Interconnected Bioreactors

• US 20110217690A1
• Filed: 05/13/2011
• Published: 09/08/2011
• Est. Priority Date: 05/13/2011
• Status: Active Grant

• Current Assignee: Adello Biologics, LLC
• Original Assignee: Therapeutic Proteins Inc.
• Inventors: Niazi, Sarfaraz K.
• Granted Patent: US 9,068,215 B2
• Time in Patent Office: Days
• US Class Current: 435/3
• CPC Class Codes: C12M 23/14 Bags
• CPC Class Codes: C12M 23/58 Reaction vessels connected in series or in parallel combinations of bioreactors with other apparatus, C12M43/00
• CPC Class Codes: C12M 27/16 Vibrating; Shaking; Tilting
• CPC Class Codes: C12Q 3/00 Condition responsive control processes apparatus therefor C12M1/36; controlling or regulating in general G05

Abstract

A method of combining the content of bioreactors allowing homogeneous mixing in accordance with CFR21 is described that allows processing of variable size batches using a single validated bioreactor is described.

Claims

1. A method of homogenously mixing the contents of a plurality of bioreactors comprising:

(a) a hard platform with an upper surface and a lower surface, and four edges;

(b) a fulcrum stand to support the hard platform and allow movement of the hard platform to a pre-determined angle on either side of the plane parallel to the ground;

(c) a means of lowering and raising at least one edge of the hard platform;

(d) installing a plurality of bioreactors, 1 though n, in a series on the upper surface of the hard platform, the bioreactors comprising a bioreactor container with at least two surfaces and two opposing sides, to hold a liquid further comprising a nutrient media and a biological culture, a means of gassing the liquid further comprising a gas inlet, a gas sterilizing filter and a gas sparging filter, a gas exhaust, at least one nutrient media inlet/outlet, at least two liquid ports installed one on the first side and the second on the second side of the bioreactor container with means of closing or opening the liquid ports, a means of agitating the nutrient media, a plurality of sensors installed in the bioreactor container with at least a sensor for measuring the weight of the bioreactor container;

(e) connecting the liquid port on the second side of the first bioreactor in the series of bioreactors to the liquid port of the next bioreactor on the first side in the series, and continuing the connectivity till the nth bioreactor in the series and keeping the liquid port on the first side of the first bioreactor and the liquid port on the second side of the nth bioreactor sealed;

(f) adjusting the angle of the hard platform in line with the plane of the ground;

(g) operating the bioreactors;

(h) opening all liquid ports except the liquid port on the first side of the first bioreactor and the liquid port on the second side of the nth bioreactor;

(i) raising the side of the hard platform closer to the first bioreactor to a sufficient height to allow flow of the liquids of the bioreactors across all bioreactors;

(j) measuring the increase in the weight of the nth bioreactor to a pre-determined level;

(k) lowering the side of the hard platform closer to the first bioreactor to the same degree as the platform was raised from the plane of the ground in step (f);

(l) measuring the increase in the weight of the first bioreactor to a pre-determined level;

(m) repeating the steps (i) to (l) periodically or continuously.

6. The method of homogenously mixing the contents of a plurality of bioreactors according to claims 1-5, wherein the first and the last bioreactor is replace with an empty receiving container capable of holding a volume of liquid recalculated within the bioreactors, generally about 1/10 to ⅕

of the volume in each bioreactor.

9. The method of homogenously mixing according to claim 6 and 7, wherein the receiving container is rocked, shaken or stirred continuously or intermittently.

10. A method of manufacturing a biological product comprising:

(a) validating the manufacturing process of a single size of manufacturing of the biological product using a bioreactor;

(b) providing a plurality of bioreactors arranged in a configuration according to claims 1-4;

(c) operating the bioreactors;

(d) mixing the contents of the plurality of bioreactors according to claims 1-9 continuously, periodically or at the end of the bioreaction process.

11. The methods of homogeneously mixing according to claim 1-10, wherein the bioreactor container is a two-dimensional flexible bag, a three dimensional flexible bag with a surrounding support or a hard-walled container.

2. A method of homogenously mixing the contents of a plurality of bioreactors comprising:

(a) a hard platform with an upper surface and a lower surface, and four edges;

(b) a fulcrum stand to support the hard platform and allow movement of the hard platform to a pre-determined angle on either side of the plane parallel to the ground;

(c) a means of lowering and raising at least one edge of the hard platform;

(d) installing a plurality of bioreactors, 1 though n, in a series on the upper surface of the hard platform, the bioreactors comprising a bioreactor container with at least two surfaces and two opposing sides, to hold a liquid further comprising a nutrient media and a biological culture, a means of gassing the liquid further comprising a gas inlet, a gas sterilizing filter and a gas sparging filter, a gas exhaust, at least one nutrient media inlet/outlet, at least two liquid ports installed one on the first side and the second on the second side of the bioreactor container with means of closing or opening the liquid ports, a means of agitating the nutrient media, a plurality of sensors installed in the bioreactor container with at least a sensor for measuring the weight of the bioreactor container;

(e) connecting the liquid port on the second side of the first bioreactor in the series of bioreactors to the liquid port of the next bioreactor on the first side in the series, and continuing the connectivity till the nth bioreactor in the series and connecting the liquid port on the second side of the nth bioreactor to the liquid port on the first side of the first bioreactor;

(f) adjusting the angle of the hard platform in line with the plane of the ground;

(g) operating the bioreactors;

(h) opening all liquid ports except the liquid port on the first side of the first bioreactor and the liquid port on the second side of the nth bioreactor;

(i) raising the side of the hard platform closer to the first bioreactor to a sufficient height to allow flow of the liquids of the bioreactors across all bioreactors;

(j) measuring the increase in the weight of the nth bioreactor to a pre-determined level;

(k) closing all liquid ports except the liquid port on the second side of the nth bioreactor and the liquid port on the first side of the first bioreactor;

(l) lowering the side of the hard platform closer to the first bioreactor to the same degree as the platform was raised from the plane of the ground in step (f);

(l) measuring the increase in the weight of the first bioreactor to a pre-determined level;

(m) repeating the steps (h) to (l) periodically or continuously.

3. A method of homogenously mixing the contents of a plurality of bioreactors comprising:

(a) providing a plurality of bioreactors, 1 through nth, in a series, installed on a platform capable of being raised or lowered;

the bioreactors comprising a bioreactor container with at least two surfaces and two opposing sides, to hold a liquid further comprising a nutrient media and a biological culture, a means of gassing the liquid further comprising a gas inlet, a gas sterilizing filter and a gas sparging filter, a gas exhaust, at least one nutrient media inlet/outlet, at least two liquid ports installed one on the first side and the second on the second side of the bioreactor container with means of closing or opening the liquid ports, a means of agitating the nutrient media, a plurality of sensors installed in the bioreactor container with at least a sensor for measuring the weight of the bioreactor container;

(b) connecting the liquid port on the second side of the first bioreactor in the series of bioreactors to the liquid port of the next bioreactor on the first side in the series, and continuing the connectivity till the nth bioreactor in the series and keeping the liquid port on the first side of the first bioreactor and the liquid port on the second side of the nth bioreactor sealed;

(c) arranging the bioreactors in a cascade formation such that the bioreactors are elevated with equal vertical distance between each bioreactor;

(d) operating the bioreactors;

(e) opening all liquid ports except the liquid port on the first side of the first bioreactor and the liquid port on the second side of the nth bioreactor;

(f) raising the first bioreactor to the highest position and the nth bioreactor to the lowest position to allow flow of the liquids of the bioreactors across all bioreactors;

(g) measuring the increase in the weight of the nth bioreactor to a pre-determined level;

(h) reversing the order of elevation of bioreactors, with the first bioreactor being at the lowest level and the nth bioreactor at the highest level;

(i) measuring the increase in the weight of the first bioreactor to a pre-determined level;

(j) repeating the steps (f) to (i) periodically or continuously.

4. A method of homogenously mixing the contents of a plurality of bioreactors comprising:

(a) providing a plurality of bioreactors, 1 through nth, in a series, installed on a platform capable of being raised or lowered;

the bioreactors comprising a bioreactor container with at least two surfaces and two opposing sides, to hold a liquid further comprising a nutrient media and a biological culture, a means of gassing the liquid further comprising a gas inlet, a gas sterilizing filter and a gas sparging filter, a gas exhaust, at least one nutrient media inlet/outlet, at least two liquid ports installed one on the first side and the second on the second side of the bioreactor container with means of closing or opening the liquid ports, a means of agitating the nutrient media, a plurality of sensors installed in the bioreactor container with at least a sensor for measuring the weight of the bioreactor container;

(b) connecting the liquid port on the second side of the first bioreactor in the series of bioreactors to the liquid port of the next bioreactor on the first side in the series, and continuing the connectivity till the nth bioreactor in the series and connecting the liquid port on the second side of the nth bioreactor to the liquid port on the first side of the first bioreactor;

(c) arranging the bioreactors in a cascade formation such that the bioreactors are elevated with equal vertical distance between each bioreactor;

(d) operating the bioreactors;

(e) opening all liquid ports;

(f) raising the first bioreactor to the highest position and the nth bioreactor to the lowest position to allow flow of the liquids of the bioreactors across all bioreactors;

(g) measuring the increase in the weight of the nth bioreactor to a pre-determined level;

(h) closing all liquid ports except the liquid port from the second side of the nth bioreactor and the first side of the first bioreactor;

(i) raising the nth bioreactor to a position higher than the first bioreactor;

(j) measuring the increase in the weight of the first bioreactor to a pre-determined level;

(k) repeating the steps (e) to (j) periodically or continuously.

5. The method of homogenously mixing according to claim 4, wherein the bioreactors are arranged vertically and the liquid port is installed at the bottom and top surface of the bioreactors.

7. A method of homogenously mixing the contents of a plurality of bioreactors comprising:

(a) providing a plurality of bioreactors, 1 through nth, in a series, installed on a same plane either in a series or in a circular pattern, the bioreactors comprising a bioreactor container with at least two surfaces and two opposing sides, to hold a liquid further comprising a nutrient media and a biological culture, a means of gassing the liquid further comprising a gas inlet, a gas sterilizing filter and a gas sparging filter, a gas exhaust, at least one nutrient media inlet/outlet, at least one liquid ports installed on the bottom with means of closing or opening the liquid port, a means of agitating the nutrient media, a plurality of sensors installed in the bioreactor container with at least a sensor for measuring the weight of the bioreactor container;

(b) providing a receiving container capable of holding a appropriate quantity of the liquid and means of raising or lowering the receiving container;

(b) connecting the liquid port on bottom of each bioreactor to the receiving container;

(c) operating the bioreactors;

(e) opening all liquid ports;

(f) lowering the receiving container a position below the position of bioreactors;

(g) measuring the increase in the weight of the receiving bioreactor to a pre-determined level;

(h) raising the receiving container to a position higher than the bioreactors;

(j) measuring the decrease in the weight of the receiving container;

(k) repeating the steps (f) to (j) periodically or continuously.

8. The method of homogenously mixing according to claim 8, wherein the bioreactors are arranged on a variable plane.