In biomanufacturing, a production scale change is required to either meet the market growth demand or when a product moves from clinical to commercial manufacturing. How that volume is increased depends on whether a scale up or scale out philosophy is used. The industry standard has been to scale up, which translates to increasing the size of the bioreactors used in manufacturing runs. However, due to the recent availability and ease of single-use technologies, coupled with improvements in cell culture productivity; scale out may soon create a shift in the way biologics are manufactured.
Dr. Jie Chen, Vice President of CMC Management, WuXi Biologics recently presented a webinar on the advantages of scale out biomanufacturing. Key advantages include:
- Enables single-use bioreactor technology to replace traditional stainless steel, fixed-tank bioreactors in commercial manufacturing plants
- Reduces product quality and process performance scale-up risks
- Flexible process design and validation strategies
- Accommodates a wide range of product levels and market demands
Dr. Chen then discussed in more detail the advantages of a scale-out strategy. First, it reduces process scale-up risk. One challenge with the scale up approach is that the upstream process of “scaling up” changes the cell culture microenviroment, thus impacting product quality and process characteristics. Therefore, ensuring the success of process scale-up, from early toxicology studies to clinical and commercial manufacturing, is often a critical task.
Operating risk is also reduced. In scale up, an unexpected loss of a bioreactor would create huge financial and time losses. However with scale out, you would lose just one of the several bioreactors used in the production run, thus the material from the other bioreactors could still be harvested and product could be provided to the market on schedule.
Another important advantage is in process validation. As Dr. Chen points out, with a scale-up approach, process validation can only be done at the defined commercial scale. This would inhibit any adjustments to manufacturing scale based on shifts in product demand and limits flexibility over the product’s life cycle. However, in a scale-out validation strategy, process validation could occur at different scales at the same time by using a bracket validation design.
Cost control for scale out process and facility can be a challenge. Dr. Chen shared some cost reducing strategies based on WuXi Biologics’ best practice, such as utilizing continuous processing or designing a facility using a disposable/stainless steel hybrid system. Using these aforementioned factors and factoring in the initial production facility construction and validation costs, the costs per production run begin to look similar if not in favor of the scale-out strategy.
With the increasing maturity of disposables, coupled with improved understanding and guidance on extractables and leachables, concerns over regulatory compliance for single-use technologies in commercial manufacturing are quickly diminishing. In addition, regulatory agencies continue to encourage the adoption of new technologies for biomanufacturing, including continuous bioprocessing. A scale out approach allows for the implementation of several innovative biomanufacturing approaches.