Manufacturing Vaccines in Adherent Cell Lines Using Disposable Multi-tray Bioreactors

By allowing a single system to be used from laboratory- to commercial-scale, multi-tray bioreactors can facilitate scale up and accelerate vaccine development.
Aug 02, 2007


The recent growth in the vaccine market has led to renewed interest in using adherent human cell lines for vaccine production. Traditionally, small-scale adherent cell line production has been carried out in roller bottles or T-flasks. Over the past few years, however, a number of companies have found multi-tray disposable bioreactors an effective method for producing high-quality drug products using adherent cells. These disposable, expandable systems have also facilitated scale up from laboratory to clinical-scale.

For some time, the preferred format for producing biopharmaceuticals has been the suspension cell model using Chinese hamster ovary (CHO) cells). Recently, however, there has been a renewed interest in adherent cell production techniques. Researchers have observed that 95% of all human cell types are adherent, and that it may be more practical in the long run to culture human cell lines rather than to humanize an animal cell line for propagation in a suspension format.

In the field of vaccines, adherent cell culture is best known for its use in development, rather than as a production technique. Nevertheless, despite the popularity of large-scale cell suspension systems, many important vaccines, such as polio vaccines, have been produced using adherent cell lines.

Given the use of adherent cell lines in vaccine development in the 1970s, methods to facilitate the scale-up of adherent cell production were needed. First, roller bottles were developed as a logical progression from glass bottles. Roller bottles were then further refined by industry to include various sizes and shapes, and equipment for automated handling and processing was introduced. A significant drawback of a roller bottle, however, is that it is an open system that requires repeated opening and closing of individual bottles. For production, this is not an efficient process and requires increased deployment of labor and equipment. A better approach was needed.

In 1978, scientists at Rentschler Biotechnologie GmbH in Germany described a multi-tray cell-culture system designed to improve efficiencies for producing interferon beta with adherently growing human fibroblasts. In order to scale-up production without changing methods and format, they glued T-flasks together. This invention, referred to as a multi-tray bioreactor, later became a standardized industry device, and has been implemented by many major pharmaceutical manufacturers for the production of vaccines for polio and other diseases.

A Flexible Option

Today, multi-tray bioreactor technology may be a suitable solution for developing vaccines using human cell lines. This flexible, closed-system technology was developed as a way to easily scale up production directly from a single laboratory cell culture flask. An individual tray is similar to a commonly used tissue culture flask, but with an expanded surface area. A single tray can be used exactly like a common 175 cm2 cell culture flask in preclinical work, and then, as more cells are needed, researchers can use the multiple tray versions to scale up adherent cell propagation. The system also facilitates quality control, because cells are easily examined by inverted microscope.

Because no cell line or equipment changes are needed when scaling up production with multi-tray bioreactors, using this technology can speed up new drug development. Cell propagation may be performed on a small- or large-scale, depending on the amount of cell mass required. Another benefit is that multi-tray systems are designed for single-use, and thus eliminate the need for efforts and infrastructure required for cleaning and validation.

Using adherent systems also can facilitate product quality when using human cell lines. Manipulating human cell lines for propagation in a suspension format heightens the risk of inadvertently producing antibodies and other proteins with distorted three-dimensional configurations that render the product useless. This risk is avoided with adherent systems.

Vaccines have been undergoing a resurgence over the past few years. Many institutions and companies are involved, and they must address the ever-present issues of productivity and cost-efficiency. Because preclinical studies can take 5 to 10 years, many companies try to keep multiple drug or vaccine candidates moving through the drug development pipeline at the same time. Multi-tray bioreactor systems provide a flexible and cost-efficient approach to implementing multiple projects simultaneously.

Case Studies: Multi-tray Bioreactors in Production

As the case studies below explain, several companies that are using multi-tray bioreactors have found the method allows for efficient production of high-quality products for preclinical and clinical studies.

lorem ipsum