Achieving investigational new drug (IND) approval at an increasingly faster rate than competitor drugs is a widespread desire of biologics developers. This has been further amplified by the need for treatments and vaccines for the COVID-19 pandemic. As a result, the pressure to achieve speed in drug formulation development has escalated to new heights.
With research and development into new drug modalities and technological advances in manufacturing processes over the past decade, biologic drug formulation development requirements have evolved. These range from finding new formulation conditions for multiple new drug modalities to minimising the burden of treatment, easing patient administration, and ensuring device development for drug compatibility.
In this article, Heonchang Lim of Samsung Biologics offers insight into the common hurdles that must be overcome in formulation development to meet these various requirements. Lim also explores the need for manufacturers to adopt strategies considering these challenges that will enable timelines to be reduced and essential drugs to be delivered to patients faster.
Tools to Assess Drug Formulation Feasibility
The formulation of biological drugs, such as protein-based products like monoclonal antibodies (mAbs) is a difficult and time-consuming process, in part due to the often-complex protein structure. The success of most biologics is dependent on the active form being delivered to its site of action. To achieve this goal, there are many characteristics of the drug that must be considered, including pharmacokinetics, toxicity, clinical indication, and physicochemical stability.
Prior to formulation development, verifying drug formulation feasibility will help developers to select an optimal candidate in terms of developability among several molecular candidates. Formulation feasibility studies can be conducted using various in silico and in vitro assessment tools.
In silico assessments rely on data on the molecule’s amino acid sequence and structure and aim to minimise the risks in terms of the molecule’s stability. For mAbs, this could include evaluating the liability of the molecule’s complementarity-determining region (CDR) using its protein sequence.
If utilising deep learning technologies for the prediction of a protein’s tertiary structure, in silico assessments can be used exclusively for feasibility studies. However, deep learning systems are at an early stage and may not be suitably effective for all analytical functions.
Therefore, in silico assessments will more commonly utilize SWISS-modelling-based structural predictions. These can be used to evaluate mAb formulation feasibility. However, the structure of proteins like bispecific antibodies (BsAbs) or Fc fusion proteins, including the folding and other aspects of their tertiary structure are generally too complex for SWISS-modelling methods. Therefore, most developability evaluations are confirmed using in vitro methods.
In vitro tools can be used to evaluate the molecule’s thermal and chemical stability using various techniques. For example, the stability of the drug can be determined using size-exclusion chromatography (SEC) analysis after high-temperature treatment in low-pH conditions. At present, these in vitro analytical tools are generally more accurate in predicting the molecule’s stability and developability than in silico assessments.
Challenges in Formulation Development
During formulation development, feasibility studies can help select optimal candidates but there are still a number of challenges that can arise throughout the process. Expertise and experience are needed to identify these challenges early and to solve them with minimal disruption to the project.
Visible Particle Issues
One of the biggest challenges that formulation developers will encounter is the need to overcome visible particle issues. This includes formulations having visible particulate, sub-visible particulate, turbidity, and opalescence. These phenomena can occur with various root causes such as aggregation or precipitation. Having particulate matter in drug formulations is a significant problem, as these particles can lead to severe side effects including inflammation issues following injection.
