Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
  • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
  • A61L2/186—Peroxide solutions

Definitions

• This invention relates to methods and compositions for carrying out decontamination procedures on apparatus and equipment that has been in contact with biological materials, in particular blood and blood products. More specifically, the invention relates to an improved procedure (which may be operated manually and/or automatically) for reprocessing used dialysers.
• Extracorporeal hemodialysis therapy provides today a means whereby patients with end stage renal failure can be sustained for prolonged periods by removing the body uremic toxins.
• the principle of hemodialysis involves the circulation of blood and of dialysis fluids within a dialysis machine on the opposite sides of a membrane device (called a "hemodialyser”) .
• the hemodialyser permits the passage of metabolites which become elevated as the consequence of renal failure, but restricts the transfer of blood proteins and cells.
• the therapy is in general applied three times a week for a duration of four hours per session.
• the hemodialyser plays a central role in hemodialysis by determining the ultrafiltration rate and the selective effect required for removal of uremic toxins.
• Hemodialysers vary from one another in many respects, in particular in respect of the material used to form the membrane. These materials have a wide range of chemical compositions, but generally, the nature of the material determines the blood-compatibility or biocompatibility, the membrane pore structure, the membrane sieving, and the membrane transport properties.
• the membranes are in general made from regenerated cellulose, modified cellulose or synthetic (plastics) materials.
• the membrane may be constructed in a wide variety of configurations, but the most usually membrane hemodialysers are in the form of hollow fibers which are encased in tubular housing made with polycarbonate.
• the ends of the fibers are embedded in polyurethane binding material.
• the fibre bundle is bonded at the two end of the housing and a skew cap manifold may be used.
• Hemodialysis devices are in general intended for only a single use. However, with the increased health care service in renal replacement therapy, attempts have been made on economical grounds to adopt procedures for reusing the hemodialyser more than once in order to reduce costs.
• reusable hemodialysers are restricted for use for a single patient.
• Equipment designed to carry out dialysis using reusable hemodialysers are commercially available and gradually, the reprocessing and reusing of new dialysers has become more widespread in clinical practice.
• the cost benefits achieved by reprocessing dialysers are significant, and the costs of dialysis can be reduced by approximately 75% by reprocessing and reusing dialysers 10 to 20 times.
• hemodialysis centers use machines which process the regeneration of many hemodialyser devices simultaneously. All of these machines generally operate using the following sequence of steps: 1. washing and flushing the blood compartment of the dialyzer with water;
• the dialysers should be stored until the next hemodialysis.
• the disinfection step employs chemicals which are effective for killing of microorganisms (bacteria and fungi) which may contaminate the blood compartment of the dialyser during the reprocessing.
• the disinfectant chemicals should also prevent the growth of microorganisms during the storage of the regenerated hemodialyser.
• the quality control of these methods involves the determination that: 1 ) the regenerated hemodialyser is equivalent to a new dialyzer in terms of performance and in terms of biocombatibility of the dialysis membrane, and 2) sterilization of the reprocessed hemodialyser.
• These controls are performed by measuring the volume of the blood compartment, clearance data and blood compatibility parameters.
• the conventional methods of controlling microbial growth involve the use of high concentrations of organic biocides or germicides (many of these are well known in the food industry).
• the substances are in general oxidative chemicals and act on the microorganisms in many ways by attacking the cell wall, or the cytoplasmic membrane, or vital cellular constituents.
• aqueous or aqueous-ethanol peracetic acid solutions have been used typically to sterilize many surfaces of instruments (see, e.g. Machelwsky, P.S., Artificial Organs 1993, 17, pages 147-152).
• problems are associated with known sterilants as regards the quantities that need to be employed, as well as with the high concentrations that are needed.
• the known chemical sterilization methods react chemically with the used dialyser and produce chemical by-products within the reused dialyzer. These by-products are believed to be associated with adsorbed proteins that are present on the surfaces of the dialyser.
• oxidative chemicals used for disinfection oxidize adsorbed protein in the dialysers membrane during sterilization and storage.
• the oxidized adsorbed proteins may enter the patients and may react extracorporally with the biological system, thus increasing the risk of adverse reactions (including the contact phase activation due to the interaction between the blood and oxidized protein at the membrane level).
• the effects of oxidative chemicals are poorly tolerated in uremic disease (Richard, M.S. et al., Nephron 1991 , 57, pages 10-15; Trnadel, K. etal.
• a method for decontaminating a surface of device that has been in contact with a biological fluid which comprises contacting the surface with one or more aqueous disinfectant solutions characterised, in that at least one of the solutions comprises a germicidal sterilant and at least one of the solutions comprises urea.
• the surface is contacted with an aqueous disinfectant solution comprising both a germicidal sterilant and urea in a single solution.
• the invention comprises contacting the surface with one or more aqueous disinfectant solutions characterised, in that at least one of the solutions comprises both a germicidal sterilant and urea.
• the germicidal sterilant is preferably selected so as to result in a synergism with urea to prevent the growth of bacteria and to prevent the oxidation of proteins.
• the germicidal sterilant may be selected from peracetic acid formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, quaternary ammonium compounds, 4,5-dichloro-2-N-octyl-4- isothiazolin-3-one, and 4,5-dichloro-1 ,2-dithio-3-one.
• the concentration of urea (weight per volume) is preferably in the range between 50-200 mmol/l and the concentrations of the germicidal sterilant is less than 300 and preferably less than 200 ppm.
• the method described above is of particular utility in preparing hemodialysis apparatus for reuse, i.e. the "device” referred to is a part of a dialysis apparatus.
• the invention provides a method for performing a biocompatible reprocessing operation on a hemodialysis device to allow its reuse and of controlling the growth of bacteria therein, comprising the step of introducing urea and a sterilant into the hemodialiser.
• the reprocessing operation preferably includes the step of filling the blood and dialysate compartments of the hemodialysis device with a aqueous solution containing a mixture comprising urea and a germicidal sterilant.
• concentration of urea (weight per volume) is preferably in the range between 50-200 mmol/l.
• the germicidal sterilant is preferably peracetic acid, but other sterilants may be used, such as formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, a quaternary ammonium compound, 4,5- dichloro-2-N-octyl-4-isothiazolin-3-one, or 4,5-dichloro-1 ,2-dithio-3-one.
• sterilants such as formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, a quaternary ammonium compound, 4,5- dichloro-2-N-octyl-4-isothiazolin-3-one, or 4,5-dichloro-1 ,2-dithio-3-one.
• a typical regeneration procedure includes the step of filling the blood and dialysate compartments of the hemodialyser device with a aqueous solution containing a mixture comprising as a first component urea, as second compound a germicidal sterilant and as a third compound another germicidal sterilant.
• the "second compound” may be peracetic acid and the "third compound” may be selected from formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, quaternary ammonium compounds, 4,5-dichloro-2-N-octyl-4-isothiazolin-3-one, and 4,5-dichioro-1 ,2-dithio- 3-one.
• the total of the concentrations of peracetic acid and the third germicidal sterilant is less than 200 ppm.
• ascorbic acid w/v
• Aqueous disinfectant solutions for decontaminating hemodialysers prior to reuse comprising a germicidal sterilant and urea form a further aspect of the invention.
• the present invention provides an improved method for the reprocessing of hemodialysers without the use of high levels of germicidal sterilants.
• the present invention further provides compositions for use in hemodialyser reprocessing machines.
• the composition include very low concentrations of peracetic acid or other germicide sterilants and an effective amount of urea.
• the formulation of the composition of the present invention consists of a mixture of urea and a low concentration of germicidal sterilant which provides a synergistic activity against microorganisms and fungi and prevents the oxidation of adsorbed proteins.
• the invention also provides a method of perfusing the dialyzer before use with a composition comprising one or more anti-oxidants.
• the present invention in its preferred embodiments provides a method for inhibiting the growth of microorganisms in reusing hemodialysers.
• the method includes the step of adding manually or through an automated machine to the water a very low amount of germicidal sterilant and an effective amount of urea. Combining the germicidal sterilant with urea has been found to enhance the effectiveness of the sterilization by reducing the risk of protein oxidation.
• perfusion of the reprocessed hemodialyser manual or through an automated machine
• an antioxidative compound such ascorbic acid will further clean the dialyzer and neutralize possible oxidized adsorbed protein.
• the biocide may be chosen from the group consisting of: peracetic acid, formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, quaternary ammoniumcompounds, 4, 5-dichloro-2-N-octyl-4-isothiazolin-3-oneand 4,5-dichloro-1 ,2-dithio-3-one.
• peracetic acid is the germicidal sterilant used.
• a mixture of the germicidal sterilants can also be used.
• peracetic acid or an other germicidal steriliant is added to the water system.
• Alternative germicidal sterilant to peracetic acid may be chosen from the group consisting of formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, isothiazolin, quaternary ammonium compounds, 4,5-dichloro-2-N-octyl-4-isothiazolin-3-one, or 4,5-dichloro- 1 ,2-dithio-3-one.
• a concentration of at least 200 ppm is optimal to inhibit bacteria growth and also to reduce the risk of protein oxidation.
• An alternative is a mixture of two ore more germicidal sterilants comprising peracetic acid and second chemicals from the group consisting of formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, isothiazolin, quaternary ammonium compounds, 4,5-dichloro-2-N-octyl-4-isothiazoiin-3-one, and 4,5-dichloro-1 ,2-dithio-3-one.
• the total concentration of peracetic acid and the second germicidal sterilant is in the range between 100 and 500 ppm.
• a concentration of 100 ppm of peracetic acid and 100 ppm for the second sterilant is optimal to reduce the risk of protein oxidation.
• urea is added prior to the germicidal sterilant in the water system.
• the main advantage of this invention is that by using a mixture of germicidal sterilant and urea there is provided an improved composition on the one hand for inhibiting the growth of organism in the hemodialyser and on the other hand, for desorbing protein from the dialyzer membrane.
• concentration of urea used is preferably between 20 and 50 mmol/l.
• the hemodialyser is washed with a ascorbic acid solution.
• the main advantage of this procedure is to neutralize the possible residual germicidal sterilants which were not removed by washing.
• the invention as a result of the reduced need for germicidal sterilants, provides an improved anti-oxidative method for reprocessing, storage and preparation of dialyzers.
• the improved procedure comprises the steps of: flushing and washing, sterilizing with the composition of the invention, storing with the composition of the invention, washing with pure water, and flushing with an anti-oxidative solution.
• an advantage of the present invention is that it provides a more cost effective and environmentally friendly method for reprocessing hemodialysers. Additional features and advantages of the present inventions are incorporated in the following preferred embodiments.
• the present invention provides, for reprocessing of a dialyser, improved methods and chemical compositions to be administrated in a fluid system.
• the invention relates to the application of a mixture of a sufficient amount of urea and low amount of peracetic acid or other biocides that exhibits a synergistic effect when added to a fluid.
• the invention also proposes the flushing of the dialyser prior clinical use with an antioxidative solution, preferably an acid ascorbic solution
• the most suitable germicidal sterilant to be mixed with urea is peracetic acid.
• other germicidal sterilants which can be used in this invention include: peracetic acid, formaldehyde, glutaraldehyde, hydrogen peroxide, methylene bisthiocyanate, carbamate, DBNPA, quaternary ammonium compounds, 4,5- dichloro-2-N-octyl-4-isothiazolin-3-one, and 4,5-dichloro-1 ,2-dithio-3-one.
• the germicidal sterilants can be obtained from a number of chemical suppliers.
• the composition also may include a mixture of sufficient amount of urea, peracetic acid and second germicidal sterilant.
• the invention also provides a method of preparing the reprocessed dialyser with an ascorbic acid solution prior clinical use.
• the invention can be used for a variety of dialysers in which the semi- permeable membrane is in the form of hollow fibers or in form of sheet or plates.
• the invention can be used for reprocessing dialysers for blood purification. But, it also can be used for reprocessing filters for plasmapheresis and for washing used peritoneal dialysis fluids from dialysers after use.
• Urea, ascorbic acid, peracetic acid or other germicidal sterilants solutions used in the practice of the invention are preferably drug grade and dissolved in ultrapure water, i.e. water which was been treated by reverse osmosis and which has been filtered to remove bacteria and pyrogens.
• the method of reprocessing the dialyser is preferably based on the use of a composition of a concentration of 20-40 mmol/l of urea with peracetic acid or other germicidal sterilant at the concentration of 200 ppm. Such use provides an unexpected synergistic effect for inhibiting the growth of microorganisms but has no measurable oxidative effects on the adsorbed proteins during sterilization and storage.
• the beneficial effect in the inhibition of the protein oxidations is primarily due to the fact that the oxidative germicidal sterilants is considerably reduced to a lower concentration.
• the synergistic relationship is present in that the cooperative action of the combined urea with peracetic acid yields a total effect which is greater than peracetic acid at 200 ppm (in this context, "ppm" means 1 part per million by wight per volume), compared to use of peracetic acid at higher concentration.
• ppm means 1 part per million by wight per volume
• composition comprising 20-40 mmol/l urea with a mixture of peracetic acid with one or more germicidal sterilants with the end concentration of 200 ppm can be used in this invention.
• the synergistic relationship of urea and peracetic acid is increased by the presence of other germicidal sterilant.
• the overall process of the invention can follow the following reprocessing steps.
• the used dialyser will undergo a flushing and washing procedure through the blood compartment of the dialyzer using reverse osmosis (RO) water.
• RO reverse osmosis
• the cleansing of the used dialyser is preferably performed using ultrapure RO water to avoid bacterial endotoxin contamination and the introduction of water impurities in the dialyser.
• the procedure applied involves filling the blood and dialysate compartments of the dialyzer with chemical composition.
• the solution of 200 ppm of peracetic acid (alternatively with another germicidal material as discussed above, or a mixture) and 10-50 mmol/l urea is primed in the dialyser.
• the blood and the dialysate compartment will be closed, and the dialyser can be stored closed at room temperature, or preferably at + 4 °C.
• the dialyser Prior to reusing the dialyser, it is necessary to remove all the chemicals from both the blood and dialysate compartments.
• possible residues of oxidative chemicals are neutralize by filling of the blood compartment with a 0.9% saline solution containing 5mg/ml ascorbic acid (w/v). It may be preferable to circulate the solution for a period at least 30 min to neutralize residues of the germicidal sterilant. All the steps may performed manually or automatically.
• the dialysers are ready for use in a dialysis treatment.
• the mixture containing the germicidal sterilant and urea are removed from the dialysate and blood compartment using by washing with a sufficient amount RO water to remove the chemicals.
• the dialyser is then primed with sterile saline containing 5mg/ml ascorbic acid until the blood compartment is free of air.
• the ascorbic acid saline solution is recirculated through the blood compartment in a close loop fashion while the dialysate is passed though the dialysate compartment. This last procedure can be performed in an automated or in an manual fashion .
• the reprocessing of the dialyser is performed three times per week with a storage time of 48 hours. The process is thereafter repeated multiple times (normally a maximum of twenty times, preferably a maximum of sixteen times) until the dialyser fails the conventional transmembrane pressure test.
• the reprocessed dialysers should not be transferred from one patient to another (as in conventional reprocessing methods).
• Figure 1 shows the results of experiments to assess the disinfectant ability of compositions according to the invention.
• Figure 2 shows the results of experiments to assess the extent to which compositions according to the invention oxidise proteins.
• Figure 3 shows the results of assessing Bradykinin release following reprocessing of a dialyser by various methods.
• Figure 4 shows the results of assessing clearance following reprocessing of a dialyser by various methods.
• Figure 5 shows the results of assessing biocompatibility following reprocessing of a dialyser by various methods.
• This example demonstrates the synergistic effects of the compositions of the present invention to sterilize hemodialysers.
• Hemodialysers employed were made from a polysulfone membrane manufactured by Fresenius Medical Care (Bad Homburg, Germany), designated as F60, which had been clinically used forthe first time.
• F60 Fresenius Medical Care
• TSA trypticated soy agar plates
• the suspension was used to inoculate a bicarbonate dialysate solution, which was incubated by shaking at 37 °C.
• the used dialysers were flushed by recirculation for 60 minutes with the contaminating solutions.
• the dialysers were flushed and washed with sterile water to remove the contaminating solutions according to Step 1 of the invention, filled with various compositions of the invention, and stored for different incubation times. Experiments were performed for several time periods, i.e, 0 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours.
• compositions were : composition A: 50 mmol/l urea and 200 ppm peracetic acid; B: 50 mmol/li urea in 200 ppm hydrogen peroxide; C: 50 mmol urea in 200 ppm methylene bisthiocynate; D: 50 mmol/l urea in 200 ppm carbamate; E: 50 mmol/l in 200 ppm 4,5-dichloro-2-N-octyl-4-isothiazolin-3-one; F: 50 mmol/l in 200 ppm 4,5-dichloro-1 ,2-dithio-3-one.
• composition A the preferred composition of the invention was tested for its ability to kill several microorganism at room temperature: Pseudomonas maltophilia, Staphylococcus aureus, Escherichia coli, Mycobacterium chelonae, Aspergillus niger. All these organisms may accidentally contaminate hemodialysers.
• dialysers reprocessed with a composition in accordance with the invention are free of adsorbed oxidized proteins as compared with conventional hemodialysers. This leads to a better biocompatibility of the dialysis membrane in terms of not activating the contact phase of the circulating blood during hemodialysis.
• New dialysers (made with polysulfone membrane manufactured by Fresenius Medical Care Bad Homburg, Germany) were perfused with human plasma for four hours using a dialysis machine.
• the dialysers were treated according to the reprocessing procedure of the invention. The reprocessing steps were repeated 50 times for each dialyser.
• the dialyzers were rinsed with a 1 % Triton and a total volume a 100 ml eluate has been collected.
• MILLIPORE Ultrafree-15; Biomax-5
• the detection of oxidized protein was performed by competitive enzyme linked immunoassay using a polyclonal antibody DNP-derivatized proteins. The method applied is based on the fact that oxidative modification of proteins involves the introduction of carbonyl groups into protein side chains by a site-specific mechanism.
• the carbonyl groups of oxidized proteins in the samples obtained by the elluates) were derivatized to 2,4-dinitrophenyhydrazone (DNP-hydrazone).
• Figure 1 a shows the extent of the oxidation of the dialyser adsorbed proteins treated with the different compositions of the invention compared with treatment with a conventional peracetic acid composition.
• the tested compositions in accordance with the invention were : composition A:, B, C, D, E:, as described in Example 1 .
• Clinical testing the Figure 2b shows similar results during clinical trials using a the preferred composition containing urea and low concentrations of peracetic acid in comparison with the standard reprocessing procedure.
• the tested composition in accordance with the invention was composition A as described in Example 1 .
• dialysers reprocessed with the composition containing urea and low concentration of peracetic acid in accordance with the invention are effective in reducing the risk of bradykinin in patients receiving ACE- inhibitors such as Captopril.
• This performance is related to the fact that the dialyser membrane protein-layer of the dialyser reprocessed according to the invention is not negatively charged through oxidation.
• the tested composition in accordance with the invention was composition A as described in Example 1 .
• covalent coupling of the desorbed proteins onto polystyrene microwells (CovaLink NH ; Nunk) for the use in an assay was applied.
• the coupling of proteins has been achieved using N-hydroxysuccinimide (NHS esterified molecules).
• the final protein concentration was 10 g/ml; 2) 100 /vl of the protein solution were then pipetted into well of the Covalink plate and covered at the top.
• dialysers reprocessed with urea and low concentration of peracetic acid in accordance with the invention are effective in performing hemodialysis in terms of clearance of low and middle molecular weight toxins.
• An open loop dialysis circuit was mounted in a dialysis machine (4008, Fresenius Medical Care, Bad Homburg Germany) and comprised a bag reservoir containing 2 liters, sterile dialysis tubes (Fresenius Medical Care) and the dialyzer.
• the clearance rates of urea, creatinine, phosphate and Vitamin B12 were stated for the range and dialyzing fluid flow rates and include of 200ml/min, the ultrafiltration was 10ml/min.
• the blood flow rate was always measured by weighing the medium pumped.
• the dialysate fluid flow rate was 500 ml/min.
• the blood compartment was perfused with the test substances dissolved in dialyzing fluid.
• Figure 4a shows the clearance data.
• Figure 4b shows the total membrane protein adsorption due to the generation of a secondary layer.
• clearance data for small and middle molecules after different reprocessing procedures using the preferred composition in accordance with the invention were found to be substantially the same as the clearances achieved by the same dialyser before the first use.
• dialysers reprocessed with urea and low concentrations of peracetic acid in accordance with the invention are effective in performing hemodialysis biocompatibility in terms of platelet and complement activations.
• the blood-compatibility testing circuit used was a close system according to ISO 8636 in which the test medium was heparinized fresh human blood.
• Thrombin antithrombin III (TAT) measurements were performed using ELISA (Enzygnost TAT micro) purchased by Behring (Germany, Marburg).
• Complement C3a measurements were performed by commercially available ELISA test provided by Amersham.
• Figure 5 shows the blood-compatibility data. As shown, TAT and C3a after different reprocessing series using the preferred composition in accordance with the invention, were found to be substantially better as the same dialyser before the first use. These data demonstrated the blood compatibility performance of a dialyser reprocessed with the composition in accordance with the invention.

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