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?
The intent of the first set of questions is for the applicant to provide the specifications for routine release testing of
the drug product; and to ensure that all critical drug product quality attributes are included in the specifications. The
critical quality attributes (CQA) are linked to the intended use, function and performance of the product and are chosen based
on the desired quality target product profile (QTPP). The CQAs may be based on compendial specifications and/or the attributes
of the reference listed drug (RLD); and also information in the associated labeling. Development studies may be conducted
by the ANDA holder to assure that the drug product meets the attributes of identity, purity, potency, assay, and quality.
Examples of typical CQAs for solid oral and solution dosage forms are provided in ICH Q6A (3) and the QbR–FAQ (4).
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.
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
- 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.