Applied Microbiology and Biotechnology (2021) 105:2225–2242

https://doi.org/10.1007/s00253-021-11180-7

MINI-REVIEW

An overview of drive systems and sealing types in stirred bioreactors

used in biotechnological processes
Cedric Schirmer 1 & Rüdiger W. Maschke 1 & Ralf Pörtner 2 & Dieter Eibl 1

Received: 4 December 2020 / Revised: 5 February 2021 / Accepted: 14 February 2021 / Published online: 2 March 2021
# The Author(s) 2021

Abstract
No matter the scale, stirred tank bioreactors are the most commonly used systems in biotechnological production processes.
Single-use and reusable systems are supplied by several manufacturers. The type, size, and number of impellers used in these
systems have a significant influence on the characteristics and designs of bioreactors. Depending on the desired application,
classic shaft-driven systems, bearing-mounted drives, or stirring elements that levitate freely in the vessel may be employed. In
systems with drive shafts, process hygiene requirements also affect the type of seal used. For sensitive processes with high
hygienic requirements, magnetic-driven stirring systems, which have been the focus of much research in recent years, are
recommended. This review provides the reader with an overview of the most common agitation and seal types implemented
in stirred bioreactor systems, highlights their advantages and disadvantages, and explains their possible fields of application.
Special attention is paid to the development of magnetically driven agitators, which are widely used in reusable systems and are
also becoming more and more important in their single-use counterparts.

Key Points
• Basic design of the most frequently used bioreactor type: the stirred tank bioreactor
• Differences in most common seal types in stirred systems and fields of application
• Comprehensive overview of commercially available bioreactor seal types
• Increased use of magnetically driven agitation systems in single-use bioreactors

Keywords Bioreactor agitation . Magnetic coupling . Mechanical sealing . Lip seal . Hygienic requirements . Application trends

Introduction quality, increase chemical and biological turnover, and accel-

erate heat and mass transfer (Pahl 2002; Meyer et al. 2016).
Stirred systems have a long tradition in biotechnological pro- Their fields of application range from non-sterile applications
cesses, especially in the biopharmaceutical industry (Birch with microorganisms lasting a few days to axenic long-term
2010; Jossen et al. 2017; Clapp et al. 2018). It is therefore processes with plant, animal, and human cell cultures
not surprising that these systems, with their distinctive agita- (Table 1). For the microbial (including yeasts) production of
tors, are being increasingly used to primarily reduce inhomo- biofuels, copolymers, and other bioproducts, non-sterile open
geneities in fluids through mixing, and thus improve product fermentation processes are used, which can range from a few
days to processes that run continuously for months (Li et al.
2014). However, batch or fed-batch processes mainly using
* Cedric Schirmer Escherichia coli that last only a few hours or days dominate in
cedric.schirmer@zhaw.ch the microbial field (Terpe 2006; van Heerden and Nicol 2013;
Li et al. 2014). This contrasts with mammalian cell-based
1
Zurich University of Applied Sciences, School of Life Sciences and products, such as therapeutic antibodies, enzymes, hormones,
Facility Management, Institute of Chemistry and Biotechnology, and stem cell therapeutics, that usually involve fed-batch or
Grüentalstrasse 14, 8820 Wädenswil, Switzerland
perfusion processes lasting several days or weeks making
2
Hamburg University of Technology, Bioprocess and Biosystems them very expensive to produce (Meyer and Schmidhalter
Engineering, Denickestraße 15 (K), 21073 Hamburg, Germany
2226 Appl Microbiol Biotechnol (2021) 105:2225–2242

Table 1 Vulnerability to contamination (from low −− to high ++ ) of different cell lines, and typical duration of different process modes

Organism Vulnerability to Batch Fed-batch Continuous/

(example) contamination perfusion

Bacteria (E. coli) −− to + Hours [A, B] Hours-days [C, D] Weeks-months [E,F,G]

Yeast (S. cerevisiae) −− to + Hours-days [H,I] Hours-days [J,K] Days-months [J,L]
Algae (C. zofingiensis) −− to + Days-weeks [M,N] Weeks [O,P] Weeks [M,O]
Plant (N. tabacum) o to + Weeks [Q, R] Weeks [S] Weeks [Q,T]
Insect (Sf-9) + Days [U, V] Days-weeks [V,W] Weeks [V, X]
Mammalian (CHO) ++ Days-weeks [Y,Z] Weeks [AA,AB] Weeks-months [AA,AC]
Stem cells ++ Days-weeks [AD] Weeks [AD,AE] Days-weeks [AF,AG]

[A] (Hausjell et al. 2018), [B] (Schirmer et al. 2017), [C] (Kante et al. 2018), [D] (Korz et al. 1995), [E] (Tosa et al. 1974), [F] (Unrean and Srienc 2010),
[G] (van Heerden and Nicol 2013), [H] (Bruder et al. 2016) ,[I] (Scheiblauer et al. 2018), [J] (Mohd Azhar et al. 2017), [K] (Arshad et al. 2017), [L] (Li
et al. 2014), [M] (Benvenuti et al. 2016), [N] (Travieso Córdoba et al. 2008), [O] (Liu et al. 2014), [P] (Sun et al. 2020), [Q] (Lee and Kim 2006), [R]
(Holland et al. 2013), [S] (Schiel et al. 1984), [T] (Lee et al. 2004), [U] (Imseng et al. 2014), [V] (Jardin et al. 2007), [W] (Elias et al. 2000), [X]
(Akhnoukh et al. 1996), [Y] (Trummer et al. 2006), [Z] (Brunner et al. 2017), [AA] (Bausch et al. 2019), [AB] (Möller et al. 2020), [AC] (Vogel et al.
2012), [AD] (Jossen et al. 2014), [AE] (Jossen et al. 2016), [AF] (Abecasis et al. 2017), [AG] (Simaõ et al. 2016)
The vulnerability of bacteria, yeast and algae depends on the production process (e.g., biofuel production processes have a relatively low vulnerability in
comparison to biopharmaceutical production processes). For reasons of clarity, the literature sources have been summarized below the table

2014; Bausch et al. 2019; Haigh et al. 2020). Therefore, com- experimental methods and computational fluid dynamics
pliance with good manufacturing practices (GMP) and the (CFD) have also been carried out, which have significantly
absence of contaminants are of utmost importance (Haigh et al. influenced the geometric specifications of vessel designs, as
2020). In addition to animal cell culture, where Chinese hamster well as the use and configuration of a large variety of different
ovary cells (CHO) are still dominant, processes with insect and impellers and other components such as baffles and probes
plant cells and open and closed production processes with algae (Liepe et al. 1998; Nienow 1998; Zlokarnik 2001;
are well established (Meyer and Schmidhalter 2014). Hemrajani and Tatterson 2003; Mirro and Voll 2009; Zhong
The wide range of available production organisms and pro- 2010; Zhu et al. 2013; Werner et al. 2014; Meusel et al. 2016;
cesses imposes different requirements on stirred bioreactors. Schirmer et al. 2018). Furthermore, recommendations for the
For this reason, the main elements of reusable and single-use biological evaluation of bioreactor performance for different
stirred bioreactors and the most frequently used drive systems, processes (Adler and Fiechter 1983; Wagner 1987; Schirmer
including a special focus on seals, will be summarized and et al. 2017; Schirmer et al. 2019) as well as different scale-up
discussed in terms of their suitability for various processes. strategies have also been successfully established (Junker
In addition, the trend towards increased use of magnetic driv- 2004; Zlokarnik 2006; Catapano et al. 2009; Garcia-Ochoa
en agitators will be discussed, and a decision tree for selecting and Gomez 2009).
suitable seal types for use in stirred bioreactors in biotechno- In addition to the actual design of the vessel and its periph-
logical processes will also provide for the reader. Finally, eral elements, magnet-driven and direct-driven options have
emerging developments concerning popular single-use tech- also been developed for the agitator in the vessel that are
nology will be presented. specific to certain fields of application. However, increased
attention must be paid to hygienic design in order to minimize
the risk of contaminating the product and/or the environment
Stirred bioreactors and their main when using direct-driven systems (Menkel 1992; Wegel and
components Heine 1996; Hinrichs et al. 2018). As a result, and in an effort
to minimize such sterility concerns, single-use technology is
The wide acceptance and frequent use of stirred bioreactors increasingly being used in the production of high-value prod-
can be attributed to the early standardization of stirred systems ucts (Haigh et al. 2020).
and the introduction of hygienic design principles, work on
which was begun in 1982 by the German Society for
Chemical Engineering and Biotechnology (DECHEMA) and Reusable vs. single-use
is still continuing today (DECHEMA 1982; DECHEMA
1991; ASME 2019). In addition, extensive investigations of The growing acceptance of single-use bioreactor systems
transport processes, power input, and fluid dynamics based on made of plastics, which are increasingly used as alternatives
Appl Microbiol Biotechnol (2021) 105:2225–2242 2227

to gold standard stainless steel systems, especially in the bio-

pharmaceutical industry (Eibl et al. 2018; Jossen et al. 2019;
Werner et al. 2019), can be explained by the technical require-
ments and durations of cell culture processes. In mammalian
cell culture processes, a good hygienic design concept and the
avoidance of potential (cross-)contamination are essential,
which can be achieved more easily by using single-use biore-
actors. Thus, these systems, if correctly selected and handled,
are safer, more flexible, smaller, cheaper, and greener than
their reusable counterparts. These advanatges outweigh any
limitations, such as leaks, breakage, leachables, and extract-
ables. Furthermore, pre-sterilized systems can be put into op-
eration much faster, since time-consuming and expensive
cleaning and heat sterilization are eliminated. For microbial
processes, the limitations are usually due to insufficient
mixing, oxygen supply, or heat transport, which can often still
only be overcome through the use of stainless steel bioreac-
tors. Therefore, the growing market share of single-use biore-
actors can only be explained by the focus on mammalian cell
cultures in biopharmaceutical production processes (Jossen
et al. 2017; Eibl and Eibl 2019; Haigh et al. 2020).

Main components of stirred bioreactors

A conventional stirred bioreactor consists of a vessel equipped

with a motor, a shaft with impellers on it, an air inlet, and a
bottom drain (Fig. 1). The vessel is usually cylindrical, al-
though square or rectangular vessels are possible (Hemrajani Fig. 1 Classical composition of a stirred tank bioreactor (4) equipped
and Tatterson 2003; Nienow et al. 2016). The bottoms or lids with a motor (1), mechanical seal (2), air inlet (3), shaft (5), baffles (6),
impellers (7), double jacket for heat transfer (8), sparger (9) and bottom
are either flat or hemispherical, with a dished bottom being the drain (10). H, vessel height; D, vessel diameter
most common type. This provides increased pressure resis-
tance compared to planar forms and results in a lower height
than hemispherical elements. Avoiding edges and dead zones found. An example of a H/D ratio of 5:1 is the Thermo
in the connection between the bottom and the vessel wall Scientific HyPerforma Single-Use Bioreactor (Thermo
facilitates cleaning and has a positive effect on the fluid flow Fisher Scientific Inc. 2019), where the 5:1 ratio creates a better
pattern. In contrast, a flat lid would be used if the bioreactor is turn down ratio. Furthermore, the vessels are normally
located in a room with limited overall height or to improve equipped with a gassing device (sparger), heat transfer sur-
accessibility for the installation of probes, corrective devices, faces, a bottom drain, wall baffles, and sometimes draft tubes.
and additional feed streams; however, horizontal surfaces In case of centrically mounted impellers, baffles prevent the
should be avoided for hygienic design reasons (Gleich and rotation of the liquid volume and, by creating additional tur-
Weyl 2006; Nienow et al. 2016; Hinrichs et al. 2018). An bulence, cause axial mixing between the top and the bottom of
important characteristic of stirred bioreactors is the height to the tank (Hemrajani and Tatterson 2003; Jossen et al. 2017).
diameter (H/D) ratio, which varies depending on the applica- The most important element is the stirring system, as it trans-
tion. While in the chemical industry, for example, a ratio of fers the energy required for the mixing process to the fluid. It
1:1 is typical, a ratio of 2:1 is preferred for cell culture biore- usually consists of an agitator shaft with one or more impellers
actors at laboratory and pilot scales. For microbial systems, on it that is inserted into the vessel through a sealed hole in the
values of 3:1 dominate since this leads to longer residence top or bottom, with the motor located outside the bioreactor
times for supplied gases, such as air or oxygen, and better (Menkel 1992; Hemrajani and Tatterson 2003; Reichert et al.
temperature control due to the larger surface to volume ratio 2012; Chmiel and Weuster-Botz 2018). Differences between
(Menkel 1992; Jossen et al. 2017; Clapp et al. 2018). impeller types will not be discussed in detail in this review,
Nevertheless, as bioreactor size increases, H/D ratios of 5:1 since this has been well described elsewhere (Liepe et al.
(Chisti 2006) and up to 6:1 (Najafpour 2015) can also be 1998; Zlokarnik 2001; Nienow 2010; Buffo et al. 2016;
2228 Appl Microbiol Biotechnol (2021) 105:2225–2242

Scargiali et al. 2017). However, there are some vital aspects to minimum agitated liquid level. However, in contrast to top-
consider when selecting an impeller, such as the type, number, driven systems, the sealing elements are exposed to chemical,
and arrangement of the impellers on the shaft, which may limit biological, and abrasive loads (Menkel 1992; Jagani et al.
the possible application of certain seal types and influence the 2010), which result in increased periodic maintenance and
seal design. Based on the flow pattern, impellers can be divid- shorter replacement intervals (EKATO Holding GmbH
ed into axial and radial conveying impellers (Kumaresan and 2012). Agitators are mostly arranged centrically in both top-
Joshi 2006; Buffo et al. 2016; Zhang et al. 2017; Clapp et al. and bottom-driven systems (Jagani et al. 2010; Clapp et al.
2018). Radial pumping impellers, the most common type of 2018). It should be noted that in order to avoid vortex forma-
which is the Rushton turbine (Nienow 2010), produce a hor- tion and to ensure proper mixing, drives can also be installed
izontal flow. These are typically used at high speeds with high eccentrically or mounted at an angle so that baffles can be
gassing rates in microbial cultivations to ensure proper avoided (Penicot et al. 1998; Assirelli et al. 2008; Jagani
mixing, high oxygen input, and good heat exchange. Axial et al. 2010; Clapp et al. 2018). In addition to the selection of
pumping impellers, such as the 3-blade segment impeller, the motor installation location, application and process-related
generate a vertical flow field, which can be further divided factors also play a decisive role when selecting the most ap-
into upward and downward conveying agitators. The main propriate seal type, which will be discussed in the following
field of application for axial impellers is animal cell culture subsection.
processes, where gentle mixing and avoidance of sedimenta-
tion at low speeds and low gassing rates are a priority (Jossen Seal types: an overview
et al. 2017). Due to the various process requirements and
resultant differences in rotational speeds, and thermal and me- Irrespective of the installation method, the driving force of the
chanical loads, the shaft seal is considered a critical element motor must ultimately be transmitted to the fluid. In the ma-
for guaranteeing sterile operations. jority of cases, this is performed via the agitator shaft, which is
connected to both the non-sterile environment and the process
room, sterile, or axenic environment inside the vessel. For this
Drive systems and seals commonly used reason, it is important to seal the interface between the stirred
in biotechnological processes tank bioreactor and the stirrer shaft in a manner that is com-
patible with the required operating conditions. Therefore, dif-
Drive systems and their locations ferent sealing principles are implemented based on tempera-
ture, pressure, speed, and sterility requirements. Aseptic seals
A conventional drive system consisting of a motor and a gear need to be able to prevent contamination in both directions by
or a motor coupled directly to the stirrer shaft can be mounted stopping undesirable microorganisms from entering the medi-
on the top, the side, or below the vessel, depending on the um or liquids from leaking out of the vessel (Menkel 1992;
mixing task and vessel geometry. Economic and process en- EKATO Holding GmbH 2012). The sealing elements in reus-
gineering considerations also have a decisive influence on the able systems for biopharmaceutical applications must also be
positioning of the drive system (Menkel 1992; EKATO suitable for performing cleaning-in-place (CIP) and
Holding GmbH 2012). Top drives are most common and thus sterilization-in-place (SIP) procedures (ASME 2019).
the standard solution for vertical cylindrical vessels and small- As a consequence of the rotation of the shaft, it is necessary
scale bioreactors (Menkel 1992; Raj and Karanth 2005; to use radial or axial dynamic seals (Hinrichs et al. 2018).
EKATO Holding GmbH 2012). However, this makes acces- Radial seals, such as radial shaft seals, lip seals, and stuffing
sibility to the headspace for additional ports and the removal boxes, rely on radial forces acting on the seal within an axially
of the lid more difficult (Menkel 1992). For economic reasons, aligned sealing gap, meaning they are unaffected by axial
sideways installation is often used for large storage tanks, with forces. However, radial forces can lead to leakage and rapid
several small agitators usually installed to allow for variations wear due to radial shaft distortions. In contrast, axial seals,
in liquid level. In this case, the demands on the sealing tech- such as mechanical seals, act on a horizontal sealing surface,
nology are considerably higher than for a top drive (Jagani meaning they are unaffected by radial shaft deflections.
et al. 2010; EKATO Holding GmbH 2012). In contrast to Nevertherless, axial displacements can lead to leakages and
top drives, much shorter and thus thinner agitator shafts can must be taken into account in the seal design. Hermetic sealing
be used for bottom drive systems, since the effective bending is a fundamentally different approach, in which the force is
moments are smaller (Creathorn 2003). This also means that indirectly transmitted from the external motor to the impeller
there is no need for additional wear-prone shaft bearings in- in the vessel using magnetic coupling (EKATO Holding
side the vessel (Chisti 2010; EKATO Holding GmbH 2012). GmbH 2012).
Routing the shaft through the bottom of the vessel also allows The advantages and disadvantages of the individual seal
impellers to be installed lower in the tank, thus reducing the types are summarized in Table 2. There is a niche for each
Appl Microbiol Biotechnol (2021) 105:2225–2242 2229

Table 2 Comparison of typical

operation conditions for various Stuffing box Lip seal Mechanical seal Magnetic drive
seals, with scaling from very
good: ++, good: +, average: o, Max. pressure in bar 300 6 450 > 400
and comparatively poor: -, n.a.: Max. temperature in °C 520 100 450 120
not available Sliding speed in m/s 0.3 35 100 (torque dependent)
Scale Small to large Small Small to large Small to large
Shaft diameter in mm 10–200 n.a. 5–500 n.a.
Sterility - o + ++
Motor location Top Top Top/bottom Top/bottom
Lifetime o o + ++
Price low low medium high

type: stuffing boxes, which are the cheapest and simplest, are in single-use as well as glass and stainless steel systems, in
used for non-sterile applications in microbial or algae-based top- and bottom-driven systems and for both microbial and
biomass processes; simple and inexpensive lip seals are used cell culture applications (Table 3). Nevertheless, even if there
for small systems with minor sterility issues and a short ser- are no strict rules, certain trends can be identified. Magnetic
vice life (e.g., small-scale single-use bioreactors for non-GMP couplings are used in most single-use systems, which are
processes); mechanical seals are an all-round solution that are mainly designed for cell culture processes with high sterility
particularly effective at high speeds; and magnetic couplings requirements. All types of seals are used for cell culture pro-
are suitable for highly sterile scenarios and scenarios where cesses in reusable bioreactors, but double mechanical seals are
containment is an issue. However, the use of different seals suggested as a good alternative to magnetic coupling for ster-
and agitator coupling methods is also influenced by factors ile connections. Bottom agitators are more often equipped
such as motor position, bioreactor material, and the cells or with magnetic couplings and top agitators with mechanical
microbials involved. seals. It should be noted that stuffing boxes and lip seals are
To evaluate the practical application of these seals, which not used for bottom installation due to their poor hygienic
are discussed in the following subchapters, in everyday bio- suitability and tendency to leak. The dominance of top-
technological operations, numerous “off the shelf” bioreactor driven systems, as mentioned by several authors, could not
models are examined (Table 3). The focus is liter-scale biore- be confirmed in our study. For purely microbial bioreactors,
actors (benchtop and pilot scale), since larger industrial-scale mechanical and lip seals are dominant but not used exclusive-
plants are usually custom-built, and the available data is cor- ly, especially if a similar designed cell culture bioreactor is
respondingly limited. available from the same vendor. However, this overlapping
First of all, it can be stated that magnetic and mechanical use of mechanical and magnetic couplings does not necessar-
couplings are used more or less equally. Many manufacturers ily indicate a misunderstanding of the merits of the individual
offer both a direct, mechanically sealed connection and a mag- approaches. Economic and technological reasons can play de-
netic coupling as an option for their bioreactor systems, e.g., cisive roles, with targeted research increasing the area of ap-
the eZ control and pilot bioreactors (Applikon), Ralf and KLF plication and reducing price. A simplified guideline for seal
(Bioengineering), BioFlo (Eppendorf), Labfors and Techfors selection is depicted in Fig. 6.
(Infors HT), and D-DCU (Sartorius). It should be noted that Research and development are mainly being performed in
the actual differences between connection types in benchtop the field of biopharmaceutical production processes using
and pilot scales are much less pronounced than the data in magnetically sealed bioreactors, where typical application
Table 2 would suggest. volumes are 500 L for bacterial and 3000 L for mammalian
No application could be found where a stuffing box is used cell cultures. The application of magnetically drives is limited
as a sterile barrier in the investigated “off the shelf” bioreac- by the viscosity of the culture broth (Matthews 2008) and the
tors. The lip seal is preferred for simple and cost-effective inability of the torque dependent power input to disperse gases
operations, and its range of application can be clearly defined. and achieve homogeneity in the vessel (Stanbury et al. 2017).
This type of seal is used less frequently than mechanical seals The maximum possible torque is defined by the magnetic field
and, in the data examined, is primarily found in top-driven strength and is independent of the motor power, meaning the
glass bioreactors with less than 20 L working volumes, e.g., coupling breaks when the load limit is exceeded (Dickey
from Applikon, Belach Bioteknik, Broadley James, and 2015). Therefore, magnetic drives are mainly used at small
Eppendorf. However, no such strict distinctions can be made scales and in single-use vessels (Table 3). Systems of up to
for magnetic couplings and mechanical seals. These are used 20 m3 with magnetic couplings (ZETA GmbH n.d.) and even
2230 Appl Microbiol Biotechnol (2021) 105:2225–2242

Table 3 Overview of available bioreactor systems with their field of application, motor position and sealing types

Supplier Vmax Motor position Material Application Sealing

Product line [L] Top Bottom SU RU MO CC MS MC LS

Applikon
MiniBio 0.8 + - - + + + - - +
AppliFlex ST 3 + - + - + + - - +
eZ Glass 16 + - - + + + o + +
BioBench 22.5 + - - + + + - + -
Pilot Cell 100 + - - + - + o + -
Pilot Microbial 100 + + - + + - o + -

Belach Bioteknik
Greta 1 - + - + + - - + -
Ant 5 + - - + + - - - +
Dolly 6 + - - + + - + - -
Hanna 10 + - - + + + - - +
Lars 30 - + - + + + - + -
Gustav 5000 o + - + + - - + o

Bilfinger
Labqube 100 - + - + + + - + -
Pilotqube 1000 - + - + + + - + -

BioEngineering
KLF 2.5 - + - + + + + o -
Ralf 4.5 + - - + + + + o -
NLF 20 o + - + + + + o -

Bionet
F0 5 + - - + + + + - -
F1 10 + - - + + + +c) - -
F2 30 + - - + + + +c) o -
F3 200 + o - + + + +c) o -

Broadley James
Bioreactor 16 + - - + + + - oa) +

CerCell
CellVessel 27 + + + - - + + - -
BactoVessel 27 + + + - - + + - -

Cleaver Scientific
proSet A 20 + - - + - + + - -
proSet B 20 + - - + + - + - -
proSet D 10 + - - + + - + - -
CSFS 1000 + - - + + - + - -

Cytiva (formerly GE Healthcare)

Xcellerex XDRMO 500 - + + - + o - + -
Xcellerex XDR 2000 - + + - - + - + -

Distek
BiOne 5 + - - + - + - + -
Appl Microbiol Biotechnol (2021) 105:2225–2242 2231

Table 3 (continued)

Supplier Vmax Motor position Material Application Sealing

Product line [L] Top Bottom SU RU MO CC MS MC LS

Electrolab
FerMac 310/60 21 + - od) + + + - o +
FerMac 320 18 + - od) + + + - o +

Eppendorf
BioBlu c 40 + - + - - + - + -
BioBlu f 3.75 + - + - + - - + -
DASbox Mini BR 0.25 + - - + + + - - +
DASGIP Bioblock 1.8 + - - + + + - - +
DASGIP Benchtop 3.8 + - - + + + - - +
BioFlo 10.5 + - - + + + + o -
CelliGen 510 32 + - - + - + + - -

Frings
PROREACT B 1000 - + - + + - + - -
PROREACT P 1000 - + - + + - +e) - -

Infors HT
Multifors 2 1 - + - + + + - + -
Minifors 2 4 + - - + + + + - -
Labfors 5 10 + - - + + + + +b) -
Techfors 30 + - - + + + + +b) -

Lambda
Minifor 6 + - - + + + - -f) -

MDX Biotechnik
MDX 10 + - - + + + - + -

Merck
Mobius CellReady 2.4 + - + - - + - - +
Mobius CellReady 500 - + + - - + - + -

Pall
Allegro STR 2000 - + + - - + - - +
iCellis 70 - + + - - + - + -

Pierre Guerin Technologies

Primo 10 + - - + + + + + -
BioPro Evo 50 + - - + + - + + -
BioPro Lab & Pilot 300 + + - + + + + + -
Nucléo 1000 + - + - - + - + -

Solaris
Black Jar 30 - + + - - + - + -
M Series 145 - + - + + + + - -

Sartorius
Ambr 250 0.25 + - + + + + - - -
UniVessel SU 2 + - + - - + - - +
UniVessel Glass 10 + - - + + + + - -
2232 Appl Microbiol Biotechnol (2021) 105:2225–2242

Table 3 (continued)

Supplier Vmax Motor position Material Application Sealing

Product line [L] Top Bottom SU RU MO CC MS MC LS

Biostat Cplus 30 + - - + + + +c) - -

D-DCU 200 - + - + + + + ob) -
Cultibag STR 2000 + - + - - + - + -

Sysbiotech
Pro-Lab 10 + - - + + + + + -
Pilot 70 + + - + + + + + -

Thermo Fisher
HyPerforma Glass 10 + - - + + + + - -
HyPerforma S.U.B. 2000 + - + - - + - - +
HyPerforma S.U.F. 300 + - + - + - - - +
HyPerforma DynaDrive 5000 + - + - - + - - +

2mag
bioReactor 0.015 - + + - + o - + -
a
For Vmax up to 3.5 L; b for cell culture version, limited stirring speed; c double mechanical seal as option for cell culture; d utilizing CerCell vessels;
e
double mechanical seal; f utilizing vibromixing technology
Maximum working volume: Vmax, standard option; +, optional; o, not feasible; -, SU, single-use; RU, reusable; MO, microorganisms; CC, cell culture,
MS, mechanical seal; MC, magnetic coupling; LS, lip seal. The focus is on laboratory and pilot bioreactors. If the systems with the same design also exist
in m3 scale, the largest possible working volume is given

30 m3 (Dickey 2015) are especially common for applications plants (Eibl and Schindler 2004), have also contributed to their
in non-biological mixing processes or preparation systems increased acceptance. This has led to a situation in which
that do not require fast mixing times or high mass transfer. magnetic couplings are not only used for pathogenic organ-
Suppliers of such agitator systems include Alfa-Laval Mid isms, i.e., when containment is the main concern. Previously,
Europe GmbH, MAVAG AG, liquitec AG, PRG GmbH, the mechanical seal was the first choice for high-torque pro-
and ZETA GmbH. However, technical progress has also cesses that required effective CIP procedures (Krahe 2003).
recently been made in terms of the use of magnetic However, this has changed with the advent of so-called floating
couplings in larger bioprocesses. With their adapted bearings for slightly oscillating bottom-mounted magnetic ag-
magnetic system, Suleiko et al. (2020) demonstrated a drive itators with a simple bearing journal and a sufficiently large gap
with a torque of 200 Nm that is suitable for biological appli- between the impeller and containment shell. The resulting
cations at a scale of 15 m3. ZETA’s magnetic bottom-mounted slight lifting and displacement effects ensure an axial flow with
agitator for bioreactors with a torque of more than 400 Nm Taylor vortices in the gap, which support CIP and SIP strate-
was also evaluated at the same scale (ZETA GmbH n.d.; gies and prevent accumulation and subsequent contamination
Rosseburg et al. 2018; Fitschen et al. 2019), delivering results during the process (Eibl and Schindler 2004).
that predict applicability at scales up to 30 m3 (ZETA GmbH In the following sections, the four most typical seals are
2020a). Although their initial industrial use was controversial considered, starting with the stuffing box which is nowadays
because of biological (hygienic design and SIP/CIP capabili- only used for non-sterile processes.
ty), mechanical, and chemical safety (possible abrasion in
bearing-based systems) concerns, as well as the early lack of
Stuffing boxes
speed and torque monitoring (Eibl et al. 1996), magnetic ag-
itators have been able to gain more and more acceptance, as a
Stuffing boxes (Fig. 2) are one of the earliest dynamic sealing
result of increased qualification and validation. Advantages
technologies and are used almost exclusively until the 1950s
such as hermetic separation between the product side and
(Wilke et al. 1988; EKATO Holding GmbH 2012). In the
the environment, inclusion in measurement and control strat-
early days of steamships, they were often used to seal the drive
egies, and the use of bottom-mounted magnetic agitators for
shaft as it passed through the hull, usually in the form of
especially low volumes of less than 10% of the maximum
grease-soaked cloths stuffed between the stern tube and a
vessel volume, which make them suitable for multipurpose
housing. The basic structure of these versatile but very simple
Appl Microbiol Biotechnol (2021) 105:2225–2242 2233

Fig. 2 Stuffing box consisting of

the shaft (1), gland (2), screws (3),
housing (4), packing (5), and base
bushing (6)

seals, which are primarily used for top-driven systems, con- lubricants are injected into the stuffing boxes to ensure they
sists of a casing around the shaft, which is fixed to the vessel remain gas-tight, even at high pressures (Menkel 1992).
and filled with a compression sealing material that minimizes Since the packing deforms plastically and wears out due to
leakages (Dickey and Fasano 2003). This packing material is friction, the gland must be tightened from time to time and
why they are also known as packed gland seals. In the simplest eventually replaced (Ignatowitz 1997). A problem that may be
case, this packing material can be hemp strings soaked in associated with this type of seal is product impurity resulting
paraffin, which are stacked in the housing and compressed from packing material fibers, metal abrasion from the agitator
with the help of an adjustable plate and ring (gland and gland shaft, and lubricants (Dickey and Fasano 2003). Since no
follower ring) that seal the gap between the shaft and the statements can be made about the leakage rates through such
housing (Ignatowitz 1997). Nowadays, the packing tends to seals, it is difficult to comply with environmental regulations
consist of one or more packing rings of different materials and hygienic design concepts. Therefore, stuffing boxes are
with different shapes (Mörl and Gelbe 2018). For instance, being used less frequently in both the chemical and pharma-
there are lamellar packing rings, which consist of corrugated ceutical industries and are being replaced by mechanical seals
metal inserts made of chromium steel, nickel, copper, or lead (Wilke et al. 1988; Menkel 1992; EKATO Holding GmbH
layered in cotton, asbestos (Ignatowitz 1997), acrylic, PTFE 2012). Fields of application where they are still used however
(polytetrafluoroethylene), Kevlar (aramid fibers), or graphite are centrifugal pumps, compressors, and high-pressure axial-
filaments (Dickey and Fasano 2003; Haberhauer 2014). piston pumps as well as open cultivation systems (Haberhauer
Another possibility is foil packing rings, which consist of a and Bodenstein 2014).
fiber core wrapped in aluminum or other alloys (Dickey and
Fasano 2003; Mörl and Gelbe 2018). Alternatively, there are Lip seal
also self-lubricating hollow rings made of lead or copper,
which are filled with a graphite lubricant that can escape Lip seals are probably the simplest and most cost-effective
through small radial holes pointing towards the rotating shaft. seals used in stirring technology (Dickey and Fasano 2003;
In wedge sleeve packing rings, the axial tension on the wedge Jagani et al. 2010). They are used for both axial and radial
ring exerts pressure on the soft material insert, which is trans- seals (EKATO Holding GmbH 2012), with radial shaft seals
ferred to the running surface via a sleeve ring (Mörl and Gelbe being the most common application (Haberhauer and
2018). Depending on the design and the packing material, stuff- Bodenstein 2014). Compared to other seal types, they deliver
ing boxes can be used for shaft diameters of 10–200 mm, tem- low sealing efficiency (Jagani et al. 2010) but can achieve a
peratures of up to 520 °C, and pressures of up to 300 bar, but strong seal and have a long lifetime when used in small instal-
only low sliding speeds of approx. 0.3 m/s (Mörl and Gelbe lations (Haberhauer and Bodenstein 2014). Radial shaft seals
2018). Although sterile sealing cannot be achieved, a more hy- (Fig. 3) are usually used for gear shafts (Ignatowitz 1997) to
gienic seal can be achieved by using two stuffing boxes separated seal lubricating grease and oil. Although they generally allow
from each other by a steam-loaded flushing ring. Additional rotational speeds of up to 35 m/s, they often cannot withstand
2234 Appl Microbiol Biotechnol (2021) 105:2225–2242

Fig. 3 Radial shaft seal consisting

of the shaft (1), housing (2),
protective lip (3), sealing lip (4),
metal stiffening ring (5), and
tension spring ring (6)

temperatures above 100 °C and pressures above 0.5 bar axial compression on a statically mounted counter element
(Haberhauer 2014; Haberhauer and Bodenstein 2014). that is located on the vessel. To ensure a permanent seal at a
Nevertheless, they can be used in stirred vessels by variety of temperatures at the same time as the sealing ele-
implementing sophisticated shaft bearings that only allow ments are being subjected to abrasion, the dynamic seal is
shaft deflections of up to 0.01 mm, so that even higher pres- spring-mounted in the axial direction so that the seal gap is
sures of up to 6 bar can be sealed (EKATO Holding GmbH kept tight. It is also necessary to create a liquid film between
2012). Even if the seal is initially satisfactory, over time and both elements in order to form a seal, since otherwise heat
particularly at high speeds, rapid wear does occur, which will would be generated and excessive wear would occur
cause the system to leak. Therefore, these seals are not suitable (Menkel 1992; Dickey and Fasano 2003). This simple ar-
for long-term or continuous cultures in the pharmaceutical rangement is called a single mechanical seal, which is usually
industry, since a permanent sterile barrier cannot be guaran- lubricated by the medium present in the vessel (Matthews
teed (Jagani et al. 2010). They are therefore commonly used to 2008). However, even these single mechanical seals pose a
keep dirt out of tanks at atmospheric pressure and to prevent risk of contamination, leakage of the entire contents of the
the unhindered release of process vapors into the environment vessel in bottom-mounted systems, or aerosol formation in
(Dickey and Fasano 2003). top-mounted systems. For these reasons, and especially for
The dynamic seal with the shaft is created by a sealing lip higher risk category organisms, double (Fig. 4) or even
made of an elastomer or PTFE, with the required contact pres- triple-acting mechanical seals are used. These consist of sev-
sure in the radial direction being achieved by a tension spring eral pairs of single mechanical seals connected in series. In the
ring. In addition, a rubber-like outer surface creates a static case of a double mechanical seal, one pair of sealing elements
seal with the container (Ignatowitz 1997; Haberhauer 2014). seals the inside of the product chamber and a second pair the
outside (Menkel 1992; Matthews 2008; Jagani et al. 2010;
Mechanical seal Hinrichs et al. 2018). The space between the two sealing pairs
serves as a flushing chamber, which is filled with a sterile
Mechanical seals, which are considered to be technically tight, sealing liquid. This provides lubrication, cooling, and a dis-
have been an alternative to the previously mentioned sealing charge of abrasion while also preventing liquid from escaping
systems in agitator technology since the 1950s (EKATO from the vessel and stopping contaminants from entering from
Holding GmbH 2012), and they still meet today’s require- the atmospheric environment. A product-compatible sealing
ments for agitated cultivation systems in the biopharmaceuti- liquid is pressurized so that the sterile barrier is maintained,
cal industry (Menkel 1992; ASME 2019). The seal is formed even in the event of a small leakage. This and sterilization of
by two sealing elements sliding axially against each other. the intermediate space are carried out using pressurization
One of these elements is dynamic because it is attached to systems, which in their simplest form use clean steam or clean
the rotating agitator shaft. The dynamic element slides under steam condensate and compressed air (Chisti and Moo-Young
Appl Microbiol Biotechnol (2021) 105:2225–2242 2235

Fig. 4 Double mechanical seal

consisting of the shaft (1),
bushing (2), housing (3), springs
(4), spacer ring (5), O-rings (6),
on the housing mounted static el-
ements (7), on the shaft mounted
dynamic elements (8), and flush-
ing chamber with sealing liquid
(9)

1994; Ignatowitz 1997; EKATO Holding GmbH 2012). A limited by the maximum torque, which is itself limited by
more detailed description of pressurization systems is provid- the strength of the magnets. Furthermore, these magnets often
ed by EKATO Holding GmbH (2012). include rare earth materials (Dickey 2015). The field of appli-
In addition to static and dynamic sealing elements, which cation of such systems is defined by the temperature resistance
are often made of silicon carbide, carbon graphite, or compos- of the magnets, which means that this type of coupling is
ites of both materials, static fluorocarbon, O-ring seals are also mainly implemented for processes operating at moderate tem-
required to seal the contact surfaces between the vessel, the peratures and sterilization processes at temperatures of up to
shaft, and the sealing elements (EKATO Holding GmbH 120 °C (Suleiko et al. 2020). This is due to the deterioration of
2012). This allows mechanical seals to be used for shaft di- ferromagnetic properties at high temperatures. These prob-
ameters ranging from 5 to 500 mm at temperatures from −200 lems can be resolved by using very strong magnets made of
to +450 °C, pressures up to 450 bar, and rotational speeds of neodymium in combination with transition metals to provide
up to 100 m/s (Mörl and Gelbe 2018). resistance to temperatures up to 300 °C (Weir et al. 2020). In
Although mechanical seals are the most commonly used industry, both bearing-based and levitated magnetic drive sys-
seals in agitator systems, due to their superior durability and tems (as described below) are used.
lower probability of contamination (Jagani et al. 2010), they
are often the main cause of contamination problems. This is Bearing-based systems
usually due to improper operation or failure to carry out pro-
active maintenance intervals in order to save costs (Junker In bearing-based systems, the impeller is set in motion using
et al. 2006). permanent magnets located on the drive and the stirrer shaft,
which are separated from each other by the containment shell.
Hermetic seal—magnetic coupling Since the bearing for the stirrer shaft and/or impeller is located
inside the vessel, CIP-compatible ceramic plain and roller
In order to stir a hermetically sealed vessel, and thus reduce bearings made of zirconium oxide (EKATO Holding GmbH
the risk of contamination to a minimum (Menkel 1992) and 2012) are often used for hygienic reasons (Hinrichs et al.
enable high-pressure processes at far more than 400 bar with- 2018). The drive shaft outside the vessel is powered by a
out the risk of leakage (Dickey 2015), the energy to the im- traditional motor element (Dickey 2015), which in some cases
peller must be supplied through the closed vessel wall can require a large construction on top of or below the vessel
(EKATO Holding GmbH 2012). For this purpose, power is (Sun et al. 2013). A further disadvantage is that if there is
transmitted using magnetic fields. Different impeller or stirrer insufficient lubrication of the bearing, friction will occur,
shaft assemblies for magnetically agitated bioreactors are which may result in attrition of the material and impact prod-
depicted in Fig. 5. This results in a coupling system that, uct purity (Reichert et al. 2012; Haberhauer 2014). The system
unlike the systems described above, can be completely wear- is generally lubricated by the medium or culture broth; there-
free, thus guaranteeing longevity (Hinrichs et al. 2018). fore, running the system dry should be avoided. Particularly in
However, the rotational power that can be transmitted is bottom-driven systems, in which single bearing journals are
2236 Appl Microbiol Biotechnol (2021) 105:2225–2242

Fig. 5 Hermetically sealed vessel

with magnetic coupling of a
bearing-mounted impeller (a), a
bearing-mounted shaft with an
impeller (b), a levitating impeller
with interior rotor (c), a levitating
impeller with exterior rotor (d),
and a magnet-superconductor in-
teraction-based impeller (e). The
components involved are plain or
roller bearings (1), passive (2) and
active or passive magnets (3) for
magnetic coupling, a drive (4), a
stator and power electronics unit
(5), and a drive using
superconducting material (6)

located directly in the medium (Dickey 2015), care must be vessel (Koyama et al. 2006). The superconducting material
taken to ensure there is a sufficiently large gap between the detects the magnetic field generated by the permanent mag-
containment shell and the directly mounted impeller in order nets, stores it and attempts to fix it in a position of equilibrium
to avoid highly damaging shear rates (ZETA GmbH 2020b) to keep the magnets and the impeller in position when external
and to enable CIP and SIP procedures to be easily performed. forces are applied. The very stable coupling resulting from the
Should hydrodynamic flow effects not provide sufficient magnet-superconductor interaction allows speeds of up to
cleaning in the gap between the containment shell and the 210 rpm and a temperature range of 4–60 °C. Since the drive
impeller, plain bearings with additional radial and axial unit is mobile, it can be used successively with several vessels
grooves on the sliding surfaces to achieve optimal cleaning up to fluid volumes of 1000 L (Sartorius Stedim Biotech
are also available (Hinrichs et al. 2018; ASME 2019). In con- GmbH 2013; Pall Corporation 2016).
trast, top-driven systems are either also supported by ceramic A different approach is usually applied in bearingless pump
roller bearings or are equipped with commercial oil-lubricated systems, which are used in biotechnology (Schöb 2002) as
roller bearings inside a bearing chamber, separated from the well as in medicine as left ventricular assist devices for the
vessel interior by a mechanical seal (EKATO Holding GmbH treatment of heart disorders (Schöb and Loree 2008) or to
2012). These systems are available for vessels up to 400 L maintain blood circulation during heart transplants (Sung
with torque ratings from 0.7 to 115 Nm, while bottom- et al. 2015). Bearingless pump systems are characterized by
mounted systems are available for applications up to 150 low shear stresses (Blaschczok et al. 2013; Dittler et al. 2014;
Nm in containment vessels of up to 30 m3 (Dickey 2015). Schirmer and Eibl 2018), which has led to their use in the
operation of bioreactors (Reichert et al. 2009; Schirmer et al.
Levitated systems 2018) and mixing systems in the pharmaceutical industry
(Sartorius Stedim Biotech GmbH 2019).
A basic distinction can be made between two different types A brushless drive and the necessary magnetic bearing are
of levitation drive technology, in which the impeller is mag- accommodated in a single unit, meaning a shaft and mechan-
netically supported inside the vessel. ical bearing for driving the rotor are not required. As a result,
Superconducting mixers use non-contact magnetic cou- maintenance and service costs are reduced, since there are no
pling between conventional permanent magnets in the impel- wearing parts and lubrication is not required (Reichert et al.
ler and a superconducting material in the drive below the 2012). Using electromagnets makes the magnetic bearing
Appl Microbiol Biotechnol (2021) 105:2225–2242 2237

Table 4 Sealing recommendations based on organism, product and process mode

Organism (example) Target Batch Fed-batch Continuous/perfusion

Bacteria Biofuels, small molecules Stuffing box/lip seal Lip seal Mechanical seal
Biopharmaceuticals Mechanical seal Mechanical seal Mechanical seal
Yeast Ethanol fermentation Lip seal Lip seal Mechanical seal
Protein production Mechanical seal Mechanical seal Mechanical seal
Algae Phototrophic biomass production Stuffing box/lip seal Lip seal Mechanical seal
Heterotrophic product synthesis Mechanical seal Mechanical seal Mechanical seal
Plant Secondary metabolites Mechanical seal Mechanical seal Mechanical seal
Recombinant proteins Mechanical seal/magnetic coupling Mechanical seal/magnetic coupling
Mechanical seal/magnetic
coupling
Cellular agriculture Mechanical seal Mechanical seal Mechanical seal
Insect BEVS, biopesticides Mechanical seal/magnetic coupling Mechanical seal/magnetic coupling Magnetic coupling*
Mammalian Recombinant proteins Mechanical seal/magnetic coupling* Magnetic coupling* Magnetic coupling*
Stem cells Regenerative medicine Magnetic coupling* Magnetic coupling* Magnetic coupling*

BEVS Baculorvirus protein expression vector system

*For these processes, the authors recommend the use of single-use systems

active, while using permanent magnets results in a passive diametrically to the rotor plane (Bösch 2004). Three of the
magnetic bearing. To stabilize the impeller, rotation and trans- six degrees of freedom are stabilized either passively or ac-
lation along the three axes of motion must all be controlled. tively. A permanent magnet ring can be used to stabilize both
However, only five of the total of six degrees of freedom rotations along the x- and z-axes and translation along the y-
require stabilization, since the rotation of the rotor along the axis. Centering the rotor on the x- and z-axis origin is achieved
main axis is determined by the drive. Stabilization of the re- by two active magnetic bearings, and the last degree of free-
maining five degrees of freedom is achieved by a combination dom, rotation around the y-axis, is actively controlled by the
of passive and active magnetic bearings. Passive magnetic motor drive (Schöb and Loree 2008; Nussbaumer et al. 2011).
bearings use permanent magnets made of rare earth elements, To stabilize the radial position of the rotor at high speeds, the
which are characterized by their high-energy density and magnetic field is adjusted 10,000 times per second (Levitronix
small space requirements. In contrast, active magnetic bear- GmbH 2020).
ings are used when precise position control or bearing rigidity Levitation-driven impellers create no friction or mechani-
is required (Nussbaumer et al. 2011). cal stress during the mixing process, meaning no particles are
The simplest design for a bearingless magnetic motor is the generated that could contaminate the product. Therefore,
bearingless slice motor, which was first developed by Barletta levitated systems are suitable for ultrapure and sterile
(1998). In this type of drive, the rotor consists of a ring- mixing processes (Schöb 2002; Sartorius Stedim
shaped, two-pole, permanent magnet that is magnetized Biotech GmbH 2013).

Fig. 6 Sealing selection: A

decision tree based on bioprocess
demands and economic
considerations. Cheaper sealing
approaches may be replaced by
ones that create a tighter seal (e.g.,
lip seal by mechanical seal)
2238 Appl Microbiol Biotechnol (2021) 105:2225–2242

Decision tree for seal type selection GmbH n.d.), has also accelerated development up to current
scales of 30–40 m3 (MAVAG AG 2020; ZETA GmbH
This section provides recommendations for the selection of a 2020a). Similarly, increased use of levitating bottom-
suitable seal based on the expression organism and process mounted agitator systems, which are almost all based on the
mode. The selection is based on a compromise between sterility pump drive technology commercialized by Levitronix AG,
requirements and economic considerations. In most cases, a can also be observed. Due to the wide performance range,
higher quality seal can of course be used, provided that the pro- these systems are suitable for both powerful and low shear
cess conditions do not prohibit this (e.g., high speeds for micro- mixing applications. This flexibility has also been demonstrat-
bial processes can be achieved more easily with a mechanical ed in a 2 L bioreactor system using Levitronix pump drives
seal than with a magnetic coupling). A simple procedure for (BPS-i30 and BPS-i100) (Schirmer et al. 2018).
selecting the correct seal for a given purpose is shown in
Fig. 6. The classification is primarily based on sterility
requirements and secondarily on economic or contain- Code availability Not applicable
ment considerations. Open microbial and algae-based
Authors’ contributions CS and RM conducted literature research, pre-
processes as well as short experiments in single-use
pared the tables and figures, and wrote and designed the manuscript.
systems can therefore be carried out with simple me- RP and DE contributed to the conception and reviewed the manuscript.
chanical seals. Cell culture processes and processes in All authors read and approved the manuscript.
which the escape of organisms or their products into the
environment must be avoided at all costs should be car- Funding Open Access funding provided by ZHAW Zürcher Hochschule
für Angewandte Wissenschaften.
ried out with multiple mechanical seals or magnetic cou-
plings. A more precise matching of seal types to individ-
Data Availability Not applicable
ual organism types and process modes, also taking into
account the products to be obtained, is given in Table 4. It
Declarations
should be noted that neither the decision tree nor Table 4
are rigid rules and many processes can also be performed Ethical approval Not applicable
with other seals, but this assignment allows a safe and at
the same time inexpensive selection to be made. Consent to participate All authors have given their consent to partici-
pate in the publication

Conclusions and perspectives Consent for publication All authors have given their consent for
publication

The use and selection of seals or motor couplings are of ut- Conflict of interest The authors declare no competing interests.
most importance for ensuring sterility in biotechnological pro-
duction processes. The most commonly used seals at labora- Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tory and pilot scales are the lip seal, the mechanical seal, and
tation, distribution and reproduction in any medium or format, as long as
the magnetic coupling. The lip seal is the simplest of the seal you give appropriate credit to the original author(s) and the source, pro-
types and is mainly used in smaller top-driven systems. vide a link to the Creative Commons licence, and indicate if changes were
Mechanical seals and magnetic couplings are used for micro- made. The images or other third party material in this article are included
in the article's Creative Commons licence, unless indicated otherwise in a
bial and cell cultures in single-use or reusable bioreactors sys-
credit line to the material. If material is not included in the article's
tems with top or bottom drives, depending on the manufac- Creative Commons licence and your intended use is not permitted by
turer. The advantages of either system—better sterility of statutory regulation or exceeds the permitted use, you will need to obtain
magnetic coupling and higher possible torques with mechan- permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
ical seals—do not seem to significantly influence manufac-
turers’ seal choices, particularly at smaller scales. Increasing
demands on sterility and process safety favor magnetically
coupled systems, which are the subject of increased research.
Therefore, the basic torque limitation problem of magnetically
driven systems should be minimized by progressing technol-
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