FDA Issues New Guidance for Industry on ANDAs: Impurities in Drug Products

Published on: 

The US Food and Drug Administration issued late last week a new guidance for industry on impurities in drug products.

The US Food and Drug Administration issued late last week a new guidance for industry on impurities in drug products. The guidance provides recommendations on the type of chemistry, manufacturing, and controls (CMC) information sponsors should include in their abbreviated new drug applicatons (ANDAs) and related supplements regarding the reporting, identification, and qualification of impurities that are classified as degradation products in drug products.

Specifically, the document includes information about establishing acceptance criteria for degradation products (i.e., degradation products of the active ingredient or reaction products of the active ingredient with an excipient[s] and/or immediate container–closure system) in generic-drug products. The new guidance replaces the 1998 guidance of the same name.

FDA issued the new guidance, according to the document, to update information on listing degradation products, setting acceptance criteria, and qualifying degradation products (e.g., thresholds and procedures) in ANDAs to be more in line with the 2006 revision of the International Conference on Harmonization Q3B(R) guideline, Impurities in New Drug Products. Some sections, for example, in the 1998 draft guidance were removed because ICH Q3B(R) covers them.

The new guidance describes what to include in the drug-product specification of an ANDA for degradation products such as stability studies, chemical-development studies, and routine batch analyses. “It is important that the list of degradation products for the drug product specification be based on degradation products found in the batch(es) manufactured by the proposed commercial process,” states the guidance.  A rationale for including or excluding degradation products in the specification should also be part of the filing.


The guidance further identifies what it calls “specified degradation products,” which are defined as individual degradation products with specific acceptance criteria that can be identified or unidentified. Specified identified degradation products are recommended to be included in the filing’s list of degradation products “along with specified unidentified degradation products that are estimated to be present at a level greater than the identification threshold given in Q3B(R),” says the guidance. The guidance also discusses acceptance criteria, including using the levels set in the US Pharmacopeia.

With regard to the qualification of degradation products, the document asks that sponsors include in their filings a rationale for establishing degradation-product acceptance criteria that includes safety considerations. Qualification thresholds and procedures for degradation products are also discussed.

Finally, the new guidance document includes a decision tree involving questions about toxicity studies, reference products, threshold limits and more, to help in the identification and qualification of degradation products in generic drugs.