Devices and methods for integrated continuous manufacturing of biological molecules

Patent metadata

Field	Value
Publication number	US-9133433-B2
Application number	US-201313795298-A
Country	US
Kind code	B2
Filing date	Mar 12, 2013
Priority date	Sep 30, 2004
Publication date	Sep 15, 2015
Grant date	Sep 15, 2015

Abstract

The present invention relates to a process and apparatus for purifying a molecule of interest from a heterogeneous clarified fluid mixture. The apparatus of the invention generally comprises a continuous perfusion fermentation system, a continuous particle removal system integrated with the perfusion fermentation system; and a continuous purification system integrated with the particle removal system, which is maintained under sterile conditions. The process comprises filtering a heterogeneous clarified fluid mixture by continuous ultrafiltration at a specific flow rate below the transition point of the molecule of interest in the pressure-dependent region of the flux versus TMP curve, wherein the specific flow rate is maintained substantially constant throughout the continuous ultrafiltration.

First claim

We claim:

1. An apparatus for separating a protein of interest from a heterogenous tissue culture fluid mixture, comprising:
(a) a continuous perfusion fermentation system adapted to continuously produce a tissue culture fluid containing a protein of interest at a substantially constant volumetric flow rate;
(b) a continuous particle removal system integrated with and adapted to continuously receive the tissue culture fluid from the perfusion fermentation system and continuously produce a clarified tissue culture fluid; and
(c) a continuous purification system integrated with and adapted to continuously receive the clarified tissue culture fluid from the particle removal system and continuously produce a product isolate containing the protein of interest;
wherein the continuous purification system is an ultrafiltration system, wherein the ultrafiltration system comprises an ultrafiltration membrane having an area in square meters equal to a range of between 0.1 to 2 times the volumetric flow rate of the continuous perfusion fermentation in liters/hour and wherein the apparatus is maintained under sterile conditions.

2. The apparatus of claim 1 , wherein the ultrafiltration system comprises an ultrafiltration membrane having an area in square meters equal to a range of between 0.3 to 1 times the volumetric flow rate of the continuous perfusion fermentation in liters/hour.

3. An apparatus for separation of a protein of interest from a tissue culture fluid stream, comprising:
(a) a continuous perfusion fermentation system adapted to continuously produce a tissue culture fluid containing a protein of interest;
(b) a continuous particle removal system integrated with and adapted to continuously receive the tissue culture fluid from the reactor and continuously produce a clarified tissue culture fluid;
(c) a continuous surge vessel integrated with and adapted to continuously receive the clarified tissue culture fluid from the particle removal system and semi-continuously release the clarified tissue culture fluid, and
(d) a intermittent purification system integrated with and adapted to semi-continuously receive the clarified tissue culture fluid from the surge vessel and produce a product isolate containing the protein of interest; wherein the purification system comprises a convective adsorption/desorption system, and wherein the apparatus is adapted to maintain sterile conditions.

Assignees

• Bayer Healthcare Llc

Inventors

• Vogel Jens Holger
• Giovannini Roberto
• Konstantinov Konstantin B
• Nguyen Huong My
• Wu Paul

Classifications

• B01D61/145 Primary

  Ultrafiltration · CPC title

• C07K1/34

  by filtration, ultrafiltration or reverse osmosis · CPC title

• B01D2311/16

  Flow or flux control · CPC title

• C12M47/12 Primary

  Purification (C12M47/04 takes precedence) · CPC title

• B01D2313/105

  Supply manifolds · CPC title