Process and apparatus for removal of DNA, viruses and endotoxins

• US 5,221,483 A
• Filed: 11/04/1991
• Issued: 06/22/1993
• Est. Priority Date: 06/29/1990
• Status: Expired due to Term

• Current Assignee: Coulter International Corp. (Danaher Corporation)
• Original Assignee: Coulter Corporation (Danaher Corporation)
• Inventors: O'Connell, Edward, Smariga, Paulette, Butchko, Gregory, Glenn, Stephan D.
• Primary Examiner(s): Dawson, Robert A.
• Assistant Examiner(s): KIM, SUN U
• Application Number:
  US07/787,061
• Time in Patent Office: 596 Days
• Field of Search: 210/641, 210/651, 210/655, 210/321.64, 210/335, 210/446, 210/500.29, 210/506, 210/507, 210/508, 424/89, 422/1, 422/101, 935/19, 435/311
• US Class Current: 210/641
• CPC Class Codes: A61L 2/0017 Filtration
• CPC Class Codes: B01D 61/18 Apparatus therefor
• CPC Class Codes: B01D 67/0088 Physical treatment with compounds, e.g. swelling, coating or impregnation
• CPC Class Codes: B01D 71/10 Cellulose; Modified cellulose

Abstract

A single filtration device containing coated filter membranes and absolute pore filters is provided in which the membranes and absolute pore filters are present in two sections of the filter device. The filter device will remove up to about 98% of the endotoxins in addition to removing viruses with an efficiency of at least 4.6×10⁵ and DNA to less than 10 picograms per 500 mg sample.

Claims

1. A process for the removal of DNA, viruses and about 98% of endotoxins from aqueous buffer solutions, aqueous pharmaceutical solution and aqueous biological pharmaceutical solutions comprising, passing one of said aqueous buffer solutions, aqueous pharmaceutical solutions and aqueous biological pharmaceutical solutions through a first DNA/endotoxin filter section and a second virus/endotoxin filter section, wherein said DNA, viruses and endotoxins are substantially removed;

and collecting said aqueous buffer solutions, aqueous pharmaceutical solutions or aqueous biological pharmaceutical solutions;

(I) said first DNA/endotoxin filter section having;

(A) (i) a first absolute pore filter,

(ii) a first and second filter selected from one of the group consisting (a) a DEAE cellulose filter membrane, and (b) an absolute pore filter coated with at least one of the group consisting of diethylaminoethyl salts, quaternary aminoethyl salts and quaternary aminomethyl salts, and

(iii) a second absolute pore filter;

or

(B) plurality of absolute pore filters at least one of which is coated with at least one selected from the group consisting of dimethylaminoethyl salts, quaternary aminoethyl salts, and quaternary aminomethyl salts; and

(ii) said second virus/endotoxin filter section having absolute pore filters of a smaller diameter than the absolute pore filters or coated absolute pore filters in the DNA/endotoxin filter section

2. The process in accordance with claim 1 wherein the yield of pharmaceuticals, including biological pharmaceuticals, in the filtered solutions is 90% or higher compared to the starting solution.

3. The process in accordance with claim 1 wherein the virus removal is 99.9999997% or higher when the virus is 0.100 microns or larger, and the yield of pharmaceutical or biological pharmaceutical in the filtered solution of same is 90% or higher compared to the starting solution.

4. The process in accordance with claim 1 wherein said DNA in the filtered solutions is preferably less than 10 picograms per 100 ml of solution.

5. The process in accordance with claim 4 wherein said DNA in the filtered solutions is less than 1 picogram per 100 ml of solution.

6. The process in accordance with claim 1 wherein the aqueous buffer solutions, aqueous pharmaceutical solutions and aqueous biological pharmaceutical solutions have a pH in the range of 3 to 9.

7. The process in accordance with claim 1 wherein the aqueous buffer solutions, aqueous pharmaceutical solutions and aqueous biological pharmaceutical solutions each have a specific salt content of less than 0.5 Molar, said specific salt being one or more selected from the group consisting of the lithium, sodium, potassium and ammonium salts of the phosphate, chloride, bromide, iodide, sulfate, and acetate anions.

15. A process in accordance with claim 1 or 8 wherein said aqueous buffer solutions, aqueous pharmaceutical solutions and aqueous biological pharmaceutical solutions are passed through said DNA/endotoxin filter and said virus/endotoxin filter by a vacuum means or a pressure means.

8. A process for the removal of DNA, viruses and about 98% of endotoxins from aqueous pharmaceutical solutions "and aqueous biological pharmaceutical solutions", said process comprising passing either one of the solutions through a first DNA/endotoxin filter section and a second virus/endotoxin filter section to obtain a filtered aqueous pharmaceutical solution or a filtered aqueous biological pharmaceutical solution having substantially reduced DNA, virus and endotoxin levels, said solutions passing through:

(a) a first 0.2 micro absolute pore filter, a first diethylaminoethyl cellulose filter, a second diethylaminoethyl cellulose filter and a second 0.2 micron absolute pore filter in the first DNA/endotoxin filter section, and

(b) a first 0.1 micron absolute pore filter, a second 0.1 micron absolute pore filter, a first 0.04 micron absolute pore filter and a second 0.04 micron absolute pore filter in the virus/endotoxin filter section; and

collecting the filtered solutions.

9. A process in accordance with claim 8 wherein the yield of the pharmaceutical, including biological pharmaceutical, in the filtered solution is 90% or higher.

10. A process in accordance with claim 8 wherein the virus removal is 99.9999997% or higher when the virus is 0.100 microns or larger, and the yield of the pharmaceutical or biological pharmaceutical in the filtered solution is 90% or higher.

11. A process in accordance with claim 8 wherein the DNA in the filtered pharmaceutical or biological pharmaceutical solution is reduced to less than 10 picograms per 100 ml of solution.

12. The process in accordance with claim 11 wherein the DNA in the filtered pharmaceutical of biological pharmaceutical solution is reduced to less than 1 picogram per 100 ml of solution.

13. A process in accordance with claim 8 wherein the pharmaceutical solution or biological pharmaceutical solution has a pH in the range of 6 to 8.

14. A process in accordance with claim 8 wherein the pharmaceutical or biological pharmaceutical has a specific salt content, excluding salts of pharmaceuticals or biological pharmaceuticals, of less than 0.5 Molar, said specific salts being at least one selected from the group consisting of the lithium, sodium potassium and ammonium salts of the phosphate, chloride, bromide, iodide, sulfate and acetate anions.

16. An improved device for the removal of DNA, viruses and about 98% of endotoxins from aqueous buffer solutions, aqueous pharmaceutical solution and aqueous biological pharmaceutical solutions, said device having a housing with suitable inlet/outlet means, internal gaskets and filter supports, and internal filters, wherein the improvement comprises:

(a) a first DNA/endotoxin filter section having, from inflow to outflow, a first 0.2 micron filter and a second 0.2 micron filter, the filters having face-to-face contact;

(b) a second virus/endotoxin filter section having, from inflow to outflow, a first 0.1 micron filter, a second 0.1 micron filter, a first 0.04 micron filter and a second 0.04 micron filter, said filters having face-to-face contact; and

(c) DEAE functional groups, QAE functional groups, QAM functional groups or other quaternary amine functional groups bonded directly to one or more of the 0.2, 0.1 and 0.04 micron absolute pore filters.

17. An improved device in accordance with claim 16 wherein said 0.2, 0.1 and 0.04 filters are absolute pore filters.

18. The improved device of claim 16 wherein said device is capable of removing 99.9999997% of virus when the virus is 0.100 microns or larger.

19. The improved device of claim 16 wherein the device gives a yield of pharmaceutical or biological pharmaceutical in the filtered solution of 90% or higher compared to the unfiltered solution.

20. The improved device of claim 16 where the solution to be filtered is passed through said device by pressure or vacuum means.

21. The improved device of claim 16 wherein said device is a means of administration of said aqueous buffer solution, aqueous pharmaceutical solution or said aqueous biological pharmaceutical solution to a patient which means contains said DNA/endotoxin and virus/endotoxin filter sections.

22. The improved device of claim 16 wherein said device is a syringe filtration apparatus containing sad DNA/endotoxin and virus/endotoxin removal filters.

23. The improved device in accordance with claim 16 wherein aid device is preferably capable of removing DNA to a level of less than 10 picograms per 100 ml solution.

24. The improved device in accordance with claim 23 wherein said device is capable of removing DNA to a level of less than 1 picogram per 100 ml of solution.