Journal of Pharmaceutical Sciences 108 (2019) 382-390

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Journal of Pharmaceutical Sciences

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Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Determining Maximum Sublimation Rate for a Production

Lyophilizer: Computational Modeling and Comparison With Ice
Slab Tests
Vaibhav Kshirsagar 1, Serguei Tchessalov 2, Frank Kanka 3, David Hiebert 4,
Alina Alexeenko 1, *
1
School of Aeronautics and Astronautics, Purdue University, West Lafayette, Indiana 47907
2
Pfizer Biotherapeutics R&D, Andover, Massachusetts 01810
3
Pfizer Global Supply, Kalamazoo, Michigan 49001
4
Pfizer Global Supply, Peapack, New Jersey 07934

a r t i c l e i n f o a b s t r a c t

Article history: Equipment capability is an important factor in scale up and technology transfer for lyophilized phar-
Received 9 April 2018 maceutical products. Experimental determination of equipment capability limits, such as the maximum
Revised 20 October 2018 sublimation rate at a given chamber pressure, is time-intensive for production lyophilizers. Here, we
Accepted 22 October 2018
present computational fluid dynamics modeling of equipment capability and compare it with experi-
Available online 8 November 2018
mental data for minimum controllable pressure ice slab sublimation tests in a 23 m2 shelf area freeze
dryer. It is found that the vapor flow in the production scale is characterized by turbulent effects at high
Keywords:
freeze-drying sublimation rates. For the considered freeze dryer configuration, the onset of turbulence occurs at a
lyophilization sublimation rate of 17 kg/h and leads to an increase in the minimum controllable pressure by 3-4 mTorr
heat and mass transfer for the flow rates up to 40 kg/h. Variations in the shelf and duct orientations as well as the valve stroke
quality by design
distance and their effect on the equipment limit and pressure uniformity are also discussed. The mini-
mum controllable pressure measured experimentally agreed within 5% with computational fluid dy-
namics results. For high vapor sublimation rates at final stages of ice slab testing, the condenser load
affects the product chamber pressure control. Estimate of condenser pressure changes because of ice
accumulation has been included.
© 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction vapor cannot be removed fast enough by the flow to a lower-

Freeze-drying is widely used in the manufacture of biophar-
maceutical products to achieve long-term stability and is a time-
and energy-intensive operation. A significant heat input is required
to sustain water sublimation, which accounts for about 45% of en-
ergy input in freeze-drying, whereas maintaining the vacuum
environment takes an additional 26% of energy use.1 The devel-
opment of a successful freeze-drying process for a given product
requires understanding of capability of a given freeze-drying
equipment in terms of maximum sublimation rate2 or minimum
controllable pressure. The shelf temperature and chamber pressure
are the 2 main control parameters of the freeze-drying process. The
increase in shelf temperature leads to increase in heat transfer rate
to the product and a higher vapor sublimation rate. If the sublimed
* Correspondence to: Alina Alexeenko (Telephone: 765-496-1864).
E-mail address: alexeenk@purdue.edu (A. Alexeenko).
pressure region of condenser, the vapor pressure in the chamber
will rise. The coupled effects of chamber pressure, shelf tempera-
ture, and corresponding sublimation rate and product temperature
can be shown as a graph of design space for freeze-drying. The
boundaries of design space are defined by the equipment limit
curve giving maximum sublimation rate supported by the equip-
ment for a given chamber pressure and the product limit given by
the maximum allowable product temperature. The concept of
design space is a key element of quality by design3 approach for
pharmaceutical manufacturing. The construction of design space
for freeze-drying and the importance to the development of
lyophilized parenteral drug products has been previously discussed
by Nail and Searles.4 As the design space contains information
pertaining to the product, the process, and the freeze dryer
equipment, it is indispensable for design of robust lyophilization
processes.5
An overall understanding of the freeze dryer operation includes
the determination of equipment capability. Changes in freeze dryer

https://doi.org/10.1016/j.xphs.2018.10.061
0022-3549/© 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390
may result in a variation of the design space for a given product. The
equipment capability limit for a freeze dryer is limited by the
choked flow in the connecting duct between the chamber and the
condenser, the refrigeration capacity, condenser surface area, and
the upper temperature limit for the shelves. The limit on the sub-
limation rate due to choked flow in the duct was investigated by
Searles,6 where different experiments run on production and pilot
scale freeze dryers revealed a loss in chamber pressure control. The
loss in chamber pressure control can also be seen in lab scale freeze
dryers as investigated by Patel et al.7,8 In addition, quantifying
equipment capability is important for improvement of freeze-
drying process performance and designing equipment with better
performance, which is one of the current challenges in
lyophilization.9
The experimental setup required for equipment capability
testing in large production-scale freeze dryers is expensive and
time consuming, and the cost of operation also needs to be
considered. Different experimental protocols to obtain the equip-
ment capability can be used. One such known as the minimum
controllable pressure test was discussed by Rambhatla et al.,10
which is the protocol used in the experiments in this article. This
protocol can be used as a tool to characterize freeze dryers and for
scale-up between laboratory, pilot, and production equipment as
previously presented by Tchessalov et al.11 It is also interesting to
observe the nonuniform nature of the heat and mass transfer in the
freeze dryer. The edge vial effect, in which the vials near the edges
of the shelf dry faster than the vials in the center, is discussed by
Pikal et al.12 In this, the problem of scale-up from the perspective of
the edge vial effect is presented. The freeze dryer operation also
depends on the load as observed by Patel et al.,7,8 where product
temperatures and surface area are monitored in lab, pilot, and
production-scale freeze dryers. The differences in freeze dryers can
be observed by looking at the shelf temperature nonuniformity,
refrigeration system, and duct resistance, which was investigated
by Rambhatla et al.13
Computational modeling of the vapor flow in the freeze dryer
can give not only the desired design parameters but also reveal
the vapor flow patterns, the distribution of pressure as well as the
relative concentration of water vapor, and noncondensable gases
in the freeze dryer product chamber. Computational fluid dy-
namics (CFD) computations can explain the pressure variation in
the chamber as investigated by Barresi et al.14 for pilot-scale
freeze dryers and confirmed by comparison of CFD and experi-
mental measurements for laboratory scale by Ganguly et al.15
Input from CFD can be used to design a process as done by
Rasetto et al.16 Ganguly et al.17 investigated the amount of radi-
ation, convection, and conduction for different vial arrangements
and concluded that convection contribution to vial heat transfer
can be significant. CFD can also be coupled with 1-D heat transfer
equations to generated unsteady-state calculators for process
design.18
In some cases, particularly in the condenser, the environment is
too rarefied for continuum Navier-Stokes equations-based CFD.
Thus, a method called the direct simulation Monte Carlo (DSMC)
needs to be used. This method was used by Ganguly et al.18 to
investigate production-scale freeze dryers. CFD also makes it easy
to investigate the effects of changing geometry on the freeze dryer
Table 1
Geometric Design Parameters for the 23 m2 Freeze Dryer
Number of Total Shelf Diameter of Length of
Shelves Area (m2) Duct (m) the Duct (m)
14 23 0.61 4.5
383
operations,19 where comparisons are made for models with and
without clean-in-place/sterilize-in-place systems.
In this article, we present computational modeling to obtain the
equipment capability limit for a production-scale freeze dryer and
verify it by comparison with ice slab sublimation measurements. By
changing different design parameters, trends in performance are
also established with respect to the chamber pressure and onset of
choking.
Experimental Methods
The freeze dryer under consideration is a 23 m2 shelf area
lyophilizer in use at a Pfizer facility. This section presents detailed
information about experimental and computational aspects of
determining freeze dryer performance in terms of vapor flow
capability. We also describe here the information needed about a
freeze dryer for accurate modeling of its performance in terms of
vapor removal capability.
The experimental determination of equipment capability limits
is performed using ice slab placed in trays on the shelves of the
freeze dryer. In this section, we outline the testing protocols,
measurements, and present the data collected. Table 1 outlines the
key design features for the production-scale freeze dryer, which are
critical to this study.
Figure 1 shows the schematic of the freeze dryer and the
computer-aided design model used in computational modeling is
shown in Figure 2.
Testing Methods
Experimental determination of equipment capability limits is
done using a minimum controllable pressure test. The minimum
controllable pressure test adjusts the sublimation rate by changing
the shelf temperature setpoint. The protocol followed for the
minimum controllable pressure test is outlined in the following:
(1) Fourteen metal rings (200  5700  4200 -average tray area 1.545
m2) were used in experiments. Black trash bags were
attached to the rings to form trays with a flexible bottom.
(2) Trays were filled with approximately 65 L of purified water
each (approximately 4 cm of water in tray). The filling was
performed by slow pumping of preweighted amount of wa-
ter into the tray avoiding splashing. If during filling leaks
were identified, water was removed from this particular tray,
new bag was attached to the ring, and filling was repeated.
(3) Ellab temperature sensors (resistance temperature detectors
[RTD], made by ELLAB Inc., Centennial, CO) were used to
measure both ice and shelf surface temperatures.
(4) To measure the ice temperature, Ellab sensors were secured
in heavy rubber stopper at the measured distance from the
bottom of tray (Fig. 3, left)
(5) To measure the shelf surface temperature, Ellab sensor was
inserted in brass disc that was placed on the surface of shelf
(Fig. 3, right). Brass disk was covered with aluminum boat to
separate disk from the tray bottom. Tray with flexible bottom
was placed over the aluminum weigh boat and filled with
water. The area of weigh boat was about 80 cm2, which is less
Mushroom Valve Total Chamber Position of the Duct
Stroke (inches) Volume (m3) With Respect
to Shelves
6 14.711 Center and Perpendicular
384 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390
Figure 1. Schematic of 23 m2 freeze dryer showing different components.
than 1% of tray area and it was considered having negligible
impact on calculation of sublimation surface.
(6) When freeze dryer was fully loaded, shelves were chilled
to 50 C at 1 C/min and held for about 12 h (for scheduling
convenience).
(7) Condenser was chilled below 60 C and vacuum initiated.
(8) When vacuum reached a minimum point (below 30 mT),
shelf temperature was increased to 20 C. After pressure
was equilibrated, shelf temperature was increased to 0 C
monitoring pressure increase and equilibration. The pro-
cedure was repeated at 20 C and 40 C shelf temperature set
points (Fig. 4).
(9) After completion of sublimation test, the chamber was
equilibrated to atmospheric pressure with dry nitrogen. The
mushroom valve between chamber and condenser was
closed. Shelf temperature was increased to 25 C and main-
tained at this temperature until all product temperatures
were within the range of 20 C-21 C. Water was removed
from the trays using a peristaltic pump, weighed and weight
loss was calculated.
Figure 2. Schematic of boundary conditions for the CFD model.
The sublimation rate at each process step was calculated using
the following equation,13

  
dm kg
¼ 53:25K v T shelf_surface  T p (1)
dt h*m2
where 53.25 is the unit conversion coefficient (53.25¼3600*10,000/
676,000), Kv (Cal/s/cm2/K) is the heat transfer coefficient of the
“plastic” bottom of tray (calculated using Eq. 2), TShelf_surface,  C is the
average shelf surface temperature (measured independently on 3
shelves), Tp,  C is calculated (Eq. 3) ice temperature at the bottom of
ice slab
The heat transfer coefficient of black trash bag (Kv) was calcu-
lated using equation modified from the study by Rambhatla et al.13
by adding fudge factor of 1.59,


Cal 0:7 þ 33:2*1:59*Pch ðTorrÞ
Kv *104 ¼ (2)
s*cm2 *K 1 þ 2:88*1:59*Pch ðTorrÞ
where Pch, Torr is the chamber pressure.
To estimate the temperature of ice at the bottom of slab, Tp, Ellab
sensor was firmly positioned at the distance a (cm) (Fig. 3) from the
bottom of tray. Equation 3, derived from the principle of heat flux
continuity, was used to calculate Tp.
Kbag Tshelf_surface þ Kaice Tice ðaÞ
Tice_bottom ¼ (3)
Kbag þ Kaice
where
Kice ðCal=s=cm=KÞ ¼ 0:00511  0:0000316*Tice ðaÞ (4)
Equation 4 that describes the ice conductivity as a function of ice
temperature Tice(a), measured by Ellab sensor at the distance a, was
derived from the ice thermal conductivity data from Haynes.20 The
total amount of water Dm (kg), sublimed during test, was calculated
as:
Zt
dm
DmðtÞ ¼ N*Atray dt (5)
dt
o
where N is the number of trays, Atray (m2) is tray area.
When original equation from the study by Rambhatla et al.13
was used, calculated value of removed by sublimation water was
23% lower than actual weigh loss measured gravimetrically. The
tray size was large (fitting almost all surface of the shelf); it was
hard to establish very good contact between plastic and shelf sur-
face. Few wrinkles were seen before filling water into the tray. Loss
in area of contact between plastic and shelf believed to be the major
factor for error in calculations. Because wrinkles produce some
gaps between plastic and shelf, the heat conduction through this
gap could be pressure dependent. Therefore, fudge factor in
Equation 2 was used to compensate for the error in calculations.
The fudge factor of 1.59 resulted in less than 1.5% difference be-
tween actual (155.8 kg) and calculated weigh loss (153.6 kg).
Additional experiments at laboratory scale utilizing TDLAS (data
not shown) confirmed accuracy of original equation.13 The use of
fudge factor in calculations may be necessary when heat transfer
between bags and shelf is somewhat restricted.
The data collected from the minimum controllable pressure test
is given in Figure 4. The regions of stable pressure clearly show that
the pressure in the chamber has equilibrated. The solid circles show
the data points used in the computational calculations. The water
used in this experiment had some dissolved salts (detected by
 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390 385

Figure 3. Measurement of ice temperature (left) and shelf surface temperature (right) with Ellab temperature sensor. The distance between temperature sensor and bottom of tray
(ice slab) “a” was about 4 mm. The second sensor (distance “b” ¼ 14 mm) was used to estimate the pressure over sublimation surface and assess the beginning of sublimation phase.

conductivity measurementsddata not shown), which is evident in Knudsen number is 0.0013 for a characteristic length of 0.61 m
the fluctuating pressure data points collected between hours 9 and equal to the diameter of the duct. The governing equation for mass,
10 while performing the experiment. Because of the mixture momentum, and energy for a laminar, compressible single species
reaching the eutectic melt temperature (with onset of 27.8 C, fluid are given by
measured by DSC), there were sudden spikes in the chamber
 !
pressure because of, likely, bursts of ice slabs. This is a source of V rV ¼ 0 (6)
error in the experiments and should be taken into consideration
while evaluating the data for the sublimation rate of 38.7 kg/h.  !!
V r V V ¼ Vp þ V,ðtÞ (7)
Numerical Methods



 
! 1! ! !  !
In addition to the experiments to determine the minimum V V r e þ V ,V þ p ¼ V, q þ t: V (8)
2
controllable pressure, a computational approach can also be taken.
This section describes the equations involved in solving the CFD
! !
problem of ice slab sublimation tests in freeze-drying. The CFD p V ,V
solver takes many inputs such as the sublimation rate, condenser e¼h þ (9)
r 2
pressure, material properties, and the computer-aided design
!
(CAD) model of the freeze dryer. where r is the density in kg/m3, P is the pressure in Pa, V is the
The flow in this 23 m2 freeze dryer is governed by Navier-Stokes ! 2
velocity in m/s, q is the heat flux in W/m , e is the internal energy
continuum equations. The extent of noncontinuum effects can be in J/kg, and t is the viscous stress tensor.


estimated based on a nondimensional number known as Knudsen ! ! !
Using constitutive relations, t ¼ m ðV V þ V V T Þ  23V, V I and
number, Kn ¼ lL, where L is the characteristic length scale (such as !
q ¼ kVT; the Equations 6-9 are numerically solved in the compu-
the shelf separation or the diameter of the connecting duct in this
tational solver with the appropriate boundary conditions.
case) and l is the mean free path. The continuum hypothesis holds
A variable viscosity model is used where the viscosity (m) is
for Kn < 0.01. The mean free path for water vapor at a pressure of
given by,
100 mTorr and 250 K temperature is 0.77 mm. The corresponding
T
m ¼ mref (10)
Tref

where mref ¼ 8.9007*1016 kg/m-s and Tref ¼ 273.15 K.1

Figure 4. Process data for the minimum controllable pressure test.
In a production-scale freeze dryer, turbulent effects can be seen
for higher sublimation rates. A k-u turbulence model is used with a
turbulent intensity of 10% and a length scale of 1 m. The usual
length scale for simulations is l ¼ 0.07 L, where L is the significant
dimension in the flow. Because the direction of the flow in the
freeze dryer is axial, L~10 m, hence an approximation of 1 m for
turbulent length scale is used.
The mesh was generated in ANSYS and the solver FLUENT was
used. The number of cells is 470,000 with a maximum aspect ratio
of 8 and an average cell size of 0.35 mm. A semi-implicit methods
for pressure-linked equations (SIMPLE) scheme21 is used, and the
simulations are performed until the residuals for continuity are less
than 103 and for energy are less than 106. The density of water
vapor is obtained using the ideal gas law. Because the temperature
of the water vapor subliming is different for each sublimation rate
and it varies throughout the freeze dryer geometry, the density will
also vary accordingly. A grid convergence study indicated that the
386 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390

pressure variation when the number of cells was increased from
470,000 to 1,500,000 was 1.5%. Thus, the base case of 470,000 cells
was used in all the calculations.
The boundary conditions are shown in Figure 2. The chamber
walls are adiabatic no-slip walls. The shelves are modeled as a va-
por flow inlet and the condenser is modeled as a pressure outlet.
The outlet condenser pressure is calculated from the condenser coil
temperature. The mushroom valve stroke is 6 inches.
The minimum controllable pressure in the chamber is calculated
as follows:
 Input conditions of the CFD model are specified in terms of the
sublimation rate specified as an inlet from the shelves in the
product chamber and the condenser pressure specified as the
outlet in the condenser.
 The CFD solver obtains the pressure, velocity, and temperature
of the fluid throughout the domain.
 The highest value of pressure in the product chamber zone is
determined as the minimum controllable chamber pressure.
Experimental Determination of Minimum Controllable Pressure
The loading and unloading of water into trays for a production-
scale freeze dryer is a tedious task. Following the protocol out-
lined, 4 data points for the minimum controllable pressure were
obtained. A second order polynomial was fit to 3 of the data points,
and 3 coefficients A, B, and C of the polynomial were determined.
Thus, a polynomial for minimum controllable pressure, which is a
function of the sublimation rate, was used to empirically calculate
the pressure for any given mass flow rate. For the experiment per-
formed on the production-scale freeze dryer, the polynomial curve
was fit to Pchamber ¼ Cm _ 2 þ Bm
_ þ A. For this 23 m2 freeze dryer, the
equation for minimum controllable pressure obtained experimen-
tally is Pmin ¼ 0.0859x2 þ 3.4354x þ 14.401 with an R2 value of 0.99.
Condenser Pressure Determination
The 2 inputs to the computational model are the sublimation
rate and the condenser pressure. The condenser pressure in-
fluences the chamber pressure significantly. The flow chocking is
characterized by a critical pressure ratio and the ratio between
chamber and condenser pressures. When the condenser pressure
increases, the minimum controllable pressure also increases. As ice
accumulates on the condenser coils, the pressure in the condenser
may rise. Temperature sensors measure the condenser coil tem-
perature and the temperature of the refrigeration fluid. The outlet
condenser pressure in the CFD simulations is based on the vapor
pressure of ice at the condenser temperature,
! ( ) discharge coefficients is also compared with theoretical calculations.
Pcd DH  1 1
ln ¼ 
Pref R Tref Tcd
mTorr, DH is the enthalpy of sublimation of water in kJ/kg, and R is
the gas constant for water vapor in kJ/kg-K.20 The condenser
temperature varies from 62 C to 38 C in this experiment and
the corresponding estimated condenser pressure ranges from 8 to
120 mTorr. These estimates of condenser pressure neglect any re-
sidual noncondensable gas such as nitrogen, which is removed by
the vacuum pump.
A significant source of error in the CFD simulations is the
condenser pressure. As there is no capacitance manometer in the
condenser in the considered production-scale freeze dryer, the only
option to estimate condenser pressure is from the condenser
temperature. However, the thickness of ice on the coils of the
condenser will change the temperature on the surface of the
formed ice, thus changing the condenser pressure. In the following
calculations, 3 different ice thicknesses are assumed and the cor-
responding condenser pressure is estimated. It can be assumed that
all the heat from the sublimating water is taken away by the
refrigeration system. Therefore,
_
mDH s dT xice
¼k and Tice ¼ _
mDH s þ Tcoil (12)
Acond dx Acond kice
where xice is the thickness of ice in cm, Tcoil is the temperature of the
ice condenser coil, Tice is the temperature at the surface of the ice,
and Acond is the total condenser coil surface area. Note that as a rule,
condenser surface area in production-scale freeze dryer is larger or
equal to the shelf surface area.
From the calculated surface ice temperature, the condenser
pressure is calculated from the Clausius-Clapeyron equation.
Table 2 shows the estimated condenser pressure values for ice
thickness varying from 0.5, 1, and 1.5 cm.
As the sublimation rate increases, the dependence of the
condenser pressure on the ice thickness increases. This calculation
assumes a uniform buildup of ice on the condenser coils, which is
not the case for higher sublimation rates where the coils near the
duct exit have the highest buildup of ice.22 This is only to illustrate
the impact of condenser parameters on the minimum controllable
chamber pressure.
Results and Discussion
In this section, we present results of the computational fluid
dynamics simulations for the 23 m2 surface area lyophilizer. The
computational results are compared with the experimental data.
Different CFD models were generated that explore the effect of
mushroom valve stroke, turbulence, shelf configuration, and duct
orientation on the chamber pressure. A study of discharge co-
efficients, which is the ratio of the experimental to the ideal mass
flow rate, is included. A comparison of different freeze dryer
(11)
Comparison of CFD With Experimental Data

where Pref is a reference pressure for water of 611.15 Pa at a refer- The mushroom valve stroke (maximum opening) was 6 inches
ence temperature Tref of 273.15 K, Pcd is the condenser pressure in during the experiment. The results presented here show a

Table 2
Condenser Pressures for Varying Ice Thickness

_ (kg/h)
m Coil Temp ( C) kice (W/m-K) Pressure at Tcoil (mTorr) Ice Temperature ( C) Pressure (mTorr)

5 mm 10 mm 15 mm 5 mm 10 mm 15 mm

5.8 62 2.90 6.2 61.7 61.3 61.0 6.5 6.8 7.1
13.7 57 2.90 12.2 56.2 55.4 54.6 13.4 14.9 16.6
24.7 47 2.76 42.8 45.5 44 42.5 51.0 61.0 72.4
38.7 38 2.63 120.6 35.5 33.0 30.5 158.5 207.4 270.5
 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390
Figure 5. Comparison of Mach number and pressure contours for a sublimation rate of 5.8 kg/h (left) and 24.7 kg/h (right).
comparison between the experimental and computational results
obtained. Figure 5 shows a schematic of the setup with the
boundary conditions for CFD and the Mach number and pressure
contours for the sublimation rate of 24.7 kg/h Table 3 shows the
minimum controllable pressure as a function of the sublimation
rate.
Choked flow limits the maximum sublimation rate through the
duct for a given chamber pressure. The flow for the sublimation rate
5.8 kg/h is choked. However, on further reducing the condenser
pressure from 42 mTorr to 30 mTorr for the sublimation rate of 24.7
kg/h, the chamber pressure reduces from 147 mTorr to 141 mTorr.
This flow rate of 24.7 kg/h is not choked. The minimum controllable
pressure in this case is thus limited by the condenser pressure,
which cannot be reduced further because of the already accumu-
lated ice on the coils.
The CFD results establish a good comparison with the experi-
ments with a difference of 4.15% between experiments and CFD at a
mass flow rate of 24.7 kg/h. The minimum controllable pressures in
the chamber are 79 and 147 mTorr, which agree with the experi-
ments for the mass flow rates of 5.8 and 13.7 kg/h, respectively. The
minimum controllable pressure computed using CFD for a subli-
mation rate of 38.7 kg/h falls within the experimental error range.
The flow does not enter the duct axially and has a swirl component,
which can be seen from the streamlines in Figure 6. Note that a
shelf fluid inlet temperature of > þ40 C resulted in the condenser
temperature increasing above 40 C, which may potentially
impact the ability of condenser in capturing water. Therefore,
sublimation rate of 38.7 kg/h may be considered as a maximum
sublimation rate for this dryer based on condenser limitations. As
an additional comment, we believe it would be beneficial to have
pressure measurements (with capacitance manometers) in both
Table 3
Comparison of Minimum Controllable Pressure Between Experiments and CFD
Shelf Temperature ( C) Sublimation Rate (kg/h)
20 5.8
0 13.7
20 24.7
40 38.7
387
chamber and condenser as a tool for estimation of sublimation rates
when advanced PAT tools such as TDLAS are not available.
Turbulent Flow in Production Freeze Dryers
The water vapor accelerates in the duct connecting the chamber
and condenser. Because of the high mass flow rates involved in
production-scale freeze-drying, the flow tends to be turbulent. The
internal flow of water vapor is said to be turbulent for Reynolds
number higher than 2300. A check on the variation of Reynolds
number for the sublimation rate data collected in the experiments
for this production-scale freeze dryer reveals that the nature of the
flow is turbulent. This establishes a limit on the sublimation rate
equal to 17 kg/h and above which the flow would likely be
turbulent.
The flow turbulence is modeled using the turbulent length scale
and the turbulent intensity at the inlet, which is assumed to be 10%.
The comparison of CFD calculations with turbulence to the exper-
imental data and laminar calculations is shown in Figure 7. Because
turbulence causes a higher pressure drop in the connecting duct,
the minimum controllable pressure rises in the chamber. This rise
in pressure is found to be about 4 mTorr for a sublimation rate of
24.7 kg/h. In all the simulations presented below, turbulence effects
are included unless explicitly stated otherwise.
Effect of Mushroom Valve Separation
The mushroom valve separates the chamber from the
condenser. The presence of the mushroom valve during primary
drying has an important effect on the minimum controllable
pressure. For the range of sublimation rates, 3 different mushroom
Minimum Controllable Pressure Condenser Temperature ( C)
(mTorr)
Experiments CFD
38 36.8 62
76 78.7 57
153 146.6 47
276 247.2 38
388 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390
Figure 6. Flow streamlines in the chamber for a sublimation rate of 38.7 kg/h.
valve strokes were considered e 4, 6, and 8 inches. These represent
practical ranges of operation of the mushroom valve. Keeping the
duct length constant, the geometry was modified to include the
variations of the mushroom valve geometry. In these cases, instead
of the duct exit being modeled as an inlet to the condenser, the
outlet of the mushroom valve was given as pressure outlet
boundary conditions. The mesh near the duct exit and the mush-
room valve was refined to improve the quality of the solution.
A comparison of the CFD results with the experimental data is
shown in Figure 8. The pressure in the chamber increases with a
decreasing valve separation, because of a lesser area available for
the exiting water vapor. For a valve separation of 6 and 8 inches, the
results show little difference for sublimation rates of 5.8 kg/h and
13.7 kg/h, because the flow is already choked, and a further
reduction in the valve stroke does not increase the flow velocity.
However, the influence of the mushroom valve stroke becomes
apparent as the sublimation rate increases to 24.7 kg/h and
Figure 7. Comparison of CFD simulations with experimental measurements for min-
imum controllable pressure in a production-scale lyophilizer.
Figure 8. Comparison of minimum controllable chamber pressures for different valve
strokes.
38.7 kg/h. Although there is almost no difference between chamber
pressure at a valve stroke of 8 inches, the chamber pressure in-
creases by 18.5% for a sublimation rate of 38.7 kg/h when the valve
stroke is changed from 6 to 4 inches. The difference between
minimum controllable pressure measured experimentally and
from CFD is 4.15% at a separation of 6 inches. The error bar for the
point with sublimation rate of 38.7 kg/h represents the uncertainty
in the experimental data. Figure 9 shows the contours for pressure
comparing each of the 4 cases.
Effect of Freeze Dryer Configuration
This production freeze dryer is a vertical configuration dryer
with the chamber, duct, and condenser stacked on different floors.
The shelves are thus perpendicular to the duct with the bottom-
most shelf closest to the duct. Another configuration of the freeze
dryer is possible where the chamber, duct, and condenser are
parallel to each other and located on the same level. In this case, the
duct is parallel to the direction of the shelves. This orientation will
be referred to as the horizontal duct configuration.
Using the same experimental data collected for the minimum
controllable pressure test, the 2 configurations were simulated. In
addition to comparing the chamber pressure, another important
feature to consider is the pressure variation in the chamber along
the shelves and from one shelf to another. Because batch uniformity
is an important aspect of pharmaceutical lyophilization, the spatial
variation of pressure in the chamber is important. In these simu-
lations, the pressure variation is reported as follows:
Phighest  Plowest
Pvar ¼  100 (13)
PEXP
It is also possible to get an estimate of the chamber pressure by
performing 2 days axisymmetric CFD simulations. However, after
carefully examining these simulations it becomes clear that they do
not accurately represent the minimum controllable chamber
pressure for a given sublimation rate. The difference between 2
days and experiments is about 18.8% on average.
Figure 10 shows the contours for pressure in the chamber, which
highlights the pressure variation for 5.8 kg/h sublimation rate. The
horizontal duct configuration gives the lowest minimum control-
lable pressure as well as the lowest chamber pressure variation of
 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390 389

Figure 9. Minimum controllable pressures (from left to right) No valved220 mTorr, 800 gapd220 mTorr, 600 gapd247 mTorr, 400 gapd293 mTorr for a sublimation rate of 38.7 kg/h.

less than 0.1%. The pressure variation for the 2D vertical duct case is
2.2%. The vertical duct configuration, which is how the current
production-scale freeze dryer under study is designed, shows a
pressure variation of 5.4%. To maintain uniformity in the simula-
tions, the mushroom valve is not included in any of these config-
urations, which is the reason behind the difference between
experimental and CFD results.
Effect of Shelf Orientation
As previously discussed, the spatial variation of pressure in the
lyophilization product chamber is important. The variation of
pressure in the chamber is also a result of the walls on the side of
the shelves and the slots for shelf movement. The shelf support
walls might be available in some production- or lab-scale freeze
dryers. For illustrating the effect of these walls on the flow fields
and chamber pressures, they have been added for this part of the
CFD calculations. These walls change the nature of the flow around
the edges and add a swirl component to the velocity. The flow
curves around the edges as it accelerates and does not enter the
duct axially. For any freeze dryer configuration, there are 2 possible
ways to orient the shelves and thus align the shelf walls in 2
different directions. Here, we present an analysis on the horizontal
duct configuration freeze dryer with the shelves oriented in 2
different directions and analyze the impact on pressure variation in
the chamber.
In case A, the shelf walls are perpendicular to the duct and in
case B; the shelf walls are parallel to the duct. Figure 11 shows a
schematic of the different shelf orientations considered in this
study. Using the same sublimation rates as obtained in the exper-
iments, CFD simulations are conducted on each configuration. It is
found that case A (which has shelf walls perpendicular to the duct)
exhibits much less pressure variation along the shelves as
compared to case B. The pressure variation for a sublimation rate of
5.8 kg/h is 0.1% for case A, whereas it is 3.21% for case B. In case B,
the pressure varies along the shelves as well from 30 to 32 mTorr
instead of just between different shelves. For a sublimation rate of
24.7 kg/h, the minimum controllable pressure in case A is 119 mTorr
and that in case B is 117 mTorr. Thus, configuration A is preferable
for decreasing inhomogeneity of local pressure, whereas configu-
ration B has a better equipment capability in terms of minimum
controllable pressure.

Figure 10. Pressure variations in different production-scale freeze dryer configurations at a sublimation rate of 5.8 kg/h.
390 V. Kshirsagar et al. / Journal of Pharmaceutical Sciences 108 (2019) 382-390
Figure 11. Pressure variation illustrated for case A (top) and case B (bottom) for a sublimation rate of 5.8 kg/h.
Conclusions
In this article, we present results of computational modeling to
determine the sublimation rate capability limits of a production-
scale lyophilizer. The computational fluid dynamics results are
compared with ice slab sublimation tests. The critical parameters
such as duct and valve geometry important for a production-scale
freeze dryer design and the equipment capability limits are dis-
cussed. The results obtained show that the valve stroke is impor-
tant in determining the minimum controllable pressure and in turn
the maximum allowable sublimation rate. In a production-scale
freeze dryer, the equipment capability limit is dependent on the
phenomenon of choked flow and the refrigeration capacity of the
condenser. The onset of choked flow is dependent on the design
parameters such as the valve stroke.
The dynamics of fluid flow in a production-scale freeze dryer
are different from that in a lab-scale freeze dryer. This can be
seen from the Reynolds number in the turbulent regime while in
most lab-scale freeze dryers, the flow is primarily laminar. This
affects the equipment capability of the freeze dryer. Computa-
tional simulations also give information about the product
chamber. Variability in the product chamber pressures will lead
to a variability in drying times of the product. The different
studies presented in this article show that a freeze dryer with
shelf support walls perpendicular to the duct ensure minimum
variation of pressure along and between the shelves. Further
studies are needed to understand the dynamics of the condenser
and the impact of ice growth on the refrigeration capacity and
the performance of the overall freeze-drying system.
Acknowledgments
The work has been funded by Pfizer. The authors thank IMA Life
North America for providing the geometrical information of the
production-scale freeze dryer.
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