Meera Raghuram- Director of Regulatory and Sustainability Strategy, Lubrizol
Why do you believe excipient innovation has lagged, even as drug molecules themselves have become increasingly complex?
Many commonly used excipients were developed decades ago and may not be optimal for formulating today’s increasingly complex molecules into effective therapeutics. This is especially true for the growing number of poorly soluble and poorly bioavailable BCS Class II and IV active pharmaceutical ingredients (APIs) in the development pipeline.
Yet excipient innovation has lagged. In a risk-averse culture created by the ambiguity surrounding regulatory approval for excipients, formulators prefer to stick to familiar ingredients, even when better novel options exist. In turn, this has made excipient manufacturers reluctant to invest in developing excipients whose market success is essentially dependent on the drug approval process. It’s a catch-22.
Given regulatory uncertainties, what are the main factors preventing drug developers from adopting novel excipients, and how can these concerns be addressed?
One of the most significant hurdles for the broader acceptance of novel excipients is their lack of a direct regulatory approval pathway. Unlike APIs, excipients are not independently assessed, but only as part of a complete drug product submission package – leaving drug developers to shoulder the risk of using them.
The U.S. FDA’s Novel Excipient Review Pilot Program, launched in 2021, sought to address this issue by considering an independent safety review for novel excipients for acceptability for human use that would provide some level of assurance to drug manufacturers. The excipient would still be subject to review as part of the drug approval process for specifics related to indications of use, patient population, etc. The industry expectation was that, if successful, the pilot would be developed into a full regulatory pathway. However, the pilot program’s status is currently unknown, leaving drug developers and excipient suppliers in the same regulatory limbo that has been stifling innovation for decades.
How do current limitations in excipient diversity impact the ability of formulators to bring poorly soluble or bioavailable APIs to market?
Given the high costs involved in drug development, many formulators will only consider excipients with precedence of use, as listed in the FDA’s Inactive Ingredient Database (IID). The critical issue with relying on a limited formulation of excipients is that it may result in suboptimal drugs or even prevent a promising brick-dust API from coming to market.
What are some of the key benefits offered by new excipient technologies—such as Apisolex™ and Apinovex™—compared to traditional, precedent-listed ingredients?
Novel excipients offer distinct advantages over traditional ingredients, particularly for poorly soluble and poorly bioavailable APIs. Lubrizol’s Apisolex™ polymer excipient, for example, enhances solubility in parenteral and injectable applications by up to 50,000-fold, with high drug loading of up to 40:100 API to solubilizer. For oral dosage forms, Lubrizol’s Apinovex™ polymer excipient offers up to a ten-fold improvement in crystalline API dissolution and high drug loading of up to 80% via spray drying. High drug-loading capabilities also enable smaller dosage sizes and multiple APIs in one dose, aligning with regulatory bodies’ growing focus on improving the patient experience to optimize compliance.
New excipient technologies can support more efficient manufacturing processes that minimize processing complexity and waste. For instance, Apisolex™ enables simple formulation techniques such as solution mixing or oil-in-water emulsion formation, with over 90% API recovery. Additionally, novel excipients can be important drivers of innovation, suitable for the FDA’s 505(b)(2) accelerated regulatory pathway for drug approval, and providing IP protection not offered by traditional products.
Could you discuss how early collaboration between drug developers and excipient suppliers can help de-risk the development and adoption of novel excipients?
Lubrizol believes that early collaboration between drug developers and excipient suppliers is the solution to building formulator confidence in using novel excipients. Crucially, it enables identification of the developer’s specific unmet needs, for which the supplier may have suitable solutions. For example, including the excipient in a drug product’s non-clinical toxicology studies helps to demonstrate safety and highlight any data gaps.
We actively support this model by working with partners to co-develop data and regulatory submissions. Our Drug Master Files (DMFs) in the US, China, and Canada – or data-sharing agreements in regions where DMFs are not used, such as Europe – help streamline the approval process.
In what ways can “bridging” strategies or collaborative data generation help mitigate regulatory risk when introducing a novel excipient for a new drug application?
To help mitigate the regulatory risk of including a novel excipient in a new drug application, bridging arguments can be used. For instance, with a novel excipient that is chemically similar to an approved counterpart, the latter’s safety data may support the new application. Some older grades of Lubrizol Carbopol® polymer excipients were manufactured using benzene, which is no longer a preferred solvent, while newer Carbopol® grades utilize acceptable solvents such as ethyl acetate. If a manufacturer wants to switch to a benzene-free grade, we can provide data showing that the physical, chemical, and safety characteristics of the legacy and new grades are comparable.
Looking ahead, what practical steps can the pharmaceutical industry take to accelerate regulatory clarity and foster greater innovation in excipient technology?
It’s essential for drug manufacturers to engage early with excipient suppliers, discuss unmet formulation needs, and collaborate to develop new technologies. Novel excipients should be considered as strategic assets, not regulatory liabilities, with bridging strategies and collaborative data generation used to de-risk their use. By taking these steps – alongside pushing for regulatory clarity and global harmonization – the pharmaceutical industry can foster greater innovation and unlock the potential of much-needed new therapeutic technologies.
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