ICH Q3D - Where We Stand: 12 Months and Counting
The regulations are already in operation and have been since June 2016 for New Chemical Entities (NCEs) so a number of users are already familiar with implementation. Numerous manufacturers are either in the process of analysing products or have completed their studies. The re-alignment of the USP and ICH variants of the regulations now mean that previous differences in requirements have been unified into one set of elemental impurity requirements.
From an implementation point of view the IWG (Implementation Working Group) is active and has been looking at the issues surrounding the implementation of the regulations. IPEC (International Pharmaceutical Excipients Council) have also been active through the Coalition for Rational Implementation of the USP Elemental Impurities Requirements. The Technical and Analytical Challenges sub-committee (TAC) has organised and completed an international round robin study to look into the current reliability of elemental analysis. A series of laboratories from pharmaceutical manufacturers, raw material manufacturers, contract laboratories, a government laboratory and an academic laboratory were involved in the study. The participants analysed an ‘experimental formulation’ manufactured at Liverpool John Moores University. The samples were made from excipients only and had two forms, a spiked and unspiked version. The spiked version had elemental impurities from Class 1 and 2A close to the levels required by the regulations (As, Cd, Hg, Pb, Co, Ni and V). The unspiked version was just the inherent levels from the excipients used. The study indicated issues related to the unspiked version mainly because of the lower levels being determined and in some cases the unreliability of the data generated. A second study is now being planned with a new ‘experimental formulation’ with higher levels of elemental impurities. Such a study will allow the study of data from not only ICPMS but also ICPOES. It is hoped that this study will get underway in early 2017.
The question of validation has presented a number of issues throughout the implementation. Much of the current data has been validated using spiked addition. This in part has been due to the unavailability of a standard reference material containing elemental impurities representative of the levels required by the regulations. A reference material is available (NIST 3280) but it contains a limited number of elements and at much lower levels than those required by the regulations and hence has not been adopted for the testing of the digestion method. Digestion methods have been based on extractions rather than totals to avoid the use of hydrofluoric acid. In this case, assessment of recoveries is advantageous to answer question such as, has the correct temperature for the digestion been used, has the acid been capable of extracting the required elementals. Without a material of known composition this has proved difficult to assess. A wide variety of formulations are currently used and getting a uniform digestion method that is capable of extracting the elemental impurities from all of these formulations my prove difficult to achieve.
Ultimately the question of what will be deemed to be acceptable in terms of the data will come down to acceptance by the regulatory bodies.
This blog post was written by guest blogger Dr. Phil Riby of LJMU.
Dr Phil Riby is a professor at Liverpool John Moores University in the School of Pharmacy and Biomolecular Sciences. Dr Riby's work focuses primarily on trace metals analysis and, in particular, in impurities in pharmaceutical formulations. Dr Riby has numerous publications on the topic of developing methods for metal impurities in regards to ICH Q3D regulations.