Considerations for a Successful Reformulation Strategy

Traditional drug development is costly and time-consuming, with many hours, days, and years spent researching and developing novel chemical entities that, for the most part, will likely fail to get to the commercial finishing line. Repurposing a drug can offer companies an approach to drug development that is much more time- and cost-efficient and offers a higher chance of success. According to research, 30% of repurposed drugs gain approval, which is three times higher than the rate for new drugs (1).

There are three main strategies to repurposing a drug product: determining a novel therapeutic indication for an already known drug (repositioning); developing a new formulation of a drug product (reformulation); and combining two or more drugs that were already being used as single drug products (combination) (2). Despite the various benefits of repurposing existing drug products can offer, each strategy also has certain challenges to overcome that can act as a deterrent to developers.

Benefits of reformulation

“Reformulation can be used very effectively to develop improved medicines and treatment options for patients,” confirms Jan Jezek, chief scientific officer of Arecor. “For example, creative formulation can be used to improve the pharmacodynamics and pharmacokinetics of a drug.” Highlighting a specific case of creative formulation, Jezek points to the development of a novel formulation of insulin that has is being developed by Arecor, which accelerates the drug’s absorption post-injection, leading to improved glycemic control.

“Another example benefit of reformulation is to convert a lyophilized powder medicine to stable liquid ready-to-use (RTU) product formats, which are becoming increasingly important to enable fast, safe, and effective treatment of patients,” Jezek continues. “Innovative formulation approaches can also lead to improvement in stability of small- and large-molecule products and enable their use outside the cold chain, which can significantly improve convenience of use.”

Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm, emphasizes that reformulation can be performed for several key reasons. “[Reformulation] can allow developers to improve the performance and patient centricity of an existing drug. For example, it may be done to create a version of an existing drug that is more convenient and easier to use for the patient, increasing quality of life or boosting adherence and, in turn, therapy success,” he says.

Additionally, Jagdish remarks that reformulation can be used to enhance solubility, to improve absorption, or to boost the stability of a drug product formulation. “In all cases, reformulation can save a considerable amount of time and financial resource compared with the discovery and development of an entirely new chemical entity,” he states.

Moreover, it is possible to use reformulation as a way of extending the line of an older drug product, Jagdish points out. “[Reformulation] offers an opportunity to change an excipient or evolve the manufacturing process to deliver marginal gains in performance or ensure compliance with new regulatory requirements,” he says. “Regardless of the reasons for the reformulation, assessment of the regulatory implications of reformulation is essential.”

Regulatory considerations

First and foremost, Jagdish stresses that it is critical for companies to be aware of the regulatory requirements of the target geography of the reformulated drug product. “There is considerable variation in the regimes in each country, so pharmaceutical companies should evaluate their compliance needs on a case-by-case basis,” he says. “For example, the US Food and Drug Administration (FDA) has published its guidance for industry on Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, which can help companies understand the regulatory requirements in the [United States]” (3).

For Jezek, considering the formulation excipients and whether those being used in the reformulated product are indeed approved for the intended use—administration route and desired dosage regimen—is critical. “[Whether or not the excipients are considered novel] impacts the complexity of development as it is necessary to justify the use of the excipients and to demonstrate the safety of the excipients required. Novel excipients will carry a higher regulatory and development burden,” he specifies.

When approaching a reformulation strategy for a drug product, developers should define the target product profile at the outset, Jezek continues. “In other words, the formulation scientist needs to understand the desired stability and other requirements that the products must meet, such as specific impurity levels, to be approved by the regulatory authorities,” he says.

Other challenges

After defining the target product profile, the developer needs to understand the degradation pathways that can potentially impact the stability of the drug product during storage, Jezek adds. Appropriate methods must be established so that any degradation pathways can be measured and understood. “Such methods are often referred to as stability‑indicating methods,” he notes.

“The last challenge, which is most critical for successful reformulation, is to be able to select the right combination of inactive ingredients that will collectively interact with the small- or large-molecule drug in a way that reduces the degradation rate and thus enables the desired product profile,” Jezek confirms.

According to Jagdish, the challenges that pharmaceutical companies need to overcome when approaching a reformulation project depend upon the type of reformulation they are undertaking. “For example, when developing a new formulation of a drug for the same indication, achieving bioequivalence for the new formulation with the existing one poses a significant challenge, because it is no longer a like-for-like comparison,” he asserts.

“Reformulation can also be considered to reduce the size of the dose of a medication, to improve safety profile and patient compliance,” Jagdish continues. “Again, in this case, there is a need to demonstrate that the efficacy of the lower dose is equivalent to that of the already clinically proven and approved higher dose.”

Providing another example, Jagdish points out that when developing a fixed-dose combination therapy from two independently approved drugs, demonstration of the bioequivalence can also be tricky. “Here, in addition to maintaining bioequivalence with the two existing single-dose products, companies have to ensure the compatibility of the two drugs when in the same formulation,” he says.

When reformulating large molecules, Jagdish emphasizes that additional challenges—when compared with those facing small-molecule formulators—need to be addressed. Challenges such as solubility, absorption, and stability, he specifies.

Because large molecules are commonly administered via intravenous injection, it can be desirable and more patient-friendly to reformulate a drug product to be administered in an alternative way. “Often the focus of a change in the route of administration for a biological medicine is to enable a change from a time-intensive intravenous administration to a single subcutaneous injection,” Jezek confirms. “This [change] requires developing a highly concentrated formulation of the product that can be delivered via a small volume in a single injection.”

However, by reducing the volume of injectable product, the viscosity can become problematic. “Challenges that need to be overcome in developing these high concentration formulations is high viscosity (which can make the product too difficult to inject) as well as the propensity of proteins to aggregate (resulting in the formation of particles, which are unacceptable in pharmaceutical compositions),” Jezek explains. “In addition, proteins are subject to chemical degradation such as hydrolytic cleavage or oxidation. Innovative approaches to formulation design are often required to overcome these challenges.”

Yet, there are relatively easier reformulation routes, such as updating the excipients or the manufacturing process to extend the product’s line, Jagdish states. “Reformulation in these cases often simply involve step changes in the production process or the preparation of ingredients to enhance product quality or to improve manufacturing efficiency,” he specifies. “New ingredients are not generally involved, reducing the number of challenges that need to be overcome.”

References

1. N. Sommerford, “Drug Repurposing Basics,” Blog, IQVIA, May 12, 2022.
2. S. Murteira, et al., J. Mark. Access Health Policy, 2 (1) 22813 (2014).
3. FDA, Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, Guidance Document, FDA.gov (October 2015).

About the author

Felicity Thomas is the senior editor for BioPharm International.