Interview with:
Dingjiang Liu, Ph.D., Fellow Scientist, Development, Regeneron Pharmaceuticals Inc.

1. In your opinion, what are the major challenges to be resolved in formulating high concentration protein therapeutics?

The major challenges are protein solubility, stability and viscosity of the high concentration protein formulations. Traditionally, protein stability has been the primary concern for the development of protein therapeutics; the formulation development is focused on optimizing and maintaining the shelf life stability. At a high protein concentration, such as > 100 mg/mL, in addition to protein stability, protein solubility and viscosity of the formulation need to be studied and optimized to enable the commercial manufacturing process development, such as filtration and fill finish process, and to implement the robust drug delivery devices.

2. How do you think Quality by Design concepts will impact formulation development programs in the future?

Quality by Design can have many profound impacts on formulation development, simply because formulation is the most critical part of the protein drug product development. First, during the formulation development process, it is important to have a clear understanding of the critical quality attributes (CQA) associated with the product and then implement appropriate analytical methods to monitor the CQAs during the formulation development. To achieve this goal, a closer collaboration among the formulation development scientists and the other functional areas in product development, such as analytical science and clinical development groups, is required. The second area I’d like to mention is that the formulation development process needs to incorporate the concept of ‘design space’ at the very beginning of the formulation development. This may require designing formulation studies using statistical approaches, such as Design of Experiment (DOE), instead of the traditional one-factor-at-a-time approach. At the later stage of development, the same approach should be applied to demonstrate the formulation robustness within the formulation space, primary container/closure and delivery devices. Lastly, I think implementation of QbD concepts in formulation development may shift the formulation development paradigm to a more scientific driven and comprehensive process, mainly because now the critical quality attributes associated with the final product are considered from the beginning to the end of the drug product development. This can lead to, not only better product formulations, but also potential savings in the overall cost of the product development.

3. Do you have any tips for those new to formulation development?

Protein formulation development is definitely a multidiscipline and relatively young field. With the complexity of the manufacturing, storage and end use (delivery) of the drug product, there is much to learn in drug product development. So, be open-minded and prepare to learn. In particular, learn from literature and from the experienced scientists, because what is in the textbooks is limited and often not up to date.

Since formulation scientists are responsible for development of reagents which can be used to improve people’s life around the world, we should be proud of what we are doing; at the same time, we should also feel a sense of responsibility in developing formulation and products with considerations regarding patient safety and experience.

Interview with:
W. Aaron Pruett, Bioprocess Engineer III, Drug Product Sciences, Human Genome Sciences Inc

1. In your opinion, what are the major challenges to be resolved in formulating high concentration protein therapeutics?

When formulating at high concentrations, drug product manufacturability can become a challenge. Much of the conventional wisdom around process compatibility is based on studies performed using low concentration protein solutions. While this body of knowledge is useful, it is important to understand that the effects of processing stresses on product quality can be complex. Extrapolating low concentration data may not predict manufacturing related stresses that may occur over the potential range of product concentration. For example, the viscosity of high concentration products can vary significantly based on temperature and concentration. Product viscosity can affect many manufacturing operations, including UF/DF, sterile filtration, mixing and filling. In addition to affecting manufacturability, viscosity can affect mechanical stresses occurring during manufacturing, which in turn may affect product quality. It is also important to evaluate concentration dependent effects not just at the product concentration but at the higher concentration of bulk intermediates.

2. How do you think Quality by Design concepts will impact formulation development programs in the future?

Significant opportunities exist to improve small-scale, high throughput stress testing so that formulation screening can more accurately reflect process related quality risks early in the development cycle. Early identification of “process-robust” formulations can improve product quality and reduce risk. Conversely, early identification of risks and process limits in optimal formulations can inform process development and selection of manufacturing equipment. Formulation development must often be done with a limited amount of material. This can make it difficult to assess compatibility of a formulation with all potential stresses encountered during manufacturing. Developing improved scaling models of stresses associated with manufacturing operations will increase the effectiveness of QbD formulation protocols.

3. Do you have any tips for those new to formulation development?

The potential effects of the freeze-thaw process and frozen storage on product quality are often overlooked in the early stages of formulation development. Thermal analysis, such as low temperature DSC, can be used to identify sub-freezing thermal transitions. Early assessment of stability over a range of frozen storage temperatures (i.e. -20, -40, 80oC) is helpful not just in identifying an appropriate storage temperature, but also in the assessing how the product will react to changes in temperature which may occur due to handling or equipment malfunction. Thermal cycling and small-scale process simulation may be used to evaluate process compatibility early in the development process.