However, global commercialization of new excipients is currently hindered by the fact that they are only reviewed by regulatory agencies in the context of new drug applications (NDAs). As a result, pharmaceutical manufacturers are reluctant to include them in their formulations because any questions about the excipients could cause delays or rejection of their applications, thus adding additional uncertainty to the process.
To address this situation, the International Pharmaceutical Excipients Council (IPEC) of the Americas has developed a New Excipient Evaluation Procedure. The goal of this process is to provide independent evaluation of the regulatory acceptance of a "new" excipient before a regulatory filing. The process is meant to mirror that of regulatory agencies, ideally providing confidence to pharmaceutical manufacturers that the excipient will be acceptable in their formulations. This process will not provide any type of regulatory approval.Current regulatory status of new excipients
In the United States, specific requirements for "new" excipients are detailed in the USFood and Drug Adminisration's Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, published in May 2005. Globally, the International Conference onHarmonization (ICH) has no specific excipient safety evaluation guidelines, but the FDA guidance cites ICH safety testing guidance documents as reference materials for conducting safety tests.
These guidelines, however, address only one aspect of the approval process, leaving a major gap: the precise definition of "newness." According to ICH, an excipient is considered "new" or novel if it is used for the first time in a human drug product or by a new route of administration. In the US, FDA maintains the Inactive Ingredient Database, which lists excipients used in approved drug products, their route of administration, and their maximum dosage. The database is somewhat difficult to use because of the lack of standardization of chemical names and the time between approval of an excipient and inclusion in the database. In addition, the definition does not distinguish between completely new chemical entities and approved excipients that have been modified, co-processed mixtures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for food or cosmetics—the latter of which may require less safety testing as a result of extensive human exposure. Finally, few similar specific safety guidelines for excipients exist outside the US.
Supporting information for a new excipient can be provided in a drug application or in an appropriately referenced drug master file (DMF). This information includes full details of chemistry, manufacturing, and controls as well as supporting safety data. The information provided is similar in the level of detail to that provided for a drug substance. The level of information, however, may be less depending on the "newness" of the excipient.
The IPEC procedure
Under IPEC's New Excipient Evaluation Procedure, currently used in the US, excipient manufacturers or users submit a dossier in DMF format containing available safety information for their proposed "new" excipient. The file goes to an expert panel that evaluates the information in the context of the FDA excipient guidance and appropriate ICH guidance documents. The expert panel is made up of highly qualified individuals known throughout academia, industry, and the regulatory community. Upon evaluation, the panel issues a statement of conformance or nonconformance to the sponsor. The evaluation is limited to safety information and chemical characterization information as tied to safety for a specific intended use and exposure level. Global applications of the procedure are currently under consideration.
If the review panel concludes that the requirements of the FDA and ICH guidance documents are not met, it recommends specific steps to bring the dossier information into compliance. The sponsor then has the opportunity to resubmit the dossier with the requested changes. The panel's report is owned by the sponsor and released at their discretion.