2.3.S / 3.2.S Drug Substance
2.3.S.1 General Information
The second question in the QbR–QOS pertains to drug-substance properties. This question is inconsistently answered by the
sponsors of most applications. A full understanding of the drug-substance properties is essential in the development of formulation,
manufacturing process, analytical methodology, and product stability. In many instances, this critical information is lacking
and triggers a question requesting the identification of crucial aspects of the drug substance that are essential in making
a quality drug product. An understanding of the drug-substance properties is paramount to ascertaining the critical material
attributes (CMA). The properties may or may not be CMAs based on the intended use or performance, the formulation, manufacturing
process, analytical methodology, and product stability. Examples are as follows:
- Solubility may be critical to determining the formulation, the process, and the performance of the product. A study of pH-related
solubility and solubility in various organic solvents can also be used to justify manufacturing process steps and in providing
information useful for developing suitable analytical methods.
- Knowledge of hygroscopicity may have an impact on choices made in the formulation or the manufacturing process; and may also
provide insight into potential stability challenges if the drug substance or the formulation is sensitive to moisture.
Providing an answer to this question and identifying the drug-substance aspects that are critical to product quality can eliminate
this request coming from the reviewer.
With respect to section 2.3.S.2, reference is usually made to the associated DMF(s). If questions are asked regarding the
manufacturing of the drug substance, it is because of additional processing of the drug substance by the ANDA sponsor such
as micronization. If the ANDA sponsor performs post-DMF drug substance processing such as micronization, the effect of such
processes on drug substance stability should be addressed.
An additional question that is often asked by reviewers in this section is whether the drug substance will be manufactured
at multiple manufacturing sites. It is recommended that the DMF holder be consulted to address which site will be used to
supply commercial material and if multiple sites will likely be used. This fact should be included in the exhibit batch information
(i.e., the possibility of manufacturing multiple exhibit batches). If there is a possibility of a change in source site after
approval, this information should be included in the ANDA sponsor's regulatory strategy.
For drug-substance characterization information, the ANDA sponsor typically refers to the applicable portions of the referenced
DMF. This section, however, also provides the introduction to potential impurities that may or may not be adequately controlled
by the DMF holder. A summary of the potential impurities (organic and inorganic), related substances, residual solvents, and
residual reagents should be included in this section (see section 2.3.S.4 below for a discussion of criteria for the impurities).
Many times, the information with respect to International Union of Pure and Applied Chemistry (IUPAC) names, structures, and
classification as process related and/or degradation impurities is missing from the ANDA. This type of information is part
of a complete response to the QbR question found in section 2.3.S.3. Additionally, justification should be provided for any
potential impurities including, in some cases compendial impurities (e.g. USP monograph specified impurities), that are process
specific and are not specified in the drug-substance specifications.
2.3.S.4 Control of Drug Substance.
Common questions with respect the control of the drug substance can be grouped into four major categories. These categories
include: control of impurities (i.e. organic, inorganic, residual solvents, and residual reagents), drug substance identity,
physical characteristic controls, and analytical methodology. Each category will be expounded upon with respect to common
questions asked after the reviewer assesses sections 2.3.S.4 and 3.2.S.4.