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Mammalian Cell Bioreactors 1. Well-Mixed Stirred-Tank Reactor: in An Ideal Well-Mixed Bioreactor, The Mixing Is Assumed To

The document discusses different types of bioreactors that are used in vaccine manufacturing, including stirred-tank bioreactors, tubular reactors, microcarrier bioreactors, fixed bed bioreactors, and hollow fiber bioreactors. Bioreactors provide optimal growth conditions for cells and can increase productivity and reduce costs compared to static culture methods. Larger scale bioreactors also allow more efficient production.

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26 views3 pages

Mammalian Cell Bioreactors 1. Well-Mixed Stirred-Tank Reactor: in An Ideal Well-Mixed Bioreactor, The Mixing Is Assumed To

The document discusses different types of bioreactors that are used in vaccine manufacturing, including stirred-tank bioreactors, tubular reactors, microcarrier bioreactors, fixed bed bioreactors, and hollow fiber bioreactors. Bioreactors provide optimal growth conditions for cells and can increase productivity and reduce costs compared to static culture methods. Larger scale bioreactors also allow more efficient production.

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Vaccination represents the most effective strategy to prevent infectious diseases, and vaccine

manufacturing is crucial for worldwide disease control and eradication. Vaccination implies the
administration of attenuated or inactivated infectious agents (or their components) delivering
antigenic structures that stimulate the adaptive immune system in order to elicit an effective
response against specific pathogens to prevent future infections.
On mammalian cell culture based vaccine production, cell line selection is a critical step.
Initially, diploid cells were favored for production because of safety due to their non-
tumorigenic potential in animals. In 1980s vero cell line gained approval for production of
vaccines with the production of Polio vaccines. The latest mammalian cell line to be used in an
approved vaccine is the Madin Darby Canine Kidney (MDCK) line that has been adapted to
suspension culture, used in the manufacture of Flucelvax by Novartis.
Bioreactors In Vaccine Production
Bioreactors are currently being used in vaccine manufacturing and their use will likely continue
to expand. Bioreactors can provide cells the optimum environment, which can lead to an
increase in productivity and reduced overall cost. While many vaccines are still manufactured
using static culture or roller bottles, several studies have shown that manufacturing can be
greatly improved by employing bioreactors. The principal advantage of bioreactors and the
reason for their successful implementation in vaccine manufacturing processes is the
unsurpassed scale-up advantage.
Mammalian cell bioreactors
1. Well-mixed stirred-tank reactor: In an ideal well-mixed bioreactor, the mixing is assumed to
be intense enough that the fluid is homogeneous through the reactor. The mathematical
description of ideal continuous flow stirred-tank reactor is described by the following first-order
differential equation.

V is the culture volume in the bioreactor, CA the concentration of nutrient or product A, t is


time, F is the flow rate, and rVA is the volumetric consumption rate of nutrient or production
rate of product A. In an ideal continuous stirred-tank reactor, there is no flow bypass and no
shunt of substrate from inlet to outlet, no dead zones or clumps of undissolved solid substrate
floating around. Any substrate added through feeding is instantaneously distributed throughout
the entire reactor, and when gas sparging is employed, the agitator provides an intimately
mixed gas– liquid.
2. Tubular Reactor: The basic model for the tubular reactor (such as hollow fiber and many
other membrane bioreactor systems) is that liquid phase moves as a plug-flow, meaning that
there is neither variation of axial velocity over the cross section nor backmixing in the
longitudinal direction. The mass balance for component A in a volume element S∂z that
described an ideal plug-flow reactor is as follows:

where vz is the linear velocity in the z direction and S is the cross-sectional area.

Furthermore, a variety of stirred-tank bioreactors (STRs) with well characterized hydrodynamic


properties are available for cell culture, enabling seamless transfer of cultivation processes onto
the several thousand-liter scale. In order to maintain most suitable cultivation conditions over
such scale, new equipment is continuously developed to keep shear forces in large-scale
bioreactors low, while still enabling high oxygen transfer rates.

Microcarriers and stainless steel or single-use stirred tank bioreactors(SUBs)

Bioreactors can be used when cells are in suspension or adherent by employing another
technology – microcarriers. Microcarrier materials are typically porous (macroporous) or non-
porous beads made of glass, plastic or dextran. Microcarriers enable more cells per milliliter of
culture by expanding the surface area for cell proliferation. More cells in culture increases
overall vaccine titer (yield). With an increase in the use of stirred-tank or single-use bioreactors,
microcarrier innovations have been necessary to allow adherent cells to be cultured in these
conditions. In addition, the use of microcarriers allow manufacturers to increase the number of
cells that can be cultured in one tank enabling more efficient large-scale production and
permitting the use of greater than 1,000 liter bioreactors. SUBs are, in theory, relatively simple
to install and universally applicable by plug and play connections. They are replaced within
shortest time after the process, saving cleaning and sterilization steps while reducing cross-
contamination risks.

Fixed bed bioreactors

Another type of bioreactor being utilized in vaccine manufacturing is a disposable fixed-bed


bioreactor. These bioreactors contain multiple individual, hydrophilized microcarriers. Each of
these has a surface area and is compacted into a fixed bed. These fixed-bed matrices are then
incorporated within a bioreactor. An internal centrifuge pump within the bioreactor ensures a
homogeneous distribution of media and cells throughout the fixed bed.

Hollow fiber bioreactors

Hollow fiber bioreactors have also been used to manufacture viruses. Hollow fiber bioreactors
employ perfusion culture with semipermeable hollow fibers in a cartridge that contains inlet
and outlet ports. The media flows through these fibers providing nutrients to cells. Spent media
can then be filtered and replaced with fresh media or oxygenated and returned.

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