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FDA Finalizes ICH Guidance on Elemental Impurities

Posted 07 August 2018 | By Ana Mulero 

FDA Finalizes ICH Guidance on Elemental Impurities

The US Food and Drug Administration issued final guidance Tuesday that explains when to conduct risk assessments for elemental impurities in drug products.
The new implementation date of 1 January 2018 coincides with when the requirements set forth in revised versions of US Pharmacopeia (USP) general chapters <232> and <233> came into effect. The initial deadline was 1 June 2016, according to the draft version of the guidance.
Recommendations outlined throughout the guidance provide a risk-based approach to the control of elemental impurities for applicants and holders of new drug applications or abbreviated new drug applications (ANDAs).
The approach is intended to ease the regulatory burden in conducting this type of risk assessment as it was developed via the International Council for Harmonization (ICH). Europe and Canada are among the other ICH member countries that have already adopted the guideline.
Those with an official USP monograph are expected to implement the requirements in the revised chapters. Further, documentation that demonstrates compliance must be maintained at manufacturing facilities and made available to agency investigators during site inspections.
Firms are also required to document any changes made to the conditions established in approved applications in upcoming annual reports, though FDA recommends including a risk assessment summary in these reports “even if no changes are made.”
“FDA anticipates that most approved drug products marketed in the United States do not contain any elemental impurities that exceed [permitted daily exposure or PDE] described in general chapter <232> and ICH Q3D,” the agency clarified.
The finalized guidance contains other changes in response to comments submitted to FDA. These include clarifications on determining whether testing each product is necessary.
“If the risk that the amount of an elemental impurity will exceed its PDE in the drug product is sufficiently low, it may not be necessary to test each lot of drug product for that impurity,” FDA added in the final guidance, as requested in GlaxoSmithKline’s comment. The control threshold is defined by FDA as “being 30 percent of the established PDE in the drug products.”
Earlier this year, FDA told Focus “Applications that do not meet these requirements are unable to be approved and may receive a request for this information through an information request or complete response letter (CRL).” The statement was made based on an increase in the number of ANDA CRLs as of this January, partly due to the USP requirements.
Elemental Impurities in Drug Products: Guidance for Industry

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