As practitioners in the world of pharmaceutical manufacturing and quality control, you’ll know that the U.S. Pharmacopeial Convention (USP) 232 and its requirements for trace element determination in APIs, excipients and all other materials that make their way into, or are in contact with your finished products is on the horizon. The implementation date for meeting the demands of this regulation, as set by the U.S. Pharmacopeial Convention, and its companion protocol, USP 233, was, until last week, 1st December 2015, but on 14th January this year, the USP announced that this date was to be pushed back to 1st January 2018. The final specifics of USP 232 have yet to be agreed upon, with further changes having been recently (October 2014) proposed for elemental impurities, with the aim of aligning USP 232 with its European counterpart guidelines, as described in the publication, Guideline for Elemental Impurites Q3D, (downloadable PDF) and referred to as ICH Q3D.
The development of ICH Q3D has followed a series of steps since its initial guideline proposal was issued in late 2011. Almost 3 years after its initial release, on 7th July 2014, the ICH Steering Committee announced that the finalization (Step 4) of the ICH Q3D Guideline on Elemental Impurities was planned for September 2014 and, then on 18th July 2014, the Commission explained their approach to the integration of the content of ICH Q3D in the European Pharmacopoeia (see The European Pharmacopoeia Commission validates its strategy regarding elemental impurities and the ...). The Step 4 ICH guideline was eventually issued on December 16th, 2014 but the final implementation (Step 5) dates for Europe, the U.S. and Japan have yet to be announced.
The International Conference on Harmonization (ICH) has committed to preparing training materials to help the pharmaceutical industry implement this new method by Q1 2015, following final alignment of the elements listed in the USP 232 and ICH Q3D protocols and their permitted daily exposure limits (PDEs). The intention of the ICH is to then have these training materials completed by March 31, 2015.
Many in the pharmaceutical industry have concerns about the practical implications of USP 232 and ICH Q3D and have formed a group to represent the views of the industry. This group, The Coalition for the Rational Implementation of the USP Elemental Impurity Measurements, was instrumental in delaying the implementation of USP 232 from its original planned date of 1st May 2014, after voicing concerns about the complexity of implementing USP 232 and the need to harmonize it with ICH Q3D in order to provide a rationalized, globally agreed protocol. It would seem that these views have been considered and the USP have reacted by extending the formal implementation date of the 232 and 233 protocols to 2018 to allow time for the rationalization process. In the meantime, the USP have proposed that individual laboratories can decide whether to adopt the current General USP 232 and 233 chapters or continue to use the existing USP 231 chapter.
Dr. Phil Riby (Senior Lecturer, Chemical and Pharmaceutical Analysis, Liverpool John Moores University, UK) who is part of the Technical and Analytical Challenges (TAC) sub-committee of the Coalition suggests that “the recent ‘partial alignment’ of the USP and ICH requirements has helped to clarify some issues particularly with regard to requirements for As analysis, but there are still some significant differences that need to be clarified for routine use." To aid in the rationalization of the two protocols, TAC is carrying out a round-robin study on an experimental formulation to try and assess the variability in trace metal data generated by different labs.
Additionally this work may help to assess whether this formulation could be used as a potential reference material for laboratories undertaking USP/ICH Q3D analyses. Phil notes that “the lack of a suitable solid reference material (pharmaceutical product/excipient based) with trace metal data appropriate to the regulations is a significant issue in the validation, particularly for extraction methods."
My conversations with Phil and other scientists tasked with developing analytical methods for these new regulations suggest that relatively few pharmaceutical laboratories currently feel ready to implement them. Indeed, the ongoing revisions to USP 232 mentioned above, resulting from feedback acquired from consultation with the pharmaceutical industry, seems to be delaying some laboratories from developing methods, as they (understandably) don’t want to carry out extensive and expensive validation to conform to the current USP 232 requirements only to see the regulations change again.