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P.Sharma1, L. Amico2, T. Zwack2, F. DeMarco2, W. Kessler3, M. J. Pikal1

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, 06269, USA,

IMA Life North America Inc., Tonawanda, New York, 14150, USA
Physical Sciences Inc., Andover, Massachusetts, 01810, USA

A Tunable diode laser absorption spectroscopy
(TDLAS) sensor is used to measure instantaneous
water vapor mass flow rate (dm/dt) during
lyophilization, which can be used in conjunction with
steady state heat and mass transfer model equations to
calculate lyophilization cycle parameters such as
product temperature and product resistance. The utility
of single line-of-sight TDLAS sensor as a non invasive
technique for measuring the product temperature on a
lab scale dryer has been previously demonstrated1. The
aim of this study was to demonstrate the applicability
of a more sensitive dual line-of-sight TDLAS sensor to
monitor product temperature (bottom, T b) and
resistance (Rp) during lyophilization in a lab and a pilot
scale dryer.
Bovine serum albumin (BSA) was used as a model
protein. For calculation of Tb in both the lab scale
(Lyostar II, FTS systems) and pilot scale dryer (IMA
Life North America Inc.), the position dependent batch
average vial heat transfer coefficient (Kv) was
determined gravimetrically on the same vials as used
for the product run (2% BSA/5% sucrose). The K v
value used in the calculation of T b in pilot scale dryer
was corrected for the dryer load and emissivity.
TDLAS sensor was installed in the duct
connecting the chamber and condenser. The dm/dt
(g/sec) was provided by the Lyoflux 200 software
(Physical Sciences, Inc.). The Tb and Rp were
calculated throughout the pilot scale experiment using
steady state heat and mass transfer equations. All the
experiments were performed in 20cc tubing vials with
5 ml fill volume.
Kv determination: Accurate determinations of Kv
are required to for the determination of batch average
product temperature, Tb. Using the relation, Tb = Ts((660* dm/dt)/(Kv*Av)), for the same dm/dt, vial outer
cross sectional surface area (Av), shelf temperature (T s)
and dryer load, a change in Kv from 3.0 to 4.0 x 10-4
cal/sec.cm2.K leads to ~ 3C error in Tb at high dm/dt
typical of that observed during early primary drying.
At the same pressure (65 mT), the batch average
Kv were different for different suppliers. Vials
manufactured from Schott showed batch average K v of
3.0 x 10-4 cal/sec.cm2.K and those from Wheaton 3.3 x
10-4 cal/sec.cm2.K. This 0.3 unit shift in Kv would
cause a temperature difference of 1.5C between the
two vial types. Vials manufactured by the same

supplier (Schott) but different lot numbers did not

show any significant difference in the batch average
Kv. Consequently, the error in T b measurement is small
TDLAS performance: During the pilot scale
drying experiment the gas flow velocity varied from
~17 m/s to ~2 m/s during primary drying and from 1
m/s to ~0.65 m/s during secondary drying. The 3sigma velocity measurement precision was 0.27 m/s
during a 1-hour measurement window during primary
drying. The 3-sigma velocity measurement precision
was 0.05 m/s during a 30-minute measurement window
at the end of secondary drying. These precision values
include the variation in the velocity due to the freeze
dryer operation.
Tb measurement: For both the lab and the pilot
scale freeze dryer, TDLAS product temperature was
within 1-2C of the weighted average thermocouple
temperature during steady state (Fig 1).

Figure 1. Temporal profile of temperature as determined from

TDLAS and thermocouple sensors in Pilot scale dryer (EV: Edge
Vial; CV: Centre vial)

Rp measurement: TDLAS calculated dm/dt and

Tb were used to measure the ice thickness (Lice) as a
function of time, product temperature at the
sublimation interface (Tp) and finally, Rp. The Rp was
also calculated from the thermocouple data and the
average dm/dt. Compared with the Rp determined using
thermocouple data, Rp determined using TDLAS
increases sharply towards the last 20-30% of primary
drying due to the heterogeneity in the product drying
behavior in different vials. This heterogeneity leads to
i) different mass flow rate per vial and ii) different P ice
(vapor pressure of ice) in different vials, both of which
are used in the calculation of Rp using TDLAS.

These results establish the utility of TDLAS sensor
as an effective lyophilization process monitor.
Determination of vial heat transfer coefficient is
critical for accurate determination of product
temperature. Using accurate Kv from gravimetric
experiments and instantaneous mass flow rate
measurement using TDLAS, product temperature and
resistance can be measured online.
1. Schneid et al. J Pharm Sci. 2009. 98, 3406-3418