Best Practices in Dealing with Novel Excipients

Mariya Gromova and Noemi Lupo

by Mariya Gromova and Noemi Lupo

Novel excipients play a crucial role in bringing new, improved and safer drugs to the pharmaceutical market. There are however significant challenges in the development of innovative excipients, mainly because of the absence of globally aligned regulatory mechanisms. Biopharma Excellence has successfully supported several projects involving novel excipients. In this article, we provide an overview of the regulatory landscape and strategic considerations for the development of novel excipients in the EU and US.

Excipients are the main components of any pharmaceuticals’ formulation and crucial for its safe and effective use. The functionality of excipients is very diverse: They can be used as fillers, lubricants, coloring matters, antioxidants, preservatives, adjuvants, stabilizers, emulsifiers, solubilizes, permeation enhancers, etc. Although the majority of approved products only contain traditional, well-studied compendial excipients, the use of novel excipients is unavoidable for the formulation of some advanced products. Also, progressively more companies prefer to develop sophisticated and innovative formulations involving novel excipients. This opens the way for advanced drug delivery systems aimed to improve the therapeutic profile of drug substances or to meet the need for more convenient routes of administration.

What is a novel excipient?

ICH, EMA: A novel excipient is an excipient which is being used for the first time in a drug product, or by a new route of administration. It may be a new chemical entity or a well-established one which has not yet been used for human administration and /or for a particular human administration pathway.

FDA: New excipients are any inactive ingredients that are intentionally added to the therapeutic and diagnostic products, but that:

1) are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g. enhance absorption or control release of the drug substance),

2) are not fully qualified by the existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.

Regulatory landscape

Under the current regulatory framework novel excipients are not evaluated independently, but as part of a submitted IND/IMPD. Therefore, applying guidelines for the EU and US (as described in Figure 1) should be taken into account early in the development of drug products containing novel excipients.

Figure 1: US and EU Guidelines: what is important for the development of novel excipients?

Hurdles and challenges in the development of novel excipients

Pharmaceutical companies are often reluctant to introduce novel excipients in their formulations due to the amount of additional data required to support regulatory approval. Indeed, full details on the novel excipient´s manufacture, characterization and controls, with cross references to supporting non-clinical and clinical safety data must be provided. Data should be presented in a format similar to the active substance format – meaning a significant amount of detail is expected. This results in increased costs and time required for the development of the final drug product – even more so as, specific regulatory requirements are not yet available for novel excipients and expectations are not aligned worldwide. Lastly, a significant proportion of generated novel excipient data contains commercially sensitive and proprietary details and is therefore the intellectual property of the novel excipient manufacturer. To protect this sensitive data, a Type IV Excipient Drug Master File can be used for the US, but there are no equivalent procedures available in Europe.

Figure 2: Challenges vs benefits of using novel excipients in your product development

How to approach a novel excipient project: Strategic considerations

As outlined in Figure 3, the highly variable approach to a novel excipient strategy begins with a comprehensive literature search, which should determine all available chemical and toxicological data for the excipient of interest. Particular attention should be paid to monographs of the major international compendia (Ph. Eur., USP and JP), the international specifications (FAO/WHO/JECFA), FDA Inactive Ingredient Database, Handbook of Pharmaceutical Excipients, historical usage as a food additive or cosmetic product and Food Chemicals Codex. As a second step, crucial product-specific points, like compatibility and functionality-related attributes should be identified and addressed according to the heterogenous information available from guidelines. Only then the strategy for the development of the novel excipient of interest can be shaped, taking into account the current regulatory framework and aiming at a minimization of required resources while ensuring a high-quality product.

Figure 3: Strategy to approach a novel excipient project

Biopharma Excellence is offering a customized strategic approach to overcome challenges linked to novel excipients, allowing to maximize the benefits of novel excipients throughout product classes. We were successfully involved in several novel excipients projects, focusing on both strategic and regulatory questions, and can support your project with all the required documentation. Could you use a boost of your novel excipient program? Then please do not hesitate to contact us.

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