Control of Genotoxic and Elemental Impurities

Documentation and control strategy

Filing expectations for new drugs

Risk assessment for elemental impurities – (Summation option). Contribution of components of the drug product to be included in the “Pharmaceutical Development Report”, section P2.3 of the application.

Specifications for elemental impurities to be set according to ICH Q3D limits.

Testing methods and validation for controlled EI to be included in the drug substance and drug product sections of the application, sections S4.2 and 3, P5.2 and 3.

Excipient contributions may be included in their controls or referenced to a Drug Master File (MF) of the supplier, Type IV.

GMP expectations for EI

EI test data documentation rational for setting specifications in the drug substance and drug product.

Testing Laboratories are subject to GMPs. Full validation of analytical methods at the site and in the application is needed.

Justification for EI higher than established PDE

Intermittent dosing; short term dosing (i.e.,30 days or less); and specific indications (e.g., life threatening, unmet medical needs, rare diseases).

Proposed level higher than an established PDE should be justified case-by-case.

Can periodic testing be applied to elemental impurities?

Caste Study: An applicant has developed a new tablet form medicine. The active substance is manufactured by a route where the last step is a catalytic hydrogenation with platinum on carbon as catalyst.

After filtration to remove the catalyst, the substance is isolated by crystallization.

In the risk assessment the applicant concludes that the filtration and the crystallization are likely to reduce the levels of Pt.

This is also confirmed on three production scale batches where Pt were found in 24%, 19% and 22% of an amount corresponding to a PDE calculated by Option 2b. For these three batches the levels of Pt is below 30% of the PDE.

However, impurities introduced late in the synthesis constitutes a higher risk of being carried through and the control threshold could be exceeded.

A specification for the drug substance was set that ensures compliance of the drug product with the PDE. The applicant proposed to apply Periodic Testing after confirmation on 10 batches.

Industry Challenges

The most significant challenges for the industry is the practical implementation of ICH Q3D guideline.

Elemental impurity assessment presents new challenges which include: determining how to assess or quantify the risks associated with factors such as water, container-closure systems and excipients; and defining where in the assessment process data may be required and identifying where risks can be determined to be negligible through a thorough scientific theoretical risk assessment also present significant questions.

Development and validation of analytical method used to determine elemental impurities; time consuming analytical method and increase in analysis cost; and requirement of costly and sophisticated instrument are the other challenges.

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