Addressing The Challenges In Biopharm Manufacturing

By Uwe Gottschalk, group VP for purification technologies, Sartorius Stedim Biotech

Biopharmaceuticals are more in demand than ever, but the biomanufacturing industry faces increasing pressure to reduce costs without sacrificing quality. Some might say this is an impossible dilemma. One way to address the challenge is to increase the productivity of bioprocessing without increasing its footprint, which means producing more of the same product without increasing facility space requirements or the use of raw materials.

In this context, a line tends to be drawn between upstream production and downstream processing/purification. In monoclonal antibody (mAb) manufacturing, upstream production methods have improved more than 100-fold over the past 25 years, thanks to strain development and improved media and bioreactor technology. In process development, companies are regularly achieving titers of 5 to10 grams of mAb per liter of culture broth without a significant increase in the footprint. But downstream processing is a different story. Although there have been significant productivity improvements, they have been incremental rather than game changing, and therefore, much of the improvement in upstream productivity has been matched by increasing the scale of the purification train, including peripheral utilities. Such changes use more space and raw materials, and therefore, equate to a larger footprint, which makes it much more difficult to keep the costs of production under control.

INNOVATION IS THE KEY
Under pressure from all sides, biopharmaceutical manufacturing needs to embrace smart new ways to produce high-quality products without escalating costs. Incremental changes are no longer sufficient to keep up with demand, so innovative approaches are required.

For example, both product developers and CMOs are increasingly turning to disposable solutions. Single-use concepts in biomanufacturing are not new. Disposable filters have been with us for many years. However, the scope of single-use equipment is increasing as more manufacturers come to appreciate its benefits. For example, as disposable bioreactors, filters, and chromatography modules become more common, it becomes more likely that the processing train of the future could be assembled completely from disposable units, thus reducing investment in bricks and mortar and allowing production to move from centralized “superfacilities” to regional centers serving local markets.

Vaccine and mAb manufacturers, in particular, are beginning to take advantage of leaner processes with reduced construction, technology transfer, and validation requirements. This trend will gain further momentum with the success of biosimilars, which seem to be gaining the most attention from innovator companies. Disposable manufacturing is being considered for the rapid production of clinical material and — with the current trend toward smaller process trains — such approaches are bound to be applied more often at the commercial scale.

INNOVATIVE REINTRODUCTION OF OLDER TECHNOLOGIES
Innovation implies a requirement for novel technologies, but this is not always necessary, as shown by the innovative reintroduction of older technologies, once abandoned, but now considered from a fresh perspective. Lessons can be learned from other manufacturing industries where these inexpensive bulk-processing technologies have been highly successful. Several recent developments suggest that simpler technologies could indeed find a niche in biopharm manufacturing, particularly in the early processing steps where the complex mixture of particulates and solutes has the greatest potential to foul expensive membranes and resins. Therefore, although tangential flow microfiltration, depth filtration, and (continuous) centrifugation are seen as the industry workhorses for clarification, simpler approaches, such as flocculation and precipitation, are now being introduced as alternative clarification steps.

Novel technical solutions currently appear to be favored for upstream production, including new media compositions, new bioreactor designs, and new cell strains with greater intrinsic productivity. However, closer scrutiny shows that cutting-edge technologies (e.g. convective media such as membrane chromatography modules) are being used to improve the closing stages of downstream processing, providing new strategies to overcome known bottlenecks.