For non-compendial excipients which are comprised of definite mixtures of compendial excipients, the mixture composition and
ingredient identifications are requested. Specifications should include all meaningful controls for quality and purity (e.g.,
identity, assay, impurities, heavy metals etc.) that are found in the individual USP–NF monographs. Additionally, other sources
of tests and criteria for non-compendial excipients may include the manufacturer's information, the CFR and the FCC (14, 15). It is often observed that the compendial methods of analysis for the individual components in the mixture
may not be suitable in these cases due to interference from the other components. Thus, information regarding the validation
of non-compendial test methods for these excipients needs to be provided.
A novel excipient is defined as one which has not been previously approved by the Agency. These excipients are typically approved
as part of the new drug approval process. In certain cases a DMF and clinical and safety evaluation (9) is required as a minimum
criteria for approval of the excipients. A good reference for the format of an Excipient Master File Guide is the International
Pharmaceutical Excipients Council of the Americas (IPEC-Americas) (16).
Excipients of animal origin.
Bovine or transmissible spongiform encephalopathy (BSE/TSE) statement and country of origin should be provided for excipients
of animal origin. For excipients which may be of both animal and vegetable origin, if the firm proposes to switch from one
to another in near future, the effect of the switching on the manufacturability of the product should be addressed. Common
excipients in this category are Magnesium Stearate, Calcium Stearate and Stearic Acid. Submitting merely the COAs for both
grades of the excipient is usually not enough. Sponsors are requested to provide information regarding pharmaceutical development
studies which may have been performed to evaluate the product manufactured using both the grades, for appearance (sticking
and picking), content uniformity, tablet friability, tablet dissolution (at target hardness) and manufacturing yield, to assure
Retest dates of excipients.
This rather simple information is often missing from the submissions. Although this is covered under cGMPs (21 CFR 211), one of the reasons for requesting this information is to confirm that excipients which support microbial grown are
tested frequently, preferably once a year.
Reduced testing based on vendor validation.
Firms often provide information in their application regarding proposed reduced testing of the excipients, once the vendor
has been validated. As valuable as this information is a firm may be reminded in these cases that vendor validation is a field
function based on 21 CFR 211.84(d)(2) and not reviewed or approved by OGD (17). The firm is advised to consult with the district office regarding
the appropriateness of their vendor validation policy. Acknowledging this in the original ANDA submission is recommended.
This concludes our discussion on the commonly cited deficiencies for sections 3.2.P.1, Description and Composition of the
Drug Product and 3.2.P.4, Control of Excipients. It is noted that the deficiencies and comments cited in these sections of
the ANDA are not as numerous as in other sections. However, appropriate information in these two sections are crucial in demonstrating
that the sponsor has adequate understanding of the QTPP of their drug product and has strived to manufacture a robust formulation
with desired performance over shelf life.
1 Numbering in section heads correspond to those in the Common Technical Document (CTD).
The authors wish to acknowledge Lawrence Yu, PhD, OGD Deputy Director for Science, and Vilayat A. Sayeed, PhD, OGD Director
of Chemistry Division III, for their encouragement and invaluable insight.
The views and opinions in this article are only those of the authors and do not necessarily reflect the views of policies
Aloka Srinivasan, PhD,* and Robert Iser, M.S., are team leaders, and Devinder S. Gill, PhD, is a deputy director, at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug
Administration's Center for Drug Evaluation and Research, Aloka.Srinivasan@fda.hhs.gov
*To whom all correspondence should be addressed.