ANDAs: Impurities in Drug Products:
Qualification is the process of acquiring and evaluating data that establish the biological safety of an individual degradation product or a given degradation profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing degradation product acceptance criteria that includes safety considerations.
A specified identified degradation product is considered qualified when it meets one or more of the following conditions:
* When the observed level and proposed acceptance criterion for the degradation product do not exceed the level observed in the RLD.
* When the degradation product is a significant metabolite of the drug substance.
* When the observed level and the proposed acceptance criterion for the degradation product are adequately justified by the scientific literature.
* When the observed level and proposed acceptance criterion for the degradation product do not exceed the level that has been adequately evaluated in toxicology studies.

Although quantitative structure activity relationships (QSAR) programs may be used for prediction of toxicity of an individual degradation product or a given degradation profile, the results are not generally considered conclusive for qualification purposes.

Qualification Thresholds
Recommended qualification thresholds(Qualification threshold is defined as a limit above (>) which a degradation product should be qualified) for degradation products based on the maximum daily dose of the drug are provided in Q3B(R). When these qualification thresholds are exceeded, we recommend that degradation product levels be qualified. In some cases, it may be appropriate to increase or decrease the qualification threshold for qualifying degradation products. For example, when there is evidence that a degradation product in certain drug classes or therapeutic classes has previously been associated with adverse reactions in patients, it may be important to establish a lower qualification threshold. Conversely, when the concern for safety is low, a higher threshold for qualifying degradation products may be appropriate. The US FDA may consider proposals for applications for alternative qualification thresholds on a case-by-case basis after considering issues such as patient population, drug class effects, and historical safety data.
Qualification Procedures
The decision tree in the attachment describes considerations for the qualification of degradation products when the usual qualification threshold recommended in ICH Q3B(R) is exceeded. In some cases, decreasing the level of the degradation product below the threshold rather than providing additional data can be the simplest course of action. Alternatively, adequate data could be available in the scientific literature to qualify the degradation product. The studies considered appropriate to qualify the degradation product will depend on a number of factors, including the patient population, daily dose, and route and duration of drug administration. Such studies can be conducted on the drug product containing the degradation product to be controlled, although studies using isolated degradation products can sometimes be appropriate. The following are descriptions of methods for qualifying degradation products.

Comparative Analytical Studies
A degradation product present in a drug product covered by an ANDA can be qualified by comparing the analytical profiles of a generic drug product with those in an RLD using the same validated, stability-indicating analytical procedure (e.g., comparative HPLC studies). However, the profile may be compared to a different drug product with the same route of administration and similar characteristics (e.g., tablet versus capsule) if samples of the reference listed drug are unavailable or in the case of an ANDA submitted pursuant to a suitability petition. It is essential that maximum daily doses of the degradation product and routes of administration be taken into account for qualification by comparative analytical studies. The qualified threshold of a degradation product in a dosage form may not be applicable to all drug products containing that degradation product if the maximum daily doses or the routes of administration are different. We recommend that you conduct the stability studies on comparable samples (e.g., age of samples) to get a meaningful comparison of degradation profiles.

A degradation product present in the generic drug product is considered qualified if the amount of identified degradation product in the generic drug product is similar to the levels observed in the RLD.

Scientific Literature and Significant Metabolites
If the level of the specified identified degradation product is adequately justified by the scientific literature, no further qualification is considered necessary. In addition, a degradation product that is also a significant metabolite of the drug substance is generally considered qualified.

Toxicity Studies
Toxicity tests are the least preferred method to qualify degradation products. US FDA recommend the tests be used only when degradation products cannot be qualified by either of the above procedures. The tests are designed to detect compounds that induce general toxic or genotoxic effects in experimental systems. If performed, such studies should be conducted on the drug product or drug substance containing the degradation products to be controlled, although studies using isolated degradation products may also be used.

1.ANDAs: Impurities in Drug Products

2.ANDAs: Impurities in Drug Products:List of the types of degradation products:

3.ANDAs: Impurities in Drug Products: Setting Acceptance Criteria for Degradation Products

4.ANDAs: Impurities in Drug Products: Qualification of Degradation Products

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