Accepted Manuscript

Title: Heat transfer characteristics of a stirred single-use

bioreactor

Authors: Matthias Müller, Ute Husemann, Gerhard Greller,

Matthias Kraume, Wolfram Meusel

PII: S1369-703X(18)30357-7
DOI: https://doi.org/10.1016/j.bej.2018.09.022
Reference: BEJ 7051

To appear in: Biochemical Engineering Journal

Received date: 30-7-2018

Revised date: 23-9-2018
Accepted date: 27-9-2018

Please cite this article as: Müller M, Husemann U, Greller G, Kraume M, Meusel W,
Heat transfer characteristics of a stirred single-use bioreactor, Biochemical Engineering
Journal (2018), https://doi.org/10.1016/j.bej.2018.09.022

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Research Article
Heat transfer characteristics of a stirred single-use bioreactor

Matthias Müller1,3*
Ute Husemann1
Gerhard Greller1
Matthias Kraume2

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Wolfram Meusel3

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1
Sartorius Stedim Biotech GmbH, Göttingen, Germany
2
Technische Universität Berlin, Chair of Chemical and Process Engineering, Berlin, Germany

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3
Hochschule Anhalt, Köthen, Germany

* U
Correspondence: M. Müller, matthias.mueller@sartorius-stedim.com, Sartorius Stedim Biotech
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GmbH, August-Spindler Str. 11, 37079 Göttingen
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Highlights

 Determination of overall heat transfer coefficients in single-use bioreactors

 Comparison of determination approaches: Transient vs. steady state measurements
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 Application of Wilson plot technique for detail investigation and scale-up considerations
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Abbreviations: stirred tank reactor (STR), diluted oxygen (DO)

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1 Introduction
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Stirred tank reactors represent an important class of reaction equipment, fulfilling various tasks within
the chemical, food and biotechnology industries. Primary tasks are suspending, gas-liquid dispersion
and generally mixing in order to reduce gradients and support (bio-) chemical conversion reactions.
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Based on this, heat transfer is a secondary task of a stirred tank to either quickly change the bulk
temperature or keep it constant on a desired setpoint. Knowing the heat transfer capabilities of a
system enables its comparison to the processes requirements, e.g. to check upfront if an exothermic
reaction can be carried out safely.
Stirred tanks are operated in a wide range of process conditions. To adapt to a dedicated task, the
detailed construction and existence of installations may vary strongly, which led to many
investigations determining their influence on heat transfer. As the full reactor assembly can be split
into the process side, i.e. the inner, agitated bulk fluid, and a cooling organ, e.g. a jacket or cooling
coil, most authors consider only one part. For example, Chilton et al. is usually cited as the classical
work for describing the stirred flow within the process side [1]. On the other hand, an approach on
describing the jacket-side flow was given by Lehrer [2]. The list of work on factors influencing heat
transfer in stirred tanks can be extended arbitrarily. Therefore, the review of Mohan et al. is
recommended, as it gives a very broad and comprehensive overview on this topic [3].
The described concepts have been developed mainly for conventional stainless steel plants. Up to now,

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there is less knowledge about heat transfer characteristics of single-use bioreactors. These types of

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bioreactors are mainly used in biopharmaceutical cell culture processes. As cells grow slowly, they
only produce small amounts of metabolic heat and thus, maintaining optimal growth temperature is

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usually less challenging, compared to high demanding exothermic chemical reactions. Therefore,
investigations regarding heat transfer are not wide spread. On the other hand, microbial processes, e.g.

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E. coli or yeast cultures, release significant heat of up to 70 W/L [4][5]. As microbial processes still
play an important role in biopharmaceutical manufacturing, it becomes more relevant knowing the

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cooling capabilities of single-use bioreactors. For example P. pastoris is a microbial host that offers
interesting opportunities for the production of high-value substances in the future [6]. Furthermore,
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successful microbial fermentations in disposable wave-mixed [7] and stirred tank reactors [8][9][10]
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have already been performed. Some work has also been done determining heat transfer coefficients for
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disposable orbitally shaken bioreactors and setting up correlations over process parameters [11,12].
There are further applications of calorimetric methods to determine the specific power input of such
systems by the temperature method [13], which is often not trivial by common methods like torque
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measurement for the various drive concepts present in single-use technology. In contrast, methods to
derive other important process parameters have already been adapted to single-use bioreactors, like
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kLa, mixing time and, under some constraints, power input [14][15], as they play a major role in scale-
up of bioprocesses [16].
Some aspects of single-use bioreactors can be considered limiting by means of heat transfer, compared
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to conventional steel vessels. First, the bag-film acts as additional heat conductivity resistance. This
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effect is similar to scaling/ fouling, known from heat exchangers [17]. Although being thin, the low
heat conductivity of the polymer-film could significantly contribute to the overall resistance. Another
aspect relates to the heat transfer area. Due to the mild reaction conditions in biotechnological
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processes, the driving force, i.e. the temperature difference between process and jacket side, is limited.
In stainless steel vessels, this is usually compensated by introducing additional heat transfer surfaces,
e.g. cooling coils. However, this is not easily possible in single-use bioreactors. There, the count of
installations is kept low intentionally and thus, heat transfer usually only takes place at the vessel wall.
In this work, the specific implications of a stirred single-use bioreactor were investigated by means of
heat transfer and, whenever possible, the concepts known from stainless steel vessels were applied.
2 Theoretical background
2.1 Heat balance
Characterization of heat transfer processes within an apparatus can be realized in different ways. Often
this kind of task refers to the determination of the overall heat transfer coefficient, U, and its
dependencies on the specific circumstances, i.e. geometry [18] or fluid properties [19]. As the global
value represents only an average, there are some methods in the literature determining local effects
[20–22]. Especially if strong variations along the heat transfer area are present, this approach can

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improve the understanding of heat transfer processes in stirred tanks significantly. However, in most

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cases, including this work, it is sufficient to determine average values, as they are easier to derive and
interpret. It would even be possible that one overall heat transfer coefficient represents different

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cooling organs, e.g. jacket and tube coils, within one single stirred tank [23], if necessary.
For the experimental determination of overall heat transfer coefficients the global heat balance around

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the stirred bioreactor is set up. In real-life applications, like fermentation processes, these balances can
become very complex, if many heat flows are present [24]. On the other hand, simplified versions are

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applied for chemical engineering characterization. A scheme of heat flows considered for the used
bioreactor type is given by figure 1. One fundamental regarding the given system is that it actually
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joins two balance spaces. Thus, two equations can be derived for the reaction side (equation 1), i.e. the
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stirred part, and the jacket side (equation 2):
𝑑𝐻𝑟
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= −𝑞𝑟𝑗 + 𝑞𝑝 + 𝑞𝑠 − 𝑞𝑟,𝑙𝑜𝑠𝑠 (1)

𝑑𝑡

𝑑𝐻𝑗
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= 𝑞𝑟𝑗 + 𝑞𝑗,𝑖𝑛 − 𝑞𝑗,𝑜𝑢𝑡 − 𝑞𝑗,𝑙𝑜𝑠𝑠 (2)

𝑑𝑡

The left hand side of equation 1 represents the heat accumulation term under transient conditions,
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dH/dt. The equations right-hand contains a heat source, qp, the power input by the stirrer, qs, and a heat
loss term, qr,loss, as the jacket does not fully cover the reaction chamber and thus, a free surface is
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exposed to the environment. The jacket on the other side is a flow-through system. Therefore, a heat
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flow at the inlet, qj,in, and outlet, qj,out, needs to be considered in equation 2. Again, a heat loss term,
qj,loss, is present. As already stated, both balance spaces are coupled via the heat transfer term, qrj,
where heat is exchanged over the common heat transfer area. For further application, the general
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equations can be written in more detail, again for the reactor (equation 3) and jacket side (equation 4).
𝑑𝑇̅𝑟
∑𝑛𝑖=1(𝑚𝑖 ∙ 𝑐𝑝,𝑖 ) ∙ = −𝑈𝑟𝑗 ∙ 𝐴𝑟𝑗 ∙ Δ𝑇𝑙𝑜𝑔,𝑟𝑗 + 𝑞𝑝 + 𝑞𝑠 − (𝑈𝐴)𝑟,𝑙𝑜𝑠𝑠 ∙ Δ𝑇𝑎𝑟 (3)
𝑑𝑡

𝑑𝑇̅𝑗
∑𝑛𝑖=1(𝑚𝑖 ∙ 𝑐𝑝,𝑖 ) ∙ = 𝑈𝑟𝑗 ∙ 𝐴𝑟𝑗 ∙ Δ𝑇𝑙𝑜𝑔,𝑟𝑗 − 𝐹𝑗 ∙ 𝜌𝑗 ∙ (𝑇𝑗,𝑜𝑢𝑡 − 𝑇𝑗,𝑖𝑛 ) − (𝑈𝐴)𝑗,𝑙𝑜𝑠𝑠 ∙ Δ𝑇𝑎𝑗 (4)
𝑑𝑡
The accumulation term is represented by the sum of the heat capacities, as product of mass, m, and
specific heat capacity, cp, of all temperature-varying parts that are assigned to this balance space, i.e.
installations, vessel wall and liquid, as well as the time derivative of the temperature, dTi/dt,
accordingly. However, it is assumed all parts within the balance space are in equilibrium by means of
̅r or T
a common temperature, T ̅j , respectively.

𝑇̅𝑟 = 𝑇𝑟 (5)

𝑇 −𝑇
𝑇̅𝑗 = 𝑗,𝑜𝑢𝑡𝑇 𝑗,𝑖𝑛 (6)
𝑗,𝑜𝑢𝑡

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𝑙𝑛( )
𝑇𝑗,𝑖𝑛

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The product of the overall heat transfer coefficient, Urj, the heat transfer area, Arj, and the mean

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logarithmic temperature difference, ΔTlog, according to equation 7, gives heat transfer between reactor

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and jacket, qrj.
(𝑇𝑗,𝑜𝑢𝑡 −𝑇𝑗,𝑖𝑛 )
Δ𝑇𝑙𝑜𝑔,𝑟𝑗 = 𝑇𝑟 −𝑇𝑗,𝑖𝑛
(7)
𝑙𝑛( )
𝑇𝑟 −𝑇𝑗,𝑜𝑢𝑡

U
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Heat loss to the environment is calculated from the exposed surface and an assumed heat transfer
coefficient for free convection in gasses on a flat plate, Uloss, of 5 W m-2 K-1, times the driving force
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(equation 8 and 9).
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Δ𝑇𝑎𝑟 = 𝑇̅𝑟 − 𝑇𝑎 (8)

Δ𝑇𝑎𝑗 = 𝑇̅𝑗 − 𝑇𝑎 (9)
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From the theoretical point of view, there is no difference in which balance space is considered for the
calculation of the overall heat transfer coefficient. However, by evaluating both equations, the
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differences in the results gained from equation 3 or 4 are a measure of accuracy. In this work, the
deviation was usually < 10 %. For consistency, the values for overall heat transfer coefficients given in
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this work were always calculated from the jacket side balance. The heat balance, as given here, did
provide an adequate representation of the experimental data, which is shown in the experimental
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sections. Nevertheless, some further terms that might be present, e.g. heat loss between headspace and
environment, have been neglected, as they would add complexity to the equations but do not increase
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the overall validity of the model. This assessment must be carried out carefully for each individual
case.

2.2 Modelling of heat transfer processes

Since it is desired to gain deeper insights into the underlying processes, it is necessary to subdivide the
overall heat transfer coefficient into its single terms
1 1 1 𝑠
𝑈𝑟𝑗
= 𝛼 + 𝛼 + ∑𝑛𝑖=1 𝜆𝑖 (10)
𝑟 𝑗 𝑖
It shall be noted, that the overall heat transfer coefficient is always smaller, than the smallest
contributing term, i.e. one insulating layer limits the overall performance, even if other parts show a
high heat transfer capability. In a jacketed stirred tank bioreactor, heat often is first transferred from
the bulk liquid to the vessel wall by heat transfer. This process can be characterized by the heat
transfer coefficient, α.
𝜆𝑙 𝜆𝑙
𝑞=𝛿 (𝑇𝑤 − 𝑇∞ ) (11)𝑤𝑖𝑡ℎ: 𝛼 = 𝛿
𝑙𝑎𝑚 𝑙𝑎𝑚

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Within the vessel wall, heat conductivity takes places, which is dependent on the wall thickness, s, and

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the heat conductivity, λ, of the material. Multiple layers, e.g. a stainless steel wall and a polymer film,
add up. A liquid cooling media, mostly water, then absorbs the heat. Thus, equation 11 represents heat

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transfer to a wall, similar to heat conduction through a wall, with the laminar sublayer being the region

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where heat conductivity occurs.
To estimate the heat transfer of a given apparatus, dimensionless relationships are used [25],
𝛼∙𝐿
𝑁𝑢 = 𝜆
(12)

U
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with the Nusselt number, Nu, being a function of Reynolds, Re, and Prandlt number, Pr, respectively.
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For stirred tanks the following power function is considered adequate for most applications [26]:
𝑁𝑢𝑟 = 𝐶 𝑅𝑒𝑟 𝑎 𝑃𝑟𝑟 𝑏 𝑉𝑖𝑟 𝑐 (13)
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The pre-factor, C, combines geometric effects. Most known correlations further consider a viscosity
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term, Vi. An extensive selection of such Nu-correlations for a great variety of flow forms and process
equipment is given by [27].
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3. Materials and Methods

3.1 Bioreactor and experimental setup
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The given setup, as shown by figure 2, based on a standard 50 L, stirred single-use bioreactor
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(BIOSTAT® STR, Sartorius Stedim Biotech GmbH, Germany), equipped with a disposable bag
(Flexsafe®, Sartorius Stedim Biotech GmbH, Germany). The bag contained a two-stage three-blade
segment impeller. The bag was pressurized upfront to ensure good contact between bag and stainless
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steel wall. No major crinkles or lacking wall contact was observed which could have influenced later
measurements. Experiments were carried out at maximum filling volume of 50 L or 200 L,
respectively. Tap water was used, as it sufficiently represents the water-like fluid properties of cell
culture media. There was no sparged aeration, because gassing rates of mammalian cell cultures are
commonly less than 0.1 vvm and thus, only limited impact on the overall flow and heat transfer
characteristics were to be expected. Further, there was no additional insulation as it would have meant
manipulation of the original design. To enable heat transfer measurements, extra sensors were
integrated. First, T-style flow-through Pt100 Class A (TS2789, ifm electronic GmbH, Germany)
temperature sensors were placed in the forerun and return of the jacket (± 50 mK). The signal was
converted to a voltage by a transducer (MINI MCR-SL-PT100-UI, Phoenix Contact, Germany) and
connected to the external signal inputs of the control tower. The jacket flow was measured in the
jacket return by a magnetic-inductive flow sensor (HygenicMaster 300, ABB, Germany; ± 0.01∙Fj). To
vary the jacket flow, a by-pass, equipped with a hand valve, was introduced. A fully closed by-pass
valve represented the standard configuration. Therefore, the jacket flow could only be reduced from its
initial value. The jacket flow was constant, as the pump of the tempering circuit worked steadily. Cold

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water was provided by a cooling unit (FRIGOMIX 2000, Sartorius Stedim Biotech GmbH, Germany).

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The vessel bulk temperature was measured with the standard Pt100 (± 50 mK) and placed in the
bottom part of the bag, within the dedicated port. The temperature controller of the DCU worked in a

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way that the jacket inlet temperature was set to a required level, accordingly. To ensure accurate
measurements, the jacket side temperature sensors were calibrated against the bulk sensor.

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Finally, to enable steady state measurements, up to two electrical immersion heaters (WEMA,
Germany), each with a net power of max. 800 W, were used, which were introduced through the top of

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the bag. A scheme of the experimental setup is given by figure 3.
For scale related experiments, a 200 L bioreactor of the reactor series was used and connected to the
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same control tower. Other equipment properties and process conditions were analogue to the 50 L
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system. An overview of the geometric dimensions for the bioreactor scale series up to 1000 L working
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volume is given by table 1.

3.2 Experimental procedure

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When determining overall heat transfer coefficients experimentally, there are generally two options
available. During transient experiments, a forced temperature shift is induced, while during steady
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state experiments, a constant temperature is maintained. The latter is advantageous by means of well-
defined process conditions and temperatures throughout the determination procedure. Although a
steady state approach does more represent an isothermal bioprocess it becomes hard to apply with
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increasing scale. Therefore, large vessels are usually investigated by transient experiments. In the
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literature transient [28], as well as steady state experiments for conventional [29] and single-use
reactors [30] can be found.
If not stated otherwise, experiments mainly have been carried out in transient mode, of which only the
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cooling curve was evaluated for given process conditions, i.e. stirring speed and jacket flow. During a
measuring cycle, the reactor temperature was set to 40 °C and after the system settled, a step change to
20 °C was induced.

3.3 Data evaluation

Only a subset of the cooling curve was evaluated, namely the range from 35 to 25 °C, resulting in a
reference temperature of 30 °C. This sectioning of the experimental data is analogue to determining
kLa-values of bioreactors, where also only a subsection, e.g. from 10 to 90 % DO, is used for
calculation. This reduces non-linear effects that often occur on start and end of transient processes.
Due to the temperature sensitivity of heat transfer processes, care must be taken when defining the
temperature range as it might lead to undesired effects. To be practically useful, the reference
temperature should be in a range of the final application.
The data evaluation fundamentally bases on the proposal of Johnson et. al [31]. Under certain

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assumptions, the procedure allows the determination of overall heat transfer coefficients from transient

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experiments. If heat accumulation and heat loss of the jacket is neglected,
𝑑𝑇𝑗
𝑑𝑡
; (𝑈𝐴)𝑗,𝑙𝑜𝑠𝑠 ∙ Δ𝑇𝑎𝑗 ≈ 0

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equation 4 can be rewritten as:
−𝑈𝑟𝑗 ∙ 𝐴𝑟𝑗 ∙ Δ𝑇𝑙𝑜𝑔,𝑟𝑗 = 𝐹𝑗 ∙ 𝜌𝑗 ∙ 𝑐𝑝,𝑗 (𝑇𝑗,𝑜𝑢𝑡 − 𝑇𝑗,𝑖𝑛 ) (14)

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Although the temperature of the jacket is not fully constant during an experiment, the change is slow,
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resulting in a small accumulation term. On the other hand, the temperature is close to ambient and
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thus, heat loss is reduced as well. Nevertheless, such simplifications are possible error sources.
Further, the definition of the mean logarithmic temperature difference (equation 7) can be rewritten as:
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𝑈𝑟𝑗 ∙𝐴𝑟𝑗
𝑇𝑗,𝑜𝑢𝑡 = 𝑇𝑟 + (𝑇𝑗,𝑖𝑛 − 𝑇𝑟 ) ∙ 𝑒𝑥𝑝 (− 𝐹 ) (15)
𝑗 ∙𝜌𝑗 ∙𝑐𝑝,𝑗
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Equation 15 is then introduced into 14, substituting the jacket outlet temperature. Next, this
intermediate is further introduced into the process side heat balance (equation 4) via the heat transfer
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term, 𝑈𝑟𝑗 ∙ 𝐴𝑟𝑗 ∙ Δ𝑇𝑙𝑜𝑔,𝑟𝑗 , which leads to the final target equation:

𝑑𝑇𝑟 𝐹𝑗 ∙𝜌𝑗 ∙𝑐𝑝,𝑗 𝑈𝑟𝑗 ∙𝐴𝑟𝑗 (𝑈𝐴)𝑟,𝑙𝑜𝑠𝑠 𝑞𝑠

𝑑𝑡
= 𝑚𝑟 ∙𝑐𝑝,𝑟
∙ (1 − 𝑒𝑥𝑝 (− 𝐹 )) ∙ (𝑇𝑗,𝑖𝑛 − 𝑇𝑟 ) − ∙ (𝑇𝑟 − 𝑇𝑎 ) + 𝑚 (16)
𝑗 ∙𝜌𝑗 ∙𝑐𝑝,𝑗 𝑚𝑟 ∙𝑐𝑝,𝑟 𝑟 ∙𝑐𝑝,𝑟
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This differential equation was not further integrated, but solved numerically and fitted against the
experimental data via a simplex based error minimization algorithm (fminsearch) implemented in
MATLAB R2014b (The MathWorks, Inc.). Equation 16 was used as cross-validation of the derived
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overall heat transfer coefficient by recalculating the jacket outlet temperature and comparing to the
experimental values. The original approach differs from this, as for example stirrer power input and
heat loss is originally neglected, which allows integration and linearization and thus, enables
determination of the overall heat transfer coefficient by linear regression. An underlying drawback of
transient methods, is that the fluid properties of water do change. For example, liquid dynamic
viscosity rises about 20 % from 35 °C (7.2 mPas) to 25 °C (8.9 mPas).
As it is relevant during transient experiments, the heat capacities for the process side balance spaces of
the 50 L and 200 L bioreactor were calculated as follows (kJ K-1):
 STR50: water (208), steel (10), bag (10)
 STR200: water (832), steel (161), bag (63)

Figure 4 exemplarily represents the outcome of the approach for both scales, 50 and 200 L. The
overall heat transfer coefficient is determined from fitting the model to the experimental process-side
temperature, Tr. and validation is done by re-calculation the jacket-outlet temperature. The good

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alignment of measured and calculated temperature curves indicates the validity of the underlying

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balance model.
In contrast to the transient experiments, evaluation of steady-state experiments is simplified, since the

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heat accumulation term is approximately zero:
𝑑𝑇
≈ 0 (17)

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𝑑𝑡

The resulting algebraic equation can then be set-up for both balance spaces. In this work, the jacket

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side was chosen. Considering equation 17, equation 4 can be rearranged as follows:
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𝐹𝑗 ∙𝜌𝑗 ∙(𝑇𝑗,𝑜𝑢𝑡 −𝑇𝑗,𝑖𝑛 )−(𝑈𝐴)𝑗,𝑙𝑜𝑠𝑠 ∙Δ𝑇𝑎𝑗
𝑈𝑟𝑗 = 𝐴𝑟𝑗 ∙Δ𝑇𝑙𝑜𝑔,𝑟𝑗
(18)
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To achieve adequate results, a jacket-side temperature difference between inlet and outlet must be
present. This is facilitated by introducing adjustable heat sources on the process side, simulating the
metabolic heat production of cells. Here, electrical immersion heaters were used. For adequate data
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quality (𝑇𝑗,𝑜𝑢𝑡 − 𝑇𝑗,𝑖𝑛 ) should be greater than 1.5 K [30].

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4 Results and discussion

4.1 Comparison of the experimental approach
In this section, experiments have been carried out in both ways, transient and steady state. Table 2
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shows the results from these experiments. Cooling curves have been performed as triplicates. The
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accuracy and reproducibility was adequate, with a mean deviation of a repetition over all process
conditions of less than one percent. While the span of results is actually low, from 171W m-2 K-1 being
the lowest, to 218 W m-2 K-1 being the highest overall heat transfer coefficient, this accuracy allowed a
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detail investigation of the influencing factors, though. Further, steady state experiments were carried
out at two reactor temperature levels, 35 and 40 °C, respectively. The power input of the electrical
immersion heaters was kept constant. Since only a smaller number of experiments was done,
measurements at 35 °C were done as single, while at 40 °C duplicates were carried out. However,
again a high accuracy could be observed for the repetition with a deviation of less than one percent to
the mean value. A data subset of both approaches, where the jacket flow was considered equal, was
compared, which is represented by a parity plot (figure 5). For better comprehensibility, data that were
used in the given figure is marked by corresponding superscripts to the overall heat transfer
coefficients listed in table 2.
The averaged deviations between both methods were 9 %, with results from the transient method
always underestimating those derived from the steady state approach, thus, a systematic error must be
present. In this regard, the different reference temperatures must be considered. Since the reference
temperature of transient experiments was 30 °C, compared to 35 °C and 40 °C for the steady states,
respectively, different fluid properties may be the root cause for the observed deviations. This

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highlights the implications when deciding for a certain experimental procedure and temperature level,

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as this can lead to significant variations of the final results. However, depending on the application and
accuracy requirements, deviations within 10 % might be acceptable, though.

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4.2 Statistical evaluation

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For better understanding, a statistical evaluation of the transient data using a software tool (Modde Pro
v11, Umetrics, Sweden) was executed. The regressions performance metrics indicated an adequate

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representation of the data, with R2 = 0.996 and Q2 = 0.995. To gain insights into the relevant factors
and their impact on heat transfer, considering the factor coefficients of the regression model is helpful.
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The coefficients for both process parameters, i.e. stirring frequency and jacket flow, as well as their
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quadratic terms and interaction are listed in table 3. It can be seen that the jacket flow has a fourfold
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higher impact on the overall heat transfer coefficient. However, the manipulation range needs to be
taken into account here, too. While the stirring speed was only varied in a narrow range from 100 to
200 min-1, i.e. two times the lowest setting, the jacket flow range was broader from 179.6 L h-1 to
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438.1 L h-1, which is about 2.5 times the lowest setting. Important to note is that all factors, including
the quadratic terms and interactions, are statistically significant, i.e. they do not include zero within the
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confidence interval. However, transient experiments do not allow accurate evaluation of temperature
dependent effects. This is only possible by steady state experiments. Another statistical evaluation of
the steady state data showed the significant effect of the temperature level (data not shown), although
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only a small temperature range was investigated in this work. The temperature sensitivity of heat
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transfer coefficients impedes distinguishing between temperature related effects and those due to flow
characteristics. Even for the majority of flowed through systems, like jackets or more general, tube
heat exchangers, defining representative mean temperatures under steady state conditions is often non-
A

trivial [32].
While such statistical approach might be sufficient for some cases where only simple relationships
between process parameters and overall heat transfer coefficients are of interest, it does not give
information about the physical processes that are actually responsible for the observable effects.
Summarizing, the evaluation already shows the importance of the jacket side flow, which shall be
investigated in the following sections.
4.3 Comparison against dimensionless correlations
In chemical engineering, dimensionless correlations are utilized to describe process equipment based
on fundamental, generally valid relations. In the context of heat transfer, the concept of Nu numbers is
predominantly used, as already described in the introductory section. To estimate an overall heat
transfer coefficient, the single terms of equation 10 must be evaluated, which was done as follows. It
shall be noted that for this comparison only steady state data at 35 °C was used, as it enables a more
straightforward definition of reference temperatures.

T
Process side. For the lowest impeller frequency of 100 min-1, a Re number of 4.3∙104 is present. Since

IP
the system is not equipped with baffles, this flow lies in the upper range of transitional flow, which
lies between Re = 20 to 5∙104 and thus, might not be fully turbulent [33]. However, for a stirred flow

R
without baffles, the equation given by Nagata et al. is commonly used [34]. The viscosity term is
neglected, as it is assumed to have no significant impact.

SC
𝑑 −0.25 ℎ 0.15 ℎ 0.15 2⁄ 1⁄
𝑁𝑢𝑟 = 0.54 (𝑑𝑠 ) (𝑑𝑠 ) ( ℎ0 ) 𝑠𝑖𝑛(𝛾)0.5 𝑍 0.5 𝑅𝑒 3 𝑃𝑟 3 (19)
𝑣 𝑣 𝑙

U
This equation contains many geometrical factors, relating to the impeller construction. However, the
N
segment impeller used in this work is not covered directly by the literature. The geometric validity
A
ranges were fulfilled, with one exception. While an impeller angle of 90 to 45° is represented, the
given angle was 30°. Therefore, the maximum angle of 45° was used to evaluate the equation. Taking
M

all geometric terms into account, a pre factor of C = 0.45 resulted. If a multi-stage impeller is used,
this must be considered under specific circumstances as well. Two Rushton-type impellers are known
ED

to operate independently if Δhs/dv > 0.75 [35]. For the given impeller configuration, this is not the
case as the relation is only about 0.5. On the other side, the threshold could be different for the three-
blade segment impellers. Additionally, the heat transfer area is only placed in the bottom part of the
PT

bioreactor and therefore the contribution of both impellers must have been differentiated. Although
there are obvious deviations and uncertainties related to the literature, it was decided to use the single-
E

stage Nu number as representation of the process-side. This results in αr ranging from 1200 to 2200 W
CC

m-2 K-1, at 100 and 200 min-1, respectively.

Jacket. The jacket construction is complex, as the flow is guided by internal baffles in a meandering
fashion. Further, the flow is split at the inlet into two streams. A scheme of the jacket geometry is
A

given by figure 6. There is no correlation, representing such a complex structure. Therefore, as an

abstraction, the given jacket can be approximated as flow over a flat plate of a rectangular cross-
section, with one sided heat transfer. The outer area, exposed to air, is neglected in this case. For the
highest jacket flow rate, a Re number of 1.5∙103 is estimated under these assumptions and thus, no
fully turbulent flow is present. Under these conditions, the following set of equations were used to
estimate the jacket-side Nu number [27]:
 3
𝑁𝑢𝑗 = √𝑁𝑢13 + 𝑁𝑢23 + 𝑁𝑢33 (20)

with:

Single-side heat transfer boundary condition

𝑁𝑢1 = 4.861 (21)

T
Thermal onset
3 𝑑

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𝑁𝑢2 = 1.841 √𝑅𝑒 𝑃𝑟 𝑒𝑞⁄𝑙 (22)

R
Laminar onset

SC
1⁄ 1⁄
2 6 𝑑𝑒𝑞 2
𝑁𝑢3 = {1+22 𝑃𝑟} (𝑅𝑒 𝑃𝑟 ⁄) (23)
𝑙

U
The length of the flow path, l, was estimated to be 2.3 m, which is the path along the baffles, for one
N
half of the jacket. Application of these equations results in jacket side heat transfer coefficients of 237
A
for the lowest and 344 W m-2 K-1 for the highest jacket flow, respectively.
Heat conductivity. If the heat transfer terms are low and only a steel wall is present, heat conductivity
M

might be neglected [36]. However, for the given single-use bioreactor, these terms needed to be
calculated (W m-2 K-1): polymer-film (1300), steel wall (5000).
ED

Comparison. Figure 7 shows a parity plot of the measured overall heat transfer coefficients against the
theoretical values, reconstructed from Nu-correlations and equation 10. As can be seen, the theoretical
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values systematically underestimate the true values. The plot further distinct two groups of different
jacket flow rates. While the results at low flow rate lie close to the 10 % error range, this discrepancy
is more pronounced with increased flow. This indicates a major impact on the theoretic description on
E

the jacket-side equations. Therefore, the high degree of abstraction might not be fully adequate to
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describe the given geometry. However, definition of required parameters, e.g. the length of the flow
path or the equivalent diameter, is difficult and error prone. On the other hand, no further correlations
were found in the literature and thus, none were applied here. An alternative approach would be fitting
A

of the jacket-side Nu number, but this would bear any physical foundation. Another aspect often
discussed in context of heat transfer of single-use bioreactors is whether a thin air-layer is enclosed
between polymer film and steel wall, acting as additional heat transfer barrier. This could not be
confirmed finally, since it would result in a constant offset within the parity plot. If present, such effect
would be small and, most important, lumped with the jacket-side limitation.
To sum this up, there are differences between the plain theoretic description and the experimental
determination. On the other side, the mean deviation of about -11 % would be considered very small
when usually applying Nu-correlations to real-life process equipment, especially if the overall
constellation, i.e. a multistage impeller with transient flow corresponding to a laminar jacket-side
flow, is complex.

4.4 Wilson plot method

A very common concept of determining one-sided heat transfer coefficients, α, from their overall
equivalent, U, was first proposed by Wilson and thus, is called Wilson plot method [37]. This
approach allows the determination of the single terms from measurements of the overall heat transfer

T
coefficient, by varying one side, while keeping the other constant. The general approach has been

IP
widely adopted throughout the process industry, though many examples deal with heat exchangers,
e.g. [38]. As the classical approach allows determination of only two parameters, there are many

R
modifications in the literature extending this number [39]. Although this concept is generally accepted,
its application needs proper handling. Since this topic represents its own field of research, it shall be

SC
referred to corresponding reviews that cover the specific implications of temperature interference [40],
accuracy of thermal measurements [41], and modifications made to the basic approach [42][43].

U
In this section, the Wilson plot method is adapted to a jacketed, stirred tank reactor.
In case of investigating the impact of the jacket flow on the heat transfer of a stirred tank reactor, the
N
stirring frequency would be manipulated. To determine the jacket effect, a mathematic relationship on
A
the process-side needs to be made upfront, which is given by equation 13. A linear equation is derived,
M

by combining equation 10 and 13, which yields

1 1
𝑈
=𝑚∙ 2⁄ 1
+ 𝑛 (24)
𝑅𝑒𝑟 3 𝑃𝑟𝑟 ⁄3
ED

with the slope

𝑑𝑣
𝑚= (25)
PT

𝐶∙𝜆𝑟

and intercept
E

𝑠𝑠𝑡𝑒𝑒𝑙 𝑠𝑓𝑖𝑙𝑚 1
𝑛=( + )+ (26)
CC

𝜆𝑠𝑡𝑒𝑒𝑙 𝜆𝑓𝑖𝑙𝑚 𝛼𝑗

Transient experiments were carried out as triplicates at given stirring frequency and three different
A

jacket flow rates. The corresponding Wilson plot is given by figure 8. From a linear regression, the
specific parameters could be calculated. Of interest were the geometric pre factor, C, calculated from
the slope, as well as the jacket-side heat transfer coefficient, αj, derived from the intercept, where the
intercept represents the interpolation to an infinite process-side heat transfer coefficient. The mean pre
factor over all three flow rates was 0.40, compared to 0.45 calculated from the proposal of Nagata et
al., given by equation 19 [34].
Results of the jacket-side heat transfer coefficient is listed in table 4, together with the theoretic values,
as calculated previously. This evaluation supports the above statement that the theoretical description
of the jacket-side leads to systematic deviations, which increase with jacket flow rate, accordingly.
Further, the pronounced impact on the jacket side becomes obvious.
This evaluation shows the beneficial insights, which can be derived from applying the Wilson plot
technique. However, a broader variation of stirring frequencies would further improve the general
validity of the given statements.

T
4.5 Influence of polymer film layer

IP
Additionally to the default bag type, in this section referred to as film B, tests with another polymer-
film bag have been carried out (film A). The polymer films differed in both, thickness and heat

R
conductivity (µm, W m-1 K-1): film A (200, 0.26), film B (400, 0.33). Another difference was the
impeller configuration. The bottom impeller of the film A bag was a Rushton-type. However, as was

SC
shown in the previous sections, the process-side heat transfer coefficient was the highest partial
resistance and thus, considered as non-limiting. Therefore, the impact of impeller configuration was

U
neglected here. The results of the comparison are shown in table 5. Linear interpolation was necessary
regarding the jacket flow rates of the film A bag, which is reasonable within the range from 389 to
N
558.6 L h-1. Compared to film A, film B results in a -20 % decrease in the overall heat transfer
A
coefficient. Although being only a few hundred micrometers thick, the impact of film type on heat
M

transfer can therefore is measureable and pronounced. On the other hand, single-use polymer films of
stirred tank bioreactors are not designed to give highest heat transfer capabilities, but to support cell
growth [44]. From the viewpoint of mechanical robustness, a thicker film is advantageous.
ED

Nevertheless, this evaluation represents more of a trend and therefore needs to be evaluated in more
detail by further experiments.
PT

4.6 Scale dependency

Heat transfer is an important scale-up issue [45][46], as the surface to volume ratio decreases with
E

scale. For single-use bioreactors this effect is even pronounced, since additional heat transfer surfaces
CC

cannot easily be integrated. Therefore, transient experiments have been carried out in a 200 L stirred
tank bioreactor, equipped with a two stage three-blade segment impeller and a film B type bag, at two
stirring frequencies of 64 and 128 min-1, which corresponds to a tip speed of 0.75 and 1.5 m sec-1,
A

respectively. This again is the same tip speed as the 50 L bioreactor at 100 and 200 min-1. Generally
the impeller tip speed is a common, yet easy to use, scale-up parameter in the bioprocess industry.
Cooling curves in the larger scale were done as single determination, only. Comparison of the jacket
flow rates at different scales need to take the jacket volume into account. An overview of the derived
data is given by table 6. In general, the overall heat transfer coefficient was slightly lower, compared
to the smaller scale. For example at 1.5 m sec-1, the overall heat transfer coefficient for the 50 L at 438
L h-1 was 218 W m-2 K-1 and for the 200 L bioreactor at 420 L h-1 it was 194 W m-2 K-1, respectively,
which represents a decrease of -11 %. The data foundation was not accessible to be evaluated by the
Wilson plot method, because there were only two data points per jacket flow to determine the linear
coefficients. Hence, a simplified approach was used to investigate scale-dependent effects that relates
the overall heat transfer coefficients determined at both scales to the jacket dilution rate, D (figure 9).
The relation follows the shape of a root function with flattening influence towards a further increase of
the jacket dilution rate. For a deeper analysis, the jacket side heat transfer coefficient could be
calculated for the 200 L bioreactor, if the process side was assumed to be characterized by the same

T
pre factor, as the smaller scale, i.e. C = 0.4. Although the parameter has been proven to be scale

IP
dependent [47], this effect is negligible for the given bioreactor as the volume increase is small.
This relationship is very straightforward but might still be easy to use and setup for a given reactor

R
scale series, which is characterized by a high geometric similarity. Applying this relationship would
then result in heat transfer coefficients normally lying within acceptable error tolerances required for

SC
biochemical engineering purposes.

5 Conclusion
U
N
Heat transfer characteristics of stirred, single-use bioreactors can be accurately determined by both,
transient and steady state experiments. The decision on which to carry out depends on the specific aim.
A
While transient experiments are easier to perform, a steady state provides more defined process
M

conditions and thus, temperature dependent effects can be evaluated in detail, which is not possible
from cooling curves. Both modes need an accurate heat balance model, taking into account all major
ED

heat flow terms, though. For detail investigation, the overall heat transfer coefficient was derived from
the jacket side heat balance. The derived values lie in the bottom range of what is expected from
jacketed, stainless steel bioreactors operated with water as cooling liquid. Therefore, single-use
PT

bioreactors have a reduced heat transfer capability, but it was less pronounced than initially expected.
However, the cooling capacity should be interpreted in context to the requirements of real
E

fermentation processes, which is possible with the proposed heat balance model in this work. The
comparison of experimental data with theoretical derived values, based on Nu numbers, showed
CC

already good agreement. To achieve this, a high level of abstraction on the jacket-side was necessary,
as no dedicated correlations for such complex geometry were available. Nevertheless, a systematic
A

deviation was present. This could be proven by a Wilson plot data evaluation, from which the jacket-
side heat transfer coefficient was calculated. Therefore, to improve the agreement, effort needs to be
made considering this aspect. On the other side, if technical accuracy is sufficient, these already
available models can be applied satisfactorily. By the chosen approach, the limiting term could be
identified as the jacket-side and not the polymer film-layer. Thus, when aiming to increase the cooling
capacity, the jacket flow rate is the relevant parameter to be optimized, since it is not easily possible to
compensate a low overall heat transfer coefficients by increasing the heat transfer area in single-use
bioreactors.

Nomenclature
A m2 heat transfer area
-1 -1
cp J kg K specific heat capacity
D h-1 dilution rate
d m diameter

T
F L h-1 flow rate

IP
H J Enthalpy
h m height

R
l m flow path length

SC
L m characteristic length
m kg mass
N min-1 stirring frequency
q W heat flow
U
N
Q2 - coefficient of predictive correlation
2
R - coefficient of correlation
A
s m layer thickness
M

t s time
T K temperature
ED

U W m K-1 -2
overall heat transfer coefficient
V m3 volume
Z - impeller blade number
PT

Greek symbols
E

α W m-2 K-1 heat transfer coefficient

γ ° impeller blade angle
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Δ Difference
δ m thickness of laminar layer
A

λ W m-1 K-1 heat conductivity

ρ kg m-3 density

Indices
0 bottom to first impeller
a ambient
eq equivalent
in jacket inlet
j jacket
l liquid
lam laminar
log logarithmic
loss heat loss
out jacket outlet
r reactor

T
s stirrer

IP
p heat source
v vessel

R
SC
References

[1] T.H. Chilton, T.B. Drew, R.H. Jebens, Heat Transfer Coefficients in Agitated Vessels, Ind.
Eng. Chem. 36 (1944) 510–516. doi:10.1021/ie50414a006.
U
N
[2] I.H. Lehrer, Jacket-Side Nusselt Number, Ind.Eng.Chem.Process Des.Develop. 9 (1970) 553–
558.
A
[3] P. Mohan, A. Nicholas Emery, T. Al-Hassan, Review heat transfer to Newtonian fluids in
M

mechanically agitated vessels, Exp. Therm. Fluid Sci. 5 (1992) 861–883. doi:10.1016/0894-
1777(92)90130-W.
ED

[4] R. Biener, A. Steinkämper, J. Hofmann, Calorimetric control for high cell density cultivation of
a recombinant Escherichia coli strain, J. Biotechnol. 146 (2010) 45–53.
doi:10.1016/j.jbiotec.2010.01.004.
PT

[5] R. Biener, A. Steinkämper, T. Horn, Calorimetric control of the specific growth rate during
fed-batch cultures of Saccharomyces cerevisiae, J. Biotechnol. 160 (2012) 195–201.
E

doi:10.1016/j.jbiotec.2012.03.006.
[6] A. Berlec, B. Štrukelj, Current state and recent advances in biopharmaceutical production in
CC

Escherichia coli, yeasts and mammalian cells, J. Ind. Microbiol. Biotechnol. 40 (2013) 257–
274. doi:10.1007/s10295-013-1235-0.
A

[7] M. Mikola, J. Seto, A. Amanullah, Evaluation of a novel Wave Bioreactor?? cellbag for
aerobic yeast cultivation, Bioprocess Biosyst. Eng. 30 (2007) 231–241. doi:10.1007/s00449-
007-0119-y.
[8] T. Dreher, B. Walcarius, U. Husemann, F. Klingenberg, C. Zahnow, T. Adams, D. De Wilde,
P. Casteels, G. Greller, Microbial High Cell Density Fermentations in a Stirred Single-Use
Bioreactor, in: Dispos. Bioreact. II, 2014: pp. 127–147. doi:10.1007/10.
[9] P.M. Galliher, G. Hodge, P. Guertin, L. Chew, T. Deloggio, Single-Use Bioreactor Platform for
 Microbial Fermentation, in: Single-Use Technol. Biopharm. Manuf., John Wiley & Sons, Inc.,
Hoboken, NJ, USA, 2011: pp. 241–250. doi:10.1002/9780470909997.ch20.
[10] N. Jones, Single-use processing for microbial fermentations, Bioprocess Int. 13 (2015).
[11] Y. Kato, C.P. Peter, A. Akgün, J. Büchs, Power consumption and heat transfer resistance in
large rotary shaking vessels, Biochem. Eng. J. 21 (2004) 83–91. doi:10.1016/j.bej.2004.04.011.
[12] K. Raval, Y. Kato, J. Buechs, Characterization of heat transfer of large orbitally shaken
cylindrical bioreactors, Biochem. Eng. J. 86 (2014). doi:10.1016/j.bej.2014.02.011.
[13] K. Raval, Y. Kato, J. Büchs, Comparison of torque method and temperature method for

T
determination of power consumption in disposable shaken bioreactors, Biochem. Eng. J. 34

IP
(2007) 224–227. doi:10.1016/j.bej.2006.12.017.
[14] T. Dreher, U. Husemann, T. Adams, D. de Wilde, G. Greller, Design space definition for a

R
stirred single-use bioreactor family from 50 to 2000 L scale, Eng. Life Sci. 14 (2014) 304–310.
doi:10.1002/elsc.201300067.

SC
[15] C. Löffelholz, U. Husemann, G. Greller, W. Meusel, J. Kauling, P. Ay, M. Kraume, R. Eibl, D.
Eibl, Bioengineering Parameters for Single-Use Bioreactors : Overview and Evaluation of

[16] U
Suitable Methods, Chemie Ing. Tech. 85 (2013) 1–18. doi:10.1002/cite.201200125.
M.P.C. Marques, J.M.S. Cabral, P. Fernandes, Bioprocess scale-up: Quest for the parameters to
N
be used as criterion to move from microreactors to lab-scale, J. Chem. Technol. Biotechnol. 85
A
(2010) 1184–1198. doi:10.1002/jctb.2387.
M

[17] M. Bohnet, Fouling of heat transfer surfaces, Chem. Eng. Technol. - CET. 10 (1987) 113–125.
doi:10.1002/ceat.270100115.
[18] G. Havas, A. Deák, J. Sawinsky, The effect of the impeller diameter on the heat transfer in
ED

agitated vessels provided with vertical tube baffles, Chem. Eng. J. 27 (1983) 197–198.
doi:10.1016/0300-9467(83)80076-8.
PT

[19] W. Kai, Y. Shengyao, Heat transfer and power consumption of non-Newtonian fluids in
agitated vessels, Chem. Eng. Sci. 44 (1989) 33–40. doi:10.1016/0009-2509(89)85229-7.
[20] S. Haam, R.S. Brodkey, J.B. Fasano, Local heat transfer in a mixing vessel using heat flux
E

sensors, Ind. Eng. Chem. Res. 31 (1992) 1384–1391. doi:10.1021/ie00005a020.

CC

[21] J. Karcz, Studies of local heat transfer in a gas-liquid system agitated by double disc turbines in
a slender vessel, Chem. Eng. J. 72 (1999) 217–227. doi:10.1016/S1385-8947(99)00005-4.
[22] I. Bielka, M. Cudak, J. Karcz, Local heat transfer process for a gas-liquid system in a wall
A

region of an agitated vessel equipped with the system of CD6-RT impellers, Ind. Eng. Chem.
Res. 53 (2014) 16539–16549. doi:10.1021/ie503003t.
[23] E. Kumpinsky, Heat-Transfer Coefficients in Agitated Vessels. Sensible Heat Models, Ind.
Eng. Chem. Res. 34 (1995) 4571–4576. doi:10.1021/ie00039a052.
[24] D. Voisard, P. Pugeaud, a. R. Kumar, K. Jenny, K. Jayaraman, I.W. Marison, U. Von Stockar,
Development of a large-scale biocalorimeter to monitor and control bioprocesses, Biotechnol.
 Bioeng. 80 (2002) 125–138. doi:10.1002/bit.10351.
[25] Gröber, Erk, U. Grigull, Die Grundgesetze der Wärmeübertragung, Springer Berlin Heidelberg,
Berlin, Heidelberg, 1963. doi:10.1007/978-3-662-29015-6.
[26] K. Wichterle, Heat transfer in agitated vessels, Chem. Eng. Sci. 49 (1994) 1480–1483.
doi:10.1016/0009-2509(94)85075-5.
[27] VDI-Wärmeatlas, Springer Berlin Heidelberg, Berlin, Heidelberg, 2013. doi:10.1007/978-3-
642-19981-3.
[28] E. Kumpinsky, Experimental Determination of Overall Heat Transfer Coefficient in Jacketed

T
Vessels, Chem. Eng. Commun. 115 (1992) 13–23. doi:10.1080/00986449208936025.

IP
[29] V.T. Perarasu, M. Arivazhagan, P. Sivashanmugam, Heat Transfer Studies in Coiled Agitated
Vessel with Varying Heat Input, Int. J. Food Eng. 7 (2011). doi:10.2202/1556-3758.2211.

R
[30] M. Müller, W. Meusel, U. Husemann, G. Greller, M. Kraume, Measurement of heat transfer
coefficients in stirred single-use bioreactors by the decay of hydrogen peroxide, Eng. Life Sci.

SC
(2017). doi:10.1002/elsc.201700099.
[31] M. Johnson, P.J. Heggs, T. Mahmud, Assessment of Overall Heat Transfer Coefficient Models

U
to Predict the Performance of Laboratory-Scale Jacketed Batch Reactors, Org. Process Res.
Dev. 20 (2016) 204–214. doi:10.1021/acs.oprd.5b00378.
N
[32] W. Roetzel, Berücksichtigung veränderlicher Wärmeübergangskoeffizienten und
A
Wärmekapazitäten bei der Bemessung von Wärmeaustauschern, Wärme- Und
M

Stoffübertragung. 2 (1969) 163–170. doi:10.1007/BF00751163.

[33] M. Zlokarnik, Rührtechnik, Springer Berlin Heidelberg, Berlin, Heidelberg, 1999.
doi:10.1007/978-3-642-58635-4.
ED

[34] S. Nagata, M. Nishikawa, T. Takimoto, F. Kida, T. Kayama, Turbulent heat transfer from the
wall of a jacketed tank, Heat Transf. Japanese Res. 1 (1972) 66.
PT

[35] H.-J. Henzler, Verfahrenstechnische Auslegungsunterlagen für Rührbehälter als Fermenter,

Chemie Ing. Tech. 54 (1982) 461–476. doi:10.1002/cite.330540510.
[36] M.T. Dhotre, Z.V.P. Murthy, N.S. Jayakumar, Modeling & dynamic studies of heat transfer
E

cooling of liquid in half-coil jackets, Chem. Eng. J. 118 (2006) 183–188.

CC

doi:10.1016/j.cej.2006.02.008.
[37] E.E. Wilson, A basis for rational design of heat transfer apparatus, J Am Soc Mech Engrs. 37
(1915) 546–551.
A

[38] H. Shokouhmand, M.R. Salimpour, M.A. Akhavan-Behabadi, Experimental investigation of

shell and coiled tube heat exchangers using wilson plots, Int. Commun. Heat Mass Transf. 35
(2008) 84–92. doi:10.1016/j.icheatmasstransfer.2007.06.001.
[39] D.E. Briggs, E.H. Young, Modified Wilson plot techniques for obtaining heat transfer
correlations for shell and tube heat exchangers, in: Chem. Eng. Prog. Symp. Ser., AIChE, New
York, NY, 1969: pp. 35–45.
[40] K. Wojs, T. Tietze, Effects of the temperature interference on the results obtained using the
Wilson plot technique, Heat Mass Transf. 33 (1997) 241–245. doi:10.1007/s002310050184.
[41] J.W. Rose, Heat-transfer coefficients, Wilson plots and accuracy of thermal measurements,
Exp. Therm. Fluid Sci. 28 (2004) 77–86. doi:10.1016/S0894-1777(03)00025-6.
[42] E. van Rooyen, M. Christians, J.R. Thome, Modified Wilson Plots for Enhanced Heat Transfer
Experiments: Current Status and Future Perspectives, Heat Transf. Eng. 33 (2012) 342–355.
doi:10.1080/01457632.2012.611767.
[43] J. Fernández-Seara, F.J. Uhía, J. Sieres, A. Campo, A general review of the Wilson plot method

T
and its modifications to determine convection coefficients in heat exchange devices, Appl.

IP
Therm. Eng. 27 (2007) 2745–2757. doi:10.1016/j.applthermaleng.2007.04.004.
[44] R. Eibl, N. Steiger, C. Fritz, D. Eisenkrätzer, J. Bär, D. Müller, D. Eibl, Empfehlung für

R
Leachable-Studien Standardisierter Zellkulturtest zur Identifizierung kritischer Filme, 2014.
[45] A. Mersmann, W.-D. Einenkel, M. Käppel, Auslegung und Maßstabsvergrößerung von

SC
Rührapparaten, Chemie Ing. Tech. 47 (1975) 953–964. doi:10.1002/cite.330472302.
[46] R. Poggemann, A. Steiff, P.-M. Weinspach, Wärmeübergang in Rührkesseln mit einphasigen

[47] U
Flüssigkeiten, Chemie Ing. Tech. 51 (1979) 948–959. doi:10.1002/cite.330511007.
F.S. Chapman, H. Dallenbach, F.A. Holland, Heat transfer in baffled, jacketed, agitated
N
vessels, Trans. Inst. Chem. Eng. 42 (1964) T398–T406.
A
M
ED
E PT
CC
A
Figures

T
IP
Fig. 1: Schematic of the full heat balance for the stirred single-use bioreactor showing all major heat

R
flows that are considered in this work. To enable steady state measurements, an electrical immersion

SC
heater was introduced through the top of the bag. As can be seen, only the bottom part of the
bioreactor was jacketed and thus, the overall heat transfer coefficient only relates to this part.

U
N
A
M
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Fig. 2: (A) Hardware assembly of a BIOSTAT STR® 50 (Sartorius Stedim Biotech GmbH, Göttingen).

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Doors in the upper part facilitate bag installation. (B) Simplified scheme of the used bag configuration,
which contains a dual-stage three-blade segment impeller on a single shaft. Due to production of a

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polymer-based bag, the shape differs from an ideal cylinder.

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Fig. 3: Schematic of the experimental setup. As the bioreactor is the main part, the digital control unit
enabled process control in the field. To manipulate the jacket flow rate, a bypass and a hand valve

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were introduced in the cooling circuit. A dedicated cooling unit supplied cold water.

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Fig. 4: Exemplarily representation of cooling curves for both reactor sizes. (A) STR50 at 150 rpm and

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438 L min-1 resulted in an overall heat transfer coefficient of U = 213 W m2 K-1. (B) STR200 at 128
rpm and 211 L min-1 resulted in an overall heat transfer coefficient of U = 160 W m2 K-1. The straight

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black lines indicated calculated temperatures, which align well to the experimental data. This indicates

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adequate model accuracy.

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Fig. 5: Parity plot of heat transfer coefficients determined by transient and steady state experiments
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performed in the 50 L scale. Both approaches show good agreement in the investigated range. In table
2, the overall heat transfer coefficients that were used to set up this plot are indicated by matching
PT

superscripts a-h. The straight line depicts parity.

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Fig. 6: Schematic drawing of the inner construction of the jacket. Rod-shaped baffles induce a guided

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flow through the body. However, as the stream is split at the inlet, the flow velocity halves, which

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might affect the heat transfer capabilities of the overall system. Based on this construction, flow
through a flat plate with single-sided heat transfer was considered the best estimate representing this

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complex geometry.

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Fig. 7: Parity plot of theoretical overall heat transfer coefficients, based on Nu numbers, compared to
their experimental counterpart determined in the 50 L scale. In this case, steady state data was taken as
reference, since temperatures and thus, fluid properties were accurately defined. However, the plot
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indicates a systematic deviation, which tends to correlate with the jacket flow rate. The straight line
depicts perfect parity.
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Fig. 8: Wilson plot evaluation of data derived from transient experiments in the 50 L single-use
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bioreactor. From this plot it was possible to estimate the geometric pre factor of the process-side Nu-
equation, C, to be 0.4, as well as the jacket-side heat transfer coefficient for a given jacket flow rate,
PT

accordingly.
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Fig. 9: Scale-related exponential relationship of jacket-side dilution rate and its corresponding overall
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heat transfer coefficient at different stirring frequencies. Although not being dimensionless, such
simplified relationships could enable scale-up within a given bioreactor scale series.
E PT
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Tables

Tab. 1: Overview of the geometric properties of the bioreactor scale series. In this work, the 50 and
200 L scale were used.

STR® 50 STR® 200 STR® 500 STR® 1000

vessel diameter, dv [mm] 370 585 815 997

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max. liquid height, hl [mm] 480 783 1005 1360

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impeller diameter, ds [mm] 143 225 310 379
ds/dv [-] 0.39 0.38 0.38 0.38

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distance betw. impellers, Δhs [mm] 186 300 403 493

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bottom to first impeller, h0 [mm] 89.5 137 200 247
heat transfer area, Arj [m2] 0.33 0.88 1.6 2.5
jacket liquid volume, Vj [L] 2.5 6.0 14.0 19.5

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Tab. 2: Overview of the overall heat transfer coefficients, determined in the 50 L bioreactor at
different process conditions, i.e. stirring frequency and jacket flow rate for both experimental
procedures, transient and steady state, respectively. Superscripts a-h indicate data for the parity plot
(figure 4).
Tr Fj N U
-1 -1
[°C] [L h ] [min ] [W m-2 K-1]
Transient

T
179.6 100 171a

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150 177
200 180b

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181.6 100 171

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200 176
267.9 100 187
150
200 U 193
196
N
270.0 100 186
A
150 192
438.1 100 206c,f
M

150 213d,g
200 218e,h
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Steady state
40 180.6 100 189a
PT

150 197
200 200b
439.7 100 225c
E

150 233d
CC

200 238e
35 436.6 100 219f
150 229g
A

200 240h
Tab. 3: Coefficients derived from a statistical analysis, based on the transient data of the 50 L
bioreactor, cp. table 2.
Factor N Fj N2 Fj2 N Fj
Effect 4.9 18.8 -1.4 -3.9 1.1
Conf. int. (±) 0.5 0.5 0.8 0.8 0.6

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Tab. 4: Comparison of jacket-side heat transfer coefficients derived from the Wilson plot method and
the theoretical evaluation. As the deviation increases with the jacket-flow rate, accordingly, a
systematic error in the theoretic description can be assumed.
Fj [L h-1] 180 270 440
αj [W m-2 K-1]
Wilson plot 271 308 364
Theory 272 298 339

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Discrepancy [%] -0.4 -3.2 -7.0

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Tab. 5: Comparison of different film types evaluating their impact on heat transfer performance at 50
L scale. As there were no dedicated experiments carried out, linear interpolation was necessary to
match a corresponding jacket flow rate. However, a measurable difference was present, which is
considered due to the film layer thickness, since film B is as twice as thick as film A.
*Calculated from linear interpolation based on the greyed out values.
N Fj U ΔU
[min-1] [L h-1] [W m-2 K-1] [%]

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100 388.8 254

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Film A
100 558.6 277
Interp. 100 438.1 261*

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Film B 100 438.1 206 -21.1

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200 385.8 278
Film A
200 558.6 298
Interp.
Film B
200
200
438.1
438.1 U
284*
218 -23.2
N
*Calculated from linear interpolation based on the greyed out values.
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Tab. 6: Overview of overall heat transfer coefficients of the 200 L single-use bioreactor.

Fj Dj N U
[L h-1] [h-1] [min-1] [W m-2 K-1]
64 159
202.1 33.7
128 160
64 183
420.4 70.1

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128 194

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