The FDA 505(b)(2) regulatory pathway for drug approval, which allows applicants to use existing safety data as evidence, continues to grow in popularity. Innovators are keen to leverage the 505(b)(2) pathway to create a streamlined journey to market. Meanwhile, the ability to cite existing studies also means reduced risk when compared to the risk of an investigative drug failing safety checks.

Often, the 505(b)(2) route is chosen when developing a differentiated dosage form for a drug already on the market. Drug product developers gain a competitive edge by enhancing the drug’s properties, such as providing improved compliance through easier dosing or better biological performance by using a different route of administration.

Selecting appropriate inactive ingredients, or excipients, is crucial when optimizing a new formulation for the 505(b)(2) pathway. For instance, innovators seeking improved solubility of an active pharmaceutical ingredient (API) and IP protection can turn to an excipient that offers these advantages. Novel excipients supported by adequate safety data for the intended use can be the key to unlocking the benefits of the 505(b)(2) pathway.

We sat down with Lubrizol Life Science – Health’s (LLS Health’s) Director of Regulatory and Sustainability Strategy, Meera Raghuram, and LLS Health’s CDMO division President, Robert Lee, to discuss important considerations for 505(b)(2) drug development and best practices for leveraging novel excipients.

Benefits of the 505(b)(2) pathway

The advantages offered by the 505(b)(2) pathway are not limited to reduced risk and competitive differentiation. The 505(b)(2) route can also help with lifecycle management, spanning all companies from small to large pharma.

“For example, TriCor used nanomilling technology to develop an improved version of their fenofibrate product to eliminate the fed-fast effect along with increasing oral bioavailability to help TriCor differentiate itself from generic competition.” –Robert

Meanwhile, the ability to leverage existing safety data has the additional impact of potentially increasing speed and reducing cost, which is especially beneficial for smaller companies.

“For example, if you converted an oral tablet to a transdermal patch, the burden of safety/toxicity is much lower because you are leveraging the established safety/toxicity profile and bridging to the new route of exposure. Any incremental data would be limited to filling any gaps for assuring safety for the new route of exposure. – Meera

The 505(b)(2) route allows companies to concentrate on how to make the best formulation – one that will allow differentiation in the marketplace and that can enable incremental improvements such as more patient-friendly dosage forms.

Key considerations in 505(b)(2) product development

“Key considerations in excipient selection usually boil down to ‘Does it work, is it safe, and, very importantly, does it enable IP protection?’” – Robert

With this in mind, there are a few key points to keep top of mind when deciding on an excipient. Firstly, the choice of excipient is one that should be made during the early stages and after the target product profile (TPP) has been defined. The TPP specifies the desired characteristics of a drug, which can include safety or efficacy-related properties. This is crucial because from a technical standpoint, a drug may need improved solubility or to achieve higher drug loading to meet the TPP.

Physicochemical properties are not the only area of importance in drug development, however. If the project is to be successful, patient concerns and commercial factors should also be considered when choosing an excipient, namely:

For patients, key concerns are ease of administration and reduced side effects, so excipients should ideally improve performance in these areas.

From a commercial standpoint, IP protection is critical
- Developing a robust patent portfolio is a key part of the commercial strategy for drug products.
- The patents on new drug products often reference several formulations utilizing different excipients and formulation techniques so as to provide as protection that is as broad as possible for the innovator. As such, obtaining IP protection on a 505(b)(2) product can be particularly difficult, and new ingredients and technologies may be required to navigate these IP challenges.

In many cases, utilizing new excipients can be an ideal choice to meet IP protection criteria and address patient and physicochemical concerns.

Choosing a novel excipient for 505(b)(2) reformulation

“When developing a product, you have to show what doesn’t work in addition to what does work, so novel formulations may need to look beyond IID-listed products to carve out IP on a 505(b)(2) product.” – Robert

Novel excipients, even ones that may not yet have precedence of use in the desired route of administration, can be an excellent choice if they truly enhance the formulation and you can establish a reasonable safety profile. This is especially true in cases where innovators have explored approved IID-listed excipients and the novel excipient improves desired properties.

“On the 505(b)(2) pathway, it is especially feasible to use excipients that may have precedence in another route of exposure, as in any case the safety profile from the existing product will need to be bridged to the new use. Needless to say, for any excipient either with precedence in another exposure route or a new chemical entity, adequate safety information for the intended use will be required.” – Meera

Additionally, there has been feedback from the market that the use of novel excipients is desired, so the FDA is taking steps to encourage the use of new technologies. This includes the Novel Excipient Review Pilot Program, which allows excipient manufacturers to obtain FDA review of certain novel excipients prior to their use in drug formulations. For oncology compounds in particular, the risk-to-benefit ratio can allow more flexibility from the FDA in order to get life-changing drugs on the market.

Finally, it is important to consider quality and security of supply in novel excipient selection. There is a difference between incorporating a benchtop academic polymer versus a well-characterized, GMP-manufactured excipient product from a trusted supplier. Choosing the latter can mitigate batch-to-batch variation and ensure there is supporting data to show the polymer is safe for use in commercial products.

Introducing Apinovex™ and Apisolex™ Polymers for 505(b)(2) Formulations

At LLS Health, understand the important role that novel excipients play in drug development, and that is why we have developed ground-breaking Apinovex™ and Apisolex™ polymers excipients for oral and parenteral formulations, respectively.

Apinovex™ polymers are high molecular weight polyacrylic acid excipients designed to provide both processing and formulation benefits for spray-dried amorphous solid dispersions (ASDs). These polymers allow formulators to enhance oral drug solubility, facilitate high, stable drug loading of up to 80%, and may enable smaller, easier-to-swallow tablets/capsules.

Apisolex™ polymer is a safe, GMP-compliant, injectable-grade poly (amino acid)-based excipient for use in parenteral formulations. It can enhance the solubility of hydrophobic APIs up to 50,000-fold, allows high drug loading, and is compatible with simple formulation techniques. Apisolex polymer produces injectable products with fewer adverse reactions and, when lyophilized, can be rapidly and easily reconstituted in saline.

Having excipients for both oral and parenteral use gives flexibility should the dosage form need to change depending on the drug’s properties. Meanwhile, the properties of Apinovex and Apisolex polymers can help customers who, in line with their TPP, are seeking to simultaneously overcome solubility challenges, increase drug loading, and produce more patient-friendly products.

Additionally, incorporating either Apisolex or Apinovex polymers can provide patent protection for reformulated drugs – addressing a major commercial concern. Formulators using either of these recently patented polymers will enjoy the benefit of long patent life.

Selecting an excipient supplier

Settling on the right novel excipient is important, but the quality and reliability of the supplier should also be assessed before the final choice is made.

“When selecting an excipient supplier, pharma companies should assess the quality criteria, as well as the compliance and safety information available, and the flexibility of the supplier if there are specific needs for the excipient, such as customized specifications or collaboration on patent applications.” – Meera

In summary, pharma companies should look for an experienced excipient manufacturer with:

Robust, GMP manufacturing processes in place
A polymer that can be manufactured without wide batch-to-batch variation
The information necessary to assure the FDA that the excipient is safe for use for the intended purpose, along with stability data.

“LLS Health has manufactured pharmaceutical excipients for decades, and we have the quality, regulatory, and manufacturing expertise to support drug products from early-stage development through commercial supply. We understand global regulatory requirements and act as a true partner in drug product development, especially when you are working with our novel Apinovex and Apisolex polymers.” – Robert

Novel excipients for 505(b)(2) success

When reformulating drugs on the 505(b)(2) regulatory pathway, the choice of excipient is critical and must balance technical, patient, and commercial needs. Novel excipients from an experienced supplier with the right processes in place – as in the case of Apinovex and Apisolex polymers – can be a key cornerstone of successful 505(b)(2) development.

By both enhancing the formulation in line with the TPP and conferring patent protection, drugs incorporating novel excipients such as Apisolex and Apinovex polymers are well positioned to both benefit from a competitive edge in the market and improve patients’ quality of life.

Request a sample or get in touch to learn more about our novel Apisolex and Apinovex excipients.

The power of novel excipients in 505(b)(2) products