ANALYSIS OF ALTERNATIVES Public version

Legal name of applicant(s): Eli Lilly S.A. Irish Branch

Submitted by: Eli Lilly S.A. Irish Branch

Substance: 1,2-Dichloroethane (EC No. 203-458-1, CAS No. 107-06- 2)

Use title: Industrial use as a reaction medium and a solvating agent in mediating subsequent chemical transformation reactions leading to the manufacture of an Active Pharmaceutical Ingredient, Raloxifene Hydrochloride

Use number: 1

The information in this document is the property of Eli Lilly and Company. It may not be copied without the express written consent of Eli Lilly and Company. The information is given in good faith based upon the latest information available to Eli Lilly and Company. Disclaimer

This report has been prepared by Risk & Policy Analysts Ltd, with reasonable skill, care and diligence under a contract to the client and in accordance with the terms and provisions of the contract. Risk & Policy Analysis Ltd will accept no responsibility towards the client and third parties in respect of any matters outside the scope of the contract. This report has been prepared for the client and we accept no liability for any loss or damage arising out of the provision of the report to third parties. Any such party relies on the report at their own risk.

Note

This public version of the Analysis of Alternatives includes some redacted text. The letters indicated within each piece of redacted text correspond to the type of justification for confidentiality claims which is included as Annex 6 (Section 13) in the complete version of the document. Table of contents

1 Summary ...... 1 1.1 The applied for use ...... 2 1.2 Efforts made to identify potential alternatives ...... 2 1.3 Assessment of suitability and availability of possible alternatives ...... 4 1.4 Actions needed to improve feasibility and availability of possible alternatives ...... 6

2 Analysis of substance function ...... 9 2.1 Role of the substance ...... 9 2.2 Conditions of use and technical feasibility criteria ...... 14 2.3 Summary of functionality of EDC in the “Applied for Use” ...... 18

3 Annual tonnage ...... 21 3.1 Tonnage band ...... 21 3.2 Trends in the consumption of EDC ...... 21

4 Identification of possible alternatives...... 23 4.1 List of possible alternatives ...... 23 4.2 Description of efforts made to identify possible alternatives ...... 24 4.3 Screening of potential alternatives ...... 28

5 Suitability and availability of possible alternatives ...... 33 5.1 Alternative 1 – DCM ...... 33 5.2 Alternative 2 – Chlorobenzene ...... 41

6 Overall conclusions on suitability and availability of possible alternatives ...... 49 6.1 Technical feasibility of possible alternatives ...... 49 6.2 Economic feasibility of possible alternatives ...... 51 6.3 Reduction of risks from the use of possible alternatives ...... 51 6.4 Availability of possible alternatives ...... 52 6.5 Overall conclusion ...... 52 6.6 Next steps during an Authorisation review period ...... 53

7 List of information sources ...... 57

8 Annex 1 – Regulatory controls on the use of EDC in the pharmaceutical industry ...... 59 8.1 Requirements of Marketing Authorisations and their variations ...... 59 8.2 Regulatory controls on residual solvents ...... 59

9 Annex 2 – Screening of the master list of potential alternatives ...... 61

10 Annex 3 – Economic feasibility of possible alternatives ...... 71 10.1 Introduction ...... 71 10.2 Economic feasibility of dichloromethane ...... 71 10.3 Economic feasibility of chlorobenzene ...... 74

11 Annex 4 – Risk evaluation of alternatives ...... 77 11.1 Background ...... 77 11.2 Reference values (DNELs, PNECs) for EDC and alternative substances ...... 78 11.3 Exposure Assessment ...... 94 11.4 Results of the comparative exposure assessment and risk characterisation ...... 97 11.5 References for Annex 4 ...... 98

12 Annex 5 – Theoretical conversion timeline ...... 103

13 Annex 6 – Justifications for confidentiality claims ...... 105

1 Summary

• EDC is used in the manufacture of an Active Pharmaceutical Ingredient (API) for a medicinal product used for the treatment of osteoporosis and reducing the risk of oestrogen-dependent breast cancers1

• The consumption of EDC in the applied for use is declining due to challenging market pressures from generics manufacturers

• Eli Lilly has undertaken extensive R&D on 23 solvents including EDC (mostly halogenated hydrocarbons). EDC is the only solvent that met all technical feasibility criteria including satisfactory yield, product quality and crystal form. Alternative solvents should ideally be listed in the relevant ICH guidelines on residual solvents in pharmaceutical products

• Of the 22 solvents investigated (excluding EDC), 15 were initially discarded due to the insolubility of the starting materials. Seven were shortlisted for more extensive development work. The performance of the 7 shortlisted solvents was still poor when compared to EDC against the pre-selected technical feasibility criteria and hazard profile (see Annex 2, Table 9-1 and Table 9-3).

• Eli Lilly selected two alternative solvents for detailed assessment, dichloromethane (DCM) and chlorobenzene. EDC replaced DCM in the 1990s when the manufacturing process was altered and improved (see Section 4.2). Both selected alternatives are technically infeasible as they face problems with process safety (static build-up), the reaction kinetics, reaction mixture homogeneity, the crystal form of the product and product purity (see Table 1-1). DCM is a suspected carcinogen (recently classified 2A by the International Agency for the Research on Cancer)

• Only the development of an alternative synthetic route could enable the use of an alternative solvent. Significant effort was made in the initial R&D to identify an alternate route and the commercial route executed today is deemed the only solution to difficult synthetic challenges. An alternate route is therefore not deemed to be achievable by the Sunset Date

• This AoA considers a theoretical timeline for converting to a yet unknown solvent alternative. As shown in Annex 5 (Section 12) to this AoA , such a theoretical timeline requires a period of at least 7 years before a commercially viable and technically feasible alternative could be identified and a minimum of 5 years for plant conversion and execution of all engineering, process validation, quality and regulatory requirements. For instance, for the variation of the existing Marketing Authorisations alone, an estimated 2-3 years would be required.

• Eli Lilly’s future action plan will aim at monitoring scientific developments while improving the handling and use of EDC to reduce potential worker exposure

1 In the EU - Evista® is authorised by the European Medicines Agency (EMA) for the treatment and prevention of osteoporosis. Whilst in the US the Food and Drug Administration (FDA) has approved Evista® for osteoporosis and the reduction of the risk of invasive breast cancer in both post-menopausal women with osteoporosis and post-menopausal women at high risk for invasive breast cancer.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 1

1.1 The applied for use

1,2-Dichloroethane (hereafter referred to as EDC) is used by Eli Lilly S.A. Irish Branch (hereafter referred to as Eli Lilly) in Kinsale, Ireland as a solvent to mediate three chemical reaction transformation steps and a crystallisation step to generate a technical grade (Raloxifene Hydrochloride Technical) of an Active Pharmaceutical Ingredient (API, Raloxifene Hydrochloride). A subsequent processing step produces the final API, namely Raloxifene Hydrochloride. This API is the basis of the Selective Estrogen Receptor Modulator (SERM) Evista®, which is a medication for osteoporosis (in post-menopausal women) and breast cancer reduction2. For patient safety and in accordance with the Marketing Authorisations for this medicinal product, virtually all of the EDC used during manufacture remains in the production waste streams, which are disposed of in accordance with local authority and national environmental regulations.

The typical consumption of EDC by Eli Lilly is currently in the 100-1,000 t/y range. Consumption will decline in the future due to an envisaged loss of market share due to the loss of patent protection and competition from generic forms of the medicinal product.

1.2 Efforts made to identify potential alternatives

Eli Lilly’s original detailed R&D work performed in the 1990s generated a large database on the performance of a wide range of potential alternative solvents none of which proved to be a viable alternative to EDC in the Raloxifene Hydrochloride manufacturing process. Given the extent of past R&D work, the lack of potential new alternative solvents becoming available in the intervening years, allied to the fact that Eli Lilly has used EDC successfully under controlled conditions in accordance with existing legislation on pharmaceuticals, additional research on alternatives was not performed. However, for the purposes of this REACH Authorisation Application, a review of existing data and the most recent literature regarding potential solvent alternatives was undertaken; this updated review confirmed and reinforced the outcome of past R&D assessments, which concluded that EDC is the only feasible option for the manufacturing process covered by Eli Lilly’s Marketing Authorisations.

As with any API, the development of an efficient, safe and reliable synthesis of Raloxifene Hydrochloride underwent several iterations before selection of a final synthetic route for commercial manufacture. Indeed, the route used today was the solution to difficult synthetic challenges including those centred on minimising impurities, streamlining work-ups and isolating the desired final form of the product. A number of different synthetic routes were critically assessed by Eli Lilly’s R&D group. Safety (both personal and process) was of primary importance with consideration also given to the following parameters: environmental, economics, regulatory and throughput.

In 1993, a synthetic route was selected that proved useful for supplying material for early development needs but the chemistry was not deemed suitable for long term commercial manufacture. This initial route had similarities to the commercial manufacture synthetic route executed today whereby the structures of the isolated intermediates were the same. However, in this initial synthetic route the process for generating the Raloxifene Hydrochloride Technical

2 In the EU - Evista® is authorised by the European Medicines Agency (EMA) for the treatment and prevention of osteoporosis. Whilst in the US the Food and Drug Administration (FDA) has approved Evista® for osteoporosis and the reduction of the risk of invasive breast cancer in both post-menopausal women with osteoporosis and post-menopausal women at high risk for invasive breast cancer.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 2

penultimate intermediate (Step (c)) was slightly different. The process used was also a one-pot process with three chemical transformation steps (chlorination, acylation and de-alkylation), all conducted in dichloromethane (DCM). The first step used ''''''''''''''' ''''' to generate an acid chloride intermediate, which was subsequently exposed to #A#, #E# (all Section 1.2) ''''''' ''''''''''''''''''''' '''''''''''''. Finally, '''''''''''''''' ''''''''' was used to produce Raloxifene Hydrochloride Technical that was isolated following crystallisation.

The majority of issues facing commercialisation of the synthetic route centred on manufacturability issues with Step (c) which used DCM as the solvent. Development efforts focused on addressing five key issues with the step:

1. The ''''''''''''''''''' '''''''''''''''''' waste stream from this step posed a significant concern owing to the large quantities (e.g., ''' '''''''''''' kg campaign of Raloxifene Hydrochloride Technical would generate ''''''' metric tonnes of ''''''''''''''''''''' waste).

2. The route required large volumes of DCM

3. There were concerns with the use of ''''''''''''''''' ''''''''' and related requirements to eliminate odour associated with the commercial handling of this reagent. In addition, odoriferous impurities in the technical product were carried into the final API crystallisation step (Step (d)).

4. The reactions were prone to ''''''''''''''' '''''''''''''''''''', which posed a difficult problem upon scale-up.

5. The process produced a poor quality isolated Raloxifene Hydrochloride Technical due to high quantity of impurities, which included residual ''''''''''''''''''' '''''''''.

R&D efforts led to the identification of alternatives to the use of '''''''''''. '''''''''''' '''''''''''''''''' '''''''''' was eventually selected to replace both ''''''''''' and '''''''''''''''' '''''''''. Initial development work using this reagent was in DCM but this was not without its challenges:

• While chlorination and acylation could be achieved, de-alkylation proved more difficult as optimum conditions were challenging. In particular, the reaction mixture needed to be heated above the boiling point of DCM and required sealing of the reaction vessel, which increased the risk of safety incident and/or the potential for fugitive emissions due to excess pressure in the vessel • Large quantities of the Lewis acid reagent ''''''''' were required to achieve the desired reaction completion criteria for acylation.

In particular, the acylation was extensively examined and the quantity of ''''''' could be reduced if the chemistry was run in chlorobenzene solvent. However, while initial success was seen with a switch to chlorobenzene, its use was also considered unsuitable as:

• It led to the formation of ''''''''''''' ''''''''''''''''''' ''''''' ''''''''''''''''''''''''' ''''''''''''''' ''''''''''''''' '''' '''''' '''''''''''''''' '''''''''''''' '''''''''''' '''''''''' '''''''''''''' '''' ''''''''''' • The Raloxifene Hydrochloride Technical made from the chlorobenzene-mediated process crystallised as a solvate. The stability of this solvate was such that it could not be easily converted to Crystal Form ''' the pharmaceutically elegant and required form of the API.

An investigation into alternative solvents was initiated and the list of 22 substances that were evaluated is provided in Table 4-1 (also see Annex 2, Table 9-1). Because of the de-alkylating nature

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 3

of the '''''''''' reagent, common ether and ester solvents would not be applicable for the reaction. An additional complicating factor to the choice of solvents is the poor solubility of the starting materials and the product itself. In addition, many alternative solvents evaluated resulted in new impurities. EDC exhibited favourable reaction characteristics with a homogeneous reaction '''''''''''''''' '''''''''''''' '''''''''' '''''''''''''''''. In addition, Raloxifene Hydrochloride Technical produced in EDC crystallised as a solvate (Crystal form ''') whose solubility profile allowed for easy recrystallisation and conversion to the required Crystal Form '.

The EDC synthetic route was implemented for commercial manufacture at Eli Lilly, Kinsale in 1995. The process continued to undergo optimisation post-launch. ''''''' '''''''''''''' ''''''''''' '''''''''''''''' '''''' ''''''''''''''''''''' '''' ''' '''''''''' ''''''' ''''''''''''''''' (see Section 6.6.2 for a comprehensive list of past improvements).

1.3 Assessment of suitability and availability of possible alternatives

Extensive lab investigation was undertaken at the time that EDC was established as the preferred solvent to assess the feasibility of alternative solvents for use in the Raloxifene Hydrochloride Technical manufacturing process. Of the 22 substances investigated, seven were identified (see Table 4-1, Table 9-1) as potentially feasible for use in Eli Lilly’s manufacturing process. As a result, the focus of this analysis is on these seven solvents. These seven potential alternatives have been screened for technical feasibility, market availability and hazard profile to identify those substances that are most promising and which warrant more detailed consideration (for more information see Tables 4-4, 4-7 & 4-8). This screening process resulted in the following conclusions:

• All shortlisted solvent alternatives technically perform far worse than EDC and result in low product yields with unacceptable crystal forms and impurity profiles. For some alternatives, reaction mixture heterogeneity for the chemical transformation steps also occurs. In addition, tar-like mixtures were also seen to form during the crystallisation step for some alternatives

• Several of the shortlisted alternatives would not necessarily result in an improvement in comparison to EDC in terms of potential worker exposure hazards. Such substances include 1,2,3-trichloropropane (a carcinogen and reprotoxic substance already on the Candidate List), DCM, chloroform, and 1,1,2,2-tetrachloroethane (suspected carcinogens). All substances are halogenated solvents and thus their long-term sustainability is uncertain

• 1,1,2,2-Tetrachloroethane, 1,2,3-trichloropropane, 1,2-dichlorobenzene and fluorobenzene also suffer from poor market availability and/or absence from the relevant ICH Guidelines on residual solvents.

Overall, none of the identified alternatives appear to be a suitable replacement for EDC. However, in order to provide a more detailed analysis of the practical and economic implications of a conversion from EDC to an alternative solvent, two of the alternative substances have been selected for detailed analysis as possible alternatives for EDC, DCM (EC No. 200-838-9, CAS No. 75-09-2) and chlorobenzene (EC No. 203-628-5, CAS No. 108-90-7). These solvents met <50% of the technical feasibility criteria during early development studies but were ruled out later because they did not meet the remaining criteria.

This detailed assessment of DCM and chlorobenzene focused on the technical performance, economic feasibility, risk reduction and availability of the two possible alternatives. A summary of

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 4 findings is provided in Table 1-1. The conclusion of this assessment is that neither of the two possible theoretical alternative solvents match EDC’s performance in the current Raloxifene Hydrochloride Technical synthetic route and conversion to either of them would be accompanied by significant investment costs. In addition, both alternatives would increase process safety risks, even if their hazard profiles (in terms of CMR3 properties) are more benign than EDC’s. In any case, their use would require a new manufacturing process. Therefore, these alternatives are both technically and economically infeasible, and are not currently registered for use.

Table 1-1: Overview of the suitability and availability of the possible alternatives Assess- DCM Chlorobenzene ment area Technical Pros - Complete dissolution of starting Pros - Complete dissolution of starting feasibility materials materials - Homogeneity of reaction mixture - Acceptable levels of impurities in which is achieved at high intermediate temperatures and high pressures - Acceptable solvent rejection - Electrical conductivity capability - Electrical conductivity Cons - Uncertain reaction completion Cons - Heterogeneity of reaction - Increased impurities in mixture A#,#E#************** intermediate ** *** ************* - Inappropriate crystal form - ********* ******** ********* - #A#,#E#********************* **** ** ************* **** *************** - Inappropriate crystal form - Unknown solvent rejection - **** *********** ** ********* capability ***************** - Meets minimum level of yield but - Meets minimum level of yield but much lower than EDC lower than EDC - Low dielctric conductivity - Low dielectric conductivity Economic Investment R&D costs: not costed Investment R&D costs: not costed feasibility costs Plant conversion costs: '#D#'''''''''''' costs Plant conversion costs: '#D#''''''''''''' ''''''''''''' (range: €10-100 million) '''''''''''' (range: €10-100 million) Downtime: not costed Downtime: not costed Market authorisation variations: Market authorisation variations: '#D#'''''''' ''''''''''''' (range: €1-10 million) '#D#'''''' ''''''''' ''''''''''''' (range: €1-10 million) Lost €14.4 million Lost €14.4 million investment investment Changes to '#D#'''''''''''' ''''''''''''''''' (<€1 million/y for Changes to '#D#'''''''''''' ''''''''''''''''' (<€1 million/y operating solvent). operating for solvent). costs Other costs are not possible to costs Other costs are not possible to estimate estimate Risk Human Suspected carcinogen (recent IARC 2A Human No obvious concerns reduction health classification), lower comparative risk health potential than EDC Environ- Slightly higher RCRs for the aquatic Environ- Higher RCRs for the aquatic ment environment compared to EDC ment environment compared to EDC Safety Increased safety hazards in respect of Safety Increased safety hazards in respect of static/charge build up static/charge build up Sustain- Also a halogenated solvent Sustain- Also a halogenated solvent ability ability Availability Quantity REACH registered and on ICH Quantity REACH registered and on ICH Guidelines Guidelines Quality No issue identified Quality No issue identified

3 CMRs Carcinogens, Mutagens, Reprotoxins - Hazard Classification Categories 1A & 1B

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Table 1-1: Overview of the suitability and availability of the possible alternatives Assess- DCM Chlorobenzene ment area Access to Alternative synthetic route would be Access to Alternative synthetic route would be technology required; not available technology required; not available Conclusion Technically poor, economically infeasible, posing Technically poor, economically infeasible, posing greater safety risks and requiring a new greater safety risks and requiring a new manufacturing process - Unsuitable manufacturing process - Unsuitable

1.4 Actions needed to improve feasibility and availability of possible alternatives

Table 1-2 summarises the analysis presented in this AoA with regard to the actions that Eli Lilly might be able to undertake in order to improve the technical and economic feasibility and availability of the possible alternatives.

Table 1-2: Actions that could be taken to improve the feasibility and availability of the possible alternatives Assessment DCM Chlorobenzene area Technical Area Action required Area Action required feasibility Reaction Heating past DCM’s boiling Heteroge Unclear how this can be resolved; rate point required  process neous major issue safety risks reactions Crystal Requires extensive R&D on Crystal Requires extensive R&D on form industrial scale form industrial scale Purity/ Requires extensive R&D on Purity/ Requires extensive R&D on quality industrial scale quality industrial scale Safety Safety review of risks from Safety Safety review of risks from static static build-up. build-up. Upgrade existing site fume Upgrade existing site fume abatement systems. abatement systems. Environmental impact Environmental impact assessment assessment to assess needs for to assess needs for changes to changes to incineration incineration Process New re-crystallisation step to Process New re-crystallisation step to remove DCM remove chlorobenzene Overall: significant investment required, shortcomings largely based on physico-chemical properties meaning a new manufacturing process is needed Economic Not relevant, if technical feasibility remains poor feasibility Availability Need to develop an alternative synthetic Need to develop an alternative synthetic process (or, theoretically, revert to the process. This would include: process abandoned in the 1990s). This would - Validation, on the industrial scale, of the include: intermediate process and the API step - Validation, on the industrial scale, of the - Characterisation of new impurities intermediate process and the API step - Variations to marketing authorisations - Characterisation of new impurities - Possibly, additional clinical trials - Variations to marketing authorisations - Possibly, additional clinical trials

The key shortcomings of both DCM and chlorobenzene are of a technical nature and are directly linked to the physico-chemical properties of the two substances. These are clearly impossible to alter; therefore, considerable effort and R&D work would be required towards the development of a

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 6

new manufacturing method that could accommodate the properties of these solvents. Even if a new method could be developed, further R&D would be required for its validation and the successful variation of the Marketing Authorisations held by Eli Lilly. It is therefore Eli Lilly’s conclusion that these alternatives cannot become realistic replacements for EDC in the foreseeable future. This AoA (and the accompanying SEA) explains that following the lapse in patent protection in the EU and the USA in 2013-2014 and the upcoming loss of patent protection in Japan (in 2018), sales of Evista® have shown a decline which is expected to exceed '#C#''''% in the period 2013-2017 and which is expected to continue into the future as generic medicines are growing their global market share. Therefore the current commercial value of the product is too low to support the high costs that would be incurred in developing an alternative.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 7

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 8

2 Analysis of substance function

2.1 Role of the substance

2.1.1 Introduction

EDC is used by Eli Lilly as a reaction medium and solvating agent in the chemical synthesis of the penultimate step in a three-step sequence used to manufacture 6-hydroxy-2-(4-hydroxyphenyl)- benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone (Raloxifene Hydrochloride). Eli Lilly’s use of EDC in the EU is restricted to one site at Kinsale, Ireland (address: Dunderrow, Kinsale, Co. Cork, Ireland).

Raloxifene Hydrochloride is the API of the Selective Estrogen Receptor Modulator (SERM) marketed by Eli Lilly under the trade name Evista® (Eli Lilly, 2011).

SERMs selectively bind to oestrogen receptors (ERs), acting as agonists (activators) or antagonists (repressors) of gene expression, depending on the tissue type and receptor isoform (ERα and ERβ). The protonated amino group of Raloxifene Hydrochloride (Figure 2-1) forms a hydrogen bond with oestrogen receptors, locking the conformation and preventing recruitment of specific coactivators. Consequently, Raloxifene Hydrochloride antagonises ERβ, but both agonises and antagonises ERα, thereby acting as an oestrogen in bone and lipid tissues, but an anti-oestrogen in the breast and endometrium. Thus, Raloxifene Hydrochloride treats osteoporosis4 by increasing bone density, but also limits progression of oestrogen-dependent breast cancers5. Evista® is prescribed to patients for the following indications6:

• Treatment and prevention of osteoporosis in post-menopausal women • To reduce the risk of invasive breast cancer in post-menopausal women with osteoporosis • To reduce the risk of invasive breast cancer in post-menopausal women at high risk of invasive breast cancer.

EDC is utilised in the manufacturing sequence of Raloxifene Hydrochloride and is removed from the final API product prior to formulation, in order to adhere to patient safety requirements. Permissible residual concentration levels of solvents (i.e. EDC), in pharmaceuticals, are defined by the European Medicines Agency (EMA) safety limits (see discussion on the Guideline for Residual Solvents later in this AoA). Consequently, virtually all the EDC used during manufacture remains in the production waste streams, which are disposed of in accordance with local authority and national environmental regulations.

4 Osteoporosis is a condition in which the bones lose density, becoming weak and breaking easily. 5 Blocking the effects of oestrogen in breast tissue ‘starves’ oestrogen-dependent tumours, thereby decreasing the risk of invasive breast cancer, i.e. cancer that has spread outside of the milk ducts or lobules, into the surrounding tissue. 6 In the EU Evista® is authorised by the European Medicines Agency (EMA) for the treatment and prevention of osteoporosis. Whilst in the US, the Food and Drug Administration (FDA) has approved Evista® for osteoporosis, and the reduction of the risk of invasive breast cancer in both post-menopausal women with osteoporosis and post-menopausal women at high risk for invasive breast cancer.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 9

2.1.2 Synthesis of the Active Pharmaceutical Ingredient

Importance of crystal form of the EDC solvate

The process used to manufacture Raloxifene Hydrochloride is outlined in patents US 6,399,778 (Smith LaBell, et al., 2002) and US 6,458,811 (Arbuthnot, et al., 2002). These documents describe a novel process, identified by Eli Lilly, for the preparation of a crystalline solvate7 intermediate (see Figure 2-1) which enables the subsequent precipitation of crystalline Raloxifene Hydrochloride (drug substance).

EDC is used in the manufacture of the final intermediate, which is isolated as a crystalline solvate. EDC is the solvent for the formation of the crystalline solvate which in turn has the desired solubility profile to achieve dissolution in the subsequent production step. Purification and conversion to the desired non-solvated crystal form of the drug substance is achieved through this dissolution.

It must be noted that the crystal form of the drug substance is critical to the performance of the medicinal product. Crystal form can influence many properties like solubility, hygroscopicity8 and chemical stability of the product. The medicinal product is administered orally; consequently, the solubility of the API plays a significant role in drug performance. Raloxifene Hydrochloride has low solubility in water and gastric fluid. Two related physical properties of the drug substance, particle size and surface area, define the dissolution rate of the medicinal product. Compounds which have poor solubility profiles can have their bioavailability enhanced by increasing the surface area of the particles. Crystal form specifications for this product are modulated to maximise bioavailability of the API to the patient.

+ + O H N H O H N H

Cl – – O Cl O Cl S S

Cl

H O H O O 0.5 equiv. O

(a) (b) Figure 2-1: (a) Crystalline solvate* of Raloxifene Hydrochloride Raloxifene Hydrochloride Technical) and (b) the active substance Raloxifene Hydrochloride

7 The term “solvate” means an aggregate of one or more molecules of the solute with a molecule of solvent. In this case, the crystalline material is an EDC solvate having a 1:2 ratio of solvent to solute (Raloxifene Hydrochloride) molecule. In chemistry, a solvate containing one molecule of solvent per two molecules of solute, or per two unit cells, is defined as a hemi-solvate. 8 Pertaining to a substance whose physical characteristics are appreciably altered by the effect of water vapour.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 10

Process description

Transportation and storage of raw solvent (EDC)

EDC (liquid) is supplied by road tanker with each delivery containing approximately 27,000 litres of solvent. The transport and delivery of EDC is covered by dangerous goods requirements as the substance is classified as a flammable liquid. In particular, the EU-based distributor must ensure that the requirements of ADR (European Agreement Concerning the International Carriage of Dangerous Goods by Road) and IMDG Code (International Maritime Dangerous Goods Code) are met.

Prior to use, EDC is stored in a dedicated raw solvent bulk storage tank, which has a capacity of 55 m3. Transfer of the solvent from the bulk storage tank to the reaction vessel in the manufacturing facility is via fixed piping. Approximately '#A#'''''' kg/batch (range: 1,000-10,000 kg/batch) of EDC is added to the reaction vessel at the beginning of the process.

Preparation of Raloxifene Hydrochloride

Preparation of Raloxifene Hydrochloride occurs at a dedicated manufacturing facility in closed equipment. The main steps in the Raloxifene Hydrochloride process involving the use of EDC are described below. The use of EDC is fundamental to the success of three chemical transformation steps in a one pot-reaction sequence. A simplified flow diagram (see Figure 2-2) accompanies this narrative.

• Chlorination (Step (a)): The starting material9 (a carboxylic acid) is converted to the corresponding acid chloride, by reaction with ''#A#'''''''''' ''''''''''''''' in EDC at ''#A#'''' ''''' °C. EDC was chosen for this step as it was preferable to carry out this reaction in the same solvent as the subsequent reaction thereby avoiding the need for a solvent exchange

• Acylation reaction (Step (b)): A second starting material, (a benzothiophene) undergoes Friedel Crafts acylation10, with the acid chloride generated in Step (a). This is promoted by a a Lewis acid reagent '#A#''''''''''' '''''''''''''''''' '''''''''''''. The product, an '#A#''''' ''''''''''''' '''''''''', is not isolated and remains in-situ for a subsequent reaction (Step (c))

• De-alkylation reaction (Step (c)): The desired intermediate is generated when the '#A#''''''' ''''''''''''' '''''''''' generated in Step (b) is reacted with a Lewis Acid reagent '#A#'''''''''' '''''''''''' and heated. Following the three reactions above, the product mixture is transferred to another vessel

• Quench/Crystallisation (Step (d)): The de-alkylation reaction mixture is quenched11 with a heated mixture of alcohol solvents ''#A#''''''''''''''''''''''''''''''. When quenching is performed in this manner, Raloxifene Hydrochloride crystallises from the resulting mixture, as a solvate of 1:2 EDC solvent to Raloxifene Hydrochloride solute molecules

9 A raw material or an intermediate, used in the production of an API and incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in- house. API Starting Materials are normally of defined chemical properties and structure. 10 Friedel-Crafts is a type of reaction in which the alkyl group of a haloalkane or acyl halide is substituted on a benzene ring, to produce an alkylbenzene 11 Quenching terms the process of reduction or inhibition of a chemical reaction.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 11

• Isolation of the crystalline solvate (Step (e)): The crystallisation slurry is cooled prior to filtration. The product is washed with alcohol to displace any mother liquor before it is dried and isolated. The material is tested prior to use in the subsequent process step. This material is referred to as Raloxifene Hydrochloride Technical. Mother liquor from the filtration step is highly acidic and must be neutralised with a base prior to transfer into the site liquid waste treatment system

• Use of the crystalline solvate in the final process step (Step (f)): The non-solvated crystalline form (drug substance) is prepared by re-crystallisation of the EDC solvate. The EDC solvate is dissolved in ''#A#''' ''''''''''''''''' ''''' solution. Purification and conversion to the desired non-solvated crystal form are effected by dissolution in '#A#'''''' ''''''''''''''''''''''''''''', concentration by distillation and subsequent crystallisation

• Distillation & crystallisation (Step (g)): The solution of the Raloxifene Hydrochloride Technical is concentrated by atmospheric distillation. The purpose of this distillation is two- fold, to concentrate the solution for the subsequent crystallisation step and secondly to remove the EDC that had been incorporated into the crystalline solvate. The distillate containing EDC is pumped into the site liquid waste treatment system, whilst the Raloxifene Hydrochloride product slurry remains in the distillation vessel for further processing

• Isolation of the non-solvated crystalline form of Raloxifene Hydrochloride (Step (h)): After filtration and drying of the non-solvated crystal form, it is milled to achieve the desired particle size. The milled material is packaged and stored. Product analysis includes testing for residual EDC. The specification must meet, at a minimum, the specific concentration limit value outlined in European Medicines Agency (ICH) guidance on residual solvents. X- ray diffraction analysis also serves to confirm that the desired non-solvated crystalline form has been obtained.

In summary, EDC is used as a solvent to mediate three chemical transformation steps – Step (a): chlorination; Step (b): acylation reaction; and Step (c): de-alkylation reaction.

Waste generation and handling

The liquid waste stream containing EDC is generated from mother liquors and equipment rinses during the preparation of the crystalline solvate molecule. The distillate from the subsequent re- crystallisation step contains the EDC from the Raloxifene Hydrochloride Technical . Liquid waste streams are pumped to storage tanks via fixed piping and is destroyed by an on-site incinerator.

Solvent and gaseous vapours emitted from manufacturing equipment (tanks, dryers, vacuum pumps, and scrubbers) are collected via site fume ducts, for on-site destruction in a fume incinerator. Both incineration facilities operate under Environmental Protection Agency (Ireland) License Number P0009-03. This requires the units to be operated under the conditions of the Waste Incineration Directive (2000/76/EC) as amended by Directive 2010/75/EU thus meeting all associated emission limit values for both air and water.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 12

Figure 2-2: Preparation of Raloxifene Hydrochloride

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 13

2.2 Conditions of use and technical feasibility criteria

2.2.1 Introduction

Eli Lilly developed a process for producing Evista® in the early 1990s, filing patent applications in 1995 and 1997 which ultimately granted patents US6,399,778 and US6,458,811, respectively. The very detailed research undertaken concluded that EDC offers the best combination of technical performance parameters and forms the foundations on which the technical feasibility criteria for potential alternative solvents may be built.

2.2.2 Technical feasibility criteria

Overview

Eight technical feasibility criteria have been developed by Eli Lilly as those relevant to a systematic comparison of EDC to alternative solvents. These are shown in Table 2-1. Their importance and relevant threshold values are discussed below the table.

Table 2-1: Overview of technical feasibility criteria for potential alternatives for EDC # Technical feasibility criterion 1 Solubility of starting materials 2 Reaction mixture viscosity 3 Reaction completion 4 Crystal form of product 5 Product impurities in the isolated product 6 Residual level of solvent in the active substance 7 Yield 8 Dielectric properties of the liquid

Criterion 1: Solubility of starting materials

Importance of the criterion

Solubility is key for reaction completion and impurity control, as a delay in reaction completion will lead to impurity/degradant formation. For the chlorination reaction (Step (a)), a slower reaction rate can lead to hydrolysis of the acid chloride intermediate. For the acylation reaction (Step (b)), a slower reaction rate can also lead to hydrolysis of the acid chloride precursor. In addition, for Step (b), de-alkylation of the starting material can also occur. Where solubility of starting materials is poor, the formation of tar-like mixtures may result.

Threshold

No quantified threshold is available. The solvent must ensure the complete dissolution of the starting materials.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 14 Criterion 2: Reaction mixture viscosity

Importance of the criterion

The viscosity of the reaction mixture has direct relevance to the reaction performance and the control of impurities. Solvent viscosity is important in determining reaction rates: in highly viscous solvents, dissolved particles diffuse much more slowly than in less viscous solvents and can collide less frequently per unit time. Thus, the reaction rates of most reactions decrease rapidly with increasing solvent viscosity. As discussed under solubility above, reduced reaction rates can lead to impurities.

Moreover, the viscosity of the mixture affects the performance of the subsequent crystallisation and product isolation steps.

Threshold

No quantified threshold is available. The solvent must lead to a homogeneous, free-moving solution.

Criterion 3: Reaction completion

Importance of the criterion

As described earlier, three reactions take place in the presence of EDC. Due to the nature of the three reactions, different materials may be present at different stages of the reaction. The completion of each reaction is important, as incomplete conversion to the product would mean there would be higher levels of the intermediate (i.e. starting materials or precursor) present in the reaction mixture. This intermediate is not easy to remove during the crystallisation step. The intermediate has a similar solubility profile to the desired product and thus is not well rejected/purged in the crystallisation step or final API process step (i.e. the intermediate will precipitate with the product and not be rejected in the mother liquor) which would affect product quality and yield.

Threshold

The solvent used must ensure that the following regulatory required12 thresholds are met for each of the reactions:

• Step (a): >98% of the acid chloride is consumed • Step (b): <3% of the starting material remains • Step (c): <0.2% of the intermediate remains

12 In the submission documents supporting the Marketing Authorisations worldwide, these measures of reaction completeness are registered requirements for each batch of material produced by the Marketing Authorisation holder.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 15 Criterion 4: Crystal form of product

Importance of the criterion

The EDC hemi-solvate has a solubility profile that is key for the crystallisation in the subsequent API production step and allows for the formation of the desired crystal form of the API.

Threshold

The product of the three subsequent reactions must be a hemi-solvate with a specific crystal form, Crystal Form '#A# '13, and solubility profile. The Raloxifene Hydrochloride hemi-solvate needs to be completely soluble in the '#A#''''''''''''''''''''''' mixture used in subsequent steps.

Criterion 5: Product impurities in the isolated product (intermediate)

Importance of the criterion

Impurities in the intermediate product that is obtained after the three reactions mediated by EDC need to be as low as possible to ensure the quality of the API and to minimise cost that would arise from the removal of any impurities.

Threshold

The level of impurities in the isolated intermediate product should not exceed '#A#'''''%.

Criterion 6: Residual level of solvent in the active substance

Importance of the criterion

Residual solvents in pharmaceuticals are typically defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to an extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data (ICH, 2011).

Solvents that are known to cause unacceptable toxicities (Class 1, EDC is one of them) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity

13 X-ray Diffraction (XRD) is a non-destructive analytical technique which provides detailed information about the internal lattice of crystalline substances, including unit cell dimensions, bond-lengths, bond-angles, and details of site-ordering i.e. crystal structure. The crystal structure is sometimes referred to as the crystal form. The lattice of the Raloxifene Hydrochloride crystal differs depending on which solvate it exists as. The EDC solvate lattice exists as Crystal Form #A#' when the product is crystallised from '#A#''''''''''''''''', the EDC lattice exists as Crystal Form '#A#' when the product is crystallised from methanol. The chlorobenzene lattice exists as Crystal Form '#A#''', and DCM and chloroform solvates exist as Crystal Form '#A#''.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 16 (Class 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3) should be used where practical (ICH, 2011).

Threshold

The process should meet the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, which are discussed later in this AoA. The upper limit for EDC residues is 5ppm and is currently met by Eli Lilly’s production process.

Criterion 7: Yield

Importance of the criterion

A lower yielding process would mean poorer economics of production as it would result in an increase in the number of batches required to produce the same quantity of material. This in turn will increase solvent usage and the subsequent process waste streams.

Threshold

The current yield achieved with EDC is '#A#''''''%. The product yield needs to exceed '#A#''''% (assay corrected14), as this is a regulatory commitment.

Criterion 8: Dielectric properties of the liquid

Importance of the criterion

Dielectric properties refer to the polarisation and displacement of positive charges, towards the field of negative charges (and vice versa). A material’s dielectric properties affect the storage and dissipation of electric and magnetic energy. Risk of charge/static build-up must be mitigated in the Raloxifene Hydrochloride manufacturing process. The potential for such build up can result from:

• Solids charging for Reaction (a) • Agitation of the resulting (initial) heterogeneous mixture (Note: this goes into solution upon heating) • The necessary use of a glass lined tank. This is required because the reaction/process mixture is highly acidic. Acidic mixtures are corrosive to metal vessels, whereas glass lined tanks demonstrate high chemical resistance to acidic mixtures • Agitation of the mixture in a glass lined tank.

Static charge that builds up will dissipate, by migrating through the liquid mixture, to an earthing point. The rate at which charge is accumulated and subsequently lost from a liquid is governed by the electrical conductivity and the permittivity, which in turn is reflected in the dielectric constant value of the liquid. Any factor which decreases the ability of the system to dissipate charge increases the potential for static build up and thus static electricity accidents.

14 Typically, yield refers to the physical amount recovered from a process (sometimes referred to as an ‘isolated yield’). Assay refers to the potency/purity of the product i.e. what quantity of the product is present. As the process in question generates a solvate, an assay corrected yield is calculated which takes into account the portion of solvent in the isolated product, e.g. a 100 kg isolated yield may have an assay of 90% i.e. 90% of the 100 kg contains the desired molecule (i.e. 90 kg).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 17 EDC is a semi-conductive solvent with a high dielectric constant and the solvent properties together with the equipment configuration and design means the risk of static/charge build-up is minimised.

Threshold

A replacement solvent would have to be at least comparable in its ability to dissipate charge. A conductive solvent (>100,000 pS/m) would be a preferred replacement. At a minimum, the replacement would have to have a comparable relaxation time. Relaxation time is governed by the dielectric constant and the electrical conductivity. The higher both numbers are, the faster the relaxation time/time for charge to dissipate.

The following thresholds must be met by an alternative solvent:

• Electrical conductivity: ≥4000 pS/m • Dielectric constant: ≥10.

It is of note that the current EDC process is classified within the company as a HRO – higher risk operation, due partially to the risk around static/charge build up.

2.3 Summary of functionality of EDC in the “Applied for Use”

Table 2-2 summarises the parameters of use of EDC by Eli Lilly.

Table 2-2: Parameters for EDC use Functional aspect Explanation Solvent in three chemical transformation steps – (a) chlorination; (b) acylation Task(s) performed by the reaction; and (c) de-akylation reaction. The intermediate product is isolated as a substance hemi-solvate of EDC Physical form of the Liquid; purity cannot be below 99.0% (registered specification listed in the product marketing authorisation for the medicinal product) Concentration of the Reaction conditions/concentration is optimised for quality and yield of the substance in the product product. EDC is not intended to be present in the final product, Raloxifene Hydrochloride. As per exising legislation (see below), the maximum residual solvent in the products is 5 ppm (ICH, 2011) - Adequate solubility of starting materials - Sufficient reaction mixture viscosity - Reaction completion - Product is a hemi-solvate crystal of EDC of specific solubility and crystal form Critical properties and parameters that are needed in the subsequent synthetic steps quality criteria EDC must - Favourable impurity profile of reaction product fulfil - Yield exceeds '''''% (assay corrected) – EDC well exceeds this threshold ('''''''%) - High dielectric constant prevents the build-up of static/charge - Solvent meets the relevant ICH guidelines on residual solvents (see below) Consumption of EDC is variable, depending on production output (i.e. number of batches) of the plant. Typical quantity of EDC used per batch is '''''''''''' kg Frequency of substance (including ''''''' kg for the rinsing of the reactors) (range: 1,000-10,000 kg per use and usage quantities batch). EDC is charged at the beginning of the process; quantity per batch is pre- defined and product requirements are reviewed annually

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 18 Table 2-2: Parameters for EDC use Functional aspect Explanation Reactions are run at atmospheric pressure Temperature ranges from -5 to 50 °C Complex reaction, typically <24 hrs reaction time Recycling is not possible due to the mixture composition post-reaction: once all Process and performance three transformations are complete (chlorination, acylation and de-alkylation), constraints concerning '''''''''''''''' is added to the reaction mixture. The product precipitates and is the use of the substance isolated. The liquid (mother liquor) contains the EDC, ''''''''''''''' and other impurities. It is this mixture, which contains EDC, that cannot be recycled. The EDC removed from the process contains ''''''''''''''. Due to the similarity of the boiling points of these components, recycling of EDC is not feasible Removal of EDC from the process is not an option, due to solubility, yield and Conditions under which quality outcomes. Other alternatives have been examined and have been the use of the substance proven to be unsatisfactory in technical, commercial, economic and could be eliminated environmental terms Not relevant. The product is an intermediate which is produced as a hemi- solvate of EDC. This hemi-solvate product is used in-house for further Customer requirements processing. associated with the use of EDC does not play a role in the action of the final medicinal product (but may be the substance present as a residue at concentrations below 5ppm, as per the relevant ICH Guidelines) Medicinal Products Directive: The use of EDC in the manufacture of an API falls within the scope of Regulation (EC) No 726/2004 and Directive 2001/83/EC, relating to medicinal products for human use. Industry sector and legal Residual Solvents: EMA (European Medicines Agency) guidance on residual requirements for solvents (EMA/CHMP/ICH/82260/2006) contains a specific concentration limit technical acceptability for EDC (class 1 solvent). The ICH guideline Q3C(R5) (ICH, 2011) on impurities: that must be met and the guideline for residual solvents as adopted by the CHMP (EMA/CHMP/ function must deliver ICH/82260/2006) recognises that if the use of class 1 is unavoidable, then the level should be restricted to ICH limits for class 1 solvents (5 ppm).

See details in Annex 1

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 19

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 20 3 Annual tonnage

3.1 Tonnage band

Annual tonnage band: 100-1,000 tonnes per year.

Confidential annual tonnage (2014): '#B#'''''''' tonnes of EDC 99.0% (see discussion on trends below).

The following table provides information on the quantity of EDC purchased and consumed in recent years. ''#B#''''' ''''''' ''''''''''''' ''''''' ''''''' ''''''''''''''''' ''''' '''''''' ''''''' '''''''''''''' ''''' '''''''''' '''' '''' '''''''''''''' ''''' ''' ''''''''''''' '''' '''''''' ''''''''''

Table 3-1: Purchase and consumption of EDC Year Purchased tonnage Consumed tonnage 2013 '#B# all Table 3-1''''''''' '''''''''' 2014 ''''''''' '''''''''

3.2 Trends in the consumption of EDC

'#C#''' ''''''' '''''''''''' '''''''''''''''''''' '''' ''''''' '''''''''''''''''''' ''' '''''''''''''''''''''''' ''''''''''''''''''' '''' ''''''' ''''''''''''''''''''''''' '''' ''''''' ''''''''''''' '''''''''''''''' ''''''''' ''''''' '''''''''''' ''''''' '''' ''' ''''''''''''''''''' ''''''''''''''' ''''' '''''' '''''''''''''' ''''''''''''''''''''''''''' '''''''''''''''' ''''''' '''''''''''''''''''''' '''' ''''''' '''''''' '''''''''' ''''''''''' '''''''''''''''''''''''' '''''''''''''''' '''' '''''''''

'#C#'''''' '''''''''' '''''''''''''''''''''''''''''''''''''''' '''''''''''' ''''''''' ''''''' ''''''''''''''''''''''''''''' '''' ''' ''''''''''''' '''''''''' '''''''''' ''''''' '' '''''''''''''''''' '''' '''''' ''''''''' '''''''''''' '''''''' ''''' ''''''''''''''''' '''''''''''''''''''' '''' ''''''' ''''''''''''''''''' ''''''''''''''''''' ''''''''''' ''''''' ''''''' '''''''''''''''''''''''''' ''''''''' ''''''''''''' '''''' ''''''''''' ''''''''''''''''''''''''''' '''' '''''''' '''''''''''''''''''' '''' '''''' ''''''''' '''' '''''''''''''' ''''''' ''''''''' '''''''''' '''''''''''' '''''' ''''''' ''''''' ''''''''''''''''' '''' ''''' '''''''''''''''''''''''''''''' '''' '' ''''''''''' '''''''''' '''''''''''' ''''''' ''''''''''''''' ''''' '''''''''' ''''' ''''''''' ''''''' '''''''''''''' ''''' ''''''''''''''''''''' '''''''''''''''''''''''''''' '''''''' ''''''' ''''''''''''''''' '

The plan post-2015 is to conduct a Raloxifene Hydrochloride Technical campaign every second year (i.e. in 2016, EDC consumption is expected to be zero '#C#''''''' '''' '''''''''' '''' ''''''''''''' ''''' ''' ''''''''' '''''''''''''' '''' ''''''''''. Sales of Evista® are experiencing significant market pressures as a result of the expiration of relevant patents. In Europe, the relevant patent expired in July 2013 and in the USA it expired in March 2014. In Japan, patent protection expires in 2018. Therefore, sales are expected to decline, which will be accompanied by a decline in the consumption of EDC and associated worker exposure to the substance.

An overview of projected EDC consumption under the “Applied for Use” Scenario is given in Table 2- 3 in Section 2.2 of the SEA and is reproduced overleaf as Figure 3-1. The figure projects that by 2025, EDC consumption will reduce to '#C#''''' '''''' tonnes every other year.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 21

Figure 3-1: Projected consumption of EDC by Eli Lilly for the “Applied for Use” Scenario (#C#)

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 22 4 Identification of possible alternatives

4.1 List of possible alternatives

4.1.1 History of EDC use

EDC has been used as solvent in the production of Raloxifene Hydrochloride since 1994, having replaced DCM. Around that time, a very detailed investigation of potentially suitable solvents was undertaken, and as will be explained below, EDC eventually prevailed as the only feasible option. In light of the outcome of past R&D work, no further lab research has been undertaken on the development of alternatives since the mid-1990s, as EDC has been used with success and under controlled conditions in accordance with existing legislation on pharmaceuticals. More recently, a review of the data and analysis completed in the 1990s and a literature search have confirmed this conclusion.

4.1.2 Master list of potential alternatives and shortlist of possible alternatives

The following table presents the master list of potential alternatives that have been identified in the preparation of this AoA.

Table 4-1: Master list of potential alternatives considered in the preparation of this AoA No Name EC Number CAS Number Source 1 Dichloromethane 200-838-9 75-09-2 Eli Lilly’s own R&D 2 Chloroform 200-663-8 67-66-3 Eli Lilly’s own R&D 3 1,1,2,2-Tetrachloroethane 201-197-8 79-34-5 Eli Lilly’s own R&D 4 1,2,3-Trichloropropane 202-486-1 96-18-4 Eli Lilly’s own R&D 5 Chlorobenzene 203-628-5 108-90-7 Eli Lilly’s own R&D 6 1,2-Dichlorobenzene 202-425-9 95-50-1 Eli Lilly’s own R&D 7 Fluorobenzene 207-321-7 462-06-6 Eli Lilly’s own R&D 8 '#A#, #E# all Table 4-1'''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 9 ''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 10 '''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 11 ''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 12 ''''''''''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''''' Eli Lilly’s own R&D 13 ''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 14 '''''''''''''''''''''''''''''' '''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 15 '''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''''' Eli Lilly’s own R&D 16 '''''''''''''''''''''''''''''''''''' '''''''''''''''''' '''''''''''''''' Eli Lilly’s own R&D 17 '''''''''''''''''''''''''''''''''''' '''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 18 '''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' '''''''''''''''' Eli Lilly’s own R&D 19 '''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 20 '''''''''''''''''''''''''' '''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 21 ''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' Eli Lilly’s own R&D 22 ''''''''''''''' '''''''''''''''''' '''''''''''''''''' Eli Lilly’s own R&D

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 23 The text below presents a detailed analysis of the investigation Eli Lilly has undertaken towards the identification of a suitable solvent for certain steps in the production of Raloxifene Hydrochloride. The systematic screening of these alternatives has concluded that no feasible alternative to EDC exists for Eli Lilly’s Raloxifene Hydrochloride production process.

However, for completeness, Eli Lilly shortlisted two possible (theoretical) alternative substances, which are further elaborated in Section 5 of this AoA. Reasons why the selected alternative substances shown below were shortlisted is discussed in Section 4.3.4.

Table 4-2: Shortlist of possible (theoretical) alternatives for detailed assessment in Section 5 of this AoA No Name EC Number CAS Number 1 Dichloromethane 200-838-9 75-09-2 5 Chlorobenzene 203-628-5 108-90-7

4.2 Description of efforts made to identify possible alternatives

4.2.1 Research and Development by Eli Lilly

Background to the manufacture of the Raloxifene Hydrochloride Technical before the use of EDC

The synthetic process for Raloxifene Hydrochloride Technical is a one-pot synthesis, which involves three successive reactions/transformation steps [(a)-(c)]: (a) chlorination; (b) acylation reaction; and (c) de-alkylation reaction.

The process was originally designed ca. 1993 with DCM as the solvent. This initial synthesis had an acylation reaction under Friedel-Crafts conditions ''''''''''''', followed by Lewis acid-assisted '''''''''' ' '''' #A#, #E# all Section 4.2.1'''''''''''''''' ''''''' ''''''''''''' ''''''''''' '''''''''''', the entire reaction sequence being run as a one-pot synthesis. '''''''''''''' '''''''''''''''' and later '''''''''''''''''' were used for the Step (a).

Environmental issues, particularly odour ''''''''''' and waste disposal associated with the large volume of ''''''''''''''''''', necessitated a re-evaluation of the chemistry employed. Replacement of '''''''''' '''''''''' ''''''''' solved the three key issues facing large-scale manufacturing of the process chemistry:

• It eliminated the need to use a ''''''''' and hence the severe odours present in both this process step and the subsequent API step • It resolved the issues associated with precipitation and disposal of '''''''''''''''''' '''''''''''''' • It eliminated reaction heterogeneity issues during the acylation, de-alkylation and crystallisation steps. Note: high temperatures and high pressures were needed to obtain homogeneous mixture for DCM, these conditions were not necessary when EDC was used.

The new and improved process was developed using EDC. The use of DCM in this improved process required high temperatures and pressures for transformation [Step (c)] to ensure the reaction went to completion. In addition, larger volumes of DCM were required: in comparison to EDC, the use of DCM requires three times higher volumes of solvent, which, notably, was not recycled.

The benefits of using EDC and the shortcomings of a range of alternative solvents were investigated and established in this specific R&D programme that aimed to eliminate the aforementioned three key issues that were associated with the use of DCM. This R&D programme is described below.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 24 Investigation of potential alternative solvents for DCM (1993-1994) – Master list

As noted above, Eli Lilly decided to switch from the '''''''''' ''''''''''''' to the ''''''''' '''''''''''''''', and the latter was based on the use of EDC. At the time, Eli Lilly undertook extensive laboratory testing for the selection of the optimal solvent, using EDC as a benchmark. This solvent screening exercise was performed in 1993-1996 and alongside DCM and EDC, another 21 solvents were considered. The master list of alternative substances that Eli Lilly considered is shown in Table 4-1.

It is important to note that the table generally includes halogenated hydrocarbons plus a small number of other substances (nitro compounds '''''''' ''''''''''''''). There is a notable absence of common families of solvents such as ethers and esters, as these either react with a Lewis acid reagent '''''''''' or bind to it as a Lewis base. Moreover, '''''''''' used in Eli Lilly’s process (this is further discussed later in this Section of the AoA), is highly reactive with most organic functional groups in solvents severely limiting the options to ''''''''''''''''''''' '''''''''''''' ''''''' '''''''''''''''''''' ''''''''''''''' ''''''''''''''''''. Other classes of solvents would undesirably react with the ''''''''' '''''''''''''' used in the reaction and, in addition, the starting materials/intermediates would not be soluble in such solvents.

Investigation of potential alternative solvents for DCM (1993-1994) – Screening against technical feasibility criteria

The laboratory testing undertaken by Eli Lilly on the master list of 22 alternatives to DCM (21 substances plus EDC) looked into whether, and to what extent, these alternative solvents met the technical feasibility criteria described in Section 2.2.2 for the newly developed ''''''''' process that would replace the DCM-based ''''''''' process. An overview of the results obtained is shown in Table 9-1 of Annex 2. Brown cells in Table 9-1 indicate technically problematic areas for the investigated substances.

The key conclusions were:

• Out of the 22 substances, 15 substances could not be fully tested as they could not show complete dissolution of the reaction reagents under the process conditions and therefore, they would be impossible to use to replace DCM • Of the 7 substances other than EDC that offered adequate dissolution, none could ensure that the reaction would be completed to a degree comparable to that of EDC, neither would they be able to deliver the required final crystal form which ensures the solubility in the final API manufacturing step. • Some of the tested alternatives formed tar-like mixtures, which impacted upon the impurity profile of the product in addition to the long-term manufacturability of such a process. • The product yield was lower for all solvents compared to when EDC is used, ('''''''' ''''''' ''''''''''''''''''' '''' ''''''''''' ''''''''''''' ''''''' '''''''''''''''''' ''''''''''''''''''' '''''''''''''').

Overall, only eight potential substances were found to be usable, and out of these, EDC and chlorobenzene were those that showed most promise. More specifically, the R&D work revealed the following:

• Chlorobenzene: '''''''''''''''' ''''''' '''''' ''''' '''''''''' '''' ''''''''''''''''''''''''''''' ''''''''''''''''' '''''''''' '''''''''''''''''''''''''''''' '''''''' ''''''''''' ''''''' '''''''''''''''''''''''''''' '''''''''' ''' ''''''''''''''' '''' ''''''''''''' ''''''''''''''''''''''''''' '''''''''''''' ''''' '''''' '''''''''''''''' '''' '''''''''''''' ''''''''''''''''''''' '''''''' '''' ''''''''''''''''''''''''' '''''''' '''''''''''''' ''''''''''''''''''''''' ''''''''''''''' ''''''''''''''''' ''''''''' '''''''''''''''' '''''''' ''''''''''''''' '''' ''''''' '''''''' '''''''''''''' '''''' ''''''' '''''' ''''''' '''''''''''''' '''''' ''''''''''''''''''''' '''''''''''''''''''''''''''' '''''''' '''''''''''''' ''''''' '''''''''''''' '''' ''' ''''''''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''''''''' '''''''''''''' '''''''' ''''''''''''''''' '''''''''''' '''' '''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 25 '''''''''''''''''''''''''''' '''''''''' '''''''''' '''' '''''' '''''''''''''''''' ''''' ''' ''''''''''''' ''''''''''' '''''''' '''''''''' ''''' '''''''''''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''' '''''''''''''' ''''''''''' ''''''' '''''''''''''''''' ''''''''''''''''' ''''''''''''''''''''''''' '''' '''''' '''''''''''''''''''''''''''' ''''''''''''''''''''''''''' '''''''''''''' ''''''' ''''''' ''''''''''''' ''' ''''''' '''''''''''''' '''' '''''' ''''''''''''''''''''''' '''''''' '''''''' ''''''''''''' ''''''''' ''''''' ''''''''''''''' '''' '''''' '''''''' '''''''' '''' '''' '''''''''' ''''''' ''''''''''''''''''' ''''''''''''''''''''''''''' '''''''''''''''' '''''''''''''''' '''''''''''''''''''''''''''''''''' ''''''' '''''''' ''''''''''''''

• EDC: all three reactions were homogeneous when performed in EDC with no ''''''''''''''' '''''''''''''''' forming. In addition, the hemi-solvate produced (EDC-Raloxifene Hydrochloride) was soluble in the final step thereby facilitating the necessary removal of impurities and residual solvents and generating the API in the appropriate crystal form and in acceptable purity. Thus, EDC was selected for commercial use.

In conclusion, EDC was the only solvent capable of delivering the required product under the ''''''''' manufacturing process. Further assessment of the remaining solvents cannot be justified as their shortcomings are based on their physicochemical characteristics which cannot be improved.

The R&D work that Eli Lilly has undertaken resulted in a series of relevant patents. These name some of the alternatives that have been considered. For example, the two 2002 patents mentioned earlier identify the following solvents (Arbuthnot, et al., 2002; Smith LaBell, et al., 2002):

• DCM • Chloroform • 1,1,2,2-Tetrachloroethane • 1,2,3-Trichloropropane • Chlorobenzene • 1,2-Dichlorobenzene • Fluorobenzene.

The solvent screen evaluation which led to the selection of EDC involved at least ''' research scientists, lasted ''''' months and had an estimated cost of ''''''''' '''''''''' (in 2014 prices)15 (<€1 million).

Investigation of potential alternative solvents – 2014

For the purposes of the preparation of this AoA, the Eli Lilly ‘Solvent Selection Committee’ was consulted in the search for an alternative solvent, beyond what had been identified and researched in the 1990s. The Solvent Selection Committee is an established in-house technical group comprising of senior research scientists, engineering, EHS compliance, and a toxicologist. Out of the 23 members of this working group, nine are PhD organic chemists. The committee carried out a literature search using the SciFinder® search engine described in Section 4.2.2 followed by a technical review of the Raloxifene Hydrochloride process. This review captured both up to date academic literature on Green Chemistry Solvent Selection Guides16 as well as years of organisational and personal knowledge. No suitable alternative for EDC was identified.

15 This estimate for 2014 is based on past experience and on conservative assumptions such as a flat rate of '''''''''''''''’’'''''''''' (2014 price) and does not include plant time/equipment time.

16 Notable literature sources include: Adams J. P. et al (2013): Development of GSK's reagent guides – embedding sustainability into reagent selection, available online: http://pubs.rsc.org/en/Content/ArticleHtml/2013/GC/c3gc40225h

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 26 4.2.2 Literature searches

Literature consulted by Eli Lilly

Eli Lilly has considered the available literature, including key patents. The SciFinder® Database17, was used to complete these searches. This database, which is produced by Chemical Abstracts Service (CAS), is a comprehensive database for the chemical literature, indexing journal articles and patent records (and other document types), as well as chemical substances and reactions. CAS, a division of the American Chemical Society, is a world-renowned authority on chemical information.

The literature searches included (a) a search using the chemical structure of Raloxifene Hydrochloride, and (b) a search for the general synthetic transformation that is carried out in Eli Lilly’s Raloxifene Hydrochloride manufacturing process. The structural searches retrieve reactions that match the structures of participating reactants, reagents, and/or products. In this case, the structures of the starting material and product were entered into the search engine. Eli Lilly’s literature search did not identify any alternative solvent beyond what was previously identified during Eli Lilly’s research effort in the 1990s as discussed above.

The only relevant (recent) results that were returned by the literature search are:

∋#A#∋∋∋∋∋∋∋∋ ∋∋∋∋ • ''''''''''''''’’’’’’’’’’''''''' • ''''''''''''' '''’’’’’’’’' '''' ∋∋∋∋∋∋∋∋∋∋∋∋ ∋∋∋∋ ∋∋∋∋

All these sources discuss similar transformations that use DCM '#A#'''''''' ''''''''''' ''''' '''''''''''''' ''''''' ''''''''''''''''' '''' '''''''''''''''''' '''' '''''''''''''' '''''''''' these syntheses are not suitable for commercial manufacturing.

In addition, a 1995 patent also outlined an alternative route to make Raloxifene Hydrochloride (Cameron, et al., 1995). ''#A#'''''' ''''''''''''''''''''' ''''''''''''''' '''' '''''' '''' '''''''' ''''''''''''''''''' ''''''''''''' '''''''''''''''' ''''''' ''''''''''''''' ''''''' ''''''' ''''' ''''''''' ''''''' ''''''''''''' ''''''' ''''''''

Solvents used by other market players

Eli Lilly is familiar with two main competitors that market Raloxifene Hydrochloride medicinal products. Both companies are providing generic versions of Eli Lilly’s Evista® medication. Eli Lilly does not know what process competitors are using to manufacture Raloxifene Hydrochloride. According to EMEA guidance (European Medicines Agency, 2007), detailed information on the synthesis or manufacture of the active substance, including details on the by-products and degradation products of active ingredients and validation of the manufacturing / synthesis process, is commercially confidential information.

Prat D et al (2013): Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes, available online: http://pubs.acs.org/doi/pdf/10.1021/op4002565 Prat D, Hayler J & Wells A (2014): A Survey of Solvent Selection Guides, available online: http://pubs.rsc.org/En/content/articlepdf/2014/gc/c4gc01149j?page=search. 17 http://www.cas.org/products/scifinder

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 27 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 may be present as a solvent residue at levels below 5 ppm, as per the relevant ICH Guidelines) in combination with the fact that Raloxifene Hydrochloride is used internally by Eli Lilly in the manufacture of the final medicinal product, consultation with actors along the supply chain was not deemed necessary for the purposes of the AoA and was not undertaken.

4.3 Screening of potential alternatives

4.3.1 Screening for technical feasibility

Table 4-3 summarises the findings of the lab test-based assessment of the technical feasibility of the alternative substances that have been investigated by Eli Lilly (see Table 9-1 of Annex 2). The table provides a shortlist of the seven substances that could be feasibly used in the lab tests. However, their technical performance was still poor when compared to EDC against the pre-selected technical feasibility criteria.

Table 4-3: Summary of technical feasibility of shortlisted potential alternative substances No Potential alternative substance EC Number CAS Number Conclusion 1 Dichloromethane 200-838-9 75-09-2 Technically poor 2 Chloroform 200-663-8 67-66-3 Technically poor 3 1,1,2,2-Tetrachloroethane 201-197-8 79-34-5 Technically poor 4 1,2,3-Trichloropropane 202-486-1 96-18-4 Technically poor 5 Chlorobenzene 203-628-5 108-90-7 Technically poor 6 1,2-Dichlorobenzene 202-425-9 95-50-1 Technically poor 7 Fluorobenzene 207-321-7 462-06-6 Technically poor

These seven substances are further screened for market availability and hazard profile below.

4.3.2 Screening for market availability and commercialisation

The second screening step is to assess the availability and commercialisation status of the potential alternatives in the manufacture of Raloxifene Hydrochloride. This includes the following considerations:

1. Availability of alternative solvents in the quantity required by Eli Lilly. Table 9-2 in Annex 2 looks at the availability of REACH Registrations for each substance. Brown colours indicate problematic areas. Eli Lilly consumes, on average, ''#A#''''''''' t/y EDC but this volume will decline in the future as described in Section 3. Eli Lilly would need an amount of alternative solvent in a tonnage of at least the same order of magnitude (later in the document, it is indicated that three times more DCM would be needed to replace EDC).

2. Availability of alternative solvents in the quality required by Eli Lilly. The purity of each solvent can be specified by its suppliers and this information is not currently available to Eli Lilly (as no attempt has been made to obtain any of the shortlisted alternatives on the market). As the alternatives did not meet technical feasibility criteria this activity was not undertaken therefore quality issues are not considered.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 28 3. The solvent should ideally be listed in the ICH Q3C(R5) guidelines in respect to the approved residual concentration limits. If it were not, the solvent would not be considered as immediately available as it would require new testing to establish residual levels and the associated hazards and to secure ICH guideline listing. This is also presented in Table 9-2.

4. With regard to the commercial use of the potential alternatives on the industrial scale, with the exception of past DCM use by Eli Lilly under a different manufacturing process, Eli Lilly has not used any of the remaining shortlisted alternatives in its production process and cannot be certain as to whether any of its competitors has ever used any of the alternatives in the manufacturer of Raloxifene Hydrochloride on an industrial scale.

Table 9-2 shows that only a sub-set of the potential alternatives is available on the market and listed in the ICH guidelines, namely DCM, chloroform and chlorobenzene.

4.3.3 Screening for hazard profile

The intrinsic hazard properties of these substances were screened to identify and deselect those substances, which have critical hazard properties (e.g. CMR properties), thus making them unsuitable as substitutes for EDC. The following information was retrieved:

• Registration status (which is also a first indication of market availability, as discussed earlier) • EU Classification according to the CLP criteria • Any other relevant information on SVHC properties (e.g. existing restrictions, evaluations of carcinogenicity by other organisations (e.g. the International Agency for the Research on Cancer (IARC)), evidence for endocrine disrupting activity).

To this end, ECHA’s website18 was consulted and the respective substance searched by CAS Number. Registration status as well as the classification of substances was retrieved from this site. Also, any information on other REACH-related activities (e.g. listing as SVHC, information on restrictions, authorisation) were followed and evaluated regarding their potential consequences for using the substance as an alternative to EDC.

Furthermore, eChemPortal19 was consulted to check any involvement in other regulatory programmes and existing evaluations (e.g. OECD SIDS reports, US High Production Volume Information System (HPVIS), EU Risk Assessment Reports).

Relevant findings are summarized in Table 9-3 of Annex 2. Among the seven potential alternatives, four raise concerns:

• 1,2,3-Trichloropropane has recognised CMR properties and is already on the Candidate List for REACH Authorisation. This cannot be considered a suitable alternative for EDC

• DCM, chloroform and 1,1,2,2-tetrachloroethane are suspected carcinogens (chloroform is also a suspected reprotoxic substance); DCM is currently under investigation by IARC. These

18 http://echa.europa.eu/search-chemicals

19 http://www.echemportal.org/echemportal

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 29 substances might only be considered acceptable alternative substances if they were determined to be technically and economically equal to or superior than EDC (based on Eli Lilly’s lab tests, this is not the case).

The remaining three potential substances have a sufficiently large database to allow their evaluation in comparison to EDC. Notably, one of them, 1,2-dichlorobenzene, is currently undergoing substance evaluation under REACH.

4.3.4 Summary of screening process

Finally, Table 4-4 (overleaf) summarises the findings of each step in the screening process and concludes on the overall feasibility of each of the shortlisted potential alternatives as replacements for EDC.

The following conclusions can be reached:

• All shortlisted potential alternatives technically perform far worse than EDC and result in low product yields with unacceptable crystal forms and impurity profiles. These poor performance prospects make all shortlisted potential alternatives technically infeasible and unrealistic EDC replacements.

• Several of the shortlisted potential alternatives would not necessarily result in an improvement in comparison to EDC in terms of the hazards to which workers are currently potentially exposed. Such substances include 1,2,3-Trichloropropane (carcinogen and reprotoxic substance on the Candidate List), DCM, chloroform, and 1,1,2,2- tetrachloroethane (all three being suspected carcinogens).

• 1,1,2,2-Tetrachloroethane, 1,2,3-trichloropropane, 1,2-dichlorobenzene and fluorobenzene also suffer from poor market availability and/or absence from the relevant ICH Guidelines on residual solvents.

Overall, 1,1,2,2-Tetrachloroethane, 1,2,3-trichloropropane and fluorobenzene are not eligible for the substitution of EDC, while the remaining four shortlisted potential alternatives are not realistic options on grounds of poor technical feasibility and, in the case of DCM and chloroform, a hazard profile that raises concerns.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 30 Table 4-4: Conclusion of screening of shortlisted potential alternatives Identified potential Technical Availability and commercialisation Hazard profile Conclusion of screening process alternatives feasibility status Available and listed in ICH Suspected carcinogen, eligible only if there are Guidelines but with poor hazard DCM Technically poor Available other strong arguments in favour of the profile and performance. It was substance (e.g. technical feasibility) replaced by EDC in the 1990s. Not a realistic option Suspected carcinogen and reproductive toxicant, Available and listed in ICH Available but commercial use eligible only if there are other strong arguments Guidelines but with poor hazard Chloroform Technically poor unclear in favour of the substance (e.g. technical profile and performance. feasibility) Not a realistic option Suspected carcinogen, notable acute toxicity, Unavailable with poor hazard Unavailable and commercial use eligible only if there are other strong arguments 1,1,2,2-Tetrachloroethane Technically poor profile and performance. unclear; not in the ICH Guidelines in favour of the substance (e.g. technical Not an option feasibility) Very poor hazard profile; Limited availability and commercial Carcinogenic and reprotoxic, on the Candidate unavailable with poor 1,2,3-Trichloropropane Technically poor use unclear; not in the ICH List, not eligible to replace EDC performance. Guidelines Not an option Available and listed in ICH No obvious CMR properties, but relevant aquatic Available but commercial use Guidelines but with poor Chlorobenzene Technically poor toxicity, eligible. unclear performance. Sufficient data for assessment Not a realistic option No obvious CMR properties (but on CoRAP on Not listed in ICH Guidelines and Available but commercial use CMR suspicions), notable aquatic toxicity, 1,2-Dichlorobenzene Technically poor with poor performance. unclear; not in the ICH Guidelines eligible. Not a realistic option Sufficient data for assessment Unavailable and commercially Unavailable with poor No obvious CMR properties, eligible. Fluorobenzene Technically poor unproven; not in the ICH performance. Sufficient data for assessment Guidelines Not an option

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 31 This analysis reinforces Eli Lilly’s view that EDC is the only solvent that can deliver the manufacture of Raloxifene Hydrochloride under acceptable conditions and with satisfactory yield and product quality and supports Eli Lilly’s request for an Authorisation for this use of EDC. However, in order to provide a more detailed analysis of the practical and economic implications of a conversion from EDC to an alternative solvent, two of the shortlisted potential alternative substances are further assessed in the analysis in Section 5. The selected possible alternatives are DCM and chlorobenzene. The reasons for these choices are:

• Chlorobenzene is better placed than other potential alternatives to, theoretically, replace EDC on grounds of:

− Its market availability and ICH Guidelines listing − Its product yield as demonstrated in laboratory tests conducted by Eli Lilly − The lack of any recognised CMR/SVHC properties

• DCM was previously used by Eli Lilly in the manufacture of Raloxifene Hydrochloride before being replaced by EDC. In addition, DCM delivers a homogeneous reaction mixture (albeit at high temperatures and at high pressures). Chlorobenzene does not yield such a homogeneous mixture and its use ''#A#'''''''''''''''''' '''''''''''''''''''.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 32 5 Suitability and availability of possible alternatives

5.1 Alternative 1 – DCM

5.1.1 Substance ID and properties

Name and other identifiers of the substance

The following table presents the identity of the substance.

Table 5-1: Identity of DCM Parameter Value Source EC number 200-838-9 1 EC name Dichloromethane 1 CAS number 75-09-2 1 IUPAC name Dichloromethane 1 DCM; Dichloride, methylene; Methane dichloride; Methylene dichloride; Other names 2 Chloride, methylene Molecular formula CH2Cl2 1 SMILES notation CH2Cl2 2 Molecular weight 84.93 2

Molecular structure 1

Sources (searches undertaken on 1 December 2014): 1: European Chemicals Agency: http://echa.europa.eu/ 2: Chemspider: http://www.chemspider.com/

Physico-chemical properties

The following table presents the key physico-chemical properties of DCM. The information has been collected from the ECHA dissemination portal (search undertaken on 1 December 2014).

Table 5-2: Physico-chemical properties of DCM and comparison to EDC DCM EDC Property Value Source Value Source Physical state at 20°C and 101.3 Liquid 1 Liquid 1 kPa Melting/freezing -95 °C at 101.3 kPa 1 -36 °C 1 point Boiling point 40 °C at 101.3 kPa 1 83.6 °C at 101.3 kPa 1 Density 1.33 g/cm³ at 20 °C 1 1.2455 g/cm³ at 20 °C 1 Granulometry Not applicable 1 Not applicable 1 Vapour pressure 584 hPa at 25 °C 1 102.47 hPa at 25 °C 1

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 33 Table 5-2: Physico-chemical properties of DCM and comparison to EDC DCM EDC Property Value Source Value Source Calculated log Pow: 1.34 Partition Experimental log Pow: log Pow 1 Experimental log Pow: 1.45 at 20 1 coefficient 1.25 at 20 °C °C Water solubility 13.2 g/L at 25 °C 1 7.9 g/L at 25 °C 1 Surface tension No data 1 32.45 dynes/cm at 20 °C 1 Flash point The substance has no flashpoint 1 ca. 13 °C at 1013 hPa 1 Auto- 605 °C at 101.3 kPa 1 440 °C at 1013 hPa 1 flammability Gas Lower explosion limit (%): 13 Gas Lower explosion limit (%): 6.2 Flammability 1 1 Gas Upper explosion limit (%): 22 Gas Upper explosion limit (%): 16 Explosiveness Not relevant 1 Not relevant 1 Oxidising Not relevant 1 Not relevant 1 properties Viscosity 0.42 mPa s (dynamic) at 25 °C 1 0.829 mPa s (dynamic) at 20 °C 1 Sources: 1: European Chemicals Agency: http://echa.europa.eu/

5.1.2 Technical feasibility

Comparison of DCM to EDC against the technical feasibility criteria

Table 5-3 summarises the comparison of DCM to EDC against the technical feasibility criteria described in Section 2.2.2. Light brown colour in the table indicates areas of uncertainty, while dark brown indicates areas where DCM falls short of the thresholds set for the individual technical feasibility criteria.

The table confirms the following:

• DCM fully meets only two of the eight criteria, the complete solubility of the starting materials, which is the minimum any solvent needs to achieve in order to be considered as a potential alternative, the reaction mixture viscosity and the yield criterion. However, DCM only marginally meets the yield criterion and in doing so performs significantly worse than EDC. The aim of a switch to an alternative would be to convert to a process that would have a yield equivalent to the current process in order to maintain the same cycle-time and cost for production; a decrease in yield would lead to an increased number of batches and thus an increased amount of starting materials, reagents, intermediates and solvent. This in turn would impact the exposure profile of workers and potential emissions to the environment. • There are areas where the technical performance of DCM is uncertain, as it has not been used on the industrial scale under the conditions and parameters of the current production process of Raloxifene Hydrochloride ''#A#, #E#'''''''''' '''''''''''''' '''''''' '''' ''''''''''''''' '''' '''''''''' ''''''' '''''''' '''' ''''''' '''''''''' ''''''''' ''''''' ''''''' ''''''''''''''' ''''''''''''''''' ''''' ''''' ''''''''''''' ''''''''''''''. These include the completion of the three reactions that take place in the presence of the solvent and the levels of DCM residues in the final product • For the remaining criteria (reaction mixture viscosity and crystallisation step outcome, product impurities, crystal form of product and its solubility at the re-crystallisation step, and dielectric conductivity) DCM falls short of the requirements of Eli Lilly’s manufacturing process.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 34 Table 5-3: Comparison of DCM to EDC against the technical feasibility criteria Result or numerical Threshold or acceptable Result or numerical Criteria value achieved by EDC range for replacing EDC value achieved by DCM 1 Solubility of starting Complete dissolution Complete dissolution Complete dissolution materials 2 Reaction mixture Homogeneous, free Homogeneous, free Homogeneous reaction viscosity & moving moving only at high temperature crystallisation step and pressure outcome 3 Chlorination reaction >98% >98% #A#, #E# all Table 5-3 completion (Regulatory '''''''''''''''' '''''''''' ''''' '''''''''' commitment) '''''' ''''''''''''''''' '''' '''''''''''' Acylation reaction <3% starting material <3% starting material '''''''' '''''''''''' '''''''''' ''''''' completion remaining remaining ''''''''''''''' ''''''''''''' ''''' ''''''''' (Regulatory commitment) De-alkylation <0.2% starting material <0.2% starting material ''''''' ''''''''''''' ''''''''''' ''''''' reaction completion remaining remaining '''''''''''''' '''''''''''' ''''' ''''''''' (Regulatory commitment) 4 Crystal form of Crystal Form ' Crystal Form ' – to aid Crystal Form ''''' product dissolution in proceeding step Solubility in Complete dissolution Complete dissolution '''''''' ''''''''''''' subsequent re- (Regulatory crystallisation step commitment) 5 Product impurities in ''''''''''% '''''''''% '''''''''% isolated product (intermediate) 6 Solvent rejection Listed on ICH Guidelines Must meet ICH Listed on ICH Guidelines capability in API step – Class 1 guidelines – Class 2 <5 ppm EDC (limit: 600 ppm) '''''''''' '''''''' '''''''''' ''''' ''''''''''''''''' ''''''''''' ''''''' ''''''''''''''' ''''''''''''''''''''' '''''''''''''''''''''''''''' ''''''''''''''' ''' '''''''''''''''' 7 Yield '''''''% ''''''''% '''''''''''% 8 Electrical 4,000 pS/m ≥4,000 pS/m 4,300 pS/m conductivity of solvent Dielectric constant 10.3 ≥10 8.9 (relative permittivity) Note: Brown cells in the table indicate technically problematic areas for the investigated substances

In summary, for DCM to be able to be used as a replacement for EDC, the return to the '''''''''''''''''''''''' process or a completely different synthetic route would be needed. The R&D required to develop an alternative synthetic route cannot be elaborated in detail, as all efforts made to date have been unsuccessful. Overall, DCM cannot be considered a technically feasible alternative for EDC.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 35 Actions required for making the alternative technically feasible

The practical implications of the shortcomings of DCM, which are currently infeasible to implement include:

1. Reaction Rate: to achieve a reasonable reaction rate using DCM, in transformation (c) the mixture has to be heated past the boiling point of DCM and in turn the reactor needs to be sealed, which has safety implications.

2. Crystal form of product: use of DCM in the place of EDC generates an intermediate with a different crystal form, Crystal Form '#A#, #E#'''. The impact of this crystal form downstream would have to be assessed on the industrial scale (considering solubility profile, DCM removal, impurity rejection).

3. Purity/quality: the DCM process for the intermediate step would have to be assessed on the industrial scale to determine if it is capable of delivering the intermediate in the desired purity and quality. Laboratory tests indicate a yield that is much lower than what can be achieved by EDC.

4. Safety and emission control: larger volumes of solvent used would increase the frequency of tasks such as road tanker deliveries and sampling. A chemical agents risk assessment would be completed to determine the potential impact on the exposure profile of workers. A process safety review would have to be completed to determine what additional measures would be required to ensure that the risk of static could be appropriately managed. In addition, given the low boiling point and high vapour pressure of DCM, it is highly probable that significant capital investment would be required to upgrade existing site fume abatement systems. On the other hand, while a significant impact on liquid waste incineration capacity would not be expected, this could only be confirmed as part of environmental impact assessment prior to the implementation of the alternative solvent

5. Subsequent process steps: a switch to DCM would mean a new final re-crystallisation step would be required in order to obtain the non-solvated API from the DCM-solvate while ensuring that the process can deliver the product in the non-solvated form with DCM residual levels below 600 ppm (as per ICH Guidelines).

Based on prior R&D efforts, Eli Lilly is firmly of the view that DCM will not become technically feasible within the existing manufacturing process, as its shortcomings are largely due to its physico- chemical properties, which cannot be altered.

As shown in Section 3.2, there has been a strong decline in the global sales of Evista®. '#C#'''' ''''''' '''''''''''''''''''''''' '''''''''''''''''''' ''''''''' ''' '''''''''''''' '''''''' ''''''''''''''''''' '''' ''''''''''' '''''''''''''''' '''''''''''''''' ''''''''' '''''''' '''''''' Intense pressure from generic medicines is impacting the market share of Eli Lilly. In this context, further investment into the manufacturing process in the form of fundamental changes to the manufacturing facility and the process used, are impossible to justify from a business and commercial perspective, particularly since the new process would be unlikely to match the efficiency of the current one.

While some of the technical challenges outlined above could be addressed by investing in the process (i.e. improving the fume abatement systems and re-designing the final re-crystallisation step), high costs would be incurred in developing an alternative, particularly if clinical trials were involved.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 36 5.1.3 Economic feasibility

Due to the lack of technical feasibility, the analysis of economic feasibility of DCM presented in Section 10.2 (Annex 3) is only of a theoretical nature.

Table 5-4 summarises the estimates of the costs when switching from EDC to DCM. These estimates are clearly a rough and incomplete approximation as DCM is not a realistic alternative, thus a detailed assessment of costs cannot be undertaken. Nevertheless, it is anticipated that the theoretical plant conversion costs would dominate the overall cost and make this technically infeasible alternative solvent economically infeasible as a replacement for EDC.

Table 5-4: Overview of estimated costs from conversion to DCM Cost estimate Category Cost element Estimate Indicative range Investment R&D work Not costed – Unknown Not costed costs Plant conversion '#D# all Table 5-4'''''''''''' ''''''''''''' €10-100 million ''''''''''''' ''''''''''''' '''''''''' ''''''''''' '''''''''' ''''' ''''''' '''''''''''''''''''' ''''''''''''' '''' '''''''''' Downtime Not costed – Likely to be Not costed significant Market Preparatory work Not costed Not costed authorisations (labour cost) variations Residual solvent ''''''''''' '''''''''''' <€1 million tests Toxicology '''''''''' '''''''''''' or higher if clinical <€1 million (minimum) assessment trials needed Internal labour '''''''''''''''''''''' ''''''''''''' €0.03-0.1 million costs Fees ''''''''' '''''''''''''' <€1 million Sub-total '''''''' '''''''''''''' ''''' '''''''''''' €1-10 million Loss of Plant improvements no longer €14.4 million As shown past needed investment IP expenditure '''''' '''' '''''''' ''''''''''''' – Not taken Not taken into account into account Changes to Increased solvent cost ''''''''''''''''''''' ''''''''''''' ''''''''''''''''' <€1 million/y operating Costs arising from changes to Not costed – Unknown Not costed costs process

Actions required for making the alternative economically feasible

Since the alternative is not a technically feasible substitute for EDC, its economic feasibility can neither be evaluated in detail nor can it be improved.

5.1.4 Reduction of overall risk due to transition to the alternative

Comparison of hazard profiles of DCM and EDC

A search of the ECHA C&L Inventory (undertaken on 1 December 2014) shows that harmonised classification and labelling information is available for DCM. This information is presented in Table 5-5. The table confirms that DCM has a more benign hazard profile than EDC, but it is a suspected carcinogen which is expected to be reclassified by IARC as 2A (Probably carcinogenic to humans).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 37 On the other hand, the use of DCM would introduce increased safety hazards with respect to static/charge build up. Relaxation time (static/charge) is governed by the dielectric constant and the electrical conductivity. The higher both numbers, the faster the relaxation time/time for static to dissipate. While the electrical conductivity of DCM is comparable to EDC, DCM has a lower dielectric constant than EDC. Additional studies would need to be carried out to evaluate if this difference would reduce the ability of the system to dissipate charge, thereby increasing the safety risk to the process. The low boiling point of DCM introduces additional process safety risk, as reactions must be carried out at higher temperature and pressure. In addition, a process using DCM would require higher volumes of solvent resulting in an increased number of road tanker deliveries, sampling event, and batches required for API demand quantities. This inevitably would lead to an increased worker exposure profile.

More broadly, the substance is a halogenated solvent like EDC, therefore, its long-term sustainability cannot be assumed to be significantly improved in comparison to EDC.

Table 5-5: Harmonised classification of DCM and comparison to EDC DCM EDC Hazard Class and Hazard Statement Hazard Class and Hazard Statement Category Code(s) Code(s) Category Code(s) Code(s) - - Flam. Liq. 2 H225 - - Acute Tox. 4 H302 - - Skin Irrit. 2 H315 - - Eye Irrit. 2 H319 - - STOT SE 3 H336 Carc. 2 H351 Carc. 1B H350 Source: European Chemicals Agency (C&L Inventory): http://echa.europa.eu/regulations/clp/cl-inventory

Comparative risk assessment of DCM and EDC under Eli Lilly-specific exposure scenario

A comparative risk assessment of DCM and EDC is provided in Section 11 (Annex 4) to this AoA.

- For this comparative risk assessment a DMELlong-term inhalation workers for EDC associated with a 1 x 10 5 risk level was derived from the exposure-risk relationship published by the Risk Assessment Committee (ECHA, 2015).

For the environmental assessment a PNECfreshwater was used, which is the same as derived in the registration dossier and by other evaluating bodies.

DCM was evaluated as a potential alternative substance.

DCM is a suspected human carcinogen (Cat 2, H351). Recently it was reclassified by IARC to Group 2A “probably carcinogenic to humans”, based on limited evidence from epidemiological studies, in addition to the proven carcinogenicity in animal models (Benbrahim-Tallaa, et al., 2014)

For this comparative assessment a DMELlong-term inhalation workers was derived using a cancer risk estimate presented by the US Environmental Protection Agency, which was transformed to the occupational situation.

A tentative PNECfreshwater was derived, taking into account available aquatic toxicity data.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 38 EDC and DCM were evaluated using a scenario of handling the substance in a predominantly closed system with unloading of the substance from large, dedicated facilities and handling samples of the substance in the laboratory for quality control purposes.

ERC: Industrial use of processing aids in processes and products, not becoming part of articles (ERC 4)

PROC: Use in closed, continuous process with occasional controlled exposure (PROC 2)

Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at dedicated facilities (PROC 8b)

Use as laboratory reagent (PROC 15).

Based on the quantitative results of this comparative assessment, the alternative substance DCM seems to be advantageous with regard to its potential carcinogenic properties, due to a low assumed carcinogenic potency. It appears to lead to slightly higher RCRs for the aquatic environment compared to EDC.

Taking into account that the IARC only recently upgraded its carcinogenicity classification for DCM, based on new (albeit limited) findings regarding a potential carcinogenic activity in humans, the substance nevertheless is not to be a suitable alternative to EDC:

• Potency considerations are associated with a relevant uncertainty; the exposure-risk relationship used is based on animal experiments and does not include information from epidemiological studies

• The substance might be reclassified into Cat 1B according to Regulation (EC) No 1272/2008 in the near future, which would make it a candidate for Authorisation itself and would limit its usability.

In conclusion, DCM, although it appears to be a less potent carcinogen, is not considered a viable alternative to EDC.

5.1.5 Availability

Market availability

As shown in Table 5-6, DCM as a substance is readily available on the EU market and Eli Lilly has already identified a potential supplier.

Table 5-6: Market availability of DCM Number of suppliers Envisaged Has Eli Lilly researched Alternative identified changes to REACH registration the market for substance Outside market status suppliers In the EU the EU availability Fully registered DCM Yes 1 - Staying the same 100,000 – 1,000,000 t/y

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 39 Quality issues

Quality issues have not been identified for the DCM that is available on the EU market. Given that DCM was used in the past by Eli Lilly, it can be safely assumed that quality issues would not arise.

Commercialisation prospects

Irrespective of market availability, a manufacturing process is not available that (a) is based on DCM, (b) meets the technical requirements of Eli Lilly and (c) adheres to the Marketing Authorisation held for the Evista® medicinal product . The manufacturing process that was based on DCM and was used in the 1990s does not adhere to the manufacturing requirements of Eli Lilly or those of the marketing authorisations currently held. Therefore, DCM is not considered an alternative solvent because the manufacturing method (synthetic route) that would allow its implementation is not available. On the other hand, the ICH Guidance on residual solvents mentions DCM.

Actions required for making the alternative available

To make DCM available for use in Raloxifene Hydrochloride production, Eli Lilly would need to develop an alternative synthetic process (or, theoretically, revert to the process abandoned in the 1990s). However, the outcome of laboratory tests suggests that the development and evaluation of a new synthetic route is merely a theoretical possibility.

As discussed earlier, if a new synthetic route using DCM were to be developed, characterisation of new impurities in the API under the new route would be required before submittal of an application for variation of the Marketing Authorisation and relevant information would need to be generated for the associated regulatory submissions.

5.1.6 Conclusion on suitability and availability of DCM

Based on prior R&D efforts, Eli Lilly is firmly of the view that DCM is not technically feasible and its physicochemical properties prevent it from becoming an alternative solvent for the current synthetic route of Raloxifene Hydrochloride. Moreover, even if a new, alternative synthetic route could be developed to accommodate DCM, the commercial value of the product is too low to support the high costs that would be incurred in developing an alternative; '#C#'''''' ''''''''''''' '''' '''''''''' '''' '''''''' '''' '''''' ''''''''''' ''''''''''''''''''' ''''''''' '''' ''''''''''''' '''''''''' ''''''''''''''''''' '''''' ''''''''''' '''' '''''''''''''' '''''''''''''. Therefore, DCM cannot be considered a feasible alternative for Eli Lilly. Moreover, the comparative assessment of risks from DCM and EDC suggests that, despite its lower carcinogenic potency, the uncertainty over the future classification of the substance renders it an option that would offer insufficient reduction in risk for Lilly workers currently working with and potentially exposed to EDC.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 40 5.2 Alternative 2 – Chlorobenzene

5.2.1 Substance ID and properties

Name and other identifiers of the substance

The following table presents the identity of the substance.

Table 5-7: Identity of chlorobenzene Parameter Value Source EC number 203-628-5 1 EC name Chlorobenzene 1 CAS number 108-90-7 1 IUPAC name Chlorobenzene 1 Monochlorobenzene, Benzene, chloro-, Benzene chloride, Phenyl chloride, Other names Chlorobenzol, Monochlorbenzol, Chlorbenzol, Monochlorbenzene, 2 Chlorobenzene, mono- Molecular formula C6H5Cl 1 SMILES notation c1ccc(cc1)Cl 3 Molecular weight 112.5569 g/mol 2

Molecular structure

Sources (searches undertaken on 28 October 2014): 1: European Chemicals Agency: http://echa.europa.eu/ 2: Pubchem: http://pubchem.ncbi.nlm.nih.gov/ 3: Chemspider: http://www.chemspider.com/

Physicochemical properties

Table 5-8 presents the key physicochemical properties of chlorobenzene. The information was collected from the ECHA dissemination portal (search undertaken on 28 October 2014).

Table 5-8: Physico-chemical properties of chlorobenzene and comparison to EDC Chlorobenzene EDC Property Value Source Value Source Physical state at 20°C Liquid 1 Liquid 1 and 101.3 kPa Melting/freezing point -46 °C 1 -36 °C 1 Boiling point 131-132 °C at 1013.25 hPa 1 83.6 °C at 101.3 kPa 1 Density 1.107 g/cm³ at 20 °C 1 1.2455 g/cm³ at 20 °C 1 Granulometry - 1 Not applicable 1 Vapour pressure ca. 11.73 hPa at 20 °C 1 102.47 hPa at 25 °C 1

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 41 Table 5-8: Physico-chemical properties of chlorobenzene and comparison to EDC Chlorobenzene EDC Property Value Source Value Source Log Pow are listed below: - column chromatographic method and HPLC (25°C): 2.98 ± 0.02 - RP-HPLC method (25°C): Partition coefficient 1 Experimental log Pow: 1.45 at 1 2.98 ± 0.04 20 °C - RP-HPLC method: 3.00 - slow stirring method: 2.898 ± 0.004 - method not given: 3.79 Water solubility 0.207 g/L at 20 °C 1 7.9 g/L at 25 °C 1 Surface tension 33.28 mN/m at 20 °C 1 32.45 dynes/cm at 20 °C 1 Flash point 28 °C 1 ca. 13 °C at 1013 hPa 1 Auto-flammability 590 °C 1 440 °C at 1013 hPa 1 Gas Lower explosion limit (%): 6.2 Flammability Not relevant 1 1 Gas Upper explosion limit (%): 16 Explosiveness Not relevant 1 Not relevant 1 Oxidising properties Not relevant 1 Not relevant 1 0.829 mPa s (dynamic) at 20 Viscosity ca. 0.756 mPa·s 1 1 °C Sources: 1: European Chemicals Agency: http://echa.europa.eu/

5.2.2 Technical feasibility

Comparison of chlorobenzene to EDC against the technical feasibility criteria

Table 5-9 (overleaf) summarises the comparison of chlorobenzene to EDC against the technical feasibility criteria described in Section 2.2.2. Light brown colour in the table indicates areas of uncertainty, while dark brown indicate areas where chlorobenzene falls short of the thresholds set for the individual technical feasibility criteria.

The table confirms the following:

• Chlorobenzene fully meets four of the eight criteria: the complete solubility of the starting reagents (, the level of product impurities in the isolated intermediate product, the yield criterion, and the ability to extract the solvent so that the residual concentration is below the ICH guidelines (<360 ppm). However, the yield is lower with chlorobenzene than with EDC. As described earlier for DCM, a switch to an alternative solvent should ideally result in a process that has a yield equivalent to the current one. Therefore, while chlorobenzene meets the minimum criterion described above, it would perform worse than EDC

• There are certain areas where the technical performance of chlorobenzene is uncertain, as this solvent has not been used on the industrial scale under the conditions and parameters of the current Raloxifene Hydrochloride production process. These include the completion of the chlorination and acylation reactions that need to take place in the presence of solvent

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 42 Table 5-9: Comparison of chlorobenzene to EDC against the technical feasibility criteria Threshold or Result or numerical Result or numerical value Criteria acceptable range for value achieved by EDC achieved by chlorobenzene replacing EDC 1 Solubility of Complete dissolution Complete dissolution Complete dissolution starting materials 2 Reaction mixture Homogeneous, free Homogeneous, free Heterogeneous reactions viscosity & moving moving #A#, #E# all Table 5-9 crystallisation step '''''''''''''''''''''''''' ''''''''''''''''' '''''' ''' outcome 3 Chlorination >98% >98% ''''''' '''''''''''' reaction (Regulatory completion commitment) Acylation reaction <3% starting material <3% starting material ''''''' ''''''''''''' completion remaining remaining (Regulatory commitment) De-alkylation <0.2% starting material <0.2% starting material ''''''''' '''''''''''''''' '''''''''''''''' reaction remaining remaining ''''''''''''''''' completion (Regulatory commitment) 4 Crystal form of Crystal Form ' Crystal Form '' – to aid Crystal Form '''' product dissolution in proceeding step Solubility in Complete dissolution Complete dissolution ''''''' '''''''''''''' subsequent re- (Regulatory crystallisation step commitment) 5 Product impurities '''''''''''% '''''''''% ''''''''% in isolated product (intermediate) 6 Solvent rejection Listed on ICH Must meet ICH Listed on ICH Guidelines – capability in API Guidelines – Class 1 guidelines Class 2 step <5 ppm EDC (limit: 360 ppm) ''''''''''' ''''''''''' ''' '''''''''''''''' '''''' ''''''''' ''' '''''''''' ''''''''''' ''''' '''''' '''''''''''' '''''''''''''''''''''' '' 7 Yield '''''''% ''''''''''' '''''% 8 Electrical 4,000 pS/m ≥4,000 pS/m 7,000 pS/m conductivity of solvent Dielectric constant 10.3 ≥10 5.6 (relative permittivity)

• For the remaining criteria, i.e. reaction mixture viscosity, de-alkylation reaction completion, crystal form of product and its solubility at the re-crystallisation step, and dielectric conductivity, chlorobenzene falls short of the requirements of Eli Lilly’s manufacturing process. ''#A#, #E#''' ''''''''''''''''''' '''' '''''''''''''' ''''''''''' '''' ''''''' ''''''''''''''''''' ''''''''' ''''''''''''''''''''''' ''''''''' ''''''''''''''''''''''''''''' ''''''''''''''''' ''''''' ''''''' ''''' '''''''''' ''''' ''''''''''''''''''''''''''' '''''''''''''''' ''''''' '''''''''''''''''''''''''''' '''''''''' '''' ''''''''''''' ''''' ''''''''''''' '''''''''''''''''''''''''''' ''''''''''''''' '''''' ''''''' '''''''''''''''' '''' ''''''''''''''' '''''''''''''''''''' '''''''' '''' ''''''''''''''''''''''' '''''''' ''''''''''''''' '''''''''''''''''''' ''''''''''''' '''''''''''''''' ''''' ''''''''' ''''''''''''''''''' '''''''' '''''''''''''''' '''' ''''''' ''''''''' '''''''''''''''' ''''' ''''''' ''''''' ''''''' ''''''''''''''' '''''' '''''''''''''''''''''' '''''''''''''''''''''''''''' ''''''' ''''''''''''' '''''''' ''''''''''''' '''' ''' '''''''''''''''''''''''''''''''''''''''''''''''' '''''''''''''''''''''''''''' '''''''''''''' '''''''' ''''''''''''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 43 '''''''''''' '''' ''''''' '''''''''''''''''''''''''''''' ''''''''''' ''''''''' ''''' '''''' '''''''''''''''''' '''' ''' ''''''''''''' '''''''''''''' ''''''''' ''''''''''''' ''''''''''' ''''' '''''''''''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''' ''''''''''''''' '''''''''' '''''' '''''''''''''''''' ''''''''''''''' ''''''''''''''''''''''''' '''' '''''' ''''''''''''''''''''''''''' ''''''''''''''''''''''''''' ''''''''''''' ''''''' ''''''' ''''''''''''' ''' ''''''' ''''''''''''''' '''' ''''''' '''''''''''''''''''''''' '''''''' ''''''''' ''''''''''''''' ''''''''' ''''''' '''''''''''''' '''' ''''''' ''''''''' ''''''''' ''' ''''' ''''''''''' ''''''' ''''''''''''''''''' ''''''''''''''''''''''''' '''''''''''''' '''''''''''''''' '''''''''''''''''''''''''''''''''' ''''''' ''''''' ''''''''''''''''''''''''''''' '''' ''''' ''''''''''''''''''' ''''''' ''''''''''''''''’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’'''' ''''''''''''''''

In summary, for chlorobenzene to become an appropriate replacement for EDC, an alternative synthetic route would be needed, but such an alternative manufacturing process is currently unknown. The R&D required to develop such an alternative cannot be elaborated in detail as all efforts made to date have been unsuccessful. Overall, chlorobenzene cannot be considered a technically feasible alternative for EDC.

Actions required for making the alternative technically feasible

The practical implications of the shortcomings of chlorobenzene, which are currently infeasible to implement include the following:

1. Heterogeneous nature of the chlorination reaction: the heterogeneous nature of transformation (a) (chlorination reaction) will need to be resolved. Such a mixture is not practical from a manufacturing perspective, as described above.

2. Crystal form of product: as noted above, use of chlorobenzene in place of EDC generates the intermediate with a different crystal form, Crystal Form ''#A#, #E#''', which is not soluble in the subsequent API step. The impact of this crystal form downstream would have to be assessed on the industrial scale (considering solubility profile, chlorobenzene removal, impurity rejection).

3. Purity/quality: a chlorobenzene process for the intermediate step would have to be assessed on the industrial scale to determine if it is capable of delivering the intermediate in the desired purity and quality. Laboratory tests indicate that the yield is lower than what can be achieved by using EDC, see Table 5-9.

4. Safety and emission control: a chemical agents risk assessment would be completed to determine the potential impact on the exposure profile of workers. A safety review would have to be completed to determine what additional measures would be required to ensure the risk of static could be appropriately managed. A significant impact on liquid waste incineration capacity is not to be expected, however this would be confirmed as part of environmental impact assessment prior to the implementation of the alternative solvent.

5. Subsequent process steps: a switch to chlorobenzene would mean a new final re- crystallisation step would be required in order to obtain the non-solvated API from the chlorobenzene-hemi-solvate while ensuring that the process can deliver the product in the non-solvated form with chlorobenzene residual levels below 360 ppm (as per ICH guidelines).

In comparison to DCM, chlorobenzene does not have the low boiling point of DCM. In addition, the R&D work by Eli Lilly has confirmed that chlorobenzene may be accompanied by a product yield of ''#A#, #E#''''%, ''#A#, #E#'''''''''''' '''' ''''''''''''''' to the yield of '#A#, #E#''''''''''''% for DCM. ''#A#, #E#'''''''''''''''''''''''' '''''''''''' '''''' '''''' ''''''''''''' ''''''''''''''' '''''''''''''''''''''''' '''''''''' ''''''''''' ''' ''''''''''''' '''''''' ''' '''''''''' ''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 44 ''''''''''''''' and, thus, Eli Lilly is firmly of the view that neither chlorobenzene nor DCM will become technically feasible as their shortcomings are largely based on their physico-chemical properties which cannot be altered.

While some of the technical challenges outlined above could be addressed by investing in the process (i.e. re-designing the final re-crystallisation step), the commercial value of the product is too low to support the high costs that would be incurred in developing an alternative (see discussion above on recent and future trends in sales/turnover).

5.2.3 Economic feasibility

As for DCM, due to the lack of technical feasibility, the analysis of economic feasibility of chlorobenzene presented in Section 10.3 (Annex 3) is only of a theoretical nature. A summary of theoretical cost estimates is provided in Table 5-10.

Table 5-10: Overview of estimated costs from conversion to chlorobenzene Cost estimate Category Cost element Estimate Indicative range Investment R&D work Not costed – Unknown Not costed costs Plant conversion '#D# all Table 5-10''''''''''''' €10-100 million '''''''''''''' ''''''''''' ''''''''''' '''''''''''' ''''''''''' '''''''''''' '''''''''' ''''' '''''''' '''''''''' Downtime Not costed – Likely to be Not costed significant Market Preparatory work Not costed Not costed authorisations (labour cost) variations Residual solvent ''''''''''' '''''''''''' <€1 million tests Toxicology '''''''''' '''''''''''' or higher if clinical <€1 million (minimum) assessment trials needed Internal labour '''''''''''''''''''''''' ''''''''''''' <€0.03-0.1 million costs Fees '''''''' ''''''''''''' <€1 million Sub-total '''''''' '''''''''''' '''' '''''''''''' €1-10 million Loss of Plant improvements no longer €14.4 million As shown past needed investment IP expenditure '''''' '''' ''''''''' ''''''''''''' – Not taken Not taken into account into account Changes to Increased solvent cost ''''''''''''''''' ''''''''''''' ''''''''''''''''' <€1 million/y operating Costs arising from changes to Not costed – Unknown Not costed costs process

Actions required for making the alternative economically feasible

Since the alternative is not a technically feasible substitute for EDC, its economic feasibility can neither be evaluated in detail nor can it be improved.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 45 5.2.4 Reduction of overall risk due to transition to the alternative

Comparison of hazard profiles of chlorobenzene and EDC

A search of the ECHA C&L Inventory (undertaken on 28 October 2014) shows that harmonised classification and labelling information is available for the substance. This information is presented in Table 5-11. The table confirms that chlorobenzene has a more benign hazard profile than EDC, as it does not display any CMR properties; however, it does appear to pose risk to the aquatic environment, which EDC’s classification does not include.

Table 5-11: Harmonised classification of chlorobenzene and comparison to EDC Chlorobenzene EDC Hazard Class and Hazard Statement Hazard Class and Hazard Statement Category Code(s) Code(s) Category Code(s) Code(s) Flam. Liq. 3 H226 Flam. Liq. 2 H225 Acute Tox. 4 H332 Acute Tox. 4 H302 - - Skin Irrit. 2 H315 - - Eye Irrit. 2 H319 - - STOT SE 3 H336 - - Carc. 1B H350 Aquatic Chronic 2 H411 - - Source: European Chemicals Agency (C&L Inventory): http://echa.europa.eu/regulations/clp/cl-inventory

On the other hand, the use of chlorobenzene would introduce increased safety hazards in respect of static/charge build up. The dielectric constant and the electrical conductivity govern the relaxation time (static/charge). The higher both of these governing numbers are, the faster the relaxation time/time for static to dissipate. While the electrical conductivity of chlorobenzene is comparable to EDC, chlorobenzene has a notably lower dielectric constant than EDC. In order to evaluate if this difference would reduce the ability of the system to dissipate charge and increase the safety risk to the process. additional studies would need to be carried out.

More broadly, the substance is a halogenated solvent like EDC, therefore, its long-term sustainability cannot be assumed to be significantly improved in comparison to EDC.

Comparative risk assessment of chlorobenzene and EDC under Eli Lilly-specific exposure scenario

A comparative risk assessment of chlorobenzene and EDC is provided in Section 11 (Annex 4) to this AoA.

- For this comparative risk assessment a DMELlong-term inhalation workers for EDC associated with a 1 x 10 5 risk level was derived from the exposure-risk relationship published by the Risk Assessment Committee (ECHA, 2015).

For the environmental assessment a PNECfreshwater was used, which is the same as derived in the registration dossier and by other evaluating bodies.

Chlorobenzene was evaluated as a potential alternative substance.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 46 For this comparative assessment tentative DNELlong-term inhalation workers and DNELlong-term dermal workers were derived, based on available toxicological information. A tentative PNECfreshwater was derived, taking into account available aquatic toxicity data.

Eli Lilly evaluated EDC and chlorobenzene using a scenario of handling the substance in a predominantly closed system with unloading of the substance from large, dedicated facilities and handling samples of the substance in the laboratory for quality control purposes.

ERC: Industrial use of processing aids in processes and products, not becoming part of articles (ERC 4)

PROC: Use in closed, continuous process with occasional controlled exposure (PROC 2)

Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at dedicated facilities (PROC 8b)

Use as laboratory reagent (PROC 15).

Based on the quantitative results of this comparative assessment, the alternative substance chlorobenzene demonstrates advantages over EDC with respect to human health. Due to a higher aquatic toxicity, RCR for the freshwater compartment is higher by a factor of 16, but still below 1 in the comparative assessment.

In conclusion, chlorobenzene, from a human health and environmental risk perspective is considered to fulfil the requirement of leading to overall reduced risks when used as an alternative to EDC, but its high aquatic toxicity needs to be carefully controlled.

5.2.5 Availability

Market availability

As shown in Table 5-12, chlorobenzene as a substance is readily available on the EU market and Eli Lilly has already identified a potential supplier.

Table 5-12: Market availability of chlorobenzene Number of suppliers Envisaged Has Eli Lilly researched Alternative identified changes to REACH registration the market for substance Outside market status suppliers In the EU the EU availability Chloro- Fully registered Yes 1 - Staying the same benzene 10,000 – 100,000 t/y

Quality issues

Eli Lilly did not identify quality issues for the chlorobenzene that is available on the EU market.

Commercialisation prospects

Irrespective of market availability, a manufacturing process that is based on chlorobenzene, meets the technical requirements of Eli Lilly and adheres to the marketing authorisation held for the Evista® medicinal product, is not available. Therefore, this alternative solvent cannot be considered

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 47 available, as the manufacturing method (synthetic route) that would allow its implementation is not available. On the other hand, the ICH guidance on residual solvents mentions chlorobenzene.

Actions required for making the alternative available

To make chlorobenzene available for use in Raloxifene Hydrochloride production, Eli Lilly would need to develop a new, alternative synthetic process. However, laboratory scale work confirms that chlorobenzene is technically infeasible. Therefore, the development and evaluation of a new synthetic route is merely a theoretical possibility. As discussed above, if a new synthetic route using chlorobenzene were to be developed, characterisation of new impurities in the API under the new route would be required before submittal of an application for a variation of the marketing authorisation and relevant information would need to be generated for the associated regulatory submissions.

5.2.6 Conclusion on suitability and availability of chlorobenzene

Based on prior R&D efforts, Eli Lilly is firmly of the view that chlorobenzene is not a technically feasible alternative and its physicochemical properties prevent it from becoming an alternative solvent for the current synthetic route of Raloxifene Hydrochloride. Moreover, even if an alternative synthetic route could be developed to accommodate chlorobenzene, the commercial value of the product is too low to support the high costs that would be incurred in developing an alternative. Therefore, chlorobenzene cannot be considered a feasible alternative for Eli Lilly. In addition, the comparative assessment of the risks from chlorobenzene and EDC has confirmed that the use of chlorobenzene would indeed reduce risks to worker population; however, its high aquatic toxicity would need to be carefully controlled.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 48 6 Overall conclusions on suitability and availability of possible alternatives

6.1 Technical feasibility of possible alternatives

Two possible alternatives were shortlisted for detailed analysis, DCM and chlorobenzene. Both of these substances have been subjected to laboratory scale testing by Eli Lilly alongside several other potential alternative solvent for their ability to substitute EDC in the Eli Lilly’s current Raloxifene Hydrochloride manufacturing process. A total of eight technical feasibility criteria have been developed by Eli Lilly spanning the key parameters of

• Reaction completion • Product impurities • Product yield • Product crystal form which influences bioavailability and medical efficacy • Safety of production process.

A summary of the comparison of the two possible solvent alternatives against the technical feasibility criteria is provided in Table 6-1.

Table 6-1: Overview of the technical feasibility of the possible alternatives Result or Threshold or Result or numerical Result or numerical Criteria numerical value acceptable range value achieved by value achieved by achieved by EDC for replacing EDC DCM chlorobenzene 1 Solubility of Complete Complete Complete Complete starting dissolution dissolution dissolution dissolution materials 2 Reaction mixture Homogeneous, Homogeneous, free Homogeneous Heterogeneous viscosity & free moving moving reaction only at reactions'''''''''''''''''''' crystallisation high temperature '''''''''' '''''''''''''''''' ''''''' step outcome and pressure '''''''''''''' ''''''''''''''' ''''''' ''''''''' '''''''''''' 3 Chlorination >98% >98% #A#, #E# all Table '''''''' '''''''''''''' reaction (Regulatory 6-1''''''''''''''''''''''''''''' completion commitment) ''''''''''''' '''''''''' ''''''' ''''''''''''' '''''''' '''''' '''''''''''''''''' '''' ''''''''''' Acylation <3% starting <3% starting ''''''' ''''''''''''' '''''''''''' '''''''' '''''''''''' reaction material material remaining '''''' '''''''''''''''' ''''''''''' completion remaining ''''' ''''''''' (Regulatory commitment) De-alkylation <0.2% starting <0.2% starting ''''''' '''''''''''' '''''''''' ''''''''' '''''''''''''''' reaction material material remaining '''''' '''''''''''''' '''''''''' '''''''''''''''' ''''''''''''''''''' completion remaining ''''' '''''''' (Regulatory commitment)

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 49 Table 6-1: Overview of the technical feasibility of the possible alternatives Result or Threshold or Result or numerical Result or numerical Criteria numerical value acceptable range value achieved by value achieved by achieved by EDC for replacing EDC DCM chlorobenzene 4 Crystal form of Crystal Form '' Crystal Form ' – to Crystal Form '''' Crystal Form '''' product aid dissolution in proceeding step Solubility in Complete Complete ''''''' '''''''''''''' ''''''' ''''''''''''' subsequent re- dissolution dissolution crystallisation (Regulatory step commitment) 5 Product ''''''''''''% '''''''''% ''''''''% ''''''''% impurities in isolated product (intermediate) 6 Solvent rejection Listed on ICH Must meet ICH Listed on ICH Listed on ICH capability in API Guidelines – Class guidelines Guidelines – Class 2 Guidelines – Class 2 step 1 (limit: 600 ppm) (limit: 360 ppm) <5 ppm EDC '''''''' '''''''''''' ''''''''''' ''''''''''' ''' '''''''''''''''' '''''' '''''''' ''' '''''''' ''''''''''' ''''' ''''' '''''''''''''' '''''''' ‘’’’’ ‘’’’’’’’’’’’ ‘’’’’’’ ‘’’ ‘’’''''''''''' '' 7 Yield '''''''% ''''''''% '''''''''''% '''''% 8 Electrical 4,000 pS/m ≥4,000 pS/m 4,300 pS/m 7,000 pS/m conductivity of solvent Dielectric 10.3 ≥10 8.9 5.6 conductivity of solvent Note: Brown cells in the table indicate technically problematic areas for the investigated substances

The table confirms that both alternatives have significant shortcomings particularly with the reaction mixture viscosity, the crystal form of the product, the solubility of the intermediate in subsequent steps of the manufacturing process and the yield. Between the two substances, chlorobenzene may result in a heterogeneous mixture, which poses great practical challenges, unlike DCM. Whilst DCM can deliver a homogeneous reaction mixture, reactions must be run at a high temperature and pressure, which presents a number of safety implications. In addition, there is significant uncertainty regarding the alternatives’ ability to facilitate the completion of the three successive reactions under the current manufacturing process. This causes major problems as the completeness of the reactions is an integral and very significant aspect of the manufacturing process for which Eli Lilly has received a marketing authorisation for its medicinal product from the relevant competent authorities.

Overall, both alternatives are not able to perform to the required standard in Eli Lilly’s manufacturing process and only the development of an alternative synthetic route could theoretically enable either of the two solvents to be used as a substitute for EDC. This cannot be achieved by the Sunset Date for EDC. Moreover, given the cost that would be involved in developing such an alternative route and the discouraging lab test results that Eli Lilly has obtained during a previous testing campaign, there are no realistic prospects for either of the two alternative solvents,

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 50 in the foreseeable future, particularly given that the shortcomings are based on these alternatives’ physico-chemical properties.

6.2 Economic feasibility of possible alternatives

As a result of the clear conclusion of technical infeasibility both at present and in the foreseeable future, coupled by the non-existence of an alternative synthetic route that would accommodate the properties of the identified alternatives, issues of economic feasibility are of secondary importance and of only theoretical relevance.

In general, the implementation of either of the two possible alternative solvents would entail the costs presented in Table 6-2.

Table 6-2: Overview of the economic feasibility of the possible alternative substances Category Cost element DCM Chlorobenzene Investment R&D work Not costed – Unknown costs Plant conversion '#D# all Table 6-2''''''''''' '''''''''''''' ''''''''''' ''''''''''' ''''''''''''' '''''''''' ''''''''''''' '''''''''' ''''' ''''''' '''''''''''''''''' '''''''''''''''' '''' Downtime Not costed – Likely to be significant Market Preparatory work (labour Not costed authorisations cost) variations Residual solvent tests '''''''''' '''''''''''''' Toxicology assessment ''''''''''' '''''''''''' or higher if clinical trials are needed Internal labour costs '''''''''''''''''''' '''''''''''' Fees '''''''' ''''''''''''' Sub-total ''''''''' ''''''''''''' '''' '''''''''' Total investment costs '''''' ''''''''''''' '''''''''''' (range: €10-100 million) Loss of Plant improvements no longer needed €14.4 million past IP expenditure ''''' ''''' '''''''' '''''''''''''' ''' '''''''' '''''''''''''''''' investment Total lost investment €14.4 million Changes to Increased solvent cost '''''''''' ''''''''''''' '''''''''''''''' '''''''''' ''''''''''''' ''''''''''''''''' operating Costs arising from changes to process Not costed Not costed costs Overall change to operating costs Cannot be estimated Cannot be estimated

The table shows that conversion to any alternative would be accompanied by significant investment costs associated with plant conversion and work on market authorisation variations and, if a new synthetic route were to be developed, past investments made to the existing plant which operates on a specific manufacturing process could be forfeited. Even with the limited knowledge available, the two possible alternatives appear to be economically infeasible, particularly in light of the declining sales of Evista®.

6.3 Reduction of risks from the use of possible alternatives

Both DCM and chlorobenzene have a hazard classification for human health effects that is more benign than that of EDC; however, DCM is under investigation for its carcinogenic properties (IARC has decided on a 2A classification – probable human carcinogen) and chlorobenzene poses risks to the aquatic environment. From a process safety perspective, the use of either of the two alternative

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 51 solvents could increase the incidence of static/charge build up, but this would need to be established through additional studies.

The comparative risk assessment did confirm the findings of the initial screening for hazards. DCM has lower carcinogenicity potency, however, the uncertainty over its future classification renders it an alternative that might not deliver sufficient reduction in carcinogenicity risks to Eli Lilly’s workers in the longer term. Chlorobenzene, on the other hand, poses lower worker health risk but its risks to the aquatic environment would require careful control.

6.4 Availability of possible alternatives

Table 6-3 summarises the findings of this AoA on the availability of the possible alternatives. Whilst both solvents are widely available on the EU market and are listed in the relevant ICH guidelines for solvent residues in medicinal products, their implementation in Eli Lilly’s plant would require an alternative synthetic process for Raloxifene Hydrochloride. This is not available and is unlikely to become available in the near future. Therefore, neither DCM nor chlorobenzene can be considered ‘technologies’ that are available to Eli Lilly.

Table 6-3: Overview of the availability of the possible alternatives Name of Column 1 DCM Chlorobenzene Good Good Market availability of the solvent REACH registered at >100,000 t/y REACH registered at >10,000 t/y Quality issues None identified None identified ICH Guidelines listing Yes – Class 2 Yes – Class 2 Commercialisation of a suitable Not available to Eli Lilly Not available to Eli Lilly alternative synthetic route

6.5 Overall conclusion

The overall outcome of this analysis is shown in Table 6-4.

Table 6-4: Overall conclusions on suitability and availability of possible alternatives for Eli Lilly Potential timeframe for Technical Economic Alternative Reduction in risk Availability the alternative becoming feasibility feasibility feasible and suitable HH: () Substance:  Impossible to estimate; DCM  () ENV: - Process:  unlikely to materialise Process safety:  HH:  Substance:  Impossible to estimate; Chlorobenzene  () ENV:  Process:  unlikely to materialise Process safety:  : acceptable performance : unacceptable performance Parentheses show areas of particular uncertainty

Neither of the two possible alternatives are realistic alternatives for EDC and this conclusion supports Eli Lilly’s request for the Authorisation of the continued use of EDC in the manufacture of Raloxifene Hydrochloride. Eli Lilly believes that the practical implementation on the industrial scale of the above alternatives is unlikely to become possible in the foreseeable future. If novel solutions

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 52 (solvents/technology) emerge, it is most likely these would provide for a better solution over chlorobenzene, DCM, and EDC. The Lilly Solvent Selection Committee will continue to closely monitor developments in the scientific community for alternative methods of manufacturing Raloxifene Hydrochloride. Until such time as an alternative becomes available, additional research, internally or externally, cannot be initiated.

In addition, as the commercial value of the product is in decline,, the high costs that would be incurred in developing an alternative route, using a novel and commercially available alternative solvent, would also need to be evaluated. These high costs would result during development activities, toxicology assessments, plant conversion and manufacturing costs and regulatory activities – see Scheme in Annex 5 for theoretical timeline.

In conclusion, EDC is deemed to be technically and economically the most feasible solvent for the Raloxifene Hydrochloride manufacturing process. Owing to experience it is highly unlikely that a feasible (and commercially available) alternative will be identified in the near future (approx. 7 years).

6.6 Next steps during an Authorisation review period

The following paragraphs describe what actions Eli Lilly could potentially undertake with regard to the use of EDC during the requested review period.

6.6.1 Actions relating to a potential replacement of EDC by an alternative

As concluded above, it is highly unlikely that a feasible alternative will be identified in the near future. However, Eli Lilly will continue monitoring the open scientific literature for any publication that might offer fresh ideas on the replacement of EDC. In this context, the Eli Lilly ‘Solvent Selection Committee’ (see Section 4.2.1) will continue monitoring any Green Chemistry Solvent initiatives through literature reviews and collaboration with the American Chemical Society Solvent Selection and Reagent Guide Teams.

If Eli Lilly discovers a viable, commercially available alternative solvent it is estimated that it would take approx. 5 years to implement the required process change (see Annex 5).

6.6.2 Actions relating to a potential reduction of use of EDC and associated exposure

Past actions on improved EDC handling and exposure control

Eli Lilly has taken continuous improvement initiatives beyond the discovery of a suitable solvent for the manufacturing process. Relevant actions have included the following:

• Better controls on the usage of solvent and the prevention of potential worker exposure and environmental releases

− 2007-2008: '#A#, #C#''''''''' '''''''''''''''''''''' '' ''' '''''''''''''' '''''''''''''''' ''''''' '''''''''''''''' '''' '''''''''''''' '''''''''''''' ''''' '''''''''''''''''''''' ''''''''''''''' '''''''''''''''''''''' '''' ''''''' '''''''' '''' ''''' '''''''' − 2009-2010: '#A#, #C#'''''''''''''''''' '''''''''' ''''''' ''''''''''''''''''''' ''''' ''''''''''''''' ''' ''''' '''''''''''''''' '''' '''''''''''''''' '''''''''''''''''''''''''''''' '''''''''''''' ''''''''''''''''' ''''''' ''''''''''' '''''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 53 • Other improvements to safety controls

− 2003-2006: ''#A#, #C#'''''''''''''' '''''''''''''''''''''' ''''''''''''' '' '''''''''' ''''''' ''''''''''''' ''''''' '''' '''''' '''''''''' '''' '''''''''''''''' ''''''' ''''''' '''' ''''''''''''''''''' ''' '''''''''''' '''''''''' ''''''' '''' ''''''''''''''''''''''''' '''''' ''''''' '''''''' '''''''''''''''' ''''''' ''''''' ''''''''''''''' '''' '''''''''''''''''''' ''''''''' ''' ''''''''''''' ''''''''''''''' '''''' '''''''''''''''''''''''''''' ''''''' '''''''''''''''' ''''''''''' '''''''''''''' ''''' '''''' '''''''''' '''''''''''''''''''' ''' ''''''''''' '''''''''''''''' ''''''' ''''''''''''' ''''''' '''''''''''' − 2005-2006: '#A#, #C#'' '''''''''' '''''''' '''''''' ''''''''''' ''''''' ''''''''''''''''''''' ''''''''''''''''''''' ''''''' '''''''''''''''''' '''' '''''''''' '''''''''''''''' ''' '''''''''''''''''' '''''''''' '''''''''''''''''' ''''''''''''' ''''''''''''''''''''' ''''''''''''''''' ''''''' '''' ''''''''''''' − 2007-2008: ''#A#, #C#'''''''''''''''''' '''' '''''''''' '''''''''' ''''''' '''''''''''''''''''''' '''''''''''' '''''''''''' ''''''''''''''''''''''''' ''''''' '''''''''''''''' ''''' ''''''' ''''''' '''' ''''''''''''''' ''''''''''''''''''''''''' '''''''' '''''''''''''' ''''''''''''''''' ''''''''''''''''''' ''''''''''''''''''' ''''''''''''''''''' − 2013: ''#A#, #C#' '''''''''''''''' ''''''''' '''''''''''''''' '''''' ''''''' '''''''''''''''''''''' ''''''''''''' ''''''' '''''''''''''''''''' − 2014: '#A#, #C#''''''''''''''''' ''''''''''''''''' ''''''''' ''''''''''''''''''''' '''''''''' '''''''''''''''''''' '''''' '''''''''''''''''''''' '''' ''''''' '''''''''''''''' '''''''''''''''' ''''''''''' ''''' ''''''' ''''''''''''' ''''''' ''''''''' ''''''''''''''''''' ''''''''''' '''' '''''' '''''''''''' '''' ''' '''''''''''' '''''''''' − 2014: '#A#, #C#'' ''''''''' '''''''''''''''' '''''''''''''''' ''''''''''''' '''''''''' '''''''' ''''''''''''''''''''' '''''' ''''''''''''''''' '''''' '''''''''''''' '''''''''''''''''' ''''''' ''''''''''''' ''''''' ''''''''''''''''''''' '''' '''''''''''''''' ''''''' '''''''''''' ''''' '''''' '''''''''''''' '''''''' '''''''''''''' − 2014-2015: ''#A#, #C#'''''''' '''''''''''''' ''''''''''' '''''''''''''''' ''''' '''''''''''''''''''' ''''''' '''''''''' '''' ''''''' '''''''''''''''' '''''''' ''''''''' '''''''''''''''''''' ''''''''' ''''''''''''''''''''''' ''''''''''''''''''''' '' '''''''''''''''''' '''' ''''''''''''' '''''' ''''''''''''''' ''''' '''''''' ''''''''' ''''' ''''''' '''''''''''''''''''''''''' '''''''''''''''' ''''''' '''''''''''''' ''''''' '''''''''''''''''''''' ''''''''''''''''''''''''''' ''''' ''''''''''''''' '''''''''''''''''''''' ''''''' '''''' '''' ''' '''''' '''''''' '''''''''''''''''' '''' ''''''''' ''''''''''''''''''''' ''''''''' ''''''' ''''''''''' '''''''''' ''' '''''''''''''' ''''''''''' ''''''''''''''''''''''''''' ''''''''''''''''''''''''' '''''' ''''''' '''' ''''''''' '''''''''''''' ''''''''' '''''' ''''''''''''' '''' ''''''''''''''''' ''

Table 6-5 summarises the duration and the significant cost of the important plant and process improvements that Eli Lilly has so far undertaken.

Table 6-5: Duration and cost of past and current plant and process improvements by Eli Lilly Year of Duration Estimated cost Action Number of workers involved expenditure (months) in 2014 prices* (end) '#A#, #C# all Table 6- '''' ''''''''' ''' '''''''''''''' 5''''''''''''''' '''' '''''''''''''''' '''''' '''''''''' ''''''''''''''''' ''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''''''''''''' ''''''''''''''' ''''''''''''''''''''''''''''' ''''' ''''' '''''''''' ''''''''''''''''''' '''''''''' ''' ''''''''''''''''' ''''''''''''''''' '''''''''''''''''''''''' '''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''' '''''''''' ''' '''''''''''''''' ''''''''''''''' ''' ''''''''' '''''''''''''''' '''''''' ''' '''''''''''''''' '''''''''''''''''''''' ''''' '''''''''' '''''''''' '''''''' ''''''''''''''''''''' '''' ''''''''' ''' '''''''''''''''''''' ''''' '''''''''' '''''''''''''''''' '''''''''''''' ''''''''''''' ''''''''''' '''''''''''''''''''' '' ''''' '''''''''' ''' '''''''''''''''''' ''' ''''''''' ''''''''''''''''' '''''''''''''' '''''''''''''''' ''''''''''''''' ''''''''''' '''''''' '''' ''''''''' '''''' '''''''''''''''''''' ''' '''''''''' '''''''''''''''' ''''''''''''''' '''''''''''''' '''''''''''''''' '''''''''''''' '''' ''''''''' ''' '''''''''''''' '''''''''''''''' ''' '''''''''' '''''''''''''''''' '''''' '''''''' '''''''''''''''' '''''''' ''' '''''''''''''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 54 Table 6-5: Duration and cost of past and current plant and process improvements by Eli Lilly Year of Duration Estimated cost Action Number of workers involved expenditure (months) in 2014 prices* (end) ''''' '''''''''' ''' ''''''''''''''' '''''''''''''''' '''''''''' '''''''''''''''''''' ''' ''''''''' '''''''''''''''' '''''''' ''' '''''''''''''''' ''''''''' '' ''''''''' '''''''' ''''''''''' ''''' '''''''''' ''' ''''''''''''''' ''''''''''''''''' ''''' '''''''''' ''''''''''''''''''' ''''''''' '''''''''' '''''''' '''''''''''' ''' '''''''''' '''''''''''''''''' '''''' '''''''''' '''''' ''''''''''' '''''' '''''''' '''''''''''''''''''' ''''''' ''''' '''''''''''''''''''''' '''''''''''''''''''''''''' ''''''''' '''' ''' '''''' ''''''''' '''' ''''''''''''''''' '''''''''''''' ''''''''''' ''''''''''' ''''''' ''''' ''''''' '''''''''''''' ''''''''' '''''''''''''''''''''''''''''''' '''''''''

Current and planned future actions on improved EDC handling and exposure control

As of the time of writing this AoA (December 2015), Eli Lilly undertook further improvements to '#A#, #C#''''' ''''''''''''''' '''''' ''''''' ''''''''''''''''''' ''''' '''''''''''''''''''''' ''''''''''''''' '''' '''''' '''''''' '''''''''''' '''''''' ''''''''''' '''''''''''' ''''''''''''' '''''''''''' ''''''' ''''''''''''' '''''''''''''''' '''''' '''''''''''''''''''''' '''' ''' ''''''''''''' '''''''''''''''' ''''''''' ''''' '''''' '''''''''''''''''''''''''' '''''''' ''''''''' '''''' '''''''' ''''''''''''' ''''''''''''' '''''''' ''''''' ''''''''''''' '''''''''''''''' ''''''''' '''''' '''''''''''' ''''''''''''' ''''''''''''' ''''''''''' '''' ''''''' '''''''''

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

In practice, sales of Evista® are in continuing decline. As discussed earlier, ''#C#'''' ''''''' '''''''''''''''''''''''' ''''''''''''''''''' ''''''''' ''' '''''''''''''' ''''''''' ''''''''''''''''''' '''' ''''''''''''' '''''''''''''''' '''''''''''' '''''''''''''''''''''''' ''''''''' '''''''' '''''''''''. Irrespective of any other action or R&D that Eli Lilly might undertake, this decline in sales is expected to continue resulting in significantly smaller future production campaigns and a corresponding decline in consumption of EDC (see Figure 3-1).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 55

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 56 7 List of information sources

Arbuthnot, G. N. et al., 2002. Benzothiophenes formulations containing same and methods. USA, Patent No. US6458811 B1.

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

Benbrahim-Tallaa, L. et al., 2014. Carcinogenicity of perfluorooctanoic acid, tetrafluoroethylene, dichloromethane, 1,2-dichloropropane, and 1,3-propane sultone. Lancet, 15(9), pp. 924-925.

Britton, L. G., 1999. Avoiding Static Ignition Hazards in Chemical Operations. [Online] Available at: chemistry-chemists.com/chemister/Labtechnika/avoiding-static-ignition-hazards.pdf [Accessed 2 December 2014].

Cameron, K. O. et al., 1995. Benzothiophenes and related compoundsm as estrogen agonists. World, Patent No. 95/10513.

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

ECHA, 2015. Application for Authorisation: Establishing a Reference Dose Response Relationship for Carcinogenicity of 1,2-Dichloroethane. RAC/33/2015/09 Rev1 Final, Helsinki: ECHA.

Eli Lilly, 2011. Medication Guide - EVISTA. [Online] Available at: http://pi.lilly.com/us/evista-ppi.pdf [Accessed 28 October 2014].

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

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

European Medicines Agency, 2013. Explanatory note on fees payable to the European Medicines Agency. [Online] Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/07/WC500146978.pdf [Accessed 2 February 2015].

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 57 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/Q3 C_R5_Step4.pdf [Accessed 13 June 2014].

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/Q3 C_R5_Step4.pdf [Accessed 13 June 2014].

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

Smith LaBell, E., McNeill McGill, J. & Miller, R. S., 2002. Crystalline solvate. USA, Patent No. US 6399778 B1.

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

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 58 8 Annex 1 – Regulatory controls on the use of EDC in the pharmaceutical industry

8.1 Requirements of Marketing Authorisations and their variations

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

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

Medicinal Authorisations, of which there may be several for the different countries where the relevant medicinal product is being sold, would be subject to re-assessment following any major change to the manufacturing process. The replacement of the solvent EDC or the selection of an alternative route of synthesis would constitute a substantial change that would require a variation to existing Marketing Authorisations, a variation Type II. Commission Regulation (EC) No 1234/2008 (the Variations Regulation) defines a major variation of Type II as a variation that is not an extension and that may have a significant impact on the quality, safety or efficacy of a medicinal product.

Applying for a variation not only requires effort but also incurs a fee. Moreover, Marketing Authorisations are required per country and per dose, so the total number of Authorisations can be large. In addition, changes to the manufacturing facility would also attract requirements to notify the relevant national authorities of such changes.

8.2 Regulatory controls on residual solvents

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

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

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 59 and describes levels considered toxicologically acceptable for some residual solvents. Residual solvents in pharmaceuticals are defined in the guideline as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The content of solvents in such products should be evaluated and justified.

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

Residual solvents assessed in this guideline are listed in its Appendix 1. They were evaluated for their possible risk to human health and placed into one of three classes as follows:

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

EDC is found in Class 1 due to its toxicity and is accompanied by a concentration limit of 5 ppm. The EDC manufacturing process used in Kinsale is controlled to deliver and meet this specification. Class 1 solvents should be avoided in the production of medicinal substances, excipients, or medicinal products unless their use can be strongly justified in a risk-benefit assessment. Class 2 solvents associated with less severe toxicity should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3) should be used where practical.

The choice of an alternative solvent to replace EDC should be mindful of the requirements of the guideline, and should ideally be of Class 2 or 3, unless the choice of a Class 1 replacement can be justified by a risk-benefit assessment and the level can be restricted to the prescribed concentration limits.

The ICH Q3C(R5) guidance indicates that the solvent lists it contains are not exhaustive and other solvents can be used and later added to the lists. In addition, recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data becomes available. However, the Marketing application for a drug product that contains a new solvent needs to include safety data on the new solvent. Whilst the safety data may be based on concepts in this guideline, if the medicine is made with a new solvent (a replacement for EDC) and this has a poorly characterised impurity profile then additional testing will be required to establish its safety. This will require time and involve considerable cost. Therefore, it would be very important that Eli Lilly could select a well- characterised solvent, as this would affect the costs of converting to the alternative.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 60 9 Annex 2 – Screening of the master list of potential alternatives

Table 9-1: R&D screening of the master list of alternative substances against the technical feasibility criteria Technical feasibility criteria used in the 1990s R&D

b

Potential

CAS

No alternative EC Number Conclusion Number

substance

Solubility of starting materials Reaction mixture viscosity & crystallisation step outcome Reaction completion (% intermediate remaining) Final crystal form Yield Dielectric Constant Electrical conductivity (pS/m)* Complete Homogeneous '#A#, #E# all - EDC 203-458-1 107-06-2 <0.2% ''''''''''''' 10.3 4,000 Preferred choice dissolution mixture Table 9-1 '''''''' Homogeneous '''''''''''''''' '''''''' Complete reaction only at 1 Dichloromethane 200-838-9 75-09-2 ''''''''''' ''''''''''''' '''''''' ''''''''''''''' 8.9 4,300 Technically poor dissolution high temperature ''''''''''' '''' and pressure ''''''''''''''''' ''''''''' Complete ''''''''''''''''''''''''''' 2 Chloroform 200-663-8 67-66-3 '''''''''''' ''''''''''''' '''''''''' ''''' '''''''' 4.8 <10,000 Technically poor dissolution ''''''''''''' '''''''''' '''' 1,1,2,2- Complete '''''''''''''''''''''''''''''' '''''''''''''''' ''''''''' Not 3 201-197-8 79-34-5 ''''''''''' '''''' '''''''' 8.2 Technically poor Tetrachloroethane dissolution '''''''''''''' ''''''''''''' ''''''''' known '''''''''''''''''' '''''''' 1,2,3- Complete '''''''''''''''''''''''''''' '''''' Not 4 202-486-1 96-18-4 '''''''''''' '''''''''''' '''''''''' 2.4 Technically poor Trichloropropane dissolution ''''''''''''''' ''''''''' known '''''''''' '''''''' Heterogeneous mixture '''''''''''''' ' ''''''''''''''''' ''''''''' Complete 5 Chlorobenzene 203-628-5 108-90-7 ''''''''''''' '''''''''''''''''' '''''''''''' ''''''''''''' ''''''''' '''''' ''''''' 5.6 7,000 Technically poor dissolution '''''''''''''' ''''''''''' '''''''''' '''' ''''''''''''''''''''''''''' '''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 61 Table 9-1: R&D screening of the master list of alternative substances against the technical feasibility criteria Technical feasibility criteria used in the 1990s R&D

b

Potential

CAS

No alternative EC Number Conclusion Number

substance

Solubility of starting materials Reaction mixture viscosity & crystallisation step outcome Reaction completion (% intermediate remaining) Final crystal form Yield Dielectric Constant Electrical conductivity (pS/m)* Complete Homogeneous '#A#, #E# all - EDC 203-458-1 107-06-2 <0.2% ''''''''''''' 10.3 4,000 Preferred choice dissolution mixture Table 9-1 '''''''' ''''''''''''''''''''''''''''''' '''''''''''''' ' ''''''''''''''' 1,2- Complete ''''''''''''''' ''''''''' 6 202-425-9 95-50-1 '''''''''''''''' ''''''''''''''' '''''''''''' '''''' '''''''' 9.9 3,000 Technically poor Dichlorobenzene dissolution ''''''''''''' ''''''''' '''''''''''' ''''''''''''''''''''''''' '''''''' Complete '''''''''''''' '''''''''''''''' ''''''''''''''''' ''''''''' '''''' Not 7 Fluorobenzene 207-321-7 462-06-6 ''''''''''' 5.4 Technically poor dissolution '''''''''''''''''''''''' ''''''''''''' ''''''''' ''''''''' known Technically ''''''''''''''' 8 '''''''''''''''''''' ''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''' ''''' ''''''''''''' '''''''''''' '''''''''''''''''''' '''''' ''' ''' ''''''''' infeasible, not ''''''''''''''''''''''''' real alternative Technically ''''''''''' '''''' ''' 9 '''''''''''''''''''' ''''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''''' ''''' ''''''''''''''' ''''''''''''' ''''''''''''''''''''''' '''''' infeasible, not ''''''''''''''''''''''''''''' '''''''' real alternative Technically ''''''''''' ''''''' 10 '''''''''''''''''' ''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''''' ''''' ''''''''''''' '''''''''''' '''''''''''''''''''' '''''' infeasible, not ''''''''''''''''''''''''''''''' ''''''''''''' real alternative Technically ''''''''''''' 11 '''''''''''''''''''' ''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''''''' '''''' '''''''''''' ''''''''''''' ''''''''''''''''''''''' '''''' ''''''' infeasible, not '''''''''''''''''''''''''''''''''' real alternative

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 62 Table 9-1: R&D screening of the master list of alternative substances against the technical feasibility criteria Technical feasibility criteria used in the 1990s R&D

b

Potential

CAS

No alternative EC Number Conclusion Number

substance

Solubility of starting materials Reaction mixture viscosity & crystallisation step outcome Reaction completion (% intermediate remaining) Final crystal form Yield Dielectric Constant Electrical conductivity (pS/m)* Complete Homogeneous '#A#, #E# all - EDC 203-458-1 107-06-2 <0.2% ''''''''''''' 10.3 4,000 Preferred choice dissolution mixture Table 9-1 '''''''' '''''''''''' Technically ''''' ''' 12 ''''''''''''''''''''''''''''''''''' '''''''''''''''''' ''''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''''''' ''''' '''''''''''''' '''''''''''' ''''''''''''''''''''' '''''' infeasible, not ''''''''' ''' ‘’’’’’’’’’’’’’’’’''' real alternative ''''''''''''''''''''''''''''''' Technically ''''''' ''''''' 13 ''''''''''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' '''''''''''''''''''' '''''''''''''''''''' ''''' '''''''''''''' ''''''''''''' ''''''''''''''''''''''' infeasible, not '''''''''''''' ''''''''''''' ''' real alternative Technically ''''''' 14 '''''''''''''''''''''''''''''''' '''''''''''''''''''' '''''''''''''' '''''''''''''''''''' '''''''''''''''''''''' '''''' ''''''''''''' '''''''''''''' '''''''''''''''''''''' ''''''' infeasible, not '''''''''''' real alternative Technically ''''''' 15 ''''''''''''''''''''''''''' ''''''''''''''''''''' ''''''''''''''''' ''''''''''''''''''''' '''''''''''''''''''''' ''''' ''''''''''''' ''''''''''''' '''''''''''''''''''' ''''''' infeasible, not '''''''''''' real alternative Technically ''''''''' '''''''' 16 '''''''''''''''''' '''''''''''''''' '''''''''''''''''''' '''''''''''''''''''''' ''''' ''''''''''''' '''''''''''''' ''''''''''''''''''''''' '''''' infeasible, not ''''''''''''''''''''''''''' ''''''''''''' real alternative Technically '''''''' '''''''' 17 ''''''''''''''''''' '''''''''''''''' '''''''''''''''''''''' '''''''''''''''''''''' ''''' ''''''''''''' '''''''''''' ''''''''''''''''''''' '''''' infeasible, not ''''''''''''''''''''''''''''''' '''''''''''''' real alternative

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 63 Table 9-1: R&D screening of the master list of alternative substances against the technical feasibility criteria Technical feasibility criteria used in the 1990s R&D

b

Potential

CAS

No alternative EC Number Conclusion Number

substance

Solubility of starting materials Reaction mixture viscosity & crystallisation step outcome Reaction completion (% intermediate remaining) Final crystal form Yield Dielectric Constant Electrical conductivity (pS/m)* Complete Homogeneous '#A#, #E# all - EDC 203-458-1 107-06-2 <0.2% ''''''''''''' 10.3 4,000 Preferred choice dissolution mixture Table 9-1 '''''''' Technically ''''''''''''' '''''' 18 '''''''''''''''''''' ''''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''' ''''' ''''''''''''' ''''''''''''' ''''''''''''''''''''''' ''''''' infeasible, not ''''''''''''''''''''''''''''''' '''''''''''' real alternative Technically '''''''''''''' '''''''' 19 ''''''''''''''''' '''''''''''''''' ''''''''''''''''''''' ''''''''''''''''''''' ''''' '''''''''''''' '''''''''''''' '''''''''''''''''''' '''''' infeasible, not '''''''''''''''''''''''''''''''' '''''''''''' real alternative Technically 20 '''''''''''''''''''''''' ''''''''''''''''''''' ''''''''''''''' ''''''''''''''''''''' '''''''''''''''''''''' '''''' ''''''''''''' ''''''''''''' '''''''''''''''''''''' '''''''' ''' ''' ''''''' infeasible, not real alternative Technically ''''''''' 21 ''''''''''''''''''''''''''' '''''''''''''''''''' ''''''''''''''' '''''''''''''''''''' ''''''''''''''''''''''' ''''' ''''''''''''' '''''''''''''' '''''''''''''''''''' ''' ''' '''''''' infeasible, not '' ''''' real alternative Technically 22 '''''''''''''' ''''''''''''''''''''' '''''''''''''''''' '''''''''''''''''''' ''''''''''''''''''''' ''''' '''''''''''''' '''''''''''''' '''''''''''''''''''''' ''''' ''''' infeasible, not real alternative Note: Brown cells in the table indicate technically problematic areas for the investigated substances * information on electrical conductivity was obtained from Britton (1999). Typically solvents are categorised as Conductive (>10,000 pS/m), Semiconductive (>100, <10,000 pS/m) and non-conductive (<100 pS/m) '''''' ''''''' '''' '''''' '''''''''''''' ''''''''' '''''''' '''''''' '''''' '''''''' '''''''' '''''''''''''''' '''''''''''' '''''' ''''''''''''''''''''''''''' '''''''''' '''' ''''''' '''''''''' '''''''''''' *** Crystal form ''' was isolated with 1,2,3-trichloropropane when ''''''''''''''''' was used as the crystallising solvent. Eli Lilly now uses '''''''''''''''' ''''''''' '''''''''''' '''''''''''''''''''''''' ''''''''''''' '''''''''''''''' ''''''''' ''''''''''''''''''''' '''' '''''' '''''''''''''''' ''''''''''''''' ''''''''''''''''' ''' '''''''''' '''''''''''' ''''''''''''''''''' '''''''' '''''''''''''' ''''''' ''''''''' ''''' ''''''' '''''''''''' ''' '''' '''''' '''''''''' ''' ''''''' '''''''''''''''''''''' ''''''''''''' ''''' ''''''' '''''''''' ''''''''''''''' ''''''''''''''''''''''''''''''' '''''''''''''''''' ''''' '''''' '''''''''''''''''''''''''' ''''''''' '''' ''''''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 64 Table 9-2: Summary of market availability and commercialisation status of shortlisted potential alternative substances Identified potential Registration status as of 8 ICH Q3(R5) listing Conclusion on No EC Number CAS Number Known commercial use alternative solvents October 2014 (limit) availability Previously used by Eli Lilly. Registered Class 2 Unknown use by others but 1 Dichloromethane 200-838-9 75-09-2 100,000 - 1,000,000 t/y Available (600 ppm) frequent references in the Named registrants: 11 open literature Registered Available but Class 2 Unknown if used in the 2 Chloroform 200-663-8 67-66-3 100,000 - 1,000,000 t/y commercial use (60 ppm) manufacture of Eli Lilly’s API Named registrants: 7 unclear Unavailable and 1,1,2,2- Unknown if used in the commercial use 3 201-197-8 79-34-5 Not registered - Tetrachloroethane manufacture of Eli Lilly’s API unclear; not in the ICH Guidelines Limited availability Registered Unknown if used in the and commercial 4 1,2,3-Trichloropropane 202-486-1 96-18-4 1 - 10 t/y - manufacture of Eli Lilly’s API use unclear; not in Named registrants: 4 the ICH Guidelines Registered Available but Class 2 Unknown if used in the 5 Chlorobenzene 203-628-5 108-90-7 10,000 - 100,000 t/y commercial use (360 ppm) manufacture of Eli Lilly’s API Named registrants: 2 unclear Available but Registered Unknown if used in the commercial use 6 1,2-Dichlorobenzene 202-425-9 95-50-1 10,000 - 100,000 t/y - manufacture of Eli Lilly’s API unclear; not in the Named registrants: 3 ICH Guidelines Unavailable and Registered Unknown if used in the commercially 7 Fluorobenzene 207-321-7 462-06-6 Intermediate use only - manufacture of Eli Lilly’s API unproven; not in Named registrants: 2 the ICH Guidelines Source: Eli Lilly’s data; http://echa.europa.eu/information-on-chemicals/registered-substances (accessed on 8 October 2014); (ICH, 2011); http://www.sigmaaldrich.com/technical-service-home/product-catalog.html (accessed on 2 November 2014)

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 65 Table 9-3: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status Dichlorometha 200-838-9 75-09-2 Fully Carc. 2 H351 REACH Annex XVII (Restrictions) Suspected ne registered STOT Single Exp. 3 H336 Paint strippers containing DCM in a carcinogen, eligible 100,000 - Skin Irrit. 2 H315 concentration equal to or greater than 0,1 % by only if there are other 1,000,000 t/y Eye Irrit. 2 H319 weight shall not be placed on the market for strong arguments in supply to the general public or to professionals favour of the CoRAP List (Draft List for 2016-2018) substance (e.g. Italy, Carcinogen/suspected Mutagen/suspected technical feasibility) Reprotoxic/suspected sensitiser, high (aggregated) tonnage, new entry IARC Classification 2A (Probably carcinogenic to humans), Vol 71, 110 In prep ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 600 ppm

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 66 Table 9-3: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status Chloroform 200-663-8 67-66-3 Fully Acute Tox. 4 H302 PIC Suspected carcinogen registered Skin Irrit. 2 H315 Annex I Part 1: Industrial chemical for public use – and reproductive 100,000 - Eye Irrit. 2 H319 Banned toxicant, eligible only 1,000,000 t/y Acute Tox. 3 H331 Regulated under ESR if there are other Carc. 2 H351 There is a need for limiting the risks in relation to the strong arguments in Repr. 2 H361d use of chloroform as a solvent for the aquatic favour of the STOT RE 1 H372 compartment (including sediment), and in relation substance (e.g. to certain production sites, to all uses and to technical feasibility) unintended releases for the sewage compartment REACH Annex XVII (Restrictions) Shall not be placed on the market, or used, — as substance, — as constituent of other substances, or in mixtures in concentrations equal to or greater than 0.1 % by weight, where the substance or mixture is intended for supply to the general public and/or is intended for diffusive applications such as in surface cleaning and cleaning of fabrics. By way of derogation this provision shall not apply to: (a) medicinal or veterinary products as defined by Directive 2001/82/EC and Directive 2001/83/EC; (b) cosmetic products as defined by Directive 76/768/EEC IARC Classification 2B (Possibly carcinogenic to humans), Vol 73, 1999 ICH Q3C(R5) Guidelines Class 2 (solvents to be limited), 60 ppm

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 67 Table 9-3: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status 1,1,2,2- 201-197-8 79-34-5 Pre-registered Acute Tox. 1 H310 REACH Annex XVII (Restrictions) Suspected Tetrachloroeth only Acute Tox. 2 * H330 Shall not be placed on the market, or used, carcinogen, notable ane Aqua Chronic 2 H411 — as substance, acute toxicity, eligible — as constituent of other substances, or in only if there are other mixtures in concentrations equal to or greater strong arguments in than 0.1 % by weight, where the substance or favour of the mixture is intended for supply to the general public substance (e.g. and/or is intended for diffusive applications such as technical feasibility) in surface cleaning and cleaning of fabrics. By way of derogation this provision shall not apply to: (a) medicinal or veterinary products as defined by Directive 2001/82/EC and Directive 2001/83/EC; (b) cosmetic products as defined by Directive 76/768/EEC IARC Classification 2B (Possibly carcinogenic to humans), Vol 106, 2014 US EPA IRIS Likely to be carcinogenic to humans 1,2,3- 202-486-1 96-18-4 Fully Acute Tox. 4 * H302 REACH Annex XIV (Authorisation) Carcinogenic and Trichloropro- registered Acute Tox. 4 * H312 SVHC Proposal, Carcinogenic and toxic to reprotoxic, on the pane 1,000 – 10,000 Acute Tox. 4 * H332 reproduction, ECHA, 21/02/2011 Candidate List, not t/y Carc. 1B H350 H350 Candidate List, 20/06/2011 eligible to replace Repr. 1B H360F *** IACR Classification EDC (additional C): 2A (Probably carcinogenic to humans), Vol 63, 1995 Acute Tox. 3 H301 US EPA IRIS Acute Tox. 3 H311 Likely to be carcinogenic to humans Acute Tox. 3 H331 Eye Irrit. 2 H319 Muta. 2 H341 STOT RE 1 H372 STOT RE 2 H373 Aqua Chronic 2 H411

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 68 Table 9-3: Screening of shortlisted potential alternative solvents for hazards Example EC No. CAS No. Registration Classification Comments Conclusion solvents status Chlorobenzene 203-628-5 108-90-7 Fully Flam. Liq. 3 H226 RAC Opinion on harm. classification (Mar 2014) No obvious CMR registered Acute Tox. 4 * H332 Chlorobenzene should be classified as Acute Tox. 4, properties, but 10,000 - Aqua Chronic 2 H411 H332 and Skin Irrit. 2 relevant aquatic 100,000 t/y ICH Q3C(R5) Guidelines toxicity, eligible. Class 2 (solvents to be limited), 360 ppm Sufficient data for assessment 1,2-Dichloro- 202-425-9 95-50-1 Fully Acute Tox. 4 * H302 Dossier Evaluation No obvious CMR benzene registered Skin Irrit. 2 H315 Registration dossier underwent compliance check properties (but on 10,000 - Eye Irrit. 2 H319 CoRAP List CoRAP on CMR 100,000 t/y STOT SE 3 H335 Hungary, 2013, Human health/Suspected CMR; suspicions), notable Aqua Acute 1 H400 Exposure/Wide dispersive use; Aggregated tonnage, aquatic toxicity, Aqua Chronic 1 H410 on-going eligible. (additional C): IACR Classification Sufficient data for Skin Sens. 1B H317 3 (Not classifiable as to its carcinogenicity to assessment Acute Tox. 4 H332 humans), Vol 73, 1999 US EPA IRIS D (Not classifiable as to human carcinogenicity) Fluorobenzene 207-321-7 462-06-6 Registered for Flam. Liq. 2 H225 In US HPVIS; BG Chemie report (monograph) No obvious CMR intermediate Eye Dam. 1 H318 properties, eligible. use only Aqua Chronic 2 H411 Sufficient data for assessment Sources: ECHA Registered Substances database (http://echa.europa.eu/information-on-chemicals/registered-substances, accessed on 28 October 2014) ECHA Classification and Labelling Inventory (http://echa.europa.eu/information-on-chemicals/cl-inventory-database, accessed on 28 October 2014) Draft CoRAP update for 2016-2018 (http://echa.europa.eu/documents/10162/13628/corap_2016_2018_en.pdf, accessed on 15 January 2016) IACR Cancer Classifications (http://monographs.iarc.fr/ENG/Classification/, accessed on 28 October 2014) US EPA Integrated Risk Information System (http://www.epa.gov/iris, accessed on 16 December 2015) * Bold letters indicate harmonised classification under the CLP Regulation, normal letters indicate notified classification (joint entry from registration); italics indicate most commonly notified classification only

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 69

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 70 10 Annex 3 – Economic feasibility of possible alternatives

10.1 Introduction

As both possible alternative substances are not technically feasible and their feasibility cannot be improved as it is dependent on their physico-chemical properties, issues of economic feasibility are not critical in this AoA. However, a discussion on economic feasibility is provided here for completeness.

10.2 Economic feasibility of dichloromethane

10.2.1 One-off investment costs

R&D costs

Given the technical shortcomings of the alternative, Eli Lilly is not in a position to estimate the cost of a theoretical R&D programme aimed at preparing the implementation of DCM as the process solvent (i.e. the development of a new synthetic route).

Plant conversion costs

Given the technical infeasibility of DCM, a manufacturing process that uses this alternative has not been identified and conceptualised for the implementation of this solvent. As a result, investments that might be required for plant and process modifications cannot be estimated or quantified in monetary terms. However, it must be assumed that significant investment costs would indeed be required. By way of example, when the EDC process was introduced into the manufacturing facility in Kinsale, Ireland the plant conversion costs are estimated to be ca. '#D#'''''''''''''''''20 (range: €10-100 million); in 2014 prices this is ca. '#D#'''''''''''''''''21 (range: €10-100 million). It may be assumed that a process change involving solvent replacement with DCM could have a plant conversion cost of a similar order of magnitude.

Downtime costs

It is not possible for Eli Lilly to estimate for how long production would need to stop during the conversion of the plant, as DCM is conclusively believed to be technically infeasible. During that period, sales would be affected. Moreover, plant conversion would not allow the immediate production of the API at current capacity levels. Prior to marketing commercially available material, the new manufacturing process must be validated internally and the minimum requirement is the manufacture and submission of three lots of ‘new’ product. The material from the validation lots cannot be marketed whilst waiting for the variations to marketing authorisations to be approved. The paragraphs below explain that the process of variation of the marketing authorisations might

20 Capital investment costs incurred in the six-year period it took to get both the crystalline solvate and drug substance production processes from initial validation runs to stable, full scale manufacturing.

21 Original capital investment costs were adjusted to reflect inflation and current project engineering practice requirements.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 71 take up to 3 years of which 2 years (at least) would be needed for obtaining approvals from authorities in all countries where the medicinal product is sold. Therefore, during this period the ability of Eli Lilly to market its medicinal product would be impaired and would only gradually improve thereafter.

It is also worth noting that, several manufacturing campaigns need to be completed before the plant can ready a ‘steady-state’. For instance, when the EDC process was introduced at the Kinsale plant in the 1990s, it took ca. 6 years before a ‘steady-state’ of manufacture was reached; while this period may not be relevant for the plant in 2015 or 2017, it is clear that a considerable time would be required.

Costs from variations to marketing authorisations

If essential stages of the manufacturing process of Raloxifene Hydrochloride were to change, the agreement of all affected state regulatory authorities would be required. As discussed earlier, the replacement of EDC by DCM would mean that the crystal form, impurities, and the residual solvent levels would change. The residual solvent levels would need to be assessed for impact on the drug product formulation. The following costs elements could be envisaged:

• Testing for residual solvent levels: Eli Lilly would need to undertake analytical method development work in the laboratory. In particular, an analytical method would be required to measure levels of DCM residues in the API. These should not exceed the limit of 600 ppm prescribed in the ICH Guidelines. The analytical method development work in the QC laboratory required to support a process change such solvent replacement will require:

− Analytical chemist – at least 4 months − Laboratory analyst – at least 6 months

'#D#'''''''''' ''' '''''' '''''''' '''' ''''''''''''''''' ''''''''''''''' '''''''''''' the labour cost of this work would be ''''''''''' '''''''''''' (<€1 million).

• Notification of major variation to the marketing authorisation at the EU level: a submission of a notification of variation would need to be made to the European Medicines Agency22. In accordance with Commission Regulation (EC) No 1234/2008, it can be assumed that the changes to the production process and the final product would be such that a Type II variation of the existing marketing authorisation (12/09/2013 Evista -EMEA/H/C/000184 - N/0066) would be required. According to the Regulation, “Major variation of type II means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned” (European Commission, undated). To estimate the costs associated with the variation, information is available from the European Medicines Agency. The Agency indicates that the Worksharing fees for one centralised marketing authorisation would be €61,800 (European Medicines Agency, 2013)

• Notification of major variation to the marketing authorisations at the global level: as explained earlier, market authorisations are required per country and per dose, so the total

22 The European Medicines Agency is responsible for the centralised authorisation procedure for human and veterinary medicines. This procedure results in a single marketing authorisation that is valid in all EU countries, as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 72 number of authorisations might be particularly large. The API is used in a solid oral dosage form (60 mg) which is registered for use '#D#''''' markets ''#D#''''' ''''' '''''''''''''' '''''''''''' '''''''''''23. Different Authorities have different requirements; for example, in the USA, Eli Lilly would need to file a Prior Approval Supplement, while in Japan a Partial Change would be required. The cost of such filings cannot be estimated with accuracy; for estimation purposes, the cost of a Prior Approval Supplement in the USA would cost US$29,370 or ca. €26,000 (as of February 2015). If it is provisionally assumed that each of the remaining countries would request an average variation fee of €10,000, the overall cost for all '#D#'''' national registrations could be ''#D#''' ''''''''''' ''''''. If this is added to the cost for the EU-wide Authorisation Variation, the overall fee can be assumed to be '#D#''''' ''''''''''''''''' (<€1 million, excluding the internal cost to Eli Lilly associated with the regulatory preparation activities described below)

• Notification of changes to the manufacturing site: if DCM were to replace EDC, Eli Lilly would need to re-validate and re-register the supply site with the European Medicines Agency. This would be dealt with in the Type II variation submission to the European Medicines Agency under the centralised procedure

• Toxicology assessment: if there are any new impurities present in the API from an alternate route, additional qualification may be required if they are above the ICH threshold. This would be through an Ames assay24 and take approx. 4 months to complete (Report and animal study) and would cost '#D#''''' '''''''''''''''''''''' '''' ''''' ''''''''''' '''''''''''''' (<€1 million). Theoretically, the need for clinical trials would also be considered. For the US/EU, historically there has not been a requirement for a bioequivalence study to introduce new API to an existing commercial product. However, for the rest of the world, there may be individual country requirements that do require a bioequivalence study. Only one such study would be required and it would typically last 6 months; costs would range between ''#D#''''''''''' ''''''''''''' '''''''''''' '''''''''''''' (range: <€1 million to €10 million). Overall, this analysis will assume that ''''''''''' ''''''' (<€1 million) would be the overall costs but this, for some alternatives, could prove an underestimate.

The variation of the marketing authorisations is estimated to require up to 3 years, including:

• Regulatory preparation: this is estimated at 6-9 month Full-Time-Equivalent (FTE) of a regulatory affairs representative, spread over 24 months. '#D#'''''''''' ''' '''''' '''''''' '''' ''''''''''''''''''' '#D#''''''''''''' ''''''''''' '''''''''''' the labour cost of this work would be '#D#'''''''''''''''''''''''''''' (€0.03- 0.1 million). This would involve the development of the regulatory strategy (determination of number of markets impacted by change, depth of submission, etc.) submission and then tracking of changes • Approval time: a minimum of 24 months is estimated for approval in all markets.

23 ‘’’#D#’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ ‘’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’

24 An Ames assay is a biological assay to assess the mutagenic potential of chemical compounds.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 73 10.2.2 Loss of past investment

Eli Lilly has invested significantly into the improvement of the manufacturing process in Kinsale and the protection of its intellectual property by filing a series of relevant patents.

Many important investments in the plant have not yet run their full lifecycle and therefore, significant changes to the equipment and process parameters could render such improvements obsolete and the associated funds invested and still not recouped would be lost. Table 10-1 summarises the important investments made by Eli Lilly from 2003 ('#D#'''''''''''''''''' '''' '''''''' ''''''''''''''''' '''''''''''') to 2014 ('#D#''''''''''''''''''' '''' '' '''''''''''''''' '''''''''''''' '''''''''''''''''''''' '''''''''''''''''). The table shows what the expected lifetime of each investment has been and the amounts invested at each time. The table also calculates the residual value of these investments at the beginning of 2020 (in 2014 prices). 2020 is chosen in accordance with the analysis in the SEA (see Section 2.4.3 of the SEA) which shows that even if Eli Lilly had to stop using EDC on the Sunset Date, Eli Lilly’s Raloxifene Hydrochloride safety stock would allow sales of Evista® until around the end of 2019. Table 10-1 shows that ca. €14.4 million would stand to be forfeited in 2020 if Eli Lilly could no longer use EDC and the existing plant would be unable to manufacture Raloxifene Hydrochloride under the existing manufacturing process.

An additional '#D#'''''' ''''''''''''' (<€1 million) has been expended by Eli Lilly in IP activities. It is difficult to estimate any ‘residual value’, particularly as the API is now outside patent protection, thus this figure is not aggregated with the above estimate.

10.2.3 Changes to on-going operating costs

As noted earlier, a manufacturing process that uses this alternative has not been conceptualised for the implementation of this solvent and therefore it is not possible for Eli Lilly to estimate the changes in operating costs that would arise from the use of DCM.

One cost element that could be readily estimated is the cost of the replacement solvent. Eli Lilly’s R&D work suggests that 1 kg of EDC would be replaced with ca. '#C#, #D#'' kg DCM. In a typical year with an EDC consumption of '#C#, #D#''' ' t/y, the consumption of DCM would be ca. '#C#, #D#'''’ ' t/y. However, consumption of EDC is projected to decline over time and stabilise at '#C#, #D#''' t/y by 2025 (see Figure 3-1). If we assume that the market price of EDC and DCM that Eli Lilly pays/would pay is '#C#, #D#''''''' and ''#C#, #D#'''''' respectively, the cost increase from the change of solvent would be '#C#, #D#''''''''''''' ''' ''''''''''' ''''''''''''''' in a typical year‘#C#, #D#’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’’ (both <€1 million/y).

10.3 Economic feasibility of chlorobenzene

10.3.1 One-off investment costs

The starting point of the analysis of the economic feasibility of chlorobenzene is in essence the same as that for DCM. The substance is clearly technically infeasible, therefore, a detailed assessment of economic feasibility is unnecessary. On the other hand, the technical infeasibility of the substance, which has been proven in lab tests, prevents Eli Lilly from developing a detailed analysis of economic feasibility as it is currently impossible to estimate the economic parameters and costs of the development of a new synthetic route to Raloxifene Hydrochloride which would allow the use of chlorobenzene as a solvent. The limited analysis presented for DCM above would also apply here for chlorobenzene. By way of summary, the following cost elements can be envisaged:

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 74 Table 10-1: Past investments by Eli Lilly on the affected plant – Residual value at the beginning of 2020 (2014 prices) Originally ‘End of life’ % lifetime Value not Residual value Original cost Year of expected Inflation Description of past expenditure of remaining in written off in 2020 (2014 in € investment lifetime (in rate* investment 2020 in € prices in €) years) ''#C#, #D# all Table 10-1''''''''''''''''' ''''''''''''''''''''' '''''''''' ''''' ''''''''' '''''' ''' '''''''''' ''' '''' ''''''''''' ''''''''''''''''''''''' ''''' '''''''''''''''''''' ''''''''' '''''''''''''' '''''''''' ''''' ''''''''' '''''' ''' '''''''''' ''' '''''''' ''''''''''''''''''' '''''''''''' '''''''''''' ''''''''''''''''' '''''''''' ''''' ''''''''' '''''' ''' '''''''''' ''' ''''''''''''''''''''''''' '''''''''''''''' '''''''''''''''''''''''''' '''''''''''''' ''''''''''''''''' ''''''''' ''''' '''''''''' ''''''''' ''''''''''''''' '''''''''''' '''''''''''''''' '''''''''''''''''''''' '''' '''''''''''''''' '''''''''''''''

'''''''''''''''''''' ''''''' '''''''''''''''' '''' '''''''''''''' ''''''''' ''''''' ''''''''''''''' '''''''''''' '''''''''' '''''''''''''''''''''' ''' ''''''''''''''''''' '''''''''''''''''''' ''''''''' ''''' '''''''''' '''''''' ''''''''''''''' ''''''''''' '''''''''''''''' '''''''''''''''''''' ''''''''''''' ''''''''''''''''''''' '''''' ''''''''' '''''''' '''''''''''' '''''''''' ''''''''''''' ''''''''''''''''''' ''''' '''''''''' ''''''''' ' '''''''''''''''''''' '''''''''''''''''''' ''''' '''''''''' ''''''''' ''''''''''''''' ''''''' '''''''''' '''''''''''''''''''''' '''''''''''''''''''''' '''''''''''''' ''''''''''''' '''''''''''''''''''''''''''' Capital equipment Capital ''''''''''''''' '''' '''''''''''''''''''' ''''''''''''''''' '''''''''''''''' ''''''''' ''''' ''''''''' ''''''' '''''''''' '''''''''' ''''''''''' '''''''''' ''''''''' ''''''''''''''' '''''''''' ''''''''''''''''''''''''''' ''''''''''''''' ''''''''' ''''' '''''''''' ''''''''' ''''''''''''' ''''''''''' '''''''''''' '''''''''''''' '''''''''''''''''''' ''''' ''''''''' ''''''' ''''''''''''' ''''''''' ''''''''''''' ''''''''''''''''''''' ''''' '''''''''''''''' '''''''''''''' '''''''''''''' ''''''''' ''''' ''''''''' '''''''' '''''''''''''''' ''''''''''' '''''''''''''' ''''''''''''' '''''' ''''''''''''''' ''''''''''''''''' Total '''''''''''''''''''' '''''''''''''''''''' (€10-100 (€10-100 14,410,865 million) million)

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

IP ''''''''''''''''''''''''''''''''' ''''''' '''''''''''''''''''' ''''''''''''' ''''''''''''' '''''''''''''''''''' '''''''''''''''''''' ction prote ''''''''''''''''''''''''' ''''''''''''' ''''''''''''''' ''' ''''''''''''''''' '''' '''''''''' ''''''' ''''''''''''''''''''' ''''''''''' ''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''''''''''''' ''''' ''' ''''''''''''''''''''' ''''''''''' ''''' '''' ''''''''''''''''' '''''' '''''''''''''' '''''''''''''''''''' '''''' '''''''''''''''''''''''''''''''''' ''''''' ''''''''''''''''''''''' ''' '''''''''''' ''''''' ''''''''''' '''''''''''''''''''''' '''''''''' ''''''''''''''''''''''''' ''''''' '''''''' ''' ''''''' ''''''''' '''''''''' '''' '''''''''''

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 75 • R&D work: cost is not possible to estimate • Plant conversion: cost is not possible to estimate; conversion from DCM to EDC had costed '#C#, #D#''''''''''' ''''''''''''' (range: €10-100 million) in 2014 prices • Downtime: cost is not possible to estimate but is likely to be significant • Marketing authorisation variations: '#C#, #D#''''''''''''' (range: €1-10 million) over 3 years.

10.3.2 Loss of past investment

Table 10-1 summarised the important investments made by Eli Lilly from 2003 and showed that ca. €14.4 million in past investments (in 2014 prices) would stand to be forfeited if Eli Lilly could no longer use EDC and the existing plant would be unable to manufacture Raloxifene Hydrochloride following the existing manufacturing process.

10.3.3 Changes to on-going operating costs

As noted earlier, a manufacturing process that uses this alternative has not been identified and conceptualised for the implementation of this solvent and therefore it is not possible for Eli Lilly to estimate the changes in operating costs that would arise from the use of chlorobenzene.

One cost element that could be readily estimated is the cost of the replacement solvent. Eli Lilly’s R&D work suggests that 1 kg of EDC would be replaced with ca. '#C#, #D#'' kg chlorobenzene. Taking into account the current consumption of EDC, the envisaged consumption of chlorobenzene would be '#C#, #D#'''''' ''''''' t/y.

However, consumption of EDC is projected to decline over time and stabilise at '#C#, #D#''''' '''''' '''''' '''' '''''''''' (see Figure 3-1). If we assume that the market price of EDC and chlorobenzene that Eli Lilly pays/would pay is '#C#, #D#''''''''''''' and '#C#, #D#'''''''''''''''' respectively, the cost increase from the change of solvent would be '#C#, #D#''''''''' '' '''''''''''' ''' ''''''''' ''' ''''''''''''''''' in a typical year'#C#, #D# ''''''''''''''' ''''' '''''' ''' '''''''''''' '' '''''' ''' ''''' '''''''''' (both <€1 million/y).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 76 11 Annex 4 – Risk evaluation of alternatives

11.1 Background

Article 60 (5) of REACH requires Eli Lilly to investigate whether the use of the alternative substance “would result in reduced overall risks to human health and the environment” (as compared to the Annex XIV substance EDC).

A first hazard screening was carried out to rule out from an initial list of potential alternatives those substances which are not eligible due to a critical hazard profile (CMR substances or substances with similar levels of concern) (see Section 4.3.3).

From the remaining substances the candidates which provide the highest chances for substituting EDC from a technical and economical perspective were selected. In conclusion, two substances were selected for in-depth analysis (see Section 4):

• Dichloromethane (CAS No. 75-09-2) • Chlorobenzene (CAS No. 108-90-7)

In order to comply with the REACH requirement in this chapter the hazard profiles of these substances are presented and suitable reference values for a quantitative comparison (DNELs for human health assessment, PNECs for an assessment of environmental toxicity) are either identified or (if no such reliable basis could be found in the public domain) derived (Section 11.2).

Literature searches (up to January 2015) for the alternative substances selected for in-depth evaluation were performed in bibliographic other databases when appropriate (after consultation of existing assessments) and assessments available from eChemPortal and other sources were screened.

In detail, the following sources and search steps were used to retrieve relevant information:

• ECHA CHEM database (http://echa.europa.eu/search-chemicals) • eChemPortal (http://www.echemportal.org/echemportal/), with all related sources • bibliographic database Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) • the US NLM portal TOXNET (http://toxnet.nlm.nih.gov/ including the bibliographic database Toxline and other databases • ECOTOX database (http://cfpub.epa.gov/ecotox/) • the aquatic toxicity database CHRIP of the Japanese Ministry of Environment (http://www.safe.nite.go.jp/english/db.html).

As not only a comparison of hazard profiles is required but a comparison of substance properties on a risk basis, a human health and environmental exposure scenario is developed (Section 11.3). Exposure within this scenario is estimated using the Tier I tool ECETOC TRA v.3.1. This approach is different to that used in the CSR, as it should be applicable in a similar way for all alternative substances assessed and therefore is of a more generic nature, which does not rely on specific data (e.g. measured data). The outcome of the exposure assessment should not be considered a realistic estimate of exposures, but is expected to describe relative exposure intensities.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 77 Section 11.4 presents the comparative risk characterisation and the overall conclusions on risks from using the alternative substances.

11.2 Reference values (DNELs, PNECs) for EDC and alternative substances

11.2.1 Introduction

In the following chapters DNELs and PNECs are discussed, which can be used for a comparative assessment. Available monographs, data from registration dossiers as available at ECHA CHEM (ECHA, 2015a) as well as published data (in case of inconsistencies or data gaps) are used for this purpose.

Where no DNELs/PNECs or similar reference values are available that are compliant with requirements according to ECHA Guidance (ECHA, 2008; 2012a) (or if there is not enough information available on the rationales for deriving the values), then based on available data, tentative DNELs/PNECs are derived to be used in this comparative assessment. The tentative values should not be considered as a final evaluation of the effects of the substances. These values are used for this comparative assessment only and are not intended to represent a full assessment of the substances concerned.

For human health considerations, DNELlong-term inhalation workers and DNELlong-term dermal workers for all alternative substances are used. For EDC the inhalation concentration associated with a risk level of 10-5 (DMEL) is used for comparison with the alternative substances.

For the environmental assessment, PNECfreshwater will be used as reference values for the comparative assessment. In case of organic substances and in absence of compartment-specific toxicity data reference values for other compartments (sediment, soil) are often calculated with the equilibrium partitioning method (EPM). As the EPM method is also used for calculating exposure levels (“predicted environmental concentrations”, PEC), risk characterisation ratios calculated this way are the same as for the freshwater compartment. Therefore, RCRs calculated for freshwater are taken as indicative for risks for all environmental compartments.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 78 11.2.2 1,2-Dichloroethane (CAS 107-06-2)

Classification

Classification of EDC is shown in Figure 11-1. This is the harmonised classification that appears in Table 3.1 of CLP, with an Index number of 602-012-00-7.

Figure 11-1: Classification of EDC Source: http://echa.europa.eu/web/guest/home, assessed on 6 August 2014

Human Health

A reference value for long-term, inhalation exposure of workers of 24.7 µg/m3 associated with a risk level of 1 x 10-5 is used for the comparative assessment with the alternative substances here. This value is based on the exposure-risk relationship presented by RAC (ECHA, 2015b).

This reference value is used for the RCR calculations in the tables in the comparative assessment below.

RAC (ECHA, 2015b) also proposed an exposure-risk relationship for dermal exposure. As this exposure route is considered to be negligible compared to inhalation exposure, due to the substance’s high volatility, no DMEL for dermal exposure is set here and this exposure route is not considered for this comparative assessment.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 79 Ecotoxicity

Existing reference values

Table 11-1: PNECs for EDC – values from ECHA CHEM compared to other assessments Reference value ECHA CHEM25 OECD SIDS (2002) CEPA (Canadian Environmental Protection Act, 1994)

PNECfreshwater (assessment 1100 µg/L (10) 1100 µg/L (10) 130 µg/L (20) factor)

PNECmarine-water 110 µg/L (100) (assessment factor)

PNECintermittent-releases 1360 µg/L (100) (assessment factor) PNECSTP (assessment 27800 mg/L (100) factor) PNECsediment freshwater 11.1 mg/kg sed. dw. (EPM)

PNECsoil 1.8 mg/kg soil dw. (EPM) Sources: http://echa.europa.eu/web/guest/home, assessed on 6 August 2014 OECD SIDS (2002) CEPA (Canadian Environmental Protection Act, 1994)

Discussion of suitability of reference values for comparative assessment

Basis for PNECfreshwater derived in ECHA CHEM and OECD SIDS (2002):

Acute and long-term aquatic toxicity data for species from three trophic levels are available. The lowest NOAEC observed was 11 mg/L from daphnia magna life cycle toxicity study. An assessment factor of 10 was used to derive PNECfreshwater.

Basis for PNECfreshwater derived by CEPA (Canadian Environmental Protection Act, 1994):

A study reporting effects on larval survival of north-western salamander (Ambystoma gracile) was used as key study, with a LC50 of 2.54 mg/L (Black et al., 1982, unpublished). An assessment factor of 20 was applied.

The study by Black et al also investigated the toxicity of EDC to fish in several species. LC50 values obtained were consistently and substantially lower than those obtained by other fish toxicity studies with this substance. The Black et al. study was criticised in OECD SIDS and was considered not reliable enough to be used for PNEC derivation, due to the non-reproducibility in other studies.

Conclusions: PNECs for comparative assessment

The PNECfreshwater as derived in the registration dossier (ECHA CHEM) and by OECD SIDS (1100 µg/L) is used for the comparative assessment.

25 http://echa.europa.eu/web/guest/home, assessed on 6 August 2014.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 80 11.2.3 Dichloromethane (methylene chloride, CAS 75-09-2)

Classification

Classification of DCM is shown in Figure 11-2. This is the harmonised classification that appears in Table 3.1 of CLP, with an Index number of 602-004-00-3.

Figure 11-2: Classification of DCM Source: http://echa.europa.eu/web/guest/home, assessed on 22 September 2014

Human Health

Existing reference values

Table 11-2: DNELs (or DMELs) for dichloromethane from ECHA CHEM ECHA CHEM ECHA CHEM Reference value (joint submission) (individual submission) DNEL long-term workers 353 mg/m³ * 132.14 mg/m³ (DMEL for short- inhalation term exposure) ** DNEL long-term workers dermal 12 mg/kg bw/day - DNEL long-term general 88.3 mg/m³ * 5 mg/m³ (DMEL for short-term population inhalation exposure) ** DNEL long-term general 5.82 mg/kg bw/day - population dermal DNEL long-term general 0,06 mg/kg bw/day - population oral Source: http://echa.europa.eu/web/guest/home, assessed on 22 September 2014 * based on SCOEL assessment ** given as inhalative DMEL, short-term exposure, derived from NOAEC by using assessment factors; no further information available

As shown above, in the EU DCM is classified as a suspected carcinogen (Cat 2, H351). Similarly, US EPA classified the substance as “likely to be carcinogenic in humans”26. IARC recently upgraded its

26 US EPA: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showQuickView&substance_nmbr=0070 (Integrated Risk Information System, IRIS, accessed on 22 September 2014).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 81 classification of DCM to Group 2A “probably carcinogenic to humans” (Benbrahim-Tallaa et al., 2014) in comparison to its previous classification (Group 2B, possibly carcinogenic to humans) (IARC, 1999). This new classification is based on new (limited) evidence that the substance causes biliary-tract cancer and non-Hodgkin lymphoma in humans. Also, NTP in its 13th edition of the Report on Carcinogens (2014) classified the substance as “reasonably anticipated to be a human carcinogen”.27

DCM was tested in several oral and inhalation carcinogenicity studies with rats and mice. Only the mouse inhalation studies showed clear evidence of carcinogenicity. Lung and liver tumours were observed in these studies. Benign fibroadenoma of the mammary gland were found in inhalation studies with rats of both sexes (IARC, 1999).

DCM was consistently positive in mutagenicity assays with microorganisms and induced chromosomal aberrations in human cells in vitro. Inconclusive or negative results were obtained for gene mutations in mammalian cells (IARC, 1999).

Metabolism via a glutathione S-transferase-dependant pathway was linked to metabolites considered responsible for the carcinogenic action of the substance in mice. The fact that this enzymatic activity is expressed to a greater extent in mouse tissues compared to rats or humans might explain the differences in the study outcome in mice and rat studies (IARC, 1999). In its recent evaluation IARC considered the fact that this metabolism pathway, which is associated with the genotoxicity of DCM, is active in humans (Benbrahim-Tallaa et al., 2014).

In 2011, the US EPA reviewed and re-evaluated human health risks of DCM28. A cancer risk estimate was performed for both oral and inhalation exposure. The carcinogenicity data from the inhalation mouse (B6C3F1 mice) studies of Mennear et al. (1988) and NTP (1986), where hepatocellular carcinomas and adenomas, bronchoalveolar carcinomas or adenomas of the lung were observed, were used as a basis. Dose-response modelling was applied to derive a point of departure (benchmark dose) and PBBK modelling to consider differences in toxicokinetic in mice and humans. An inhalation unit risk of 1 × 10-8 per µg/m3 was derived for continuous, lifetime exposure. This risk estimate includes considerations for taking into account the potentially increased risk of sub- populations which are carriers of the GST-T1+/+ homozygous genotype (genetic polymorphism of the glutathione-S-transferase).

This inhalation unit risk of 1 × 10-8 per µg/m3 corresponds to life-long continuous exposure (general population). In order to convert it to an occupational risk factor, the procedure as used by RAC (see e.g. RAC’s exposure-risk relationship for trichloroethylene)29:

• Adjustment for exposure only during work shift (inhalation volume during activity 10 m3 versus 20 m3/d (low activity, whole day average) • Adjustment for exposure only during 5 days per week • Adjustment for exposure only during 58 weeks per year • Adjustment for exposure only during working life (40 years).

27 http://ntp.niehs.nih.gov/ntp/roc/content/profiles/dichloromethane.pdf#search=dichloromethane

28 http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showQuickView&substance_nmbr=0070, accessed 10.11.2014; a link is provided at this site to the comprehensive literature review on the substance

29 http://echa.europa.eu/applying-for-authorisation/evaluating-applications

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 82 In conclusion, the unit risk is divided by the following factors:

1 x 10-8 / (20 m3/d/10m3/d × 7d/5d × 52w/48w × 70y/40y) = 1.9 x 10-9

Continuous exposure at the workplace at 1 µg/m3 is therefore associated with an excess risk of 1.9 x 10-9.

This corresponds to a concentration at the 1 x 10-5 risk level of 5.3 mg/m3 (DMEL).

Although the methodology to extrapolate to low doses as applied by US EPA differs slightly to that in the ECHA Guidance (ECHA, 2012a), it can be assumed that this risk estimate is close to what would result if the ECHA Guidance had been applied.

Another, but much older cancer risk estimate by Health Canada leads to a very similar risk estimate (lower by a factor of 2) (for details see ITER, International Toxicity Estimates for Risk30).

In 2009, the Scientific Committee on Occupational Exposure Limits (SCOEL) evaluated the substance and concluded that based on the current knowledge on activation pathways and the experimental and human data available DCM probably poses a small risk “under conditions of current occupational exposures” (SCOEL, 2009). In consequence, SCOEL assigned DCM to the group C and assumed a “practical” threshold with the consequence that an OEL was derived based on non-cancer endpoints. SCOEL recommended an 8 hour TWA OEL of 100 ppm (353 mg/m3), which was mainly based on experiences at the workplace, where no adverse effects were observed at these concentrations (SCOEL, 2009).

Discussion of suitability of reference values for comparative assessment

Relevant uncertainties exist regarding the mode of action of the carcinogenic activity of DCM. SCOEL considered the substance to be a weak carcinogen at most and derived an OEL based on other, non- carcinogenic endpoints.

A recent evaluation of IARC reported some evidence for carcinogenic effects in humans and considers the metabolic pathway leading to genotoxic metabolite in mice also relevant for humans. Therefore, in order to use an approach equivalent to that used for EDC in this application for authorisation, DCM is considered a non-threshold carcinogen and the cancer risk estimate as calculated by US EPA is used in this assessment.

It must be emphasised that a detailed and final assessment of the relevance of carcinogenic effects of DCM in humans cannot be performed in the context here.

Conclusion: Tentative DNELs for comparative assessment

For the comparative assessment, a tentative DMEL of 5.3 mg/m3, corresponding to a cancer risk of 1 x 10-5, and derived from the cancer risk estimate of the US EPA, is used.

As the dermal exposure route is considered to be negligible compared to inhalation exposure, due to the substance’s high volatility, no DMEL for dermal exposure is set here and this exposure route is not considered for this comparative assessment.

30 http://www.tera.org/iter/index.html, accessed on 10 November 2014.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 83 Ecotoxicity

Existing reference values

Table 11-3: PNECs for DCM – values from ECHA CHEM compared to other assessments ECHA CHEM ECHA CHEM Reference value (joint submission) (individual submission)

PNECfreshwater (assessment factor) 310 µg/L (20) 130 µg/L (100) PNECmarine-water (assessment factor) 31 µg/L (200) 130 µg/L (100) PNECintermittent-releases (assessment 270 µg/L (100) -- factor) PNECSTP (assessment factor) 26 mg/L (100) PNECsediment freshwater 2.57 mg/kg sed. dw. (EPM) 0.163 mg/kg sed. dw. (--) PNECsoil 0.33 mg/kg soil dw. (EPM) 0.173 mg/kg soil dw. (AF 1000)

Basis for PNECfreshwater derived in ECHA CHEM:

All data regarding the individual submission by ECHA CHEM are based on QSAR, only. Because of this, the resulting PNEC is not regarded as reliable and consequently will not be discussed further.

Relevant data from ECHA CHEM used for PNECfreshweater derivation in case of the joint submission are as follows:

Aquatic invertebrates, acute toxicity: LC50 (48h, Daphnia magna, mort) = 27 mg/L (nom.)

Aquatic invertebrates, chronic toxicity: NOEC by QSAR: 6.2 – 13.3 mg/L (different approaches)

Aquatic plants / algae: no reliable studies, WOE toxicity threshold (8d, blue algae): 550 g/L (Bringmann and Kühn, 1978).

Fish, acute toxicity:

• Key study 1 (fresh water): LC50 (96h; Pimephales promelas; flow through; meas.) = 193 mg/L;

• Key study 2 (salt water): LC50 (96h; Fundulus heteroclitus - mummichog; static; meas) = 97 mg/L;

Fish, chronic toxicity:

Key study: NOEC (28d; growth rate; Pimephales prom; flow through; meas.): 83 mg/L

Obviously, PNECfreshwater according to ECHA CHEM was derived interpreting the QSAR-result for aquatic invertebrates as information on chronic exposure in addition to chronic data on fish and algae. According to R.10, an AF of 10 would result. Presumably to account for limited reliability regarding the studies on algae and/or imponderabilities concerning the value for aquatic invertebrates (QSAR), the factor of 20 was selected and used on the most sensitive trophic level (NOEC of 6.2 mg/L for Daphnids derived by QSAR).

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 84 Further studies are available from the literature, which are not reported in the dossier published in ECHA CHEM:

Aquatic plants / algae:

According to Brack and Rottler (1994), the published data on algae by Bringmann and Kühn (1978) are not reliable for volatile solvents, because no measures were taken to prevent evaporation, which may have led to high effect concentrations.

Brack and Rottler (1994) reported effects of DCM on Chlamydomonas reinhardtii (green alga) Algae were grown in sealed test vessels including a CO2 source (carbonate/bicarbonate buffer) connected via the gas phase to the growth chamber. Actual concentrations were measured at the end of the test (2 replicates for each test item concentration, 3 replicates for controls). Growth of controls was logarithmic throughout the exposure phase, and multiplication during 72 hours was at least by a factor of 100. For DCM, the following effect concentrations reduction of biomass were derived:

EC10 (72h, measured, biomass) = 115 mg/L (95% C.I.: 79.1 – 146)

EC50 (72h, measured, biomass) = 242 mg/L (95% C.I.: 202 – 286)

The data determined by Brack and Rottler (1994) on Chlamydomonas reinhardtii (green alga) growth inhibition by DCM provide reliable information on the effect of dichloromethane on algae. However, as they report the effects on a biomass basis (and did not report effects on algal growth rate) the reported EC10 and EC50 values are considered conservative (biomass based effect concentrations in general are more sensitive than growth rate based values).

Chronic toxicity data on aquatic vertebrates (fish and frog larvae):

Black et al. (1982) published reliable data (flow through, analytical verification of test item concentrations, closed tanks to prevent evaporation of volatile solvents, detailed reporting of material and methods as well as results) on toxicity of DCM to embryo-larval stages of fish and amphibians (partial life cycle tests: exposure initiated within 30 minutes of fertilization through embryogenesis to 4 days post-hatch). For DCM, most sensitive species were Rainbow trout (Oncorhynchus mykiss, reported as Salmo gairdneri) and the European common frog (Rana temoraria). For evaluation of the results, teratic organisms were counted as dead. The following results are reported:

1) Rainbow trout

• LC50 (27 d) = 13.16 (95% CI: 10.95-15.32) mg/L • LOEL for teratogenic effects (23 d) = 5.55 mg/L (+/- 1.06)

• Approximated (from reported single data points, not reported) LC10 (27 d): 0.13 mg/L 2) Rana temporaria

• LC50 (9 d) = 16.93 (95% CI: 10.95-29.04) mg/L • LOEL for teratogenic effects (5 d) = 18.9 mg/L (+/- 1.8)

• reported LC10 (9d) = 0.8224 (95% CI: 0.2526-1.643) mg/L 3) Fathead minnow (Pimephales promelas)

• Approximate LC50 (9 d, i.e. 5 days till hatching plus 4 days post-hatch): 34 mg/L

• Approximate EC10 (concentration level showing 10% lethality): 0.11 mg/L (+/- 0.02). This disagrees pronouncedly with the NOEC (28d; growth rate; Pimephales prom; flow through; meas.) of 83 mg/L in the fish study reported in ECHA CHEM.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 85 Further toxicity data are available for the free living nematode Panagrellus redivivus (Samoiloff et al., 1980). The testing method is well described (see also Samoiloff, 1990) and implies closed vials for testing. 54% and 85% inhibition of transition from L4 to adult molt were observed at 0.85 µg/L and 84.9 µg/L, respectively. The corresponding increase of frequency of X-chromosomal lethal mutations per locus compared to the background of control animals was 27 and 46-fold at these concentrations.

Discussion of suitability of reference values for comparative assessment

The effect concentrations determined by Black et al. (1982) for aquatic vertebrates are consistently lower than those reported by ECHA CHEM, especially with regard to low effect concentrations (LC10- values). While no methodological deficits become obvious from the original publication, data on fish for EDC tested in the same publication by Black et al. (1982) were criticised in OECD SIDS on EDC (OECD, 2002) to be consistently and substantially lower than those from other fish toxicity studies with the substance. In the SIDS report, the study was considered not reliable enough to be used for PNEC derivation, due to the non-reproducibility in other studies. Therefore, data from this study on the toxicity of DCM are not used for derivation of a tentative PNECfreshwater.

While the study on the nematode Panagrellus redivivus was regarded as relevant within the Canadian assessment report on DCM (Canadian Environmental Protection Act, 1993), it is a non- standard test, and while potentially mutagenic effects were observed, it is difficult to interpret these effects on a population level. The results on Panagrellus redivivus are therefore not included into the data for derivation of a tentative PNECfreshwater.

In conclusion, the following data are regarded as relevant and used for tentative PNECfreshwater derivation:

• Fish, (sub)chronic: NOEC (28d; growth rate; Pimephales prom; flow through; meas.): 83 mg/L • Algae, chronic: EC10 (72h; Chlamydomonas reinhardtii; measured; biomass) = 115 mg/L

• Invertebrates, acute: LC50 (48h, Daphnia magna, mort) = 27 mg/L (nom.)

While chronic data are available for two trophic levels, these do not cover the acutely most sensitive trophic level aquatic invertebrates. Because the acute LC50 for aquatic invertebrates is lower than the lowest long-term result, the tentative PNECfreshwater is derived from the acute LC50 for Daphnia magna with an assessment factor of 100 according to REACH guidance document R.10 (ECHA, 2008):

PNECfreshwater = 270 µg/L

Conclusions: Tentative PNECs for comparative assessment

The PNECfreshwater from ECHA CHEM based on the individual submission is considered not to be reliable (based on QSAR, only). With regard to PNECfreshwater based on the joint submission (ECHA CHEM), methodology for derivation is unknown. To be equivalent with PNECfreshwater derived for other compounds being part of the alternatives assessment, the tentative PNECfreshwater derived above will be used for comparative assessment:

PNECfreshwater = 270 µg/L.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 86 11.2.4 Chlorobenzene (CAS 108-90-7)

Classification

Classification of chlorobenzene is shown in Figure 11-3. This is the harmonised classification that appears in Table 3.1 of CLP, with an Index number of 602-033-00-1.

Figure 11-3: Classification of chlorobenzene Source: http://echa.europa.eu/web/guest/home, assessed on 19 January 2015

Human Health

Existing reference values

Table 11-4: DNELs (or DMELs) for chlorobenzene from ECHA CHEM ECHA CHEM ECHA CHEM Reference value (joint submission) (individual submission)

DNEL long-term workers inhalation 23 mg/m³ 42.3 mg/m³ DNEL long-term workers dermal 5 mg/kg bw/day 12 mg/kg bw/day DNEL long-term general population inhalation 1 mg/m³ - DNEL long-term general population dermal 3 mg/kg bw/day - DNEL long-term general population oral 3 mg/kg bw/day - Source: http://echa.europa.eu/web/guest/home, assessed on 19 January 2015

The basis for derivation of the DNEL for inhalation exposure of workers in the registration dossiers (joint submission and two individual submissions) is not apparent from the given information.

The occupational exposure limit (OEL) in the EU and other European countries is 5 ppm, 23 mg/m3, in Germany it is 10 ppm, 47 mg/m3 and in the UK it is 1 ppm, 4,7 mg/m3 (DFG, 2014; HSE, 2008; IFA, 2015). With the exception of the Workplace Exposure Limit (WEL) in the UK, OEL are based on systemic effects in animal studies as well as sensory irritation and narcotic effects in studies with volunteers (Greim, 1995; SCOEL, 2003). The WEL is not formally based on definite toxicological data, but considers also usual workplace concentrations (“The available toxicological data do not identify clear positive evidence for serious effects on human health at 1 ppm or 5 ppm; rather, the position is one of uncertainty. … Exposure data demonstrate that control to less than 5 ppm (8-hour TWA) is

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 87 reasonably practicable, and that most results are below 1 ppm…. WELs have been based on the levels of exposure that is reasonably practicable for all sectors of industry to achieve”)(HSE, 2008).

Discussion of suitability of reference values for comparative assessment

Chlorobenzene has a low acute toxicity, it is slightly irritating to skin and mucous membranes and has narcotic properties. Studies with volunteers revealed a LOAEC of 60 ppm (282 mg/m3, 7 hrs with 3 hrs of exposure, 1 hr break, 4 further hrs of exposure) for headache, drowsiness and dry throat, with a NOAEC of 12 ppm, 56 mg/m3 (Greim, 1995; 2001; SCOEL, 2003).

Target organs of repeated inhalation exposure of laboratory animals were mainly liver (increased organ weight and liver enzyme values, fatty degeneration and necrosis), kidneys (increased organ weight, focal degeneration and necrosis of the proximal tubules) and the haematopoetic system (changes in white blood cell, lymphocyte, monocyte and neutrophil numbers, indicating bone marrow damage, mouse as most sensitive species) (Greim, 1995; HSE, 2008; SCOEL, 2003). The LOAEC for liver and kidney effects in several subchronic studies is 75 ppm (353 mg/m3), the lowest concentration tested (6 hr/d exposure). A LOAEC for first liver effects of 50 ppm (235 mg/m3) is reported in a two-generation study by Nair et al. (1987), again representing the lowest exposure concentration at a 6 hr/d exposure. The oral NOAEL and LOAEL of the study by NTP are 60 and 120 mg/kg x d, respectively, for pathological liver changes (Greim, 1995; HSE, 2008; SCOEL, 2003). For comparison these oral doses can be converted to air concentrations of 207 and 414 mg/m3, respectively, using a respiratory volume of 0.29 m3/kg bw for 6 h of exposure (ECHA, 2012a). The converted oral NOAEL is thus only slightly below the inhalative LOAEC, but due to the different dose spacing there is no evidence of clear differences in path-specific toxicities.

The LOAEC for haematotoxicity in mice was 21 ppm (99 mg/m3) in a subchronic study, but this study is criticized with respect to documentation and characterisation of exposure (HSE, 2008; Montelius, 2003) and the effects are suspected to be caused by contaminants (EPA, 1988). The results are contradictory to those from the NTP carcinogenicity study without haematological alterations after two years of exposure to doses up to 120 mg/kg x d. However, reduced white blood cell and reticulocyte counts and lymphoid and/or myeloid depletions in thymus, spleen and bone marrow were observed in the corresponding 90 days studies at ≥ 500 mg/kg x d. Nevertheless there are conflicting results from other studies and information with respect to haematological effects is lacking from further studies. Therefore uncertainty still remains whether or not the changes are findings by chance or indicative of a real treatment-related effect (HSE, 2008; Montelius, 2003).

A degeneration of the germinal cell epithelium was observed in the two-generation study by Nair et al. (1987) with a NOAEC of 50 ppm (235 mg/m3), and atrophy of the seminiferous epithelium was noted in dogs, exposed for 90 days to 273 ppm (1283 mg/m3). Such lesions were not observed in the NTP carcinogenicity study. Delayed ossification was evident in offspring of pregnant rats exposed to concentrations of 75 to 590 ppm (353-2773 mg/m3), but without clear dose-response relationship and associated with maternal toxicity at the highest exposure concentration. Such fetal effects were not observed in rabbits (John et al., 1984).

Chlorobenzene is suspected to be at most a weak genotoxic substance. It was negative in most studies on genotoxicity, as are Ames tests, mutational assays in yeast, induction of chromosomal aberrations and unscheduled DNA synthesis in vitro, and mutations in Drosophila, tests in mice on induction of chromosome aberration, sister chromatid exchange and micronuclei and a dominant lethal test in mice. The exceptions with positive results are one mouse lymphoma assay in L5178Y cells, where a positive response was evident with and without metabolic activation, induction of sister chromatid exchange in CHO cells (positive only without metabolic activation) and an in vivo

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 88 mouse micronucleus assay. The latter result was not reproducible by others and the study was criticized with respect to methodology and documentation. A weak DNA-binding was shown in vitro and in vivo (Greim, 1995; HSE, 2008; SCOEL, 2003). A recently published study reported the induction of chromosome aberrations and micronuclei in rats in vivo. The incidence of micronuclei was significantly and dose-dependent increased 24 hrs after exposure, but not significant after 12 or 48 hrs. The same profile was observed for the induction of chromosome aberrations, with a significant and dose-dependent increase only at 24 hrs after exposure (Faisal Siddiqui et al., 2006).

In the carcinogenicity study by NTP with rats and mice given chlorobenzene by oral administration, the incidence of neoplastic nodules in the liver was increased in the male rats of the highest dose group (120 mg/kg bw/day). No effects were seen in the female rats or in the mice (Greim, 1995; SCOEL, 2003). SCOEL did not consider these findings indicative of a carcinogenic potential of chlorobenzene. The substance is not classified with respect to carcinogenicity (harmonized), but with a self-classification of one notifier as Cat Carc. 1A31. The US-EPA carcinogenicity classification is D (EPA, 2015).

Inhalation exposure

As the basis for derivation of the DNEL for inhalation exposure of workers in the registration dossiers is unknown, it cannot be directly used for the comparative assessment.

No NOAEC for systemic effects is reported in the available inhalation studies. A LOAEC of 75 ppm (353 mg/m3) for liver and kidney effects is reported in several subchronic inhalation studies, and a LOAEC of 50 ppm (235 mg/m3) for first liver effects in a two-generation rat inhalation study. The LOAEC of 21 ppm (99 mg/m3) for haematotoxicity does not seem to be sufficiently validated for its use in risk assessment. Therefore the LOAEC of 50 ppm (235 mg/m3) is used as point of departure for deriving the DNEL. According to ECHA guidance R.8 (ECHA, 2012a), this LOAEC (based on 6 hr/d exposure) is converted by

• Correcting for 6 hr exposure in the experimental study compared to an 8 hr shift • Correcting for physical activity (6.7 m3/ 10 m3) into a human equivalent workplace concentration of 118 mg/m3.

Using assessment factors of 3 (extrapolation of a NAEC under consideration of the slight effects at the LOAEC), 2.5 for further interspecies differences, 5 for intraspecies variance in workers, a tentative DNEL of 3.2 mg/m3. An additional assessment factor of 2 accounting for the subchronic exposure duration is not used, because the chronic oral NOAEL of 60 mg/kg x d (207 mg/m3 after path-to-path extrapolation) from the NTP-study is only slightly lower than the LOAEC of 235 mg/m3 from the subchronic inhalation study and supports the assessment of chronic toxicity, based on the subchronic inhalation study.

Dermal exposure

The dermal DNEL presented in ECHA-CHEM cannot be used for comparative assessment without a full understanding of its origin.

31 http://echa.europa.eu/web/guest/information-on-chemicals/cl-inventory-database, assessed on 22 January 2015.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 89 No quantitative data on dermal absorption are available. From the physico-chemical properties of chlorobenzene and by analogy with other chlorobenzenes it is predicted that chlorobenzene will be readily absorbed via the dermal route (HSE, 2008). However, based on data on acute toxicity data, a lower dermal toxicity can be assumed:

The dermal LD50 is lower compared to the oral LD50 route, because no mortality was observed after dermal exposure of rabbits to 2212 or 7500 mg/kg bw, whereas the oral LD50 in rabbits was 2250- 2830 mg/kg bw (BUA, 1991; HSE, 2008).

However, as further information is lacking, in a conservative approach the inhalation DNEL is converted into a dermal DNEL, by multiplying the inhalation DNEL with 10 m3/day (respiratory volume per shift) and dividing it by 70 kg body weight.

Conclusion: Tentative DNELs for comparative assessment

The following tentative DNELs are derived and used for the comparative assessment:

3 • DNEL long-term workers inhalation: 3.2 mg/m • DNEL long-term workers dermal: 0.46 mg/kg d.

Ecotoxicity

Existing reference values

Table 11-5: PNECs for Chlorobenzene – values from ECHA CHEM compared to other assessments Reference value ECHA CHEM, ECHA CHEM, joint WHO (2004) MOE Japan (MoE, individual submission 2014) submission

PNECfreshwater 25 µg/L (10) 32 µg/L (10) 20 µg/L (50) 2.5 µg/L (100) (assessment factor)

PNECmarine-water 2.5 µg/L (100) 3.2 µg/L (100) 3 µg/L (50) (assessment factor)

PNECintermittent-releases 66 µg/L (100) -- (assessment factor) PNECSTP 1.4 mg/L (100) 1.4 mg/L (100) (assessment factor) PNECsediment 0.675 mg/kg sed. 0.922 mg/kg sed. freshwater dw. (EPM) dw. (EPM)

PNECsoil 0.118 mg/kg soil 0.166 mg/kg soil dw. (EPM) dw. (EPM) Source: http://echa.europa.eu/web/guest/home, assessed on 11 December 2014

Discussion of suitability of reference values for comparative assessment

The respective basis for PNECfreshwater values derived according to ECHA CHEM individual submission, ECHA CHEM joint submission WHO (2004) and MOE Japan (MoE, 2014) is outlined in the following tables below together with selected results from further identified published studies deemed to be potentially relevant. With the exception of algae only (sub)chronic results are shown, while in

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 90 addition a considerable number of other, mostly acute results are available from the published literature. The data used for PNEC derivation as well as the applied assessment factors vary considerably. In the following, for each trophic level a short reasoning is given as to why one result is regarded here as most relevant for derivation of a tentative PNEC for comparative assessment as an alternative (given in bold face in the tables on fish, aquatic invertebrates and algae).

With regard to fish, the early life stages test by Black et al. (1982) results in the lowest chronic value (LC1, including severe malformations counted as deaths) which was determined with rainbow trout. The data are published in detail including measured concentrations and exposure conditions implying closed tanks to prevent evaporation of volatile solvents. From this study, and other mostly acute data not shown here (see e.g. WHO, 2004), it seems that rainbow trout is indeed one of the most sensitive fish with regard to chlorinated benzenes. Still, the value is lower by a factor of 18 compared to the result with Oryzias latipes in the same test. Further, data on fish for EDC tested in the same publication by Black et al. (1982) were criticised in OECD SIDS on EDC (OECD, 2002) to be consistently and substantially lower than those from other fish toxicity studies with the substance. In the SIDS report, the study was considered not reliable enough to be used for PNEC derivation, due to the non-reproducibility in other studies. Therefore, data from this study on the toxicity of chlorobenzene are not used for derivation of a tentative PNECfreshwater. Rather, the 43-days NOEC of 0.247 mg/L determined in the early life stages test with Oryzias latipes will be used for the trophic level fish.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 91 Table 11-6: (Sub)Chronic toxicity in freshwater fish Decisive Study result for PNEC according to NOEC / EC ECHA ECHA Species Study type Duration (d) E(L)C [mg/L] 10 Add. inform. Reference 50 [mg/L] CHEM CHEM WHO MoE individ. joint (2004) (2014) subm. subm. Oryzias Early life stage 43 -- 0.247 Presumably meas. / X -- -- X MOE Japan, 2003 latipes (OECD 210) flow through (see MoE (2014) and (1)) Danio rerio Early life stage 28 10.3 (95% CI: 4.8 Measured semi- -- X X -- van Leeuwen et al. (OECD 210) 9.1-11.9) static (3x/w) (1990) Oncorrhyn- Early life stage 27 (4d post- 0.11 (95% CI: 0.0143 (LC1; 95% Measured, flow Black et al. (1982) ------chus mykiss (OECD 210) hatch) 0.09-0.13) CI: 8.1-21.4) through (1) See J-CHECK

Table 11-7: Chronic toxicity in freshwater Invertebrates Decisive Study result for PNEC according to NOEC / EC NOEC / EC ECHA ECHA Species Study type Duration (d) 10 10 Nom. / meas. Reference growth [mg/L] reprod. [mg/L] CHEM CHEM WHO MoE individ. joint (2004) (2014) subm. subm. Daphnia Reprod. test acc. 16 d (3-4 0.32 Nominal, semi- -- X -- X Hermens et al., magna to Dutch Standard broods) static (3x/w) (1984) Daphnia Reprod. test acc. until 4 broods 0.317 1.00 Nominal, semi- -- sup- X -- magna to Dutch Standard in controls static (3x/w) por- (reprod.) ting De Wolf et al. (1988) Daphnia Reprod. test acc. 21 d 0.72 Presumably X ------magna to OECD 211 measured MOE Japan. 2003 (1) (1) See J-CHECK

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 92 Table 11-8: Freshwater algae toxicity Decisive Study result for PNEC according to Dura- EC growth EC growth ECHA ECHA Species Study type 50 10 Nom. / meas. Reference tion (h) rate [mg/L] rate [mg/L] CHEM CHEM WHO MoE individ. joint (2004) (2014) subm. subm. Pseudokirchneriella sim. to OECD 201 96 12.50 Nominal, X ------ECHA CHEM (1981)* subcapitata closed system Desmodesmus OECD 201 (RL1) 72 11.40 5.80 Measured, suppor- X -- -- ECHA CHEM (2011) subspicatus sealed ting Pseudokirchneriella sim. to OECD 201 72 29.66 -- Nominal, ------Aruoja et al. (2014) subcapitata sealed * Presumably Galassi and Vighi, (1981)

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 93 For aquatic invertebrates, the result of the reproduction study by Hermens et al. (1984) (16-day NOEC for effects on reproduction) is supported by the NOEC reported by De Wolf et al. (1988) with regard to the endpoint growth reduction. Therefore, the NOEC (Daphnia magna, 16 d, reproduction) of 0.32 mg/L is taken for derivation of a tentative aquatic PNEC.

For freshwater algae, data are mostly restricted to EC50 values, and most data are not reliable because no measures were taken to prevent volatilization from solution. The key study from the joint submission (ECHA CHEM) is the only one giving a reliable EC10 (72 hr, growth rate) value, i.e. 5.8 mg/L. The corresponding EC50 value (72 hr, growth rate) compares well with the result reported by Galassi and Vighi (1981), giving support to the EC10 value.

In conclusion, for the derivation of a tentative aquatic PNEC, chronic data for three trophic levels are available. Fish is the most sensitive species with a NOEC (43 days, early life stages) of 0.247 mg/L. According to REACH guidance on information requirements and chemical safety assessment, part R.10 (ECHA, 2008), an assessment factor of 10 applies to this value, giving the following result (rounded value):

PNECfreshwater (tentative value): 25 µg/L

This value is identical to the one according to the joint submission (ECHA CHEM).

Conclusions: PNECs for comparative assessment

The PNECfreshwater as derived in the registration dossier of the joint submission (ECHA CHEM) (25 µg/L) is reliable and used for the comparative assessment.

11.3 Exposure Assessment

11.3.1 Exposure scenario

EDC is used in a closed system as process chemical (solvent) in the in the chemical synthesis of an active pharmaceutical ingredient. The following use descriptors are assigned to this use:

Exposure scenario: Use as process and extracting solvent in fine chemical processes.

ERC: Industrial use of processing aids in processes and products, not becoming part of articles (ERC 4)

PROC: Use in closed, continuous process with occasional controlled exposure (PROC 2)

Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at dedicated facilities (PROC 8b) (i.e. unloading of road tankers – sampling, maintenance and cleaning activities, which are additional activities to which PROC8b was assigned are not considered here)

Use as laboratory reagent (PROC 15)

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 94 This scenario was used for performing a comparative exposure assessment and risk characterisation. Exposure modelling was done using ECETOC TRA, version 3.1.32

The following DNELs/DMELs and PNECs are used for the comparative risk characterisation (for details see Section 11.2).

Table 11-9: DNELs/DMELs and PNECs used for EDC and alternative substances for the comparative risk characterisation

Substance D(M)NELlong-term inhalation workers D(M)NELlong-term dermal workers PNECfreshwater w EDC 16.7 µg/m3 Not applicable 1100 µg/L DCM 5300 µg/m3 Not applicable 270 µg/L Chlorobenzene 3200 µg/m3 0.46 mg/kg d 25 µg/L

Dermal exposure

ECHA Guidance on Information Requirements and Chemical Safety Assessment, R.14, Appendix R.14- 1, discusses evaporation rates and time required for complete loss of volatile substances from gloves (ECHA, 2012b). For intermittent exposure (due to splashes, as can be assumed here) and substances with vapour pressures of 10,000 Pa (at ambient temperatures) such as cyclohexane the evaporation time is calculated to be 12 seconds only. For toluene with a vapour pressure of approx. 3,000 Pa it is still only 39 seconds.

Therefore, dermal exposures to EDC and DCM with vapour pressures > 50,000 Pa (see table below) are considered negligible, as for all activities with direct contact (sampling procedures, loading, de- loading, maintenance activities; PROC8b) operators wear protective clothing and gloves. Occasional small splashes may occur at most and these are expected to evaporate rapidly from gloves. In addition, direct contact via contaminated gloves when taking them off is not possible; therefore, for the purpose of this comparative assessment inhalation exposure is considered the only relevant pathway for these two substances.

For substances such as chlorobenzene with vapour pressures around 1,200 Pa, the evaporation time according to the guidance document is more than 1 minute. Although exposure will be reduced by volatilisation it cannot be completely excluded and will be modelled below. It is expected that ECETOC TRA modelling will overestimate dermal exposure as it does not consider volatilisation and the reduced contact time.

32 http://www.ecetoc.org/tra

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 95 11.3.2 Input data for exposure modelling

The following data are used for the exposure modelling in the standardised exposure scenario:

Table 11-10: Physico-chemical and environmental fate properties data of alternative substances

Substance Molecular Vapour Log PO/W Biodegra- Water solubility weight (g/Mol) pressure (Pa) dability [mg/L] EDC 98.96 81,300 (20°C) 1.45 Not ready 8,490-9,000 (20 biodegradable °C)

DCM 84.93 58,400 (25°C) 1.25 Ready 13,200 (25°C) biodegradable * Chlorobenzene 112.56 1,173 Pa (20°C) 2.98 Not ready 207 (20°C) biodegradable Source: ECHA CHEM (if not stated otherwise; ECHA, 2015a); data for EDC are from OECD (2002) *In the OECD SIDS report it was concluded that the substance is not readily biodegradable under non-adapted conditions, based on results from several non-standard biodegradation studies. A new OECD 301 D (closed bottle test) study is reported in the registration dossier in ECHA CHEM33, which showed ready biodegradability of the substance

About '#B#'''''' tonnes/year are used on average in the single plant (Kinsale, Ireland) where EDC is used for producing an active pharmaceutical ingredient '#B#''''''' ''''''''''''' '''''''''''''''' '''''''''' ''' '''''''''' '''''''''''''''' ''' '''' ''''''''''''''''''''''' ''''''' '''''''''''''''' ''' '''''''''''''''''' '''' '''''''''''''' '''''''' ''''''' ''''''''''''''''''''''' ''''''''''''''' '''' '''''' '''''''''''''' '''''''' ''''''' ''''''''''''''''''' '''''''''''''''''''''''''''''''''''''''''.

From R&D activities, some information is available about the relative efficiency of the alternatives compared to EDC. Based on this information in the following it is concluded that

∋∋∋∋∋∋∋∋∋∋∋∋∋∋ ∋∋∋∋∋∋∋∋∋∋∋ ∋∋∋∋∋∋∋∋∋ ∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋ ∋∋∋∋∋∋∋ ∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋∋ is required per unit of production.

Therefore, for this assessment, a tonnage of '#B#'''''' tonnes/year is applied for EDC, '#B#''''''' tonnes/year for DCM and '#B#'''''' tonnes/year for chlorobenzene is used for performing the environmental assessment.

The following assumptions were used for modelling:

• Workers assessment:

− PROC 2: exposure duration 8 hrs, indoors, LEV (efficiency 90%), gloves (efficiency 95%) − PROC 8b: exposure duration 1-4 hrs, outdoors, no LEV, respiratory protection (efficiency 95%), gloves (efficiency 95%) − PROC 15: exposure duration 8 hrs, indoors LEV (fume cupboard, efficiency 90%), gloves (efficiency 95%)

33 http://echa.europa.eu/web/guest/home, accessed on 13 October 2014.

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 96 • Environmental assessment:

− ERC 4: Release factors and the number of emission days according to ESVOC SpERC 1.1v1, for annual tonnage used at site see above, STP available, all other conditions (e.g. STP discharge rate, river flow rate) with identical default values.

11.4 Results of the comparative exposure assessment and risk characterisation

The following tables show the results of the comparative exposure assessment and risk characterisation.

11.4.1 Occupational exposure

Similar exposure concentrations are obtained for EDC and dichloromethane with respect to inhalation exposure of workers. However, as risks are substantially lower per exposure unit for DCM compared to EDC, RCRs are much higher for the latter (> factor 200).

Inhalation exposure to chlorobenzene is slightly lower compared to the two other substances (factor 2 to 4). Dermal exposure of chlorobenzene, conservatively estimated, leads to lower RCRs for PROC2 and 15 and a similar RCR for PROC 8b, compared to inhalation exposure to chlorobenzene. Total RCRs are similar for chlorobenzene and for DCM and substantially lower compared to EDC.

Table 11-11: Result of the comparative exposure and risk characterisation, workers EDC DCM Chlorobenzene PROC 2: Exposure concentration, chronic 10.3 mg/m3 8.8 mg/m3 2.4 mg/m3 inhalation RCR inhalation 617 1.7 0.73 Exposure concentration, chronic dermal 0.069 mg/kg d RCR dermal 0.15 PROC 2: RCR combined 617 1.7 0.88 PROC 8b: Exposure concentration, chronic 13.0 mg/m3 11 mg/m3 2.5 mg/m3 inhalation RCR inhalation 0.77 Exposure concentration, chronic dermal 0.41 mg/kg d RCR dermal 0.89 PROC 8b: RCR combined 778 2.1 1.6 PROC 15: Exposure concentration, chronic 20.6 mg/m3 18 mg/m3 4.7 mg/m3 inhalation RCR inhalation 1.46 Exposure concentration, chronic dermal 0.017 mg/kg d RCR dermal 0.037 PROC 15: RCR combined 1,235 3.3 1.5

11.4.2 Environmental exposure

With regard to the environmental assessment, similar exposure concentrations are obtained for 1EDC and the two alternative substances for the freshwater compartment, if calculated with release factors from ESVOC SpERC 1.1.v1. Due to its higher aquatic toxicity, the RCR for chlorobenzene is higher compared to that for EDC by a factor of 16; compared to DCM, the RCR is higher by a factor of

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 97 2. All RCRs in this comparative assessment are below 1. In conclusion, whereas environmental exposures are considered manageable for all substances, chlorobenzene is considered to be less favourable, due to a low PNECfreshwater and DCM is less favourable due to the combined effect of higher amounts of substance required and a lower PNECfreshwater.

Table 11-12: Result of the comparative exposure and risk characterisation, environment EDC DCM Chlorobenzene ERC 4 (ESVOC SpERC 1.1v1) – local PEC, 0.033 mg/L 0.059 mg/L 0.012 mg/L freshwater: RCR 0.030 0.22 0.48

11.4.3 Conclusions

Based on these quantitative considerations, the alternative substances DCM and chlorobenzene seem to be advantageous with regard to human health effects.

In the case of DCM, this conclusion comes from a low assumed carcinogenic potency. Nevertheless, taking into account that the International Agency for the Research on Cancer (IARC) only recently upgraded its carcinogenicity classification for DCM, based on new (albeit limited) findings regarding a potential carcinogenic activity in humans, the substance seems not to be a suitable alternative to EDC:

• Potency considerations are associated with a relevant uncertainty; the exposure-risk relationship used is based on animal experiments and does not include information from epidemiological studies • The substance might be reclassified into Cat 1B according to Regulation (EC) No 1272/2008 in the near future, which would make it a candidate for Authorisation itself and would limit its usability.

In conclusion, DCM, although it appears to be a less potent carcinogen, is not considered a valuable alternative to EDC.

Environmental risks are considered to be slightly higher for the alternative substances, based on the results of the comparative risk assessment, but RCRs for the freshwater compartment in the comparative assessment are below 1 for all substances and seem to be in a manageable range.

In conclusion, chlorobenzene, from a human health and environmental risk perspective is considered to fulfil the requirement of leading to overall reduced risks, when used as an alternative to EDC.

11.5 References for Annex 4

Aruoja, V.; Moosus, M.; Kahru, A.; Sihtmäe, M.; Maran, U. (2014) Measurement of baseline toxicity and QSAR analysis of 50 non-polar and 58 polar narcotic chemicals for the alga Pseudokirchneriella subcapitata Chemosphere, 96, 23-32

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 98 Benbrahim-Tallaa, L.; Lauby-Secretan, B.; Loomis, D.; Guyton, K.Z.; Grosse, Y.; El Ghissassi, F.; Bouvard, V.; Guha, N.; Mattock, H.; Straif, K. (2014) Carcinogenicity of perfluorooctanoic acid, tetrafluoroethylene, dichloromethane, 1,2- dichloropropane, and 1,3-propane sultone The Lancet Oncology, 15, 924-925

Black, J.A.; Birge, W.J.; McDonnell, W.E.; Westerman, A.G.; Ramey, B.A.; Bruser, D.M. (1982) The Aquatic Toxicity of Organic Compounds to Embryo-larval Stages of Fish and Amphibians University of Kentucky Water Resources Research Institute

Brack, W.; Rottler, H. (1994) Toxicity testing of highly volatile chemicals with green algae: a new assay Environmental Science and Pollution Research International, 1, 223-228

Bringmann, G.; Kühn, R. (1978) Grenzwerte der Schadwirkung wassergefährdender Stoffe gegen Blaualgen (Microcystis aeruginosa) und Grünalgen (Scenedesmus quadricauda) im Zellvermehrungshemmtest Vom Wasser, 50, 45-60

BUA, Beratergremium für umweltrelevante Altstoffe (1991) Chlorbenzol, BUA-Stoffbericht 54 VCH Verlag Weinheim

Canadian Environmental Protection Act (1993) Priority Substances List Assessment Report. Dichloromethane Minister of Supply and Services Canada

Canadian Environmental Protection Act (1994) Priority Substances List Assessment Report. 1,2-Dichloroethane Minister of Supply and Services Canada

De Wolf, W.; Canton, J.H.; Deneer, J.W.; Wegman, R.C.C.; Hermens, J.L.M. (1988) Quantitative structure-activity relationships and mixture-toxicity studies of alcohols and chlorohydrocarbons: reproducibility of effects on growth and reproduction of Daphnia magna Aquatic Toxicology, 12, 39-49

DFG, Deutsche Forschungsgemeinschaft (2014) MAK- und BAT-Werte-Liste 2014. Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe. Mitteilung 50 WILEY-VCH Verlag GmbH, Weinheim

ECHA, European Chemicals Agency (2008) Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://guidance.echa.europa.eu/

ECHA, European Chemicals Agency (2012a) Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version: 2.1 online: http://echa.europa.eu/documents/10162/17224/information_requirements_r8_en.pdf

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 99 ECHA, European Chemicals Agency (2012b) Guidance on information requirements and chemical safety assessment. Chapter R.14: Occupational exposure estimation. Version: 2.1 Helsinki, Finland

ECHA, European Chemicals Agency (2015a) Information on Chemicals - Registered Substances Online: http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances

ECHA, European Chemicals Agency (2015b) Application for Authorisation: Establishing a Reference Dose Response Relationship for Carcinogenicity of 1,2-Dichloroethane. RAC/33/2015/09 Rev1 Final Helsinki, Finland

EPA, Environmental Protection Agency (1988) Review of Environmental Contamination and Toxicology. Vol. 106 Springer-Verlag New York-Berlin-Heidelberg-London-Paris-Tokyo

EPA, Environmental Protection Agency (2015) Integrated Risk Information System (IRIS) online: http://www.epa.gov/IRIS/

Faisal Siddiqui, M.; Ahmad, R.; Ahmad, W.; Hasnain, A.U. (2006) Micronuclei induction and chromosomal aberrations in Rattus norvegicus by chloroacetic acid and chlorobenzene Ecotoxicology and Environmental Safety, 65, 159-164

Galassi, S.; Vighi, M. (1981) Testing toxicity of volatile substances with algae Chemosphere, 10, 1123-1126

Greim, H. (1995) Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK- Werten, Loseblattsammlung, 21. Lfg DFG Deutsche Forschungsgemeinschaft, VCH Verlag Weinheim

Greim, H. (2001) Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK- Werten, Loseblattsammlung, 33. Lfg DFG Deutsche Forschungsgemeinschaft, WILEY-VCH Verlag Weinheim

Hermens, J.; Canton, H.; Janssen, P.; De Jong, R.G. (1984) Quantitative structure-activity relationships and toxicity studies of mixtures of chemicals with anaesthetic potency: Acute lethal and sublethal toxicity to Daphnia magna Aquatic Toxicology, 5, 143-154

HSE, Health and Safety Executive (2008) DRAFT EH64 ENTRY FOR CHLOROBENZENE, WATCH/2008/2 ANNEX 2 (Last reviewed 1999, First published 1993 (C54), Amended 2002, 2008) http://www.hse.gov.uk/aboutus/meetings/iacs/acts/watch/140208/chlorobenzenea2.pdf

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 100 IARC, International Agency for Research on Cancer (1999) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 71. Re-Evaluation of some Organic Chemicals, Hydrazine and Hydrogen Peroxide (Part 1-3) WHO, World Health Organization, Geneva

IFA, Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (2015) GESTIS-Stoffdatenbank. Gefahrstoffinformationssystem der Deutschen Gesetzlichen Unfallversicherung http://www.dguv.de/ifa/de/gestis/stoffdb/index.jsp

John, J.A.; Hayes, W.C.; Hanley, T.K.; Johnson, R.A.; Gushow, T.S.; Rao, K.S. (1984) Inhalation teratology study on monochlorobenzene in rats and rabbits Toxicology and Applied Pharmacology, 76, 365-373

Mennear, J.H.; McConnell, E.E.; Huff, J.E.; Renne, R.A.; Giddens, E. (1988) Inhalation toxicology and carcinogenesis studies of methylene chloride in F344/N rats and B6C3F1 mice Annals of the New York Academy of Sciences, 534, 343-351

MoE, Ministry of the Environment Government of Japan (2014) Profiles of the Initial Environmental Risk Assessment of Chemicals. Substance: Monochlorobenzene http://www.env.go.jp/en/chemi/chemicals/profile_erac/index.html

Montelius, J. (2003) Consensus Report for Chlorobenzene In: Montelius, J., Scientific Basis for Swedish Occupational Standards XXIV, Arbete och Hälsa. Arbetsmiljöinstitutet Solna Sweden, 48-54

Nair, R.S.; Barter, J.A.; Schroeder, R.E.; Kuezevich, A.; Stack, C.R. (1987) A two generation reproduction study with monochlorobenzene vapor in rats Fundamental and Applied Toxicology, 9, 678-686

NTP, National Toxicology Program (1986) Toxicology and Carcinogenesis Studies of Dichloromethane (Methylene Chloride) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). TR 306 U.S. Department of Health and Human Services Public Health Service

OECD, Organisation for Economic Co-Operation and Development (2002) SIDS Initial Assessment Report for SIAM 14 (Paris, France, 26-28 March 2002). 1,2-Dichloroethane http://www.chem.unep.ch/irptc/sids/OECDSIDS/indexcasnumb.htm

Samoiloff, M. (1990) Technical methods section. The nematode toxicity assay using Panagrellus redivivus Toxicity Assessment, 5, 309-318

Samoiloff, M.R.; Schulz, S.; Jordan, Y.; Denich, K.; Arnott, E. (1980) A rapid simple long-term toxicity assay for aquatic contaminants using the nematode panagrellus redivivus Canadian Journal of Fisheries and Aquatic Sciences, 37, 1167-1174

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 101 SCOEL, Scientific Committee for Occupational Exposure Limits (2003) Recommendation from the Scientific Committee on Occupational Exposure Limits for Monochlorobenzene. SCOEL/SUM/42, January 2003 EC, European Commission

SCOEL, Scientific Committee on Occupational Exposure Limits (2009) Recommendation from the Scientific Committee on Occupational Exposure Limits for Methylene chloride (dichloromethane). SCOEL/SUM/130 June 2009 European Commission, Employment, Social Affairs and Inclusion http://ec.europa.eu/social/keyDocuments.jsp?type=0&policyArea=82&subCategory=153&country=0 &year=0&advSearchKey=recommendation&mode=advancedSubmit&langId=en

van Leeuwen, C.J.; Adema, D.M.M.; Hermens, J. (1990) Quantitative structure-activity relationships for fish early life stage toxicity Aquatic Toxicology, 16, 321-334

WHO, World Health Organization (2004) Concise International Chemical Assessment Document No. 60. Chlorobenzenes Other than Hexachlorobenzene: Environmental Aspects Geneva

Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 102 12 Annex 5 – Theoretical conversion timeline

2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030

Lilly Solvent Selection Committee Feasibility Testing Solvent Selection Committee continue to monitor for incl. evaluation of solvent alternatives to EDC impact on API Step

R&D A suitable alternative solvent is discovered and becomes Lab Scale Up commerically available in 2025 incl. optimisationstudies

Design Space Studies

EHS Evaluation

EHS Evaluation of Modified Process: ● Process safety and chemical agents risk assessments ● Environmental impact of waste streams

C & Q PV Commissioning & Qualification Process Validation MANUFACTURING Engineering modifications & qualification of new equipment required to complete plant conversion

Method Development

New methods requries for the following at a minimum: ● New solvent specifications ● Residual solvents & crystal form in intermediate step LABQC &

ANALYTICAL ● In process methods e.g. reaction completion ● Residual solvents in API

Vendor Evaluation Major Variation to Marketing Authorisations ● Preparation of Regulatory Submission Identification & evaluation of suitable ● Approval time in all Markets sources of raw material that meets the requried quality attributes QUALITY&

REGULATORY Stability Studies Stability study on API from modified route

Figure 12-1: Theoretical implementation timeframe outlining the steps required to Introduce a commercially available solvent into an existing manufacturing process Key assumption: no additional toxicology studies are required on the API or new solvent, if these were required the timeline would be lengthened

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Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 104 13 Annex 6 – Justifications for confidentiality claims

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

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Use number: 1 Legal name of applicant(s): Eli Lilly S.A. Irish Branch 106