On July 15, 2015, FDA held a public meeting to seek input on the reauthorization of the Prescription Drug User Fee Act (2002) (PDUFA). IPEC-Americas representative, David R. Schoneker, Director, Global Regulatory Affairs, Colorcon, IPEC-Americas Past Chairman and current Vice-Chair for User and Maker Relations, presented comments during the meeting. This presentation and comments centered on review and qualification of novel excipients.
IPEC-Americas has followed up on August 14, 2015 with a submission to the FDA docket on PDUFA Re-authorization with detailed written comments that describe the need for an independent FDA safety review/qualification process for novel excipients outside of the normal drug approval process. The key points included in the IPEC-Americas comments are summarized below.
The FDA defines new or novel excipients in their Guidance on Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients and this definition includes the following types of Novel excipients:
- New Co-Processed Excipients made from two or more previously approved excipients (usually manufactured using a physical process such as spray drying or melt extrusion)
- New uses of an Existing Excipient – examples would be:
- Higher level of use in a previously used route of administration
- Use in a new route of administration
- New Chemically Modified Grades of an Existing Excipient (minor changes to existing excipient)
- New Chemical Entity Excipients (NCEs) – these tend to be what people think of when discussing novel excipients. However the other types mentioned above are also considered to be novel excipients from a regulatory perspective.
The degree of newness for different types of novel excipients will influence the amount of safety data required to complete an appropriate assessment.
Novel excipients may be one important key to drug product improvements. They may address the following issues:
- patient compliance – through, for example, advancement of formulation of more patient-friendly dosage forms
- development of high-quality drug products – through, for example, modification of drug plasma profiles
- advancement of manufacturing science for drug products – through, for example, enabling or facilitation of continuous manufacturing or other advanced manufacturing methods for drug products
Currently neither pharmaceutical companies (as excipient users) nor excipient manufacturers have incentives to use or develop novel excipients which can produce all three potential improvements discussed above.
Pharmaceutical companies are generally unwilling to risk the use of novel excipients because of the regulatory uncertainty of the current process to get them approved in their formulation which can result in delays in approval of their application. Novel excipients could be an important factor in controlling costs of drug development since formulators might then be able to use the “best tool (excipient) for the job” instead of having to formulate around an approved but sub-optimal excipient. In some cases, certain drug products may not be able to be developed using traditional excipients and novel excipients may be needed to resolve various physical issues with APIs such as poor solubility and permeability.
In the case of excipient manufacturers, it follows that if their customers are unwilling to risk using novel excipients, there is little incentive to develop them. This can, and in some cases does result in stagnating market growth and innovation.
In the current state of affairs, there is no mechanism for evaluation of excipients alone – they are only evaluated as part of drug products in NDAs and ANDAs.
This result sometimes leads to drug products which are “good enough” but which may not be optimal.
IPEC-Americas has proposed to FDA that it adopt a new regulatory review or qualification process for novel excipients which provides for stand-alone (independent) review and qualification of excipients by the agency. The intent would be for this new regulatory review or qualification to help mitigate the uncertainty associated with novel excipient use.
It is important to note that IPEC-Americas has not suggested that novel excipients would or should be “approved” outside of the drug approval process, but rather that there could be preliminary safety and qualification assessments independent of the drug but based on safety data that exists to support the intended route(s) of administration and intended use level(s).
Currently the only mechanisms that exist for excipient manufacturers to present excipient-specific information to the agency independent of a drug application are Type IV (Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation) or Type V (FDA Accepted Reference Information) drug master files (DMFs). However, DMFs are only intended to be reviewed by the agency in conjunction with a specific drug application and there is no consistent approach to DMF reviews. This may result in refuse to receive notifications (for novel excipients that are not really new chemical entities) or application delays.
FDA toxicologists have referred IPEC-Americas to the Biomarker Qualification Program (BQP) as a possible model process for new excipients. IPEC-Americas believes that there are many important, relevant concepts in the program that, with modification, could provide a foundation for engaging FDA on modernizing a process for novel excipient safety review.
IPEC-Americas has offered to collaborate with FDA to define what the Agency would need to review in such a process. Information required for an excipient review could be similar to the type of information currently required for a Type II DMF for Active Pharmaceutical Ingredient (API) completeness assessment but with added focus on excipient safety.
There would also need to be development and implementation of a unique type of user fee system (different from the existing PDUFA user fee model) to fund FDA resources to perform independent safety assessments / qualifications of excipients.
IPEC-Americas has invited the FDA to continue discussions on possible approaches to create an improved pathway for review and acceptance of novel excipients based on defined criteria and mechanisms by which such a process could be formally recognized.