Dave Humbird

16Joined Nov 2021

Comments
2

Given recent events, it is perhaps relevant to note that half of the nuclear facilities capable of turning Co-59 into Co-60 are in Russia. Cobalt supply issues are not easing up anytime soon.

Single-use technology (SUT) in biopharmaceutical manufacture offloads many risks associated with upstream cell culture farther upstream--to media suppliers etc. A producer with a full-SUT process does not even carry the risk of cleaning and maintaining their own equipment. The purported economic and environmental benefits of SUT are related to the elimination of sterilization steam (because everything is gamma-sterilized before shipping) and the elimination of cleaning chemicals (because the bags are not cleaned for reuse). 

The size limit of 2,000 L arises from the mode of sterilization--the penetration depth of gamma radiation from a cobalt-60 source is about 30 cm. In a stirred-tank configuration, this means that the rigid impeller inside the bag can be no larger than ~50 cm in diameter when the bag is folded up and irradiated from two sides. Following typical bioreactor geometry rules for animal cell culture (vessel height/diameter ratio and vessel/impeller diameter ratio), a 50-cm impeller indeed limits the scale to 2,000 L. For typical microbial bioreactor guidelines (very high OUR), the SUT limit is rather closer to 1,000 L. The 6,000 L bags are meant for very low cell density processes (very low OUR), like vaccine production in Vero cells on microcarriers. An alternate SUT configuration is the wave bag; the largest out there today is also 2,000 L (looks like a queen-size water bed) with a 50% working volume.

From my perspective, the SUT argument got too tortured between the small maximum size, the amount of waste generated (including daily media-prep bags, filters, and hoses), the observation that large stirred bags still need to sit in a permanent stainless-steel shell, and some discussion I found in "the trades" which said that SUT automation is suboptimal, apparently because the best single-use sensors (pH, temperature, etc) are not good enough for fully automatic operation. Combined with 100% manual unpacking, setting, connect/disconnect, and teardown of bags, the single-use idea seemed very much at odds with the fully automatic plant that many propose.

Finally, the gamma sterilization industry is extremely strained right now--the cobalt supply is tapped, or at least promised to EV-makers. New production of Co-60 is barely keeping pace with attrition at existing sterilization facilities, and the industry is already in triage mode with respect to what healthcare/biotech equipment gets to go through gamma sterilization versus what can go through an alternate sterilization, like ethylene oxide. So a significant expansion in the supply chain of SUT would be out of the question today.

(Aside: yes, ATFs are incredibly expensive today and their price could be expected to come down with market volume, but it doesn't matter in the terms of my analysis. In my perfusion analysis, the perfusion devices contribute $10 out of $50/kg, and I assert an affordability threshold of $25.)