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. The completed comments form should be sent to [email protected] Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. 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 Note : This document contains only the PDE levels for three solvents: 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. 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 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 25 March Step 2 and released for public consultation (document dated 2020 14 February 2020) Legal notice: 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. 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PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol 1 PART VI: 2 IMPURITIES: RESIDUAL SOLVENTS (MAINTENANCE) 3 PDE FOR 2-METHYLTETRAHYDROFURAN, CYCLOPENTYL METHYL ETHER, 4 AND TERTIARY-BUTYL ALCOHOL 5 2-METHYLTETRAHYDROFURAN 6 Introduction 7 2-Methyltetrahydrofuran (2-MTHF, synonyms: 2-Methyloxolane, Tetrahydrosylvan; Tetrahydro- 8 2-methylfuran; CAS Number 96-47-9) is a colourless, volatile liquid with ether-like odour. 2- 9 MTHF is an organic solvent usually synthesized as a racemic mixture consisting of two 10 enantiomeric forms ((S)+ and (R)-). Solubility in water is limited and decreases with increasing 11 temperature. It has a vapour pressure of 136 mbar (20°C) (1). 12 2-MTHF is increasingly used as a catalytic solvent in exchange of Tetrahydrofuran (THF) and is 13 much less miscible with water compared to THF. 14 Genotoxicity 15 2-MTHF was not mutagenic in the AMES bacterial reverse mutation assay with Salmonella 16 typhimurium (3) and Escherichia coli WP2 uvrA (2). 2-MTHF was also tested in vitro in a L5178Y 17 mouse lymphoma cell TK+/- assay (MLA) (3), and a chromosome aberration assay in human 18 peripheral blood lymphocytes (2), and in vivo in a bone marrow micronucleus test integrated into 19 a 3-month oral repeated-dose toxicity study in rats (2). All test results were negative except for the 20 MLA in the presence of S9, which was considered inconclusive without further explanation (3). In 21 conclusion, there is no evidence that 2-MTHF is genotoxic. 22 Carcinogenicity 23 No data for 2-MTHF are available. 24 Reproductive toxicity 25 No reliable information about reproductive toxicity is available. In an acute embryo toxicity and 26 teratogenicity test in zebrafish, 2-MTHF was tested at concentrations ranging from 860 – 8600 27 mg/L (4). Acute embryo toxicity was observed for 2-MTHF at a nominal LC50 value of 2980 mg/L. 28 Sublethal effects were also observed, such as an increase in oedema at nominal concentrations ≥ 29 1720 mg/L, as well as an increased number of embryos without detectable blood circulation and 1 PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol 30 insufficient pigmentation at a nominal concentration of 2580 mg/L. Teratogenic effects were not 31 observed with 2-MTHF in this assay. 32 Repeated-dose toxicity 33 Two 3-month oral repeated-dose toxicity studies in Crl:CD (SD) rats have been described with 2- 34 MTHF; one without an additional recovery period (2) and one with an additional 1-month recovery 35 period (5). The top dose in the first study was 26 mg/kg/day (2) and in the second study 1000 36 mg/kg/day (5). 2-MTHF treatment-related observations were not seen in the first study (2). In the 37 second study, groups of 10 male and 10 female rats per dose group were treated with doses of 80, 38 250, 500 and 1000 mg/kg/day (5). An additional 1-month treatment-free recovery period was added 39 for 5 animals/sex of the control and the high dose groups. Treatment-related observations were 40 generally seen only at doses ≥ 500 mg/kg/day. Besides slight effects on kidney weights (increased 41 at ≥ 500 mg/kg/day), blood cholesterol (increase at 1000 mg/kg/day) and prothrombin time 42 (decreased at ≥ 500 mg/kg/day), the only test article-related microscopic observation was 43 hepatocellular centrilobular hypertrophy at 1000 mg/kg/day. However, no effects were observed in 44 the recovery group and the observed effects can therefore be regarded as completely reversible (5). 45 The NOEL in the second study was considered to be 250 mg/kg/day. 46 The NOEL of 250 mg/kg/day was used in the PDE calculation: 250 x 50 47 PDE = = 50 mg/day 5 x 10 x 5 x 1 x 1 48 F1 = 5 to account for extrapolation from rats to humans 49 F2 = 10 to account for differences between individual humans 50 F3 = 5 for a 3-month study in rodents 51 F4 = 1 because no severe effects were observed 52 F5 = 1 because a NOEL was established 53 Conclusion 54 The calculated PDE for 2-MTHF is 50 mg/day based upon the NOEL of the rat sub-chronic oral 55 study. Since the proposed PDE is greater than or equal to 50 mg/day, it is recommended that 2- 56 MTHF be placed into Class 3 “Solvents with low toxic potential” in Table 3 in the ICH Impurities: 57 Residual Solvents Guideline. 58 2 PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol 59 References 60 1. Aycock DF. Solvent applications of 2-methyltetrahydrofuran in organometallic and 61 biphasic reactions. Org. Process Res. Dev. 2007;11:156-159. 62 2. Antonucci V, Coleman J, Ferry JB, Johnson N, Mathe M, Scott JP, et al. Toxicological 63 assessment of 2-methyltetrahydrofuran and cyclopentyl methyl ether in support of their use 64 in pharmaceutical chemical process development. Org. Process Res. Dev. 2011;15:939-41. 65 3. Seifried HE, Seifried RM, Clarke JJ, Junghans TB, Sanet RH. A compilation of two decades 66 of mutagenicity test results with the Ames Salmonella typhimurium and L5178Y mouse 67 lymphoma cell mutation assays. Chem Res Toxicol 2006;19(5):627-44. 68 4. Bluhm K, Seiler TB, Anders N, Klankermayer J, Schaeffer A, Hollert H. Acute embryo 69 toxicity and teratogenicity of three potential biofuels also used as flavor or solvent. Sci 70 Total Environ. 2016;566-7:786-95. 71 5. Parris P, Duncan JN, Fleetwood A, Beierschmitt WP. Calculation of a permitted daily 72 exposure value for the solvent 2-methyltetrahydrofuran. Regul Toxicol Pharmacol 73 2017;87:54-63. 74 75 3 PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol 76 CYCLOPENTYL METHYL ETHER 77 Introduction 78 Cyclopentyl methyl ether (CPME: CAS Number 5614-37-9) is used in pharmaceutical chemical 79 development as an alternative to its more common analogues such as tetrahydrofuran and tert-butyl 80 methyl ether (1,2). 81 The vapour pressure of CPME is 44.9 mmHg at 25°C, the Log Pow is 1.59 and the water solubility 82 is 1.1 g/100 g (23 °C) (3,4). 83 CPME is classified as an irritant to skin (H315) and eye (H319) in accordance with EC No 84 1272/2008, in the Globally Harmonized System of Classification and Labelling of Chemicals 85 (GHS).