WO2008110587A1

WO2008110587A1 - An electrolytic cip-cleaning process for removing impurities from the inner surface of a metallic container

Info

Publication number: WO2008110587A1
Application number: PCT/EP2008/052971
Authority: WO
Inventors: Per MØLLER; Jette Schreiner Hansen; Daniel Minzari
Original assignee: Novo Nordisk A/S
Priority date: 2007-03-13
Filing date: 2008-03-13
Publication date: 2008-09-18
Also published as: US20140203044A1; US20120018298A1; EP2126160A1; US20130299520A1

Abstract

The invention relates to a novel electrolytic process for removing impurities from the inner surface of a metallic container. The process is particularly useful for cleaning process reactors used for culturing microorganisms, and storage tanks used for storing metabolites formed in the process reactor, as well as containers for dairy products.

Description

AN ELECTROLYTIC CIP-CLEANING PROCESS FOR REMOVING IMPURITIES FROM THE INNER SURFACE OF A METALLIC CONTAINER

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

For industrial scale processes, e.g. for culturing microorganisms and cells and for handling, processing and purifying biological materials, e.g. microorganisms, cells, polypeptides, proteins, DNA, RNA, lipoproteins, lipids (steroids, terpenes, waxes and fatty acids), high- molecular carbon hydrates and the like, it has proven to be particularly difficult to completely remove all traces of material on nano-scale from the inner surface of the container(s) which have been involved in such processes.

It turns out that biological materials, e.g. proteins, strongly adhere to metal surfaces, e.g. stainless steel surfaces, and that a monolayer of high molecular weight compounds or biological materials, e.g. proteins, can be extremely difficult to completely remove without costly, energy demanding and time-consuming cleaning processes, which further may cause environmental problems.

Residues of proteins that are partly degraded are potentially immunogenic. Residues of proteins may act as nuclei (seeds) for denaturation of proteins during a subsequent manufacturing campaign. To avoid cross-contamination when tanks are used to produce different proteins and protein products, it is essential that the inner surface of the container is clean at a nano-scale level.

US 7,090,753 Bl discloses an electrolytic cell which can produce charged water having excellent performance of improving surface cleaning or treatment.

KR 1082761 A discloses a method for grinding the inner walls of a drug tank in order to maintain the degree of purity of stored drugs by minimizing the gush of metal components from the inner walls of the drug tank. In the process, the inner wall is i.a. grinded by an electrolytic solution, and subsequently an oxide membrane is formed by reacting the surface with 20% nitric acid solution. It is stated that the use of high purity detergents can be reduced and that the cleaning time can be shortened.

However, there is still a need for cost- and time efficient processes for cleaning the surface of containers of the above-mentioned type on a nano-scale, in particular such methods which due to their simplicity are environmentally acceptable.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides an electrolytic process for removing impurities, e.g. contaminants and residues, in particular impurities consisting of biological materials, from the inner surface of a metallic container (5), said process comprising the step of

a) establishing an electrical circuit comprising (a) the wall of the container as a first electrode (1), (b) a second electrode (2), and (c) an electrolyte solution (3) forming electrical connection between said first electrode and said second electrode, the connection between the first electrode and the electrolyte solution defining a contact area (4); and

b) facilitating that said contact area (4) is moved across at least a substantial part of said inner surface so as to allow said electrolyte solution (3) to contact said inner surface to be depleted of the impurities, and simultaneously applying a predetermined current density at said contact area (4).

The process has to the best of the inventors' knowledge never been used before for "clean in place" (CΙP)-cleaning of the inner surface of containers (e.g. production or storage tanks or pipes for medical production).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates a process reactor (reaction vessel) (5) having a wall (1) used as the anode, and having arranged therein a ratable tubular member (2) for facilitating flow of the electrolyte solution (3) provided via a pump (not shown). The tubular member is also used as the cathode (as shown) or can have a cathode arranged therein (alternative embodiment). Upon rotation and up-and-down movement of the tubular member, the contact area (4) is moved across a substantial part of the inner surface. Figure 2 illustrates a process reactor (reaction vessel) (5) having a wall (1) used as the anode, and having arranged therein a ratable member (2) for facilitating flow of the electrolyte solution (3) provided via a pump (not shown). The tubular member is moved close to the inner wall and has a slit which allows the electrolyte solution to exit the tubular member. The tubular member is also used as the cathode (as shown) or can have a cathode arranged therein (alternative embodiment). Upon rotation of the tubular member around the axis (show with a dashed line), the elongated contact area (4) is moved across a substantial part of the inner surface.

Figure 3 illustrates various embodiments of the cross-section of the tubular member illustrated in Figure 2.

Figures 4 and 5 illustrate the arrangement of a ratable spraying device within a process reactor. After having served to establish electrical connection between the spraying device (second electrode; cathode in Figure 4 and anode in Figure 5) and the inner wall of the container (first electrode; anode in Figure 4 and cathode in Figure 5), the electrolyte solution is collected in the lower part of the container and is pumped back through the ratable spraying device via the pump. It is noted that the spraying device provides several streams (3') collectively representing the electrolyte solution (3), and that the "contact area" (4) is a collection of a number of individual contact areas (4').

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention provides an electrolytic process of removing impurities from the inner surface of containers, i.e. containers having an inner surface of a metallic material, such as stainless steel, titanium, tantalum or niobium. Containers of stainless steel are of particular importance.

Containers for which the present process is particularly relevant are reactors for culturing microorganisms and cells and for storing, handling, processing and purifying biological material, e.g. microorganisms, cells, polypeptides, proteins, DNA, RNA, lipoproteins, lipids (steroids, terpenes, waxes and fatty acids), high-molecular carbonhydrates and the like. Hence, in the present context, the term "container" encompasses process reactors, tubes, pipes, storage tanks, etc. Containers for handling diary products are also highly relevant.

It is understood that the process of the invention is particularly relevant for industrial scale equipment; hence the container preferably has a volume of at least 10 L, such as at least 100 L, or even at least 1,000 L. The invention resides in the finding that electrolytic cleaning of the inner surface of a metallic surface of a container can be obtained by application of a high current density by means of an electrical circuit comprising (a) the wall of the container as a first electrode (1), (b) a second electrode (2), and (c) an electrolyte solution (3) forming electrical connection between said first electrode and said second electrode, wherein the connection between the first electrode and the electrolyte solution defines a contact area (4). Means are included which facilitate that the contact area can be moved across at least a substantial part of the metallic inner surface of the container, while a predetermined current density is simultaneously applied at said contact area (4), i.e. the electrolytic process is effectuated over a substantial part of the inner surface.

In the most typically embodiments, the current density is in the range 1-60 A/dm², e.g. in the range of 1-30 A/dm², such as 3-20 A/dm².

It should be understood that the contact area at any time of the process only represents a fraction of the total area to be treated. Hence, preferably, the ratio between (i) the total area of the part of the inner surface which the contact area is moved across and (ii) the contact area is at least 10: 1, such as at least 20: 1, or even at least 50: 1.

It should be understood that the contact area in question may be the sum of a number of individual contact areas, e.g. as illustrated in Figures 4 and 5.

Upon application of a high current density between the first electrode and the second electrode (one of which being the anode and the other being the cathode) having an aqueous electrolyte solution there between, hydrogen gas will be formed at the cathode and oxygen gas will be formed at the anode.

The chemical reactions involved are:

Anode reaction: 2H₂O → O₂ + 4H⁺ + 4e^'

Cathode reaction: 2H₂O + 2e^~ → H₂ + 2OH^"

Under the real cleaning process, the surface chemistry gets very alkaline at the cathode and in that way acts as the builder chemistry in conventional cleaning chemistry.

The rational behind the invention is that the high cathodic current density applied to the metallic surface, e.g. a stainless steel surface, will result in the formation of hydrogen bubbles at the inner surface of the container, and that any material which adheres to the surface thereby will be removed under the influence of the formed hydrogen and hydroxyl ions. Furthermore, the electrochemical interaction with the immobilized organic impurities at the surface will be destroyed thereby leaving the surface cleaned upon molecular or nano- scale. This is illustrated in Example 2.

The process according to the invention cleans the inner surface using only electricity and an electrolyte solution. The electrolyte solution needs in principle only to contain very dilute amounts of non-toxic chemicals, such as alkali-metal hydroxides, such as NaOH and KOH, or a neutral salt, such as Na₂SO₄ or K₂SO₄, in purified water. For environmental reasons, and for reasons of disposal, the electrolyte solution is preferably a solution of one or more components selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium sulphate and potassium sulphate.

The ionic strength of the electrolyte solution is typically in the range 0.05-2.0 N, such as 0.1- 1.0 N.

Moreover, the electrolyte solution may in some interesting embodiment additionally comprise one or more complexing agent, such as one or more selected from gluconates, EDTA, and hydroxyl carboxylic acid (e.g. citric acid).

On the other hand, and contrary to conventional methods for cleaning process reactors which utilizes various types of detergents, the electrolyte solution is preferably essentially free of detergents.

Apart from the requirement of a sufficient current density, the contact time should preferably be sufficiently long so as to allow for an efficient removal of the impurities. The movement of the second electrode relative to the inner surface of the container will determine the period at which an incremental area of the inner surface is exposed to the applied current. Hence, typically, the movement of the contact area is such that the contact time of the contact area is at least 1 second.

The equipment used for facilitating the movement of the contact area across the inner surface (or at least a part thereof), may include motors, e.g. stepper motors, as well as robots. Further, the movement may - although not particularly preferred - be effected manually.

The electrical circuit comprises the first electrode, the second electrode and the electrolyte solution. In one embodiment, the first electrode is the cathode and the second electrode is the anode. In this embodiment, hydrogen gas is formed at the inner surface of the container.

In another embodiment, the first electrode is the anode and the second electrode is the cathode. In this embodiment, oxygen gas is formed at the inner surface of the container.

That constellation makes it also possible - in a special embodiment - to passivate the stainless steel surface as a post treatment after the electrolytic CIP-cleaning, where the first electrode is used as a cathode.

Under the passivation process, the first electrode act as the anode and that makes it possible to form a passivating layer consisting of oxides, i.e a treatment very similarly to the passivation in nitric acid. The Pourbaix-diagram in figure 6 indicates the possible area for passivation.

The anodic current density which is necessary to render the process effective is typically at least 1 A/dm² corresponding to a potential (SHE) between +400 mV and +1500 mV. For

practical reasons, the current density is typically in the range 1-60 A/dm², e.g. in the range of 1-30 A/dm².

In one particularly interesting embodiment, the second electrode is a tubular member facilitating a flow of the electrolyte solution. The tubular member may be designed as a low pressure spray nozzle to ensure a coherent beam of the electrolyte, which form a linear contact area with some extent. Alternatively, the electrode is placed in the water beam formed by a spray nozzle. This embodiment corresponds to the one illustrated in Figure 1.

In another interesting embodiment, the electrolyte solution is fed to the gap between the first electrode and the second electrode by means of a tubular member having a slit. This embodiment corresponds to the one illustrated in Figure 2. In this embodiment the residence time of the electrolyte solution may be increased by arranging a porous structure in the before-mentioned gap.

In a further variant, the electrolytic process is carried out within a jet beam between the area to be cleaned (the first electrode; a cathode) and a cleaning nozzle. An anode is inserted into the tank in appropriate distance allowing a non-interrupted and coherent beam of electrolyte to connect to the anode and cathode (tank wall). The beam is moved to cover the whole area of the tank. Within this embodiment, the flow of the electrolyte solution is preferably predominantly laminar.

In an alternative embodiment, the electrolyte solution which forms electrical communication between said first electrode and said second electrode is held in a porous structure, e.g. in a sponge or a brush. Such a porous structure may be moved across the inner surface my mechanical means, e.g. by a motor/motors or a robot.

In one particularly preferred embodiment, the process according to invention comprising the step of:

a) establishing an electrical circuit comprising (a) the wall of the container as the anode (1), (b) a cathode (2), and (c) an electrolyte solution (3) of one or more components selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium sulphate and potassium sulphate, optionally further comprising a complexing agent, said electrolyte solution forming electrical connection between said anode and said cathode, the connection between the first electrode and the electrolyte solution defining a contact area (4); and

b) facilitating that said contact area (4) is moved across at least a substantial part of said inner surface so as to allow said electrolyte solution (3) to contact said inner surface to be depleted of the impurities, and simultaneously applying a current density in the range 1-60 A/dm²,

wherein the ratio between (i) the total area of the part of the inner surface which the contact area is moved across and (ii) the contact area is at least 50: 1, and

wherein the movement of the contact area is such that the contact time of the contact area is at least 1 second.

The cleanness of the surfaces treated according to the process according to the present invention can be verified via XPS (X-ray photon Spectroscopy), e.g. as described in the Examples section.

The process of removing impurities as defined herein is believed to reduce the cleaning cycle of the equipment significantly; as compared to conventional CIP cleaning and will "re-set" the surface. This is illustrated by the results presented in the examples section which shows that X-ray photon spectroscopy measurements of a pristine stainless steel surface and a stainless steel surface treated in accordance with the process of the invention appear to be essentially the same.

The process according to the invention can suitably be used for cleaning process reactors being contaminated with a variety of organic constituent, e.g. proteins, milk, etc., and the use is therefore not restricted to the drug industry.

EXAMPLES

XPS (X-ray photon Spectroscopy)

XPS is a versatile technique for analyzing the top ~10 nm of a surface, providing information on the elements present at the surface and the chemical state they are in.

Example 1

Table 1 shows the XPS measurement of a pristine surface of stainless steel type 316. The surface is seen to consist of oxides of mainly chromium and less amounts of iron oxide. Table 1

XPS average values of the reference surface. All results are in atomic %

Example 2

In Table 2, below, the elemental compositions of surfaces after immersion in insulin solution and additional various cleaning processes are given. The presence of nitrogen and sulfur along with the increased carbon signal show that insulin is still present at the surface after cleaning by water immersion, water spray and conventional CIP detergent (CIP 100 supplied by Steris, UK), while a surface that is practically identical to the pristine surface is obtained after conducting the process in accordance with the present invention.

Table 2

XPS average values of surface after immersion in insulin and additional cleaning processes. All results are in atomic %

Claims

1. An electrolytic process for removing impurities from the inner surface of a metallic container (5), said process comprising the step of:

2. The process according to claim 1, wherein the current density is in the range 1-60 A/dm².

3. The process according to any one of the preceding claims, wherein the ratio between (i) the total area of the part of the inner surface which the contact area is moved across and (ii) the contact area is at least 10: 1.

4. The process according to any one of the preceding claims, wherein the electrolyte solution is a solution of one or more components selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium sulphate and potassium sulphate.

5. The process according to any one of the preceding claims, wherein the electrolyte solution additionally comprises one or more complexing agent.

6. The process according to any one of the preceding claims, wherein the electrolyte solution is essentially free of detergents.

7. The process according to any one of the preceding claims, wherein the movement of the contact area is such that the contact time of the contact area is at least 1 second.

8. The process according to any one of the preceding claims, wherein the first electrode is the cathode and the second electrode is the anode.

9. The process according to any one of the claims 1-7, wherein the first electrode is the anode and the second electrode is the cathode.

10. The process according to any one of the preceding claims, wherein the second electrode is a tubular member facilitating a flow of the electrolyte solution.

11. The process according to claim 10, wherein the flow of the electrolyte solution is predominantly laminar and coherent.

12. The process according to any one of the claims 10-11, wherein the electrolyte solution is fed to the gap between the first electrode and the second electrode by means of a tubular member having a slit.

13. The process according to any one of the preceding claims, wherein the electrolyte solution which forms electrical connection between said first electrode and said second electrode is held in a porous structure.

14. The process according to claim 1 comprising the step of: