# US 7,465,397 B2 · Process for removing protein aggregates and virus from a protein solution

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- Number: US 7,465,397 B2
- Document ID: US7465397B2
- Status: Granted
- Kind: B2
- Application number: 11/489,232
- Filed: 2006-07-19
- Published: 2006-11-09
- Granted: 2008-12-16
- Earliest claimed: 2002-02-04
- Assignees: Millipore Corporation
- Inventors: Martin Siwak; Hong An; Jason R. Comier; Dana Kinzlmaier
- Web page: https://patentgrep.com/patent/US7465397B2

## CPC

- C07K 1/36: by a combination of two or more processes of different types
- B01D 61/145: {Ultrafiltration}
- B01D 61/146: {comprising multiple ultrafiltration steps}
- B01D 61/16: Feed pretreatment
- C07K 1/34: by filtration, ultrafiltration or reverse osmosis
- B01D 2311/04: Specific process operations in the feed stream; Feed pretreatment
- Y10T 436/255: including use of a solid sorbent, semipermeable membrane, or liquid extraction
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

A process is provided for selectively removing protein aggregates from a protein solution in a normal flow (NFF) filtration process. Preferably, it relates to a process for selectively removing protein aggregates from a protein solution in a normal flow (NFF) filtration process and virus particles from a protein solution in a two-step filtration process. In a first step, a protein solution is filtered through one or more layers of adsorptive depth filters, charged or surface modified microporous membranes or a small bed of chromatography media in a normal flow filtration mode of operation, to produce a protein aggregate free stream. The aggregate free protein stream can then be filtered through one or more ultrafiltration membranes to retain virus particles at a retention level of at least 3 LRV and to allow passage therethrough of an aggregate free and virus free protein solution.

## Claims

### Claim 1

A process for viral filtration of a protein containing stream comprising:
(a) providing a filtration system comprising: (i) a pressurized reservoir comprising a solution which comprises one or more protein aggregates and viruses; (ii) a first conduit connecting the reservoir to a first filtration step comprising a device selected from the group consisting of one or more layers of adsorptive depth filters and one or more layers of charged or surface modified microporous membranes; (iii) a second conduit from the first filtration step to a second filtration step comprising one or more ultrafiltration membranes having a molecular weight cut off of between about 200 kD and about 1000 kD to retain virus particles in said one or more ultrafiltration membranes at a level of at least 3 LRV; and (d) an outlet conduit connected to the second filtration step;
(b) pumping the solution from the pressurized reservoir through the first conduit to the first filtration step;
(c) running the first filtration step in a normal flow filtration mode with the one or more protein aggregates and viruses being retained by the first filtration step;
(d) discharging the solution from the first filtration step to the second conduit;
(e) passing the solution from the second conduit through the second filtration step; and
(f) discharging the solution from the second filtration step to the outlet conduit.

### Claim 2 (depends on 1)

The process of claim 1 wherein the process is run in a constant pressure mode of operation.

### Claim 3 (depends on 1)

The process of claim 1 further comprising the step of flushing retained protein from said one or more ultrafiltration membranes.

### Claim 4 (depends on 1)

The process of claim 1 wherein the filtration is through one or more layers of adsorptive depth filters.

### Claim 5 (depends on 1)

The process of claim 1 wherein the filtration is through one or more layers of one or more layers of charged or surface modified microporous membranes.

### Claim 6 (depends on 1)

The process of claim 1 wherein the filtration is through one or more layers of adsorptive depth filters made of a material selected from the group consisting of cellulosic fibers, synthetic fibers and blends thereof.

### Claim 7

A process for the viral filtration of a protein containing stream comprising:
(a) providing a filtration system comprising a non-pressurized reservoir comprising a solution which comprises one or more protein aggregates and viruses; (ii) a first conduit connecting the reservoir to a pump, wherein the pump is connected to a second conduit which connects the pump to a first filtration step comprising a device selected from the group consisting of one or more layers of adsorptive depth filters and one or more layers of charged or surface modified microporous membranes; (iii) a third conduit from the first filtration step to a second filtration step comprising one or more ultrafiltration membranes having a molecular weight cut off of between about 200 kD and about 1000 kD to retain virus particles in said one or more ultrafiltration membranes at a level of at least 3 LRV; and (iv) an outlet conduit from the second filtration step;
(b) pumping the solution from the reservoir through the first conduit to the pump and from the pump through the second conduit to the first filtration step;
(c) running the first filtration step in a normal flow filtration mode with the one or more protein aggregates and viruses being retained by the first filtration step;
(d) discharging the solution from the first filtration step to the third conduit;
(e) passing the solution from the third conduit through the second filtration step in a normal flow filtration mode; and
(f) discharging the solution from the second filtration step to the outlet conduit.

### Claim 8 (depends on 7)

The process of claim 7 wherein the process is run in a constant flow mode of operation.

### Claim 9 (depends on 7)

The process of claim 7 further comprising the step of flushing retained protein from said one or more ultrafiltration membranes.

### Claim 10 (depends on 7)

The process of claim 7 wherein filtration with said one or more ultrafiltration membranes is effected by tangential flow filtration.

### Claim 11 (depends on 7)

The process of claim 7 wherein filtration with said one or more ultrafiltration membranes is effected in a normal flow filtration mode of operation.

### Claim 12 (depends on 7)

The process of claim 7 wherein the first filtration step is through one or more layers of adsorptive depth filters.

### Claim 13 (depends on 7)

The process of claim 7 wherein the first filtration step is through one or more layers of charged or surface modified microporous membranes.

### Claim 14 (depends on 7)

The process of claim 7 wherein the first filtration step is through one or more layers of adsorptive depth filters made of a material selected from the group consisting of cellulosic fibers, synthetic fibers and blends thereof.