An industry coalition has emerged in response to the new USP requirements. The authors are a subgroup of the Coalition for
the Rational Implementation of the USP Elemental Impurities Requirements, and herein, state their position on USP’s new chapters
and the pending harmonization of heavy metal limits and procedures across the bio/pharmaceutical industry.
Background: Compendial and regulatory changes affecting elemental impurity limits in pharmaceuticals
As has been reported previously in Pharmaceutical Technology, the United States Pharmacopeial Convention (USP) has published changes to control the levels of elemental impurities in
bio/pharmaceutical drugs, scheduled to become official on Dec. 1, 2012, with an implementation date of May 1, 2014 (1). Specifically,
these changes are included in two new USP General Chapters: <232> Elemental Impurities—Limits, and <233> Elemental Impurities—Procedures (2, 3). These chapters will
replace USP General Chapter <231> Heavy Metals (4). Because USP requirements apply to all products in the marketplace through USP–National Formulary (NF) monographs, the changes will have a significant impact on pharmaceutical manufacturers, ingredient suppliers, and others involved
in the supply chain. Determining exactly how to implement these requirements, through a combination of analytical testing
and risk assessment, is already consuming a good deal of effort and resources in the industry.
In addition to USP's activities, the International Conference on Harmonization (ICH) is working on a new guideline on metal
impurities, ICH Q3D, to complement existing harmonized guidelines on organic impurities (ICH Q3A and Q3B) and residual solvents
(ICH Q3C) (5). There is broad industry support for development of this guideline—indeed, the initial proposal to establish
the ICH Q3D working party was made by industry (specifically the Pharmaceutical Research and Manufacturers Association of
America [PhRMA] and the European Federation of Pharmaceutical Industries and Associations [EFPIA]).
The ICH effort is especially valuable because it will ensure that consistent requirements will be applied by regulatory agencies
throughout the affected regions: Europe, Japan, and the United States. However, the ICH metal impurities guideline is in an
early stage of development and the working group is still gathering feedback from affected parties. An initial draft of the
ICH Q3D pre-step 2 document has been circulated for comments. The approved guideline will not be available before 2014.
Of note, the European Medicines Agency (EMA) also has a guideline pending, Specification Limits for Residues of Metal Catalysts or Metal Reagents, which becomes effective for all pharmaceutical ingredients in September 2013. The EMA guideline, focused on metals deliberately
used in manufacturing, has strongly influenced related USP and ICH efforts.
Meanwhile, USP has maintained its intention to make its requirements for the new General Chapters effective May 1, 2014. USP
originally planned to make implementation effective September 2013, but based on feedback from the industry, the organization
delayed it until May 2014 (6). This delay does not impact the real issue, which is the disconnect between USP and ICH. There
is a real concern among many in the industry that USP requirements will differ significantly from those that will eventually
be applied with the finalization of ICH Q3D.
The International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) is leading an industry coalition* to address
these issues (see section on "Coalition Activities" below).
USP staff has stated in industry forums that it will make every effort to ensure that USP's requirements align with those
of ICH, and it has already updated acceptance criteria for various metals to agree with the initial draft from ICH (6). However,
until the final ICH guideline is approved, it is the authors' view that USP cannot accurately predict its contents.
As a result, manufacturers will have to implement USP's elemental impurities requirements, which call for new analytical procedures,
specifications and specification limits, and then later revise practices to meet the later, finalized ICH upon acceptance
and publication by FDA, EMA and other regulatory agencies. The potential impact that this will have on the industry is described
in detail later in this article.
It is important to note that it is not the intent of either the coalition or the authors to express any concerns with the
ICH or EMA implementation strategies or timelines, but rather to voice concerns for both the strategy and implementation timelines
communicated by USP. The primary objective of this article is to present a case for harmonization of requirements in USP with
those in the upcoming ICH guideline, and to encourage USP to act responsibly in its implementation plans to ensure the safety
of patients without causing unnecessary expense, confusion, and potential drug shortages.