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Control of Elemental Impurities
The European Pharmacopoeia (Ph. Eur.) traditionally collaborates closely with European regulatory authorities. The Ph. Eur. Convention specifies that member states nominate their delegates for the Ph.Eur. Commission, the governing body of the Ph. Eur.Currently, all delegations include at least one representative from a health authority who normally also serves as head of the delegation. It is not surprising, therefore, that the texts of the Ph. Eur. are much aligned with regulatory developments in its 37 member states. This is a true benefit for users, as it ensures that compliance with the legally binding Ph. Eur. standards makes it easier to obtain marketing authorizations from competent authorities throughout the continent.
Changing the strategy
In 2008, the CHMP adopted a EU guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000). CHMP’s Safety Working Party developed this guideline in close collaboration with the Joint CHMP/CVMP Quality Working Party. It defines specification limits for 14 metal elements according to their route of administration and came into effect in September 2008 for new drug products while defining a five-year transition period for existing drug products. When it was adopted, it was intended that the requirements of the guideline would apply to existing products by September 2013 at the latest.
Revising compendia tests on heavy metals
At the international level, in October 2009, the ICH Steering Committee endorsed a concept paper on the development of a harmonized ICH Guideline for Elemental Impurities, a project known as ICH Q3D. Step 2b of this guideline was completed in June 2013, and the document is currently published in the EU for comments until December 31, 2013. While the limits defined in the CHMP guideline referred to previously have been used as a basis for ICH Q3D discussions, the latter has a different scope in terms of both geography (which is normal for an ICH guideline) and the elements covered, notably in that it defines limits for the so-called “big four” contaminants arsenic, cadmium, mercury, and lead among the 24 elements it deals with. At present, these are not covered by the current CHMP guideline. In addition, certain limits proposed in the current version of the ICH document differ from those that have already been implemented via the CHMP guideline in Europe. For some of the elements the limits are wider (e.g., chromium, nickel, and platinum), while for others they are stricter (e.g., copper, molybdenum, and vanadium). A certain degree of disharmony between the current European and the future ICH guideline should be noted.
In the meantime, the ICH document has reached step 2b, but some of the limits are different from the ones previously defined by European regulators and applied by the Ph.Eur. Normally, according to the CHMP guideline, the latter requirements should have become applicable to existing products as well in September 2013. Likewise, the Ph. Eur. would have made these requirements legally binding for all substances for pharmaceutical use as of Supplement 8.1, which will come into force in April 2014. This would have created further disharmony for industry. To avoid this, the CHMP decided at its July 2013 meeting to postpone the application of its guideline to existing products and to await the outcome of discussions at the ICH level before taking any further measures. As an integral part of the European regulatory network and to ensure continued consistency between the policies applied by regulatory authorities and the pharmacopoeia, the Ph. Eur. Commission has decided to defer the addition of a reference to the general chapter in the general monograph “Substances for pharmaceutical use.” This should not be confused with the decision of the USP Executive Committee of Council of Experts to postpone the implementation of its respective General Chapters <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures, which was made for different reasons.
The decision to postpone the implementation of the full scope of the CHMP Guideline on the specification limits for residues of metal catalysts or metal reagents made by the CHMP and the Ph. Eur. Commission are an excellent example of the benefits of close collaboration between regulators and the pharmacopoeia authority, not only for themselves, but also for industry. Just imagine the situation if one party had decided to defer the extension of the scope of the CHMP guideline to existing products while the other had made them mandatory.
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