Waiting for ICH Q3D (Step 4): Revision and Implementation of national Regulations delayed!

For over the past 3 years, the testing of metallic impurities has been the subject of ICH's efforts on harmonisation. The committee is responsible for the creation of guidelines for the pharmaceutical and APIs industry to be used - when finalised - in the three economic zones Europe, USA and Japan. The publication of a final guideline goes through a 4-step process; in the fifth and last step, the document is incorporated (i.e. "adopted") into the respective guidelines fund by the three partners.

At the end of 2011, the draft of a ICH Q3D guideline was published as a pre-step 2 document which first contained the requirements on the testing of metallic impurities in medicinal products and APIs. At the end of July 2013, the Draft Consensus Guideline "Guideline for Elemental Impurities" (step 2b document) was released and open for comments 6 months long. After considering all the comments received, the corresponding adaptation of the content and its publication should take place in June 2014. That was at least the working plan presented by the ICH Expert Working Group in the agenda of the ICH meeting which took place from 31 May till 5 June in Minneapolis. It stated: "Step 4 of the ICH Q3D Guideline is expected in June 2014". If this deadline can't be respected, the adoption of the finalised guideline would be expected only in autumn this year.

The delay in the acceptation and publication of the ICH Q3D guideline (step 4) also has consequences on the revision of some important national regulations in the three ICH regions.

• EMA's "Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents" from 2008 contains provisions about the testing of impurities through 14 metals in different dosage forms as well as a classification for those metals. The scope of this guideline includes newly developed as well as already authorised medicinal products. For the latter, a 5-year transition period had been set which ended on 1st September 2013. As at this time, the publication date of the ICH Q3D Draft Consensus Guideline couldn't be determined, the validity period of EMA's guideline for "legacy" medicinal products was suspended. It thus still applies - until the publication of the ICH Q3D (step 4) - only to medicinal products prior authorisation.
• Chapter 5.20 "Metal Catalysts or Metal Reagents Residues" of the European Pharmacopeia includes the complete requirements of EMA's guideline and is referenced in the monograph 2034. Because of this cross-reference in a general monograph,  Chapter 5.20 becomes binding. Moreover, as the implementation date of the monograph 2034 was the 1st of April 2014, Chapter 5.20 (as thus the provisions of EMA's guideline) would have been applying since that date. The European Pharmacopeia Commission found the solution out of this dilemma and suspended the publication of Ph. Eur. Supplement 8.1 which contains the monograph 2034 with the cross-reference to Chapter 5.20. This approach has been justified in a press release of the EDQM published on 29 August 2013 (see also our News dated 26 September 2013).
• USP's General Chapters <232> Elemental Impurities - Limits and <233> Elemental Impurities - Procedures were published in their revised form on 1st March 2014 in the Pharmacopoeial Forum 40(2) with 90-day comment period. The USP released a detailed schedule for each revision step of the Chapters <232> and <233>. According to the "USP Revision and Implementation Plan", both chapters should apply to the pharmacopoeial monographs as of 1 December 2015. That date also corresponds to the validity date of the "General Notices section 5.60.30" which will implement the chapters. A Q&A document provides more details about the revision procedure.

The current situation is unsatisfactory for the pharmaceutical industry as it is not clear how different the expected final ICH Q3D guideline is from last year's published draft (step 2). Furthermore, long-term preparation (investments in technology and resources) is difficult. In particular, uncertainties remain with regard to large volume parenterals and the inclusion of already marketed medicinal products. Another issue concerns the different standards used in ICH and non-ICH regions which will emerge when the final ICH Q3D will be binding. How should global pharmaceutical industry as well as supervisory and licensing authorities manage that? The answer to that question is currently still open.