FDA Issues Guidance Regarding the Agency’s Refuse to Receive Policy for Certain Abbreviated New Drug Applications

On Wednesday, August 24^th FDA released a final guidance document, entitled “Abbreviated New Drug Application Submissions – Refuse to Receive for Lack of Justification of Impurity Limits,” which applies to applicants of abbreviated new drug applications (ANDAs) and prior approval supplements (PASs) to ANDAs who are seeking approval of a new strength of a drug product.  In its guidance, FDA states that the document “highlights deficiencies in relation to information about impurities that may cause FDA to refuse to receive (RTR) an ANDA.”

What is an “RTR” decision?

“An RTR decision indicates that FDA determined that an ANDA is not sufficiently complete to permit a substantive review.”  According to FDA’s guidance, the following are typical deficiencies that can lead to an RTR decision:

1. Failing to provide justification for proposed limits in drug substances and drug products for specified identified impurities that are above qualification thresholds.
2. Failing to provide justification for proposed limits for specified unidentified impurities that are above identification thresholds.
3. Proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds.

The guidance also states that this is not a comprehensive list of the deficiencies that could lead to an RTR decision being made.

FDA’s Recommendations

FDA states that all ANDAs must contain a description of the composition, manufacture, and specifications of the drug substance and the drug product.  Applicants are also required to submit all of the following information:

• Full description of the drug substance including, but not limited to –
  • Method of synthesis (or isolation) and purification of the drug substance
  • Process controls used during manufacturing and packaging
  • Specifications necessary to ensure the identity, strength, quality, and purity of the drug substance
• List of all components used in the manufacture of the drug product (regardless of whether they appear in the drug product)
• Statement of the specifications for each component and the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product.

In addition, FDA recommends that applicants propose and justify appropriate limits on the impurities in their drug substances and drug product in order to ensure purity.

RTR for Lack of Impurities Information

An ANDA may receive an RTR determination if it is not sufficiently complete because its face does not contain all of the required information, which includes a demonstration of the purity of the drug substance and drug product and information on impurities and residues.  FDA states that it expects all applicants to “develop and use appropriate analytical methods to detect all observed impurities.”  The guidance states that all applicants are encouraged to review FDA’s draft guidance, entitled “ANDA Submissions – Content and Format of Abbreviated New Drug Applications,” for additional information on the characterization of impurities for drug substances and drug products.

Justifying Impurity Limits

According to the FDA, “if a generic product contains specified identified impurities that exceed the qualification thresholds or specified unidentified impurities that exceed identification thresholds, the ANDA should propose impurity limits and include supporting data to demonstrate that:

1. The observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product,
2. The impurity is a significant metabolite of the drug substance,
3. The observed impurity levels and proposed impurity limits are adequately justified by the scientific literature, or
4. The observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.”

For additional information, view FDA’s full guidance document.

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