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.
Outsourcing reformulation expertise
Reformulating an existing drug product can be a time- and cost-effective way of rejuvenating a product line while also making a therapeutic more patient-friendly. To find out more about how external expertise can help sponsor companies achieve success in reformulation strategies, BioPharm International spoke with Jan Jezek, chief scientific officer of Arecor, and Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm.
BioPharm: How might companies benefit from using a partner for reformulation tasks?
Jezek (Arecor): An innovative formulation technology company, such as Arecor, can use its expertise, know-how, and technology to develop novel formulations of therapeutic medicines with enhanced properties, enabled by the formulation, which would otherwise not be possible. These enhancements can improve treatment options and outcomes for patients. The technology can be applied to a variety of new products in development to maximize their benefit for patients. However, the reformulation technology can also be applied to existing marketed products as part of life cycle management.
Jagdish (Recipharm): Reformulations are often considered by big-brand pharmaceutical companies as a strategy for enhancing the lifecycle management of their patented product and to delay generic entry as far as possible. These companies often have many lead molecules to work upon, meaning it can be hard to find the capacity required for reformulation in-house. Working with a contract development and manufacturing organization (CDMO) partner can help them find that additional resource, enabling them to manage multiple reformulations simultaneously while freeing in-house capacity to focus on innovation.
For generic companies, reformulation gives them an advantage in terms of 505 b(2) filing. [FDA] 505 b2 approvals give additional exclusivity to a product. When applied to a reformulated drug, it can help to prevent generic entry until the expiry of the filing. As such, they keep development in-house, provided they have the internal capacity and infrastructure. However, if the generic company is reformulating to change excipient or manufacturing process, they may well prefer to outsource to a CDMO to provide the necessary expertise and infrastructure so they can concentrate on other projects.
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.
Article details
BioPharm International
Vol. 35, No. 10
October 2022
Pages: 16–17, 48
Citation
When referring to this article, please cite it as F. Thomas, “Adopting Smart Development Strategies,” BioPharm International 35 (10) 2022.
