Control of impurities
The authors noted above that two common question topics regarding the drug substance are polymorphism and DMF inadequacy.
Other than these two, the most commonly asked question regards control of impurities. Impurity controls are critical for ensuring
the quality of the drug substance. The control of impurities is directly linked to the route of synthesis, choice of solvents,
and other reagents used in the synthesis. This control is also essential to developing a good understanding of the drug-substance
Generally, organic impurities should be in line with the DMF holder's criteria; however, compliance with United States Pharmacopeia (USP) monographs and the ICH Q3A(R2) guideline on impurities in new drug substances is crucial in providing justification
(4). For details, the sponsor is referred to the OGD guidance on impurities in drug substances (5). For non-USP articles,
other compendia (e.g., European Pharmacopoeia (EP) or Japanese Pharmacopoeia (JP)), comparison to the reference listed drug (RLD), or safety studies may be used to justify limits for impurities. For
highly toxic impurities (e.g., genotoxic, carcinogens), additional considerations such as those found in the draft CDER guidance
on genotoxic impurities are necessary in providing justification (6). It is advocated that the unidentified and unspecified
impurities be controlled at the recommended ICH Q3A (R2) threshold (5). It is also recommended that documentation be provided
to demonstrate efforts made toward identifying the impurities based on the synthetic process before classifying them as unidentified
or unspecified impurities.
Residual solvents are directly linked to the synthetic process and, as such, should be controlled based on the criteria in
ICH Q3C (impurities in residual solvents) and USP <467> (7, 8). However it is recommended that the DMF holder and the sponsor
have a complete understanding of the effect of the residual limits on product quality rather than accepting the limits recommended
in ICH Q3C and USP <467>. If the sponsor wishes to set a less stringent limit, they need to justify it adequately. Additional
guidance for CMC reviewers and industry is also found in the OGD questions and answers on residual solvents in ANDAs document
and the CDER guidance on residual solvents (9, 10).
Specific questions are often asked with regard to residual metals from the synthetic process. The current USP <231> test and
criteria are not comprehensive and do not cover all potential metal impurities that may be present in the drug substance.
It is thus recommended that sponsors follow the European Medicines Agency (EMEA) guidance for metal catalysts or the Stimuli article, General Chapter on Inorganic Impurities: Heavy Metals, published in the Pharmacopeial Forum (5) in establishing the specifications (11, 12). Similar to the case for residual solvents, the intended use of the product
should be taken into account when proposing a criterion.
In addition, other inorganic impurities (e.g., cyanide or thiocyante) and reagents (e.g., triethylamine, alkyl halides, etc.)
may need to be controlled in the drug substance, and established limits must be justified based on good science. Guidance
for setting meaningful criteria may be found in many of the same guidance documents noted throughout this article.
Drug substance identity
Common questions that arise during ANDA reviews regarding drug substance identity include control of counter ions, stereospecific
identity or assay tests, and compliance with USP identity tests.
Control of counter ions.
In ICH Q6A, test procedures and acceptance criteria for new drug substances and new products, it is recommended that, for
drug substances that are salts, the "...identification testing should be specific for the individual ions. An identification
test that is specific for the salt itself should suffice" (13). However, there are cases where quantitative control of counter
ions is requested by FDA. This request may be due to the information available regarding the route of synthesis for drug substance
based on the DMF. For example, in some cases, an intermediate with a specific counter ion is converted to the final drug with
another counter ion. Thus, the chemist may request a quantitative control of the counter ion to establish the completeness
and reproducibility of the manufacturing process. The above approach is consistent with our current effort to establish critical
control points based on process understanding.
Control of chirality.
With respect to identity of chiral compounds, the authors recommend that both ICH Q6A and the CDER guidance on the development
of new stereoisomeric drugs be consulted (13, 14). ICH Q6A recommends that "drug substances that are optically active may
also need specific identification testing or performance of a chiral assay." In the referenced CDER guidance for stereoisomeric
drugs, it is recommended that "applications for enantiomeric and racemic drug substances should include a stereochemically
specific identity test and/or a stereochemically selective assay method. The choice of the controls should be based upon the
substance's method of manufacture and stability characteristics" (14).
In many ANDA submissions, suitable tests are not proposed for control of stereoisomeric drug substances, and deficiencies
are often cited. A chiral identification is highly recommended for chiral drug substances in addition to the control of chiral
impurities. However, if the amount of chiral impurities is significantly high and the drug substance is prone to racemization
over shelf life, a chiral assay method may be desirable in addition to identification.
Identity Tests for USP Articles.
Often, alternate identity tests are proposed for drug substances that are official USP articles. We reference the USP General
notices, section 5.40 Identification Test, specifically noting that the "failure of an article to meet the requirements of
a prescribed Identification test may indicate that the article is mislabeled" (7). It is recommended that the USP identity
tests are part of the proposed drug substance specifications.
Physical attributes of the drug substance.
Particle size: Reviewers may ask questions regarding control of particle size when particle size of the active pharmaceutical ingredient
(API) has a significant effect on the manufacturability of the drug product and its performance. There are also APIs that
are prone to agglomeration, thus requiring particle-size control. It is recommended that the firms report the distribution
and ranges, if possible. A soon-to-be published paper will provide regulatory perspectives on particle size specifications
Water content: Based on the nature of the drug substance, water content may or may not be a CMA. However, the ANDA sponsor needs to justify
the proposed control. Water content becomes a critical control for drug substances, which may be present in any of a variety
of forms: anhydrous or one of several hydrated forms, and a specific hydrate is used. In such cases, a range may be proposed.
For hygroscopic drugs, the water content may be critical in determining the impact on the manufacturability of the product.