December 9, 2020 PAP-Q4-20-CL-004
Stainless steel facilities are on their way out. With the high titers obtained today, 2000-L single-use (SU) bioreactors are sufficient for most processes, and some vendors are developing systems up to 5000 L. When they are available, the range of SU bioreactor sizes can support the vast majority of biologic products on the market and in development, except perhaps global blockbusters.
Avid Bioservices was one of the first adopters of large-scale single-use technology. The decision to move to 1,000-L disposable bioreactors was made in 2007. However, at that time, the company had years of experience with SU biocontainers for buffer and intermediate product storage and single-use unit operations such as membrane chromatography.
Avid’s Myford facility, designed to exclusively use SUT, was completed in 2016. The facility is truly a building within a building, with modular walls, ceilings, and many other components fabricated offsite and then installed within an existing building. There was no need for extensive external renovation, and this approach significantly expedited the construction process from groundbreaking to validation and facility start-up.
Unlike with stainless-steel reactors, scaled-down models of larger SU bioreactors are available from most vendors. These smaller systems (3L, 50L, 200L) are designed to mimic performance at larger scales, allowing process development to readily advance from the lab to the pilot plant and, ultimately, to production. While some gaps and issues remain, access to these scaled-down models confer a significant advantage on disposable technology.
Product quality investigations involving stainless-steel reactors are often incredibly complicated when all of the equipment and systems involved need to be examined or tested. SU bioreactors are inherently less complex and allow manufacturers to work with the SUT vendors to test the materials involved and help determine root cause. This simplification can enable faster investigation turnaround times, reduce investigatve costs, and prevent extended equipment tag-outs.
As with any production system, SUTs have their own limitations. One of the biggest constraints is the low availability of different technologies. Only a few vendors offer bioreactors, tubing assemblies and other consumables have been limited until recently, and prepacked SU chromatography columns remain smaller than what would be ideal for commercial manufacturing. Additionally, only a few SU sensors are available, and considerable work remains to optimize their performance.
Users of disposable technology must also consider the consumables associated with SU equipment as critical raw materials. They are reliant on consumable vendors to ensure that production remains on schedule, which carries measurable risk. Vendors are impacted by natural disasters, including pandemics like COVID-19. Disrupted supplies, absent dual sourcing, or inadequate crisis plans can have a tremendous impact on the ability to continue manufacturing critical drug substances and drug products.
There are also concerns regarding the availability of testing data with respect to the integrity of biocontainer films, compatibility with various biologic and chemical compounds, and extractables and leachables (E&L). The largest vendors have been proactive in providing data packages to assess these issues, but all possible application scenarios cannot be evaluated in advance.
Going forward, it will be critical for vendors to develop products that address the limitations of existing systems to boost flow rates and increase productivity, such as larger-diameter prepacked chromatography columns and larger and more efficient membrane filtration systems for harvesting and final product filtration. Standardization of the user interface for different systems would also greatly simplify things for operators.
As a multiproduct manufacturer, there are clear advantages to SUT over stainless-steel technology, going well beyond eliminating the need for cleaning and cleaning validation, and reducing risks of cross-contamination. SUTs offer more flexibility and accelerated time to market with straightforward scale-up of upstream processes, simplified investigations, and much shorter setup and changeover times. With disposable systems, Avid produces products more quickly, expediting our ability to bring in processes, scale them up, and deliver products to customers and ultimately to patients.
Ryan MacDonald joined Avid in June 2016, supporting small- to production-scale tech transfers, risk assessments, process validations, and high-risk PQI investigations. He earned a bachelor’s degree in biomedical engineering from California State University, Long Beach.