How do pharmacopoeia monographs on excipients meet this quality concept? In light of the preference given to excipients that
are described in pharmacopoeia monographs and the acceptance by licensing authorities of pharmacopoeia specifications, it
is essential that the monograph specifies a material that is acceptable from a health point of view. This is the traditional
purpose of pharmacopoeia monographs. A close look at the monographs of PhEur—as well as the US Pharmacopeia (USP)—reveals that chemical purity tests in many cases have been supplemented by tests for physical characteristics (e.g., apparent
viscosity and degree of substitution of polymeric materials) that do not directly impose health risks, but that are highly
important in terms of the performance of the finished product. It is likely that such tests originate from the need for identification
of a specific physical grade. Another possibility is that manufacturers and expert groups of the related pharmacopoeia have
asked for the tests during the standard drafting phase.
Many excipient monographs, therefore, contain a mix of impurity specifications and test methods, some of which include acceptance
criteria for physical and even some chemical properties that are important for manufacturing and end-product performance.
Current tests for physical characteristics are generally insufficient when it comes to implementing quality by design or ICH
Q8. Not all characteristics are critical in terms of affecting formulation quality. In some cases, it may be questioned whether
compliance with current specifications of physical grades of excipients meets the needs of controls based on process analytical
technology (PAT) and establishment of a proper design space.
The European Pharmacopoeia Commission decided already in 1995 that tests for physical properties should be moved from the
body of the monographs to a new nonmandatory section on FRCs. At the same time, additional FRCs such as particle-size may
be introduced in the new section, listed according to the intended function of the concerned excipient. When FRCs are listed
according to the function of the excipient, it is clear that the section serves an information purpose. Acceptance criteria
for FRCs are often not provided; when they are provided, it is often as an example of a typical acceptable specification.
Compliance testing does not include the listed FRCs.
The European Pharmacopoeia Commission has found that the FRC section with indication of suitable test methods helps to facilitate
the communication between suppliers and users of excipients. The referenced test methods can provide regulatory bodies involved
in marketing authorization with data generated by recognized, independently assessed methods.
The work on FRCs has until now mainly been a reorganization of the PhEur monographs. New FRCs have been limited to tests widely used by pharmaceutical companies.
The work program on FRCs comprises excipients marketed in several physical grades by more than one manufacturer. The first
monographs containing a FRC section were published in 2001. For example, magnesium stearate referenced a test on specific
surface area identical with the test in the USP monograph; Anhydrous lactose referenced a test for α– and β–lactose and general methods for particle-size and bulk-density determination. Lactose monohydrate also had references to general methods for particle-size and bulk density determinations.
The Working Party on FRCs is currently reviewing the monographs contained in the European Pharmacopoeia Commission's work
program. In most cases, existing tests for physical characteristics are moved to the FRC section without any addition of new
FRCs. Where it is obvious, characteristics such as particle-size distribution, specific surface area, or powder flow are added.
The work program includes several cellulose derivatives, some of which have already been published in the new format. The
transfer of tests for apparent viscosity from the mandatory to the nonmandatory part of the monographs has given rise to lengthy
discussions that demonstrate some of the implications of the European project. The internationally harmonized monographs on
cellulose derivatives present the methodology to determine the apparent viscosity and provide acceptance criteria for the
nominal viscosity that has to be labeled. For example, some have claimed that the test for apparent viscosity in the monograph
on hypromellose is needed to allow verification by users of the desired grade of hypromellose. By requiring that verification,
the test is an indentification test and should be kept in the mandatory part of the monograph. This viewpoint seems invalid
when compared with other physical characteristics, including particle-size distribution.