(M1530-01-04) Exploring Drug Formulation Expert Perspectives on High-Concentration Subcutaneous Formulation Development: A Survey Analysis of Infrastructure, Stakeholder Preferences, and Perceptions

Purpose: The purpose of this study was to gather insights from CMC experts on formulation development challenges, infrastructure capabilities at their organizations, preferences in development approaches, and perceptions around drug delivery concerning volume. This was aimed at understanding the trade-offs between high concentration and low concentration formulations for subcutaneous (SC) delivery.

Methods: A blinded survey was conducted, garnering 80 responses from CMC experts with experience in creating high concentration liquid formulations for SC delivery. The survey included multiple-choice and open-ended questions to capture comprehensive data on current practices, challenges, and expert opinions on SC formulation development.

Results: The survey gathered responses from professionals primarily specializing in Formulation Development, with additional representation from Manufacturing Sciences and Drug Product Process Development. On average, participants reported working on 12 high concentration subcutaneous (SC) biologic drugs, with a mean experience of 13 years in Chemistry, Manufacturing, and Controls (CMC). The overwhelming majority (97%) hailed from the biotech/pharma industry, all playing decisive roles in the decision-making process. When queried on their understanding of SC injection volumes, 53% accurately estimated the volume for a bolus injection, contrasting starkly with only 17% accurately predicting volumes administered over several minutes. Respondents reported an average duration of 23 months from project initiation to achieving a commercially viable final formulation for SC high-concentration (≥100 mg/mL) liquid drugs. Furthermore, a significant majority (90%) agreed that higher concentration formulations led to reduced yields due to equipment adsorption, filling line blockages, and increased demands in analytical procedures. Viscosity-related challenges, aggregation issues, solubility concerns, additional manufacturing costs, and pharmacological or clinical intricacies emerged as the top five hurdles in developing high-concentration SC biologics. Meanwhile, Drug Substance Availability & Processing and Stability (obtaining suitable shelf-life data) were identified as rate-limiting factors for both clinical and commercial purposes. In clinical trial contexts, the Screening Process was cited as the primary bottleneck by 37% of respondents, reflecting challenges in navigating cross-functional comprehension of the time, costs, and risks involved in high-concentration SC formulation development. Despite the prevalent understanding of these challenges, 67% of respondents reported CMC sites being located within the combination product group, indicating potential organizational disparities in addressing formulation complexities. In the survey, participants were asked to rate the comprehension level of cross-functional team members without a background in drug formulation science when it comes to understanding the time, costs, and risks associated with developing a high concentration subcutaneous (SC) formulation. The findings revealed that respondents perceived limited comprehension from cross-functional team members in grasping the intricacies of high concentration SC formulation development. Interestingly, respondents frequently favored low concentration, high volume formulations over their high concentration, low volume counterparts in drug development scenarios. Moreover, formulation challenges often impacted project timelines, with 70% of respondents experiencing delays in clinical trial entry or product launches due to issues such as viscosity, aggregation, and solubility. The average delay was reported at 7.8 months, with one respondent noting program cancellation as a consequence. These results underscore the multifaceted complexities surrounding the development of high-concentration SC biologics and emphasize the critical role of comprehensive understanding and mitigation strategies in overcoming formulation hurdles.

Conclusion: The findings suggest that low concentration, high volume SC formulations could be more advantageous for pharmaceutical companies. Utilizing an on-body delivery system that supports large volume capacity (5-25 mL) may offer benefits in reducing formulation complexity and associated risks, thus potentially expediting development timelines and reducing costs. This strategic approach could mitigate some of the challenges faced in high concentration formulation development and improve market readiness.

Acknowledgements: Mehul Desai and Omar Rahman are employees of Enable Injections who funded this study