Excipient composition: additives and processing aides. As noted above, IPEC published an Excipient Composition Guide that provides details about the types of components which are
typically part of an excipient's composition and how to go about developing an appropriate excipient composition profile.
However, there is still much confusion in the industry and regulatory community related to the presence of additives and residual
processing aids. These components have always been part of various excipients' composition but have not been routinely discussed.
It is crucial in a QbD environment that information concerning the additives and residual processing aids which may be present
in an excipient be shared with the users so that adequate developmental work can be done to understand any interactions that
may occur between the additive or processing aid and the other components of a drug product. There have been many reports
of instances where the presence of a small level of an antioxidant or other additive in an excipient has affected drug-product
stability or other performance properties.
The difficulty for industry lies in how regulators may respond when they find out that an existing excipient has always had
an additive or residual processing aid in it and that this information had not been disclosed in the past. Companies are concerned
about compendia and regulatory complications if this information is brought out. Therefore, companies are currently struggling
to have appropriate discussions concerning the presence of additives and residual processing aids.
To address this situation, IPEC–Americas is compiling a list of additives and processing aids that are known to be commonly
used in a number of excipients. The actual excipients which contain these additives and processing aids are not being identified
at this point due to concerns the manufacturers have for confidentiality and unknown regulator reaction. IPEC–Americas plans
to submit this list of well-known additives and processing aids (typically GRAS or excipient materials on their own right)
to FDA. The organization also will request a meeting with FDA to discuss how best IPEC can work with the agency to find a
mechanism (possibly grandfathering) that could be used to provide a way for excipient manufacturers to provide specific additive
and processing aid information to FDA in a manner such that the presence of these materials can be considered to be acceptable
in specific excipients in the future. Ultimately, this information could then be placed into the USP–NF monographs to show that there is no problem with these materials being present as long as they are identified. In some cases,
due to confidentiality, there may need to be disclosure of this information to FDA through the use of a drug master file.
Once IPEC–Americas discusses this issue with the FDA and determines a process for handling the situation, IPEC will pursue
similar discussions with other regulatory agencies globally to try to obtain similar flexibility. It is crucial that these
discussions occur because additives and residual processing aids exist in numerous excipients and always will. It is important
that global regulators find a way to effectively deal with this issue. The alternative, regulators saying these excipients
can no longer be used, for example, would have a significant negative impact on the availability of many drugs. This issue
has caused problems in Japan already, and IPEC hopes its efforts to obtain some type of grandfathering of these materials
will lead Japanese regulators to make certain changes in its laws and guidelines to allow for these additives and processing
aids in excipients. Japanese regulators may also need to determine the appropriate levels of use for particular applications.
Visible particles. Another hot topic concerning excipient composition is the presence of visible particles (not contaminants) in excipients that
may typically exist and how users should deal with their presence. These particles may be off-color, charred particles from
heat in the manufacturing process, small amounts of metal particles which typically occur from normal manufacturing process-equipment
wear, or other types of particles that are visibly different from the main excipient particles but may be present as a part
of the normal process that cannot be easily removed. Typically, these particles have no safety implications.
IPEC has established a subcommittee of its Composition Committee to develop a guideline on how to determine when the presence
of these particles is acceptable depending on their type, number, and size. This guideline will also discuss appropriate testing
methodologies for assessing these visible particles and what may be necessary to characterize the particles' identity.