(T1230-08-47) Leveraging Extemporaneous Preparation to Accelerate the Clinical Evaluation of an Injectable Suspension

Purpose: Long-acting treatment options are of significant interest as they reduce dosing frequency and improve patient adherence. Recently, an injectable suspension for subcutaneous and intramuscular administration required clinical speed; however, the traditional development path for an injectable suspension is costly and time-consuming. To accelerate the timeline, extemporaneous preparation, or the preparation of the drug product at a pharmacy co-located with the clinic, was employed. Although extemporaneous preparation is frequently leveraged in the early development of oral pharmaceuticals, this manufacturing strategy is rarely employed for injectable products. Early clinical supplies for parenteral products are commonly supplied via traditional GMP drug product manufacturing campaigns. However, this approach requires significant production and packaging lead times, typically occurring months prior to clinical study initiation. Additionally, this traditional paradigm requires development teams to invest time and resources to ensure adequate product stability throughout the shelf-life necessitated between manufacture and clinical dosing. Leveraging extemporaneous preparation for injectable products has the potential to greatly expedite timelines and reduce resource utilization in the early clinical space by eliminating the need for traditional GMP drug product manufacturing campaigns and reducing the drug product stability requirements. This added flexibility ultimately enables development teams to get drug to patients faster, and to quickly address key clinical questions. We herein utilize this development example to highlight the benefits and limitations of extemporaneously prepared injectable products.

Methods: Extemporaneous preparation was employed in a Phase 1 study of an injectable suspension. The strategy utilized is shown in Figure 1. A sterile drug product intermediate (DPI) was first manufactured in-house by dispensing bulk drug substance into sterile vials in a grade C space, and gamma irradiating these vials to obtain a sterile powder for further processing at the clinical site. At the clinical site, the bulk sterile powder was aseptically dispensed into dosing vials. Separately, the vehicle was prepared and sterile filtered. The vehicle was then added to the powder-in-vial, and the suspension was homogenized via vortexing prior to dosing.

Results: Employing extemporaneous preparation enabled a truncated timeline of approximately 11 months from the initiation of drug product development efforts to the initiation of the Phase 1 study, with only 2 months required for formulation definition. A traditional GMP manufacture was ultimately required to supply the sterile DPI. Accordingly, long-term storage stability of the DPI was established. However, the injectable suspension was prepared at the clinical site within hours of administration. Since the storage of the injectable suspension was limited to the in-use period of 24 hours, the time needed to develop the final product was abbreviated. Similarly, the drug substance, time, and resource demands were reduced. For a suspension product prepared extemporaneously, critical quality attributes include syringeability/injectability, content uniformity, as well as chemical and physical stability during the in-use period. Notably, the duration for which the homogenized suspension maintained content uniformity was limited. Additionally, simple physical manipulation, such as shaking and inversion, were not sufficient to achieve a homogenous suspension. However, these concerns were mitigated by the extemporaneous preparation of the suspension, as the clinical pharmacy employed vortexing for homogenization and coordinated with the clinical team to administer the suspension within the required time frame. Despite the advantages afforded by extemporaneous preparation, uncertainties in the regulatory requirements, such as sterility testing of the final drug product, necessitated early health authority engagement. Pre-administration sterility testing of the final product was of particular concern as it requires a minimum of 14 days, significantly extending the in-use period. Per health authority feedback, sterility testing of the final product was not required with a 24-hour maximum in-use period, refrigerated storage conditions, and a maximum of 1-hour room-temperature storage. Similarly, assay, identity, and degradation products were evaluated post-dosing. However, sterility, assay, identity, and degradation products were assessed and established on a mock batch prepared at the clinical site prior to the clinical study. Prior to administration, the injectable suspension was evaluated for bacterial endotoxin, appearance, and pH.

Conclusion: Although extemporaneous preparation is infrequently employed in the early development of injectable products, it has the potential to greatly expedite timelines in the early clinical space. Typically, a traditional GMP manufacture is performed months before a clinical study, whereas an extemporaneous preparation can be performed at the clinical site minutes or hours prior to administration. Since the storage of the product is truncated, an extemporaneously prepared product also requires a shorter drug product stability period, which accelerates the timeline further by reducing the time needed to develop the product. The reduced development demands in turn reduce the drug substance demand, as well as overall cost, time, and resources. However, extemporaneous preparation may not be appropriate for large studies, complex formulations, or hazardous compounds. There are also a limited number of qualified clinical sites, potentially posing a siting challenge. Notably, uncertainties in the regulatory requirements for extemporaneously prepared parenteral products may require proactive health authority engagement.


Figure 1. Schematic of extemporaneous preparation strategy for the manufacture of a sterile injectable suspension.