There have been many improvements made in biopharmaceutical manufacturing since its inception in the 1980’s. This has culminated in the most common approach to large-scale biopharmaceutical manufacturing being the fed-batch mode applied to suspension culture. Improvements made to the process have involved each of the individual steps, including advances in cloning and selection methods, removal of animal products materials, implementation of single use systems and improved purification resins and columns. This isn’t to say that other approaches haven’t been tried, even with great success. For example, Genzyme (Sanofi) and Centocor (J&J/Janssen ) have long employed perfusion culture in upstream processes of some approved biopharmaceutical manufacturing. Nevertheless, the overall paradigm of batch-fed process throughout the industry has not evolved a great deal.
While batch-fed process is still by far the most popular choice for biopharmaceutical production, recent studies signal that this may be changing. Last month there was an article in the MIT Technology Review titled “Biotech Firms in Race for Manufacturing Breakthrough,” which described how Biotech firms including Genzyme and Amgen are actively pursuing radical new technologies to improve and streamline biopharmaceutical manufacturing. This kind of major change to biopharmaceutical production is critical if biotech firms are expected to maintain reasonable drug costs and continue to improve upon current productivity levels. Biotech firms and industry leaders are looking for ways to advance biopharmaceutical manufacturing to the next level.
One technology being explored in-depth is the system-wide use of continuous processing (CP). The concept of CP is certainly not new, and is the mainstay in such other industries as steel manufacturing to paper production. In continuous processing, as the name suggests, manufacturing is conducted in one continuous process where raw materials constantly flow in and out of manufacturing equipment and are continually processed into an intermediate or final product. In biopharmaceutical manufacturing this is accomplished in a bioreactor. This is in contrast to the discontinuous “batch” production, where a specific quantity of drug is produced in a single, discrete volume during the same cycle of manufacture. The episodic batch production mode is frequently segmented into many individual steps that are often performed at separate facilities (suites, buildings or cities). In continuous processing, on the other hand, production occurs at a single location, without interruption. In CP, manufacturing is conducted with more automation and fewer human operators. It has proved a very successful approach in a number of businesses, such as in the manufacturing of foods from catsup to cookies. This industry proudly promotes their severely linear factories where materials are continually trucked in at one end of the factory, and product out the other. It’s really quite fascinating to see dough constantly assembled in the front of the plant, cookies baked in a long linear oven, cooled on a conveyer belt, and finally boxed and shipped out the back without pause or interruption.
In a traditional fed-batch system there are many distinct and separate operations, from upstream to downstream processing. For years, bioreactor tanks employed in manufacturing commonly contained 10,000 liters or more. In batch type modes of protein biological production (whether fed or not) the cultured cells secrete the protein of interest into the single charge of ambient media throughout the run. The process typically last between 7-21 days with the product collected all at once, as a bolus, at the end of the run. Harvested product is also purified as a batch with yields historically ranging between 0.2 and 0.8 grams per liter depending on the clone. A number of technological improvements have supported yields to increase to 1-4 grams per liter in current routine manufacturing with some specialized instances reaching 5-20 grams per liter. While this has resulted in many products requiring smaller reactors, other challenges with fed-batch production remain. For example, individual steps of the overall process are often performed in different areas and at different times, causing such issues as interruptions in production and storage of large volumes of intermediate product. This contributes to such issues as expanse of facilities, expense in processing and reduced product quality.
In contrast, continuous bioprocessing uses a smaller bioreactor continually providing product-containing media to specialized chromatography that can continuously separate the product from the surrounding liquid. Using this method, you no longer need huge bioreactors to manufacture the same amount of product. This leads to smaller overall manufacturing footprints and eliminates harvest-hold containers and massive clarification systems.
Potential Advantages of Continuous Processing in Biopharmaceutical Manufacturing
Improved Product Quality
One driving factor in the argument for continuous processing is that product quality can be improved. In continuous processing media nutrients are constantly maintained and cells don’t experience the same kind of lags at seedlings or drop-off at the end of culture where cell viability is greatly reduced and uncharacterized reactions occur. Processing delays, more common in fed-batch systems, are greatly reduced in a continuous processing system as product is moved in a constant flow from one step to the next. In batch-fed processing, product intermediates are often stored or kept on hold as the products move through the many steps of the process. These delays, transfers and exposures can lead to product degradation, increase risks of contamination and other product safety concerns. In continuous processing, product intermediates are kept in a more consistent condition or steady state for a shorter period of time.
Continuous processing allows for easier scalability, allowing for immediate increase of production as demand requires. As production rate is determined primarily by time and not volume, increases in production can be accomplished by longer campaigns. For even greater demand, due to the smaller footprint, additional continuous processing units can be added much more easily that the much larger batch reactors and holding tanks. Scalability is a key issue as drug shortages have become a higher concern with the FDA. FDA has identified drug shortages as a major issue and according to the MIT article “The FDA reported 251 drugs in short supply in 2011; for medicines that are injected, as most biotech products are, it said that about 20 percent of the time, the problem was that companies’ manufacturing capacity fell short.” Related to this is the remarkably improved “technology-transfer” afforded by CP. In fact, process development can be economically accomplished in the exact equipment that will be employed on the manufacturing floor. This greatly reduces or eliminates many tech-transfer and scale-up issues.
There are two major components to increasing profitability using continuous processing. Profits can be increased through both more efficient and economical facility design/ utilization and by a reduction in the cost of goods. One of the primary advantages to utilizing CP in biopharmaceutical manufacturing is the improvement in manufacturing facility utilization. Continuous processing employs equipment that has a smaller footprint than the huge tanks required in batch-fed processing, and typically requires less energy consumption. The smaller footprint reduces the size requirement of manufacturing facilities and allows for a system that is more “portable”. This supports the addition of more units as demand requires without requiring a large facility build out or outsourcing. In addition, the initial capital investment is lower because the overall facility is smaller. Other cost savings occur through an increase in automation, reduction in service requirements, and reduction in operator labor.
Cost of goods is also reduced in a continuous processing scenario due primarily to a simplified process stream with fewer opportunities for product loss or reprocessing. Shorter processing times and better material utilization, mentioned before, are also factors in cost reduction. The volumetric productivity and increased process efficiency results in reduced CPA and higher product yields per facility.
Continuous Processing Research
While a fully continuous process is not currently employed in approved biopharmaceutical manufacturing, there are elements of existing biopharmaceutical manufacturing that fit well into a fully continuous processing system. One example is the use of perfusion bioreactors. Perfusion bioreactors fit into continuous processing because unlike batch-fed systems they culture cells over much longer periods, even months, by continuously feeding the cells with fresh media and removing it when exhausted. In perfusion bioreactor systems the protein can be theoretically constantly separated from the continuously harvested liquid media. Single use systems also compliment the idea of CP by supporting some of the benefits of continuous processing including easy product changeover and facility utilization. In fact, one emerging technology growing in popularity is the application of single-use equipment supporting enhanced perfusion culture with single use bioreactors, supporting single-use upstream production with disposable product-contact surfaces. In the downstream segment of this scenario, even the Protein A resins traditionally associated with batch purification can be modified to accommodate CP through such technologies as simulated moving bed (or periodic counter-current) chromatography.
One company on the cutting edge of continuous processing research is Genzyme. Konstantin Konstantinov, Vice President Technology Development, leads Genzyme’s research team on the use of continuous manufacturing and Genzyme recently published two papers on the work that they have done in this area. “Periodic counter-current chromatography – design and operational considerations for integrated and continuous purification of proteins,” was published in Biotechnology Journal and “Integrated continuous production of recombinant therapeutic proteins,” was published in Biotechnology Bioengineering.
The publications describe how Genzyme coupled the use of a perfusion bioreactor with a periodic counter-current chromatography (PCC) operation to continuously capture and purify proteins. In the Biotechnology Journal publication, a study is described in which three proteins, two enzymes and one monoclonal antibody were manufactured using a continuous bioprocessing system. In the abstract, authors state that, “The advantages of a continuous downstream capture step are highlighted for the three case studies in comparison with the existing batch chromatography processes. The use of PCC leads to improvements in process economics due to higher resin capacity utilization and correspondingly lower buffer consumption. Furthermore, integrated and continuous bioprocessing results in a smaller facility footprint by elimination of harvest hold vessels and clarification, as well as by reducing the capture column size by one to two orders of magnitude.”
Potential Challenges to Adoption
Other than the usual concerns regarding anything new, there are a few financial, engineering and regulatory concerns to slow the incorporation of CP in pharma. Some still have concerns regarding the FDA’s response, or how such systems interface with such initiatives as the Design Space concept or FMEA. Because of significant existing batch process capacity, others see technical capability and business case analysis of ROI/NPV diverging. But many of these may simply be first-blush concerns.
In fact, CP does require some new forms of in-process testing and release approaches. And, most significantly, for a full CP processing train, new, more robust adaptive / closed loop control systems must be developed. New strategies are also needed in regulatory applications and knowledge management. While some unit operations can be very readily converted to CP, for others the means of some required parameter monitoring are not yet adequate. The number of measurement points and understanding of true CPPs for new bioproduction CP process are yet to be determined. The latter point is notable because transition from existing batch to CP does require both clear product CQA and CPP understanding.
Raw materials concerns in CP include equipment for either higher materials control or increased process robustness for known materials variability. CP usually also demands very accurate and precise materials feeding technologies.
Well-founded or not, process related concerns include those regarding start-up and shut down material loses and costs, the means of achieving the robust process throughput balancing required, fears that equipment cleaning may be more difficult or complicated, and the fact that when any unit op in CP is down for any reason, the whole process is down.
Many modern production approaches employ continuous processing. CP is supported by pharmaceutical regulatory agencies and provides many specific benefits in bioprocessing. A growing number of biopharmaceutical manufacturers currently employ CP operations and recent developments promise to stimulate even more interest in them. Industry leaders see the design of completely closed, disposable and continuous biomanufacturing systems for biopharma on the horizon.
*This content has been updated since the first publication to reflect the author’s current affiliation. The author’s previous affiliation was Senior Manager, Bioprocessing Market, Thermo Fisher Scientific
William G. Whitford
Bill Whitford is Sr. Manager, Emerging Technologies for Thermo Scientific Cell Culture and Bioprocessing in Logan, UT with over 20 years experience in biotechnology product and process development. He joined the company eleven years ago as a team leader in R&D developing products supporting biomass expansion, protein expression, and virus secretion in mammalian and invertebrate cell lines. Products he has commercialized include defined and animal product-free hybridoma media, fed-batch supplements, and aqueous lipid dispersions. He had previously served as Manufacturing Manager for PHASE-1 Molecular Toxicology in Santa Fe, New Mexico producing custom and standard DNA microarrays. An invited lecturer at international conferences, Bill has published over 150 articles, book chapters and patents in a number of fields in the bioproduction arena. He now enjoys serving on the Editorial Advisory Board for BioProcess International.