Using surface heat flux measurement to monitor and control a freeze drying process
A method of monitoring and controlling a freeze drying process in a freeze drying apparatus having walls, shelves and a number of vials or trays positioned on different areas of the shelves and containing product to be freeze dried. One or more vials or trays are selected that are representative of the positions of all of the vials or trays in different areas of the shelves. One or more heat flux sensors are positioned between the selected vials or trays and adjacent portions of the walls and/or shelves. The heat transfer between the selected vials or trays and the adjacent wall or shelf portions is measured during the freezing and drying stages of the freeze drying process.
1. A method of monitoring and controlling a freeze drying process in a freeze drying apparatus having walls, one or more shelves and one or more vials or trays positioned on different areas of the shelves and containing product to be freeze dried, comprising:
selecting one or more vials or trays that are representative of the positions of all of the vials or trays in different areas of the shelves,
positioning one or more heat flux sensors between the selected vials or trays and adjacent portions of the walls and/or shelves,
measuring the heat flow between the selected vials or trays and adjacent wall or shelf portions during a freezing stage of the freeze drying process, and
controlling the shelf temperature to keep the heat flow at a predetermined level throughout a crystal growth phase of freezing to produce a homogeneous ice crystal structure in the product during the freezing stage.
2. The method of claim 1 wherein one or more heat flux sensors are mounted on a top or bottom surface of adjacent shelf portions.
3. The method of claim 1 wherein one or more heat flux sensors are embedded inside shelf portions adjacent to the selected vial or trays.
4. The method of claim 1 wherein one or more heat flux sensors are mounted on or embedded inside the wall portions adjacent to the selected vials or trays.
5. The method of claim 1 further comprising using the heat flow measurement information to define and plot a cycle optimization design space and an optimum shelf temperature and chamber pressure for use in a laboratory or production freeze drying apparatus.
6. The method of claim 1 further comprising using heat flow measurement information to determine the end of the freezing stage when the heat flow has reduced to a steady state condition near zero.
7. The method of claim 1 further comprising using heat flow measurement information to shorten a primary drying time and to determine that the product has been properly sublimated during a primary drying stage by controlling the shelf temperature to maintain the product below a critical temperature above which it melts and to maximize the shelf temperature during the entire primary drying stage.
8. The method of claim 7 further comprising using heat flow measurement information to determine the end of the primary drying stage when the heat flow has reduced to a steady state condition near zero.
9. The method of claim 1 wherein the temperature is controlled to produce ice crystals of a size and uniformity that will shorten drying time during a primary drying stage.
10. The method of claim 1 wherein the product is nucleated at a predetermined and controlled temperature, time and rate to produce a uniform initial ice crystal structure prior to the crystal growth phase of the freezing stage.
11. The method of claim 10 wherein heat transfer information is used to determine that the product has reached the predetermined temperature so that there is no more temperature change taking place.
12. The method of claim 1 wherein the heat flux sensor is a low thermal capacitance and low thermal impedance sensor.
13. The method of claim 7 further comprising using heat transfer measurement information to determine the critical parameters of Vial Heat Transfer Coefficient (K v ), Mass Flow (dm/dt) and Product Resistance (R p ) for control for the freeze drying process.
14. The method of claim 13 wherein once the Vial Heat Transfer Coefficient (K v ) is calculated it is used to calculate the product temperature (T b ) at the bottom of the vial.
15. The method of claim 13 wherein the Vial Heat Transfer Coefficient (Kv) is determined by the following formula:
ⅆ
q
ⅆ
t
=
K
v
A
v
(
T
s
-
T
b
)
=
>
K
v
=
ⅆ
q
ⅆ
t
A
v
(
T
s
-
T
b
)
Where
:
ⅆ
q
ⅆ
t
=
Heat
transfer
measured
from
heat
flux
sensor
K
v
=
Vial
heat
transfer
coefficient
to
be
calculated
A
v
=
Outer
cross
section
area
of
vial
T
s
=
Shelf
surface
temperature
from
measurement
T
b
=
Product
temperature
at
the
bottom
center
of
a
vial
16. The method of claim 13 wherein the Mass Flow (dm/dt) is determined by the following formula:
ⅆ
q
ⅆ
t
=
Δ
H
s
ⅆ
m
ⅆ
t
=
>
ⅆ
m
ⅆ
t
=
ⅆ
q
ⅆ
t
Δ
H
s
Where
:
ⅆ
q
ⅆ
t
=
Heat
transfer
measured
from
heat
flux
sensor
Δ
H
s
=
Heat
of
sublimation
of
ice
ⅆ
m
ⅆ
t
=
Mass
transfer
rate
to
be
calculated
17. The method of claim 13 wherein the Product Resistance (R p ) is determined by the following formula:
ⅆ
m
ⅆ
t
=
A
p
(
P
i
-
P
c
)
R
p
=
>
R
p
=
A
p
(
P
i
-
P
c
)
ⅆ
m
ⅆ
t
Vapor
Pressure
over
ice
equation
:
P
i
=
6.112
ⅇ
(
22.46
T
b
272.62
+
T
b
)
(
Guide
to
Meteorological
Instruments
and
Methods
of
Observation
2008
)
Where
:
ⅆ
m
ⅆ
t
=
Mass
transfer
rate
to
be
calculated
A
p
=
Inner
cross
section
area
of
vial
P
i
=
Vapor
pressure
of
ice
calculated
from
ice
temperature
T
b
P
c
=
Chamber
pressure
R
p
=
Resistance
of
the
dried
product
layer
to
be
calculated
T
b
=
Product
temperature
at
the
bottom
center
of
a
vial
.
18. The method of claim 7 wherein the heat flow information is used to define freeze drying protocols that can be used in different types of laboratory or production freeze drying apparatus.
19. A method of monitoring and controlling a freeze drying process in a freeze drying apparatus having walls, one or more shelves and one or more vials or trays positioned on different areas of the shelves and containing product to be freeze dried, comprising:
selecting one or more vials or trays that are representative of the positions of all of the vials or trays in different areas of the shelves,
measuring heat flow between the selected vials or trays and adjacent wall or shelf portions during a freezing stage of the freeze drying process; and
controlling the shelf temperature to keep the heat flow at a predetermined level throughout a crystal growth phase of freezing to produce a homogenous ice crystal structure in the product during the freezing stage.
20. The method of claim 19 further comprising using heat flow measurement information to determine the end of the freezing stage when the heat flow has reduced to a steady state condition near zero.