Biopharma 4.0 is often presented as an all-or-nothing proposition, when in fact its components have all been around for a while and have independent value. It appears the major challenge will be continuous processing, which is not surprising given its technical difficulty and inherent regulatory uncertainty.

In a recent examination of key enablers for continuous bioprocessing, lead author Anurag Rathore, PhD, in the department of chemical engineering, Indian Institute of Technology, Delhi, notes that although continuous manufacturing is more complex than batch processing, the added complexities (and costs) “are outweighed by the advantages associated with productivity gains and more cost-effective production.

“At the moment, most of the major biopharma companies, including Sanofi, Merck, GSK, are in the process of commissioning continuous manufacturing facilities. Others like Amgen have already been operating such facilities.”

Rathore is referring to Amgen’s Singapore facility, which opened in 2014. Not much news has emerged about this site, but it is known that the plant uses single-use equipment throughout, a “flexible, modular design,” and continuous downstream processing (at least for some products).

GEN readers are well aware of the potential benefits of continuous manufacturing, which have been known to manufacturers of cement and potato chips for many decades. The obvious question, which I also asked in last week’s bioprocess insight article: If it’s so great, why isn’t everyone doing it for every process, for every drug, at every location?

Rate limiting step

It seems almost as if this industry—as it is reflected among the punditry—has already moved on to the next buzzword, Biopharma 4.0, without having solved the practical issues involved in its core engineering component, i.e., continuous biomanufacturing. Because continuous production is hard while process control, sensors, streamlined/scalable designs, predictive modeling, digitalization, etc. are more easily attainable, it appears we are closer to our goal than we actually are. But as any chemist will tell you, the rate-limiting step—the slow step—determines reaction rate, not the easy steps.

An intriguing option, which often presents itself during paradigm shifts, is to adopt bits and pieces of the final “vision” and at some point connecting them. For Biopharma 4.0 that might mean adopting process intensification, connected or combined unit operations, advanced monitoring and process controls, digitalization, or upstream/downstream continuous processing, etc. These technologies are already available but they, too, require time and money to implement.

In fact continuous processing by itself represents a paradigm shift, with independent dynamics and economics.

“For some manufacturers, a jump from batch to fully continuous may be too steep,” Rathore says. “They may choose to implement continuous processing in those parts of the process where the impact on productivity and COGS is the maximum. “

The message here is, regardless of where your organization finds itself on its “4.0 Journey,” individual components of the New Biopharma are themselves worthy goals.

“Real time monitoring and control is desirable in general for biopharmaceutical manufacturing,” Rathore observes. “This is why the US FDA introduced PAT guidelines back in 2004. However, by and large the industry did not see much value in process-wide implementation of these concepts. A lot has been done in the past year on the topics of process modeling, real time analytics and real time data analytics and control, and today it is quite feasible for industry to implement PAT in commercial manufacturing.

The advent of continuous manufacturing has fueled interest in PAT implementation as it is not possible to perform continuous manufacturing for commercial production successfully without elements of real time monitoring and control.”

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