC. It is aimed that the hypothetical substitution plandescribed 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 ofEDC so that losses and releases are further minimised and, accordingly, worker exposure is reducedto the extent possible. Bayer Pharma AG intends to investigate options for the improvement of theequipment used. A preliminary list of areas where key improvements might be needed is shown inTable 6-1. Several other smaller improvements may be considered with the aim of minimising EDClosses to the extent possible. Further discussion is provided in the Chemical Safety Report whererecent improvements are also presented.

Table 6-1: Area of potential engineering improvements to be investigated during the requested reviewperiod

Area Area ofpotentialimprovement

Potential issue Possible improvement Implementationtimeline

Plant F Reactor 841,842 and 843

Leaky valve for filling withsubstance

Use non-leaky system Early 2017


Disconnect container at fillingoperation of reactor

Connection with wasteair pipe

Early 2017


Sample taking device for TLCnot completely closed

Introduce closed system(glove box system)

Early 2017

Plant F DryerT141,T142 andT143

Taking samples fordetermination of residual EDC

Use closed system Early 2017

Plant F Dryer T142 Reusable big bags release EDCvapours

Evacuate big bags beforeuse

Early 2017


Table 6-1: Area of potential engineering improvements to be investigated during the requested reviewperiod

Area Area ofpotentialimprovement

Potential issue Possible improvement Implementationtimeline

Distillationplant

Glass columnandneutralisationloop reactordedicated torEDC

Old plant. Expensivemaintenance. Hardly anyflange maintenance possible

Construction of a newcolumn andneutralisation loopreactor.The new plant will meetrigorous environmentalstandards and utilise thelatest state of the arttechnology. Theinvestment costs werecalculated at €3.75million

2nd

quarter 2018



7 List of references

European Commission, undated. Communication from the Commission – Guideline on the details ofthe various categories of variations to the terms of marketing authorisations for medicinal productsfor 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 CommerciallyConfidential 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 NostrandReinhold 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, ownedby Bayer AG, Bergkamen: Bayer AG.

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



8 Annex 1: Regulatory controls on the use of EDC in thepharmaceutical industry

8.1 Requirements of Marketing Authorisations and theirvariations

As noted in Table 2-4, the use of EDC in the manufacture of an API falls within the scope ofRegulation (EC) No 726/2004 and Directive 2001/83/EC, relating to medicinal products for humanuse. With this Regulation, the EU develops and improves European procedures for theauthorisation, supervision and pharmacovigilance of medicinal products, for human and veterinaryuse. No medicinal product appearing in the Annex may be placed on the European market withoutprior authorisation from the EU. Each application for authorisation must be accompanied by theparticulars and documents referred to in Directive 2001/83/EC on the community code relating tomedicinal products for human use, and by the fee payable to the European Medicines Agency. Itshould also contain a statement to the effect that clinical trials carried out outside the EuropeanUnion meet the principles of good clinical practice and the ethical requirements of Directive2001/20/EC on good clinical practice in the conduct of clinical trials on medicinal products for humanuse.

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

The entire manufacturing process for the API (Iopromide) is regulated on the basis of pharmaceuticallegislation 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 theagreement of all affected regulatory authorities is required. Medicinal authorisations, of whichthere 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; achange in the solvent would fall under this. In accordance with Commission Regulation (EC) No1234/2008, it can be assumed that the changes to the production process and the final productwould 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 extensionand which may have a significant impact on the quality, safety or efficacy of the medicinal productconcerned” (European Commission, undated). Variations not only require effort and inputs on thepart of Bayer Pharma AG and the authorities but also attract fees. It must be noted that marketauthorisations are required per country, so the total number of authorisations might be particularlylarge (see Section 0 for more details). In addition, changes to the manufacturing facility would alsoattract requirements for notifying such changes to the relevant national authorities.


8.2 Regulatory controls on residual solvents

8.2.1 ICH Guidelines

The International Conference on Harmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH) issues a variety of guidance which pharmaceuticals companiesmust follow. ICH guidance is of relevance to the use of solvents in synthetic processes and thereby ofrelevance 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 inpharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solventsand describes levels considered toxicologically acceptable, for some residual solvents.

Residual solvents in pharmaceuticals are defined in the guideline as organic volatile chemicals thatare used or produced in the manufacture of drug substances or excipients, or in the preparation ofdrug 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 wereevaluated on the potential human health concern and categorised into three classes:

Class 1 solvents: Solvents to be avoided: Known human carcinogens, strongly suspected humancarcinogens and environmental hazards

Class 2 solvents: Solvents to be limited: Non-genotoxic animal carcinogens or possiblecausative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solventssuspected of other significant but reversible toxicities

Class 3 solvents: Solvents with low toxic potential: Solvents with low toxic potential to man; nohealth-based exposure limit is needed. Class 3 solvents have a permitted daily exposure (PDE) of50 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 productsunless their use can be strongly justified in a risk-benefit assessment. However, EDC is used in thefinal intermediate step only. Iopromide contains no EDC2; therefore, no risk benefit assessment isnecessary or has been carried out. Resides of class 2 solvents associated with less severe toxicityshould also be limited in order to protect patients from potential adverse effects. Ideally, less toxicsolvents (class 3) should be used where practical.

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

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


8.2.2 Importance of the regulatory framework to the selection of analternative extraction solvent

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

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

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



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, whileretaining the current route of synthesis (TAMIP-diacetate TIP-diamide chloride as a one-potprocess). Detailed internal (unpublished) reports of the unsuccessful attempts, made in the period1990–1996, are available (Kudschus, 1990; Schenk, 1995; Schenk, 1996) and have been used in thepreparation of this AoA.

Potential alternative solvents considered

Categorised by functional group, Table 9-1 summarises the alternative solvent families that wereconsidered 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 aproticsolvents

Dimethylformamide (DMF) 200-679-5 68-12-2

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

Nitrocompounds

Nitromethane 200-876-6 75-52-5

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


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

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


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 acidicconditions and has sufficiently good dissolution properties, for the starting compound and forimpurities, or else particles start to melt and adhere.

For the second stage of synthesis (TIP-diamide TIP-diamide chloride), the solvent has to withstandthe 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 accumulatedby Bayer Pharma AG, over years of laboratory investigations, the solvent families identified in Table9-1 can be screened as shown in Table 9-3.

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

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

Representatives of the retained solvent families were subject to laboratory experiments in the1990s. 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


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


Table 9-3: Screening of solvent families for stability under the conditions of Bayer Pharma AG’s synthesis (pre-2014 R&D)

Solvent families Assessment of stability under reaction conditionsScreening

resultRelevant originalsources

Alcohols Formation of chloroalkanes and sulphurous acid esters with thionyl chloride Eliminated General chemicalknowledgeCarboxylic acids Formation of acid chlorides; solvent contains the same functional group as starting material so the

thionyl chloride would simply react with the solvent rather than the starting material.Eliminated

Ketones Being aprotic solvents, they are feasible for the reaction conditions of the 1st

synthetic stage.However, ketones react with the amine group of the starting materials to form a Schiff base* withTAMIP-diacetate (amino group + keto group react); this formation also occurs with MIBK, which issterically more demanding than acetone or MEK, making all of these solvents infeasible

Eliminated

Nitriles In principle feasible for the 1st

synthetic stage (but acetonitrile reacts considerably with thionylchloride / hydrogen chloride – see below)

Retained Kudschus (1990)

Dipolar aproticsolvents

Many common polar aprotic solvents react with thionyl chloride. Dimethylsulphoxide (DMSO) reacts

with thionyl chloride. DMF also reacts forming the strongly carcinogenic dimethyl carbamoyl chloride

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

Eliminated General chemicalknowledge

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).Nitrobenzene is the only other nitro compound that is readily available. However, it has a Repr. Cat1B classification and has a high boiling point (210 °C) making it an infeasible and unattractive solvent

Eliminated

Hydrocarbons In principle feasible. Alkylated aromatics (e.g. toluene) and alkanes, being aprotic solvents areconditionally feasible for the reaction conditions of the 1

stsynthetic stage (acylation) and formation

of acid chloride in the second

Retained Kudschus (1990)


In principle, feasible Retained

Esters In principle feasible, however esters will hydrolyse in strongly acidic or basic aqueous conditions, suchas those encountered during solvent recovery, making them sub-optimal solvent for the second step

Retained

Ethers Cyclic ethers (e.g. THF) are in principle feasible, but are liable to decompose (forming chloro alcoholswith HCl). Aliphatic ethers, being quite non-polar solvents, are feasible for the reaction conditions ofboth synthetic stages

Retained

* 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 basesin a broad sense have the general formula R

1R

2C=NR

3, where R is an organic side chain


The results are summarised in Table 9-4, with additional detail provided in the main text. Cells ingrey indicate areas where shortcomings have been identified for the alternative substances underconsideration. The criteria used for the screening of the potential alternative solvents are aligned tothose 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 thefastest reaction rate among the solvents tested in 1990 (the formation of TIP-diamide took 1 hour inreflux) and might be considered feasible for the second synthetic stage (Kudschus, 1990). Havingdemonstrated a yield of 79% in the laboratory (by comparison the yield currently achieved by usingEDC in the conversion of TAMIP-diacetate to TIP-diamide chloride is 91–92%), acetonitrile could beconsidered superior to several other potential alternative solvents. However, it reacts remarkablywith thionyl chloride/hydrogen chloride, so that yields and colour values fluctuate substantiallyaccording to reaction conditions (Kudschus, 1990). Particularly the colour values, which are decisivefor processing the final intermediate to Iopromide, are always worse than when EDC is used, so thatadditional purification might be necessary, with corresponding losses of yield (Kudschus, 1990). Intheory, purification might be undertaken by extraction via stirring with absolute ethanol at roomtemperature.

Purification of TIP-diamide chloride by stirring with ethanol would require processing of a verysignificant tonnage of the product, '#D#'''' ''''''''''' ''''''. This would disturb the synchronisation of theprocess and increase production costs. It is also doubtful whether such purification could beperformed 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 beignored, 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 ofTAMIP-diacetate to TIP-diamide. Toluene could potentially deliver TIP-diamide chloride yieldssimilar to those obtained with EDC; however, its performance is crucially dependent on the presenceof impurities in the TAMIP-diacetate batches. Employing the usual TAMIP-diacetate productionbatches brings the reaction to the limit of adhesion, requiring either (a) continuous analytical datafor 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. Thepracticalities of these options are described here:

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


Table 9-4: Second screening of identified potential solvents (pre-2014 R&D)

Potential alternativesolvent

1 2 3 4 5 6

Inertness tothionyl

chloride andHCl

Boiling point(°C)

Conversioncompleteness

Absence of adhesionQuality/colour value

(white)Yield Recyclability

Compati-bilitywith

process

EDC 83.6

(92% in2014)

Acetonitrile 81.6

Complete

conversion butreacts with thionyl

chloride

Poor colour, lowquality

Yield varies

due todecompos-

ition

Not possible

Poor (ifpurifica-

tionneeded)

Cyclohexane 80.7

Very poor solubilityof starting material

means that thereaction is not

complete

Not relevant givenpoor level of

conversion andadhesion

Notrelevant

Poor

Toluene 110.6

()Only feasible if verypure intermediate is

used

()Only feasible if verypure intermediate is

used

Intensely coloured

Yield mostcomparable to EDC

Poor

Dichloromethane 40 Boiling point too low (<50 °C), not considered further

Chloroform 62Boiling point marginally above the threshold and poor hazard profile. Chloroform is likely to form phosgene inthe 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

1,1,1-Trichloroethane 74.1

Incompleteconversion

Not relevant givenits poor level ofconversion and

adhesion

Notrelevant

Poor

Chlorobenzene 131 -132 ()

Poor colour, lowquality

Poor

Poor




1 2 3 4 5 6

Inertness tothionyl

chloride andHCl

Boiling point(°C)




Compati-bilitywith

process

Ethyl acetate 77.1 / 80.7 ()

Disappointing quality

75% Yieldafter extrapurificatio

n step

Not possible

Poor

Ethyl acetate/cyclohexane (56:44)

77.1

Very slow reaction

Intensely coloured

Notrelevant

Notconsidered

Poor

Ethyl acetate/toluene 77.1 / 110.6

1

ststep, ethyl

acetate; 2nd

step,toluene

Low quality,additional

purification needed

19% lowerthan with

EDC

toluene; ethylacetate

Poor (ifpurifica-

tionneeded)

Butyl acetate 126

Incomplete conversion and product adhesion; unusableNot

relevant

Poor

Diethyl ether 34.6 Boiling point too low (<50 °C); very poor dissolution not considered further

Di-n-butyl ether 142-143*

Incompleteconversion

Not relevant given

the poor conversionand adhesion

Notrelevant

Poor

Methyl tert-butyl ether 55.3

Very poordissolution

Not relevant given

the poor conversionand adhesion

Notrelevant

Poor

Tetrahydrofuran

Reacts withHCl

65

Positive conversion

results butdecomposes to 1,4-

dichlorobutane

Poor qualityNot considered due to decomposition

of the solvent

Dioxane / toluene

Reacts withHCl

100.8 /110.6

Dioxane would be subject to slow decomposition with formation of 2-(2-chloroethoxy)ethanol which wouldreact with Thionyl chloride to bis-(2-chloroethyl)-ether, a suspected carcinogen and acute toxicant; not

considered further




1 2 3 4 5 6

Inertness tothionyl

chloride andHCl

Boiling point(°C)




Compati-bilitywith

process

Diglyme 162

Very poordissolution

Not relevant givenits poor level ofconversion and

adhesion

Notrelevant

Poor

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 on7 October 2014)* Available at http://www.chemicalbook.com/ChemicalProductProperty_EN_CB2775063.htm (accessed on 7 October 2014)


Improvement of production parameters of TAMIP-diacetate for improvement of purity:identification of toluene as a theoretically viable EDC substitute, given its ability to reachproduction yields equivalent to those of EDC, subject to resolving the vital colour issue, led BayerPharma AG to undertake extensive optimisation operations. Specifically, for the TAMIP-diacetate synthesis operations internal manufacturing specification K296 was developed, whichenabled 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, theuse of toluene would still result in a serious discolouration problem. Crude TIP-diamide chlorideprecipitates from toluene and is heavily coloured, which is critical in the subsequent iopromideformation (this affects the quality of the final Iopromide product). The colour problem could besolved by subsequently stirring the crude product in absolute ethanol. However, this extractionincreases product losses (Kudschus, 1990). As shown above, purification of ethanol at theindustrial scale would adversely affect process synchronisation and could result in increasedimpurities in Iopromide.

Moreover, the use of toluene as a single solvent for the preparation of TIP-diamide chlorideultimately and conclusively failed, as TAMIP-diacetate synthesis could not be carried out onproduction scale according to internal specification K296. Optimisation operations carried outsubsequently (a later specification, K300, was developed) produced TAMIP-diacetate whichtended to adhere at the TIP-diamide stage, similarly to the currently ‘normal’ productionbatches. Toluene was therefore ruled out as a solvent if the current synthetic stage sequencewere to be retained. However, it should be mentioned that with the improved TAMIP-diacetatequality (using specification K296), when using EDC (instead of toluene), Bayer Pharma AG couldobtain a further increase in yield of 4% and slightly better quality could be achieved without theaforementioned 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 case5% vol. N,N-dimethylacetamide and dimethylethylurea) and relatively small additions ofacetonitrile (5, 10, 15% vol.) were also tested, but they too led to adhesion of the batches. Onlywhen 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 infeasiblesolution.

As far as the other tested hydrocarbon, cyclohexane, is concerned, it is even less polar than tolueneand 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 keepthe accompanying impurities in the mother liquor in solution. Cyclohexane is technicallyunacceptable as a substitute for EDC in Bayer Pharma AG’s process. Similarly, heptane is non-polarand thus was not tested.

Halogenated hydrocarbons

Several aliphatic halogenated hydrocarbons were excluded from laboratory testing, as they presentcomparable toxicological and ecological concerns to EDC. Dichloromethane was found to beinfeasible as substitute solvent due to its very low boiling point. Similarly, chloroform has arelatively 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


chlorinated aliphatic hydrocarbons which were not seen as viable long-term solutions for thesubstitution of EDC. Chloroform is also likely to form phosgene in the presence of air. Chloroform isstabilised with alcohols to trap formed phosgene, however, the reaction conditions are notcompatible 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 wasfound 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 conversionof TAMIP-diacetate to TIP-diamide (Kudschus, 1990). Indeed, ethyl acetate is the solvent that hasbeen assessed in the most detail; however, experiments carried out in 1986 found that it was not afeasible solvent due to the low yields obtained (Kudschus, 1990). Ethyl acetate was infeasible for thesubsequent second synthetic stage leading to the formation of TIP-diamide chloride due to a poorpurity profile; the separation of accompanying related substances was found to be insufficient in thissolvent. In particular, the colour value, which is critical for the subsequent stage in the production ofTIP-diamide chloride, was ca. 10 times higher than acceptable. The coloured product needs to bepurified in an additional step (extraction by stirring with absolute ethanol at room temperature) withcorresponding losses (Kudschus, 1990). As shown above, purification of ethanol at the industrialscale would adversely affect process synchronisation and could result in increased impurities inIopromide.

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). WhenTAMIP-diacetate in ethyl acetate is reacted first with methoxyacetyl chloride and then with thionylchloride, as with the EDC process, the quality of the intermediate deteriorates. In this case, itcrystallises from ethyl acetate. The educt3 also precipitates and, subsequently, can no longer beconverted completely (Schenk, 1996). Results obtained from Bayer Pharma AG’s research includedthe 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 "dimericester" is a by-product of the Iopromide stage and not the TIP stage, so its structural allocation isquestionable. Repeated substance isolation and structural allocation did not lead to a differentresult. This indicates that a new impurity is present at up to 1% when using ethyl acetateinstead of EDC4

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

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


Recyclability: it is difficult to separate ethyl acetate and thionyl chloride – recovery of thesolvent is almost impossible. It contains large quantities of thionyl chloride and dissolvedhydrogen chloride. In contact with water, hydrolysis of ethyl acetate to ethanol and acetic acidis unavoidable and the solvent recycling process would involve an aqueous wash stage toremove water soluble impurities. Losses occur not only directly due to hydrolysis, as thesolubility of ethyl acetate in water is increased considerably by the products of hydrolysis, whichresults in further losses.

In 1990, the azeotrope ethyl acetate:cyclohexane 56:44% w/w was also found to be feasible for theconversion of TAMIP-diacetate to TIP-diamide (Kudschus, 1990) and it was also possible tosuccessfully carry out the second synthetic step under appropriate conditions. However, thereaction rate with the azeotrope was found to be very slow; the formation of TIP-diamide took 12hours 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, wastested as a substitute solvent. However, due to its insufficient dissolution properties, completeconversion was not achieved and in some cases product adhesion occurred. Thus, this ester solventalso 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 estersin the 1990s, with the exception of 2-ethoxyethyl acetate which was considered under a separatetest following an alternative reaction sequence (see discussion below).

Ethers

Only higher boiling, relatively polar ethers were considered. Diethyl ether was found to beinfeasible due to its low boiling point, as it is extensively carried over as vapour with the reactiongases. A development report from 1986 (by Schering AG) details the unsuccessful testing of theethers, 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 bothstages. Dioxane has such a high dissolution capacity for TIP-diamide chloride that it cannot beisolated 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 slowdecomposition6 but accelerated under the reaction conditions, with formation of 2-(2-chloroethoxy)ethanol, a chlorinated hydrocarbon which causes significant concern for Bayer PharmaAG. Firstly, the solvent used must not decompose; secondly, 2-(2-chloroethoxy) ethanol would reactwith thionyl chloride to bis-(2-chloroethyl)-ether (EC No. 203-870-1, CAS No. 111-44-4). This is adouble 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 carriedout with the two solvents dioxane/toluene, and dioxane cannot be considered a technically feasiblealternative.

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

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

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


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 thisreacts further with thionyl chloride to form 1,4-dichlorobutane. This makes the solvent completelyinfeasible 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 thereaction conditions. It was also observed that this solvent reacts with methoxyacetyl chloride andthus, consumes this reaction partner.

Finally, the dissolution capacity of di-n-butyl ether was found to be insufficient. The result isincomplete conversion and in some cases product adhesion. Overall, ethers were ruled out aspotential 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 apromising substitute for EDC. Of all the tested substances, ethyl acetate has been given the mostdetailed consideration; its yield might be considered acceptable and it can deliver the partialreactions without adhesion. However, ethyl acetate faces important technical shortcomings,resulting in impurities in TIP-diamide chloride and consequently resulting in impurities, such asdimeric ester, in the Iopromide made from this TIP-diamide chloride. There are also issues withcolour and recyclability.

Toluene has also been considered as a potential alternative and has been demonstrated to befeasible in the laboratory for both steps when carried out on their own. However, as describedpreviously, the current process involves a one-pot reaction that provides no opportunity forpurification of the intermediate TIP-diamide. This means that any impurities are still present whenthe relatively reactive TIP-diamide chloride is isolated. Given this reactivity, only limited purificationis possible and Bayer Pharma AG was not able to purify this material sufficiently without reducingyield 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 wayout of the problems posed from any attempt to reconcile very different requirements (the solventneeds to be both polar and chemically inert) by using a single solvent. Bayer Pharma AG hasconsidered the possibility that each stage (TIP-diamide and TIP-diamide chloride formation) becarried out in their own optimally feasible solvent.

Under this scenario, the simplest possible and most complete substitution would have to beensured; it would therefore be appropriate for the solvent which is used last to have a significantlyhigher 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. Theprocess would therefore only be worthwhile if at least yields and product quality similar to the

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


current ones could be obtained or else a change to the production process would not beworthwhile.

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

Test synthesis using the 2-solvent combination was indeed carried out by Bayer Pharma AG. Thefollowing 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) weretested 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, theyield 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 is81.3% 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 didnot form until DMF was added as a catalyst, and then substantially more slowly. The yield was afurther 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, asdescribed 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 apotential solution for the substitution of EDC. However, laboratory testing has revealed thatalthough quality might be acceptable, the yield was poor compared to EDC (ca. 19% lower to thecurrent yield). Given the complexities of switching to a dual solvent system, this reduction in yieldand the increased reaction time of the process cannot be justified on technical and economicgrounds 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


For this to work, it would be important to combine the TAMIP-monoamide to TIP-diamide stages asa one-pot process. The isolated TIP-diamide could in theory then be converted to TIP-diamidechloride in any inert solvent or in the absence of solvent (in excess thionyl chloride as solvent). As aresult, 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 chloridepreparation (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 particularproblem 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, thefollowing 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- ortriacetate, a maximum content of 1.5% of which is permitted in the TIP-diamide or TIP-diamidechloride intermediates. Therefore, in order to perform the two-stage reaction and to remove aceticacid, 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 aceticanhydride 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 ofsolvent being lost. Alternatively, to avoid these large quantities of solvent being lost (after removalof the majority of the acetic acid), the remaining residual acetic acid could be purged by refluxingwith a molecular sieve in the vapour phase in the laboratory (Kudschus, 1990). However, removal ofresidual acetic acid with a molecular sieve was found in testing to result in slightly increased, buttolerable 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 ofsolid 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 couldtheoretically 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 isolationdifficult.

9For the formation of TIP-diamide, a more polar and for the formation of TIP-diamide chloride a less polarsolvent 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.


The maximum laboratory yields obtained were 88% for two stages. Conversion of TIP-diamide toTIP-diamide chloride was not possible, as TIP-diamide was difficult to isolate. Finally, it should benoted that 2-ethoxyethyl acetate has not been registered under REACH yet and is accompanied by aRepr. 1B (H360FD) hazard classification10; therefore, it cannot be considered an alternative eligiblefor the substitution of EDC.

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

The substitution of EDC by 2-ethoxyethyl acetate in combination with a change to the stagesequence has been tested but has not been found to be a feasible option. The removal of acetic acidwould imply large solvent losses or, if purging with a molecular sieve were to be used, impurities inthe final products might increase, and this would not be practical on production scale. Beyond theseissues, the use of 2-ethoxyethyl acetate would result in colour development and difficulties in theisolation of TIP-diamide. These obvious technical shortcomings, coupled with the unfavourablehazard profile of the solvent, render this alternative infeasible and unsuitable. No furtherconsideration 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 additionalsolvents that could be considered as substitutes for EDC. Bayer Pharma AG made the positivedecision to assess such additional solvents by undertaking desk-based studies and laboratoryexperiments. Twelve additional solvents belonging to the halogenated hydrocarbon, ester and etherfamilies were identified for assessment, as shown in Table 9-5. In addition, ethyl acetate, the onealternative that the 1990s R&D work had identified as the least infeasible among those tested in thepast, 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


1-Chlorobutane 203-696-6 109-69-3


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

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


Bayer Pharma AG undertook a first screening of the substances for general applicability using thesub-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 potentialalternative solvents

Inertness to thionyl chloride andhydrogen chloride

Boiling point (°C)

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&region=GB** http://www.sigmaaldrich.com/catalog/product/aldrich/112305?lang=en&region=GB*** http://www.sigmaaldrich.com/catalog/product/aldrich/307378?lang=en&region=GB

The above table has led to the exclusion of 2-methyl-tetrahydrofuran, as it is not inert in thepresence of HCl, thus technically infeasible. Laboratory testing of the remaining 12 potentialalternative solvents was undertaken in the period October–December 2014. The key questions thatthe 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 EDCwithout isolation of the first intermediate (product of Step 1). The first group test Bayer Pharma AGundertook in the autumn of 2014 was to subject the shortlisted 12 potential alternative solvents toscaled-down laboratory experiments to establish whether product formation and isolation would bepossible. For comparison, Bayer Pharma AG also tested EDC under the same conditions.


According to the laboratory results, seven out of the twelve alternative solvents failed as thereaction 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 reactionconditions of Step 1, but no clear solution was formed. For these five solvents, the conversion ratein Step 2 was found to be poor (10–20% formed product) (see Table 9-7). The performance of ethylacetate, which had been tested in the past, was actually much poorer than originally expected. ForEDC, under the same conditions, the measured conversion rate was 98%. It is Bayer Pharma AG’sexperience with plant batches that undissolved intermediate does not react in Step 2. If(oversaturated) reaction mixture of Step 1 precipitates, incomplete conversion to TIP-diamidechloride during Step 2 is not possible.

The conclusion of the first test batch was that five alternative substances could be subject to furthertesting 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 bequality.


Table 9-7: First round of laboratory tests in 2014 R&D

Identifiedpotentialalternativesolvent

Stage 1TAMIP-diacetate TIP-diamide

Stage 2TIP-diamide TIP diamide

chlorideConclusion and route to further

testingMixture ‘stirrability’

(viscosity)Conversion rate Notes Conversion rate

EDC – forcomparison

Can be stirred Clear Baseline 98% (in tests) Baseline

1-Chlorobutane Mixture became sticky 50% only

Eliminated from testing forStep 2 due to poor

conversion rate and stickymixture

Not tested – experimentcancelled

Not considered feasible orrealistic

ChlorobenzeneMixture hardened or

became sticky95%

Eliminated from testing forStep 2 as a new impurity

was found at 10-20%



α,α,α-Trifluorotoluene

Mixture hardened orbecame sticky

50-60% onlyEliminated from testing for

Step 2 due to poorconversion rate



FluorobenzeneMixture hardened and

became sticky80-90% only

Eliminated from testing forStep 2 due to poor

conversion rate and stickymixture

Note tested – experimentcancelled


Diethylcarbonate

Could be stirred with astronger stirrer

Not clearIncluded in testing for Step

2<20%

(formed product not isolated)Consider further testing at a

higher temperature

Ethyl acetate Could be stirred Not clearIncluded in testing for Step

2<20%

(formed product not isolated)Consider further testing with a

stronger stirrer

n-Propylacetate



2<20%

(formed product not isolated)Consider further testing at a

higher temperature

Isopropylacetate



2<20%

(formed product not isolated)Consider further testing with a

stronger stirrer

Ethylpropionate


>95%Included in testing for Step

2Solvent completely absorbed by

the reaction mixtureNot considered feasible or

realistic


Table 9-7: First round of laboratory tests in 2014 R&D

Identifiedpotentialalternativesolvent

Stage 1TAMIP-diacetate TIP-diamide

Stage 2TIP-diamide TIP diamide

chlorideConclusion and route to further

testingMixture ‘stirrability’

(viscosity)Conversion rate Notes Conversion rate

n-Butylpropionate


A hard depositformed that could

not be stirred

Eliminated from testing forStep 2 due to sticky mixture



Diisopropylether


N/A

Diisopropyl ether did notcause formation of a solid

block but the reactionmixture became too thick to

be stirred after 2 hours.Thus, it was not possible to

test in Step 2

Not testedConsider further testing with a

stronger stirrer

Cyclopentylmethylether

A stronger stirrer wasused but mixture

remained hardenedNot clear

At Step 1, a compact solidmainly formed at the

bottom of the reactor butthe stirrer could move

above this

<20% (formed product notisolated)

At Step 2, 40–50% of the solidbecame a light suspension. Thissuspension consisted of 20% of

TIP-diamide chloride



Second test batch – Laboratory testing of product formation and isolation – alternative solvents atadapted reaction conditions

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

1. Conduct tests on the completeness of the first reaction step: Reaction with methoxy aceticacid 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 ofproduct and yield

5. If yield appears to be reasonably high and the alternative seems promising, repeat tests at astandard 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

Identifiedpotentialalternativesolvents

Test No.Conversion

(completeness)Absence ofadhesion

Quality /colour value(white, 0.11-

0.15)

Yield Recovery*

EDC Be2794 102%

based onmass input

1-Chlorobutane Be2779

Step 1: 50%conversion

Chlorobenzene Be2778


10-20% by-product at

Step 1

α,α,α-Trifluorotoluene

Be2791

Step 1: 50-60%conversion

Fluorobenzene Be2792


Diethylcarbonate

Be2790



/ ?

Mo202193°C instead

of 63°C

Yellow

88% / ?


Table 9-8: Second batch of laboratory tests on potential alternative solvents in the 2014 R&D

Identifiedpotentialalternativesolvents

Test No.Conversion

(completeness)Absence ofadhesion

Quality /colour value(white, 0.11-

0.15)

Yield Recovery*

Ethyl acetate Mo2020

Step 1: >95%conversionSuspension

difficult to stirStep 2: 10%conversion

n-Propylacetate

Be2784


/ ?

Mo2018

Step 2: after 13hrs instead of 8

hrs

New impurity,Off-yellow

88% / ?

Mo2024Standard-size batch,

93 °Cinstead of

68 °C

76% / ?

Isopropylacetate

Mo2023


(with magneticstirrer)

/ ?

Be2787


(with a strongermechanical

stirrer)

/ ?

Ethylpropionate

Be2783

Step 1: >95%

Step 2: solventcompletelyabsorbed

/ Cancelled

duringStep 2

/ ?

n-Butylpropionate

Mo2022

Step 1: reactionmixture formed

a gum

/ ?

Diisopropylether

Mo2019


/ ?

Cyclopentylmethylether

Be2789


/ Borderline

/ ?

* “?” under recovery means that Bayer Pharma AG has no experience with recovery in the presence of thionylchloride. Esters and secondary ethers might be hydrolysed


The following conclusions can be reached which lead to the elimination of several substances fromfurther consideration:

Elimination on the basis of poor conversion rate at Step 1 and adhesion: several alternativeshave 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-butylpropionate

Elimination on the basis of poor conversion rate at Step 1 without adhesion: some alternativesdo not cause product adhesion but still have poor conversion at reaction Step 1, i.e. diisopropylether and cyclopentyl methylether

Elimination on the basis of poor conversion rate at Step 2: other alternatives offer acceptableconversion at Step 1 but have very low conversion in Step 2, i.e. ethyl acetate and isopropylacetate. Ethyl propionate was completely absorbed by the reaction mixture thus conversionrate could not be estimated

Elimination on the basis of poor product quality and yield: diethyl carbonate requires a highertemperature 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 ahigher temperature but has shown unexpected and insurmountable technical shortcomings:

Testing with lab-size batches under standard temperature conditions: the reaction timewas too long to fit into the synchronised synthesis, thus reducing the productioncapacity of the plant by ca. 27% thus increasing production costs and preventing BayerPharma AG from meeting market demand for Ultravist®

Testing with lab-size batches under elevated temperature conditions: at a highertemperature, the reaction time was acceptable but the yield dropped

Presence of new impurities: under both temperature conditions, a new impurity wasfound in Iopromide batches made from this TIP-diamide chloride at a concentration of0.5%. Regulations allow a concentration of only 0.03% of unknown impurities incontrast media. Notably, this unknown impurity was also found in Iopromide batchesmade 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 othercarbonic acids lead to formation of a new impurity in TIP-diamide chloride thatadversely affects the quality of Iopromide. Furthermore, the new impurity is outside theimpurity profile which is described on the Marketing Authorisations of Ultravist®. Inaddition, 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 noalternative of the 12 selected can perform as well as EDC. In most cases, poor conversion andadhesion make the alternatives wholly infeasible. In a few cases, use of the alternative solventunder high stirring and a higher temperature delivered acceptable conversion (n-propyl acetate anddiethyl carbonate), however, the quality of the product and the resulting yield were unacceptablypoor.

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 feasiblealternative for the specific manufacturing process can be identified. Only few solvents / mixtures of


solvents have been proved to allow complete conversion to of TAMIP-diacetate to TIP-diamidechloride but nor yield neither quality were within the acceptable range.

Consequently, the conclusion is that none of the identified and assessed potential alternatives couldoffer an acceptable level of technical (and economic) feasibility as a substitute for EDC. None ofthese 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 routeshown 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 Jis 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. Productprecipitated by addition of copious water – a large volume of water is required (a ratio of 1:25DMF to water, or some 50 mL per g of product obtained) making the recycling of the solventimpossible

Step 2 – reaction with aminopropanediol to form product (b): 74.5% yield in DMF andtributylamine as base. Complex extraction under reduced pressure and precipitated in DCM asanti-solvent. Finally partially purified by hot filtration using ethyl acetate (approx. 25 mL solventper g of product obtained). Product obtained as a solid (without crystallisation) after removal of


solvent. This step again requires copious solvent, and as no crystallisation is included, theproduct may be not be of high purity

Step 3 – reaction with methylaminopropanediol to form Iopromide: 81% yield in DMF andtributylamine as base. Precipitated by copious dichloromethane (DCM) (some 45 mL DCM per gof 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 obtainedby 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 BayerPharma AG and the process is not ideally suited to large scale synthesis in a process plant. Thereasons 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 copiousamounts of water as an anti-solvent to precipitate the reaction products. On plant scale, this wouldrequire vast quantities of water. For each tonne of intermediate product, some 50 m3 of waterwould 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 anaqueous solution. This step would take a very large amount of energy and, as it does not involvecrystallisation, 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 fewintermediate stages, but has the obvious disadvantage that a monoamide (b) has to be producedfrom the symmetrical diacid chloride (a). The formation of symmetrical diamide is unavoidable andcan only be decreased by using a reduced amount of the amine components, as a result of which, inaddition 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 avery similar structure to that of Iopromide (one methyl group difference) and therefore it is likelythat their separation will be difficult. In the further course of synthesis withmethylaminopropanediol, the diacid chloride (a) would also result in the formation of a relatedcompound 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 therequired conversion to monoamide (b) would not be efficient. There is an accumulation of a largequantity of the symmetrical diamide, which cannot be used for further synthesis, and the recyclingof the excess diacid chloride (a) is complex. The yield is stated as 74.5%; however, no indication ofthe 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 directlycomparable 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 massbalance, ultimately resulting in increased process costs.


9.2.2 Alternative Synthetic Route B

Description

According to the 1982 patent filed by Schering AG, Iopromide may be synthesised using the pathwaydefined 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, etal., 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 overallyield 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 ofhalogenated solvents for these steps and the intermediate product (d) is obtained in 83.8% ×96% × 92% (over two-steps in-situ) = 73.7% yield.


Step 4 – hydrogenation and iodination of product (d) to obtain product (e): the nitro group ishydrogenated using Raney nickel11 as catalysts to obtain the primary amine and the product isiodinated 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 chloridein dimethyl acetamide (DMA). This is then used to acylate the amine of product (e). The crudeproduct is obtained by removal of solvent under reduced pressure and the acetyl groupshydrolysed (alcohol deprotection) using aqueous ammonia. This results in the formation ofacetamide as the by-product. The final product is obtained from an aqueous solution aftertreatment with ion-exchange resins (Amberlite XAD-4”, as for Alternative Synthetic Route A).The yield resulting from these steps is 78.4%.


Issues with late iodination: the viability of Synthetic Route B is negatively affected by lateiodination, in which a quite complex molecule is subjected to harsh reaction conditions which mayinvolve additional secondary reactions. The relatively low yield of this step of 71.3% supports thepremise 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 amidegroups, the formation of triiodoaromates is hindered, which results in the impairment of quality andyield.

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 toxicitythis 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 thatis 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 routeshown in Example 8 in the patent. This suggests the following route, depicted in Figure 9-3. Thesynthesis is quite similar to the others; however the hydrogenation and iodination steps occurslightly earlier than in Alternative Synthetic Route B, i.e. before the introduction of themethylaminopropanediol component. ''#A#'''''' '''''''''' '''''''''''''''' ''''''''''''''''''' ''''' '''''''''''' ''''''''''''''' ''''''' ''''''''''''''''''''''' '''' ''''''' '''''''''''''''''''''''' ''''''''''''' '''' '''''''''''''''' ''''' ''' ''''''''''''''''''''''''''''''''' ''''''' ''''''''' '''' '''''''''''''''' ''''''''' ''''''''''''''''''''''''' '''''''''''''''''' ''''''' '''''''''''''''''' '''' '''''''''''''''''' '''''''''''' '''' '''''' ''''''''''''''' ''''''''''' ''''''' '''''' '''''''''''''''' '''' '''''''''''''

'#A#''''''' ''' ''' '''''''''''''''''''''' ''''' '''''''''''''''''''''''''''''''' '''''' ''''' '''' ''''''' '''''''''''''''' ''''''' '''''''''''''''' ''''''''''''''''' ''''''' '''' '''''''''''''' '''''''''' '''''''''''''''''''''''''' ''''''''''''''''''''''''''' '''' '''''' ''''''''''''''''''''''' '''''''''' '''''''''''''''''''''''' '''''''''' ''''' '''''''''''''''''''' '''''''''''''' ''''' ''''''''' ''''''' '''''''''''''' '''''''' ''''''''' '''''''''

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


''''''''' ''' ''' '''''''''''''' '''''''' '''''''''''''''''''''''''' ''''''''''''''' '''' '''''''' ''''''''''''''''''''''' '''''''''''''''' ''''''''''''''''''''''''''''''''''' '''''''''''''''' '''' ''''''''''''''''' '''' '''''''''' '''' '''''''''''''' ''''''''''' '''''''''''''' '''''''''''''''' ''''''' '''''''''''''''''''' ''''''''''''' ''''''' '''' ''''''''''' ''''''''''''''''''''''''' '''''''''' '''''' ''''''''''' '''''''''' ''''''''''''''' '''' '''''''''' '''''''''' '''''''''''''''''''''''''''''' ''''''' '''''' ''''''''''''''' '''' '''''''''''''''' ''''' '''''''''''''''''''''' ''''''''''' ''''''''' ''''''' '''''' '''' '''''''' ''''''' ''' '''''''''''''''''''''''''''' '''''''''''''' ''''''''''''''''' '''''''''''''''''' ''''' ''''''''''''''''''' ''''''''' ''''''''''''''''' '''''''''' ''''''''''''''''''''''''''''''''''' '''''''''''''' '''''''''''''' ''''''''''' ''''''''''''' '''''''''''''''

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


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

Issues with phosphorus pentachloride: phosphorus pentachloride is highly corrosive and toxic, andtherefore 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#'''''' ''''''' ''''''''''' ''''''''''''''''''''''''''''''''''' ''''' '''''' '''''''''''''''''''' '''''''''''''''''''' ''''' '''''''''''''''''''''''''''' ''''''''''''''''''' '''' ''''''''' '''''''''''''''''' ''''''''''' '''''''''''''''''''''''''''' ''''''''''' '''''''''''''''' ''''''''' '''''''' '''''''''''''''' '''''''' ''''''''''''''''''' '''''''''''''' '''''''''''''''' '''''''''''' '''''''''' ''''''' ''''''''''''''''''''''''


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, etal., 2000)

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

Steps 1-2: The methoxyacetyl group is added to the starting material, followed bydesymmetrisation by addition of aminopropanediol. The steps of the synthesis are carried outwithout isolation of the intermediates up to the unacetylated intermediate (Example 1) in a yieldof 66.1% in DMA as solvent. In a similar fashion to all of the alternative syntheses described, theintermediate product is isolated using large quantities of DCM


Step 3 – Acetylation to obtain TIP-diamide chloride (Example 2): The intermediate diol isacetylated 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.


Synthetic Route D is based on Synthetic Route A and offers a solution for the difficult separation ofthe undesirable symmetric diamide. According to the details of the patent, the introduction of theacetate protecting groups permits separation in a simple manner. Nevertheless, the problem ofpoor efficiency described in Synthetic Route A remains. The symmetric diacid chloride cannot beconverted selectively to the monoamide. Considerable quantities of waste materials containingiodine 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 reactionshas 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 synthesiscurrently 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 butthe yield would be much lower.

Table 9-9: Comparison of yields of Synthetic Route D and the current Bayer Pharma AG synthetic route

FunctionalisationSynthetic Route D(% of theoretical)

Current Bayer Pharma AGsynthetic 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 withsuch processes, and the remaining by-products need to be purified (diacid chloride) and/or disposedof (di-substituted product). In addition, the yield of Synthetic Route A (44.7%) is clearly far worsethan 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 subsequentstage occurs with a complex molecule, in which the positions to be occupied by iodine are impairedspatially by the side chains which are already present in the molecule. As a result of the aggressivereaction conditions which are required (iodination with chlorine iodide), there is a risk that amultitude of by-products will form shortly before the final stage (API), and that these will differsubstantially from those which are present in the current iopromide. In addition, the yield of


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 BayerPharma AG ('#A#'''''''' for the same conversion), thus it may not be considered a realistic, viablealternative technology to the EDC-based route.

Synthetic Route D means that the symmetric diacid chloride cannot be converted selectively to themonoamide. The reason for this is the poor selectivity in the reaction of symmetrical diacid chloridewith aminopropanediol in Synthetic Route D. In addition, the yield of Synthetic Route D (50.7%), isclearly far worse than the route currently used by Bayer Pharma AG '#A#''''''''''''''' thus it may not beconsidered 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 syntheticroute

Technical feasibility issues

Synthetic Route A(Speck, et al., 1982;Hwang, et al., 2009)

Few intermediate steps only Formation of symmetrical diamide results in unreacted diacid chlorideremaining in reaction mixture – difficult separation Recycling problems Poor overall yield (44.7%)

Synthetic Route B(Speck, et al., 1982)

Late iodisation and secondary reactions Steric hindrance affecting quality and yield Poor overall yield (41.4%)

Synthetic Route C(Speck, et al., 1982)

'#D#''''''''''''''' '''''' '''''''''''''''''''''''''''''' ''''''' ''''''''''''''''''''''' '''''''''''''''' Uses hard to recycle solvent, DMA (reprotox) Poor yield for the same transformation (70%)

Synthetic Route D(Gyu, et al., 2000)

Improvement over Synth. Route A with ready separation of symmetric diamide Iodine-containing waste losses 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 currentassessments

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


Table 9-11: Summary of technical feasibility assessment for all identified alternatives

Investigated solvents EC Number CAS Number Assessment of technical feasibility ConclusionConsidered for

further screening?Methanol 200-659-6 67-56-1 Alcohol: formation of chloroalkanes and sulphurous acid esters with

thionyl chlorideInfeasible

Ethanol 200-578-6 64-17-5 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 thesame functional group as starting material so the thionyl chloridewould simply react with the solvent rather than the starting material

Infeasible

Acetone 200-662-2 67-64-1 Ketone: reaction with the amine group of the starting materials toform Schiff bases

Infeasible

Methyl ethyl ketone (MEK) 201-159-0 78-93-3 Infeasible

Methyl isobutyl ketone(MIBK)

203-550-1 108-10-1 Infeasible

Acetonitrile 200-835-2 75-05-8 TestedFeasible for 1st synthetic stage. Reacts remarkably with thionylchloride, so that yields and colour values fluctuate substantiallyaccording to reaction conditions; additional purification would benecessary. Yield varies due to decomposition. No recycling method isknown

Infeasible

Dimethyl formamide (DMF) 200-679-5 68-12-2 Dipolar aprotic solvent: Violent reaction with thionyl chloride. Manydipolar aprotic solvents are miscible with water (all of the solventstrialed by Bayer Pharma AG) making the recovery of products verycomplex

Infeasible

Hexamethylphosphoramide(HMPTA)

211-653-8 680-31-9 Infeasible

N,N-dimethylacetamide(DMA)

204-826-4 127-19-5 Infeasible

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 TestedFeasible for 1st synthetic stage. Affected by impurities in TAMIP-diacetate batches causing adhesion and colouring even if used incombination with other solvents (e.g. acetonitrile). Ultra-pure TAMIP-diacetate batches impossible to produce at industrial scale. Yield wasclose to EDC

Infeasible




further screening?Cyclohexane 203-806-2 110-82-7 Tested

Alkane: aprotic solvent, feasible for 1st synthetic stage. Partialreactions remain incomplete. Poor solubility of starting materials.Does not have the capacity to keep the accompanying impurities inthe mother liquor in solution

Infeasible

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 TestedInfeasible for 1st synthetic stage. Dissolution is too low. Causesadhesion

Infeasible

1-Chlorobutane 203-696-6 109-69-3 Tested (2014)Poor conversion and adhesion. Unusable

Infeasible

Chlorobenzene 203-628-5 108-90-7 Tested (2014)Generation of a new impurity (10-20%). Unusable

Infeasible

α,α,α-Trifluorotoluene 202-635-0 98-08-8 Tested (2014)Poor conversion and adhesion. Unusable

Infeasible

Fluorobenzene 207-321-7 462-06-6 Tested (2014)Poor conversion and adhesion. Unusable

Infeasible

Ethyl acetate 205-500-4 141-78-6 TestedCould deliver for both synthetic stages. Substance separationinsufficient; colour values very poor; additional purification needed,with yield losses. Poor dissolution of impurities.Poor recyclability as impossible to separate from thionyl chloride.Combinations with cyclohexane and toluene were unsatisfactory(poor quality for the former, and process complexities and poor yieldfor the latter)

Infeasible For completeness; thisis the most promisingsubstance from the

past R&D work and theone most thoroughly

assessed so far

Butyl acetate 204-658-1 123-86-4 TestedBetter recyclability than ethyl acetate. Insufficient dissolutionproperties, no complete conversion was achieved and in some casesproduct adhesion occurred

Infeasible




further screening?2-ethoxyethyl acetate 203-839-2 111-15-9 Tested

Used with alternative reaction sequence. Large losses of solventduring removal of acetic acid. Issues with N-acetate impurities.Colouration issues (possibly solved with addition of acetonitrile (afterremoval of acetic acid). Unsatisfactory filterability of TIP-diamide,difficult to isolate

Infeasible

Diethyl carbonate 203-311-1 105-58-8 Tested (2014)Conversion and adhesion issues resolved at high temperature butyield is poor and product is of very low quality (yellow)

Infeasible

n-Propyl acetate 203-686-1 109-60-4 Tested (2014)Conversion and adhesion issues resolved at high temperature butyield is poor and product is of low quality (new impurity and off-yellow)

Infeasible Substance is poor

compared to EDC butalso the most

promising in the 2014lab tests

Isopropyl acetate 203-561-1 108-21-4 Tested (2014)Poor conversion and adhesion. Unusable

Infeasible

Ethyl propionate 203-291-4 105-37-3 Tested (2014)Absorbed by the mixture. Unusable

Infeasible

n-Butyl propionate 209-669-5 590-01-2 Tested (2014)Created a solid block that could not be stirred. Unusable

Infeasible

Diethyl ether 200-467-2 60-29-7 Boiling point too low (<50 °C). Dissolution capacity is too low andresults in product adhesion

Infeasible

Di-n-butyl ether 205-575-3 142-96-1 TestedDissolution capacity is too low; incomplete reactions and productadhesion

Infeasible

Methyl tert-butyl ether 216-653-1 1634-04-4 TestedDissolution capacity is too low and results in product adhesion

Infeasible

Tetrahydrofuran (THF) 203-726-8 109-99-9 TestedInfeasible for both stages; reacts with HCl slowly to form 4-chlorobutanol and this reacts further with thionyl chloride to form 1,4-dichlorobutane

Infeasible




further screening?Dioxane 204-661-8 123-91-1 Tested

Feasible for both synthetic stages. Too high dissolution capacity forTIP-diamide chloride that they cannot be isolated. Promising whenused with toluene but the two solvents could not be separatedeconomically by distillation (dioxane is water soluble and the BayerPharma AG distillation plant could not cope with a dioxane/toluenemixture). In presence of HCl, it is subject to slow decomposition withformation of 2-(2-chloroethoxy)ethanol (CAS No. 628-89-7), whichupon reaction with thionyl chloride would give the acutely toxic bis-(2-chloroethyl)-ether. A decomposing solvent such as dioxane cannot beconsidered a realistic option

Infeasible

Diglyme 203-924-4 111-96-6 TestedDissolution capacity is too low and results in product adhesion

Infeasible

2-methoxy-2-methylbutane(tert-Amyl methyl ether(TAME))

213-611-4 994-05-8 TestedSubject to ether cleavage under the reaction conditions. Reacts withmethoxyacetyl chloride and thus consumes this reaction partner

Infeasible

2-Methyl-tetrahydrofuran 202-507-4 96-47-9 Reacts with HCl Infeasible

Diisopropyl ether 203-560-6 108-20-3 Tested (2014)Created a solid block that could not be stirred. Unusable

Infeasible

Cyclopentyl methylether 445-090-6 5614-37-9 Tested (2014)Created a solid block that could not be stirred. Unusable

Infeasible




further screening?

Alternative synthetic routes

Synthetic Route AExample 6 in Schering AGpatent


(Speck, et al., 1982)KR20000061780

Dong Kook Pharm Co Ltd(Gyu, et al., 2000)

Few intermediate steps only Formation of symmetrical diamide results in unreacted diacidchloride remaining in reaction mixture – difficult separation Recycling problems Poor yield (44.7%)

Infeasible For completenessonly: process has

been demonstrated inthe lab, but clearly

worse than EDC

Synthetic Route BExample 7 in patent


(Speck, et al., 1982)

Late iodisation and secondary reactions Steric hindrance affecting quality and yield Poor yield (41.4%)



worse than EDC

Synthetic Route CExample 8 in patent


(Speck, et al., 1982)

Proceeds via TAMIP-diacetate and TIP-diamide chloride Poor yield for conversion of TAMIP-diacetate to TIP-diamidechloride (70%) Recycling problems



worse than EDC

Synthetic Route D WO 2009134030 A1LG Life Sciences Ltd

(Hwang, et al., 2009)

Improvement over Synth. Route A with ready separation ofsymmetric diamide Iodine-containing waste losses Recycling problems Poor yield (50.7%)



worse than EDC


9.3.2 Screening for market availability and commercialisation

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


Syntheticroute

Solvents used in relevant patents

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), tributylamine

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 9-13looks at the availability of REACH Registrations for each substance. Grey colours indicateproblematic areas. Bayer Pharma AG currently (2014) uses 100-1,000 ('#B#'''''') t/y EDC andwould 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 tothe approved residual concentration limits. If it were not, the solvent would not beconsidered as immediately available as it would require new testing to establish residuallevels and the associated hazards in order to achieve a Guideline listing status. This is alsopresented in Table 9-13.

3. Any alternative solvent or synthetic route should ideally have been proven at the industrialscale. No alternative meets this criterion. Bayer Pharma AG is the only company globally toproduce the specific X-ray contrast medium, Iopromide; therefore, none of the alternativeshave 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 inthe 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.


Table 9-13: Summary of market availability and commercialisation status of all identified alternatives


EC NumberCAS

NumberRegistration status as of 8

October 2014ICH Q3(R5) listing

(limit)Known commercial use

Conclusion onavailability

Alternative solvents from applicant’s R&D

Ethyl acetate 205-500-4 141-78-6Registered

100,000 – 1,000,000 t/yNamed registrants: 41

Class 3 Not in synthesis of IopromideAvailable butcommercially

unproven

n-Propyl acetate 203-686-1 109-60-4Registered

10,000 – 100,000Named registrants: 5

Class 3 Not in synthesis of IopromideAvailable butcommercially

unproven

Solvents/reagents required in alternative synthetic routes

Dimethylformamide(DMF) – Routes: A, C

200-679-5 68-12-2Registered

10,000–100,000 t/yNamed registrants: 12

Class 2880 ppm

Relevant synthetic routes havenever been used for the

production of Iopromide due totheir low efficiency. In addition,Bayer Pharma AG’s competitors

do not have the same API

Available butcommercially

unproven

Dichloromethane(DCM) – Routes, A, B,C, D

200-838-9 75-09-2Registered

100,000 – 1,000,000 t/yNamed registrants: 11

Class 2600 ppm


unproven

Ethyl acetate –Routes: A

205-500-4 141-78-6 See above See aboveAvailable butcommercially

unproven

Tributylamine –Routes: A, C

203-058-7 102-82-9Registered1,000+ t/y

Named registrants: 3-


unproven and notlisted by ICH

Methanol – Routes: B 200-659-6 67-56-1Registered

1,000,000 – 10,000,000 t/yNamed registrants: >100

Class 23,000 ppm


unproven

Acetone – Routes: B 200-662-2 67-64-1Registered

1,000,000 – 10,000,000 t/yNamed registrants: 42

Class 3Available butcommercially

unproven

Dioxane – Routes: B 204-661-8 123-91-1Registered

100+ t/yNamed registrants: 3

Class 2380 ppm

Poor marketavailability andcommercially

unproven


Table 9-13: Summary of market availability and commercialisation status of all identified alternatives


EC NumberCAS

NumberRegistration status as of 8

October 2014ICH Q3(R5) listing

(limit)Known commercial use

Conclusion onavailability

N,N-dimethylacetamide(DMA) – Routes: B, C,D

204-826-4 127-19-5Registered

10,000– 100,000 t/yNamed registrants: 13

Class 21,090 ppm


unproven

Toluene – Routes: C 203-625-9 108-88-3 See above See aboveAvailable butcommercially

unproven

Acetic acid – Routes:D

200-580-7 64-19-7Registered

1,000,000–10,000,000 t/yNamed registrants: >100

Class 3Available butcommercially

unproven

Triethylamine –Routes: D

204-469-4 121-44-8Registered1,000+ t/y

Named registrants: 9-


unproven and notlisted by ICH

Source: Bayer Pharma AG’s data; http://echa.europa.eu/information-on-chemicals/registered-substances (accessed on 8 October 2014); (ICH, 2011)


9.3.3 Screening for hazard profile

The intrinsic hazard properties of the remaining substances were screened to identify thosesubstances that have critical hazard properties (e.g. CMR properties), which would make themunsuitable 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. Inaddition, any information on other REACH-related activities (e.g. listing as SVHC, information onrestrictions, authorisation) was followed-up and evaluated regarding its potential consequences forusing the substance as an alternative to EDC.

Furthermore, eChemPortal was consulted to check any involvement in other regulatory programmesand 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 thescreening exercise. The following preliminary conclusions may be reached:

Two substances, dimethyl formamide (DMF) and dimethylacetamide (DMA), present equivalentconcern to EDC and have been proposed for inclusion in Annex XIV. Therefore, they wereexcluded from further investigation. These solvents are relevant to all alternative syntheticroutes (A and C for DMF and B, C and D for DMA)

Two more substances are suspected CMRs, dichloromethane and dioxane (Carc Cat 2). Thesealternatives would require additional consideration, had they shown evidence of technicalfeasibility

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


Table 9-14: Screening of shortlisted potential alternative solvents for hazards

Examplesolvents

EC No. CAS No. Registrationstatus

Classification Comments Conclusion

Ethyl acetate 205-500-4 141-78-6 Fullregistration100,000–1,000,000 t/y

Flam. Liq. 2 H225Eye Irrit. 2 H319STOT SE 3 H336

- No obvious CMRproperties, eligible,sufficient data forassessment available

n-Propylacetate

203-686-1 109-60-4 Fullregistration10,000–100,000 t/y


REACH Registration and C&L data reviewAssessment in registration mainly based on read-acrossOECD SIDS ConclusionsHuman health: n-Propyl acetate may present ahazard for human health (skin and eye irritation andpotential reproductive/developmental toxicity athigh doses).Environment: n-Propyl acetate may present ahazard for the environment (acute aquatic toxicityvalues between 1 and 100 mg/L). However, thechemical biodegrades rapidly and exhibits limitedpotential for bioaccumulationICH Q3C(R5) GuidelinesClass 3 (solvents with low toxic potential solventswhich should be limited by GMP or other quality-based requirements)

No obvious CMRproperties, butlimited information,assessment inregistration mainlybased on read-across

Dimethylformamide (DMF)

200-679-5 68-12-2 Fullregistration10,000–100,000 t/y

Acute Tox. 4 * H312Eye Irrit. 2 H319Acute Tox. 4 * H332Repr. 1B H360D ***

REACH Annex XIV (Authorisation)SVHC Proposal, Toxic to reproduction, Sweden,27/08/2012Candidate List, 19/12/20125

thRecommendation for Prioritisation, 06/02/2014,

Proposed latest application date: August 2016PACT-RMOA Substance ListRMOA intention, Italy, 17/01/2014, underdevelopmentRegistry of IntentionsRestriction, Italy, 17/01/2014. Placing on the market

Reprotoxic,recommended forinclusion in AnnexXIV, not eligible tosubstitute EDC



Examplesolvents



of articles containing DMF in concentrationexceeding the level specified in the restriction.PROCs and professional uses (i.e. mixtures of DMF asstrippers, paints etc.) where a risk scenario isidentifiedIARC Classification3 (Not classifiable as to its carcinogenicity tohumans), Vol 47, 71 1999ICH Q3C(R5) GuidelinesClass 2 (solvents to be limited), 880 ppm

Dichloromethane (DCM)

200-838-9 75-09-2 Fullyregistered100,000 -1,000,000 t/y

Carc. 2 H351 REACH Annex XVII (Restrictions)Paint strippers containing DCM in aconcentration equal to or greater than 0,1 % byweight shall not be placed on the market forsupply to the general public or to professionalsCoRAP ListItaly, Carcinogen/suspected Mutagen/suspectedReprotoxic/suspected sensitiser, high (aggregated)tonnage, new entryIARC Classification2A (Probably carcinogenic to humans), Vol 71, 110 InprepICH Q3C(R5) GuidelinesClass 2 (solvents to be limited), 600 ppm

Suspectedcarcinogenicsubstance (currentlyunder review),eligible only if thereare other strongarguments in favourof the substance (e.g.technical feasibility)

Tributylamine 203-058-7 102-82-9 Registered1,000+ t/y

Acute Tox. 4 H302Acute Tox. 2 H310Skin Irrit. 2 H315Acute Tox. 1 H330

- No obvious CMRproperties, eligible,sufficient data forassessment available

Methanol 200-659-6 67-56-1 Fullyregistered1,000,000 -10,000,000 t/y

Flam. Liq. 2 H225Acute Tox. 3 * H301Acute Tox. 3 * H311Acute Tox. 3 * H331STOT SE 1 H370 **

PACT-RMOA Substance ListRMOA Intention, CMR, Denmark, 10/12/2013, underdevelopmentRestriction proposalPoland, 01/08/2014, windshield washer fluids

No obvious CMRproperties, eligible,sufficient data forassessment available



Examplesolvents



CoRAP ListPoland, 2012, Human health/suspected CMR;exposure/high exposure for workers and theenvironment, wide dispersive use, consumer use,on-goingOECD SIDS ConclusionsHuman Health: Methanol exhibits potentialhazardous properties for human health (neurologicaleffects, CNS depression, ocular effects, reproductiveand developmental effects, and other organtoxicity). Rapid metabolism and excretion is noteddepending on the dose. In the US (the IntegratedRisk Information System), further work is beingperformed regarding the use and refinement ofpharmacokinetic models for extrapolating animaldata to humans.Environment: The chemical is currently of lowpriority for further work, due to its low hazardprofileICH Q3C(R5) GuidelinesClass 2 (solvents to be limited), 3,000 ppm

Acetone 200-662-2 67-64-1 Fullyregistered1,000,000 -10,000,000 t/y


ICH Q3C(R5) GuidelinesClass 3 (solvents with low toxic potential solventswhich should be limited by GMP or other quality-based requirements)


Dioxane 204-661-8 123-91-1 Fullregistration100+ t/y

Flam. Liq. 2 H225Eye Irrit. 2 H319STOT SE 3 H335Carc. 2 H351

Regulated under ESRCommission Recommendation 2002/575/ECWorkers: there is a need for specific measures tolimit the risks because of concerns for (a) defattingwith subsequent adverse skin effects as aconsequence of exposure arising from production,formulation and use of the substance or the product

Suspectedcarcinogenicsubstance, eligibleonly if there are otherstrong arguments infavour of thesubstance (e.g.



Examplesolvents



containing the substance, (b) general systemictoxicity and carcinogenicity as a consequence ofdermal exposure arising from the use of thesubstance in cleaning agents, and (c) generalsystemic toxicity and carcinogenicity as aconsequence of inhalation exposure arising fromformulation of the substanceStrategy proposed: develop at Community leveloccupational exposure limit values for the substanceIARC Classification2B (Possibly carcinogenic to humans), Vol. 11, Sup 7,71 1999ICH Q3C(R5) GuidelinesClass 2 (solvents to be limited), 380 ppm

technical feasibility)

N,N-dimethylacetamide (DMA)

204-826-4 127-19-5 Fullyregistered10,000–100,000 t/y

Acute Tox. 4 * H312Acute Tox. 4 * H332Repr. 1B H360D ***

REACH Annex XIV (Authorisation)SVHC Proposal, Toxic to reproduction, ECHA,29/08/2011Candidate List, 19/12/20114

thRecommendation for Prioritisation, 17/01/2013,

Proposed latest application date: November 2015ICH Q3C(R5) GuidelinesClass 2 (solvents to be limited), 1,090 ppm

Reprotoxic, noteligible to substituteEDC

Acetic acid 200-580-7 64-19-7 Fullyregistered1,000,000–10,000,000 t/y

Flam. Liq. 3 H226Skin Corr. 1A H314

ICH Q3C(R5) GuidelinesClass 3 (solvents with low toxic potential solventswhich should be limited by GMP or other quality-based requirements)


Triethylamine 204-469-4 121-44-8 Registered1,000+ t/y

Flam. Liq. 2 H225Acute Tox. 4 * H302Acute Tox. 4 * H312Skin Corr. 1A H314Acute Tox. 4 * H332

OECD SIDS ConclusionsHuman health: The tertiary amines categorymembers possess properties indicating a hazard forhuman health; based on read-across, TEA and DMEAmay also cause similar developmental effects by theoral route.Environment: The tertiary amines category




Examplesolvents



members possess properties indicating a hazard forthe environment (acute aquatic toxicity valuesbetween 1 and 100 mg/L). The category membersare readily biodegradable and are not expected tobioaccumulate

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 December2015)* Bold letters indicate harmonised classification under the CLP Regulation, normal letters indicate notified classification (joint entry from registration); italics indicate mostcommonly notified classification only


9.3.4 Summary of screening process

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

Table 9-15: Conclusion of screening of identified potential alternatives

Identifiedpotentialalternative

Technical feasibilityAvailability and

commercialisationstatus

Hazard profileConclusion of

screeningprocess

Alternative solvents from applicant’s R&D

Ethyl acetateInfeasible

Poor quality, poor yield,cannot be recycled


unproven

No obvious CMRproperties, eligible,sufficient data for

assessment

Technicallyunacceptable;not a realistic

option

n-Propyl acetate

InfeasibleConversion andadhesion issuesresolved at high

temperature but yield ispoor and product is of

low quality (newimpurity and yellowish)


unproven

No obvious CMRproperties, limited

information, assessment inregistration mainly based

on read-across

Technicallyunacceptable;hazard profile

could bedifficult to

establish in full;not a realistic

option

Solvents required in alternative synthetic routes

Synthetic RouteA

InfeasibleLow yield, recycling

problems, separation ofimpurities

Solvents availablebut synthetic route

is commerciallyunproven

DMF: Reprotoxic,recommended for inclusion

in Annex XIVDCM: Suspected

carcinogenic substance(currently under review)Not eligible to substitute

EDC

Technicallyunacceptable

and dependenton hazardous

solvents;not an option

Synthetic RouteB

InfeasibleLow yield and quality

due to steric hindrance,late iodisation and

secondary reactions



DMA: ReprotoxicDioxane: Suspected

carcinogenic substanceDCM: Suspected


EDC




Synthetic RouteC

InfeasibleLow yield, recycling

problems



DMF: Reprotoxic,recommended for inclusion

in Annex XIVDCM: Suspected

carcinogenic substance(currently under review)

Toluene: Suspectedreprotoxic substance

Not eligible to substituteEDC




Synthetic RouteD

Infeasible(better than Synth.

Route A)Low yield, I-containingwaste losses, recycling

problems



DMA: ReprotoxicDCM: Suspected


EDC





10 Annex 3: Justifications for confidentiality claims

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


Table 10-1: Justifications for confidentiality claims

Reference type Commercial Interest Potential Harm Limitation to Validity of Claim