FDA Releases ICH's Elemental Impurities Guideline for Public Consultation

Posted 15 October 2013 | By Alexander Gaffney, RAC 

The US Food and Drug Administration (FDA) is out with a new guidance document reflecting the Q3D guideline released by the International Conference on Harmonization (ICH) in August 2013.

Background: ICH and the Step Process

ICH includes the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and Japan's Ministry of Health, Labor and Welfare (MHLW) among its principal membership, with other countries participating in secondary roles.

The new guideline, ICH Q3D - Impurities: Guideline for Elemental Impurities (FDA) (ICH), entered step 2b of a five-step implementation process on 26 July 2013, but was only released to the public in August 2013.

The first step involves the drafting of a guideline through the expertise of a working group. In step 2a, the guideline is adopted by ICH, and in step 2b is released for consultation.

That six-month consultation process culminates with recommendations back to ICH in step 3, which are then considered and implemented into a final guideline during step 4. The fifth and final step then involves the final guidance being adopted by ICH and released for final adoption by the ICH member countries and other interested parties.

FDA Releases for Consultation

Now FDA has officially signed off on the guideline, releasing it for initial consultation as a draft guidance.

Interestingly, the guidance does not contain any information on when comments are due to the agency. While such information ordinarily appears in the Federal Register, FDA has not had any documents published in the Register since shortly after the US government shutdown began on 1 October 2013.

As such, the due date for comments is not clear. Similar documents released by FDA have enjoyed 60-day comment periods.

Edit: An FDA contact confirmed that the document will indeed have a 60-day comment period, beginning when the document is published in the Federal Register, most likely soon after the shutdown ends.

Q3D: The Basics

As ICH explained in a statement in August, the Q3D guideline is intended "to provide a global policy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients.

"The existing ICH Q3A Guideline classifies impurities as organic, inorganic, and residual solvents," ICH continued. "The Q3A and Q3B Guidelines effectively address the requirements for organic impurities. An additional Guideline Q3C was developed to provide clarification of the requirements for residual solvents. The proposed new Guideline Q3D would provide similar clarification of the requirements for metals, which are included in the ICH inorganic impurities classification."

As the guideline explains, those elemental metal impurities arise from a variety of different sources, such as contamination or additives during the synthesis process. Regardless of their source, it is their presence in the final drug product that is of the most concern to regulators, as they can be harmful to patients.

Consequently, the ICH guideline consists of three components: toxicity testing for impurities, establishment of a Permitted Daily Exposure limit for impurities of toxicological concern, and process controls for limiting the introduction of impurities into the final product. ICH notes that in some cases, a trade-off may be required, such as when manufacturing a product is impossible without introducing metal impurities, but such levels should still be noted.

The remainder of the guideline gets into the specifics of these impurities, including how to test for limits and which metals are known to be toxic to human health.

ICH added that a harmonized approach to controlling metal impurities across all three ICH regions would "be beneficial to help avoid the uncertainty and duplication of work for industry to meet requirements that may otherwise differ" between those regions. Currently, only EMA has provided guidance on such impurities, while FDA and MHLW have been silent on the matter.


Q3D Elemental Impurities


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