ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC

ANALYSIS OF ALTERNATIVES

and

SOCIO-ECONOMIC ASSESSMENT

Legal name of applicant(s): Bracco Imaging s.p.a

Submitted by: Bracco Imaging s.p.a.

Substance: bis(2-methoxyethyl) ether (diglyme):

EC 203-924-4: CAS 111-96-6

Use title: Use of bis(2-methoxyethyl) ether (diglyme) as a processing

aid in the purification of 5-amino-2,4,6-triiodoisophthalic

acid dichloride (EC 417-220-1; CAS 37441-29-5) by

precipitation.

Use number: 1


USE NUMBER: 1 BRACCO IMAGING S.P.A

2

CONTENTS

LIST OF ABBREVIATIONS 5

DECLARATION 6

1 SUMMARY 7

2 ANALYSIS OF SUBSTANCE FUNCTION 9

2.1 X-RAY CONTRAST IMAGING AGENTS 9

2.1.1 Iodine-based contrasting agent 10

2.2 SYNTHESIS ROUTE 12

2.2.1 Common Building Block 12

2.2.2 Injectable Active Pharmaceutical Ingredient (API) 13

2.2.3 Synthesis Development 13

2.2.4 Bracco Imaging s.p.a. Synthesis Route for 5-amino-2,4,6-triiodoisophthalic acid

dichloride 15

2.3 TECHNICAL FUNCTION AND SPECIFICATIONS OF DIGLYME 16

2.3.1 Chemical functionality 16

2.3.2 Process functionality 17

3 ANNUAL TONNAGE 19

4 IDENTIFICATION OF POSSIBLE ALTERNATIVES 20

4.1 LIST OF POSSIBLE ALTERNATIVES 20

4.2 DESCRIPTION OF EFFORTS MADE TO IDENTIFY POSSIBLE ALTERNATIVES 20

4.2.1 Research and development 20

4.2.2 Data searches 21

4.2.3 Consultations 21

5 SUITABILITY AND AVAILABILITY OF ALTERNATIVES 22

5.1 ALTERNATIVE SOLVENTS 22



3

5.1.1 Screening against toxicological criteria 22

5.1.2 Screening against physicochemical and commercial criteria 26

5.1.3 Laboratory assessment of selected solvents 32

5.1.4 Detailed assessment of acetone as an alternative solvent 38

5.1.5 Overall Assessment of Alternative Solvents 44

5.2 NEW SYNTHETIC ROUTE FOR IOPAMIDOL 45

6 OVERALL CONCLUSIONS 49

6.1 SUBSTANCE FUNCTION 49

6.2 OVERALL CONCLUSIONS ON ALTERNATIVES 49

7 SOCIO ECONOMIC ANALYSIS 52

7.1 SOCIO-ECONOMIC ANALYSIS (SEA) IN THE CONTEXT OF ADEQUATE CONTROL 52

7.2 THE MOST LIKELY NON-USE SCENARIO 52

7.3 ECONOMIC IMPACT ASSESSMENT 53

7.3.1 Economic impact on Bracco Imaging s.p.a 53

7.3.2 Redundancy costs 53

7.3.3 Loss of profits 53

7.3.4 Decommissioning costs 54

7.3.5 Reduced operational costs 54

7.3.6 Relocation costs 54

7.3.7 Loss of investment in research and development 54

7.3.8 Reputational context 55

7.3.9 Economic impact on the downstream supply chain 55

7.4 SOCIAL IMPACT ASSESSMENT 56

7.5 CONCLUSION 57

7.6 JUSTIFICATION FOR THE REVIEW PERIOD REQUEST 57

TABLES



4

Table 4.1 List of relevant Bracco Imaging s.p.a. Patents 20

Table 5.1 Solvent Criteria Matrix – Classification and Toxicological Profile 23

Table 5.2 Solvent Criteria Matrix – Physicochemical and Commercial Criteria 28

Table 5.3 Solvent Criteria Matrix – Laboratory Process Assessment 34

Table 5.4 Typical impurities in the synthesis of 5-amino-2,4,6-triiodoisophthalic acid chloride 37

Table 5.5 Experimental matrix in the optimisation of the use of acetone as a co-solvent 40

Table 5.6 Addition Sequence Variations 41

Table 5.7 Outstanding uncertainties in the new Iopamidol Synthesis route 47

Table 6.1 Risk Comparison of Identified Alternatives 50

Table 6.3 Summary of review period argumentation 58

FIGURES

Figure 2.1 Structures of Iohexol, Iopromide, and Iothalamate 11

Figure 2.2 Structure of Iopamidol 12

Figure 2.3 Structure of 5-amino-2,4,6-triiodoisophthalic acid 12

Figure 2.4 Synthesis of 5-amino-2,4,6-triiodoisophthalic acid chloride 13

Figure 2.5 Bracco Imaging s.p.a Synthetic Route to Iopamidol 16

Figure 5.1 Illustrative HPLC Purity Profile (at two different detection sensitivities) 38

Figure 5.2 Different synthetic pathway 46

Figure 5.3 Investment Cost for alternative synthetic route for Iopamidol Synthesis 48

Figure 6.1 Overview of the main non-use socio-economic impacts 53



5

LIST OF ABBREVIATIONS

API Active Pharmaceutical Ingredient

CIN Contrast Induced Nephropathy

CT Computer Tomography

CPME Cyclopentyl methyl ether

IOCM Iso-molar contrast media

LOCM Low osmolar contrast media

MDCT Multi-detector row computer tomography

MIAK Methyl isoamyl ketone (5-methyl-2-hexanone)

MIBK Methyl isobutyl ketone (4-methyl-2-pentanone)

MRI Magnetic Resonance Imaging

SVHC Substance of very high concern

WHO World Health Organisation



6

DECLARATION

We, Bracco Imaging s.p.a , request that the information blanked out in the “public version” of

the Analysis of Alternatives is not disclosed. We hereby declare that, to the best of our

knowledge as of today (05/02/2016) the information is not publicly available, and in accordance

with the due measures of protection that we have implemented, a member of the public should

not be able to obtain access to this information without our consent or that of the third party

whose commercial interests are at stake.

Signature: Date: February 5th

2016 Place: Milan, Italy

Fulvio Uggeri

Head of Global Research & Development

Global Business Unit Imaging

Bracco Imaging s.p.a.



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1 SUMMARY

Bracco Imaging s.p.a. are applying for an Authorisation under REACH for the use of diglyme in

an intermediate synthetic step in the manufacture of the X-ray contrast agent Iopamidol.

Iopamidol is one of the safest contrasting agents available on the market and, since its

introduction in the early 1980’s, has been administered to over 20 million patients per year in 80

different countries.

Diglyme is used as a purification aid in the synthesis of a key intermediate in the production of

Iopamidol but is not present in the final active pharmaceutical product itself.

The technical function of diglyme as a processing aid in the purification of the intermediate 5-

amino-2,4,6-triiodoisophthalic acid dichloride (EC 417-220-1; CAS 37441-29-5) by

precipitation is specific to the chemical synthesis route and the following requirements need to

be fulfilled:

• key physicochemical properties: boiling point, flash point, water solubility and stability

under acidic conditions

• specific process factors: product yield, product purity profile, final product physical

form

• specific final product quality: 5-amino-2,4,6-triiodoisophthalic acid dichloride is a key

intermediate in the synthesis of the active pharmaceutical ingredient (API) Iopamidol and

there are, therefore, specific quality criteria for final product with regard to impurity

profile that must be achieved in a validated synthetic route.

Two alternative approaches were taken to evaluate whether diglyme could be removed from this

synthesis process:

1. Use of an alternative solvent as a direct replacement for diglyme

2. Use of an alternative synthetic pathway for the manufacture of Iopamidol which avoids the

need to generate and isolate 5-amino-2,4,6-triiodoisophthalic acid dichloride.

Both an alternative solvent (acetone) and alternative process chemistry have been identified as

possible methods to achieve a commercially viable manufacturing route for Iopamidol and have

been investigated in detail.

However, there are significant remaining concerns with regard to the impact of such alternatives

on the final product quality of the active pharmaceutical Iopamidol. Additional process costs

and time would be required to determine whether a commercially viable process can be

implemented at full scale and, as the reduction in risk that might be achieved by in comparison

with the current well-controlled process is negligible, this cannot be justified on either risk

reduction or economic grounds at this time.



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Justification for the review period request

After over 30 years process research and development, Bracco Imaging s.p.a. have not identified

an alternative solvent that could be used in the existing process to manufacture the intermediate

in acceptable yield and quality for subsequent conversion to Iopamidol. Research into an

alternative synthetic pathway for Iopamidol that would avoid the need for the current purification

step using diglyme have, to date, not resulted in a commercially viable synthetic route. The

Chemical Safety Report, submitted as part of this Application for Authorisation, demonstrates

that the use of diglyme is adequately controlled, with risk characterisation ratios significantly

less than 1 for all worker contributing and man via the environment scenarios.

Therefore, Bracco Imaging s.p.a. is requesting a review period of 12 years for the use of bis(2-

methoxyethyl) ether (diglyme) as a processing aid in the purification of 5-amino-2,4,6-

triiodoisophthalic acid dichloride (EC 417-220-1; CAS 37441-29-5) by precipitation.

Please note that the phrases ‘Bracco Imaging s.p.a.’ and ‘Bracco’ are used interchangeably

throughout this document.



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2 ANALYSIS OF SUBSTANCE FUNCTION

Diglyme is used by Bracco Imaging s.p.a. as a processing aid in the purification of 5-amino-

2,4,6-triiodoisophthalic acid dichloride (EC 417-220-1; CAS 37441-29-5; Iodoftaluro) by

precipitation. This is a key intermediate in the synthesis of the iodinated X-ray contrasting agent

Iopamidol.

The use of diglyme in this process is a single addition to a heterogeneous reaction mixture.

Diglyme has been selected based on a number of criteria which are dependent on the nature of

the synthesis and this is primarily due to:

• Solvent dissolution capacity for the intermediate 5-sulfinylamino-2,4,6-

triiodoisophthalic acid dichloride

• Solvent water solubility to allow the precipitation of 5-amino-2,4,6-triiodoisophthalic

acid dichloride from the solvent

• Solvent low reactivity with the chlorinating agent, thionyl chloride

• Solvent high flash point, to limit explosive and flammability risk

The overall synthesis route and details of the function of x-ray contrast imaging agents are

outlined (Sections 2.1-2.2.2) in order to place the solvent technical function in context.

2.1 X-RAY CONTRAST IMAGING AGENTS

Contrasting agents are used extensively in health care for the visualisation of bodily tissues in

the course of medical diagnosis, particularly when it is challenging to identify the interface

between two adjacent tissues or tissues in contact with blood or other physiological fluids.

Contrasting agents perform a number of functions, including increase in the computed

tomography (CT) sensitivity, enhanced differentiation between tissues, provision of specific

biochemical information and evaluation of tissue and organ functional performance (Lusic and

Grinstaff, 2013).

CT contrast imaging agents are often injectable pharmaceutical products and are under

continuous development to maximise imaging capabilities, minimise dose requirements and

reduce potential toxicity. Lusic and Grinstaff (2013) have identified general requirements for

such agents for optimal clinical performance.

There are a number of types of contrasting agents:

• Iodine-based contrasting agents;

• Lanthanide contrasting agents;

• Gold nanoparticle contrasting agents;

• Other metallic contrasting agents;



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• Xenon gas as a contrasting agent.

The use of iodine-based contrasting agents is reviewed briefly below to set the context for the

use of diglyme in Bracco Imaging s.p.a.’s synthetic route for the production of one such

contrasting agent.

2.1.1 Iodine-based contrasting agent

Iodine-based contrasting agents have historically been the agents of choice. Iodine has a high

atomic number and therefore achieves a higher level of X-ray attenuation than that observed for

biological tissues. Covalently-bound iodine contrast agents have been the primary option for

commercially available contrasting agents over the last forty years.

There are a range of iodine-based contrasting agents:

• Small molecule iodinated contrasting agents

o Ionic

o Non-ionic

• Nano-particulate iodine-containing contrasting agents

o Liposomal

o Nanosuspensions, nanoemulsions and nanocapsules

o Polymeric nanoparticles

Small-molecule iodinated contrasting agents have been widely used in clinical applications over

the last forty years. Most ionic iodinated contrast agent are negatively charged, have a tendency

to interact with biological structures and aqueous solutions of these substances have high

osmolality, that may lead to renal toxicity and other physiological problems.

Non-ionic iodinated contrast agent have therefore been developed and optimised over the last

thirty years to avoid these problems and they have a lower osmolality and a lower incidence of

adverse health effects. The design of these agents has largely centred around the use of

functional groups attach to an aromatic nucleus, allowing the physicochemical and

pharmacological properties of the molecules to be specifically manipulated to achieve high

water solubility, low binding to biological receptors, low toxicity and high biotolerability.

There are a range of small-molecule iodinated contrast agents approved for medical use:

iohexol, iopromide, iodixanol, ioxaglate, iothalamate and iopamidol.



11

Figure 2.1 Structures of Iohexol, Iopromide, and Iothalamate

Iopamidol is a non-ionic contrast agent which was developed in the early 1980’s and

manufactured by Bracco Imaging s.p.a. The introduction of this agent allowed rapid

advancement in the field of X-ray diagnostics as it was considerably safer than other alternative

ionic contrasting agents available at that time. Iopamidol remains one of the safest X-ray

contrasting agents available and has been administered to over 20 million patients per year in 80

countries, including all member states of the European Union, the United States, Japan and

China. Bracco Imaging s.p.a.’s current annual manufacturing output of Iopamidol in 2014 was

approximately mT .



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Figure 2.2 Structure of Iopamidol

2.2 SYNTHESIS ROUTE

2.2.1 Common Building Block

The synthesis of many of the contrast agents listed above is based upon 5-amino-2,4,6-

triiodoisophthalic acid (EC 252-575-4, CAS 35453-19-1), which is converted to the

corresponding acid chloride as a key intermediate in the synthesis of this class of iodinated

substances.

Figure 2.3 Structure of 5-amino-2,4,6-triiodoisophthalic acid

There are a number of synthesis procedures described in the literature (see Gijsen et al, 1999)

and a variety of synthetic approaches to achieving an industrial scale manufacturing process in

high yield and high purity suitable for subsequent conversion to the final iodinated contrasting

agent.



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2.2.2 Injectable Active Pharmaceutical Ingredient (API)

This synthesis is an intermediate step in the manufacture of the active pharmaceutical ingredient

iopamidol and, as such, is subject to validation of the production process. All process changes

have to be validated through a regulated process which involves the following:

• Full scale production of at least three batches of the synthesis step subject to the proposed

change

• Full scale production of three batches of the following synthetic step in the

manufacturing route

• Full scale production of three batches of the final API, iopamidol.

Each of these batches must achieve the qualifying criteria of compliance to intermediate

specification and compliance to the final specification and impurity profile for iopamidol. This

initial validation of the process change is then continuously validated through the

implementation of an ongoing monitoring plan.

2.2.3 Synthesis Development

The conversion of 5-amino-2,4,6-triiodoisophthalic acid to the acid chloride is accomplished

through the reaction of the acid with thionyl chloride (see Figure 2.4). Thionyl chloride has been

used as both the chlorinating agent and the reaction solvent for the conversion of the isophthalic

acid to the chloride salt, via the N-sulfinyl intermediate.

Figure 2.4 Synthesis of 5-amino-2,4,6-triiodoisophthalic acid chloride

Thionyl chloride as reaction solvent

Thionyl chloride has been used both as the chlorinating agent and as the reaction solvent for the

conversion of the isophthalic acid to the acid chloride salt, via the N-sulfinyl intermediate.

However, use of this reagent as a solvent has given rise to a number of safety concerns, primarily

relating to the difficulties in controlling the method of addition of the reagents, and different

Isophthalic acid N-sulfinyl

intermediate Chloride



14

reaction strategies have been developed to overcome these concerns. There are literature reports

(Gijsen et al, 1999) of the use of thionyl chloride as a reaction solvent.

Use of Co-Solvents

The use of co-solvents in the chlorination reaction has been developed to make the reaction

sequence more controllable, less hazardous during the addition of thionyl chloride, and to avoid

adding a significant excess of the chlorinating reagent. A number of co-solvents have been

identified, such as:

• Ethyl and isopropyl acetates: these were discounted as they produced low conversion

yields and partially decomposed under the acidic reaction conditions.

• Chlorinated solvents: these have been used historically but have since been replaced due

to significant health (suspected carcinogenicity) and environmental (harmful to aquatic

organisms, high volatility and stabity to degradation) concerns.

• A range of aromatic and aliphatic solvents can be used.

Bracco Imaging s.p.a. introduced hydrocarbons ( ) as the co-solvent for the chlorination

reaction (Patent EP 0773924 B1).

Use of Catalysts

The chlorination requires the use of elevated temperatures (up to 90⁰C) and a reaction catalyst to

drive the reaction to completion. The use of elevated temperatures can result in the generation of

a high level of by-products and certain catalysts can undergo decomposition under the reaction

conditions. Dimethylformamide, N-methylmorpholine, tertiary amines, N-methylpyrrolidone

and tetramethylurea have all been proposed as catalysts.

Bracco Imaging s.p.a. use as the reaction catalyst.

Reaction of the amine functionality with thionyl chloride

Thionyl chloride also reacts with the amine functionality of 5-amino-2,4,6-triiodoisophthalic

acid to generate the N-sulfinyl derivative (N-sulfinyl intermediate in Figure 2.4). This

intermediate is relatively stable and can be isolated in its pure form. The hydrolysis can be

achieved by washing the solution of the crude reaction product with another suitable organic

solvent containing water but dissolution of the acid chloride product in the solvent makes

subsequent isolation and purification more difficult.

A successful alternative strategy is to perform the hydrolysis of the N-sulfinyl derivative and

purification of the acid chloride in a single step.

Simultaneous hydrolysis and precipitation process

In most organic solvents the N-sulfinyl derivative is more soluble than the acid chloride.

Addition of water to an organic solvent, in which the N-sulfinyl derivative is more soluble than

the acid chloride, will result in partial precipitation or crystallisation of the acid chloride. As the

acid chloride is being recovered from a solution of the N-sulfinyl derivative, it will always



15

contain some level of N-sulfinyl impurity and a solvent with the optimum balance of solubility

of the N-sulfinyl derivative and insolubility of the acid chloride is required to maximise recovery

and minimise product contamination. Water-miscible co-solvents are therefore used in the

precipitation process.

Bracco Imaging s.p.a. have optimised the precipitation process using diglyme as the organic co-

solvent over 20 years since 1995.

2.2.4 Bracco Imaging s.p.a. Synthesis Route for 5-amino-2,4,6-triiodoisophthalic acid

dichloride

The chlorination of 5-amino-2,4,6-triiodoisophthalic acid is executed in a 4000 L glass-lined

reactor, under nitrogen, using a hydrocarbon as the co-solvent ( ).

The reaction is carried out at 65-850C using an excess of thionyl chloride as the chlorination

agent, in presence of a catalyst. At the end of the reaction, excess thionyl chloride is distilled off

under vacuum.

The resulting suspension of N-sulfinyl derivative of 5-amino-2,4,6-triiodoisophthalic dichloride

in the hydrocarbon is cooled to approximately 500C and diglyme added to preferentially dissolve

this derivative.

Water and sodium hydroxide solution are slowly added to hydrolyse the N-sulfinyl derivative to

the desired 5-amino-2,4,6-triiodoisophthalic acid chloride and to neutralize the strongly acidic

reaction medium. The acid chloride precipitates from the diglyme solution during the addition of

water.

The heterogeneous sludge is isolated by filtration or centrifugation of the 5-amino-2,4,6-

triiodoisophthalic acid. The filter cake is rinsed with water to remove all final residues of

diglyme and then dried.



16

Figure 2.5 Bracco Imaging s.p.a Synthetic Route to Iopamidol

2.3 TECHNICAL FUNCTION AND SPECIFICATIONS OF DIGLYME

Diglyme is used as the co-solvent of preference in the simultaneous dissolution and hydrolysis of

the N-sulfinyl derivative of the acid chloride followed by the final precipitation of the acid

chloride. Diglyme is the preferred co-solvent of choice both for its inherent chemical

characteristics and for the subsequent process advantages that it provides. These characteristics

will be compared with other potential alternative solvents in Section 5. These properties are

summarised in Tables 5.1 – 5.3.

2.3.1 Chemical functionality

Miscibility with the hydrocarbon ( ) and water

Due to the nature of the process, the selected solvent has to be miscible with the hydrocarbon

( ), in order to efficiently dissolve the N-sulfinyl acid chloride derivative, and with

water, to promote the hydrolysis of the N-sulfinyl acid chloride derivative.

Differential Solubility Characteristics for acid chloride and N-sulfinyl derivative

Diglyme as a solvent provides a balance between the solubility of the N-sulfinyl derivative and

insolubility (or limited partial solubility) of the acid chloride. This is to ensure a high efficiency

of extraction of the N-sulfinyl derivative into the diglyme solvent and efficient precipitation of

the acid chloride from the diglyme solvent.



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Thermal Stability

Diglyme is stable over the temperature range at which the synthesis is carried out (20 – 50⁰C).

Solvent Stability under Acidic Conditions

The addition of diglyme occurs under strongly acidic conditions (< pH 2.5). A co-solvent used

in the hydrolysis and precipitation process has to be stable at this pH. Any partial decomposition

of the co-solvent under these acidic conditions will affect the purity of the intermediate and thus

the final product.

Flash Point

Hydrocarbons have low electrical conductivity and can undergo static build-up during processing

operations under high velocity of turbulent conditions. The risk of fire and explosion through

static discharge is reduced by earthing of process equipment and nitrogen blanking. In the

process described here, earthing is not possible on the overall equipment surface, since the

reactors are glass lined. The utilisation of diglyme, which has a relatively high flashpoint (51⁰C),

as a solvent will also further minimise this risk. This is an important consideration in the

selection of a suitable co-solvent in this industrial process.

Reactivity with the carbonyl group of 5-amino-2,4,6-triiodoisophthalic acid dichloride

The amine functional group of the acid chloride can undergo condensation with certain ketones

to generate an imine impurity:

COCl

I

I I

COClN

R2

R1+

COCl

I

I I

COClH2N R2R1

O

R1; R2= alkyl groups

(IV) "Imine"

H2O

The co-solvent used must therefore be inert in this regard. Diglyme, which has a highly

unreactive ether functionality, does not undergo this reaction with the acid chloride and therefore

fulfils this requirement.

2.3.2 Process functionality

Precipitation and Isolation Characteristics

A low impurity acid chloride (intermediate) obtained by precipitation is a key process

intermediate. The nature of the precipitation should be such that the intermediate can easily be

recovered by centrifugation, with a minimum run time for the centrifugation step to produce a



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good cake density with minimum water content. The final parameters required for the acid

chloride intermediate are:

• Purity: ≥ 97.0%

• N-sulfinyl derivative impurity: < 1.0%

• Water content: < 1.0%

The use of diglyme allows the acid chloride to be obtained in very high yield (>92%).

Process Temperature / Boiling Point

The addition of diglyme occurs at 50⁰C and, as such, the co-solvent used in the hydrolysis and

precipitation process has to be stable at the process temperature employed.

The boiling point of diglyme is 162⁰C and therefore significantly above the process temperature.

Diglyme recovery and recycling

Diglyme can be easily and economically recovered and recycled into the synthesis process (see

Section 2.2.4). This recycling reduces the overall annual consumption of the solvent by the

applicant. The recovery process is further described in the CSR. It is estimated that the annual

rate of use of diglyme in the process is the equivalent of metric tonnes per annum. Only

about metric tonnes of virgin diglyme are purchased annually, suggesting a recycling rate of

%.



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3 ANNUAL TONNAGE

Bracco Imaging s.p.a. uses metric tonnes (mT) of diglyme per annum (1.5 mT of diglyme

per batch; batches per annum) but up to % of this is recovered and recycled into the

process. Bracco Imaging s.p.a. maintains an inventory of mt on site ( mt in bulk storage

and mt in process) and purchases on average about mt of diglyme in order to replace

solvent lost from the process to on-site wastewater treatment.

All purchased diglyme is used as a co-solvent in the synthesis of 5-amino-2,4,6-

triiodoisophthalic acid dichloride.



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4 IDENTIFICATION OF POSSIBLE ALTERNATIVES

4.1 LIST OF POSSIBLE ALTERNATIVES

Bracco Imaging s.p.a. have examined two routes for the substitution of diglyme in the synthesis

of 5-amino-2,4,6-triiodoisophthalic acid dichloride:

• Alternative Solvents: screening and testing of solvents that can reproduce the technical

requirements currently fulfilled by diglyme

• Alternative Synthetic Pathway: reconfiguration of the synthetic pathway for

Iopamidol to avoid the need to incorporate the synthesis of the acid chloride as an

intermediate.

4.2 DESCRIPTION OF EFFORTS MADE TO IDENTIFY POSSIBLE ALTERNATIVES

4.2.1 Research and development

Bracco Imaging s.p.a. has been a leader in the synthesis of small-molecule iodinated x-ray

contrast imaging agents for over 80 years.

Bracco Imaging s.p.a. has undertaken a range of research and development activities for the

assessment of different strategies in the synthesis of Iopamidol. A significant internal research

programme was undertaken in the period 2010-2012 to identify alternative solvents that would

be suitable for direct substitution of diglyme and is described in Section 5.

Table 4.1 List of relevant Bracco Imaging s.p.a. Patents

Date of filing

UK Patent Number

EP Number EP

International publication

number WO

Title

11/10/93 2272218A - - Process for the preparation of L—5-(optionally substituted-

amino)2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxy-propylamide)

24/03/97 2311524A - - Preparation of an intermediate for iopamidol

17/05/96 0773924B1 96/374549 Process for the preparation of a dicarboxylic acid chloride

26/04/99 1075462B1 99/058494 Process for the preparation of S-N,N-bis[2-hydroxy-1-

(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropryl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide



21

4.2.2 Data searches

Bracco Imaging s.p.a. has undertaken an extensive literature search on the availability of

alternative co-solvents to diglyme for the synthesis of 5-amino-2,4,6-triiodoisophthalic acid

dichloride. The results of this data search are reported in Section 5.

4.2.3 Consultations

Bracco Imaging s.p.a. has not undertaken any external consultations to identify alternatives

except as identified above as part of their own Research and Development programme.



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5 SUITABILITY AND AVAILABILITY OF ALTERNATIVES

5.1 ALTERNATIVE SOLVENTS

A large number of potential alternative solvents in five solvent classes were identified from

publicly available literature. These solvents classes were alcohols, ethers, glymes, ketones and

other miscellaneous solvents. In order to identify suitable candidates to be taken forward to an

internal laboratory testing programme, solvents were initially screened against key toxicological,

physicochemical and commercial criteria as follows:

• toxicological criteria

o Does the solvent have a more benign profile? (e.g. is already classified as a

SVHC?)

• physicochemical criteria

o Is the solvent incompatible with the drastic acidic conditions used?

o Does the solvent have the required boiling point range?

o Does the industrial use of the solvent pose any additional safety issues?

• commercial criteria

o Is the solvent available for industrial application?

o Is the solvent significantly more expensive than diglyme?

5.1.1 Screening against toxicological criteria

Table 5.1 reviews the screening of solvent candidates based their toxicological profile. Any

solvent whose classification results in identification as a substance of very high concern were not

considered further.



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Table 5.1 Solvent Criteria Matrix – Classification and Toxicological Profile

Group Name CAS EC Hazard Classification REACH Annex XIV

REACH Candidate

List

Removed from Assessment

Current Solvent Bis(2-methoxyethyl) ether 111-96-6 203-924-4 H226, H360FD Yes Yes Current Solvent

AL

CO

HO

LS

1-methoxy-2-propanol 107-98-2 203-539-1 H226, H336 No No No

2-butanol 78-92-2 201-158-5 H226, H319, H335, H336 No No No

Di(propyleneglycol) monomethyl ether 34590-94-8 252-104-2 Not Classified (NC) No No No

ET

HE

RS

1,4-Dioxane 123-91-1 204-661-8 H225, H319, H335, H351 No No Yes - H351

2-methyl tetrahydrofuran 96-47-9 202-507-4 H225, H302, H315, H318 No No No

Cyclopentyl methyl ether 5614-37-9 611-360-9 H225, H302, H315, H319, H412

No No No

Dibutyl ether 142-96-1 205-575-3 H226, H315, H319, H335, H412

No No No

Diisopropyl ether 108-20-3 203-560-6 H225, H336 No No No

Methyl ter-butyl ether 1634-04-4 216-653-1 H225, H315 No No No

Tetrahydrofuran 109-99-9 203-726-8 H225, H319, H335, H351 No No Yes - H351†

GL

YM

ES

Di(propylene glycol) dimethyl ether 111109-77-4 404-640-5 NC No No No

Diethylene glycol dibutyl ether 112-73-2 204-001-9 NC No No No

Ethylene glycol diethyl ether 629-14-1 211-076-1 H225, H319, H360Df No Yes Yes - H360Df



24


REACH Candidate

List


Diethylene glycol diethyl ether 112-36-7 203-963-7 H315 No No No

Ethylene glycol dimethyl ether 110-71-4 234-294-9 H225, H304, H315, H411 No No Yes – H360Fd‡

Propylene glycol dimethyl ether 7778-85-0 404-630-0 H225 No No No

Tetraethylene glycol dimethyl ether 143-24-8 205-594-7 H360 No No Yes - H360

Triethylene glycol dimethyl ether 112-49-2 203-977-3 H360Df No Yes Yes - H360Df

KE

TO

NE

S

2,6-dimethyl-4-eptanone 108-83-8 203-620-1 H226, H335 No No No

2-butanone 78-93-3 201-159-0 H225, H319, H336 No No No

2-hexanone 591-78-6 209-731-1 H226, H336, H361f, H372 No No Yes - H361f

2-methyl-3-hexanone 7379-12-6 230-940-9 H226 No No No

2-methyl-3-pentanone 565-69-5 209-288-4 H225 No No No

2-pentanone 107-87-9 203-528-1 H225, H302, H319 No No No

3,3-dimethyl-2-butanone 75-97-8 200-920-4 H302, H319, H332, H335, H412

No No No

3-methyl-2-butanone 563-80-4 209-264-3 H225 No No No

3-pentanone 96-22-0 202-490-3 H225, H335, H336 No No No

4-methyl-2-pentanone 108-10-1 203-550-1 H225, H319, H332, H335 No No No

5-methyl-2-hexanone 110-12-3 203-737-8 H226, H332 No No No



25


REACH Candidate

List


Acetone 67-64-1 200-662-2 H225, H319, H336 No No No

Cyclohexanone 108-94-1 203-631-1 H226, H332 No No No

OT

HE

RS

1-ethyl-2-pyrrolidone 2687-91-4 220-250-6 H318, H360Df No No Yes - H360Df

1-methyl-2-pyrrolidone 872-50-4 212-828-1 H315, H319, H335, H360D

No Yes Yes - H360D

m-Xylene 108-38-3 203-576-3 H226, H312, H315, H332 No No No

Propylene carbonate 108-32-7 203-572-1 H319 No No No

Toluene 108-88-3 203-625-9 H304, H315, H336, H361d, H373

No No Yes - H361d

†at the time of the assessment the available classification for this substance did not include H351 but the substance was excluded from further consideration of the basis of possible formation of explosive peroxides and low flash point

‡at the time of the assessment the available classification of this substance included H360Fd and so was excluded at that time on this basis.



26

5.1.2 Screening against physicochemical and commercial criteria

Candidate solvents were further screened on the basis of their suitability for industrial

application, which included consideration of their suitability for recycling, any possible safety

issues or further general commercial information about availability or cost which would

adversely impact the economics of the manufacturing process.

For the general class of ketones, additional evaluation considered the potential reactivity of their

carbonyl group with the amino group of 5-amino-2,4,6-triiodoisophthalic acid dichloride to give

the corresponding imine. In order to clarify the behavior of this class of solvents and to acquire

more information on the risk of formation of these impurities, a set of preliminary tests was run

only on a selected group of representative candidates. Six ketones, differing in chemical

structure (linear, cyclic and with branched chains) and molecular weight, were selected to

represent a wide range of solvent properties in term of steric hindrance and lipophilicity. This

allowed further evaluation of the influence of these properties both on the potential formation of

the “imine” impurity and on elimination of the impurity in the subsequent work up.

Candidate solvents were further screened for the following parameters against publically

available data:

• Boiling point: selected solvents are required to have a boiling point similar to diglyme in

order to provide the same or similar opportunities for economic solvent recycling.

Solvents with boiling points > 200⁰C were not further considered on this basis.

• Water Solubility:

• Compatibility with acidic conditions: based on in-house chemical knowledge and

available literature data (e.g. R. P. Pohanish and S. A. Greene, Rapid Guide to Chemical

Incompatibilities, VNR Rapid Guide Series, Wiley, 1997; ISBN-13 978-0-471-28802-2.

Now available as Wiley Guide to Chemical Incompatibilities, 3rd

Edition, 2009, ISBN

978-0-470-38763-4)

• Cost: No limiting criteria established but high unit costs factored into the screening

process.

• Commercial availability: the current status of REACH registration of the solvents was

used as a qualifying criteria for commercial availability. Any solvent that has not yet

been registered under REACH or has been registered for intermediate use only was not

considered to be commercially available.



27

• Comparative results with similar substances already tested in phase 3 of the

screening process: some solvents were removed from screening at this stage if similar

substances had already been subject to laboratory assessment and given unfavourable

results (e.g. solvents similar to MIAK and MIBK).

The results of this second level of screening is summarised in Table 5.2.



28

Table 5.2 Solvent Criteria Matrix – Physicochemical and Commercial Criteria

Group Name Vapour pressure

Boiling point (°C)

Water solubility Compatibility

with acidic conditions

Available on Industrial scale


Current Solvent

Bis(2-methoxyethyl) ether 600 Pa @ 20 °C 162 940 g/L @ 20 °C Yes REACH

100-1,000 mt Current solvent

AL

CO

HO

LS

1-methoxy-2-propanol 1,559 Pa @ 25°C 120 > 1000 g/L @ 20 °C Yes REACH 100,000-1,000,000 mt

No

2-butanol 2,320 Pa@ 25°C 99.5 Yes REACH 100,000-1,000,000

No

Di(propyleneglycol) monomethyl ether

2,500 Pa@ 20°C 189.6 Infinitely soluble @ 25 °C

Yes REACH 10,000-100,000

No

ET

HE

RS

2-methyl tetrahydrofuran 13,500 Pa @ 20°C 34,500 Pa @ 50°C

78 140 g/L (no temperature

specified)

Yes REACH 100-1,000 mt

No

Cyclopentyl methyl ether 4,270 Pa @ 25 °C 105 - 107 12.5 g/L @ 20 °C Yes REACH 10-100 mt

No

Dibutyl ether 640 Pa @ 25 °C 140.2 0.113 g/L @ 20 °C Yes1 REACH 1,000-10,000

Yes Poor Water solubility, limited acid stability and comparison

with results for cyclopentyl methyl ether (Tier 3 screen)

1 R. P. Pohanish, S. A. Greene, Rapid Guide to Chemical Incompatibilities, VNR Rapid Guide Series, Wiley, 1997; ISBN-13 978-0-471-28802-2. Now available as Wiley Guide to Chemical Incompatibilities, 3rd Edition, 2009, ISBN 978-0-470-38763-4



29


Boiling point (°C)





Diisopropyl ether 19,865 Pa @ 25 °C 68.2 1-10 g/L @ 20 °C Yes REACH 1,000-10,000

Yes Risk of explosive peroxide

formation1 and low flash point

Methyl ter-butyl ether 33,000 Pa @ 25 °C 55.3 41.85 g/L @ 20 °C Yes1 REACH 1,000,000-10,000,000 mt

Yes Risk of explosive peroxide

formation1

GL

YM

ES

Di(propylene glycol) dimethyl ether

107.99 @ 25 °C 175 526 g/L @ 20 °C Yes REACH 100 mt

No

Diethylene glycol dibutyl ether 0.26 Pa at 20 °C 252 2.8 g/L @ 20°C Yes1 REACH 100-1,000 mt

Yes High boiling point

Diethylene glycol diethyl ether 510 Pa @ 20 °C 188 ≥ 1000 g/L @ 25 °C Yes REACH 100-1,000 mt

No

Propylene glycol dimethyl ether 6900 Pa @ 25 °C 97 895 g/L @ 20 °C Not known NONS submission Tonnage Not disclosed

Yes Not commercially available and

high cost

KE

TO

NE

S Acetone 53,000 Pa @ 40 °C 56.05 Miscible Yes REACH

1,000,000-10,000,000 mt No

2-butanone 12,600 Pa @ 25°C 79.6 >10 g/l Yes1 REACH 100,000-1,000,000 mt

No

1 R. P. Pohanish, S. A. Greene, Rapid Guide to Chemical Incompatibilities, VNR Rapid Guide Series, Wiley, 1997; ISBN-13 978-0-471-28802-2. Now available as Wiley Guide to Chemical Incompatibilities, 3rd Edition, 2009, ISBN 978-0-470-38763-4



30


Boiling point (°C)





3-pentanone 3,445 Pa @ 19.2 °C 100 - 101 45.6 g/L @ 25 °C Yes1 REACH Confidential tonnage

No

4-methyl-2-pentanone 2,640 Pa @ 25°C 116 - 118 14.1 g/L @ 20 °C Yes1 REACH 10.000-1,000,000 mt

No

5-methyl-2-hexanone 665 Pa @ 25 °C 144 5.4 mg/L @ 25 °C Yes REACH 1,000-10,000 mt

No

Cyclohexanone 700 Pa @ 30 °C 153.4 86 g/L @ 20 °C Yes REACH 1,000,000-10,,000,000 mt

No

2,6-dimethyl-4-eptanone 225 Pa @ 25 °C 168.26 0.43 g/L @ 25 °C Intermediate (no strong

acids)1

REACH 1,000-10,000 mt

Yes Excluded on the basis of

negative MIBK and MIAK results

2-methyl-3-hexanone Not available Not available

Not available Not known Not REACH Registered Yes Excluded on the basis of

negative MIBK and MIAK results

Not Commercially available

2-methyl-3-pentanone Not available Not available

Not available Not available Not REACH registered Yes Not commercially available



31


Boiling point (°C)





2-pentanone 3,280 Pa @ 20 °C 102.7 72.6 g/L @ 20 °C Yes REACH 100-1,000 mt


negative results obtained with 3-pentanone, 2-butanone and

MIBK

3,3-dimethyl-2-butanone Not available Not available

Not available Not available Not REACH registered Yes Not commercially available

3-methyl-2-butanone 7,028 Pa @ 25 °C 93 8.21 g/L @ 20 °C Yes REACH 10-100 mt


negative results obtained with 2-butanone and MIBK

OT

HE

RS

m-xylene 1,427 Pa @ 29.44 °C 144.5 0.146 g/L @ 25°C Yes REACH 100,000-1,000,000 mt

No Further tested despite poor water

solubility for information

Propylene carbonate 6 Pa @ 25 °C 243 174.8 g/L @ 25 °C Yes REACH > 1,000 mt

No Included in the screening despite

the high boiling point for information purpose



32

5.1.3 Laboratory assessment of selected solvents

Solvents selected from the first two screening exercises were then evaluated in a standard

laboratory protocol for direct comparison with diglyme under similar conditions.

Standard Protocol:

Testing was carried out on a laboratory scale using the same process conditions as the current

industrial procedure using diglyme.

Assessment:

The following criteria were used for the comparison of solvent performance:

• Solubility of the reaction mixture at the end of the thionyl chloride distillation (N-

sulfinyl derivative of 5-amino-2,4,6-triiodoisophthalic acid dichloride suspension in

): the solvent is considered suitable for this process if, on addition, it achieves

the complete dissolution of the reaction mixture at the end of the thionyl chloride

distillation, without formation of insoluble residues.

• Overall process yield for the synthesis of 5-amino-2,4,6-triiodoisophthalic acid

dichloride: the process yield with diglyme is >92% and a solvent was considered to have

achieved this criterion if a minimum yield of 92% was determined.

• Purity profile of 5-amino-2,4,6-triiodoisophthalic acid dichloride: a purity of about

98.5% (w/w) is achieved using diglyme and a solvent was considered to have achieved

this criterion if the specification limit is fulfilled (a minimum purity of 97%) and if no

new unknown impurities are detected in the impurity profile

• Maximum level of N-sulfinyl derivative of 5-amino-2,4,6-triiodoisophthalic acid

dichloride in 5-amino-2,4,6-triiodoisophthalic acid dichloride: the specification for



33

this is <1% (w/w) and a solvent was considered to have achieved this criterion if the

specification limit was fulfilled .

• Precipitated form of 5-amino-2,4,6-triiodoisophthalic acid dichloride and ease of

isolation: the product must be obtained in a filterable form and with the appearance of a

free flowing powder after drying.

The results of this laboratory process assessment in summarized in Table 5.3.



34

Table 5.3 Solvent Criteria Matrix – Laboratory Process Assessment

Group Name Dissolution of the reaction mixture

Process Yield

Purity Profile*

New impurities

Residual N-sulfinyl

acid chloride**

Final solid quality Comments

Current Solvent

Bis(2-methoxyethyl) ether

Complete >92%

( %) 98.4% 1.0% Powder Current solvent

AL

CO

HO

LS

1-methoxy-2-propanol No dissolution 94.9% 98.5% Sulfite esters 1.1% Powder High residual N-sulfinyl acid chloride Formation of sulfite esters† during N-

sulfinyl hydrolysis, potentially remaining in traces in the product and

problematic for solvent recycling

2-butanol No dissolution 92.3% 97.6% Sulfite esters 3.9% Powder

Di(propyleneglycol) monomethyl ether

No dissolution NA 99.1% Sulfite esters 2.0% Oily powder

(presence of dodecane)

ET

HE

RS

2-methyl tetrahydrofuran

Complete 56.0% 97.6% No 2.9% Powder Very low yield

High residual N-sulfinyl acid chloride

Cyclopentyl methyl ether

Not complete; formation of

insoluble residue 84.3% 98.8% No 4.6% Powder

Poor reaction mixture dissolution and formation of insoluble residues

High residual N-sulfinyl acid chloride Low yield

GL

YM

ES

Di(propylene glycol) dimethyl ether


insoluble residue 78.6% 98.6% No 3.0% Powder Poor reaction mixture dissolution and

formation of insoluble residue Low Yield

High residual N-sulfinyl acid chloride Unsatisfactory final solid aspect

Diethylene glycol diethyl ether


insoluble residue 80.5% 98.0% No 1.9%

Oily powder (presence of dodecane)



35


Process Yield

Purity Profile*

New impurities

Residual N-sulfinyl

acid chloride**


KE

TO

NE

S

2-butanone Complete 91.5% 98.0% Yes

Imine 3.8% Powder

High residual N-sulfinyl acid chloride Formation of Imine

3-pentanone Not complete 82.5% 98.4% Yes

Imine 2.9% Powder

Uncomplete reaction mixture dissolution Low Yield


4-methyl-2-pentanone Not complete; formation of

insoluble residue 76.8% 94.5% No 6.8% Powder

Poor reaction mixture solubility Low Yield Low purity


5-methyl-2-hexanone Complete 75.8% 97.8% Yes

Imine 8.6% Oily powder

Low Yield Imine formation

High residual N-sulfinyl acid chloride Unsatisfactory final solid aspect

Acetone Complete 95.8% 97.6% Yes

Imine 5.6% Powder

Formation of Imine High residual N-sulfinyl acid chloride

Cyclohexanone Complete 60.5% 97.6% Yes

Imine 0.8% Powder

Imine formation (very high content)

Low yield

OT

HE

RS

M-xylene Not complete,

insoluble residue formation

60.3% 98.0% No NA Oily powder

Incomplete dissolution of N-sulfinyl acid chloride

Low Yield Oily final product, impossible to dry



36


Process Yield

Purity Profile*

New impurities

Residual N-sulfinyl

acid chloride**


Propylene carbonate Not complete,

insoluble residue formation

NA 97.8% Yes, due to

solvent decomposition

NA Oily powder

Oily final product, impossible to dry Unacceptable impurity profile due to

solvent decomposition during work-up

*Purity is determined by HPLC analysis **Residual N-sulfinyl acid chloride content is determined by iodometric titration N.B. Because these two parameters are determined by different analytical methodologies the sum of [purity(%) + N-sulfinyl content(%)] will not equate to 100% exactly.

† Alcohols can react with N-sulfinil groups or with traces of thionyl chloride to form sulfite esters:

and

R OH ROS

OR

O

Ar-NSOR OH RO

SOR

O

SOCl2



37

Product Impurity Profile

The following table lists the typical range of impurities found in this synthesis and an example of

the HPLC analysis (HPLC conditions reported in patent n. EP0773924).

Table 5.4 Typical impurities in the synthesis of 5-amino-2,4,6-triiodoisophthalic acid

chloride

Compound Chemical structure Retention time

(min) Relative

retention time

Carboxylic acids

and

0.6 0.08

7.0 0.92

5-amino-2,4,6-triiodoisophthalic acid chloride

REACTION PRODUCT

7.5 1.00

8.3 1.10

Amide impurity 9.7 1.28

Anhydride impurity 12.3 1.63

COCl

COClH2N

II

I



38

Figure 5.1 Illustrative HPLC Purity Profile (at two different detection sensitivities)

5.1.4 Detailed assessment of acetone as an alternative solvent

Acetone is the only solvent that emerges from the three tiered screening process as a potential

alternative solvent for diglyme in this synthetic process, despite the propensity for imine

formation with this ketone as described above. Acetone has been reported in the literature

(Gijsen et al, 1999) as a solvent in the isolation of 5-amino-2,4,6-triiodoisophthalic acid

dichloride in high yield and purity, with the presence of any imine impurity surprisingly not

cited.

Five other ketones were also include in the Tier 3 screening process, as reported above, with

increasing molecular weight with both linear and branched chains, in order to evaluate ketones

with a higher flash point than acetone.

However, acetone was the most effective alternative solvent, demonstrating:



39

• excellent dissolution of the reaction mixture containing N-sulfinyl derivative of 5-amino-

2,4,6-triiodoisophthalic acid dichloride

• hydrolysis to produce the 5-amino-2,4,6-triiodoisophthalic acid dichloride in good yield

• good powder form for subsequent isolation.

Two significant quality issues remained when used under the same process conditions as

diglyme:

• higher than specification levels of the N-sulfinyl derivative of 5-amino-2,4,6-

triiodoisophthalic acid dichloride in the 5-amino-2,4,6-triiodoisophthalic acid dichloride

• presence of the imine impurity, which is not present in the product currently

manufactured using diglyme.

Further optimization studies were therefore carried out with acetone as the processing aid in the

isolation of the acid dichloride to determine whether these impurity levels could be controlled

and reduced to levels acceptable for the development of a robust commercial process.

The following process parameters were therefore evaluated:

• amount of water and profile of water addition

• the temperature at which the hydrolysis/precipitation process is performed

• addition procedure.

The experimental conditions and results are summarized in the tables below.



40

Table 5.5 Experimental matrix in the optimisation of the use of acetone as a co-solvent

Experiment Addition sequence Solvent:starting

material (acid) ratio

Temperature of reaction mixture on

solvent addition (⁰⁰⁰⁰C) Water:Solvent ratio

Yield (%)

Residual N-sulfinyl acid chloride

(%)

Imine impurity (%)

Diglyme (reference) Standard >92% %) 1.0 n.d.

1 Standard

2 Standard

3 Literature

4 Process A

5 Process A

6 Process A

7 Process B

8 Process B

9 Process B

10 Process B

11 Process B

12 Process B

13 Process B



41

Table 5.6 Addition Sequence Variations

Step Standard Literature Process A

(Direct Precipitation) Process B

(Inverse Precipitation)

1

2

3

4

5

6 Isolation



43

The results of these optimization studies have demonstrated that a repeatable process with

satisfactory yields and acceptable impurity profile comparable with the procedure with diglyme

can be achieved. A number of process criteria are, however, still problematical in the subsequent

scale of the laboratory process to a full scale process;

1. Dissolution of the N-sulfinyl derivative of 5-amino-2,4,6-triiodoisophthalic acid

dichloride may require longer processing time than experienced in the laboratory, thus

leading to the formation of the imine to a greater extent than detected in the laboratory

scale experiments.

2. Temperature control may be more difficult during the hydrolysis of the N-sulfinyl

derivative of 5-amino-2,4,6-triiodoisophthalic acid dichloride due to the exothermic

nature of the reaction, which may affect the overall impurity profile and, in particular,

lead to imine content greater than that detected in the laboratory scale experiments.

3. Formation of the imine impurity was not completely eliminated and could be limited to

within the range 0.09 – 0.22 % (w/w) in the laboratory scale experiments.

The impact of this impurity upon the final quality and subsequent acceptability of the

Iopamidol contrast agent was therefore further examined. Both the European and US

Pharmacopeia cite a maximum concentration for the presence of free aromatic amines in

Iopamidol of not more than 200 ppm.

Additional experimental testing has demonstrated that the presence of the imine impurity

in 5-amino-2,4,6-triiodoisophthalic acid dichloride at levels not exceeding 0.2% (w/w)

does not affect the quality of Iopamidol as it is removed through hydrolysis and

elimination to the mother liquors of the subsequent synthesis steps. However, if present

at higher levels (>0.5%, w/w), the imine cannot be completely eliminated and could lead

to out of specification levels of 5-amino-N,N’-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-

2,4,6-triiodobenzene-1,3-dicarboxamide, a known impurity which is subject to the

control mentioned above in final Iopamidol.

4. Increase in fire and explosion risk: the use of an hydrocarbon ) as a process

solvent poses a risk of static discharge during normal processing, due to the very low

electrical conductivity of the hydrocarbon. The risk of fire and explosion of solvent

vapour from static discharge in controlled via

a. Nitrogen inertion

b. Use of co-solvent with a high flash point. Acetone has a significantly lower

flashpoint that diglyme (-17⁰C compared with 51⁰C). The use of acetone is

therefore considered to increase overall process risk under conditions where

inertion is lost or cannot be maintained.



44

5. Solvent recovery: the literature reports examples of reactions between thionyl chloride

and acetone or methyl ketones, describing the formation of condensation or chlorination

products (Adiwidjaja et al, 1980; Pizeya et al, 1980; Hu et al, 2005; Loth et al, 1894).

Moreover, Bracco Imaging s.p.a. has laboratory evidence to indicate that acetone can

react exothermically with thionyl chloride. In the process in subject thionyl chloride is

removed by distillation before acetone addition; nevertheless residual small amounts or

traces of thionyl chloride can still be present in the reaction mixture at the end of the

distillation and could potentially react with acetone forming impurities, which may pose

additional quality, environmental or health problems during solvent recovery and re-use,

if such impurities have significant toxicity and accumulate during the solvent recovery

and recycling process. No study has been made yet of the acetone recovery process from

this reaction system and its hazard and economic profile.

5.1.5 Overall Assessment of Alternative Solvents

Reduction of overall risk due to transition to an alternative solvent

The Chemical Safety Report submitted as part of this Authorisation Application clearly

demonstrates that this use of diglyme is adequately controlled by the application of the hierarchy

of controls as follows:

• Engineering design: fully contained processing plant with limited opportunity for

exposure to diglyme.

• Containment and treatment of environmental emissions: a) emissions to air treated

through wet scrubbing or thermal oxidation process; b) emissions to water treated

through on-site biological waste water treatment plant.

• Detailed management procedures and training for the handling, storage and use of

diglyme.

• Use of Personal Protective Equipment as a measure of last resort to mitigate any potential

exposure.

The current overall risk to workers and to man via the environment is therefore already

demonstrated to be extremely low through on-site monitoring programme and quantitative and

qualitative assessments of exposure patterns described in detail in the CSR.

Bracco Imaging s.p.a. have undertaken an extensive research programme to identify a suitable

replacement solvent that can provide the same technical function, process capabilities and

economics for the large scale production of 5-amino-2,4,6-triiodoisophthalic acid dichloride.

Even if such a solvent were identified there would be no reduction in overall risk compared to

the current production operation as the risks are already very low.



45

Acetone has been identified from this extensive research and development programme as the

only potential solvent that might be used to give a robust commercial production process

resulting in comparable yield, purity profile and operability and which would not compromise

the final quality of the active pharmaceutical product, Iopamidol. However, implementation of

this solvent alternative still requires significant development work in

a. transforming the laboratory-based process onto the commercial production scale on an economic basis that does not increase operational risk. Bracco Imaging s.p.a.

have concerns about the use of a solvent of low flash point in the current equipment

configuration and have no further substantive data with regard to the potential reaction

of acetone with thionyl chloride, the generation of impurities and the impact this

would have on the economics of the solvent recovery process and on environment.

b. the control of intermediate product quality on the large scale: although the

laboratory studies indicate this may be possible, the impact of impurity carryover to

the final API and the potential need for final product revalidation has not been

examined in detail.

Availability

The commercial availability of alternative solvents was one of the screening criteria used in the

evaluation. Acetone, as the primary alternative candidate, is, of course, commercially available.

Conclusion on suitability and availability for Alternative Solvent

Given that there is no reduction in health risk to be obtained from solvent replacement and

potential increase final API product quality risk and possibly in process safety, Bracco Imaging

s.p.a. conclude the none of the alternative solvents examined offer any significant overall risk

reduction which would justify further investment in research and development at this time to

develop a commercially viable process alternative.

5.2 NEW SYNTHETIC ROUTE FOR IOPAMIDOL

Bracco Imaging s.p.a. have also conducted a thorough lab-scale study has been conducted to

develop a completely new synthetic pathway in order to allow the formation of amide bonds on

isophthalic acid groups without proceeding through the acyl chlorides, and therefore without

using thionyl chloride, hydrocarbons and diglyme.

The study led to the identification of the candidate synthesis in Figure 5.1, which is partly

covered by patent application WO2015/067601.



46

Figure 5.2 Different synthetic pathway

NO2

COOHHOOC

NO2

COOn-Bun-BuOOCn-BuOH

cat.

H2

cat.

NH2

COOn-Bun-BuOOC

5-NIPA (1) (2)

OH

OH

H2N

CONH

CONHH2N

OH

OH

OH

OH

CONH

CONHH2N

I I

I

O

B

O

O

B

O

ICl

COCl

OCOCH3

CONH

CONHH2N

OH

OH

OH

OH

I I

I

CONH

CONHCONH

OH

OH

OH

OH

I I

IOH

IOPAMIDOL

BHO OH

(6)

Alkaline hydrolysis

(7)

CONH

CONHCONH

OH

OH

OH

OH

I I

IOCOCH3

a)

b) H2O

(3)

(4) (5)

Considerable experimental effort (more than 3 years and more than 20,000 man-hours of a

multidisciplinary development team) has been devoted to process studies, to the assessment of

process robustness (presently tested up to the scale of 0.5 kg) and to the evaluation of

purity/impurity profile of the batches obtained through this synthetic pathway.

Process engineers in Bracco Imaging s.p.a. have then utilized this data to develop engineering

flow diagrams for the potential process and solvent recovery and cyclograms (diagrams

describing operational sequence and the use (in hours) for each equipment item to allow to

optimization of equipment use and calculation of plant capacity), in order to define the nature

and size of process units needed for the industrial scale production. In concept, a new plant has



47

been designed which would be located in existing buildings in Bracco Imaging s.p.a. Ceriano

site, and which would also make use common equipment from the existing Iopamidol plant,

such as the final purification, final precipitation, centrifugation, and drying and packaging

equipment.

There are, however, a number of additional process and quality issues that still need to be fully

identified and defined before a decision can be taken on whether this alternative process is

technically and economically robust enough to replace the current synthetic route to Iopamidol.

These outstanding issues are itemised in Table 5.4.

Table 5.7 Outstanding uncertainties in the new Iopamidol Synthesis route

Category Parameter Issue

Quality

Impurity profile

The impurity profile shows some differences compared to Iopamidol produced by the existing commercial process, including a new aromatic amine impurity. The impact of these differences on the product specification and subsequent regulatory approval needs to be defined.

Other genotoxic impurities The potential presence and impact of and

derivatives in the final product needs to be defined

Other quality parameters Issues with metal traces and product colour will require resolution.

Health and Safety Use of phenylboronic acid

Phenylboronic acid is used in the process. A number of issues relating to the presence of boron in effluent and potential degradation of phenylboronic acid to needs to be defined.

Business

Plant capacity/suitability Plant capacity and engineering requirements have been estimated on the basis of existing laboratory studies which need to be further confirmed.

Regulatory approval The regulatory approval process for Iopamidol derived from a new process in the different end user geographies need to be fully defined.

However, on the basis of current information available, Bracco Imaging s.p.a. have estimated an

order of magnitude capital investment cost of €55.5 million and implementation time of up to 10

years for this alternative process (Figures 5.3), including completion of the experimental

activities, new plant design and construction, plant start up, process validation, product quality

and stability demonstration, dossier submission to regulatory authorities and regulatory

approvals in all Countries in which Iopamidol is marketed.



48

Figure 5.3 Investment Cost for alternative synthetic route for Iopamidol Synthesis



49

6 OVERALL CONCLUSIONS

6.1 SUBSTANCE FUNCTION

The technical function of diglyme as a processing aid in the purification of the intermediate 5-

amino-2,4,6-triiodoisophthalic acid dichloride (EC 417-220-1; CAS 37441-29-5) by

precipitation is specific to the chemical synthesis route and the following requirements need to

be fulfilled:

• key physicochemical properties: boiling point, flash point, water solubility and stability

under acidic conditions

• specific process factors: product yield, product purity profile, final product physical

form

• specific final product quality: 5-amino-2,4,6-triiodoisophthalic acid dichloride is a key

intermediate in the synthesis of the active pharmaceutical ingredient (API) Iopamidol and

there are, therefore, specific quality criteria for final product with regard to impurity

profile that must be achieved in a validated synthetic route.

6.2 OVERALL CONCLUSIONS ON ALTERNATIVES

Two alternative approaches were taken to evaluate whether diglyme could be removed from this

synthesis process:

1. Use of an alternative solvent as a direct replacement for diglyme

2. Use of an alternative synthetic pathway for the manufacture of Iopamidol which avoids

the need to generate and isolate 5-amino-2,4,6-triiodoisophthalic acid dichloride.

Both an alternative solvent (acetone) and alternative process chemistry have been identified as

possible methods to achieve a commercially viable manufacturing route for Iopamidol and have

been investigated in detail.

However, there are significant remaining concerns with regard to the impact of such alternatives

on the final product quality of the active pharmaceutical Iopamidol. Additional process costs

and time would be required to determine whether a commercially viable process can be

implemented at full scale and, as the reduction in risk that might be achieved by in comparison

with the current process is negligible, this cannot be justified on either risk reduction or

economic grounds at this time.

Table 6.1 compares the risk profiles of the two alternatives against existing manufacturing

process.



50

Table 6.1 Risk Comparison of Identified Alternatives

Risk Current Process Alternative Solvent

(Acetone) Alternative synthetic

pathway

Solvent toxicity

Risk mitigated by closed processing and procedures. Demonstration of adequate

control

Not present Not present

Explosion due to static discharge

Risk mitigated by: equipment earthing

nitrogen inertion solvent high flash point

The solvent is not flammable

at the process temperature even in the presence of static

discharge

Risk mitigated by: equipment earthing

nitrogen inertion

The solvent is flammable at

process temperature in presence of static discharge

placing greater reliance on risk mitigation through additional

engineering measures

Not present

Quality of Iopamidol, final

active pharmaceutical

No quality risk

Higher potential levels of impurity 5-amino-N,N’-bis[2-

hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-

triiodobenzene-1,3-dicarboxamide in final API

Carry over of impurities from the reaction of acetone and

thionyl chloride

Different impurity profile

Potential presence of genotoxic impurities

Resolution of quality issues concerning metal traces and

final product colour

Environmental release

Very low risk Mitigation by on-site waste water treatment plant and

scrubbing/thermal oxidation of air emissions

Potential for formation of toxic product from acetone and

thionyl chloride which may not be treatable through

WWTP

Efficiency of phenylboronic acid recovery and extent of

degradation to unknown

Complete lifecycle risk

evaluation

Risks associated with production and

transportation of diglyme None identified

Risk associated with production of phenylboronic acid as benzene is used as a

raw material



51

Risk Current Process Alternative Solvent

(Acetone) Alternative synthetic

pathway

Business risk Low

Medium, derived from process safety and final product

quality risk. Revalidation of manufacturing process

High, derived from process safety and final product

quality risk.

High capital investment costs.

Regulatory approval required



52

7 SOCIO ECONOMIC ANALYSIS

7.1 SOCIO-ECONOMIC ANALYSIS (SEA) IN THE CONTEXT OF ADEQUATE CONTROL

The submission of an SEA is not mandatory for applicants following the ‘adequate control’

route. Bracco has not provided a full monetized SEA for the following reasons.

• The procedure for Applications for Authorisation (AfA) by the adequate control

route has been followed meticulously;

• There is no doubt in Bracco’s opinion that the adequate control of diglyme in this use

has been demonstrated;

• This is supported through quantitative monitoring for inhalation exposure and

qualitative modelling for dermal exposure;

• As the exposure levels for all workers and man via the environment are well below

the risk characterisation ratio of 1 in all cases, there is no human health impact from

Bracco’s use of diglyme; and

• Cessation of use of diglyme in this case would not provide any human health benefit.

Detail economic modelling to determine the most likely non-use scenario is deemed

disproportionate where adequate control has been clearly demonstrated. Instead, an outline of

key socio-economic considerations is presented.

This chapter is only included in case that, for some unforeseen reason, RAC disagrees with the

case for adequate control. In this event, Bracco is prepared to provide SEAC with additional

data, based on the following key socio-economic argumentation.

7.2 THE MOST LIKELY NON-USE SCENARIO

It has been clearly demonstrated in the AoA that there is currently no economically or

technically feasible alternative solvent that Bracco could use as a replacement for diglyme in the

synthesis of the key intermediate 5-amino-2,4,6-triiodoisophthalic acid dichloride. This

intermediate is used subsequently in a further two step synthesis for the manufacture of the final

active pharmaceutical ingredient, Iopamidol. Bracco is the original developer and world leader

in the manufacture of Iopamidol.

In the event that Bracco is not granted Authorisation, the non-use scenario would involve the

closure of EU-based Iopamidol API synthesis. Given that the manufacturing plant in Ceriano

Laghetto is Bracco’s only Iopamidol manufacturing facility, Bracco would potentially relocate

Iopamidol manufacturing to an (as yet non-existent) plant outside the EU, or, as a worst case,

permanently cease the manufacture of Iopamidol.



53

An overview of the most prominent socio-economic is presented in Figure 7.1.

Figure 7.1 Overview of the main non-use socio-economic impacts

* Unique to this non-use scenario

7.3 ECONOMIC IMPACT ASSESSMENT

7.3.1 Economic impact on Bracco Imaging s.p.a

The scope of the economic impact assessment is limited to Bracco’s direct impacts, as illustrated

in Figure 7.1.

Due to the high degree of uncertainty, direct economic impacts such as contract penalties and

legal fees were excluded, although these would be considerable if Authorisation is not granted.

Wider economic impacts and distributional impacts are also disregarded on the basis that they

would be unlikely to be as significant as the direct economic impacts.

7.3.2 Redundancy costs

Closure of the Bracco’s plant in Ceriano Laghetto would result in a significant number of direct

and indirect job losses. A breakdown of the redundant roles and skills is not available at this

time.

7.3.3 Loss of profits

Bracco has a % share of the world-wide global market for Low Osmolar X-ray / CT Contrast

Media, generating Iopamidol market sales of € million per annum. The loss of Bracco’s

Iopamidol sales would have a huge impact on Bracco’s profitability and cash flow, threatening

the sustainability of global operations.

Authorisation is not granted

Non-use scenario A: Relocation to outside of

the EU

Economic impacts: Redundancy costs, loss of profits, relocation

costs*, decommissioning costs, reduced operating costs

Social impacts: Loss of wages to the European economy

Non-use scenario B: Permanent closure

Economic impacts: Redundancy costs, loss of profits, loss of

investment in R&D*, decommissioining costs, reduced

operating costs

Social impacts: Loss of wages to the European economy



54

Data on the gross profits generated from Iopamidol sales is not provided at this time.

7.3.4 Decommissioning costs

In the event that Authorisation is not granted, Bracco would close and decommission the

Iopamidol manufacturing facility in Ceriano Laghetto. Bracco does not have any experience of

decommissioning in Italy, and no industry case studies of decommissioning projects in Italy

were available.

7.3.5 Reduced operational costs

The costs of closure and decommissioning would be offset to some extent by a reduction in

operational overheads. The savings from reduced operational costs would only be a fraction of

the other direct economic impacts (loss of profits, redundancy costs, and decommissioning

costs).

7.3.6 Relocation costs

The Bracco Group has links to countries throughout the world, either directly or indirectly

through branches, joint-ventures, partnerships, or distribution and agency agreements.

Manufacturing activities are located in Italy (Ceriano Laghetto, Torviscosa, and Colleretto

Giacosa), Switzerland (Geneva), Japan (Saitama) and China (Shanghai). The Torviscosa plant is

where of the other main Iopamidol intermediates manufactured; however, Iopamidol is

only manufactured at the Ceriano Laghetto facility and the Group does not operate other

manufacturing sites for this API either within or outside the European Union (EU).

In the relocation non-use scenario, investment costs in the relocation and validation of a new

manufacturing facility outside of the EU would exceed the capital investment profile of €55

million referred to in Section 5.2 and would be expected to in the order of magnitude between

€ million. In all likelihood, the magnitude of this cost would mean that the relocation

non-use scenario would not be economically feasible.

Furthermore, given that Bracco does not currently have a site available for non-EU Iopamidol

manufacture, a new site would need to be designed and built from scratch, bringing in additional

time and cost constraints, including important implications for product availability.

7.3.7 Loss of investment in research and development

Bracco does not have a specific breakdown of the investment in the development of the

Iopamidol manufacturing route; however, based on the process described in Section 5.2 for the

evaluation of an alternative synthetic pathway to Iopamidol, it is likely that investment has

exceeded € million over the last thirty years.



55

7.3.8 Reputational context

Bracco was established in 1927 but did not enter the highly specialised field of diagnostic

imaging until the 1950s when a major R&D investment strategy was launched.

During the 1970s the Group developed the Iopamidol molecule, the first ready-to-use non-ionic

contrast medium.

Following the launch of Iopamidol in 1981, Bracco established its presence in the contrast

imaging agent market and, following a programme of international expansion, achieved a

leading role in X-ray/CT within the main geographical areas around the world.

Three generations of the Bracco family have transformed a small pharmaceuticals distributor on

the Italian market into a world leader in diagnostic imaging. Despite the development of a

generic manufacturing capabilities around the world, Bracco’s reputation for a high quality,

optimum efficiency, safe product has allowed the company to retain its global market share for

Iopamidol.

Bracco has extended the company portfolio over the years, entering the MRI market with

ProHance®

(gadoteridol) and MultiHance®

(gadobenate dimeglumine), consolidating its

leadership in X-Ray/CT with Iomeprol and entering the nuclear medicine segment, with a

leading position in fast-growing niche areas of PET cardiology and hepatobiliary imaging.

7.3.9 Economic impact on the downstream supply chain

Bracco’s Iopamidol is sold in over sixty different countries worldwide, with North America

accounting for % of the market. Europe and Asia/Latin America account for % and % of

the market respectively.

In terms of Bracco’s Iopamidol usage, over % of its applications are in computed tomography

procedures, while % are in X-ray radiological procedures and % in interventional cardiology

procedures.

Iopamidol is manufactured as a generic drug (1) by a number of other companies worldwide,

including Imax Diagnostic Imaging (a pharmaceutical company subsidiary of Hovione, located

in Portugal). A number of other European and non-European (mostly Asian) companies

formulate generic Iopamidol into the final medical product. The capacity of generic Iopamidol

manufacturing operations tends to be fairly limited and is estimated to be in the region of % of

Bracco’s capacity.

In terms of the impact on the immediate downstream supply chain, if Bracco could no longer

supply Iopamidol API, customers would be forced to switch to other formulated generic products

or other similar products. The sudden loss of a % of the global capacity of this extremely

(1) According to the World Health Organisation (WHO), a generic drug is a pharmaceutical product, usually intended to be interchangeable with an

innovator product, that is manufactured without a licence from the innovator company and marketed after the expiry date of the patent or other

exclusive rights.



56

important pharmaceutical could not be taken up in either the quantity or the quality required by

the worldwide medical profession.

Iopamidol manufactured by Bracco is formulated into medicinal products that are administered

to twenty million patients per annum, the majority by injection for computer tomography

procedures where Iopamidol is a key component for the visualisation of body organs and

functions in the diagnosis and management of a number of pathologies. The high quality API

manufactured by Bracco has an extremely significant brand reputation within the worldwide

medical community for its safety and efficacy, often not achievable using generic alternatives.

The potential loss of % of the global manufacturing capacity would therefore have an

extremely significant global economic and health impact upon the diagnosis and management of

human health pathologies using X-ray procedures. This loss of Iopamidol would not be

replaceable, in the short to medium term, in the quantity and quality required by either other

equivalent products or diagnostic procedures.

Iopamidol is one of the most important and well-established representatives of this group of low-

osmolar contrast monomers (LOCM). Since its launch in 1981, it has established itself as a

leading diagnostic agent for imaging, with extensive safety records in the general population as

well as within special at-risk groups such as elderly patients, neonates, infants, children and

critically ill patients.

The main considerations in choosing a non-ionic contrast agent are image quality, product

characteristics of viscosity, osmolality, iodine content and administration volume, and safety.

Iopamidol is the forerunner of the class of non-ionic monomers.

Iopamidol is approved in a wide range of indications covering all the diagnostic imaging

procedures in conventional radiology, computed tomography (CT) and catheterisation.

Iopamidol is well accepted in both adults and children and offers excellent contrast and image

quality. Available in formulations providing a high iodine concentration, Iopamidol has

demonstrated its efficacy for use with the most advanced multidetector-row CT (MDCT)

scanners for neurological, hepatic, cardiac and vascular imaging.

In the last decade, the safety profile of Iopamidol has been proven in the highly critical context

of contrast-induced nephropathy (CIN). In various large and controlled studies, Iopamidol

proved to be associated with a very low rate of CIN, not significantly different from that

associated with the use of the iso-osmolar contrast media (IOCM). Moreover, Iopamidol has

shown a lower rate of long-term adverse events compared to IOCM following CIN.

7.4 SOCIAL IMPACT ASSESSMENT

The social impact assessment is limited to the loss of wages from the European economy in the

event that Bracco’s workers would be made redundant.

The loss of employment at Bracco’s Ceriano Laghetto plant, if the business was to cease

operations, would not have a significant impact on European society as a whole. However,

given the relatively high unemployment rate in the Lombardia region of 8.2% (2014) (1), it is fair

(1) http://www.asr-lombardia.it/RSY/employment/labour-force-survey/lombardia-and-provinces/tables/13565/



57

to assume that Bracco’s employees may not immediately find new employment. Typical

earnings in Italy are €2,167.84 per month (1), therefore for each year of unemployment, the loss

of wages for per redundant worker would be €26K.

7.5 CONCLUSION

This high-level semi-quantitative socio-economic assessment clearly shows that the cessation of

the use of diglyme in the manufacture of 5-amino-2,4,6-triiodoisophthalic acid dichloride (EC

417-220-1; CAS 37441-29-5) in the synthesis route to the final API Iopamidol would have

significant socio-economic implications, with no benefit to improvement in human health

through exposure to this substance during this use.

Furthermore, the closure of Bracco’s EU Iopamidol operations would result in a shortfall in

global capacity for Iopamidol as a contrasting agent for the diagnosis and management of a

number of human pathologies. Although not further quantified here, the enormity of the

economic and human health impacts resulting from this shortfall would alone be sufficient to

support Bracco’s continued use of diglyme in the manufacture of this beneficial pharmaceutical

product.

7.6 JUSTIFICATION FOR THE REVIEW PERIOD REQUEST

After over thirty years of process research and development, Bracco has not identified an

alternative solvent that could be used in the existing process to manufacture the intermediate, 5-

amino-2,4,6-triiodoisophthalic acid dichloride (EC 417-220-1; CAS 37441-29-5), in acceptable

yield and quality for subsequent conversion to Iopamidol.

Research into an alternative synthetic pathway for Iopamidol that would avoid the need for the

current purification step using diglyme have, to date, not resulted in a commercially viable

synthetic route. It has been estimated that any new synthetic route for the manufacture of

Iopamidol would take in excess of €55 million investment and an implementation time of ten

years.

The Chemical Safety Report (CSR), submitted as part of this Application for Authorisation

(AfA), demonstrates that the use of diglyme is adequately controlled, with risk characterisation

ratios significantly less than 1 for all worker contributing and man via the environment scenarios.

Therefore, Bracco is requesting a minimum review period of 12 years (if this is considered to be

the longest period possible) for the use of bis(2-methoxyethyl) ether (diglyme) as a processing

aid in the purification of 5-amino-2,4,6-triiodoisophthalic acid dichloride (EC 417-220-1; CAS

37441-29-5) by precipitation.

The case for a long review period is further supported by the summary presented in

Table 7.1.

(1) http://www.tradingeconomics.com/italy/wages



58

Table 7.1 Summary of review period argumentation

Criterion Situation for Applicant

The applicant’s investment cycle is demonstrably

very long (i.e. the production is capital intensive)

making it technically and economically meaningful

to substitute only when a major investment or

refurbishment takes place.

No drop-in alternative solvents have been

identified for this use.

Any alternative synthesis route would be highly

capital intensive.

The costs of using the alternatives are very high and

very unlikely to change in the next decade as

technical progress (as demonstrated in the

application) is unlikely to bring any change.

Should an alternative synthesis route become

available this would require at least €55 million

capital investment and a minimum

implementation time of 10 years.

The applicant can demonstrate that research and

development efforts already made, or just started, did

not lead to the development of an alternative that

could be available within the normal review period.

Historical activity to identify technically and

economically feasible alternative solvents for the

current synthesis route or an alternative synthesis

route to Iopamidol has been documented in this

report.

The possible alternatives would require specific

legislative measures under the relevant legislative

area in order to ensure safety of use (including

acquiring the necessary certificates for using the

alternative).

Any developments leading to alternative methods

for the synthesis of the API would require

regulatory approvals in both the EU and other

global regulatory jurisdictions.

The remaining risks are low and the socio-economic

benefits are high, and there is clear evidence that this

situation is not likely to change in the next decade.

Adequate control has clearly been demonstrated.

Based on: Setting the review period when RAC and SEAC give opinions on an application for authorisation,

SEAC/20/2013/03, 13 September 2013.



59

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Documents

ANALYSIS OF ALTERNATIVES and SOCIO-ECONOMIC