Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group

Abstract

Excipients are essential components within drug products that contribute significantly to their overall quality, effectiveness, and safety. There is a lack of global, harmonized guidance relating to the non-clinical testing of novel excipients which is perceived to create uncertainty and strategic risk, potentially hindering innovation and disincentivizing their use. To test these perceptions, the IQ Novel Excipient Working Group surveyed member companies regarding their main concerns and prior experience regarding the non-clinical evaluation of excipients. Of the 19 respondents, 13 provided, collectively, 33 non-clinical program examples supporting the development of novel excipients. Programs were distributed across a range of therapeutic areas and included a variety of drug modalities and administration routes. Package designs were variable, but where possible, employed the use of existing data, supplemented with new toxicology studies as appropriate. Of the programs which had submitted data to regional health authorities, only three received feedback requesting additional studies or that demonstrated differences in regional opinion. In addition, companies provided recommendations on how the current (or new) guidance related to non-clinical excipient evaluation (and other areas, such as Chemistry, Manufacturing, and Controls and databases) may be improved.

Introduction

The U.S. Food and Drug Administration (FDA) define an excipient as any ingredient intentionally added to a drug product (including a biological drug product) that is not intended to exert therapeutic effects at the intended dosage, although it may improve product delivery.1 The FDA further defines a “new” excipient as one not fully qualified by existing safety data with respect to its proposed context of use (e.g., proposed exposure level/duration or administration route).1 International Council for Harmonization (ICH) and European Medicines Agency (EMEA) guidance define a “novel” excipient as one being used for the first time in a drug product or by a new route of administration.2,3

Excipients may represent the major constituent of any drug product (80–90%)4 and contribute to the overall drug product performance.5 Commonly, excipients function to enhance an active pharmaceutical ingredient (API) solubility and bioavailability and control (e.g., sustain) its rate of release. Other roles may relate to drug product identification, palatability, stability, and manufacturing. Given the evolving landscape in drug development (e.g., introduction of new modalities and advanced drug delivery technologies), the need for new excipients is expected to increase with the global pharmaceutical excipient market projected to exceed $8 billion by 2023.6

The contribution to the overall safety, effectiveness, and quality of a drug product must be recognized. Existing regulatory guidance (FDA, EMA, ICH, etc.) is useful though somewhat dated; FDA guidance for the non-clinical safety evaluation of excipients was issued in 2005.1 There is no internationally harmonized guidance regarding the appropriate level of non-clinical testing to support qualification of novel excipients. Coupled with the relatively limited industry experience relating to the development of novel excipients, this is perceived to create uncertainty and strategic risk which may hinder innovation and disincentivize companies regarding their use/development. Consequently, patients may be denied access to new and valuable medicines and/or those which could significantly improve the patient experience for vulnerable groups such as geriatrics and pediatrics.7 This may also result in the conduct of non-clinical studies with limited or no value.

To test these perceptions and capture pharmaceutical industry experience, the IQ Consortium Novel Excipient Working Group (NEWG) conducted a pharmaceutical company survey to identify the main concerns or limitations regarding the non-clinical evaluation of novel excipients. Objectives included:

• Understand companies’ perspectives and drivers regarding the development of novel excipients, including perceived barriers.
• Understand how the current regulatory landscape influences the design/conduct of non-clinical studies/packages for novel excipients.
• Understand variations in regulatory non-clinical feedback and expectations across different global health authorities.
• Learn how companies successfully qualified novel excipients.
• Review opinions on current guidance and value of a future, harmonized global guidance.8

Results

Programs Employing Novel Excipients

Therapeutic area, drug modality, route of administration, and duration of exposure

Therapeutic Area

Programs were distributed across ten therapeutic areas (Figure 1), most commonly, “metabolism” (n = 8), “oncology” (n = 5), “anti-infective (n = 5), and “neurology” (n = 4).

Drug Modality

The most common drug modality for which novel excipients were being developed were small molecules (n = 17) followed by peptides (n = 7) and antibodies (n = 5). One program employed “excipients” to support the ex-vivo storage of human tissue prior to transplantation.

Route of Administration

The most common route of administration was oral (n = 13) followed by subcutaneous (n = 5) and intravenous (n = 4) injection. The majority of peptide programs (71%) and approximately half of the small molecule programs (47%) employed oral delivery. The distribution of administration routes, relative to drug modality is shown in Figure 2.

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Materials and Methods

The survey (Appendix A) was reviewed by the IQ Consortium NEWG and Drug Product and DruSafe leadership groups and ran between 11th November 2021 and 23rd February 2022; follow up responses were received by 19th August 2022. The survey was distributed to all IQ consortium member companies.

Definitions were provided for the key terms (API, excipient, novel, and new excipient) (Appendix A). The term “novel excipient” was used in the survey to describe an excipient used for the first time in any drug product or in a context different to that already approved (e.g., new administration route and longer duration).

Respondents were asked if they had developed or were currently developing any drug product containing novel excipients for which a non-clinical package was conducted. A non-clinical package was defined as one comprising new non-clinical studies and/or a review/assessment of “existing” data which may be used in-lieu of new studies (e.g., literature, approved use in another context, and data for related molecules). Companies that did not include novel excipients were asked for further details including a rational for this position. Companies that included novel excipients were asked to provide up to 5 non-clinical program examples (between 2010 and 2021) including information such as the type of API for which the excipient(s) was included, administration route, use duration, and therapeutic area and if the excipient(s) was entirely novel or not. For each example, respondents summarized the non-clinical studies conducted (type, species etc.), the key objective of the package, the regions for which the drug product was intended and the health authorities which had reviewed data (e.g., via a New Drug Application (NDA), Biologics License Application (BLA), and Investigational New Drug (IND) application or briefing documents), and if health authority feedback was consistent across regions.

All companies were asked if the current non-clinical guidance for the assessment of novel excipients could be improved (and if so, how) and whether a harmonized, global guidance would be useful (and if so, why).
No data were collected against specific company names and all responses were confidential and anonymized by an independent third-party secretariat (Faegre Drinker Biddle & Reath LLP) prior to being provided to the authors. The survey did not include any questions specific to any excipient (e.g., name and type).

Follow Up Questions and Interpretation of Responses

During data review, some weaknesses in the survey were identified, some of which required follow up questions. For example:

• A free text field to add more context to the non-clinical packages (design/drivers) would have been useful.
• The term “existing data” was not defined; the authors considered (but did not define) source of existing data as the FDA inactive ingredient database (IID) and Generally Regarded as Safe (GRAS) database and Drug Master Files (DMFs) and United States Pharmacopeia (USP). In retrospect, existing data may also comprise of in-house data or data in the literature.
• An option to provide more detail regarding the status of the program would have been useful, for example, a “complete” program may represent a one that was finalized (e.g., achieved approval) or stopped for other reasons.

Following initial data review, the secretariat sought clarification for some responses (e.g., responses omitted or contradicted other answers); not all queries were answered/clarified. In some cases, based on the follow up responses and/or answers to other questions, the authors interpreted responses to some unanswered questions which are summarized in Appendix B; three case studies were excluded from the analysis as it was not possible to fully interpret the responses.

Giffen PS, Buckley LA, Pinkstaff J. Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group. International Journal of Toxicology. 2023;42(6):480-488. doi:10.1177/10915818231189703

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