New and Unknown Challenges Facing Biomanufacturing: An Editorial

Upstream and downstream processing must be aligned and integrated.
Mar 01, 2005
Volume 18, Issue 3

Uwe Gottschalk
Upstream and downstream processing in biomanufacturing follow different rules. Upstream processing is biology-driven, and a lot of black box issues remain to be explored. On the other hand, purification is clearly engineering-driven and can be described and simulated with the precision of mathematical models. However, despite our still-limited knowledge of cells as bioreactors, it is upstream fermentation that is setting the pace. Downstream processing is having a hard time accommodating the output of this revolution in biosynthesis development. In any case, the two separate areas must be aligned and integrated in order to manage the challenges that lie ahead. But what are those challenges, and what technical solutions are available?

THE BIOTECH SECTOR TO DATE: FULL PIPELINES AND EMPTY POCKETS The days are over when time was the only thing that mattered and resources seemed unlimited in biotechnology. Initial public offerings (IPOs) poured lots of cash into startups and second-generation biotech companies, creating a big bubble that remains a liability today. Those who thought biotechnology was delivering on all the premature hopes and unrealistic expectations raised by the human genome initiative ignored serious warning signs. Nevertheless, it is fair to say that ratings in the biotech sector were never as absurd as in other areas, such as the dotcom sector.

Now that the grace period is over, consolidation is occurring and biotech must deliver on these raised expectations. Is there a doubt that the sector will deliver? Absolutely not. More than 150 new biological entities (NBEs) are on the market and hundreds of promising second-and third-generation products addressing unmet medical needs are in development. In addition, the pharma-biotech industry is generating a sustained flow of positive news and will eventually come out stronger than ever.

However, the sector is also realizing that biopharmaceutical drugs are subject to the same economical principles as products in any other industry. Therefore, requirements for efficacy, safety, and quality, as well as competitiveness and payability, are steadily increasing.

BIOMANUFACTURING: DRIVEN BY FIXED COSTS Biomanufacturing is characterized by high production costs compared to the synthesis of small-molecule products. Although the basic requirements of current good manufacturing practice (cGMP) are the same, biotech companies will never have the luxury of applying GMP just to the final steps of producing biopharmaceuticals. Rather, biopharmaceutical regulations require a strictly controlled process from the biological source all the way to the final dosage form. Regulatory authorities approve processes, not products — a logical strategy because proteins (with their multitude of microheterogeneities) cannot be sufficiently characterized with the analytical tools used with small molecules. Macromolecules must be produced within predetermined specifications and controlled with validated in-process controls.

This, together with the fact that biological drugs are typically used for systemic treatment and administered parenterally, leads to the high level of regulation. However, because comparability and bioequivalence are the cornerstones of drug safety, nobody is complaining.

Whether this leads to insurmountable obstacles for biogeneric drugs is open for discussion. The fact is, however, that substitution with biogeneric drugs, follow-on biologics, or biosimilar drugs (be it threat or reality) will lead to further pressure on manufacturing costs and raise healthcare reimbursement issues.

Biopharmaceutical production costs depend on a number of issues, the foremost being the expression system, which relates to the more or less complex nature of the target molecule and upstream and downstream particulars. In general, biomanufacturing is driven by fixed costs, which is why excellent contract manufacturing organizations (CMOs) are so successful in this sellers' market. Too early, too late, too big, too small — the cost of idle production facilities (not just production yield) is crucial. Conflicting projects can prevent the delivery of an approved product from a licensed facility to market. All other approaches are compromises, including, at best, the retrofitting of existing facilities or, at worst, mothballing a late-stage failure.

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