2.3.P.5 Control of the drug product*

The P.5 sections of the QbR–QOS and the body of data, in submitted ANDAs, should include all the proposed controls for routine analysis of the drug product batches including the proposed specifications, analytical methods with associated validations, batch analysis data for exhibit batches, and justifications for all proposed criteria. Much of the information provided in this section is relevant to both release testing (P.5) and stability or shelf-life testing (P.8). We will address the stability section later in the article.

The QbR–QOS includes two sets of questions with respect to control of the drug product. The questions are as follows:

• What is the drug product specification? Does it include all the critical drug product attributes?
• For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

Specifications are defined per ICH Q6A as "a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use"(3). Based on this definition, the typical information provided is a table or list of proposed tests, acceptance criteria, and analytical procedures for the drug product analysis. An all too common deficiency, which should always be avoided, is related to inconsistencies in the specifications listed in the QbR–QOS (CTD module 2.3) versus the body of data (CTD module 3.2). It is imperative that the two sets of specifications match. If there are differences, the CMC reviewer will be unable to ascertain which of the specifications are the final proposed product controls. The information provided in the QOS should be a summary of the detailed information found in the body of data.

The remaining comments and deficiencies will fit into specific categories related to drug product controls including impurities and degradation products, specific controls for specific dosage forms, and analytical methods.

Impurities/Degradation products. There are a number of common deficiencies with respect to impurities and degradation products in the drug product. These include inappropriate criteria and unacceptable justifications.

With respect to setting justified specifications, a commonly cited deficiency is related to control of process impurities in the drug product. In many cases the recommended ICH Q3B (R2) (5) qualification threshold (QT) is used for all specified impurities. This may be appropriate for degradation products; however, it is not appropriate for impurities that are solely linked to the drug substance synthetic route (i.e., process impurities). The drug product limits for a specified impurity that is process impurity should be set at no higher than that proposed in the drug substance limit.

Poor justification for the proposed degradation product is another common area where deficiencies are being cited. There are a number of ways to justify specified degradation product criteria including the following, which are not reported in any specific order:

• Specified impurity limits are in-line with US Pharmacopeia (USP) monograph criteria for specified impurities.
• Acceptance criteria are in-line with the qualification threshold (QT) recommended in ICH Q3B(R2) and ANDA Guidance: Impurities in Drug Products (draft) (5, 6) as long as there are no safety concerns. The guidance for calculation of the QT using recommended percentage or total daily intake of specified impurities, whichever is lower, should be followed.
• Qualification of the proposed criterion may be based on the following:

- Level of impurity observed in the reference listed drug (RLD). Data from multiple batches of the RLD at or near expiration date may be provided for qualification.
- Significant human metabolite of drug substance. Literature references should be provided to verify that the compound is a significant human metabolite.
- Scientific literature: as long as there are no safety concerns with respect to the intended use.

• Impurities that are structural alerts for genotoxicity need to be controlled at the Threshold of Toxicological Concern (TTC) of 1.5 mcg/day, as found in the European Medicines Agency (EMA) and draft FDA guidance (7, 8). However, a higher limit may be proposed based on safety studies demonstrating that the proposed limit does not pose a safety concern. These studies are typically consulted to reviewers in the Pharmacology–Toxicology division.

With respect to unspecified impurities the proposed limit should be equal to or below the recommended ICH Q3B (R2) identification threshold (IT) based on the maximum daily dose. Please be informed that in most cases when a USP monograph includes a limit for "any impurity" or "any other impurity" for unidentified impurities it is recommended that the IT be used for the criterion instead of the monograph limit.

An additional area that may lead to a deficiency is the setting the same criteria in both the release and stability specifications for a degradation product, where there is an increasing trend during stability studies. If an upward trend is observed, it is recommended that the criteria in the release specifications are set tighter so as to provide better quality assurance that all manufactured batches meet the regulatory criteria throughout the product life cycle.