FDA proposes new guidance for reporting drug impurities


The Food and Drug Administration ( has announced a new draft, Guidance for Industry: ANDAs-Impurities in Drug Substances, that provides revised recommendations on what chemistry, manufacturing and controls (CMC) information to include regarding the reporting, identification, and qualification of impurities in drug substances produced by chemical synthesis.

M. Scott Furness, senior regulatory review chemist and team leader of the FDA’s Antibiotic Drug Review Branch, explains, “This draft provides consistency between Q3A(R)-[Q3A(R) Impurities in New Drug Substances guidance issued in February 2003, developed by the International Conference on Harmonisation (ICH)]-and ANDAs Impurities in Drug Substances issued in November 1999. In addition, it more clearly defines the role of the United States Pharmacopeia (USP) when it comes to qualifying impurities and setting acceptance levels.”

International harmonization on regulations is among the FDA???s goals in its new draft guidance concerning reporting of impurities in drug substances produced by chemical synthesis.

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The revised recommendations apply to those submitting original abbreviated new drug applications (ANDAs), Drug master files (DMFs), and type II DMFs and ANDA supplements changing drug substance synthesis or process. It does not cover DMFs or ANDA supplements if the FDA previously accepted a DMF for that specific dosage form, administration route, or daily intake prior to publication of the final version of this guidance. Sections of the 1999 guidance containing recommendations addressed in the ICH Q3A(R) have also been removed.

When qualifying impurity levels, the draft guidance refers to the ICH 2003 report. But the FDA says it will consider proposals for applications for alternative qualifications on a case-by-case basis, taking into consideration patient population, drug class effects, and historical safety data. Impurities are considered qualified for ANDAs when at least one of the following conditions are met:

The observed level and proposed impurity acceptance criterion do not exceed the level justified by an FDA-approved human drug product;

When the impurity is a significant metabolite of the drug substance;

When impurity observed levels and proposed acceptance criterion are adequately supported by scientific literature;

When the observed levels and proposed acceptance criterion for the impurity do not exceed levels adequately evaluated in comparative in vitro genotoxicity studies.

Furness maintains that there is now complete consistency for threshold values established in Q3A(R) and the new draft, as well as further clarification as to impurities. The clarification prevents applicants that look to the 1999 guide to set criteria for impurities that were not covered sufficiently, but were covered in Q3A(R).

In recent months, the FDA has taken a more active role in moving towards global standards. On the heels of issuing its 21st Century Report (see “FDA initiatives aim to streamline pharma processing,” CleanRooms, December 2004), the agency recently joined the ICH to reduce the need for simultaneous filings to satisfy several global regulatory bodies, while promoting safety by making improvements to the regulation of products.

Ken Christie, senior director of consulting services at VTS Consultants (Westborough, Mass.), concurs that a globalization trend is in the works: “The biggest push for harmonization is based on the cost of trying to meet European and Japanese standards. Each regulatory body has a different set of packaging requirements.”

Christie adds, “The cost to comply is astronomical, and is the greatest impetus for standards unification.” III