Stereoisomeric drug products.
This is a class of drug products which has been gaining ground over the last two decades. With great strides made in the
field of analytical separations and also chiral reagents, use of a specific enantiomer is becoming more of a norm in the field
of pharmaceuticals. Insufficient information in the application may lead to deficiencies being cited.
There are two significant guidance documents which may be followed regarding chemistry and manufacturing controls for stereoisomeric
drug products, Development of New Stereoisomeric Drugs (9) and ICH Q6A (3). Decision Tree 5 in ICH Q6A summarizes the requirements
for the chiral drug substances and drug products.
Control of the chiral impurities.
It is preferable to include controls for the enantiomer and also diastereomers in the drug product within the constraints
of sensitivity of the analytical procedure, unless adequate pharmaceutical development studies demonstrate that racemization
or epimerization is not a possibility during the manufacturing or storage of the drug product. The limits for the chiral impurities
may be justified by comparison with the RLD product, published literature or safety studies.
In cases where racemization is found to be insignificant or a very small amount of chiral impurities are expected to be present,
a non-chiral assay may be considered sufficient as a control. However, if the active pharmaceutical ingredient (API) is prone
to racemization or formation of other diastereomers during the manufacturing or storage of the drug product, a chiral assay
The agency's guidance, Development of New Stereoisomeric Drugs (9), states that drug products which contain enantiomers should have a discriminatory identification test. This is especially
important when the racemate of the API is present in an approved drug product. Under such circumstances, a stereospecific
identification test is requested, as it clearly demarcates between the enantiospecific drug product and the one containing
Another scenario in which a stereospecific identification test is desirable is when the drug substance is prone to racemization
under the proposed manufacturing process and storage conditions of the drug product.
Additional issues with drug product controls and information.
The following is a discussion of other common deficiencies that are related to inadequate controls or justifications and missing
information with respect to the drug product.
Identity testing of the drug product is a required quality requirement, as well as, a cGMP requirement (10). Most products
include a satisfactory test for identity; however, there are cases where deficiencies have been issued based on the fact that
another identity test may be necessary, if the proposed identity test is non-specific. In some cases a specific identification
test is required, especially when there is a possibility of conversion of the active ingredient into another form (e.g., another
salt, polymorph, or stereoisomer) based on the process conditions or during typical storage.
This control may be especially important for solutions. A quantitative control for color based on comparison with the innovator's
product is desirable. A quantitative control for color is often requested for oral solutions and injections, especially where
degradation of the API may occur during storage; or where there is evidence that interactions of the API with the excipients,
manufacturing equipment or interaction amongst excipients may cause a change in color of the drug product. Again, adequate
pharmaceutical development studies demonstrating the absence of these interactions may justify not including a quantitative
control for color for solutions.
For products that are intended to be reconstituted, such as powders for injection, a meaningful criterion for reconstitution
time should be proposed. In many ANDA submissions this test is either not proposed or the limit is unreasonable based on the
observed data, the RLD, or the intended use (e.g. for emergency administration). Most importantly, the limit should be based
on a comparison with the RLD product. Additionally, ICH Q6A (3) states that test for reconstitution time can also be omitted
based on development studies, however, these studies should be clearly referenced in the appropriate P.5 section.
Many submissions include disintegration limits that are not reasonable based on the data and also the intended use. In general,
if disintegration testing is included in the drug product release specifications, the criteria should be based on data generated
from analysis of the exhibit batches. Also the disintegration time in release and stability should be commensurate with that
proposed in the in-process control during manufacturing of the drug product.