Ask the Expert: Evaluation of the “Scale-Out” Biomanufacturing Strategy — from Early Clinical Stage to Commercialization

In a BPI Ask the Expert webinar on 2 November 2017, Jie Chen (vice president of CMC management at WuXi Biologics) spoke about scale-out biomanufacturing strategies.

Chen’s Presentation
Scale-out strategies allow for the use of disposable bioreactors in commercial manufacturing. A scale-out strategy offers unique advantages over traditional scale-up manufacturing:

Changing market dynamics are driving a need for innovative biomanufacturing facility designs, especially for contract service providers. New facilities are focused on multiproduct and “scale-out” designs that offer flexibility, scalability, efficiency, safety, and regulatory compliance.

How can 2,000-L single-use bioreactors produce ≥100 kg? In a scale-out strategy design, multiple 2,000-L disposable bioreactors operate to provide the same volume of cell culture material as a single 10,000-L production run in roughly the same time.

WuXi Biologics has put those ideas into practice. Our 460,000-ft² facility is the world’s largest mammalian cell culture biomanufacturing facility using disposable bioreactors: two 1,000-L perfusion and 14 2,000-L fed-batch. The facility can make >1,000 kg of protein products per year.

WuXi Biologics discovery, development, manufacturing, and testing capabilities are located at three sites around Shanghai, China. The company has ~2,500 employees who serve clients from the United States, Europe, Asia, and China. WuXi Biologics is a contract development and manufacturing organization (CDMO) that has supported one biologics license application (BLA) and filed >60 global investigational new drugs (INDs) for its clients.

During scale-up, process development efforts to maintain comparable product and process performance while eliminating impurities can be time and resource intensive. During large-scale cell culture, the physiological microenvironment of a selected production cell line is determined by media/feed strategy as well as bioreactor design and operation. Most impurities originate from cell culture processes. Scaling-up a cell culture process changes that microenvironment and can in turn greatly influence product quality and process characteristics. A scale-out strategy can ensure that product quality is consistent throughout clinical and commercial stages because the microenvironment never changes. Similar concepts apply to downstream processing.

Process validation using a scale-out strategy can offer many potential advantages. Traditionally, a bioprocess could be validated only at its desired commercial scale — limiting flexibility if postmarket approval product demands change. By contrast, a scale-out strategy makes it possible to validate processes at different scales at the same time using a “bracket” design: A process could be validated at both 3 × 2,000-L and 6 × 2,000-L scales over the course of three to four conformance runs, for example.

Each product has its own market demand lifecycle influenced by, e.g., competition, patient population, and disease outbreak. A scale-out strategy designed with a flexible process validation package would allow drug sponsors to adapt and manage that life cycle efficiently and effectively.

Downstream processing is a major contributor to biomanufacturing cost, especially for monoclonal antibody products that require expensive protein A resin. WuXi Biologics is working with vendors to design and implement continuous downstream processing (including protein A capture) for its perfusion and fed-batch facilities.

Hybrid disposable–stainless-steel systems can provide synergistic cost control. The overall cost of a hybrid scale-out facility compared with one using traditional stainless-steel for scale-up could be similar (even better) if initial facility construction and validation costs are considered. With encouragement from regulatory agencies for new technology adaptation, the road is paved for scale-out approaches and continuous processing technologies.

Question and Answer
How are timeline-related costs lower for changeover using scale-out mode rather than traditional scale-up? Let’s compare a single-use bioreactor with a stainless-steel bioreactor: The former bioreactor needs about a day to change over; the latter needs two to three days on average because of the necessary clean-in-place (CIP) step. If it takes two to three days between production rounds through the course of the year, you probably can save almost one entire production round with disposables.

More Online
Watch the full presentation of this webcast — with slides and further discussion.