Control of excipients
There is only a single question in the QbR-QOS pertaining to control of excipients: "What are the specifications for the inactive
ingredients and are they suitable for their intended function?" However, despite its apparent simplicity, the question is
a poignant one and relates to a critical question in the pharmaceutical development section, 2.3.P.2.2, which plays a role
in ensuring the quality of the drug product and its performance based on label claim over the shelf life.
• How were the excipients and their grades selected?
Performance characteristics of excipients.
One of the least understood questions in QbR-QOS is perhaps the one in 2.3.P.2.2, where the sponsor is asked to justify the
selection of the "grade" of the excipients. Overwhelmingly, the response to this question is that the excipients are USP/NF
grade. Another common response is the verbatim information as found in the Handbook of Pharmaceutical Excipients (12) with
no specificity to the intended use in the proposed drug product. This question in the QbR-QOS is intended to demonstrate the
understanding of the performance characteristics (i.e., excipient performance or functionality related characteristics) of
the excipients which may affect the manufacturability of the drug product. The performance characteristics of excipient are
based on their form and their physical properties. For example, for a solid excipient that is to be used in dry blending and
direct compaction processes, the impact of changing physical parameters such as bulk density, surface area, particle shape
and size distribution need to be evaluated and justified. Similarly, liquid excipients may be evaluated for variation in viscosity
and pH; and polymeric excipients need to be evaluated for the impact of changes in molecular weight distribution or viscosity,
Sponsors may need to avoid using a specific grade of excipient in certain formulations, if its use is discouraged by the manufacturer
of the excipient. It has been observed, that excipients have been used in a formulation, when the suppliers certificate of
analysis (COA) clearly states that the grade is not intended for the particular dosage form. This is a serious flaw and needs
to be clearly justified. An example of this is the avoidance of certain grades of mannitol in parenteral formulations based
on manufacturer's information. Another example is Carbomer 934, which is not intended for internal use per the USP–NF monograph
Control of excipients (specifications).
The QBR-QOS question in 2.3.P.4 regarding the specifications of the excipients may be regarded as a summing up of the understanding
based on the response to the two questions in the pharmaceutical development section, discussed above.
The primary requirement for a compendial excipient is that it meets all the USP–NF requirements (13). The sponsors need to
continuously monitor the USP–NF for monograph updates to ensure excipient compliance. As part of the USP–NF monographs for
excipients there are performance related tests based on the intended use in a dosage form. The sponsors are encouraged to
refer the individual monographs, as applicable (e.g., lactose and microcrystalline cellulose).
We often see a discrepancy in acceptance criteria for certain controls between the excipient supplier's certificate of analysis
(COA) and the specifications provided by the ANDA sponsor. In these cases, the sponsor needs to clearly provide a justification
for their proposed acceptance criteria and any possible impact on the product stability and safety.