• Q3A - Q3D Impurities

    Code Document Title Previously coded
    • Finalised Guideline:
      February 2011

      Description :

      The core tripartite harmonised ICH Guideline was finalised under Step 4 in July 1997. This recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms, and sets pharmaceutical limits for residual solvents (organic volatile impurities) in drug products.

      Maintenance Process

      A Maintenance process has been done to revise Permitted Daily Exposure (PDE), as new toxicological data for solvents become available. 

      Limit values for three residual solvents in drug products were revised on basis of the newly recognised toxicity data; lower PDE for N-Methylpyrrolidone being kept in Class 2 (limited by health-basis) and for Tetrahydrofuran and Cumene being placed into Class 2 from Class 3 (no health-based).

      Both revisions (PDE for THF and PDE for NMP) reached Step 4 of the process in September 2002. A corrigendum to calculation formula for NMP was subsequently approved on 28 October 2002. As per the new coding rule, they were incorporated into the core Guideline in November 2005.

      In February 2009, Table 2, Table 3 and Appendix 1 of the Core Guideline were updated to reflect the revision of the PDEs for N-Methylpyrrolidone and Tetrahydrofuran (Q3C(R4)).

      The Q3C(R6) Guideline has reached Step 2 on the ICH Process in June 2015. A Maintenance process has been proposed to revise the Permitted Daily Exposure (PDE) of the MIBK, as new toxicological data for this solvent become available. Based on its newly lower limit values MIBK was placed into Class 2 (limited by health-basis) from Class 3 (no health-based). In addition, the new solvent Triethylamine has also been included in Class 3.

      Implementation :

      Step 5

      EU :

      Core Guideline adopted by CPMP, September 1997, issued as CPMP/ICH/283/95

      MHLW :

      Core Guideline adopted March 1998, PMSB/ELD Notification No. 307

      FDA :

      Core Guideline published in the Federal Register, 24 December 1997, Vol. 62, No. 247, p. 67377; Q3C Tables and list published in FR, Vol. 68, No. 219, p. 64352-64353, 13 November 2003

      Revised PDE for N-Methylpyrrolidone (September 2002) - View subsequent Correction

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, September 2002, issued as CPMP/ICH/1940/00

      MHLW :

      Adopted 25 December 2002, ELD Notification No. 1225006

      FDA :

      The revised PDE is reflected in the Q3C Tables and List published in the Federal Register, Vol. 68, No. 219, p. 64352-3, 13 November 2003

      Revised PDE for Tetrahydrofuran (September 2002)

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, September 2002, issued as CPMP/ICH/1940/00

      MHLW :

      Adopted 25 December 2002, ELD Notification No. 1225006

      FDA :

      The revised PDE is reflected in the Q3C Tables and List published in the Federal Register, Vol. 68, No. 219, p. 64352-64353, 13 November 2003

      Q3C(R4)

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, February 2009, issued as CPMP/ICH/28395

      Q3C(R5) Revised PDE for Cumene (February 2011)

      Implementation :

      Step 5

      EU :

      Adopted by CHMP, March 2011, issued as EMA/CHMP/ICH/82260/2006

      MHLW :

      Adopted 21 February 2011, PFSB/ELD Notification No. 0221-1

      FDA :

      The revised PDE is reflected in the Q3C Tables and List published in the Federal Register, 23 February 2012, Vol. 77, No. 36, p. 10754-5

      Q3C(R6) Revised PDE for Methyl isobutyl ketone (MIBK) and new PDE for triethylamine (TEA) (June 2015)

      Status :

      Step 3

      EU :

      Deadline for comments by 31 October 2015

      MHLW :

      Deadline for comments by 31 December 2015

      FDA :

      To be notified