“If it’s not broken, don’t fix it.” This truism is given a lot of weight in biomanufacturing, where tried-and-true methods predominate. New methods, however, are getting a hearing. They appeal to the common desire to generate products more prodigiously, more quickly, and more economically. Optimizing manufacturing is a tricky business, however, when it involves production units—living cells—that respond better to coaxing than squeezing.
The biopharma industry has been using cells to make biologics for 40 years. The first biologics were tweaked versions of naturally occurring molecules, with the earliest example being Humulin, a longer-lasting insulin launched by Eli Lilly and Company in 1982.1
Soon after, advances in molecular biology let developers harness antibodies to create therapies capable of interacting with specific targets, thereby increasing their efficacy and reducing side effects. Today, monoclonal antibodies dominate the industry. According to one study, monoclonal antibodies earned developers $75 billion in 2013, half of the total revenue generated by all biopharmaceuticals that year.2
In need of an update
Monoclonal antibodies owe their success to the early development of robust production methods. These methods, however, may have been a little too effective. They worked so well that they left biomanufacturing with little incentive to develop anything better. After all, why invest in new methods if existing methods are satisfactory?
One reason is suggested by Andrew Bulpin, PhD, executive vice president and head of the process solutions at MilliporeSigma. “Monoclonal antibodies have been made from the same templated manufacturing process for the past 20 to 30 years,” he observes. Nonetheless, he believes that new technologies and manufacturing methods could benefit biopharma firms looking to intensify production.
“When we think about MilliporeSigma’s role in biomanufacturing’s evolution,” he explains, “we start with process intensification by updating and upgrading outdated unit operations, then connecting these processes to run in a continuous flow-through fashion.” He points out that the ultimate goal is the implementation of continuous processes that are connected, digitally enabled, automated, and run as a production train. The MilliporeSigma approach to this kind of processing is called “contiGuous” processing.
“We have estimated that by the year 2025, approximately 30% of the molecules within commercial manufacturing will utilize process intensification technologies,” Bulpin states. “The conversion of batch processes to continuous manufacturing is the future of the pharmaceutical industry, employing continuous flow, end-to-end integration of manufacturing subprocesses with a complex level of control strategies.”
Process intensification is based on a simple concept: use methods like continuous manufacturing to shorten timelines and increase yields. The idea has already been embraced by several companies. The biotech firm Sanofi Genzyme, for example, has developed an intensified perfusion platform with cost reduction and speed-to-market as the main aims.
When perfusion culture is pushed toward high cell density and productivity, dramatic reductions in cost of goods manufactured can be achieved, says Shawn Barrett, associate director at Sanofi Genzyme’s Continuous Manufacturing Skill Center. However, product quality must be maintained, and processing must integrate multicolumn capture. “Incorporating intensified perfusion into a platform process,” Barrett asserts, “allows the benefits to be established early in process development, while also minimizing development timelines on the path to IND.”
Sanofi Genzyme uses an automated sampling technology to monitor culture. According to Sanofi Genzyme’s senior research engineer, Jared Franklin, the results have been impressive. “The autosampler has greatly enhanced our process understanding through increased data resolution, which is particularly helpful prior to the bioreactor reaching a state of control,” he reports. “It has also proven instrumental in predictive chemometric model building due to its rapid sampling capability. Furthermore, it has reduced our manual labor needs, which is ideal for us, given that we are a small team that is expected to have a big impact within our industry.”
Not all drug companies have embraced “new” ideas like continuous manufacturing. In part, this is because the industry is conservative and unwilling to leave its comfort zone, Bulpin says.
“Adoption remains a key challenge,” he continues. “Biologics have been made essentially the same way for more than 30 years. Therefore, some of the biggest hurdles in the transition to fully continuous manufacturing will be the fear of and resistance to change.
“Regulatory approval is likely to take longer for continuous processes. Until the approval of several molecules produced in a continuous manner, the regulatory bodies will place increased scrutiny on these processes. However, our discussions with the FDA have shown its support of continuous processing.”
Barrett has also noted biopharma’s reluctance to embrace new methods. “The main challenge to widespread adoption is perception of risk—irrespective of whether the risks are known or speculated,” he says, citing various factors related to uncertainty, including technology robustness, scale-up approach, failure mode management, and lack of experience.
Efforts to convince biopharma of the benefits of new approaches are intensifying (pun intended). Bulpin indicates that consortia, such as the BioPhorum Operations Group and the National Institute for Innovation in Manufacturing Biopharmaceuticals, are playing a pivotal role, and he adds that the technology sector is ready to support such work.
“We stand behind this need to change,” he declares. “By being the supplier of choice, we can help support our customers through that change and lead the industry through this transition. The change will happen as quickly as the slowest player.”
Interest in intensification is not limited to the monoclonal antibody sector. For example, in recent years, vaccine developers have also been trying to find ways to ramp up production while reducing costs.
One such research effort saw Batavia Biosciences team up with Univercells and Natix Separations, now a subsidiary of MilliporeSigma, to come up with better ways of making vaccines, specifically the Sabin inactivated polio vaccine. Batavia Biosciences’ director of cell technology, Alfred Luitjens, says the aim was to ensure that “affordability and availability would be significantly increased.”
The project involved the development of a bioreactor and the creation of an improved version of the Vero cell lines used to make the vaccine, which were handled by Univercells and Batavia, respectively. Natrix’ role was to implement its enhanced membrane technology for processing.
“These ideas, put together, had the potential to have a significant impact, and based on that, Univercells submitted a grant request to the Bill & Melinda Gates Foundation, which quickly approved the request and gave its full support,” Luitjens tells GEN. “Our goal was and is to reduce the production costs of vaccines by at least a factor of 10.”
The project achieved an 80-fold increase in output. “This is based on a number of factors leading to massive process intensification,” Luitjens details. “First, we subcloned a Vero cell line for polio that increases the virus production per cell by a factor of two. Second, in the scale-X bioreactor system, it is possible to increase the cell density/mL by a factor 20 to 40.
“So, with an improved cell line and the high-density bioreactor, we significantly improve the upstream productivity.”
Natrix’s purification technology also played an important role. “Compared to the conventional polio purification process,” Luitjens asserts, “we are able to reduce the number of steps needed, increase the recovery in the purification process, and reduce the operational cost.”
Scale-up and expansion
At present, the process and technology are still at a small scale. However, work is underway to increase the capacity of the growth surface in the bioreactor to 600 m2. “We expect,” Luitjens says, “that we will be able to manufacture 12 million doses on a yearly basis with one bioreactor system of around 50 L.”
The Gates Foundation has said that it will support the use of this approach to intensify the production of vaccines against other diseases as well. “The next targets will be measles and rubella,” Luitjens points out. “In this program, we will apply a different cell line, MRC5. That way, we can show that other cell lines can be applied to the platform and grown to high cell densities. As measles and rubella vaccines are less purified products compared to Sabin-inactivated poliovirus vaccine, the membrane purification technology will not be applied.
“Currently, we apply the technology to viral vaccines and improve the affordability and availability of these vaccines. However, the technology can also be applied to other products, like viral vectors for cancer vaccines or gene therapy. By applying the platform to these products, we think it would be possible to reduce costs of these very expensive products and make them available to more people.”
1. Humulin N, NPH, human insulin (recombinant DNA origin) isophane suspension. National Museum of American History.
2. Ecker DM, Jones SD, Levine HL. The therapeutic mono-clonal antibody market. mAbs 2015; 7: 9–14.