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Adopted opinions and previous consultations on applications for authorisation

Adopted opinions and previous consultations on applications for authorisation

 

This page provides further information on the applications for authorisation or review reports, which have undergone public consultation. The applications for authorisation are in the opinion development phase until the final opinions of the Committees for Risk Assessment and Socio-economic Analysis have been adopted and sent to the European Commission. The European Commission's decision-making process can be followed through the comitology register, where further information is published about the REACH Committee's past and upcoming meetings.

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Substance Details

Name
1,2-Dichloroethane (EDC)
EC Number
203-458-1
CAS Number
107-06-2
Entry Nr in Annex XIV
26
Use name
The use of 1,2 dichloroethane (1,2-DCE) as a solvent in the manufacturing of the active pharmaceutical ingredient for epirubicin.
Broad information on use applied for (conditions of use and function)
1,2-Dichloroethane (1,2-DCE) is used as a solvent in the manufacture of Epirubicin, an active pharmaceutical ingredient used for the production of a medicinal product for cancer therapy (in particular breast cancer) marketed worldwide. Anthracyclines, such as Epirubicin, are considered to be among the most active agents for the treatment of various malignancies as first or second-line treatment.

The manufacture of Epirubicin is a batch-wise process consisting of several steps. 1,2-DCE is used as a solvent for the crystallization of one of the intermediates (named hereafter Epi3, substance claimed confidential) during this multi-step process. To this end, 1,2-DCE is added to a solution of Epi3 in another solvent. The solvents are partially evaporated at elevated temperature in order to perform solvent replacement, and subsequently the solution is cooled to allow for the crystallization of Epi3. The solid Epi3 is then filtered off in a closed filter-dryer installation, rinsed and dried. The Epi3 is collected from the filter-dryer and used in the next reaction step.

The installations used for the manufacture of Epirubicin are characterized by a high level of containment (including glove boxes), which is inherent to the production of active pharmaceutical ingredients. The reactor and filter-dryer are closed equipment and all transfer of (mixtures containing) 1,2-dichloroethane occurs via fixed piping.

Additional information on the manufacture process, including OCs & RMMs per activity, is given in the exposure scenario in the CSR.

Function of 1,2-DCE: 1,2-DCE is used as a solvent for the crystallization of Epi3:

  • It helps remove residual solvents, including the reaction solvent
  • It facilitates precipitation of the intermediate by reducing its solubility, and
  • It helps purify the specific intermediate
Requirements in case of a direct substitute for 1,2-DCE:

  • Have a specific solubility for Epirubicin
  • Miscibility with the solvent used in the reaction for the synthesis of Epi3 (in the current process this solvent is methanol), to allow solvent replacement
  • Chemical compatibility with the raw materials and Epi3 itself to avoid the formation of reaction by-products and ensure optimum product quality (purity)
  • Have a specific boiling point: higher than that of the solvent used in the reaction, but not so high that evaporation of residual solvent is hampered
  • Have a specific solubilizing power to allow for a high purification (i.e. by-products remain in solution) without resulting in a too low yield of the crystallized intermediate
Market (customers): Pharmaceutics (patients)

Note: The pharmaceutical market is highly regulated. Any change in the manufacture of the API (e.g. change of solvent, production location, or change in process) would require both a requalification of the API as well as reapplying for market approval for the resulting medicinal product made. Both processes would take a long time and would be expensive.

Annual tonnage used: 9.99 tonnes/year
Review period requested: 20 years
Use applied for number in application for authorisation
1
Broad information on use applied for (Use descriptor system)
Sector of end use (SU): 9
Environmental release category (ERC): 4
Process category (PROC): 1, 3, 8b
Product category (PC): 29
Article category related to subsequent service life (AC): Not applicable
Technical Function: Solvents
Summary table of RMMs and OCs (non confidential)
Section 9 and 10 of the CSR (original and updated, if available) (non confidential)
Analysis of Alternatives (non confidential report)
Substitution Plan (non confidential summary)
Socio-Economic Analysis (non confidential report)
Joint Analysis of Alternatives and Socio-Economic Analysis (non confidential report)
Explanatory note
Additional information
ID
0111-01
Applicant(s)
OLON Spa
Application type
Initial
Status
Commission decided
Other consultations on the same/ similar use
Comments submitted to date
No comments received
Response to comments by applicant
Responses to RAC and SEAC requests by Applicant(s) (non confidential)
Compiled RAC and SEAC opinions
Minority positions
Adopted commission decision (OJ summary)
Link
Authorisation decision
C(2019)1577

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