Table I: Sample implementation of FRC section to hypromellose monograph.
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Users of excipients are familiar with the importance of particle-size distribution in certain uses and, for the most part,
have no problems specifying an appropriate quality or verifying the correct grade of a supply. It is hard to see any difference
in principle between these two physical properties. It is important that the methodology for determining the apparent viscosity
be presented in the monograph, as is the case in the newly adopted monograph containing the FRC section—users can apply the
test to identify the desired grade (See Table I).
Acceptance criteria for nominal viscosity are kept in the FRC section in accordance with internationally harmonized monographs
because of obligations to publish a standard identical with the sign-off text. Acceptance criteria for the nominal viscosity
of other polymers are included as well because manufacturers and users of the concerned excipients base their respective specifications
on information included in the pharmacopoeia, and because deviations from the established acceptance criteria may have economical
consequences.
It is a consequence of the nonmandatory status that previous labeling requirements to state the nominal viscosity are deleted.
The first drafts on cellulose derivatives submitted to public inquiry contained the labeling requirement, a regrettable mistake
that gave rise to confusion. This error has been corrected in all adopted and published monographs.
The review on cellulose derivatives made by the Working Party showed that current methods for determining the degree of substitution
should also be moved to the FRC section. In cases where such a test already existed in the monograph, it was simply moved
unchanged to the FRC section. In other cases, efforts were made to establish a method. A proposal on a general method for
determining the degree of substitution of cellulose derivatives has been submitted to the Pharmacopoeial Discussion Group
(PDG) coordinating international harmonization among PhEur, USP, and the Japanese Pharmacopeia. TriPEC is involved in the
assessment of the proposed method as well.
Comments received to date on the European Commission's FRC work suggest that all FRCs should be dealt with in the general
chapter on FRCs. Specific monographs should be cleaned up for tests on physical characteristics. Take for example, hypromellose.
As previously discussed, the FRC section of the monographs contains rather voluminous texts on apparent viscosity and degree
of substitution. It will not be user-friendly to hide all FRCs in a general chapter separated from the specific monographs.
In many cases, the suitable method for a FRC is specific for the excipient. Of course, there are rather simple FRCs such as
particle-size distribution that could be listed in the general chapter. This example and similar examples, however, are trivial
and should not give rise to any concern when presented in specific monographs.
General methods
The intended content of the FRC section is to list important physical characteristics and to indicate suitable methods for
their determination. To meet these aims, it is necessary to provide suitable methods in as many cases as possible. It is important
that a range of general methods (e.g., methods for powder characterization) be included in the work program for those international
harmonization efforts coordinated by PDG.
In addition to PDG's work, some revisions and updating of European monographs has been done already, including an update of
rheological methods to include generally used viscometers. It is expected that the work on FRCs will reveal a need for new
general methods, including laser diffraction for particle-size measurements. In this particular case, the general method was
accepted for the PDG work program. It is the hope of the European Pharmacopoeia Commission that other proposed methods can
be elaborated in the same manner.
International harmonization
From a European point of view, it would be attractive if the discussion on physical tests and their inclusion in excipient
monographs could be addressed by PDG. This review has not been possible so far, although the importance of FRCs has been recognized
by pharmaceutical manufacturers in all three ICH regions (Europe, Japan, and the United States) and in other countries.
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