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Volume 32, Issue 1
Pharmaceutical manufacturers often avoid putting new excipients in their formulations for fear of more regulatory oversight. IPEC has a solution.
Excipients play a crucial role in pharmaceutical formulations, affecting properties such as patient acceptability, rate of release of pharmaceutical actives, and delivery-to-target tissues. Researchers around the world are currently developing new excipients with improvements to these characteristics. In addition, new active pharmaceutical ingredients (APIs) often require new excipients that are compatible with their chemical properties.
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.
The panel's activities are managed by a consultant on a fee-for-service basis. The interested excipient manufacturer, through direct discussions with the consultant, provides the consultant with a table of contents and summary of the expected studies needed for the review. The consultant then provides a cost proposal and timeframe based on the expected time of review and the experts' hourly fees. After the evaluation, the consultant provides the manufacturer with a report. The report can be included in the sponsor's DMF or given directly to the drug product applicant.
IPEC only tracks the number of completed reviews and plays no role in this process. IPEC does not know any of the specifics of an expert panel project. The evaluation procedure is kept confidential between the panel and sponsor.
The details of this process were developed in conjunction with FDA staff, who, in a 2006 letter to IPEC, agreed to consider the panel's conclusions when reviewing "new" excipients within NDAs. Although the agency could not guarantee that they would agree with the panel's conclusions, they welcomed the additional level of review and acknowledged the value of the process for encouraging new excipient development.
To date, IPEC's New Excipient Evaluation Procedure panel has received one submission and several others are in the planning stages. The panel represents a potential remedy to the regulatory "logjam" facing new excipient development. The panel's independent review should provide pharmaceutical manufacturers confidence that specific "new" excipients will be acceptable in their regulatory filings, thus encouraging them to use these excipients in their formulations.
Christopher C. DeMerlis is manager of regulatory affairs at Colorcon and chair of the IPEC–Americas Regulatory Affairs Committee. Jay M. Goldring, PhD, is director of toxicology at Wyeth Consumer Healthcare and chair of the IPEC-Americas Safety Committee. David R. Schoneker is director of global regulatory affairs at Colorcon. and chair of IPEC–Americas. For more information, contact Alan Mercil at IPEC–Americas, 1655 North Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.875. 2127, fax 703.525.5157, firstname.lastname@example.org/index.html.