Dr. Mats Lundgren, Customer Applications Director, GE Healthcare Life Sciences
While vaccines are critical to the survival of many patient populations, especially children, they were previously considered low-revenue products, generating limited interest in the market. Consequently, North America has seen a significant decline in the number of vaccine manufacturers over the years. Nevertheless, new trends are changing the vaccine market, and viral vector-based vaccines and other therapies are becoming essential to the treatment of many diseases, sparking new interest across the industry. Even the groundbreaking area of cell and gene therapy is seeing the application of viral vectors as a platform for vaccines and therapeutic applications. As a shift toward high-value, low-volume vaccines and viral vector-based therapies continues, it is important to recognize the limitations of today’s production processes in order to overcome the challenges, complexity, and high cost of manufacturing these drugs.
Viral Vectors And Therapeutic Vaccines Poised To Stimulate Game-Changing Growth
Vaccine manufacturing is a complicated and diverse area of medicine that is expected to see a significant increase in revenue over the next several years. By 2025, the market is expected to reach $100 billion (up from just $2.9 billion in 2011).1 Prophylactic vaccines, such as childhood vaccinations, will always be in demand. However, viral vector platforms, such as Adenovirus, are a promising area of growth emerging at the crossroads of immunotherapy in oncology and vaccines. In 2016, there were over 700 active clinical trials exploring the use of viral vector-based vaccines for viruses, such as retroviruses and vaccinia (shown in the figure below).2
Another interesting growth area is oncolytic viruses, such as IMLYGICTM, which is “a genetically modified oncolytic viral therapy indicated for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.”3 IMLYGIC became the first approved therapy of its kind in 2015.
While these innovative new drugs are exciting for patient care, they do bring several challenges into focus when it comes to production, due to inefficient and cumbersome manufacturing processes. To understand how to resolve the issues with today’s virus production processes, it is important to first understand what challenges they present.
Virus Production Processes
The processes used today for vaccine production were developed many years ago. Scientists followed an empirical methodology that sometimes resulted in processes that were difficult to scale up or did not have optimal process economy. Considering that viral vector-based vaccines targeting smaller patient populations come at a higher price but in lower volumes, it is imperative to explore less costly ways to produce vaccines. One way to do this is by taking advantage of the rapid technology advancements in both the upstream and downstream processing of vaccines.
A major issue with legacy processes is that they are not based on platform technologies. For example, they rely on old cell substrates or, in the case of the influenza vaccine, eggs. Many cell lines are excellent for virus propagation. However, they have not been used for the production of approved vaccines and the safety track record of new cell lines is important in order to facilitate regulatory approval. Due to safety aspects and the fact that it is scalable at high volumes, animal origin-free cell culture media is preferred. Also, with anchorage-dependent cells, success is dependent on the surface the cells grow on. Adherent cells were often grown in roller bottles or cell factories, but these technologies are difficult to scale up. In this case, microcarriers can be used instead. With these, there is high volumetric output by maximizing the surface-to-volume ratio. Recently, regulatory authorities discouraged use of roller bottles because of concerns about cross-contamination. This is driving companies to move to microcarrier systems in bioreactors as well. Not only does the use of old processes make it difficult to be compliant with modern-day requirements, but regulatory requirements are also frequently increasing, making it harder to maintain compliance.
Another challenge with early vaccine processes is the use of centrifugation or size-exclusion chromatography for purification and polishing steps. While these are powerful technologies when it comes to purification, they are not easily scalable. This issue can be addressed by using a multimodal chromatography resin, such as GE’s CaptoTM Core 700, which allows efficient capture of contaminants while target molecules are collected in the flowthrough. The Capto Core 700 resin can increase speed and improve process economy, which is crucial in vaccine manufacturing in order to keep production costs competitive.
Single-Use Equipment In Vaccine Manufacturing
An effective way to improve scalability and process economy is through the use of single-use technology (SUT). Apart from a few exceptions, such as cell-based influenza, most vaccines are manufactured in batches in the range of 100 to 500 liters, which makes SUT ideal. The other characteristics of SUT, such as reduced cleaning requirements, improved batch turnaround times, and increased flexibility, also make it an attractive option. Faster turnaround time is especially appealing to those focusing on pandemic preparedness, as it requires even faster development, scale-up, and manufacturing times. While there are concerns related to the amount of consumables needed for SUT, the cost savings of a smaller footprint and fewer cleaning requirements should offset any doubts about the financial benefits. In addition, building a stainless-steel facility can take anywhere from three to five years, while the average time to build a single-use facility is 12 to 18 months. A shorter timeline translates to cost savings, but possibly more importantly, it greatly reduces the risks related to predicting capacity far before a company is sure about demand.
SUT also facilitates multi-product manufacturing, which is common in the vaccine industry, especially in smaller companies. Finally, there are regulatory advantages with SUT as it relates to live virus production, as one can, to some extent, avoid the risk of cross contamination that could come from insufficiently cleaned stainless-steel equipment. Nonetheless, SUT would not work for vaccines that have very harsh process chemistry conditions or for any drug with large-scale demand.
In summary, there is a paradigm shift taking place where vaccine production is shifting from a lab bench process to rational design that incorporates process economy calculations early. Scalability becomes critical as the industry seeks ways to address disease prevention in multiple populations across the world. Utilizing a combination of SUT and modern resin techniques yields the advantages necessary to be successful in this diverse and growing market.
Dr. Mats Lundgren has more than 25 years of experience in vaccinology. After earning his Ph.D. in Immunology, Cell, and Molecular Biology from the Karolinska Institute, Sweden, Dr. Lundgren completed post-doctoral training at the MRC Clinical Sciences Centre, Imperial College School of Medicine, UK. In his industrial career he has held positions at the bench and in management at Pharmacia (now part of GE), AstraZeneca, and several smaller biotechnology companies. In his current role as Customer Applications Director at GE, he helps companies implement modern processes with the goal of achieving more efficient production and higher vaccine quality.