Q3C (R8): Impurities: guideline for residual solvents

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. 04 May 2020 EMA/CHMP/ICH/213867/2020 Committee for Medicinal Products for Human Use Q3C (R8): Impurities: guideline for residual solvents Step 2b Transmission to CHMP 30 April 2020 Adoption by CHMP 30 April 2020 Release for public consultation 4 May 2020 Deadline for comments 30 July 2020 Comments should be provided using this template.

2 The completed comments form should be sent to PDE for 2-Methyltetrahydrofuran, Cyclopentyl methyl Ether, and Tertiary-Butyl Alcohol INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED guideline IMPURITIES: guideline FOR residual solvents Q3C(R8) PDE FOR 2-METHYLTETRAHYDROFURAN, CYCLOPENTYL methyl ETHER, AND TERTIARY-BUTYL ALCOHOL Draft version Endorsed on 25 March 2020 Currently under public consultation At Step 2 of the ICH Process, a consensus draft text or guideline , agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities Note : This document contains only the PDE levels for three solvents .

3 2-methyltetrahydrofuran, cyclopentylmethylether and tert-butanol that were agreed to be included in the ICH Q3C(R8) revision. Further to reaching Step 4, these PDEs would be integrated into a complete Q3C(R8) guideline document. PDE for 2-Methyltetrahydrofuran, Cyclopentyl methyl Ether, and Tertiary-Butyl Alcohol of the ICH regions for internal and external consultation, according to national or regional procedures. PDE for 2-Methyltetrahydrofuran, Cyclopentyl methyl Ether, and Tertiary-Butyl Alcohol IMPURITIES: guideline FOR residual solvents PDE FOR 2-METHYLTETRAHYDROFURAN (2-MTHF), CYCLOPENTYL methyl ETHER (CPME), AND TERTIARY BUTYL ALCOHOL (TBA) Document History Code History Date Q3C(R8) Endorsement by the Members of the ICH Assembly under Step 2 and released for public consultation (document dated 14 February 2020) 25 March 2020 Legal notice.

4 This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.

5 The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright for 2-Methyltetrahydrofuran, Cyclopentyl methyl Ether, and Tertiary-Butyl Alcohol 1 PART VI: 1 IMPURITIES: residual solvents (MAINTENANCE) 2 PDE FOR 2-METHYLTETRAHYDROFURAN, CYCLOPENTYL methyl ETHER, 3 AND TERTIARY-BUTYL ALCOHOL 4 2-METHYLTETRAHYDROFURAN 5 Introduction 6 2-Methyltetrahydrofuran (2-MTHF, synonyms: 2-Methyloxolane, Tetrahydrosylvan; Tetrahydro-7 2-methylfuran.)

6 CAS Number 96-47-9) is a colourless, volatile liquid with ether-like odour. 2-8 MTHF is an organic solvent usually synthesized as a racemic mixture consisting of two 9 enantiomeric forms ((S)+ and (R)-). Solubility in water is limited and decreases with increasing 10 temperature. It has a vapour pressure of 136 mbar (20 C) (1). 11 2-MTHF is increasingly used as a catalytic solvent in exchange of Tetrahydrofuran (THF) and is 12 much less miscible with water compared to THF. 13 Genotoxicity 14 2-MTHF was not mutagenic in the AMES bacterial reverse mutation assay with Salmonella 15 typhimurium (3) and Escherichia coli WP2 uvrA (2).

7 2-MTHF was also tested in vitro in a L5178Y 16 mouse lymphoma cell TK+/- assay (MLA) (3), and a chromosome aberration assay in human 17 peripheral blood lymphocytes (2), and in vivo in a bone marrow micronucleus test integrated into 18 a 3-month oral repeated-dose toxicity study in rats (2). All test results were negative except for the 19 MLA in the presence of S9, which was considered inconclusive without further explanation (3). In 20 conclusion, there is no evidence that 2-MTHF is genotoxic. 21 Carcinogenicity 22 No data for 2-MTHF are available.

8 23 Reproductive toxicity 24 No reliable information about reproductive toxicity is available. In an acute embryo toxicity and 25 teratogenicity test in zebrafish, 2-MTHF was tested at concentrations ranging from 860 8600 26 mg/L (4). Acute embryo toxicity was observed for 2-MTHF at a nominal LC50 value of 2980 mg/L. 27 Sublethal effects were also observed, such as an increase in oedema at nominal concentrations 28 1720 mg/L, as well as an increased number of embryos without detectable blood circulation and 29 PDE for 2-Methyltetrahydrofuran, Cyclopentyl methyl Ether, and Tertiary-Butyl Alcohol 2 insufficient pigmentation at a nominal concentration of 2580 mg/L.

9 Teratogenic effects were not 30 observed with 2-MTHF in this assay. 31 Repeated-dose toxicity 32 Two 3-month oral repeated-dose toxicity studies in Crl:CD (SD) rats have been described with 2-33 MTHF; one without an additional recovery period (2) and one with an additional 1-month recovery 34 period (5). The top dose in the first study was 26 mg/kg/day (2) and in the second study 1000 35 mg/kg/day (5). 2-MTHF treatment-related observations were not seen in the first study (2). In the 36 second study, groups of 10 male and 10 female rats per dose group were treated with doses of 80, 37 250, 500 and 1000 mg/kg/day (5).

10 An additional 1-month treatment-free recovery period was added 38 for 5 animals/sex of the control and the high dose groups. Treatment-related observations were 39 generally seen only at doses 500 mg/kg/day. Besides slight effects on kidney weights (increased 40 at 500 mg/kg/day), blood cholesterol (increase at 1000 mg/kg/day) and prothrombin time 41 (decreased at 500 mg/kg/day), the only test article-related microscopic observation was 42 hepatocellular centrilobular hypertrophy at 1000 mg/kg/day. However, no effects were observed in 43 the recovery group and the observed effects can therefore be regarded as completely reversible (5).