ICH Develops Another Pre-Step 2 Q3D Draft to Strengthen Consensus on Heavy Metal Standards

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In mid-December, the ICH Q3D Expert Working Group (EWG) sent out a second, pre-Step 2 draft of its elemental impurities guideline to draw further input from constituent organizations on the challenging, broadly impactful issues it encompasses, with the target of achieving a draft that meets the Step 2 ICH consensus criteria by mid-2013.

In the cover letter to the new draft, the EWG explains that the input provided on the earlier draft sent out in December 2011 "was instrumental in developing revisions to improve the clarity and content of the guideline."  The cover note includes a summary of the specific changes that were made in response to the feedback (see box below).

"At this time," the EWG explains that it is looking for further comments on "major issues that could affect the development of a Step 2 guideline" and "additional suggestions for the improvement" of the current draft. The note clarifies that this current assistance in reviewing the document "does not replace the formal public comment period, which will occur during Step 3 of the ICH process."

The EWG states that it is particularly interested in feedback on the risk-based control threshold approach and on the risk assessment approach and calculation option examples incorporated into the draft.

Also of interest are "data driven comments" on the proposed permissible daily exposure (PDE) limits, and alternative approaches that could be implemented for large volume parenteral products.

Heightening the concern regarding LVPs (generally defined as greater than 100 ml in dose) is the metals risk they pose due to their matrix, dose size and the leachables that can be contributed from the primary packaging, about which limited data may be available.

On the other hand, the EWG is sensitive to the critical need LVPs serve in the hospital setting and does not want to impose standards that would unnecessarily limit patient access to life-saving medications.

The working group is also looking for input on the implications of the Q3D standards for the extra E&L concerns that inhalation products pose.

Complicating the E&L assessments across different product types is that extractables may be able to be obtained from suppliers but leachables tend to be product-specific.  The relationship to packaging providers in making assessments is also at issue.

Mined excipients present quandaries in applying heavy metals standards, and further industry feedback on the issue to the EWG would be appropriate.

While there are known safety concerns for arsenic, lead, cadmium and mercury and a lot of experience with use of the mined ingredients, there is a lack of historical data outside of current USP lead-based testing on the array of heavy metals that the ICH guideline will be covering, and significant and unpredictable variability in their metal content. How this variation should be factored into the risk assessment is under EWG consideration.

The variability and lack of ability to control small amounts of metal impurities in mined excipients has been a concern highlighted by the International Pharmaceutical Excipients Council (IPEC) as the heavy metal discussions have advanced in the past few years. IPEC has been pointing out that while there may be many-fold differences in the metal concentrations based on where and when the mining took place. Historical evidence has shown these differences may not pose safety risks depending on their usage, the council notes.

A salient characteristic of the new ICH approach to heavy metals is its incorporation of the risk-based approaches and principles contained in Q9.

The new guideline will have a three-tiered system for classifying the metal impurities with significant implications for the degree of testing and control expectations depending on whether they are of low, medium or high risk to patient safety. The risk assessment process outlined in the guideline begins with an identification of the potential sources - ingredients, process, equipment/facilities, and primary packaging - and then runs through the analysis, evaluation, control and acceptance strategies.

Among the related interpretations drawing EWG debate is the percentage of the permissible daily exposure (PDE) limits that would create a threshold for a high-risk designation.

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Source: This article is taken from the IPQ (International Pharmaceutical Quality Journal).
IPQ's monthly format keeps subscribers "Inside the Global Regulatory Dialogue"™ where the initiatives are being defined that will reshape the landscape. The IPQ is one of the most important Journals in the GMP and regulatory environment. In co-operation with IPQ the ECA publishes selected articles in the members' area on the ECA website. Members also benefit from a special agreement with IPQ´s Editor in Chief Bill Paulson: an exclusive subscription fee for the IPQ Journal. You will find more information in the members' area.

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