The trouble with tech transfer: Overcoming scale-up risks

Whether you, as a drug developer, or a contract development and manufacturing organization (CDMO) are charged with production of a drug candidate, tech transfer is likely to be an unavoidable stage – or several stages – when aiming for commercialization.

Tech transfer already comes with numerous complexities inherent to the product and the process, and scaling-up brings a whole host of new problems, said Thomas Chattaway, a life science consultant with over 30 years of industry experience, in a BioProcess International Academy workshop, which formed part of a pre-day at BPI Europe 2024 in Vienna, Austria.

“As we scale, things typically take longer. But also how the equipment looks and works becomes quite different,” he told delegates, adding this affects all stages of up- and downstream bioproduction.

The difference in dimensions in cell culture, for example, when going from benchtop wave bioreactors to single-use bags at a 100-1,000 L scale, to a 2,000-20,000 L stainless steel tank lead to fluid dynamics change and physical limitations. This calls for changes in the management of gas transfer, shear, heat transfer, among other elements, and potentially longer mixing times incorporating additional limiting nutrients.

Meanwhile, for chromatography, bed height adjustments are often needed, columns will feel the effect of increased loads and hold times, while column packing and acceptance criteria becomes complicated and relatively unknown. Furthermore, the impurity profile is affected at scale due to sampling around peak cut during engineering runs, and buffer management must be considered.

As such, it is critical to minimize the risks associated with scale-up, Chattaway said, to ensure smooth and viable tech transfer. He stressed the importance of designing process development (PD) in anticipation, including understanding how the difficulty of procuring high grade raw materials could increase exponentially when upping scale.

Also, preplanning and carefully selecting unit operations at lower stages will pay dividends at higher scales. “There’s no point using a fermenter that generates heat of 50 kw/m³ [in early phase] as this would be beyond use at scale,” he said, as an example.

Chattaway added having as good a grasp on the development process as possible is essential as “the more you know about your process the easier it will be to scale up,” and urged delegates to undergo first principles and analogies, undertake criticality analysis and experiments, explore the potential design space, and carry out robustness studies.”

And to further minimize risk, Chattaway encouraged undertaking specific small-scale experiments early on as these can mimic and prepare the team for the effects of scale-up and scale-down, along with offering up a better understanding of hold time validations.

The information formed part of a comprehensive course that assessed all areas of tech transfer, including regulatory and reporting requirements, documentation, available technology tools, risk management, contractual obligations, and CDMO communication.