The European Directorate for the Quality of Medicines and Healthcare (EDQM), the standards-setting organization for pharmacopeial guidelines in Europe, provided an update to revisions to the European Pharmacopoeia (Ph. Eur) based on the implementation of guidelines by the International Conference on Harmonization (ICH) for elemental impurities.
ICH Q3D, Guideline on Elementral Impurities, provides a global policy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients, and the EDQM, as it has outlined previously, is seeking to align the Ph. Eur with the ICH guideline. "With the implementation of the ICH Q3D guideline on elemental impurities, the control of elemental impurities is undergoing a shift in paradigm, moving away from pure substance-based testing towards a holistic control strategy in the finished product," said EDQM in a statement. "While these approaches are not contradictory, this change has triggered the revision of numerous texts in the European Pharmacopoeia (Ph. Eur.). The Ph. Eur. Commission has already communicated its plan for the implementation of this important guideline..."
The implementation schedule in the Ph. Eur. has been aligned as "closely as possible," said the EDQM with the application timelines decided by the European Medicines Agency's Committee for Medicinal Products for Human use: June 2016 for new marketing authorization applications and December 2017 for all authorized products on the market of the European Economic Area.
In November 2016, the Ph. Eur. Commission adopted several general texts integrating the new approaches and requirements of the ICH Q3D guideline for elemental impurities into the Ph. Eur. and, in broader terms, into the global regulatory framework. These texts are to be published in Supplement 9.3 with an implementation date of January 1, 2018. The revision plan for general texts was broken down as follows:
• General chapter 5.20 Elemental impurities: reproduces parts of the Scope and the Introduction sections of the ICH Q3D guideline and refers to the guideline which can be found in full on the ICH website;
• General monograph on Pharmaceutical preparations (2619): refers to chapter 5.20, rendering it —and by extension the ICH Q3D guideline — legally binding;
• General monograph on Substances for pharmaceutical use (2034): introduces requirements for the control of elemental impurities intentionally added during production and explains the absence of a test for elemental impurities from individual monographs except for special cases (see paragraph on specific tests below);
• General method 2.4.20 Determination of elemental impurities: provides guidance for aspects of method development such as sample preparation and method validation for the determination of elemental impurities. In addition to this recent revision, this text remains a priority on the work program of the Pharmacopoeial Discussion Group (PDG), the aim being to harmonize the respective general chapters on elemental impurities in the different regions.
The Ph. Eur. Commission has also discussed the fate of specific elemental impurities (individual metal) tests (about 500 of these tests for various elemental impurities are described). Feedback gathered from stakeholders during workshops and conferences held over the past year has been used to help define the best approach to these tests. Consequently, the Ph. Eur. Commission has decided to keep the published specific elemental impurities tests in monographs on substances of natural origin only. "Given the intrinsic nature of elemental impurities in these substances, they are among the major potential sources of elemental contamination in medicinal products," said the EDQM.
The Ph. Eur. Commission has also recommended keeping in particular the different tests for elements for which no Permitted Daily Exposure limits have been established, such as those identified as “other elements” in the ICH Q3D guideline (such as aluminium and iron), in individual monographs. Conversely, specific elemental impurities tests will be deleted from monographs on other substances (i.e. not from natural origin), unless otherwise justified.
In particular, the Ph. Eur. Commission decided that, unless otherwise justified, specific tests for elemental contaminants originating from the production process will be deleted. "As these elemental impurities are specific to the production process, they will remain the responsibility of the substance manufacturer," said the EDQM. This is reflected in the new sentence added to the Production section of the general monograph on Substances for Pharmaceutical Use (2034). The EDQM said that the Ph. Eur. Commission and the corresponding groups of experts will continue their work on clearly defining on a case-by-case basis which monographs are concerned and to what extent they are impacted by the rationale developed above. The list of concerned monographs will be published in Pharmeuropa for public consultation in due time,said the EDQM.
The EDQM said that as new data become available, the groups of experts intend to examine opportunities for revision of the set of individual metal tests in monographs in order to align them with newer standards and/or to reflect more closely the actual quality of substances available on the European market. "Support from stakeholders will be crucial for the success of this initiative," said EDQM.