Biopharmaceutical Manufacturing: Historical and Future Trends in Titers, Yields, and Efficiency in Commercial-Scale Bioprocessing

Abstract

his article documents the progress, current state, and projected future trends in titer and yield as industrial and technological benchmarks for commercial-scale biopharmaceutical manufacture. Biopharmaceutical product commercial-scale manufacturing (bioprocessing) was benchmarked by tracking titers and yields over time, from the 1980s to the present, and further out ten years. This study compiled commercial-scale titer and yield data for a set of 39 major biopharmaceuticals, nearly all mammalian-expressed proteins, particularly, monoclonal antibody products. This included extensive searches of many potential data sources, including contacting knowledgeable bioprocessing professionals. In the 1980s and early 1990s, average titers at commercial scale started out at < 0.5 g/L. The current average reported commercial-scale titer is 2.56 g/L. We also confirmed that the manufacture of commercial products has, over the years, undergone repeated cycles of technical production upgrades, with titers and yields increasing incrementally, even for the oldest products. BioPlan estimates that ≥3 g/L is now the industry standard titer for new bioprocesses being developed, with ≤7 g/L now presumed to be the general industry top-end titer level that, while not unusual, is not often achieved. In terms of yields, we found a 70% yield to be the current industry average yield, not the often-cited 75%. Improvements in downstream purification technologies (e.g., as demonstrated by higher yields) have been fewer and adopted more slowly than upstream production.

Expression of Functional Anti-p24 scFv 183-H12-5C in HEK293T and Jurkat T Cells

“…Industrial pharmaceutical showed almost up to 50-60% of approved recombinant proteins and antibodies were produced in mammalian-based cell system. 21 HEK293T is among several cell lines derived from a human mammalian cell that used for the production of recombinant antibody. Frank Graham established human embryonic kidney 293 (HEK293) cells in 1973 at experiment number 293 by using DNA of Adenovirus 5.…”

Elastin‐like polypeptides: A strategic fusion partner for biologics

“…Proteins expressed in E. coli which have been purified using the ELP technology have reported yields of up to 500 mg of target protein per liter of culture medium (Hassouneh et al, ; Nettles et al, ) (Table ), which is comparable to the titers obtained for some biopharmaceutical proteins (refer to industry survey provided in the following articles (Fox, ; Langer and Rader, )). For example, Chow et al () demonstrated that ∼400–500 mg GFP per liter of culture could be obtained when GFP is fused to an ELP and expressed in E. coli using optimized medium conditions (as high as 1.6 g of GFP‐ELP was obtained per liter of optimized culture medium; molecular weight of GFP to ELP = 30:35.5; if GLP is cleaved from ELP with 50–65% protease efficiency, ∼400–500 mg of GFP is expected).…”

Applications of Machine Learning in Drug Discovery II: Biomarker Discovery, Patient Stratification and Pharmacoeconomics

“…The manufacturing methods of biotherapies are considerably more complicated and expensive than traditional small molecule therapies, which could in part account for the increasing cost of the end product. However, the efficiency of manufacture of biopharmaceuticals has increased dramatically over the same period: with typical yields increasing from 1 to 2.5 g/l during the period 2001-2014 [80]. The complexity of manufacture also creates an additional barrier to entry for new drug manufacturers.…”