Companies often prioritize small gains in a drug's activity (PK/PD data) during candidate selection, while ignoring manufacturability. This can lead to selecting a molecule that is extremely difficult or costly to produce, a problem that a slightly less active but more manufacturable alternative would have avoided.
Low-productivity R&D systems, like HEK cells, can hide product-related impurities such as truncated forms. These impurities are often at levels too low to detect. When the process is scaled up using high-productivity CHO cells, these once-invisible impurities can become a major issue, impacting yield and product quality.
Downstream purification processes can be modified and optimized throughout a product's lifecycle. However, the cell line selection is effectively permanent once the master cell bank is created. Choosing a non-robust cell line, such as one highly sensitive to minor pH shifts, will create persistent manufacturing challenges for the lifetime of the product.
The intense need to show positive clinical data to secure the next funding round forces biotech startups to prioritize speed over everything. Consequently, crucial but time-consuming manufacturability assessments are often postponed, viewed as an 'extra cost' that can be handled later, creating significant downstream technical debt.
Altering the cell culture media after a master cell bank (MCB) has been created is a high-risk decision. It forces cells to adapt during the seed train of every GMP run, introducing unpredictable, stochastic scenarios where cell behavior can vary from batch to batch, compromising process robustness and consistency.