Technology to manufacture high-dose therapeutic monoclonal antibodies (MAbs) at scale has evolved in several waves over the last two decades. Major cost reductions have been reported through the use of platform technologies upstream, downstream, and with the portfolio of analytical assays used.1 This review describes a reference downstream process developed at GE Healthcare2 and discusses technical and updated economical analysis of various process design options found in the literature and conference presentations.
Antibody titres in mammalian cell culture have improved one hundred fold over the last 20 years, mainly through the ability to grow higher cell numbers (~10 fold) and through increasing productivity of those cells (~10 fold)3 (Figure 1). Recent reports from industry demonstrate that antibody titres higher than 1g/L are the rule, and 5 g/L readings are already on the horizon for processes currently under development. At the same time, manufacturers observe new challenges, resulting from the increased generation of antibody aggregates and increased presence of host-cell proteins from the high-producer cells used in such upgraded processes.
Figure 1.Twenty years of development in mammalian cell culture have led to significant increases in product titres for monoclonal antibodies (MAbs), as a result of higher expression levels, faster process times, and higher cell densities. Factors contributing to these improvements have been seen in the media for growth and the production phase, feed composition and strategy, process control and design, and host-cell engineering.
During the same period, purification by chromatography has improved its productivity by a factor of 10–20. This improvement was achieved mainly through the introduction of products allowing significantly shorter residence time at similar or higher binding capacity than previous generations of chromatography resins (Figure 2). Recent Protein A affinity resins and ion exchangers enable processing of 50 kg of antibody per batch per day using process schemes with a normal degree of optimization and without going to extremes in dimensioning the columns.4 In combination with up-to-date process engineering strategies that remove non-productive time from the critical path of manufacturing, these products are likely to resolve the near- to mid-term bottlenecking problem in the downstream process.
Figure 2. Twenty years of development in agarose resins have led to increased stability, higher capacity, and better volumetric flow.
It is important to realize, however, that significant improvement in process economy is still possible upstream, primarily by shortening the very slow cell culture process (2–3 weeks for harvesting)5 and by de-bottlenecking the link between cell culture and the relatively fast downstream process (1–5 day batch time, depending on degree of process intensification). Frequently, several (up to 5–6) large, staggered upstream lines are needed to feed one downstream production line.
It is likely that the protein mass to be handled per batch will increase further with some "blockbuster" MAbs, but almost certainly not with all future MAb processes (i.e., for most promising medical indications). As a result, further improvements are desirable downstream of cell culture. End product purity and safety, as well as process robustness, are not debatable and cannot be compromised when considering alternate process design options or potential economic advantages. It is essential that alternatives under consideration be reviewed based on their practical value for today's process design work.