The movement of viral vectors, cell therapies and other antibody-based next-generation drug products toward commercialization is driving the need for new and different technologies and facilities. These facilities need to be more flexible and suited for multiproduct manufacturing. Large stainless steel tanks will remain part of the solution, but single-use systems for upstream and downstream operations are increasingly important.
Growing Diversity
Twenty years ago, just a few types of biologic drugs were being developed and ultimately commercialized, often using similar cell lines that required common equipment and facility designs. That is definitely not the case today. Early clinical successes with next-generation therapies based on cells, genes and viral vectors are driving investment in manufacturing facilities for these and other personalized medicine products, which require novel technologies and engineering designs. Many second- and third-generation antibody-based drugs also require different manufacturing processes.
In addition, the pharmaceutical market has become very diverse and is no longer focused solely on blockbusters; smaller-volume products that treat targeted patient populations account for a growing percentage of portfolios and pipelines. The high potency of some biologics also contributes to a need for smaller product volumes. There is also increasing investment in vaccine manufacturing.
As a result, many biopharmaceutical manufacturing plants today produce multiple products with varying properties that require different production processes. The evolution and definition around container closure has provided a greater sense of process flexibility, but companies must still decide if they are going to take a longer multiproduct view of their facility and process design. With a myriad of product options that might be in the future pipeline, ensuring that cross-contamination can be managed now and into the future is critical. For instance, large (20,000 liter) stainless steel bioreactors continue to have their place in the industry, but single-use (SU) bioreactors and systems for downstream unit operations are being increasingly adopted on the commercial scale to provide the flexibility needed to ensure safe and efficient operation of multiproduct facilities.
Access to SU technologies is also providing smaller players with the opportunity to pursue manufacturing on their own, rather than relying on contract service providers. Charting this course is challenging for many of these companies, however, because they must rapidly develop manufacturing operations capabilities in order to compete with Big Pharma companies and CDMOs. Many of these new entrants have extensive scientific expertise but lack personnel with large-scale production experience. Engineering and design firms with the right skill sets can take on an educational role, helping these companies understand the timing of investments and skills they need to develop in order to become manufacturing organizations.
While large (20,000 liter) stainless steel bioreactors continue to have their place in the industry, single-use (SU) bioreactors and systems for downstream unit operations are being increasingly adopted on the commercial scale to provide the flexibility needed to ensure safe and efficient operation of multiproduct facilities.
Maintaining the Right Balance
Perhaps the biggest driver of change in bioprocessing is the need to reduce the cost of goods. Of course, many of the changes intended to result in lower costs require up-front investment that must be captured at some point in the value stream. The biopharmaceutical industry is also challenged with legacy investments and regulatory impact when making any manufacturing change.
Despite these challenges, the drive to move to SU systems is quite strong in certain circumstances. Biopharmaceutical manufacturers are looking to identify opportunities throughout their entire production operations — from cell culture to fill/finish — for implementation of SU technologies. Most commonly, SU systems are finding a use for upstream operations. The development of downstream technologies has lagged somewhat, but vendors are improving their offerings on a continual basis. For instance, line sizes for tubing are increasing to address a major shortcoming of SU systems for process-scale chromatography.
Manufacturers must maintain a balance, however, and most adopt hybrid solutions that incorporate SU technologies where they can provide significant cost and time advantages combined with operational flexibility. Often adoption of SU systems provides manufacturers with multiple process-design options, which helps ensure that these up-front choices will be effective for the lifetime of the facility (now < 20 years). Because CDMOs by definition manufacture many different products and product types on a wide range of scales, they have been more eager to implement SU technologies. Branded pharmaceutical companies producing more conventional biologic products, on the other hand, still have requirements for large-scale production. They also generally have a longer-term visibility of production plans for a given facility. As a result, the commercial adoption of SU technologies by these firms is occurring at a slower rate compared to that of CDMOs and biosimilar producers. The one exception is branded pharmaceutical companies that are developing cell and gene therapies and other next-generation, personalized medicines, which are often produced at very small volumes.
Titers for mAb and protein production have climbed dramatically and the volumes required for these products can be sufficiently large to preclude the use of SU technologies. Though SU systems can be installed more quickly and less expensively than a stainless steel unit, the operational costs associated with the large numbers of SU bags required to meet production volumes eventually exceed the costs of operation in stainless steel. In addition, many downstream processes continue to be performed in stainless steel, so any potential savings on utilities (such as steam-in-place and clean-in-place) are not fully realized.
Design Considerations
It is crucial when designing a new facility, or expanding an existing facility, to consider where current process development efforts might lead. There is significant uncertainty because technologies that work at a smaller scale may or may not work at the commercial scale. In addition, issues such as the staging and storage of consumables and waste cannot be easily predicted, and generally storage space is limited. Media and buffer management are also important issues; shifts in operations and in scale are often limited by how much media/buffer can be processed in a facility.
It is necessary to identify all business drivers and fully understand the products and processes to ensure design of a high-quality facility. Will there be multiple products or a single product? Will there be a platform technology? Will it be a small-volume personalized medicine or large-volume product intended for the global market? This information is considered, along with the available equipment, to design a flexible facility that will help clients hedge their bets. In fact, given that the certainty of product approval after reaching phase III has noticeably declined in recent years, rather than go straight to a large production plant, many manufacturers are limiting their initial outlays by constructing launch facilities with multiple smaller reactors that provide the ability to scale-up production as needed.
Flexibility in facility design is essential to meet diverse processing needs for biopharmaceutical manufacturing.
Access to Options
Because flexibility of facility design is so crucial for biopharmaceutical manufacturing plants today, it is essential to select a design firm with the depth of knowledge and breadth of capabilities that enable the presentation of options and alternatives. Biopharmaceutical products are manufactured using complex process technologies for drug substance and require aseptic filling for drug product. An engineering firm should be able to identify, at an early stage, appropriate standards that provide the optimum solutions and align with current manufacturing practices, and be willing to argue against internal client guidelines, if required. If not, ultimately the facility may need to be redesigned at a later stage, which could impact product delivery timelines. Being able to tie process technology and facility design to regulatory expectations is also a critical skill for any engineering design firm partner. Finally, with the percentage of highly potent biologic drug products growing rapidly, it is also important for design firms to have knowledge of, and experience working with, the complex facility systems and equipment necessary to ensure the safety of operators and the environment.
Having knowledge of state-of-the-art bioprocessing technologies is not sufficient, however. A close relationship with biopharmaceutical equipment vendors is extremely important. Vendors today take part in the facility design process more than ever before, and having established working relationships facilitates the design and construction process. Notably, design firms that serve multiple sectors don’t have the same incentive to build and maintain collaborative relationships as do firms dedicated to the pharmaceutical industry.
Global Adoption
It is worth noting that the adoption of SU technologies is occurring at different rates in different geographic areas. For instance, SU systems are being implemented rapidly across many facilities in the U.S. and Europe. Manufacturers in China are focused more on biosimilar than branded drug manufacturing and thus are more prone to adopt SU systems to achieve flexibility of scale. In other Asian countries, however, SU systems are perceived to be more expensive because equipment is being disposed of. In other countries, import/export treaties can impact SU usage.
In addition, companies that have been leading adopters of SU technology have been on a learning curve. In many cases, SU technologies are being implemented in multiple spots and thus are uncovering unexpected issues, such as with the ergonomics of SU systems. The need for tubing lengths of 20-30 feet and tubing transitions between floors has also created difficulties. Optimum solutions for the connection of SU systems to stainless steel units are also needed. The question of whether to use a unidirectional or bidirectional flow in multiproduct facilities has been raised. There is no one answer, however, because the choice is very product- and facility-dependent. This is yet another reason why hiring an engineering firm with process technology and facility design expertise is critical in providing options and alternative solutions to support the decision-making process.
Conclusion
Flexibility in facility design is essential to meet diverse processing needs for biopharmaceutical manufacturing. Choosing an engineering firm that understands diverse client business drivers and has the ability to deliver a range of flexible solutions can help biologic drug producers get their products to market faster and more cost-effectively.
As a global firm offering architecture, engineering, construction management and regulatory compliance support services, as well as operational expertise, our company, IPS-Integrated Project Services, LLC, delivers technology-based business solutions that help our clients succeed. Our multidiscipline departments and service groups openly exchange ideas, work together to solve problems and incorporate lessons learned into future designs. With our years of focus on the pharmaceutical industry, we have the experience, knowledge and long-term relationships with vendors to support clients located throughout the world with projects that start at the master cell bank vial and end with the fill/finish vial, including mapping the systems needed for potent compound handling.