EMA has recently published additional questions and answers related to whether or not variations are required for removal of the general test for heavy metals (Ph. Eur.) for several types of active substances. These questions have been produced to provide clarification or additional information, and should be read in conjunction with the European Pharmacopoeia, quality guidelines and other guidance documents.
Removal of heavy metals tests from a specification – Substances with a Ph. Eur. monograph in existing marketed products
Reference to the general Heavy metals test (2.4.8) has been deleted in the Ph. Eur. 9.0 from all individual monographs for substances for pharmaceutical use (except those for veterinary use only). Instead the Ph. Eur. General Monograph Substances for Pharmaceutical Use will require that elemental impurities are considered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparations will require elemental impurities to be controlled based on a risk assessment for products outside the scope of Ph. Eur. Chapter 5.20. For these materials, compliance with the revised monographs is an expectation and therefore the deletion of the general Heavy metals test from the specification would not require a variation.
Removal of heavy metals tests from a specification – Substances without a Ph. Eur. monograph in existing marketed products
The deletion of a general Heavy metals test from the specification of an ingredient is accepted as a Variation Type 1A. The change does not have to be justified.