By Joe Makowiecki, Enterprise Solutions Director of Business Development, and Harlan Knapp, Business Development Manager, Cytiva
Over the last few decades, monoclonal antibodies (mAbs) have become a dominant force in the landscape of the pharmaceutical industry, making up over 50 percent of the current biotherapeutic market.1 Early production challenges made commercial manufacturing costly; however, improvements in science and technology eventually gave way to a new generation of mAbs that led to a promising path toward precision medicine, which has ultimately transformed how we treat a wide range of diseases.
Now, as the world stages its fight against SARS-CoV-2, there is a growing focus on viral vector-based therapies, as nearly a quarter of COVID-19 vaccines in development rely on viral vectors for delivery of the spike protein.2 Even before this, though, viral vectors were playing a critical role in the rapidly growing cell and gene therapy (CGT) market, where seven of FDA-approved CGTs, as well as those in clinical trials, are or utilize viral vectors.3,4 By 2025, the FDA predicts the agency will be approving 10 to 20 CGT products per year.5 Yet, like first-generation mAbs, cumbersome manufacturing processes threaten the ability to produce viral vectors efficiently on a larger scale. Unlocking their full potential ― and controlling the current global pandemic ― requires an understanding of existing challenges in viral vector production and what technologies are now available in upstream and downstream processing to help address them.
Your options for viral vector manufacturing
Facilitating the development and approval of products that address unmet medical needs is a top priority for regulators. This is evidenced by the fact that all approved CGTs on the market thus far have qualified for an expedited development program through the FDA, significantly cutting the time it takes for them to reach the market. If you are a company developing a CGT, this may be generating a lot of excitement within your organization; however, shortened timelines can force critical business decisions to the forefront, specifically those related to securing the manufacturing capacity and/or expertise and experience necessary to meet demand on time.
As is often the case in today’s industry, partnering with a company that has these capabilities may be an alternative you decide to turn to ― but many others already have. This has resulted in a significant strain on the CDMO industry, with lead times for viral vector manufacturing capacity as long as 18 months. Rather than risking investments from shareholders and impeding speed-to-market strategies, you may consider building the infrastructure necessary to produce these therapies on their own. Whether this is the best business strategy for your product is based on several factors, including but not limited to your existing capabilities and capacity, in-house expertise, and the segment of the market you are targeting.
Another option is modular facilities designed with the production and business needs of viral vectors in mind. Modular solutions can provide the capacity and advanced technology necessary to develop your product while also addressing other challenges related to viral vector production, such as the sensitive nature of these molecules and the higher level of biosafety classification required for their production environment. These factors can increase complexity in facility design and operation. For example, Cytiva offers the KUBio box for viral vectors or the KUBio BSL-2 modular facility, which are both end-to-end solutions that use SUT and an integrated automation platform to provide an off-the-shelf compliant solution that includes processing support and expertise. These turnkey bioprocessing platforms can be fully commissioned and qualified in as little as 10 to 12 months, which means you can be ready for commercialization long before you can even secure a production slot with a CDMO.
Before you decide which option you will use, though, it is important to understand the limitations in today’s virus production processes, in order to ensure you are selecting the right technology and/or solution for your project’s unique needs.
Upstream challenges in viral vector production
The development of platform process for mAb manufacturing played a major role in the evolution and eventual success of mAbs in today’s industry. Finding ways to efficiently scale up mAb production helped improve yields, reduce development timelines, and lower costs, paving the way for large-scale commercialization. The same must be done for viral vector production, where legacy processes currently limit the ability to quickly meet process economic and scalability demands. For example, most biopharmaceuticals rely on suspension cells that were originally adherent but adapted to work in suspension culture and then scaled up using stirred-tank reactors. However, many of the viral vector-based therapies in clinical trials today rely on inherent or attachment cell lines, which have historically been grown in cell factories or roller bottles. This approach can limit the surface area available for cell growth and the manual handling of roller bottles could introduce contaminants into your process. As FDA requirements continue to change with the maturation and modernization of the industry, using outdated methods such as these could also put your product at risk for increased regulatory scrutiny.
Newer systems utilizing fixed-bed bioreactors have been developed to address this need, but there are limitations in scalability due to the need to scale out viral vector production using multiple lines rather than traditional scale-up to larger volumes. The type of cell line being produced also has a major impact on development decisions, as it may require specific considerations around shear sensitivity, instability, as well as any engineering limitations. Process intensification efforts, such as moving from batch to continuous processing, continues to be a focus across the industry and could potentially improve viral vector production, but other technologies to support this transition are necessary to drive adoption.
Another area that should be considered is product stability with product pooling and manufacturing, where significant work has been done on cell line development to increase the stability of the product. An example of this is post-harvest or post-initial capture, in order to maintain temperature-sensitive viral vector-based products at room temperature for longer periods of time. A lack of expertise and experience in viral vector production, though, means there is little insight into the stability of the viral particles coming out of the reactor and how they should be treated.
The downstream operations for viral vector production are facing significant inefficiencies and poor recoveries, which is also related to the reliance on technologies that are not platform based. For example, affinity resins used for adenovirus vectors can present challenges, as they are not sodium hydroxide intolerant, which calls for chemotrophic agents or other alternate cleaning solutions the bulk of the industry no longer uses. Improvements in those ligands could enable more efficient capture and bulk purification. In addition, viral vectors do not have platform unit operation, such as Protein A used for mAbs. As this area continues to be explored, various types of chromatography ligands and resins as well as different chromatography devices will be introduced.
Concentration and buffer exchange steps could benefit from the adoption of single-pass devices that use a 0.2-micron filter rather than recirculating the product. A smaller filter provides the level of concentration needed and, in some cases, the ability to diafilter without stressing the product through recirculation. This provides the sensitivity needed for larger molecules like viral vectors while also increasing throughput, productivity, and efficiency. Single-use technology (SUT), in general, has become a valuable tool in viral vector production, where infectious molecules present risks to the environment, including operators. Closed systems made possible by SUT can help prevent contamination while also offering other benefits, such as lower capital investment, faster scale out, and increased flexibility and productivity. Manufacturers utilizing SUT should have a plan for managing waste, though, as there is a significant amount generated with SUT, including plastics and other materials. Reducing packaging materials and using recyclable materials are just some efforts that can be made to minimize the impact of SUT on our environment.
Integrating automation in your viral vector manufacturing line
With so many viral vector-based therapies qualifying for an expedited approval pathway, the focus is often on the race to market and not the impact design decisions could have later. For example, implementing a flexible automation platform into your manufacturing line can improve process optimization and data management, ultimately enhancing data integrity and driving regulatory compliance. However, integrating automated technologies and/or an integrated automation platform into a manufacturing line is often not considered when working with a shortened timeline, despite the long-term advantages it can offer in pharmaceutical manufacturing, especially in multi-product facilities. This could include using technologies, such as robotics, to eliminate human intervention, which minimizes contamination risks while also improving productivity.
Data historians are also an important consideration when using automation, as they can provide, among other benefits, contextualized batch reports that can be used in regulatory submissions, potentially leading to faster approval and product release. Decisions about integrating a process control system or manufacturing execution system (MES) solution can be made later once your product moves toward commercialization. Automation also drives standardization across manufacturing facilities, which is critical for distributed manufacturing in a global footprint. Standardization using SUT and/or automation are especially beneficial during tech transfer, where reproducibility issues can arise if the process is executed on different equipment than what was used at lab scale or at a different site.
Achieving the right balance between scale and process flexibility begins with understanding your design space and then having a suitable time period when the process can be executed at pilot scale. During this phase, you can then model the factors that will impact manufacturing, such as the automation approach, implementation of SUT, or understanding the functional limitations of the hardware, and apply those to the scaled-down model. Designing a robust platform that facilitates scale-up enables faster process development to pilot scale production and eventually to cGMP manufacturing.
Selecting a vendor for your viral vector manufacturing line
While securing the capacity necessary to support production of viral vector-based therapies is an essential part of bringing them to market, so too is having access to those with knowledge about how to develop and manufacture them. That is why selecting the right vendor to help you design your viral vector manufacturing line is another important consideration. Industry consultants, engineering firms, and some vendors often have pockets of knowledge about viral vectors but do not have the deep expertise needed for this market segment.
Working with a vendor with a high level of credibility and experience can envision your needs from end to end and help create a viral vector manufacturing line design that considers not only factors related to process development but also the pilot plan and cGMP manufacturing. A viral vector manufacturing line must satisfy the requirements for this space, whether that is having the right classification, segregation for post infection and pre-infection, and a virus presence throughout the workflow. Qualification must also be top of mind, including the documentation necessary to support filing as well as addressing any gaps in product knowledge. A vendor with strong regulatory knowledge ensures compliance is considered at each phase and with each decision.
Working with a vendor that relies on legacy expertise and old techniques and procedures will put you at a major disadvantage with your competitors. Understanding how to improve efficiency and utilizing advanced technologies and methods in upstream and downstream processing, including SUT, will lead to smart design and better process economy. This can help keep production costs competitive and facilitate scalability, which is essential as demand for these viral vector-based therapy increases. Your partner should have in-depth knowledge about the latest trends and how to overcome rising challenges with viral vectors, such as security of supply.
In early December 2020, Pfizer announced that early batches of raw materials for its COVID-19 vaccine had failed to meet standards, which caused them to cut their original vaccine production targets, reducing an anticipated delivery of 100 million doses down to 50 million.6 The growing concern of security of supply is a focus for many vendors but one they must take action on to prevent setbacks such as Pfizer’s, especially as the COVID-19 pandemic continues to stress the industry’s raw material supply. Make sure to ask your potential partner(s) what they are doing to address this critical issue, such as capacity expansions and other business continuity and supply strategies.
The burgeoning pipeline of drug products using viral vectors reflects their growing potential; however, effectively and efficiently scaling them up to meet demand continues to create a bottleneck that could slow their path to market. Therefore, adopting technologies and solutions to overcome the challenges of viral vector production, as well as selecting the most prepared and knowledgeable partner, is the key to commercializing the products that depend on them.
- Associated Press (2019). Global Monoclonal Antibody Industry 2019-2025 with Focus on the Chinese Market, ResearchandMarkets.com. Retrieved from https://apnews.com/af15cf4cf54e4698a93689afb4a906e8
- World Health Organization (April 6, 2021). The COVID-19 candidate vaccine landscape and tracker. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
- FDA. (March 2021). Approved Cellular And Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
- Drug Development and Delivery. (June 2020). The Role Viral Vectors Play in Current Gene Therapy Development. https://drug-dev.com/gene-therapy-the-role-viral-vectors-play-in-current-gene-therapy-development/#:~:text=About%2070%25%20of%20the%20trials,introduced%2C%20viral%20vectors%20remain%20attractive
- Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. (2019, January 15). Retrieved from https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics
- O’Donnell, Carl. (December 3, 2020). Pfizer says supply chain challenges contributed to slashed target for COVID-19 vaccine doses in 2020. Reuters. https://www.reuters.com/article/us-health-coronavirus-pfizer-vaccine/pfizer-says-supply-chain-challenges-contributed-to-slashed-target-for-covid-19-vaccine-doses-in-2020-idUSKBN28D3B9