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A new program will test the safety and suitability of new inactive ingredients to encourage the accelerated adoption of FDA-accepted excipients in drug development.
In an important step for modernizing drug formulation and biopharmaceutical development, FDA is launching a program to test the safety and suitability of novel excipients for use in new drugs and biologics. This final initiative, first proposed two years ago, will support a pilot program to test up to four novel excipients likely to improve the effectiveness and safety of important new drugs (1). The aim is to encourage sponsors of clinical trials to test new drugs formulated with excipients that FDA finds acceptable for use under this program.
FDA announced the pilot program Sept. 7, 2021, and spelled out the application process in a Federal Register notice (2). The notice explains that the pilot is open to novel excipients that have not been used previously in food or in FDA-approved products. Excipient manufacturers seeking to participate in the pilot should submit information on the novel inactive ingredient and its potential for enhancing health by offering pharmacokinetic characteristics important to developing new drugs, as described in an outline for an initial proposal (3). The sponsor also must show it can produce a complete information package in the set time frame for weighing pilot proposals. Initial pilot review proposals are due at FDA by Dec. 7, 2021.
FDA defines a novel excipient as an inactive ingredient that is not fully supported by existing safety data related to a proposed level of exposure, duration of exposure, or route of administration. Manufacturers should describe how the product addresses a public health need and advances drug development, such as by increasing solubility for an oral formulation taken chronically. Sponsors also, should describe available quality and toxicology information that support the product’s safety, such as pharmacokinetic/toxicokinetic data and other nonclinical information, as presented in FDA guidance issued in 2005 (4).
From these submissions, FDA will select four products for full review under the pilot, planning for two during the first year. Selected participants then should provide a full data package of toxicology and chemistry, manufacturing, and controls (CMC) quality data, as required for excipients. If the excipient passes muster, FDA will determine that it may be used in the formulation for an experimental drug undergoing clinical trials, provided that the sponsor demonstrates that it is safe to use in that therapy. After FDA approves a new drug or biologic utilizing the new excipient, that excipient would then be added to FDA’s Inactive Ingredient Database, making it available for use by other manufacturers, including those producing generic drugs.
Manufacturers of drugs and biologics, as well as excipient developers, have long sought a process for FDA to evaluate new inactive ingredients prior to use in a new drug or biologic. A perennial difficulty is that new drug sponsors are reluctant to delay or complicate FDA review and approval of an investigational new drug (IND) for an experimental therapy due to the need to assess an untried inactive ingredient in the product formulation. Yet, these firms increasingly face difficulties in formulating innovative products with available, established excipients. Biopharma companies have expressed support for the pilot as a way to address these development challenges, such as the need for new ways to stabilize proteins for bioavalability in new formulations. Excipient makers similarly acknowledge that they would be more willing to invest in production, controls, and characterization of novel excipients if it’s possible to gain FDA review of the product’s benefits outside of clinical testing for a new molecular entity.
FDA first proposed this process for evaluating novel excipients separate from new drug applications in a Federal Register notice posted in December 2019 (5). That draft plan asked manufacturers to comment on the proposed program, its definitions and scope, and FDA sought to address these issues in this final proposal.
It appears fitting that FDA is launching this novel excipients pilot program as the International Pharmaceutical Excipients Council, IPEC-Americas, marks its 30th anniversary. IPEC held its first meeting in March 1991, with the aim of harmonizing excipient standards set by different pharmacopeias and to address worldwide issues important to excipient use. Manufacturers of these essential ingredients in pharmaceutical formulations note that many well-known excipients that have been used for decades are not suited to the novel dosage forms and parenterals under development today (6). Industry also would like to see an update of FDA’s 2005 guidance on excipient safety testing, mentioned previously. These initiatives, as well as ongoing efforts to set international standards for excipient use, have potential to enhance drug formulation and support modern manufacturing and quality control efforts.
1. FDA, Novel Excipient Review Pilot Program, FDA.gov, accessed Sept. 14, 2021.
2. FDA, Center for Drug Evaluation and Research Office of New Drugs Novel Excipient Review Pilot Program, Notice, Sept. 8, 2021.
4. FDA, Guidance for Industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (CDER, CBER, May 2005).
5. FDA, Novel Excipient Review Program Proposal; Request for Information and Comments, Federal Register, 84 FR 66669, Dec. 5, 2019.
6. C. Challener, PharmTech 45 (3) (March 2021).
Jill Wechsler is BioPharm International's Washington editor, firstname.lastname@example.org.
Volume 34, Number 10
When referring to this article, please cite it as J. Wechsler, “FDA Moves to Advance Innovative Excipients,” BioPharm International 34 (10) 2021.