Why is process development such a lengthy activity?

Why is Process Development such a lengthy activity?

Process development is a critical and lengthy activity, which holds a key place within discovery, development and manufacturing phases.

Many clients reckon drug discovery is the lengthiest considering its pivotal and demanding aspects: they indeed go through a gruelling process to find their target molecule and then the next challenge is to get a genetically modified organism to express (produce) the molecule in some appreciable amount, also ensuring generations of cells continue this expression. This part of the drug discovery process typically takes the longest time and often resides in academic organizations and Contract Research Organizations (CROs).

A popular misconception is that the next steps of process development, analytical development and preclinical manufacturing is a predictable and rapid process, however, this is not the case. Process Development remains a lengthy activity at both Upstream and Downstream steps, and here are a few reasons why.

For the first step of development, before any Upstream Process development (USP development) is even commenced, the structure and function of the molecule (most typically protein based) must be considered. USP conditions will need to be conducive to get the cells to produce their required target molecule, but there has to be assurances that where the molecule is produced won’t be affected negatively by its environment.

In the early development process, it would likely be well known where the target molecule resides, either inside the cell, in the membrane, inside inclusion bodies or expressed outside the cell. This information coupled with structure and functional details will dictate both growth and harvest parameters. Failure to properly address these factors will potentially result in aggregation or undesired modifications along the way of Upstream Processing, which could make Downstream Processing (DSP) impossible or alternatively render the target molecule inactive or with a reduced potency.

For the reasons above, there is a careful process of selecting proper growth mediums, agitation methods, key temperature controls and the right blend of required gasses. Couple these with timing and induction methods (techniques and products used to trigger cells into production), there are a great deal of variables to orchestrate to get your optimal expression, resulting in long periods of time where Upstream Process Development has to be perfected.

On the Downstream Process Development side, the team needs to prepare based on factors mentioned above and ensure that the process follows a logical flow and amenable conditions to ensure the maintenance of the critical quality attributes of the protein of interest. The removal of process and host cell -related impurities and the scalability of the developed process must also be considered. Standard DSP development phases include multiple chromatography steps, viral clearance steps, tangential flow filtration and a final sterile filtration step. Centrifugation and dialysis are generally avoided as they are not scalable and cannot support CMC requirements for Phase III and beyond. Various chromatography techniques and resins per technique exists and a high throughput screening is required to select the optimal combination of resins and chromatography conditions. Viral clearance inactivation and filtration are also a core in the purification process of a recombinant protein.

As the use of detergent and solvents are commonly used for the inactivation and use of additives are used for the filtration, one should consider the impact of this process step on the analytical method panel as any additional reagent used during the process should be tested for its residuals.

Biodextris, an experienced CDMO with extensive GMP track-record, has helped dozens of sponsors achieve their process development targets through reliable steps and proven processes leading to facilitated biomanufacturing phases.

Our top experts at Biodextris have worked on dozens of biological products and have used this experience to streamline the lengthy steps of Process Development by anticipating potential bottlenecks and typical issues.

Please reach out to our team to discuss process development specifications and start optimizing your general timeline!