US 12,209,257 B2Granted

System and method to determine critical process parameters for a continuous viral inactivation reactor to design and manufacture same

AssigneeBoehringer Ingelheim International GmbH

InventorsMatthew R. Brown, Jonathan Coffman, Raquel Orozco

Life of this patent

Estimating the term…

Abstract

A viral inactivation device including at least one experimental continuous viral inactivation reactor having at least an inlet, an outlet, and a tubular flow path and a computer system that, based on the experimental continuous viral inactivation reactor can design, select, make, and/or manufacture a scaled actual reactor. The tubular flow path includes a set of alternating turns that form a serpentine or an interwoven pattern between the inlet and the outlet.

Claims12

Dependent claims

A method for designing an actual reactor for viral inactivation comprising:

introducing a process stream, including detectable particles/tracer, into an experimental reactor having a known radius of curvature and a known internal diameter, wherein the experimental reactor is in communication with at least one of a first detector and a second detector;
detecting a flow rate of the process stream in the experimental reactor by at least one of the first detector and the second detector;
detecting fluid-phase parameters of the process stream by at least one of the first detector and the second detector;
detecting the detectable particles exiting the experimental reactor by the second detector;
determining, based on the introduced process stream including the detectable particles, empirical values relating to at least one of experimental reactor parameters and fluid-phase parameters;
determining non-empirical values relating to at least one of the experimental reactor parameters and the fluid-phase parameters;
and
designing the actual reactor based on the determined empirical values and the determined non-empirical value;
wherein:
designing the actual reactor comprises at least one of (i)-(v):
(i) scaling dimensions of the experimental reactor to the actual reactor having a same aspect ratio as the experimental reactor, but a different internal diameter;
(ii) scaling the dimensions of the experimental reactor to the actual reactor having a same aspect ratio and a same internal diameter as the experimental reactor;
(iii) scaling the dimensions of the experimental reactor to the actual reactor having a different aspect ratio than the experimental reactor and a different diameter than the experimental reactor;
(iv) scaling the dimensions of the experimental reactor to the actual reactor having a different aspect ratio as the experimental reactor, but a same diameter as the experimental reactor;
wherein when designing the actual reactor comprises scaling the dimensions of the experimental reactor to the actual reactor having the same aspect ratio as the experimental reactor, the method:
(i) requires derivation of height equivalent of a theoretical plate (“HETP”), reactor volume, and internal diameter based on average flow velocity, utilizing equations (1a)-(1g) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
Ave
2
(
1
⁢
a
)
(1b) HETP=f(v)=(av3+bv2+cv+d), wherein a, b, c, and d are based on empirical data fits for all Dean numbers
L
=
1
2
*
(
2
⁢
5
⁢
f
⁡
(
v
)
2
±
5
*
2
⁢
5
⁢
f
⁡
(
v
)
4
+
4
⁢
f
⁡
(
v
)
2
⁢
T
⁢
min
*
v
+
2
*
T
⁢
min
*
v
)
(
1
⁢
c
)
A
=
∏
r
2
=
∏
(
i
.
d
.
2
)
2
⁢
T
Ave
Defined
=
L
v
=
CA
*
L
Q
(
1
⁢
d
)
T
Ave
Defined
=
C
⁢
A
*
L
Q
(
1
⁢
e
)
Q
*
T
A
⁢
v
⁢
e
Defined
L
*
∏
=
r
2
(
1
⁢
f
)
i
.
d
.
=
2
⁢
Q
*
T
A
⁢
v
⁢
e
Defined
L
*
∏
.
(
1
⁢
g
)
or (ii) requires derivation of HETP, reactor volume, and internal diameter based on reduced HETP and Dean Number, utilizing equations (2a)-(2e) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
Ave
2
(
2
⁢
a
)
HETP
i
.
d
.
=
h
=
(
a
⁢
D
⁢
e
3
+
b
⁢
D
⁢
e
2
+
c
⁢
D
⁢
e
+
d
)
=
f
⁡
(
De
)
(
2
⁢
b
)
T
A
⁢
v
⁢
e
=
T
min
+
(
n
*
σ
max
)
(
2
⁢
c
)
T
A
⁢
v
⁢
e
=
T
max
-
(
m
*
(
σ
max
)
)
(
2
⁢
d
)
T
A
⁢
v
⁢
e
=
R
⁢
V
Q
=
C
⁢
A
*
L
T
A
⁢
v
⁢
e
Q
(
2
⁢
e
)
and wherein when designing the actual reactor comprises scaling the dimensions of the experimental reactor to the actual reactor having a same aspect ratio and a same internal diameter as the experimental reactor, the method requires derivation of at least HETP and path length, utilizing equations (3a)-(3f) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
A
⁢
v
⁢
e
T
Ave
2
;
(
3
⁢
a
)
HETP
=
f
⁡
(
D
⁢
e
)
=
σ
t
⁢
i
⁢
m
⁢
e
*
L
T
A
⁢
v
⁢
e
T
A
⁢
v
⁢
e
=
(
a
⁢
D
⁢
e
3
+
b
⁢
D
⁢
e
2
+
c
⁢
D
⁢
e
+
d
)
;
(
3
⁢
b
)
wherein a, b, c, and d are based on empirical data fits only valid for Dean numbers ≥100
(3c) TAve=Tmin+(n*σtime);
(3d) TAve=Tmax−(m*σtime);
T
A
⁢
v
⁢
e
=
R
⁢
V
Q
=
C
⁢
A
*
L
T
A
⁢
v
⁢
e
Q
;
and
(
3
⁢
e
)
L
T
A
⁢
v
⁢
e
=
25
*
C
⁢
A
2
*
f
⁡
(
D
⁢
e
)
2
±
5
*
2
⁢
5
*
C
⁢
A
4
*
f
⁡
(
D
⁢
e
)
4
+
4
*
C
⁢
A
3
*
f
⁡
(
D
⁢
e
)
2
*
Q
*
T
min
+
2
*
CA
*
Q
*
T
min
2
⁢
C
⁢
A
2
(
3
⁢
f
)
wherein:
II=The constant pi
σmax=The largest allowed standard deviation defined by the user
σtime=Standard deviation in units of time
σ2time=Variance in units of time
A=Cross sectional Area of flow path
CA=Cross-sectional Area of flow path
De=Dean Number
f( . . . )=function of ( . . . )
h=Reduced plate height
i.d.-Internal diameter
L=Path length
LTAve-=Length of reactor required to provide targeted average residence time
m=Modifying number
n=Modifying number
O=Flowrate
r=Radius of the flow path
RV=Reactor volume
TAve=Average residence time
TAveDefined=Average residence time, user defined
Tmax=Maximum residence time
Tmin=Minimum residence time
v=Velocity.

554 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/283,286Filed 2 Oct 2019 · us provisional application
Priority: 8 Oct 2018
Published: US 2021/0388323 A116 Dec 2021
Granted: 28 Jan 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C12M 23/06
Form or structure of the vessel: tubular
C12N 7/08
Inactivation or attenuation; Producing viral sub-units: inactivation or attenuation by serial passage of virus
B01L 3/502715
By integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g.…
C12M 23/16
Form or structure of the vessel: microfluidic devices; Capillary tubes

Family

Application62/742,506Us provisional application · filed 8 Oct 2018
US 2021/0388323 A1Pre-grant publication · published 16 Dec 2021
US 12,209,257 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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Abstract

A method for designing an actual reactor for viral inactivation comprising:

introducing a process stream, including detectable particles/tracer, into an experimental reactor having a known radius of curvature and a known internal diameter, wherein the experimental reactor is in communication with at least one of a first detector and a second detector;
detecting a flow rate of the process stream in the experimental reactor by at least one of the first detector and the second detector;
detecting fluid-phase parameters of the process stream by at least one of the first detector and the second detector;
detecting the detectable particles exiting the experimental reactor by the second detector;
determining, based on the introduced process stream including the detectable particles, empirical values relating to at least one of experimental reactor parameters and fluid-phase parameters;
determining non-empirical values relating to at least one of the experimental reactor parameters and the fluid-phase parameters;
and
designing the actual reactor based on the determined empirical values and the determined non-empirical value;
wherein:
designing the actual reactor comprises at least one of (i)-(v):
(i) scaling dimensions of the experimental reactor to the actual reactor having a same aspect ratio as the experimental reactor, but a different internal diameter;
(ii) scaling the dimensions of the experimental reactor to the actual reactor having a same aspect ratio and a same internal diameter as the experimental reactor;
(iii) scaling the dimensions of the experimental reactor to the actual reactor having a different aspect ratio than the experimental reactor and a different diameter than the experimental reactor;
(iv) scaling the dimensions of the experimental reactor to the actual reactor having a different aspect ratio as the experimental reactor, but a same diameter as the experimental reactor;
wherein when designing the actual reactor comprises scaling the dimensions of the experimental reactor to the actual reactor having the same aspect ratio as the experimental reactor, the method:
(i) requires derivation of height equivalent of a theoretical plate (“HETP”), reactor volume, and internal diameter based on average flow velocity, utilizing equations (1a)-(1g) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
Ave
2
(
1
⁢
a
)
(1b) HETP=f(v)=(av3+bv2+cv+d), wherein a, b, c, and d are based on empirical data fits for all Dean numbers
L
=
1
2
*
(
2
⁢
5
⁢
f
⁡
(
v
)
2
±
5
*
2
⁢
5
⁢
f
⁡
(
v
)
4
+
4
⁢
f
⁡
(
v
)
2
⁢
T
⁢
min
*
v
+
2
*
T
⁢
min
*
v
)
(
1
⁢
c
)
A
=
∏
r
2
=
∏
(
i
.
d
.
2
)
2
⁢
T
Ave
Defined
=
L
v
=
CA
*
L
Q
(
1
⁢
d
)
T
Ave
Defined
=
C
⁢
A
*
L
Q
(
1
⁢
e
)
Q
*
T
A
⁢
v
⁢
e
Defined
L
*
∏
=
r
2
(
1
⁢
f
)
i
.
d
.
=
2
⁢
Q
*
T
A
⁢
v
⁢
e
Defined
L
*
∏
.
(
1
⁢
g
)
or (ii) requires derivation of HETP, reactor volume, and internal diameter based on reduced HETP and Dean Number, utilizing equations (2a)-(2e) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
Ave
2
(
2
⁢
a
)
HETP
i
.
d
.
=
h
=
(
a
⁢
D
⁢
e
3
+
b
⁢
D
⁢
e
2
+
c
⁢
D
⁢
e
+
d
)
=
f
⁡
(
De
)
(
2
⁢
b
)
T
A
⁢
v
⁢
e
=
T
min
+
(
n
*
σ
max
)
(
2
⁢
c
)
T
A
⁢
v
⁢
e
=
T
max
-
(
m
*
(
σ
max
)
)
(
2
⁢
d
)
T
A
⁢
v
⁢
e
=
R
⁢
V
Q
=
C
⁢
A
*
L
T
A
⁢
v
⁢
e
Q
(
2
⁢
e
)
and wherein when designing the actual reactor comprises scaling the dimensions of the experimental reactor to the actual reactor having a same aspect ratio and a same internal diameter as the experimental reactor, the method requires derivation of at least HETP and path length, utilizing equations (3a)-(3f) below:
HETP
=
σ
t
⁢
i
⁢
m
⁢
e
2
*
L
T
A
⁢
v
⁢
e
T
Ave
2
;
(
3
⁢
a
)
HETP
=
f
⁡
(
D
⁢
e
)
=
σ
t
⁢
i
⁢
m
⁢
e
*
L
T
A
⁢
v
⁢
e
T
A
⁢
v
⁢
e
=
(
a
⁢
D
⁢
e
3
+
b
⁢
D
⁢
e
2
+
c
⁢
D
⁢
e
+
d
)
;
(
3
⁢
b
)
wherein a, b, c, and d are based on empirical data fits only valid for Dean numbers ≥100
(3c) TAve=Tmin+(n*σtime);
(3d) TAve=Tmax−(m*σtime);
T
A
⁢
v
⁢
e
=
R
⁢
V
Q
=
C
⁢
A
*
L
T
A
⁢
v
⁢
e
Q
;
and
(
3
⁢
e
)
L
T
A
⁢
v
⁢
e
=
25
*
C
⁢
A
2
*
f
⁡
(
D
⁢
e
)
2
±
5
*
2
⁢
5
*
C
⁢
A
4
*
f
⁡
(
D
⁢
e
)
4
+
4
*
C
⁢
A
3
*
f
⁡
(
D
⁢
e
)
2
*
Q
*
T
min
+
2
*
CA
*
Q
*
T
min
2
⁢
C
⁢
A
2
(
3
⁢
f
)
wherein:
II=The constant pi
σmax=The largest allowed standard deviation defined by the user
σtime=Standard deviation in units of time
σ2time=Variance in units of time
A=Cross sectional Area of flow path
CA=Cross-sectional Area of flow path
De=Dean Number
f( . . . )=function of ( . . . )
h=Reduced plate height
i.d.-Internal diameter
L=Path length
LTAve-=Length of reactor required to provide targeted average residence time
m=Modifying number
n=Modifying number
O=Flowrate
r=Radius of the flow path
RV=Reactor volume
TAve=Average residence time
TAveDefined=Average residence time, user defined
Tmax=Maximum residence time
Tmin=Minimum residence time
v=Velocity.

554 more elements

Facts

Application

17/283,286Filed 2 Oct 2019 · us provisional application

Priority

8 Oct 2018

Published

US 2021/0388323 A116 Dec 2021

Granted

28 Jan 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C12M 23/06
Form or structure of the vessel: tubular
C12N 7/08
Inactivation or attenuation; Producing viral sub-units: inactivation or attenuation by serial passage of virus
B01L 3/502715
By integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g.…
C12M 23/16
Form or structure of the vessel: microfluidic devices; Capillary tubes