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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Single-use and modular technologies plus continuous manufacturing are increasingly important to biopharma scale-up and tech transfer.
It is hard to believe, but the biopharmaceutical industry is already old enough to have aging facilities that are decades old. FDA’s focus on the need for updates is creating both opportunities and challenges for biologics manufacturers involved in the scale-up and transfer of production technologies. Single-use and modular technologies, along with continuous processing approaches, are helping the industry both modernize old processes and facilities and minimize the risks associated with making significant changes to existing systems.
Aging facilities attract FDA attention
Just as time passes more quickly as people age, it seems time goes by more rapidly as industries mature. While the biopharmaceutical industry is young compared to the small-molecule pharmaceutical sector, it has been of significance for several decades. Some of the processes that are running today utilize the technologies developed when the industry was first established. “Many of these processes were licensed long ago and are quite complex, contain open steps, and are inefficient in many places,” notes Parrish Galliher, CTO of BioProcess Upstream at the Life Sciences business of GE Healthcare.
FDA has recognized the need to upgrade these older processes and facilities and is imposing updates (1). Equipment suppliers are working closely with biopharmaceutical manufacturers to develop plans for implementing the needed changes. “This situation provides a great opportunity to update those systems, facilities, and practices, but also presents the challenges associated with changing any process, including the risk of affecting product quality in some way. Fortunately, by working closely with tools and technologies suppliers and the regulators, biopharmaceutical manufacturers are better positioned to overcome such challenges,” Galliher asserts.
One of the most efficacious ways to revamp older processes as required by FDA is to upgrade with single-use technologies, according to Helene Pora, vice-president of single-use technologies at Pall Life Sciences. “Single-use systems have proven to not only reduce capital investment, but also minimize turndown time, resulting in more effective and higher-quality manufacturing processes for scale-up and tech transfer,” she states. In fact, biopharmaceutical contract manufacturers routinely assess single-use technologies as options when new equipment is introduced to meet a process need, according to Paul Bird, head of the manufacturing engineering group at Fujifilm Diosynth Biotechnologies’ Billingham, UK site.
Fujifilm develops and manufactures biologics using both microbial and mammalian production systems, and although single-use technology is a relatively new introduction, it has had an impact on mammalian manufacturing at the company. Mammalian cultures do not tend to be intensive; they do not have high oxygen demand and do not grow in very high cell densities, Bird explains. In addition, the culture growth takes place over a long period of time. As a result, a reactor for mammalian cell culture is not required to have high heat removal or provision for high oxygen supply; as such, single-use systems are well suited.
The situation is different for microbial cultures based on Escherichia coli and yeast, for example. These processes have high growth rates and densities, and thus the demand for oxygen is high, making it difficult to replicate a high-productivity process in a disposable reactor, according to Bird. “Because these cultures require very good heat removal, high oxygen transfer, and other rigorous conditions, stainless steel tends to remain the best possible option for microbial processes today,” he notes. Advances in single-use technologies designed specifically for microbial systems may, however, lead to their greater use in the future.
Galliher agrees that single-use technologies are not a panacea for the upgrading of older processes. “Most older facilities use stainless-steel manufacturing systems, so the conversion to disposable technologies is not automatically straightforward,” he observes. When single-use systems are chosen, however, he adds that they are fairly rapid to install and start-up, particularly relative to older legacy technologies, so the impact on facilities and utilities support systems is minimized. In addition, because the running costs are less for single-use systems, they can be considered enabling technologies.
Modular approach proves flexibility
While modular systems are a well-established concept and have been available in some form for several decades, they are attracting increasing attention in the biopharmaceutical industry today. In fact, the increasing availability of modular processing units is bridging the gap for many manufacturers with both established traditional facilities and new sites under construction, according to Pora. “For established facilities, modular processing units enable a quick and easy transition to the hybrid facility format, while for new facilities, they are making the fully flexible single-use facility a reality,” she says.
The popularity of modular systems is not just being driven by FDA mandates; Pora also notes that manufacturers have realized that modular solutions can help them overcome bottlenecks and become more efficient with less investment of time and money.
The global interest in standardizing facilities, harmonizing designs, and moving to a distributed facility model with a series of smaller identical facilities around the world is also driving interest in modular systems. “For this model to be successful, the facilities need to be identical in order to facilitate tech transfer, documentation, training, and essentially everything that needs to be commissioned to run these facilities in remote territories. Due to this trend, the demand for duplicate cookie-cutter-type modules has increased,” Galliher comments.
Another trend driving interest in modular technologies is a reduction in production volumes due to the switch to distributed production, increasing yields, and the trend towards personal medicine. “Smaller facilities require smaller production systems, which makes modularity increasingly possible,” says Galliher. He does note, however, that modularity will compete with stick-built facilities in places where labor is cheap. “Companies will have to consider the quality standards they want to reach and whether modules already constructed to meet cGMP and other industry requirements will better meet their needs,” he adds.
Modular technologies are also increasingly available on the production equipment level and are used to build systems and processes that are identical in different locations, which again simplifies maintenance, documentation, training, and validation. “The modular nature of machinery makes modifying or adding options possible; their plug-and-play designs allow for easy modification with additional or different functions,” Galliher observes.
Fujifilm is a good example of a biopharmaceutical manufacturer that is taking advantage of modular production systems. In particular, the company designed a single system for the final bulk filling of cGMP products that replaces numerous existing filling systems. “By adopting a modular technology approach, we generated a unique capability for biologic drug product filling that for the first time provides flexible and adaptive manufacturing,” asserts Bird. He notes that the system is flexible because the production process supports bespoke operations meeting customer requirements in full, and adaptive because the modular nature of the system enables point-of-use increases or decreases in production capacity. “This ambitious project has extended the benefits for the most critical unit operation--final bulk filling--and has standardized the operator experience without impacting the flexibility to meet customer requirements,” he adds.
Consistent, flexible, yet rigorous business processes that introduce dependable operations on-time and in full are necessary for effective technology transfer, according to Bird. “In addition to effective technology transfer between R&D sites and various business units, companies must have the ability to site, develop, and deliver into manufacturing correctly the first time. The collaboration of highly motivated and highly skilled people across multiple programs of activity is the key to success in both areas,” Bird states.
As one example of how Fujifilm is using technology to address current challenges, Bird cites the company’s “TAG” system for digitally managing the capture, conveyance, and retention of manufacturing knowledge to improve technology transfer, which provides controlled publication and distribution of manufacturing system standards and operational best practice.
Scale-down modeling for successful scale-up and tech transfer
One of the benefits of the use of smaller production facilities is a reduction in the scale-up factor for many biopharmaceutical processes. No longer are manufacturers required to scale-up from the lab to 20,000 L; more commonly processes are scaled up to 2000 or sometimes 5000 L. As a result, scale-up is less of a technological leap and therefore more predictable and lower-risk than in the past, according to Galliher.
The use of scale-down modeling, in which a large-scale system is reverse-engineered down to the lab scale so that it can be operated to model the large-scale process, has also significantly reduced the difficulties associated with process scale-up. With this approach, data that are representative of large process behavior can be collected early in the development process and at lab-scale costs, according to Galliher. He adds that better-designed model bioreactor, chromatography, and filtration systems are allowing for even smoother scale-up and tech-transfer operations.
Raw material choices are also being adjusted to improve scale-up processes. “Instead of buying small amounts of lab quality reagents and then moving to large-scale suppliers once a process has been developed, today some manufacturers are beginning the development process with materials purchased from their eventual large-scale suppliers. This approach eliminates the need to change their raw materials at the point of tech transfer and scale-up and thus avoids any potential impact on performance and product quality,” Galliher explains.
Continuous processing has potential to overcome scale-up and tech-transfer issues
The adoption of continuous processes and intensified manufacturing may have a significant impact on technology transfer and process scale-up. Pora believes that single-use technologies can also be aligned with the concept of continuous processing to address scale-up issues. “Many of the recent investments at Pall have been driven by this expectation, and our new single-pass tangential flow filtration modules and systems and inline concentrator are examples of technologies that have resulted from our recent efforts,” she says.
Galliher sees both advantages and disadvantages associated with continuous processing, and he remains uncertain whether these techniques and technologies will graduate to the commercial manufacturing stage. He does, however, believe that with their knowledge and skills, service providers can support biopharmaceutical manufacturers with the assessment of these new technologies and help them with scale-up and tech transfer into their own facilities. “When you drill down,” concludes Pora, “the particular challenge is reducing complexity.
1. J. Wechsler, “Modern Manufacturing Systems Key to FDA Quality Initiative,” Pharmaceutical Technology 39 (4) 2015.
Article DetailsBioPharm International
Vol. 28, No. 6
When referring to this article, please cite it as C. Challener, “Advanced Technologies Facilitate Scale-Up and Technology Transfer,” BioPharm International28 (6) 2015.