CS230676B1 - The way to determine the safety of rubber bays in the food industry - Google Patents

Abstract

The invention solves a method of determining the safety of rubber stoppers in healthcare. The essence of the invention of a method of determining the safety of rubber stoppers in healthcare is characterized in that the stoppers are brought into contact with model solutions a) pyrogen-free water for injection b) sodium chloride solution 0.9% to 10.0% c) glucose solution 5.0% to 40.0% d) procaine chloride solution 0.5% to 1.0% e) sodium bicarbonate solution 4.2% to 8.4% for 30 minutes at a temperature of 120 C at a pressure of 0.101 325 MPa and at least 24 hours after cooling, successive tests are performed for the presence of cations and anions, using qualitative and spectrophotometric analytical methods in the wavelength range of 220 to 360 nm.

Description

The invention solves a method of determining the safety of rubber plugs in health care.

According to the standards currently in force in Czechoslovakia, we have Czechoslovak state standards ČSN 77 4010 Rubber stoppers for health care with effect from. 1962 sub-topic of the standard plug-hole are prepared, where the accurate determination of the quality of the STN 77 4011 - _Tr ojoťworové cap as of r · 1963 and CSN 77 4015 - stoppers for blood and infusion solutions as of r. 1965 · The method of testing for all types of rubber plugs is determined by the standard ČSN 62 1156 - Chemical testing of rubber for health purposes, where the procedure for testing rubber plugs of all types intended for medical purposes is specified.

Chemical testing of water leach is considered to be the basis of testing, which is tested according to ČSN 77 4010 III for three-hole plugs for infusion solutions. Testing, item 14 ·, is prepared from rubber stoppers which, after cleaning as described in ČSN 62 1156, are washed for 5 minutes under running water at 80 ° C. They are then rinsed with distilled water and boiled in 500 ml of sodium phosphate solution (25 g / L) for 30 minutes. After boiling and rinsing carefully in 50 ml of hydrochloric acid solution (5 g / L), with stirring at room temperature. The samples were thoroughly rinsed with distilled water until the reaction to chloride disappeared, which was tested with a solution of silver nitrate. The samples thus cleaned are rinsed 3 more times with distilled water, dripped and autoclaved without drying by placing them in a conical flask, pouring 50 ml of distilled water over them, and covering with a suitable beaker. They are placed in a cold autoclave and heated for υ 20 minutes until the temperature reaches 120 ° C. From this time it is autoclaved for exactly 30 minutes at 120 ° C,

* $ 30 070 resulting in 0.126 656 MPa overpressure. jThen the steam supply is turned off, the valves are opened and the closed autoclave is allowed to cool. After autoclaving, the test samples of the rubber stoppers are rinsed with distilled water, poured onto them with 500 ml of distilled water and autoclaved again in the same SDS and under the same conditions.

The third extract is prepared by filling 4 infusion bottles of 500 ml volume well washed with 400 ml of pyrogen-free water and stoppered with the rubber stoppers provided as above.

The flasks were autoclaved down the neck and under the same conditions as described above. Prepare a blank test in the same manner. The chemical examination of the aqueous extract focuses on the determination of the water-soluble fraction, the determination of opalescence, the redox number, the determination of the concentration of hydrogen ions, the determination of the electrical conductivity and the health-ions test or the presence of lead, mercury, media, cadmium, ar of zen, antimony, tin, iron, calcium, strontium, barium, magnesium, ammonium, and chlorides, sulfides, acid sulfides and thiosulfates, sulfates. Zinc compounds are determined polarographically and must be tested within 3 days of preparation of the extract.

The said standard also requires testing of rubber plugs on model solutions, such as the resistance of the rubber to the model solutions, which results in changes in the solutions in contact with the rubber in the prescribed manner. Model solutions a / Citric acid, solution 10 g / L are tested.

(b) Tartaric acid, solution 20 g / L.

e / Mixed solution prepared by successive dissolution of 2 g oftronic acid, 10 g of sucrose in 100 ml of distilled water.

d) A mixed solution prepared by successively dissolving 2g of sodium chloride in a 400ml acetic acid solution of 40g / L.

(e) Acid solution A - medium of hydrochloric acid,

2.5 ml hydrochloric acid solution g (HCl) = 0.1mol / L is made up to 100 ml with water for injection and adjusted to pH 3.4-3.8.

f / Acid solution B - hydrochloric acid medium,

0.16 g of zinc oxide in 0.22 ml of hydrochloric acid 370 370 g / L, 14 g of glycerin, 2 g of metacresol are added and made up to 100 ml with water for injection and adjusted to a pH of 3.4 to 3.8.

230 878 ”3 g / Refined edible oil / ČSN 5θ 0220 / resp. olive oil UNM-MPP-154-55

The autoclaving of the solutions is carried out in a similar manner to the aqueous leachate of the rubber as the material. In the second autoclaving, the appropriate model solution is used instead of distilled water, then the tests are carried out as follows.

a) Appearance and taste tests - autoclaved extract solutions with model solutions must not discolour, haze, or have an unpleasant odor or bitter taste when compared to a blank sample of the model solution.

b) Determination of pH c / Fat resistance - determined in accordance with ČSN 62 1501 in olive oil UNM-MPP-154-55 grade in another oil according to ČSN 58 0220 unless stated otherwise.

(d) The determination of zinc is performed polarographically.

On the basis of experimental results, model solutions according to ČSN 62 1156 - Chemical testing of rubber are harmless to health are considered non-specific to real medicinal solutions.

They are also very aggressive to the rubber stopper. Basic knowledge of appearance control cannot be taken into account, especially sucrose and citric acid is absolutely inappropriate as a model solution, because it caramelizes during sterilization and thus excludes from further monitoring the quality of the extract. The acidic solution B has an original pinkish color and a specific odor on which the effect of the stopper odor cannot be observed. Also, acetic acid, a 50g / L solution has a characteristic odor, and it can also be seen to change in connection with the rubber stopper. Tartaric acid solutions of 20g / L and acidic solution A caused considerable tackiness of the plugs, suggesting a considerable aggressiveness of the stopper solutions. Olive oil proved to be highly aggressive to the stopper, because the oil not only took up the smell of rubber, but the stopper deformed.After sterilizing the stopper swell. The method of testing the model solutions is insufficient.

To ensure good manufacturing practice, it is necessary to follow the plug from three main aspects.

1. Physical properties summarize the essential properties that result from the primary function of the stopper to protect the drug from external influences such as atmospheric oxygen, moisture, it must provide a solution against evaporation of the fluid.

230 876

- 4 2. From the application point of view, the stopper must not be hard, it must be sufficiently flexible that the injection needle is inserted into the needle, it must not be crumbled or glued to the injection needle. It must be leakproof after injection to prevent fluid from flowing through the punctured hole.

3. The stopper must be compatible with the drug, there must be no leached components of the rubber into the drug, nor must it catalytically affect some drug change processes.

The safety aspects of chemical purity are determined by a number of criteria having a qualitative or global character. These are organoleptic tests aimed at monitoring the appearance of a leachate prepared by extracting a certain amount of stopper in a prescribed amount of leachate. The leach known to date is brewed redistilled water, oil for injection and, in some cases, ethyl alcohol. The leach is monitored for turbidity, mechanical cleansing and coloring of the solution against a blank sample prepared under the same conditions as the sample in an all-glass container. The resulting evaluation is then given as the shift towards the blank.

For chemical testing and evaluation, the preparation of a water leach is based on several methods. It can be prepared as an infusion solution, but it can also be prepared by leaching the whole stopper, or multiple whole or cut stoppers. The prepared liquor is then monitored for individual anions and cations, solutes, reducing agents, eventually organic substances, spectral absorbance in the region of 22O-36Onm, solution conductivity and actual solution acidity. Inspection of rubber plugs in foreign pharmacopoeias 2AB DDR, BP73> Comp.medic., LAB7 DDE, DAB7 BRD, QAB9, Ph.Fran £ .V ± II ^e , Ph.Helv.VI., Ph.Nord.Add.67 *, Ph.Ital.65., Ph.Jap.VIII., USP XIX., In which, in addition to an aqueous extract, ethanolic diluted extract or oil extracts are monitored.

In the regulations of German standards DIN 58 367 Blatt 1 1974 a

Blatt 2. 1974, we find a requirement to monitor the aqueous leachate of sodium chloride, in which all possible leachable constituents of the basic and auxiliary components derived from the rubber stopper should be monitored by chemical and physicochemical methods.

Compendium medicamentorum is binding for the Comecon states.

According to Lieferung XIV ”finally approved for the Board of Specialists Standardization of Drugs” in Varna on 19-24. IV.1976 requires appropriate consistency and surface properties for the articles to be stored or used for infectious and infusible solutions, shall not release toxic substances and affect the quality of the medicinal product.

230 070

- 5 The type and extent of the tests are determined according to their intended use *

For rubber stoppers it is required to prepare the extract from pieces with a total flatness of 500cm, caps divided into an area of 40cm, weight 8.0g, the pieces need to be cut from at least 2 caps. To the cut pieces was added 100 ml of water. The mixture is boiled for 20 minutes and then the hot liquid is decanted and discarded, then the pieces are rinsed with 100 ml of water.

Test solution I is prepared by adding 100 ml of science to the prepared material. In a suitable covered container, the mixture is placed in a steam sterilizer and, after the equalization time has elapsed, is left at 121 ° C for 20 minutes.

The bays thus prepared are tested for surface properties, puncture, fragmentation, puncture test, oil resistance, insoluble contaminants, solution color, odor, taste, reaction of the solution, ammonium and amines, heavy metal ions, barium, zinc, chlorides, phosphates, sulphates, sulphides, reducing pollutants, evaporation residue, testing of organic substances is intended for all plastics. For chemical testing, blank solutions must be prepared under the same conditions as the test solutions.

For diluted ethanol extracts only the evaporation residue is tested.

A wide variety of infusion solutions are currently being produced in the healthcare industry in various combinations, according to the individual need of the patient to replace cations, anions in the body, nutrition of the patient, or the administration of other medicinal components for the treatment of the patient. Usually, patients with severe blood or fluid loss are very weak. Products made for this purpose must be of high quality because they are administered intravenously in large quantities to the body.

In practice, it has been shown that the solutions required to test rubber plugs hitherto cannot be a sufficient safeguard for the safe use of a wide range of infusion solutions and transfusion service, also due to the aggressiveness of some solutions, or vice versa. the development of incompatibilities with some components of the infusion solution, and the deterioration of laborious and carefully manufactured solutions.

Also of great importance is the method of preparing the plugs for testing, in particular not to be too aggressive and, on the other hand, to be close to the practice of how the plugs are prepared prior to use for sealing infusion solutions and transfusion service.

230 070

- 6 It is known that infusion solutions must also be prepared carefully for infusion solutions and will depend on the way they are used to make the capsules and bottles. For clarity, the method for making the bottles and capsules used in the preparation of infusions is also indicated. solutions aa considers to be a common technology.

1 · Bottle washing - 500 ml infusion bottles are used for sample preparation. It is immersed for 24 hours in a degreasing solution consisting of a solution of Na2 PO4 (30 g / L) and chlorine amine BS (5 g / L) for degreasing and disinfection. After this time a and the bottles are washed in an automatic dishwashing machine with a / rinse with hot water 1.5 minutes bZ rinse with hot water 80 ° C 1.5 min o / rinse with neutralizing citric acid solution / 20g / L / 1.5 min dZ rinse with warm water 1.5 minutes eZ cold water rinse drinking 1.5 minutes f / hand rinse with pyrogen-free water per bottle consume 100ml water.

After thoroughly washing the bottles, the bottles are sterilized for 120 minutes at 180 ° C with hot air. The bottles are covered in the sterilizer.

2. Washing rubber bays aZ double rinsing with warm water to remove dust particles and coarse debris bZ soaked in Dubaryl Z5gZLZ - detergent degreaser éZ 4 times rinsing with drinking water dZ 2 times rinsing with distilled water eZ 10 minutes boiling in pyrogen-free water gZ 1x sterilized with a 30 minute boil hZ water is removed from the ZOLOL pot in aseptic box and capped into bottles.

We have officially 12 infusion solutions in CS3. We know that several dozen different mixtures of electrolytes, sugars, amino acids, artificial blood substitutes such as macromolecular dextrans, rheodextrans, hydroxyethyl starch, gelatin and many others are currently being prepared.

It can be seen from the above that the testing of bays for infusion and transfusion solutions is a topical and important issue. Only water leaching tests, given the range of solutions in the wide range of active ingredients in combination of active ingredients, Whether to look for a suitable rubber compound or to look for selected rubber compounds · The quality of rubber plugs should be tested on infusion solutions manufactured according to the required technological rules and based on the actual possible leachable components of the rubber compound ·

The above-mentioned deficiencies will eliminate the method of determining the health / safety plugs in the health by contacting the plugs with the model solution for 30 minutes at 120 ° C at a pressure of 10101 325 MPa and at least 24 hours after cooling on the model solutions and / water pyrogen-free for injection b / sodium chloride solution at a concentration of 0.9% to 10% w / v c / glucose solution 5% to 40% w / v dZ procaine chloride solution 0.5% to 1.0% w / v eZ Sodium bicarbonate solution 4,2 to 8,4% w / w Successive tests for the presence of cations and anions shall be carried out by qualitative and quantitative analytical methods and spectrophotometers in the 220-360nm wavelength.

The solutions are prepared according to the usual technique for infusion solutions in 500 ml infusion bottles, sealed with the test rubber stopper and sterilized in the prescribed manner down the throat. prepare, under the same conditions, a reference solution, sealed with a glass stopper.

The solutions thus prepared are then subjected to sequential chemical purity tests in model solutions by qualitative and quantitative, physicochemical, analytical methods, by measuring the acidity and the spectral absorption curve by measuring the y-range of 22O-36Onm.

Chemical tests should be conceivable of the possibility of migrating the components present in the rubber mixture. The evaluation of the tests is then performed by monitoring the displacement against the blank.

Case 2 - The method of determining the safety of rubber plugs in health care can also be used if more concentrated plug solutions are used, namely 8 g plugs per 100 ml of the test model solution. At the same time, prepare a reference solution without a plug in an all-glass container.

230,070 - 8 -

SUMMARY OF THE INVENTION A method of determining the health of rubber plugs is to contact the plugs with model solutions for 30 minutes at 120 ° C at a pressure of 0.101 325MPa and at least 24 hours after cooling, sequential tests for the presence of cations and anions on model solutions and / in pyrogen-free water for injection b / in sodium chloride solution 0.9 to 10% w / v.

c / in glucose solution 5 to 40% w / v

d / in procaine chloride solution 0.5 to 1.0% w / v e / in a sodium bicarbonate solution of 4.2 to 8.4% w / v. by analytical qualitative and quantitative methods as well as by physicochemical methods, they give an indication of the suitability of using rubber plugs for practical use directly on infusion solutions. The behavior of rubber plugs in relation to model solutions is a serious piece of information that can take into account the possibility of appropriately using new plug mixtures as well as the observance of perfect quality.

By testing model solutions, can the manufacturer check his products for suitability? practical use, what has been done so far on unsatisfactory model solutions and it was necessary to wait for the customer's statement.

Accurate determination of analytical testing also gives the possibility to compare and evaluate tests at several workplaces.

Accurate determination of analytical testing also gives the possibility to compare and evaluate tests at several workplaces.

By approaching the testing of model solutions in practice, it is faster to point out defects in the manufacturing process and respond to improvements in the production and quality of bays for medical purposes. By confirming suitability, the quality of the product is reflected in the quality of the final solution for infusion, resulting in benefits to human health care.

- 9 Execution example

Model solutions 230 a / pyrogen-free water b / sodium chloride solution 0.9% to 10% w / v

c / glucose solution 5% to 40% w / v

d / procaine chloride solution 0.5% to 1.0% w / v

6 / Sodium bicarbonate solution 4.2% to 8.4% are prepared from tested outgoing substances! and pyrogen - free water used in the preparation of infusion solutions. The prepared and filtered infusion solutions are filled into 500 ml infusion bottles with 400 ml. Shampoos are well washed, bottle washing technology adapts to the automatic washing program. FTas were soaked for 24 hours in Na2 PO4 (30 g / L) sodium phosphate degreasing solution and chlorine BS (5 g / L) for degreasing and disinfection. After this time, the flasks were rinsed well in running water for about 1.5 minutes and more preferably for 1.5 minutes rinsed in hot water at 80 ° C, rinsed in citric acid neutralization solution (20g / L), rinsed with warm water 1.5 minutes, cold water for 1.5 minutes, and pyrogen-free water so that 100 ml of water is consumed per 1 FSh.

After thoroughly washing the bottles, the bottles are sterilized for 120 minutes at 180 ° C with hot air.

The plug washing technology shall be modified by thoroughly washing the rubber plugs under running water to:. . deburring of surface particles and coarse debris. They are soaked in a detergent solution of Dubaryl, a degreaser, or suitable for this purpose (5g / L), the plugs are then rinsed well with potable water, poured onto the plugs and rinsed 4 times with distilled water twice, poured with distilled water and boiled. minutes in pyrogen-free water, the water is decanted and rinsed 3 more times with pyrogen-free water and the stoppers are sterilized for 30 minutes. In this way, the stoppers are ready to stop the bottles.

The bottles after filling and stoppering are sterilized at 120 ° C for 30 minutes at a pressure of 100 psig down the throat. At the same time, prepare a blank sample in an all-glass container under the same conditions.

After sterilization, the solutions are allowed to cool and, after 24 hours, the tests prescribed for each model solution are carried out. They monitor the change in appearance of the solution and the stopper, and carry out successive chemical tests on the purity of the model solutions.

- 10 230 070 by means of analytical methods qualitative and quantitative for the presence of cations, anions present in rubber precipitates and residual components from bottle and beverage washing shall also use physico-chemical methods, measurement of actual acidity, conductivity, spectral absorption curve in the 220-36Qnm wavelength range, by 10nm and other methods necessary to detect undesirable substances · Evaluation of the tests shall be carried out by monitoring the change of the sample against the blank ·

Concentrated solution can be prepared under the same conditions by sterilizing 3 plugs immersed in the model solution at a weight ratio of 8g plugs to 100 ml of the model solution. At the same time, prepare a reference solution without plugs under the same conditions as the plugs. as in the previous way ·

The preparation of a more concentrated extract to accelerate the aging information of the preparation can also be carried out according to the method of Compendium Medium andmentorum at a weight ratio of 8 g of stopper per 100 ml solution using model solutions.

Possibility of testing the produced solutions to confirm their quality ·

Claims (1)

BACKGROUND OF THE INVENTION 230 87, the safety of rubber plugs in the medical field, characterized in that the plugs are brought into contact with the model solution. For 30 minutes at 120 ° C at a pressure of 100 psig and at least 24 hours after cooling, successive tests shall be carried out for the presence of cations and anions in model solutions, namely 0 in pyrogen-free water for injection. , 9% to 10%, dP in glucose solution 5.0% to 40.0%, 91 / n procaine chloride solution 0,5% to 1,0%, ^Λ dP in sodium bicarbonate solution 4,2% to 8,4% by qualitative and quantitative analytical methods with spectrophotometry in the wavelength range 220 to 360nm ·