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Q3C (R8) Step 5 20 May 2021 EMA/CHMP/ICH/82260/2006 Committee for Medicinal Products for Human Use ICH guideline Q3C (R8) on impurities: guideline for residual solvents Step 5 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 Final adoption by CHMP 20 May 2021 Date for coming into effect 20 November 2021 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 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Document History Code History Date Parent Guideline: Impurities: Guideline for Residual Solvents Q3C Approval by the Steering Committee under Step 2 and 6 November 1996 release for public consultation. Q3C Approval by the Steering Committee under Step 4 and 17 July 1997 recommendation for adoption to the three ICH regulatory bodies. Revision of the PDE information for THF contained in the Parent Guideline Q3C(R1) Permissible Daily Exposure (PDE) for Tetrahydrofuran 20 July 2000 (THF): revision of PDE based on new toxicological Note: Prior data. to adding the revision to Approval by the Steering Committee of the new PDE the parent for THF under Step 2 and release for public Guideline in consultation. November 2005, the code was Q3C(M) for THF. Q3C(R1) Approval by the Steering Committee under Step 4 and 12 September recommendation for adoption to the three ICH 2002 Note: Prior regulatory bodies. to adding the revision to the parent Guideline in November 2005, the code was Q3C(M) for THF. ICH guideline Q3C (R8) on impurities: guideline for residual solvents EMA/CHMP/ICH/82260/2006 Page 2/51 Revision of PDE information for NMP contained in the Parent Guideline Q3C(R2) Permissible Daily Exposure (PDE) for N- 20 July 2000 Methylpyrrolidone (NMP): revision of PDE based on Note: Prior new toxicological data. to adding the revision to Approval by the Steering Committee of the Revision the parent under Step 2 and release for public consultation. Guideline in November 2005, the code was Q3C(M) for NMP. Q3C(R2) Approval by the Steering Committee under Step 4 and 12 September recommendation for adoption to the three ICH 2002 Note: Prior regulatory bodies. to adding the revision to the parent Guideline in November 2005, the code was Q3C(M) for NMP. Q3C(R3) Corrigendum to calculation formula approved by the 28 October 2002 Steering Committee. Note: Prior to adding the corrigendum to the parent Guideline in November 2005, the code was Q3C(M) for NMP. Q3C(R3) The parent Guideline is now renamed Q3C(R3) as the November 2005 two updates (PDE for N-Methylpyrrolidone and PDE for Tetrahydrofuran) and the corrigendum of the update for NMP have been added to the parent Guideline. ICH guideline Q3C (R8) on impurities: guideline for residual solvents EMA/CHMP/ICH/82260/2006 Page 3/51 Parent Guideline: Impurities: Guideline for Residual Solvents Q3C(R4) Update of Table 2, Table 3 and Appendix 1 to reflect February 2009 the revision of the PDEs for N-Methylpyrrolidone and Tetrahydrofuran. Revision of PDE information for Cumene contained in the Parent Guideline Q3C(R5) Permissible Daily Exposure (PDE) for Cumene: 26 March 2010 revision of PDE based on new toxicological data. Approval by the Steering Committee under Step 2 and release for public consultation. Q3C(R5) Approval of the PDE for Cumene by the Steering 4 February 2011 Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies. The PDE for Cumene document has been integrated as part IV in the core Q3C(R4) Guideline which was then renamed Q3C(R5). The Table 2, Table 3 and Appendix 1 have been updated to reflect the revision of the PDE for Cumene. Revision of PDE information for Methylisobutylketone contained in the Parent Guideline and to include a PDE for Triethylamine Q3C(R6) Permissible Daily Exposure (PDE) for Triethylamine 9 November 2016 and Methylisobutylketone: revision of PDE based on new toxicological data. Approval by the Assembly under Step 2 and release for public consultation. Q3C(R6) Approval of the PDE for Triethylamine and 9 November 2016 Methylisobutylketone by the Assembly under Step 4 and recommendation for adoption to the three ICH regulatory bodies. The PDE for Triethylamine and Methylisobutylketone document has been integrated as part V in the core Q3C(R5) Guideline which was then renamed Q3C(R6). The Table 2, Table 3 and Appendix 1 have been updated to reflect the revision of the PDE for Triethylamine and Methylisobutylketone. ICH guideline Q3C (R8) on impurities: guideline for residual solvents EMA/CHMP/ICH/82260/2006 Page 4/51 Correction of the PDE for Ethyleneglycol Q3C(R7) Correction for the PDE and concentration limit for 15 October 2018 Ethyleneglycol on Table 2 page 6, as per the correct value calculated in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997 S36. Q3C(R6) Further to archival searches related to the Permissible 4 October 2019 Daily Exposure (PDE) for ethyleneglycol, the Q3C(R7) Guideline was reverted back to the Q3C(R6) Guideline. Further information is provided in the cover statement dated 22 July 2019. Addition of PDE for 2-Methyltetrahydrofuran (2-MTHF), Cyclopentyl Methyl Ether (CPME), and Tertiary Butyl Alcohol (TBA) Q3C(R8) Endorsement of Part VI of Q3C(R8) (PDEs for 2-MTHF, 25 March 2020 CPME, TBA) by the Members of the ICH Assembly under Step 2 and released for public consultation. Q3C(R8) Adoption of Part VI of Q3C(R8) (PDEs for 2-MTHF, 22 April 2021 CPME, TBA) by the Regulatory Members of the ICH Assembly under Step 4 ICH guideline Q3C (R8) on impurities: guideline for residual solvents EMA/CHMP/ICH/82260/2006 Page 5/51 Q3C (R8): Impurities: guideline for residual solvents Table of contents Part I ........................................................................................................... 7 1. Introduction ............................................................................................ 7 2. Scope of the guideline ............................................................................. 7 3. General principles .................................................................................... 8 3.1. Classification of residual solvents by risk assessment ................................................ 8 3.2. Methods for establishing exposure limits ................................................................. 8 3.3. Options for describing limits of class 2 solvents ........................................................ 8 3.4. Analytical procedures .......................................................................................... 10 3.5. Reporting levels of residual solvents ..................................................................... 10 4. Limits of residual solvents ..................................................................... 10 4.1. Solvents to be avoided ........................................................................................ 10 4.2. Solvents to be limited ......................................................................................... 11 4.3. Solvents with low toxic potential .......................................................................... 12 4.4. Solvents for which no adequate toxicological data was found ................................... 13 Glossary .................................................................................................... 14 Appendix 1. List of solvents included in the guideline ............................... 15 Appendix 2. Additional background ........................................................... 20 A2.1 Environmental regulation of organic volatile solvents ........................................... 20 A2.2 Residual solvents in pharmaceuticals ................................................................. 20 Appendix 3. Methods for establishing exposure limits ............................... 21 Part II: PDE for Tetrahydrofuran ............................................................... 24 Part III: PDE for N-Methylpyrrolidone (NMP) ............................................ 26 Part IV: PDE for Cumene ........................................................................... 28 Part V: PDE for Triethylamine and PDE of Methylisobutylketone ............... 32 Part VI: PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol ............................................................................... 41 Q3C (R8): Impurities: guideline for residual solvents EMA/CHMP/ICH/82260/2006 Page 6/51 Part I 1. Introduction The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter
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