Continued improvements in recombinant protein expression yields have helped ease production capacity constraints, leading to an apparently healthy and manageable increase in idle capacity. According to BioPlan Associate’s 8th annual survey of biopharmaceutical manufacturers, the overall average yield reported for commercial monoclonal antibody this year was 2.18 g/L—up from 1.94 g/L in 2009 (Figure 1). It was not that long ago that mammalian cell culture commercial production yields were lucky to achieve 1 g/L.
The next generation of commercial products will have an even greater average yield. In fact, for late-stage clinical manufacture, the overall average this year is 2.68 g/L, up from 1.96 g/L in 2008. While protein yields over 30 grams/liter are now being reported by expression system developers and early adopters, these are the exception and yields for commercial manufacture in the 5–10 grams/L range are more likely to be common in coming years.
Calculating the growth in titers (CAGR % titer change) from 2008–2011, commercial yields increased annually by 3.7%, while late-stage clinical manufacture yields increased 11.0%. The portions reporting the highest yields, >5 g/L, have remained rather constant in recent years. This suggests that either only a few are adopting newer, high-producing expression systems or only a few are actually attaining these levels with their own facilities and products.
With single-use/disposable bioreactors and other equipment now dominating upstream noncommercial manufacture, the recent high growth in late-stage titers has been attained using this relatively new class of equipment. As single-use equipment graduates to mainstream commercial product manufacture, these increases will continue to carry over to commercial manufacture.
Industry Yields Increasing
The largest portion of survey respondents (59.7%) now report mammalian cell culture commercial production of monoclonal antibodies (mAbs) at between 0.5 and 2 g/L, with increases in this group observed in the past three years.
Another 26.6% report attaining commercial titers between 2–3 g/L, 20.5% attaining 3–5 g/L, and 8.5% attaining >5 g/L. Nearly half (46%) reported clinical-scale manufacture between 0.5 and 2 g/L, with 30.1% reporting 2–3 g/L, 25.7% reporting 3–5 g/L, and 11.5% reporting ≥5 g/L. In general, higher expression levels are now reported for late-stage compared to commercial manufacturing. This is not unexpected since process improvements generally take place at earlier development stages.
Increasing expression system yields enables use of smaller bioreactors and facilities. Bioprocessing system (bioreactor) sizes for large-scale manufacture are likely to decrease or remain steady in coming years, with companies increasingly adopting single-use 1,000–2,000 L bioreactors for late-stage and commercial manufacturing.
Particularly as single-use bioreactors begin to displace stainless steel for commercial manufacture, those needing higher capacity may begin to use multiple single-use bioreactors operating in parallel to achieve production levels and economies-of-scale now largely restricted to those operating ≥10,000 liter bioreactors.
This is especially true for recombinant mAbs with a large number of new drugs and biosimilar products in development; mAbs have high repeated dosing requirements and large amounts of protein, e.g., 100s of kilograms/year, are needed for a blockbuster product. Also, advances in bioreactor technology, particularly in smaller size perfusion systems, will likely result in overall reduction in bioreactor requirements.