August 1, 2014 (Vol. 34, No. 14)

Sartorius Stedim Biotech’s Prof. Dr. Oscar-Werner Reif Discusses Significant Emerging Trends

Over the next 5–10 years, biotechnology will face unique challenges related to innovation, regulation, and economics. The industry will attempt to overcome these challenges by developing novel drug classes and continuously improving manufacturing operations. The threat from Asian manufacturers, particularly in biosimilars, means that companies will need to continue innovating to remain competitive.

To gain a clearer view of the competitive landscape, GEN consulted with Prof. Dr. Oscar- Werner Reif, member of the executive committee and executive vp of R&D at Sartorius Stedim Biotech.

Oscar-Werner Reif, Ph.D., Executive VP

GEN: What types of innovation do you foresee in molecular classes?

Prof. Reif The immense range of drug targets accessible through biologics suggests that these molecules will, over the course of the next decade, come to dominate development pipelines. One emerging class is the biological-cytotoxic conjugate. These are proteins, usually monoclonal antibodies, to which cytotoxic small molecules have been chemically linked. The antibody seeks the tumor, while the small molecule component destroys it. Radionuclides are also possible payloads, or in some instances an enzyme may be included to initiate a therapeutic biological process.

Manufacturing these drugs will require new technology, which is currently the most significant hurdle to development and commercialization. Many very successful linking techniques have already been patented, which limits freedom of operation for developers. There are also issues related to molecule design and production, but we are very close to solving these problems.

GEN: How about cell therapies, gene therapy, and vaccines?

Prof. Reif Cell therapy will soon face an existential challenge, namely will anyone pay for it? Technical and regulatory hurdles exist as well. As usual, success depends on economics. Gene therapy is even more problematic. Although some filings have occurred, I believe these treatments will remain in the scientific or investigative realm for the foreseeable future.

Vaccine R&D, however, remains vibrant and promising. We have already begun to see more complex vaccination methodologies in the form of single-shot multivaccines or combinatorial vaccines. Vaccines may also appear within the next few years for treating cancer directly. 

GEN: How about innovation on the engineering and manufacturing fronts?

Prof. Reif Everybody is of course talking about continuous processing, a fully integrated, top-down process similar to what we see in other manufacturing or process industries. But I’m afraid I will never see such a process adapted to the manufacture of biological drugs within my lifetime. I know that sounds negative, but so many hurdles remain.

What will probably occur is for individual unit operations to run in continuous mode, for example, perfusion cell culture. Bayer’s manufacture of Factor 8 is an example of a commercial success. But even that process reverts to batch mode at critical junctures, so it’s really a hybrid process.

Regulatory remains a hurdle for continuous processing, as regulators and companies must completely rethink their documentation and release criteria: How do they define batches, what do they release, and where do they perform quality testing? I’ve asked several customers running perfusion cultures why they stop, and at what point they return to batch mode, and why. Invariably, they tell me they need a formal batch because regulators expect a certain volume that is quality checked before release. To achieve this with a continuous process is much more difficult, if not impossible.

The point of continuous processing is to gain efficiencies not provided by batch operation. In that regard, very high density cell culture, or even parallel cultures, could achieve the same result. Another avenue for efficiency, which I believe will roll out over the next five years, is a higher level of automation and control in single-use processing. Even hybrid manufacturing processes can benefit from greater utilization of sensors and controls. There will also be greater standardization of components and harmonization of procedures and definitions.

All these improvements, which we hear so much about, will entail regulatory and technical challenges. Industries like chemicals, foods, and beverages have for decades overcome these challenges, whereas biopharm is completely new to that degree of manufacturing sophistication.

GEN: With the entrance of biosimilars, biobetters, personalized medicine, and the off-shoring of manufacturing, how will biopharmaceutical companies sustain themselves over the coming decades?

Prof. Reif If I had the answer to this question, I’d be wealthy. The pull of biosimilars, particularly from Asian manufacturers, will be tremendous. The question is how large biopharmaceutical companies will manage it.

Installed and planned capacity for biosimilars is already huge, and growing. There will be so much pressure on branded versions of biosimilar drugs that even a fair number of biosimilars manufacturers may not survive.

It has been said that prices will not fall as much for biosimilars as with small molecule generics, around 90%. Still, it is difficult to imagine prices not spiraling downward as manufacturers engage in price wars. For that reason, the innovator company’s only choices will be to continue to innovate and bring new and improved products to market, or lose their market position.

A countervailing force will be governmental support of biomanufacturing through financial or tax incentives. At issue here is not only the availability of less-expensive biologicals for domestic consumption, but the strategic location of manufacturing.

An especially sensitive location issue relates to vaccines manufacturing. Specifically, it is desirable to have manufacturers within one’s borders during a pandemic. Some Asian markets are, or will be, large enough to insist that biopharma distribute production into their countries. Companies in this situation will need to deal efficiently with tech transfers, which can be risky for a variety of reasons outside countries of origin.

Personalized medicine, where treatment relies on a drug and appropriate diagnostics is already here. Companies are already dealing with it. Personalized pharmacology will continue to improve based on new diagnostics arising from genome research. One possibility might be combinatorial treatments based on prescreening.

Personalized, cell-based therapies are another matter, as each patient will require a small “factory” for himself. Not to mention batch recording, release protocols, other regulatory issues, and the resulting costs. Cell therapies might succeed in developed countries with well-financed healthcare systems or if they adopt the orphan drug model, but then only if governments step in and subsidize these treatments. I do not see any indication that they are willing to do so.

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