The registration of novel excipients

A shortage of novel excipients is stifling the ability of the pharmaceutical industry “to translate progress with small molecules and biologics into therapeutic success”.¹ Until now, the US Food and Drug Administration (FDA) has only evaluated the safety of novel excipients as part of ongoing drug submissions, ie, new drug applications (NDAs), and as such the pharmaceutical industry is reluctant to “jeopardise experimental drugs with additional excipient‑related risk”.² In addition, if the NDA submission is rejected or the file is withdrawn then any novel excipients proposed as part of the submission cannot proceed. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) and International Pharmaceutical Excipients Council (IPEC-Americas) have an established collaboration to assess some of the challenges to the use of novel excipients and identify potential solutions to facilitate the regulatory use of novel excipients. They submitted a briefing paper to FDA “to create a new pathway for qualification of novel excipients based on defined criteria”.³

In response to this strategic need, the FDA has launched a Novel Excipient Review Pilot Program (Pilot Program), to allow the regulator to review specific novel excipients prior to their use in drug formulations. FDA hopes that this programme will encourage the development of excipients that may be useful in those scenarios where the use of existing excipients has historically been challenging.⁴

This programme will be applied to novel excipients that “(1) have not been previously used in FDA-approved drug products, and (2) do not have an established use in food”.³ The programme will involve (1) the initial proposal stage providing a high-level overview of the novel excipient, including the “public health or drug development need addressed by the excipient” and (2) submission of a full data package consisting of toxicology (see CDER Guidance for industry “Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients”) and quality data (chemistry, manufacturing and controls data) comparable to the data provided in an investigational new drug application (IND).⁴

FDA will consider the following factors in assessing which proposals to select:⁴

1. Potential health benefit of any novel excipient (eg, excipients that could encourage development of new therapies for serious and life-threatening diseases, and excipients that could facilitate opioid abuse-deterrent formulations)
2. The likelihood of the excipient manufacturer being able to submit a complete IND-aligned data package within the established timeframe
3. Potential of any novel excipient to meaningfully enhance pharmacokinetic characteristics, ie, solubility enhancement for BCS class 2/4 drugs and permeation enhancement for BCS class 3/4 drugs, that could enhance drug development.

The closing date for proposals for the pilot scheme will be 7 December 2021. The pharmaceutical industry, US Pharmacopoeia (USP) and IPEC-Americas have all warmly welcomed the initiative.⁵ A spokesperson for Janssen recently indicated that the use of novel excipients would help to resolve formulation challenges with certain biologic drugs; “Novel excipients that can stabilise proteins from adsorption at air-water and solid-water interfaces in the presence of enzymes would greatly benefit the development of biologic formulations.”⁶ Novel excipients include cyclodextrin‑based excipients.⁷ Modified cyclodextrins appear to have the ability to inhibit thermally induced aggregation in proteins. Modified cyclodextrins have also shown significant promise as “non‑viral gene and siRNA delivery vectors in a range of in vitro and in vivo studies”. siRNA molecules appeared to be more susceptible to environmentally induced conformational changes than DNA systems and the stabilisation appears to be via complexation of siRNA with cyclodextrins.⁸

IPEC-Americas recently ran a successful virtual meeting on FDA’s Pilot Program.⁹ In summary, it appears that industry lobbying has been successful in persuading FDA to consider a new regulatory pathway to authorise novel excipients. It is hoped that EMA will also follow suit.

References

1. Kingwell K. Excipient developers call for regulatory facelift. Revs. Drug Discov. 09 November 2020. https://www.nature.com/articles/d41573-020-00201-1. Accessed on 06 November 2021.
2. Mullard A. Novel excipient review programme aims to bolster formulation innovation. Revs. Drug Discov. 04 October 2021. https://www.nature.com/articles/d41573-021-00169-6. Accessed on 06 November 2021.
3. Novel Excipients Working Group. Novel Excipients: A Collaborative Initiative between the IQ Consortium and IPEC Americas Submitted to the United States Food and Drug Administration. file:///C:/Users/marga/Downloads/FDA-2019-N-5464-0003_attachment_3.pdf. Accessed on 06 November 2021.
4. Novel Excipient Review Pilot Program. 07 September 2021. https://www.fda.gov/drugs/development-approval-process-drugs/novel-excipient-review-pilot-program. Accessed on 06 November 2021.
5. Brennan Z. Industry Supports FDA’s Plans to Review Novel Excipients Outside of Applications. 04 February 2020. Regulatory Affairs Professionals Society (RAPS). https://www.raps.org/news-and-articles/news-articles/2020/2/industry-supports-fdas-plans-to-review-novel-exci. Accessed on 06 November 2021.
6. Eglovitch JS. FDA’s novel excipient pilot program opens for candidates. 08 September 2021. Regulatory Affairs Professionals Society (RAPS). https://www.raps.org/news-and-articles/news-articles/2021/9/fdas-novel-excipient-pilot-program-opens-for-candi. Accessed on 06 November 2021.
7. Hardeep S, Feng H, Bhambhani A, et al. The Effects of Substituted Cyclodextrins on the Colloidal and Conformational Stability of Selected Proteins. Pharm. Sci. 2010, 99(6), 2800-2818.
8. O’Mahony AM, Cronin MF, McMahon A, et al. Biophysical and structural characterisation of nucleic acid complexes with modified cyclodextrins using circular dichroism. Pharm. Sci. 2014, 103(5), 1346-55.
9. IPEC-Americas. Novel Excipient Review Pilot Program Overview and Q&A. 27 October 2021. https://ipecamericas.org/excipient-learning-lab/webinars/novel-excipient-pilot-program-overview-and-qa. Accessed on 06 November 2021.