Manufacturability assessment offers the opportunity to evaluate the technical viability of a drug candidate at the industrial scale and functions as a bridge between discovery and process development stage. Creative Biolabs is able to evaluate key manufacturability parameters, including productivity and process yield, chemical stability, PTMs, physical stability, aggregation, electrostatic properties, and formulability (including viscosity, solubility at high concentration, and accelerated stability) through our CreDA™ platform, and the comprehensive assessment results can effectively guide the customer to select the most appropriate candidate for process development.
Fig.1 Manufacturability assessment of the drug candidates.
For comprehensive developability assessment, protein material of gram quantities is prepared by stable expression in a CHO expression system. And the final cell clone for clinical and commercial manufacturing is also identified in parallel. Then, candidates are compared using the same production system to directly visualize the impact of the molecule on expression and purification. Molecules with overall greater yield will be preferred for further development.
Protein unfolding can alter its functional activity and lead to aggregation, or even increase the risk of in vivo immunogenicity. During the late-stage candidate selection, the physical stability of biotherapeutic candidates is tested at different conditions of temperature, pH, mechanical stress, and diverse formulation buffers. These studies can be informative for downstream processing and help formulation function to select drug candidates that perform well in the preferred formulation platforms.
Chemical stability and PTMs of biologics are important quality attributes that should be fully investigated during the developability assessment campaign. Undesirable PTMs could cause partial or complete loss of activity, increase the tendency to aggregate, reduce the shelf life span of the product, and increase the sample heterogeneity. A list of modifications that will generally be investigated in our developability assessment platform is shown in the table below.
|Chemical instabilities and PTMs investigated by our developability assessment platform|
|Free cysteine residues||Glycation|
|C-terminal lysine cleavage||Pyroglutamate formation|
Protein aggregation is a key issue that can appear at different stages of the manufacturing process, including but not limited to fermentation, purification, formulation, and storage. Aggregation can impact not only the yield and economics of the process but also the drug potency and in vivo immunogenicity. From a process perspective, tackling aggregation issue through process development and manufacturing can be complicated and lead to increased cost, lengthen development timelines, and result in the limited and costly formulation and delivery options. Thus, aggregation propensity of drug candidates should be thoroughly evaluated before the process development is initiated.
Electrostatic properties of the candidates will influence the protein affinity for ion exchange resins in the purification steps. Thus, our developability assessment studies will characterize the electrostatic properties of the protein regarding isoelectric point and charge profile.
The administration route and formulation are also considered by our developability assessment platform. However, these aspects are traditionally addressed in later development phases, that is, at a time point when necessary adaptation could be very expensive. The pre-formulation assessment includes determination of viscosity and solubility at a high product concentration and accelerated stability test so that these important aspects can be considered for candidate selection.
Manufacturability assessment is an indispensable part of drug developability assessment. With expertise and dedication, advanced CreDA™ platform and services from Creative Biolabs will be your best companion in drug development. Please contact us for more information and a detailed quote.