Its Elemental, My Dear Watson

The FDA recently issued a draft Guidance document; entitled “Control of Elemental Impurities in Drug Products”.  This document provides guidance in light of the issuance of ICH Q3D Elemental Impurities and USP<232> Elemental Impurities – Limits and USP<233> Elemental Impurities – Procedures. USP <232>.  Upon implementation (scheduled Jan 1, 2018), USP<232> and USP<233> will replace USP<231> Heavy Metals.  Until Jan 1, 2018, USP <232> and USP<231> is only enforceable if specified within a monograph.

The Guidance document recommends that from June 1, 2016, applicants submitting new compendial NDAs and ANDAs should follow ICH Q3D until USP<232> and USP<231> are implemented. After June 1, 2016, for non-compendial NDAs and ANDAs, the application should demonstrate compliance with ICH Q3D.

The Guidance document recommends that marketed products that are not approved under an NDA or ANDA and that do not have an official USP monograph, have documentation to demonstrate compliance with ICH Q3D from January 1, 2018.

The Guidance document provides recommendations for changes to approved applications in order to align with ICH Q3D and USP<232> and the approach to be taken when communicating such a change to the Agency (which, in turn, is driven by the severity of the required change; for example, a manufacturing process change vs. the inclusion of additional in-process or raw material testing).

The Guidance document provides direction for how the Elemental Impurity Risk Assessment should be documented and the scenarios for when it should be either: summarized and included within the regulatory application; submitted within annual updates; maintained at the site ready for agency review.

The Guidance document states that the analytical procedures utilized for the Elemental Impurity Risk Assessment and routine testing should be validated and based upon the procedures referenced within USP<233>.  Any alternative procedure (from what is specified within USP<233>) must meet the validation requirements of USP<233>.  Validation of the elemental test procedures should provide confidence that the data afforded during the risk assessment can reliably be used to determine whether routine testing is to be included as part of the Elemental Impurity control strategy.

The scope of the Guidance provides a footprint for additional work that all marketed drug products must meet.  Firms that have not undertaken a process to assure that their products meet the requirements should begin to seriously assess that they have the resources necessary to meet the compliance dates and have a plan in place to be certain that they do not get caught short.  Remember, 2018 is right around the corner!