Developing high-dose biologic drugs for subcutaneous injection often requires high-concentration formulations. It also needs to optimize viscosity, solubility, and stability while overcoming analytical, manufacturing, and administration challenges.

To understand industry approaches for developing high-concentration formulations, we conducted several surveys that provide an industry perspective and a summary of experience and insight into the practicalities of developing these biologics.

The survey was performed by the BioPhorum Development Group’s Formulation Workstream and covered:

1. The use of predictive models to mitigate challenges associated with stability, solubility, and viscosity at high concentrations
2. Optimization of solution conditions to reduce viscosity, enhance stability and solubility
3. Optimization of primary container-closure and devices
4. Use of delivery technologies
5. Strategies associated with analysis.

The results can be found in our article An Intercompany Perspective on Practical Experiences of Predicting, Optimizing and Analyzing High Concentration Biologic Therapeutic Formulations.

“There is a lot of published literature, but never this type of intercompany discussion on this topic – that is what this paper brings,” said Brittney Mills, Principal Research Scientist at AbbVie. “We referenced literature that is currently available on these predictive tools, but also brought in the real-life experiences of various companies and people. The group viewpoint provides a larger perspective and outlook on the comparability of the high-throughput or predictive methods versus the stability studies typically performed on high-concentration formulations.” 

Published as a commentary in the Journal of Pharmaceutical Sciences, the findings include:

• Using in-silico tools is currently not very successful at predicting issues; rather, experimental approaches are relied upon when unacceptable product quality is observed during drug product development
• Most respondents agreed that predictions based on in silico or biophysical methods correlated weakly, at best, with actual experience
• A major challenge is the application of development data from studies using low-protein concentration formulations to high-protein concentration formulation stability
• To deliver a large dose within a small volume for subcutaneous administration, it is preferred to use excipients to help minimize protein interactions and reduce the viscosity of the formulation.

“This paper is valuable to me because it is the outcome of a collaborative exercise that has diverse perspectives from industry,” said Preeti Desai, Senior Principal Scientist from Bristol-Myers Squibb. “It is based on input from other companies in the workstream that have different biologics portfolios and work with different models. Having a common ground for high-concentration formulations means we hope to understand the challenges we’re all facing and then harmonize the practice for their development.”

Our survey results highlighted practical approaches that will help you develop high-concentration biologic drug products. Importantly, real-world experience has shown that there is currently no substitute for high-quality experimental data. In most cases, existing predictive tools or modeling are, at best, a guide to development.

However, practical experience has shown that a final high-concentration biologic drug product should have a foundation in solid experimental data. Therefore, more effort is needed to bring predictive models to the level that allows formulators to derive reliable information to support the development of biologic therapeutic formulations.

“The paper validates my company’s approach and experiences and provides an industry perspective that indicates we all have somewhat similar practices,” said Douglas Kamen, Associate Director at Regeneron. “It also helps us ensure we are delivering the best formulations we can to ensure patient safety and product quality.”

You can watch team members presenting the paper and reflecting on the set of survey results and discussions here.