药用丁基橡胶塞培训教材-技术部
丁基橡胶输液瓶塞安全操作规定
丁基橡胶输液瓶塞安全操作规定背景输液瓶塞是医疗器械中的一种常用物品，为了保证病人的用药安全和医护人员的健康，使用输液瓶塞时必须坚持标准化操作，特别是对于丁基橡胶输液瓶塞，更应该严格控制使用和管理。
安全操作规定以下是丁基橡胶输液瓶塞的安全操作规定：1. 瓶塞检查在使用丁基橡胶输液瓶塞之前，必须对其进行检查，确保其完好无损。
检查内容包括：•瓶塞有无裂纹、磨损、渗漏或变形；•瓶塞表面有无异物、粉末、油污等；•瓶塞与瓶口接触部分无皮肤、チ刮痕等损伤；如发现异常情况，应立即更换瓶塞并向上级报告。
2. 消毒处理丁基橡胶输液瓶塞在使用之前应进行消毒处理，消毒方法可以采用物理方法或化学方法。
物理方法可以采用蒸汽灭菌或者高压灭菌；化学方法可以采用过氧乙酸等消毒剂。
3. 瓶塞安装在安装瓶塞时，应根据相应的要求进行操作。
安装时禁止使用锤击等粗鲁操作，瓶塞的卡口应完全卡住瓶口,不能卡歪，否则将会导致漏药。
4. 输液前检查丁基橡胶输液瓶塞安装后，应进行输液前的检查，确保瓶塞无渗漏、破损等异常状况，输液管道无异物和漏气等情况。
5. 瓶塞更换瓶塞使用期限一般为4个小时，超时即应更换，禁止重复使用。
在更换时应注意避免瓶塞和其他物品碰撞，确保操作正确。
6. 瓶塞管理将瓶塞放置在光线充足、通风干燥的地方，存放温度不超过25摄氏度。
禁止紫外线照射，禁止叠压。
废弃的瓶塞应按照医院的相关要求分类存储和处理，避免对环境造成污染。
结语丁基橡胶输液瓶塞作为常用的医疗器械，对病人的用药安全以及医务人员的健康起到了至关重要的作用。
正确认识和使用输液瓶塞，严格按照操作规定进行使用、管理，是医护人员应该始终遵守和坚持的。
丁基橡胶药用瓶塞检测SOP
丁基橡胶药用瓶塞检测SOP1. 目的为规范注射液用卤化丁基橡胶药用瓶塞的检定，特制定本SOP。
2. 范围本SOP适用于直接与注射剂接触的卤化丁基橡胶塞（注射液用卤化丁基橡胶塞、预灌封注射器用氯化丁基橡胶塞、预灌封注射器用溴化丁基橡胶塞）的检定。
3. 定义无4. 职责4.1.QC负责本规程的起草、修订、培训及执行。
4.2.QA、QC组长、质量管理部经理负责本规程的审核。
4.3.质量总监负责批准本规程。
4.4.QA负责本规程执行的监督。
5. 引用标准5.1.注射液用卤化丁基橡胶塞国家食品药品监督管理局直接接触药品的包装材料和容器标准汇编5.2.预灌封注射器用氯化丁基橡胶活塞国家食品药品监督管理局直接接触药品的包装材料和容器标准汇编5.3.预灌封注射器用溴化丁基橡胶活塞国家食品药品监督管理局直接接触药品的包装材料和容器标准汇编5.4.《中华人民共和国药典》6. 材料6.1.仪器设备天平，恒温水浴箱，分光光度计，pH计，恒温干燥箱，变温电炉，干燥器，电导率仪，高温炉。
6.2.试剂溶液标准铅溶液：购入；氯化铵铵溶液：取氯化铵10.5g，加水溶解使成100ml，即得；标准锌溶液：称取硫酸锌（ZnSO4·7H2O）0.440g，置1000ml量瓶中，加水溶解并稀释至刻度，摇匀，即得（每1ml相当于100µg的Zn）；0.02mol/L高锰酸钾滴定液: 按《高锰酸钾滴定液配制及标定SOP》操作；0.1mol/L硫代硫酸钠滴定液：按《硫代硫酸钠滴定液配制及标定SOP》操作；碳酸氢钠：购入；硝酸：购入；硝酸银试液：取硝酸银17.5g，加水适量使溶解成1000ml，摇匀，即得；0.1%氯化钾溶液：取氯化钾0.1g，加水使溶解成100 ml，即得；稀硫酸：取硫酸57ml，加水稀释至1000ml，即得；淀粉指示液：取可溶性淀粉0.5g，加水5ml搅匀后，缓缓倾入100ml沸水中，随加随搅拌，继续煮沸2min，放冷，倾取上层清液，即得，本液应临用新制；碱性碘化汞钾试液：二氯化汞饱和水溶液：取二氯化汞7g，溶于100ml水中，摇匀。
药用丁基胶塞---四大药典检测标准异同
药用丁基胶塞---四大药典检测标准异同Summary1、Penetrability[YBB]Take 10 rubber closures, test according to the second method of YBB60072012, the average puncture force does not exceed 10N.[EP] Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using foreach closure a new, lubricated long-bevel(1) (bevel angle 12 ± 2°) hypodermic needle with an external diameter of 0.8 mm, pierce the closures with the needle perpendicular to the surface. The force required for piercing, determined with an accuracy of ± 0.25 N (25 gf), is not greater than 10 N (1 kgf) for each closure.[JP]None[USP]Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined, and secure with a cap. Using a new hypodermic needle as described above for each closure, pierce the closure with the needle perpendicular to the surface.Requirement—The force for piercing is no greater than 10 N (1 kgf) f or each closure, determined with an accuracy of ± 0.25 N (25 gf).2、Fragmentation[YBB]Take 10 rubber closures, test according to the second method of YBB60082012, The total number of fragments does not exceed 5.[EP] For closures intended to be pierced by a hypodermic needle, carry out the following test. If the closures are to be used for aqueous preparations, place in12 clean vials a volume of water R corresponding to the nominal volume minus4 ml, close the vials with the closures to be examined, secure with a cap andallow to stand for 16 h. If the closures are to be used with dry preparations, close 12 clean vials with the closures to be examined. Using a lubricated long-bevel(1) (bevel angle 12 ±2°) hypodermic needle with an external diameter of 0.8 mm fitted to a clean syringe, inject into the vial 1 ml of water R and remove 1 ml of air ; carry out this operation 4 times for each closure,piercing each time at a different site. Use a new needle for each closure and check that the needle is not blunted during the test. Pass the liquid in the vials through a filter having approxi mately 0.5 μm pores. Count the fragments of rubber visible to the naked eye. The total number of fragments does not exceed5. This limit is based on the assumption that fragments witha diameter equal toor greater than 50 μm are visible to the naked eye; in cases of doubt or dispute, the fragments are examined with a microscope to verify their nature and size. [JP] None[USP] Closures for Liquid Preparations—Fill 12 clean vials with water to 4 mL less than the nominal capacity. Fit the closures to be examined, secure with acap, and allow to stand for 16 hours.Closures for Dry Preparations— Fit closures to be examined into 12 cleanvials, and secure each with a cap.Procedure— Using a hypodermic needle as described above fitted to a cleansyringe, inject into each vial 1 mL of water while removing 1 mL of air. Repeat this procedure 4 times for each closure, piercing each time at a different site.Use a new needle for each closure, checking that it is not blunted during the test.Filter the toatal volume of liquid in all the vials through a single filter with a nominal pore size no greater than 0.5 μm. Count the rubber fragments on the surface of the filter visible to the naked eye.Requirement— There are no more than 5 fragments visible. This limit is based on the assumption that fragments with adiameter >50 μm are visible to the naked eye. In case of doubt or dispute, the particles are examined microscopically to verify their nature and size.3、Sealing test of rubber closure and container[YBB] Take 10 rubber closures into the beaker, boil for 5 min , take out and dry 1h at 70℃ and ready to use. Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined and secure with a cap. Heat in an autoclave so that a temperature of 121 ± 2 °C and maintain at this temperature for 30 min.Cool to room temperature and then place 24h, Immerse the vials upside down ina 10% solution of methylene blue R and reduce the external pressure by 25 kPafor 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.[EP]None[JP]None[USP] None4、Self-Sealing Capacity[YBB]Take the samples from sealing test of rubber closure and container, using for a hypodermic needle (YBB60082012 method 2), pierce each closure 3 times, change the hypodermic needle after it is used 10 times ,piercing each time at a different site.The vials upside down in a 10% solution of methylene blue R and reduce the external pressure by 25 kPa for 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.[EP]For closures intended to be used with multidosecontainers, carry out the following test. Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using for each closure a new hypodermic needle with an external diameter of 0.8 mm, pierce each closure 10 times, piercing each time at a different site. Immerse the vials upright in a 1 g/l solution of methylene blue R and reduce the external pressure by 27 kPa for 10 min. Restore atmospheric pressure and leave the vials immersed for 30 min.Rinse the outside of the vials. None of the vials contains any trace of coloured solution.[JP]None[USP]Procedure—Fill 10 suitable vials with water to the nominal volume. Fit the closures that are to be examined, and cap. Using a new hypodermic needle as described above for each closure, pierce each closure 10 times, piercing each time at a different site. Immerse the 10 vials in a solution of 0.1% (1 g per L) methylene blue, and reduce the external pressure by 27 kPa for 10 minutes.Restore to atmospheric pressure, and leave the vials immersed for 30 minutes.Rinse the outside of the vials.Requirement—None of the vials contain any trace of blue solution.5、Total Ash[YBB] Take the rubber closures, test according to YBB600212012, should be comply with the standard.[EP]The total ash (2.4.16) is within ± 10 per cent of the result obtained with the type sample.[JP]None[USP] None6、Volatile Sulfides[YBB]Take the rubber closures, according to the YBB60052012, should be comply with the standard.[EP] Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100 ml conical flask and add 50 ml of a 20 g/l solution of citric acid R. Place a piece of lead acetate paper R over the mouth of the flask and maintain the paper in position by placing over it an inverted weighing bottle. Heat in an autoclave at 121 ± 2℃ for 30 min. Any black stain on the paper is not more intense than that of a standard prepared at the same time in the same manner using 0.154 mg of sodium sulphide R and 50 ml of a 20 g/l solution of citric acid R.[JP]None[USP] Procedure—Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100-mL flask, and add 50 mL of a 20 g per L citric acid solution. In the same manner and at the same time, prepare a control solution in a separate 100-mL flask by dissolving 0.154 mg of sodium sulfide in 50 mL of a 20 g per L citric acid solution. Place a piece of lead acetate paper over the mouth of each flask, and hold the paper in position by placing over it an inverted weighing bottle. Heat the flasks in an autoclave at 121 ± 2℃for 30minutes.Requirement—Any black stain on the paper produced by Solution S is not more intense than that produced by the control solution.7、Preparation of Solution S[YBB] Put a number of uncut closures corresponding to a surface area of about 200 cm2 in a suitable glass container, cover with purified water( sample: water=1:2), boil for 5 min and rinse 5 times with the same volume of purified water. Place the washedclosures in a conical flask, add the same volume of water and weigh.Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temperature of 121 ± 2 °C is reached within 20 min to 30 min and maintain at this temperature for 30 min. Cool to room temperature.Make up to the original mass with purified water. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each test Blank. Prepare a blank in the same manner using 400 mL of water for purified water.[EP] Solution S.Introduce a number of uncut closures corresponding to a surface area of about 100 cm2in a suitable glass container, cover with water for injections R, boil for 5 min and rinse 5 times with cold water for injections R.Place the washed closures in a wide-necked flask (glass type I, 3.2.1), add 200 ml of water for injections R and weigh. Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temper ature of 121 ±2 °C is reached within 20 min to 30 min and maintain at this temperature for 30min. Cool to room temperature over about 30 min. Make up to the original mass with water for injections R. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each testBlank. Prepare a blank in the same manner using 200 ml of water for injections R.[JP] Wash the rubber closures with water, and dry at room temperature. Place them in a glass container, add water exactly 10 times the mass of the test material, close with a suitablestopper, heat at 121℃ for 1 hour in an autoclave, take out the glass container, allow to cool to room temperature,then take out immediately the rubber closures, and use the remaining solution as the testsolution. Prepare the blank solution with water in the same manner. Perform the following tests with the test solution and the blank solution[USP] Place whole, uncut closures corresponding to a surface area of 100 ± 10 cm2 intoa suitable glass container. Cover the closures with 200 mL of Purified Water orWater for Injection. If it is not possible to achieve the prescribed closure surface area (100 ± 10 cm2) using uncut closures, select the number of closures that will most closely approximate 100 cm2, and adjust the volume of water used to the equivalent of 2 mL per each 1 cm2 of actual closure surface area used. Boil for 5 minutes, and rinse five times with cold Purified Water or Water for InjectionPlace the washed closures into a Type I glass wide-necked flask (see Containers—Glass 660 ), add the same quantity of Purified Water or Water for Injection initially added to the closures, and weigh. Cover the mouth of the flask with a Type I glass beaker. Heat in an autoclave so that a temperature of 121 ± 2℃ is reached within 20 to 30 minutes, and maintain this temperature for30 minutes. Cool to room temperature over a period of about 30 minutes. AddPurified Water or Water for Injection to bring it up to the original mass. Shake, and immediately decant and collect the solution. [NOTE—This solution must be shaken before beingused in each of the tests]Prepare a blank solution similarly, using 200 mL of Purified Water or Water for Injection omitting the closures8、Appearance of solution[YBB]According to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅨB and appendix IX A, standard solution is not more opalescent than reference suspension II. Standard solution is not more intensely coloured than No.5 reference solution[EP] Solution S is not more opalescent than reference suspension II for type I closures and is not more opalescent than reference suspension III for type II closures(2.2.1). Solution S is not more intensely coloured than reference solution GY5(2.2.2, Method II).[JP] Place 5 mL of the test solution in a glass-stoppered test tube of about 15 mm in inner diameter and about 200 mm in length, and shake vigorously for 3 minutes.The foam arisen disappears almost completely within 3 minutes.[USP] Determination of Turbidity (Opalescence)Procedure A: Visual Comparison— Use identical test tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, one tube to the same depth with water, and four others to the same depth with Reference Suspensions A, B, C,and D. Compare the solutions in diffuse daylight 5 minutes after preparation of the Reference Suspensions, viewing vertically against a black background. The light conditions shall be such that Reference Suspension A can be readily distinguished fromwater and that Reference Suspension B can be readily distinguished fromReference Suspension A.REQUIREMENT—Solution S is not more opalescent than Reference Suspension B for Type I closures, and not more opalescent than Reference Suspension C for Type II closures. Solution S is considered clear if its clarity is the same as that of water when examined as described above, or if its opalescence is not more pronounced than that of Reference Suspension A (refer to Table 3).Procedure B: Instrumental Comparison—Measure the turbidity of theReference Suspensions in a suitable calibrated turbidimeter (see Spectrophotometry and Light Scattering 851 ). The blank should be run and the results corrected for the blank. Reference Suspensions A, B, C, and D represent 3, 6, 18 and 30 Nephelometric Turbidity Units (NTU), respectively. Measure the turbidity of Solution S using the calibrated turbidimeter. REQUIREMENT—The turbidity of Solution S is not greater than that for Reference Suspension B (6 NTU FTU) for Type I closures, and is not greater than that forReference Suspension C (18 NTU FTU) for Type II closures (refer to Table 3).Determination of ColorColor Standard—Prepare a solution by diluting 3.0 mL of Matching Fluid O (see Color and Achromicity 631 ) with 97.0 mL of diluted hydrochloric acid. Procedure—Use identical tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, and the second with Color Standard. Compare the liquids in diffuse daylight, viewing vertically against a white background. Requirement—Solution S is not moreintensely colored than the Color Standard.9、Acidity or Alkalinity(PH)[YBB]Take each of 20 ml blank solution and solution S, respectively with KCl solution1 ml, According to the part2 of Chinese pharmacopoeia, 2010 edition ofappendixⅥH, the difference between the two may not be over 1.0.[EP] To 20ml of solution S add 0.1ml of bromothymol blue solution R1. Not more than 0.3ml of 0.01 M sodium hydroxide or 0.8 ml of 0.01 M hydrochloric acid is required to obtain either a blue or a yellow colour, respectively.[JP] T o 20 mL each of the test solution and the blank solution add 1.0 mL each of potassium chloride solution, prepared by dissolving 1.0 g of potassium chloride in water to make 1000 mL. The difference of pH between the two solutions is not more than 1.0[USP] Bromothymol Blue Solution—Dissolve 50 mg of bromothymol blue in a mixture of 4 mL of 0.02 M sodium hydroxide and 20 mL of alcohol. Dilute with water to 100 mL.Procedure—To 20 ml of Solution S add 0.1 ml of Bromothymol Blue Solution.If the solution is yellow, titrate with 0.01 N sodium hydroxide until a blue endpoint is reached. If the solution is blue, titrate with 0.01 N hydrochloric acid until a yellow endpoint is reached. If the solution is green, it is neutral and no titration is required.Blank Correction—Test 20 mL of Blank similarly. Correct the results obtained for Solution S by subtracting or adding the volume of titrant required for the Blank, as appropriate. (Reference Titrimetry 541 .)Requirement—Not more than 0.3 ml of 0.01 N sodium hydroxide produces a blue color, or not more than 0.8 ml of 0.01 N hydrochloric acid produces a yellow color, or no titration is required.10、Absorbance[YBB] Filter solution S on a membrane filter having approximately 0.45 μm pores.Measure the absorbance of the filtrate at wavelengths from 220 nm to 360 nm using the blank as compensation liquid. At these wavelengths, the absorbance does not exceed 0.1(according to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅣA).[EP] Carry out the test within 5 h of preparation of solution S. Filter solution S on a membrane filter having approximately 0.45 μm pores rejecting the first few milliliters of filtrate. Measure the absorbance (2.2.25) of the filtrate at wavelengths from 220 nm to 360 nm using the blank (see solution S) as compensation liquid. At these wavelengths, the absorbance does not exceed 0.2 for type I closures or 4.0 for type II closures. If necessary, dilute the filtrate before measurement of the absorbance and correct the result for the dilution. [JP] Read the absorbance of the test solution between 220 nm and 350 nm against the blank solution as directed under Ultraviolet-visible Spectrophotometry <2.54>: it is not more than 0.20.[USP] Procedure — [NOTE—Perform this test within 5 hours of preparing Solution S.] Filter Solution S through a 0.45-μm pore size filter, discarding the first few mL of filtrate. Measure the absorbance of the filtrate at wavelengths between 220 and 360 nm in a 1-cm cell using the blank in a matched cell in the reference beam. If dilution of the filtrate is required beforemeasurement of the absorbance, correct the test results for the dilution.Requirement—The absorbances at these wavelengths do not exceed 0.2 for Type I closures or 4.0 for Type II closures.11、Reducing Substances[YBB] To 20.0 mL of solution S add 1 mL of dilute sulfuric acid R and 20.0 mL of0.002 M potassium permanganate. Boil for 3 min. Cool. Add 0.1 g of potassiumiodide R and titrate immediately with 0.01 M sodium thiosulfate until the colorturned light brown , using 5 drops of starch solution R as indicator. Carry out atitration using 20.0 mL of the blank. The difference between the titrationvolumes is not greater than7.0mL.[EP] Carry out the test within 4 h of preparation of solution S. To 20.0 ml of solution S add 1 ml of dilute sulphuric acid R and 20.0 ml of 0.002 M potassium permanganate. Boil for 3min. Cool. Add 1 g of potassium iodide R and titrate immediately with 0.01 M sodium thiosulphate, using 0.25 ml of starch solution R as indicator. Carry out a titration using 20.0 ml of the blank. The difference between the titration volumes is not greater than 3.0 ml for type I closures and7.0 ml for type II closures.[JP] Measure 100 mL of the test solution in a glass-stoppered,Erlenmyer flask, add10.0 mL of 0.002 mol/L potassium permanganate VS and 5 mL of dilutesulfuric acid, and boil for 3 minutes. After cooling, add 0.10g of potassium iodide,stopper, mix by shaking, then allow to stand for 10 minutes,and titrate<2.50> with 0.01 mol/L sodium thiosulfate VS(indicator: 5 drops of starch TS).Perform the blank test in the same manner, using 100 mL of the blank solution.The difference in mL of 0.002 mol/L potassium permanganate VS required between the tests is not more than 2.0 mL.[USP] Procedure— [NOTE—Perform this test within 4 hours of preparing Solution S.] T o 20.0 mL of Solution S add 1 mL of diluted sulfuric acid and 20.0 mL of0.002 M potassium permanganate. Boil for 3 minutes. Cool, add 1 g ofpotassium iodide, and titrate immediately with 0.01 M sodium thiosulfate, using0.25 mL of starch solution TS as the indicator. Perform a titration using 20.0mL of blank and note the difference in volume of 0.01 M sodium thiosulfaterequired.Requirement—The difference between the titration volumes is not greater than 3.0 mL for Type I closures and not greater than 7.0 mL for Type II closures.12、Residue on evaporation[YBB]Evaporate 100 mL of solution S and blank solution to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 4.0 mg. [EP]Evaporate 50.0 ml of solution S to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 2.0 mg for type I rubber and notmore than 4.0 mg for type II rubber.[JP]Measure 100 mL of the test solution, evaporate on a water bath to dryness, and dry the residue at 1059 C for 1 hour.The mass of the residue is not morethan 2.0 mg.[USP]None13、Ammonium[YBB] Precision measuring 10 ml of solution S, adding alkaline potassium iodide solution 2 ml, place 15 minutes, should not be color; if it colored , compare with reference solution (with 2.0 ml ammonium chloride solution (take ammoniumchloride 31.5 mg, add right amount chlorine free water and dissolve diluted to1000 ml), 8 ml blank reference solution, 2ml alkaline potassium mercuric iodide solution for mixing), should not be more intensely colored (0.0002%)[EP] maximum 2 ppm.Dilute 5 ml of solution S to 14 ml with water R. The solution complies with limit test A.[JP]None[USP] Alkaline Potassium Tetraiodomercurate Solution—Prepare a 100 mL solution containing 11 g of potassium iodide and 15 g of mercuric iodide in water.Immediately before use, mix 1 volume of this solution with an equal volume ofa 250 g per L solution of sodium hydroxide.Test Solution— Dilute 5 mL of Solution S to 14 mL with water. Make alkaline if necessary by adding 1 N sodium hydroxide, and dilute with water to 15 mL.Add 0.3 mL of Alkaline Potassium TetraiodomercurateSolution, and close the container.Ammonium Standard Solution—Prepare a solution of ammonium chloride in water (1 ppm NH4). Mix 10 mL of the 1 ppm ammonium chloride solution with5 mL water and 0.3 mL of Alkaline Potassium Tetraiodomercurate Solution.Close the container.Requirement—After 5 minutes, any yellow color in the Test Solution is no darker than the Ammonium Standard Solution (no more than 2 ppm of NH4 in Solution S).14、Extractable Zinc[YBB] Filter solution S on a membrane filter having approximately 0.45μm pores, Precision measuring filtrate 10 ml, add 1 ml 2 mol/L of hydrochloric acid and 3 drops of potassium ferrocyanide test solution(weight 4.2 g potassium ferrocyanide trihydrate, dissolve and diluted with water to 100 ml, shake evenly, this product should be new prepared) for mixing, should not be color; if it colored, compare with reference solution( with 3 ml standard zinc solution (weight 44.0g Zinc sulfate seven hydrated compounds, with new boiled and cooled purified water dissolved and diluted to 1000 ml, this product should be new prepared), shall not be deeper(0.0002%)，7ml blank reference solution, 1ml 2mol/L hydrochloric acid and 3 drops of potassium ferrocyanide solution for mixing), should not be more intensely colored.(0.0003%)[EP] maximumof 5 μg of extractable Zn per millilitre of solution S.Atomic absorption spectrophotometry (2.2.23, Method I). Test solution. Dilute10.0 ml of solution S to 100 ml with 0.1 M hydrochloric acid.Reference solutions. Prepare the reference solutions using zinc standard solution(10 ppm Zn) R diluted with 0.1 M hydrochloric acid.Source: zinc hollow-cathode lamp.Wavelength: 213.9 nm.Flame: air-acetylene.[JP]T o 10.0 mL of the test solution add diluted dilute nitric acid (1 in 3) to make 20 mL, and use this solution as the sample solution. Further, to 1.0 mL of Standard Zinc Solutionfor atomic absorption spectrophotometry add diluted nitricacid (1 in 3) to make exactly 20 mL, and use this solution asthe standard solution. Perform the tests according to the Atomic Absorption Spectrophotometry <2.23>,using these solutions, under the following conditions.The absorbanceof the sample solution is not more than that of the standardsolution.Gas: Combustible gasóAcetylene.。
药用丁基胶塞---四大药典检测标准异同
Summary1、Penetrability[YBB]Take 10 rubber closures, test according to the second method of YBB60072012, the average puncture force does not exceed 10N.[EP] Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using for each closure a new, lubricated long-bevel(1) (bevel angle 12 ± 2°) hypodermic needle with an external diameter of 0.8 mm, pierce the closures with the needle perpendicular to the surface. The force required for piercing, determined with an accuracy of ± 0.25 N (25 gf), is not greater than 10 N (1 kgf) for each closure.[JP]None[USP]Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined, and secure with a cap. Using a new hypodermic needle as described above for each closure, pierce the closure with the needle perpendicular to the surface.Requirement—The force for piercing is no greater than 10 N (1 kgf) for each closure, determined with an accuracy of ± 0.25 N (25 gf).2、Fragmentation[YBB]Take 10 rubber closures, test according to the second method of YBB60082012, The total number of fragments does not exceed 5.[EP] For closures intended to be pierced by a hypodermic needle, carry out the following test. If the closures are to be used for aqueous preparations, place in12 clean vials a volume of water R corresponding to the nominal volume minus4 ml, close the vials with the closures to be examined, secure with a cap andallow to stand for 16 h. If the closures are to be used with dry preparations, close 12 clean vials with the closures to be examined. Using a lubricated long-bevel(1) (bevel angle 12 ±2°) hypodermic needle with an external diameter of 0.8 mm fitted to a clean syringe, inject into the vial 1 ml of water R and remove 1 ml of air ; carry out this operation 4 times for each closure, piercing each time at a different site. Use a new needle for each closure and check that the needle is not blunted during the test. Pass the liquid in the vials through a filter having approxi mately 0.5 μm pores. Count the fragments of rubber visible to the naked eye. The total number of fragments does not exceed5. This limit is based on the assumption that fragments with a diameter equal toor greater than 50 μm are visible to the naked eye; in cases of doubt or dispute, the fragments are examined with a microscope to verify their nature and size. [JP] None[USP] Closures for Liquid Preparations— Fill 12 clean vials with water to 4 mL less than the nominal capacity. Fit the closures to be examined, secure with acap, and allow to stand for 16 hours.Closures for Dry Preparations— Fit closures to be examined into 12 cleanvials, and secure each with a cap.Procedure— Using a hypodermic needle as described above fitted to a cleansyringe, inject into each vial 1 mL of water while removing 1 mL of air. Repeat this procedure 4 times for each closure, piercing each time at a different site.Use a new needle for each closure, checking that it is not blunted during the test.Filter the toatal volume of liquid in all the vials through a single filter with a nominal pore size no greater than 0.5 µm. Count the rubber fragments on the surface of the filter visible to the naked eye.Requirement— There are no more than 5 fragments visible. This limit is based on the assumption that fragments with a diameter >50 µm are visible to the naked eye. In case of doubt or dispute, the particles are examined microscopically to verify their nature and size.3、Sealing test of rubber closure and container[YBB] Take 10 rubber closures into the beaker, boil for 5 min , take out and dry 1h at 70℃ and ready to use. Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined and secure with a cap. Heat in an autoclave so that a temperature of 121 ± 2 °C and maintain at this temperature for 30 min.Cool to room temperature and then place 24h, Immerse the vials upside down ina 10% solution of methylene blue R and reduce the external pressure by 25 kPafor 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.[EP]None[JP]None[USP] None4、Self-Sealing Capacity[YBB]Take the samples from sealing test of rubber closure and container, using for a hypodermic needle (YBB60082012 method 2), pierce each closure 3 times, change the hypodermic needle after it is used 10 times ,piercing each time at a different site.The vials upside down in a 10% solution of methylene blue R and reduce the external pressure by 25 kPa for 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.[EP]For closures intended to be used with multidose containers, carry out the following test. Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using for each closure a new hypodermic needle with an external diameter of 0.8 mm, pierce each closure 10 times, piercing each time at a different site. Immerse the vials upright in a 1 g/l solution of methylene blue R and reduce the external pressure by 27 kPa for 10 min. Restore atmospheric pressure and leave the vials immersed for 30 min.Rinse the outside of the vials. None of the vials contains any trace of coloured solution.[JP]None[USP]Procedure—Fill 10 suitable vials with water to the nominal volume. Fit the closures that are to be examined, and cap. Using a new hypodermic needle as described above for each closure, pierce each closure 10 times, piercing each time at a different site. Immerse the 10 vials in a solution of 0.1% (1 g per L) methylene blue, and reduce the external pressure by 27 kPa for 10 minutes.Restore to atmospheric pressure, and leave the vials immersed for 30 minutes.Rinse the outside of the vials.Requirement—None of the vials contain any trace of blue solution.5、Total Ash[YBB] Take the rubber closures, test according to YBB600212012, should be comply with the standard.[EP]The total ash (2.4.16) is within ± 10 per cent of the result obtained with the type sample.[JP]None[USP] None6、Volatile Sulfides[YBB]Take the rubber closures, according to the YBB60052012, should be comply with the standard.[EP] Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100 ml conical flask and add 50 ml of a 20 g/l solution of citric acid R. Place a piece of lead acetate paper R over the mouth of the flask and maintain the paper in position by placing over it an inverted weighing bottle. Heat in an autoclave at 121 ± 2℃ for 30 min. Any black stain on the paper is not more intense than that of a standard prepared at the same time in the same manner using 0.154 mg of sodium sulphide R and 50 ml of a 20 g/l solution of citric acid R.[JP]None[USP] Procedure— Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100-mL flask, and add 50 mL of a 20 g per L citric acid solution. In the same manner and at the same time, prepare a control solution in a separate 100-mL flask by dissolving 0.154 mg of sodium sulfide in 50 mL of a 20 g per L citric acid solution. Place a piece of lead acetate paper over the mouth of each flask, and hold the paper in position by placing over it an inverted weighing bottle. Heat the flasks in an autoclave at 121 ± 2℃for 30minutes.Requirement—Any black stain on the paper produced by Solution S is not more intense than that produced by the control solution.7、Preparation of Solution S[YBB] Put a number of uncut closures corresponding to a surface area of about 200 cm2 in a suitable glass container, cover with purified water( sample: water=1:2), boil for 5 min and rinse 5 times with the same volume of purified water. Place the washed closures in a conical flask, add the same volume of water and weigh.Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temperature of 121 ± 2 °C is reached within 20 min to 30 min and maintain at this temperature for 30 min. Cool to room temperature.Make up to the original mass with purified water. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each test Blank. Prepare a blank in the same manner using 400 mL of water for purified water.[EP] Solution S.Introduce a number of uncut closures corresponding to a surface area of about 100 cm2in a suitable glass container, cover with water for injections R, boil for 5 min and rinse 5 times with cold water for injections R.Place the washed closures in a wide-necked flask (glass type I, 3.2.1), add 200 ml of water for injections R and weigh. Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temperature of 121 ±2 °C is reached within 20 min to 30 min and maintain at this temperature for 30min. Cool to room temperature over about 30 min. Make up to the original mass with water for injections R. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each testBlank. Prepare a blank in the same manner using 200 ml of water for injections R.[JP] Wash the rubber closures with water, and dry at room temperature. Place them in a glass container, add water exactly 10 times the mass of the test material, close with a suitable stopper, heat at 121℃ for 1 hour in an autoclave, take out the glass container, allow to cool to room temperature,then take out immediately the rubber closures, and use the remaining solution as the testsolution. Prepare the blank solution with water in the same manner. Perform the following tests with the test solution and the blank solution[USP] Place whole, uncut closures corresponding to a surface area of 100 ± 10 cm2 intoa suitable glass container. Cover the closures with 200 mL of Purified Water orWater for Injection. If it is not possible to achieve the prescribed closure surface area (100 ± 10 cm2) using uncut closures, select the number of closures that will most closely approximate 100 cm2, and adjust the volume of water used to the equivalent of 2 mL per each 1 cm2 of actual closure surface area used. Boil for 5 minutes, and rinse five times with cold Purified Water or Water for InjectionPlace the washed closures into a Type I glass wide-necked flask (see Containers—Glass 660 ), add the same quantity of Purified Water or Water for Injection initially added to the closures, and weigh. Cover the mouth of the flask with a Type I glass beaker. Heat in an autoclave so that a temperature of 121 ± 2℃ is reached within 20 to 30 minutes, and maintain this temperature for30 minutes. Cool to room temperature over a period of about 30 minutes. AddPurified Water or Water for Injection to bring it up to the original mass. Shake, and immediately decant and collect the solution. [NOTE—This solution must be shaken before being used in each of the tests]Prepare a blank solution similarly, using 200 mL of Purified Water or Water for Injection omitting the closures8、Appearance of solution[YBB]According to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅨB and appendix IX A, standard solution is not more opalescent than reference suspension II. Standard solution is not more intensely coloured than No.5 reference solution[EP] Solution S is not more opalescent than reference suspension II for type I closures and is not more opalescent than reference suspension III for type II closures(2.2.1). Solution S is not more intensely coloured than reference solution GY5(2.2.2, Method II).[JP] Place 5 mL of the test solution in a glass-stoppered test tube of about 15 mm in inner diameter and about 200 mm in length, and shake vigorously for 3 minutes.The foam arisen disappears almost completely within 3 minutes.[USP] Determination of Turbidity (Opalescence)Procedure A: Visual Comparison— Use identical test tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, one tube to the same depth with water, and four others to the same depth with Reference Suspensions A, B, C,and D. Compare the solutions in diffuse daylight 5 minutes after preparation of the Reference Suspensions, viewing vertically against a black background. The light conditions shall be such that Reference Suspension A can be readily distinguished from water and that Reference Suspension B can be readily distinguished fromReference Suspension A.REQUIREMENT—Solution S is not more opalescent than Reference Suspension B for Type I closures, and not more opalescent than Reference Suspension C for Type II closures. Solution S is considered clear if its clarity is the same as that of water when examined as described above, or if its opalescence is not more pronounced than that of Reference Suspension A (refer to Table 3).Procedure B: Instrumental Comparison—Measure the turbidity of theReference Suspensions in a suitable calibrated turbidimeter (see Spectrophotometry and Light Scattering 851 ). The blank should be run and the results corrected for the blank. Reference Suspensions A, B, C, and D represent 3, 6, 18 and 30 Nephelometric Turbidity Units (NTU), respectively. Measure the turbidity of Solution S using the calibrated turbidimeter. REQUIREMENT—The turbidity of Solution S is not greater than that for Reference Suspension B (6 NTU FTU) for Type I closures, and is not greater than that forReference Suspension C (18 NTU FTU) for Type II closures (refer to Table 3).Determination of ColorColor Standard— Prepare a solution by diluting 3.0 mL of Matching Fluid O (see Color and Achromicity 631 ) with 97.0 mL of diluted hydrochloric acid. Procedure—Use identical tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, and the second with Color Standard. Compare the liquids in diffuse daylight, viewing vertically against a white background. Requirement—Solution S is not more intensely colored than the Color Standard.9、Acidity or Alkalinity(PH)[YBB]Take each of 20 ml blank solution and solution S, respectively with KCl solution1 ml, According to the part2 of Chinese pharmacopoeia, 2010 edition ofappendixⅥH, the difference between the two may not be over 1.0.[EP] To 20ml of solution S add 0.1ml of bromothymol blue solution R1. Not more than 0.3ml of 0.01 M sodium hydroxide or 0.8 ml of 0.01 M hydrochloric acid is required to obtain either a blue or a yellow colour, respectively.[JP] To 20 mL each of the test solution and the blank solution add 1.0 mL each of potassium chloride solution, prepared by dissolving 1.0 g of potassium chloride in water to make 1000 mL. The difference of pH between the two solutions is not more than 1.0[USP] Bromothymol Blue Solution—Dissolve 50 mg of bromothymol blue in a mixture of 4 mL of 0.02 M sodium hydroxide and 20 mL of alcohol. Dilute with water to 100 mL.Procedure— To 20 ml of Solution S add 0.1 ml of Bromothymol Blue Solution.If the solution is yellow, titrate with 0.01 N sodium hydroxide until a blue endpoint is reached. If the solution is blue, titrate with 0.01 N hydrochloric acid until a yellow endpoint is reached. If the solution is green, it is neutral and no titration is required.Blank Correction—Test 20 mL of Blank similarly. Correct the results obtained for Solution S by subtracting or adding the volume of titrant required for the Blank, as appropriate. (Reference Titrimetry 541 .)Requirement— Not more than 0.3 ml of 0.01 N sodium hydroxide produces a blue color, or not more than 0.8 ml of 0.01 N hydrochloric acid produces a yellow color, or no titration is required.10、Absorbance[YBB] Filter solution S on a membrane filter having approximately 0.45 μm pores.Measure the absorbance of the filtrate at wavelengths from 220 nm to 360 nm using the blank as compensation liquid. At these wavelengths, the absorbance does not exceed 0.1(according to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅣA).[EP] Carry out the test within 5 h of preparation of solution S. Filter solution S on a membrane filter having approximately 0.45 μm pores rejecting the first few milliliters of filtrate. Measure the absorbance (2.2.25) of the filtrate at wavelengths from 220 nm to 360 nm using the blank (see solution S) as compensation liquid. At these wavelengths, the absorbance does not exceed 0.2 for type I closures or 4.0 for type II closures. If necessary, dilute the filtrate before measurement of the absorbance and correct the result for the dilution. [JP] Read the absorbance of the test solution between 220 nm and 350 nm against the blank solution as directed under Ultraviolet-visible Spectrophotometry <2.54>: it is not more than 0.20.[USP] Procedure — [NOTE—Perform this test within 5 hours of preparing Solution S.] Filter Solution S through a 0.45-µm pore size filter, discarding the first few mL of filtrate. Measure the absorbance of the filtrate at wavelengths between 220 and 360 nm in a 1-cm cell using the blank in a matched cell in the reference beam. If dilution of the filtrate is required before measurement of the absorbance, correct the test results for the dilution.Requirement—The absorbances at these wavelengths do not exceed 0.2 for Type I closures or 4.0 for Type II closures.11、Reducing Substances[YBB] To 20.0 mL of solution S add 1 mL of dilute sulfuric acid R and 20.0 mL of0.002 M potassium permanganate. Boil for 3 min. Cool. Add 0.1 g of potassiumiodide R and titrate immediately with 0.01 M sodium thiosulfate until the colorturned light brown , using 5 drops of starch solution R as indicator. Carry out atitration using 20.0 mL of the blank. The difference between the titrationvolumes is not greater than7.0mL.[EP] Carry out the test within 4 h of preparation of solution S. To 20.0 ml of solution S add 1 ml of dilute sulphuric acid R and 20.0 ml of 0.002 M potassium permanganate. Boil for 3min. Cool. Add 1 g of potassium iodide R and titrate immediately with 0.01 M sodium thiosulphate, using 0.25 ml of starch solution R as indicator. Carry out a titration using 20.0 ml of the blank. The difference between the titration volumes is not greater than 3.0 ml for type I closures and7.0 ml for type II closures.[JP] Measure 100 mL of the test solution in a glass-stoppered,Erlenmyer flask, add10.0 mL of 0.002 mol/L potassium permanganate VS and 5 mL of dilutesulfuric acid, and boil for 3 minutes. After cooling, add 0.10 g of potassium iodide,stopper, mix by shaking, then allow to stand for 10 minutes,and titrate<2.50> with 0.01 mol/L sodium thiosulfate VS(indicator: 5 drops of starch TS).Perform the blank test in the same manner, using 100 mL of the blank solution.The difference in mL of 0.002 mol/L potassium permanganate VS required between the tests is not more than 2.0 mL.[USP] Procedure— [NOTE—Perform this test within 4 hours of preparing Solution S.] To 20.0 mL of Solution S add 1 mL of diluted sulfuric acid and 20.0 mL of0.002 M potassium permanganate. Boil for 3 minutes. Cool, add 1 g ofpotassium iodide, and titrate immediately with 0.01 M sodium thiosulfate, using0.25 mL of starch solution TS as the indicator. Perform a titration using 20.0mL of blank and note the difference in volume of 0.01 M sodium thiosulfaterequired.Requirement—The difference between the titration volumes is not greater than 3.0 mL for Type I closures and not greater than 7.0 mL for Type II closures.12、Residue on evaporation[YBB]Evaporate 100 mL of solution S and blank solution to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 4.0 mg. [EP]Evaporate 50.0 ml of solution S to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 2.0 mg for type I rubber and notmore than 4.0 mg for type II rubber.[JP]Measure 100 mL of the test solution, evaporate on a water bath to dryness, and dry the residue at 1059 C for 1 hour.The mass of the residue is not morethan 2.0 mg.[USP]None13、Ammonium[YBB] Precision measuring 10 ml of solution S, adding alkaline potassium iodide solution 2 ml, place 15 minutes, should not be color; if it colored , compare with reference solution (with 2.0 ml ammonium chloride solution (take ammoniumchloride 31.5 mg, add right amount chlorine free water and dissolve diluted to1000 ml), 8 ml blank reference solution, 2ml alkaline potassium mercuric iodide solution for mixing), should not be more intensely colored (0.0002%)[EP] maximum 2 ppm.Dilute 5 ml of solution S to 14 ml with water R. The solution complies with limit test A.[JP]None[USP] Alkaline Potassium Tetraiodomercurate Solution— Prepare a 100 mL solution containing 11 g of potassium iodide and 15 g of mercuric iodide in water.Immediately before use, mix 1 volume of this solution with an equal volume ofa 250 g per L solution of sodium hydroxide.Test Solution— Dilute 5 mL of Solution S to 14 mL with water. Make alkaline if necessary by adding 1 N sodium hydroxide, and dilute with water to 15 mL.Add 0.3 mL of Alkaline Potassium Tetraiodomercurate Solution, and close the container.Ammonium Standard Solution— Prepare a solution of ammonium chloride in water (1 ppm NH4). Mix 10 mL of the 1 ppm ammonium chloride solution with5 mL water and 0.3 mL of Alkaline Potassium Tetraiodomercurate Solution.Close the container.Requirement—After 5 minutes, any yellow color in the Test Solution is no darker than the Ammonium Standard Solution (no more than 2 ppm of NH4 in Solution S).14、Extractable Zinc[YBB] Filter solution S on a membrane filter having approximately 0.45μm pores, Precision measuring filtrate 10 ml, add 1 ml 2 mol/L of hydrochloric acid and 3 drops of potassium ferrocyanide test solution(weight 4.2 g potassium ferrocyanide trihydrate, dissolve and diluted with water to 100 ml, shake evenly, this product should be new prepared) for mixing, should not be color; if it colored, compare with reference solution( with 3 ml standard zinc solution (weight 44.0g Zinc sulfate seven hydrated compounds, with new boiled and cooled purified water dissolved and diluted to 1000 ml, this product should be new prepared), shall not be deeper(0.0002%)，7ml blank reference solution, 1ml 2mol/L hydrochloric acid and 3 drops of potassium ferrocyanide solution for mixing), should not be more intensely colored.(0.0003%)[EP] maximumof 5 μg of extractable Zn per millilitre of solution S.Atomic absorption spectrophotometry (2.2.23, Method I). Test solution. Dilute10.0 ml of solution S to 100 ml with 0.1 M hydrochloric acid.Reference solutions. Prepare the reference solutions using zinc standard solution(10 ppm Zn) R diluted with 0.1 M hydrochloric acid.Source: zinc hollow-cathode lamp.Wavelength: 213.9 nm.Flame: air-acetylene.[JP]To 10.0 mL of the test solution add diluted dilute nitric acid (1 in 3) to make 20 mL, and use this solution as the sample solution. Further, to 1.0 mL of Standard Zinc Solutionfor atomic absorption spectrophotometry add diluted nitricacid (1 in 3) to make exactly 20 mL, and use this solution asthe standard solution. Perform the tests according to the Atomic Absorption Spectrophotometry <2.23>,using these solutions, under the following conditions.The absorbanceof the sample solution is not more than that of the standardsolution.Gas: Combustible gasóAcetylene.Supporting gasóAir.Lamp: Zinc hollow-cathode lamp.Wavelength: 213.9 nm.Standard Zinc Solution for atomic absorption spectrophotometry: Measure exactly 10 mL of the Standard Zinc Stock Solution, and add water to make exactly 1000 mL. Prepare before use. One mL of this solution contains 0.01 mg of zinc(Zn).[USP] Test Solution—Prepare a Test Solution by diluting 10.0 mL of Solution S to 100 mL with 0.1N hydrochloric acid. Prepare a test blank similarly, using the Blank forSolution S.Zinc Standard Solution— Prepare a solution (10 ppm Zn) by dissolving zinc sulfate in 0.1 N hydrochloric acid.Reference Solutions—Prepare not fewer than 3 Reference Solutions by diluting the Zinc Standard Solution with 0.1 N hydrochloric acid. The concentrations of zinc in these Reference Solutions are to span the expected limit of the Test Solution.Procedure—Use a suitable atomic absorption spectrophotometer (see Spectrophotometry and Light Scattering 851 ) equipped with a zinc hollow-cathode lamp and an air–acetylene flame. An alternative procedure such as an appropriately validated inductively coupled plasma analysis (ICP) may be used.Test each of the Reference Solutions at the zinc emission line of 213.9 nm at least 3 times. Record the steady readings. Rinse the apparatus with the test blank solution each time, to ensure that the reading returns to initial blank value.Prepare a calibration curve from the mean of the readings obtained for each Reference Solution. Record the absorbance of the Test Solution. Determine the ppm zinc concentration of the Test Solution using the calibration curve.Requirement— Solution S contains not more than 5 ppm of extractable zinc.15、Cadmium[YBB]None[EP]None[JP]Wash the rubber closures with water, dry at room temperature, cut into minute pieces, mix well, place 2.0 g of them in a crucible of platinum or quartz, moisten them with 2 mL of sulfuric acid, heat gradually to dryness, and ignite between 4509 Cand5009 C until the residue is incinerated. When in cineration was insufficient, moisten the residue with 1 mL of sulfuric acid, heat to dryness, and ignite again. Repeat the above-mentioned procedure if necessary. Cool the crucible,moisten the residue with water, add 2 to 4 mL of hydrochloric acid, heat on a water bath to dryness, add 1 to 5 mL of hydrochloric acid, and dissolve by heating. Then add 0.5 to 1 mL of a mixture of a solution of citric acid monohydrate (1 in 2) and hydrochloric acid (1:1) and 0.5 to 1 mL of a warmed solution of ammonium acetate (2 in 5). When any insoluble residue remains, filter through a glass filter. To the solution thus obtained add 10 mL ofa solution of diammonium hydrogen citrate (1 in 4), 2 drops of bromothymolblue TS and ammonium TS until the color of the solution changes from yellow to green. Then add 10 mL of ammonium sulfate solution (2 in 5) and water to make 100 mL. Next, add 20 mL of a solution of sodium N,N-diethyldithiocarbamate trihydrate (1 in 20), mix, allow to stand for a few minutes,add 20.0 mL of 4-methyl-2-pentanone, and mix by vigorous shaking.Allow to stand to separate the 4-methyl-2-pentanone layer from the solution, filter if necessary, and use as the sample solution. On the other hand, to 10.0 mL of Standard Cadmium Solution add 10 mL of a solution of diammonium hydrogen citrate (1 in 4) and 2 drops of bromothymol blue TS, proceed in the same manner as for the sample solution, and use this solution as the standard solution.Perform the tests according to the Atomic Absorption Spectrophotometry <2.23> under the following conditions, using the sample solution and the standard solution. The absorbance of the sample solution is notmore than that of thestandard solution.Gas: Combustible gas—Acetylene or hydrogen.Supporting gas—Air.Lamp: Cadmium hollow-cathode lamp.Wavelength: 228.8 nm.[USP] None。
胶塞质量控制与常见质量问题培训课件
胶塞表面缺陷：可能导致药液污染或影响药液质量
4
3
质量问题分析与解决
质量问题原因分析
原材料质量问题：原材料质量不达标，导致产品质量下降
01
生产工艺问题：生产工艺不规范，导致产品质量不稳定
02
设备问题：设备故障或老化，导致产品质量下降
03
人员问题：员工操作不规范，导致产品质量不稳定
04
环境问题：生产环境恶劣，导致产品质量下降
质量检测标准
外观检查：观察胶塞表面是否有划痕、污渍、气泡等缺陷
01
物理性能测试：进行拉伸强度、压缩强度、耐磨性等测试
03
生物性能测试：进行生物相容性、无菌性等测试
05
尺寸测量：测量胶塞的直径、长度、厚度等尺寸是否符合要求
02
化学性能测试：进行耐酸碱、耐高温、耐腐蚀等测试
04
包装检查：检查胶塞的包装是否完好，是否有破损、污染等现象
05
加强售后服务，及时解决客户反馈的质量问题
06
预防措施与质量管理
01
制定严格的质量标准和检验流程
03
定期进行质量检查，及时发现问题
02
加强员工培训，提高质量意识
04
建立质量管理体系，确保质量控制有效进行
谢谢
06
质量控制措施
原材料控制：选用优质原材料，确保胶塞质量
01
生产工艺控制：优化生产工艺，提高胶塞质量
02
质量检测：加强质量检测，确保胶塞质量合格
03
质量管理体系：建立完善的质量管理体系，确保胶塞质量持续改进
04
2
常见质量问题
胶塞外观缺陷
胶塞表面粗糙，有颗粒感
胶塞表面有气泡、杂质
药用丁基胶塞资料
药用丁基胶塞的使用安全性药用丁基胶塞的生产背景丁基橡胶瓶塞的内在洁净度、化学稳定性、气密性、生物性能都很好，但是因配方复杂及所加原材料浓度梯度的关系，与一些分子活性比较强的药物封装后，被药物吸收、吸附、浸出、渗透，产生了胶塞与药物的相容性问题，比较突出的是部分头孢菌素类、部分大输液类、以及较多中药注射液制剂等。
所以通过选用一种惰性柔软涂层，覆盖在胶塞表面，隔离药品与橡胶瓶塞的直接接触，这样可以明显改善与药物的相容性。
国家至2004年底前所有药用胶塞(包括输液、口服液等各剂型用胶塞)一律停止使用普通天然胶塞;所有药厂的药品橡胶塞都要使用丁基胶塞。
药品是一种特殊的商品, 其药效与质量直接关系到人身健康和安全, 药品包装的材料与结构形式, 尤其是直接接触药品的包装材料, 对保证药品稳定性起决定性作用。
不适宜的包装材料可引起活性药物成分的渗出、吸附, 甚至发生化学反应, 导致药品失效, 有时还会产生严重的毒副作用。
因此, 药包材的选择是否合适, 是评价药品质量的一项重要指标，丁基胶塞具有吸湿率低, 化学性好, 气密性好, 无生理毒副作用等显著特点, 特别适宜于用作药品密封。
因此天然胶塞已列入被淘汰之列, 而用丁基胶塞取代。
丁基橡胶是由异丁烯和少量异戊二烯(≤3 %)在超低温(- 95 ℃) 条件下聚合而成的共聚物[ 3] ,为白色或暗灰色透明性弹体,其结构式可用下列通式表示:丁基橡胶是气密性最好的橡胶, 其气体透过率约为天然橡胶的1 /20 , 丁基橡胶的耐热性、耐候性和耐臭氧氧化性都很突出。
最高使用温度可达200 ℃, 能长时间暴露于阳光和空气中而不易损坏。
丁基橡胶耐化学腐蚀性好, 耐酸、碱和极性溶剂。
此外, 丁基橡胶的电绝缘性和耐电晕性能比一般合成橡胶好。
耐水性能优异, 水渗透率极低。
减震性能好, 在- 30 ～50 ℃具有良好的减震性能。
在玻璃化温度(- 37 ℃) 时仍具有屈挠性。
丁基橡胶的缺点是硫化速度很慢, 需要高温或长时间硫化, 自黏性和互黏性差, 与其它橡胶的相容性差, 难以并用[ 4] 。
丁基橡胶抗生 素 瓶 塞 洗涤、灭菌、干燥 标 准 操 作 规 程
1、目的：建立KJQS-12E型胶塞清洗机操作规程，明确胶塞清洗机操作方法，使胶塞清洗机操作规范化。
2、范围：适用于粉针综合车间洗胶塞岗的丁基橡胶洗涤、干燥、灭菌岗位操作。
3、责任：车间主任、车间工艺员、质检员及当班工人对此规程的实施负责。
4、程序：4.1 操作前准备：4.1.1 操作工按进入十万级洁净区更衣标准操作程序更衣。
4.1.2 检查室内清场清洁情况。
4.1.3 按班组长要求核对本批药品品名、批号、规格、数量。
4.1.4 将检验合格丁基橡胶塞在电梯间除去外包装，拿到操作间。
4.1.5 用壁纸刀划开料袋，将胶塞倒入法兰桶内。
4.1.6 打开纯化水阀门，检查纯化水压≥0.3Mpa。
4.1.7 打开注射水阀门，检查注射水压≥0.3Mpa。
4.1.8 打开洁净压缩空气阀门，检查洁净压缩空气压力≥0.4Mpa。
4.1.9 打开蒸汽阀门，检查蒸汽压力≥0.3Mpa。
4.2 生产操作过程：4.2.1 目检，挑出次塞。
4.2.2 打开控制柜的电源开关，此时触摸屏显示原始画面，操作员点击主操作屏按钮，屏幕转到主屏幕操作屏，再点击自动屏进入操作画面。
4.2.3 真空进料：在自动屏上点击真空进料，出现自动真空进料作业界面，当进料口上方的绿灯亮时，表示进料位置定位完毕，操作员可以打开进料门，（当红灯亮时，严禁打开进料口）连接好进料管，把进料管一端接到胶塞上，按总停按钮，打开纯化水，在主屏上，点击真空泵，点击执行按钮，真空进料作业开始，真空系统开启，开始进料．进料结束后，点击取消按钮结束，然后关闭机器内转筒上的小门，进料口旋紧，关注射用水。
4.2.4 在主操作屏，点击设定屏，在设定屏设定以下参数：冲洗时间：15—18min 清洗转速：2蒸汽灭菌温度：12l℃灭菌时间：35min 灭菌后真空时间：17min 烘干温度：105℃干燥时间:17min真空干燥时间：7min 真空干燥循环：2 冷却温度：90—99℃出料转速：4-8 启／停时间：1－44.2.5 冲洗：点击8。
丁基橡胶药用瓶塞检验规程
编号：ZL-SOP-QC-001-00目的：建立丁基橡胶药用瓶塞检验操作规程范围：本规程适用于丁基橡胶药用瓶塞的检验责任人：质检科内容：1.器具：量筒、烧杯、刻度吸管、pH计、移液管、100ml容量瓶、TU-1800型紫外分光光度计、微孔滤膜、10ml移液管、电炉、天平、锥形瓶、电热恒温干燥箱、瓷蒸发皿、干燥器、纳氏比色管、高温电炉。
2.试剂：淀粉指示液、高锰酸钾液（0.002mol/L）、硫代硫酸钠滴定液（0.01mol/L）、醋酸盐缓冲液（pH3.5）、碱性碘化汞钾、氯化铵溶液、2mol/L 盐酸、亚铁氰化钾试液、标准锌溶液、标准铅溶液（1ml相当于10μg的Pb）、硫代乙酰胺试液、混合液、碘化钾、稀硫酸、0.1%氯化钾溶液。
3.检查：3.1外观：3.1.1操作步骤：取样品100个，目视检测。
3.1.2结果判定：表面色泽应均匀，不得有污点、杂质、气泡、裂纹、缺胶、粗糙、胶丝、海绵状毛边；不得有除边造成的残缺或锯齿现象；不得有模具造成的明显痕迹，判为合格。
3.2灰分：3.2.1操作步骤：3.2.1.1分别称取样品1.0g两份，放入已炽灼至恒重的两个坩埚中，精密称定；3.2.1.2放入高温电炉中，缓缓炽灼至完全炭化；3.2.1.3再放入800℃炽灼至完全灰化，移置干燥器内；3.2.1.4放冷至室温，精密称定后，再在800℃炽灼至恒重。
4.2.2结果判定：遗留残渣不得过45％，判为合格。
3.3澄清度与颜色：3.3.1操作步骤：取供试液10.0ml置纳氏比色管中。
4.3.2结果判定：溶液应澄清无色。
如显浑浊，与2号浊度标准液比较，不得更浓；如显色，与黄绿色5号标准比色液比较，不得更浓，判为合格。
3.3.3注：试验液S1和空白液S0的制备按《丁基橡胶药用瓶塞质量标准》进行。
3.4酸碱度3.4.1操作步骤3.4.1.1用量筒分别量取试验液S1和空白液S0各20ml，置两个小烧杯中。
3.4.1.2向两个小烧杯中各加入氯化钾溶液（1→1000）1.0ml。
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卤化丁橡胶的特点 IIR 由于其硫化速度慢、相溶性较差等原因， 人们又开发了卤化丁基橡胶。 1、硫化速度快，硫化剂用量较少。 2、能用各种硫化剂硫化。 3、能与 NR、SBR、NBR、CR 并用，相溶 IIR。
橡胶的性能 ——配方 1、目的： 改善使用性能；改进工艺性能；降低成本。 2、配方的组成 主体材料 包括生胶和再生胶 1-2 种 硫化体系 硫化剂、促进剂、活性剂、防焦剂 2-5 种 防护体系 包括各种防老剂、稳定剂等 补强与填充体系 增塑体系 包括各种软化剂、增塑剂、操作助剂等 特种体系 塑解剂、分散剂、改性剂、着色剂等 我公司所用配方的体系一般包括：主体材料、硫化体系、 补强与填充体系、增塑体系、 补强与 填充体系、增塑体系、特种体系
胶塞的历史 橡胶在发现可以被硫化，可以用作密封制 品前，人们一直使用木塞外加石蜡作为药 品的密封。 天然橡胶远在 1929 年前中美州和南美洲的 1929 当地居民已开始使用，它是从某些树木的 树皮 割下，所得的胶乳经干燥处理而制成 的，直到有人发现使用硫黄硫化能表现出 优异的物理性能 后，才得到广泛的应用。 天然橡胶在发现可以被硫化后不久，即开始用于 制造瓶塞，它的特点是弹性好、针刺落屑少等， 缺点是气密性差，并含有少量异性蛋白，易引起 过敏，硫化时需大量的硫黄和促进剂，硫化后 的 制品中迁移物多等，这样就易引起药品的失效。 这一直是医药行业比较头痛的问题，人们一 直在 探讨、研究，寻找一种天然橡胶的替代材料。十 九世纪三十年代，人们合成了丁基橡胶， 1943 年 丁基橡胶的工业化生产，对人们的探索指明了道路。 由于丁基橡胶气密性好、耐候性好、耐酸碱性好、 内在洁净度高等特点，人们发现丁基橡胶比 天然 橡胶有明显的优势后，就用丁基橡胶取代了天然 橡胶作为胶塞的基体材料，丁基橡胶就很 快取代 了天然橡胶生产药用瓶塞。日本 1957 年开始生产 丁基药用瓶塞，到 1965 年就实现了药 用瓶塞丁基 化，欧美各经济发达国家也均于 70 年代初实行了 药用瓶塞丁基化。我国多年来一 直采用天然橡胶 瓶塞，直到 1992 年才开始批量生产丁基橡胶药用 瓶塞。 目前国内外著名的胶塞生产企业有：美国 的 WEST 公司、日本的大协、比利时的 Helvoet、法
橡胶瓶塞的相关知识 一、定义：是由橡胶添加适当助剂经硫化制成的， 用于封装药品容器的密封制品。 二、性能：用于橡胶瓶塞的硫化胶的物理性能， 如硬度、定伸强度、拉伸强度不象其它橡胶制 品 要求的那样严格，而压缩永久变形及硫化胶的物 理性能要求，如落屑和磨擦性是非常重要的 性能， 针刺落屑用于描述皮下注射时针刺瓶塞后的掉渣 性能，磨擦性能则表示瓶塞受到针刺时 的滑动阻 力，在包装水汽敏感或干燥药品时，药瓶和瓶塞 应具有良好的抗气体和水汽的渗透能 力，因此， 应选用最低透气性的橡胶。
橡胶瓶塞的性能 由于绝大多数瓶塞都用于包装制备液体药品的， 故瓶塞的低吸水性或溶剂吸收性以及对药品成 份 的吸收性也是重要的选择标准，此外，瓶塞必须 在冲洗、漂洗、高温烘干及整个产品使用寿 命期 性能保持不变，因而要求瓶塞所用橡胶具有所规 定的耐热老化性。 总之，要求瓶塞要具有低透气性、低抽出率、低 吸收性等。理想的瓶塞是：无渗透、化学惰性、 不吸收或被吸、无滤、高弹性、无碎渣等。
胶塞尺寸
T 型胶塞的结构 d1 为冠部直径,d2 为颈部直径，又称为塞径,h1 为 冠部厚度,h2 为总高
生产工艺流程 工艺流程 原材料仓库，材料配合，炼胶（密炼开炼），硫化，除边，预清洗，清洗
配合和炼胶 配合：是按生产配方的要求把各种合格原材料放 到待检区，准备炼胶。炼胶是在炼胶机上将生 胶 中加入各种配合剂制成混炼胶的过程。 炼胶分密炼和开炼 密炼又称密闭式炼胶，优点是可以避免粉料的飞 扬，提高混炼胶的质量。密炼机与混炼胶质量 相关的结构有上顶栓、密炼室、转子、冷却回路等， 整个过程可分为塑化、浸润、混入、分散、 混合 等阶段，一般有特定密炼工艺要求。 开炼又称开放式炼胶，与密炼相比，缺点 是生产效率低，劳动强度高、环境较差， 安全性小， 优点是灵活机动，适用于小规 模小批量生产。开炼可分为包辊、吃粉、和翻炼三个过程。 最佳混炼胶就是胶料及其硫化胶的溶合性 能达到最佳值时的混炼状态，混炼胶停放 ４小时后才 能使用。
按化学结构分 碳链橡胶 1、不饱和非极性 2、不饱和极性 3、饱和非极性 4、饱和极性 杂链橡胶
橡胶的分类
我公司常用橡胶的有关知识 目前在胶塞上使用的橡胶主要是天然橡胶 和丁基橡胶，其它种类的橡胶也有，但数量有限，这 里不作详细介绍。 天然橡胶简称 NR，丁基橡胶简称 IIR。
天然橡胶
NR 的性能 1.加工性能好，不易粘辊。 2.弹性好。弹性模量为 2－4Mpa，回弹率在 0－100℃范围内可达 50－85%以上。 3.机械强度比较高。纯胶硫化胶的拉伸强度 为 17－25 Mpa，炭黑补强的硫化胶可以提 高到 25 －35 Mpa，纯胶硫化胶 500%定伸 定力 2－4 Mpa，200%定伸强力在 7－10 Mpa。 4.纯胶硫化胶耐屈挠性好，屈挠 20 万次以上 才出现裂口。这是由于天然的滞后损失小， 在多 次变形时生热低的效果。
配方的分类 基本配方 是以生胶为 100 份，其余以此为基准调配的配方。 生产配方 是生产中使用的一种配方表示形式，目的是便 于进行生产，它用胶料的密度乘以炼胶 机的工作容积，得 出炼胶机每批混炼胶料的总重量，再将总重量除以基本配 方合计数所得到的 倍数，乘以每种配合剂的分数，可得实际生产用各种组分的重量，将各种组分列表，即得生产配 方。 试验配方是专供研究鉴定新胶种或新配合剂用的。 性能配方是为了满足产品性能以及工艺上的要求，提高某 些特性及新的特性配合剂。 制品配方是在性能配方的基础上，根据产品使用要求并结 合实际生产条件所作的实用投产配方。
国的 Stelmi、湖北华强、郑州翱翔等。 天然橡胶瓶塞传统上又称为翻边胶塞，丁 基橡胶瓶塞又称为 T 型胶塞，这是根据胶塞 的使用 方法上来命名的。
胶塞所采用的标准及内容 天然胶塞的质量要求 见 GB9890－88 医用输液橡胶塞。 HG4－559－74 抗生素橡胶瓶塞。 丁基橡胶瓶塞的质量要求 丁基橡胶瓶塞的相关标准。 YY0169.1－94 YY0169.2－94 YY0169.3－94 ? ISO8362
硫化参数的确定
通过分析硫化曲线，一般至少可以获得四个数据： 最小转矩，反映胶料在一定温度下的流动性 或可 塑性；最大转矩（或平衡转矩），它反映硫化胶 的模量；T10 为转矩 M 达到 ML+10% （MH-ML） 的时间，常反映胶料的焦烧时间，意思是胶料从 此开始硫化但尚可以流动，T90 为转矩 M 达到 ML+90%(MH-ML)的时间,它反映胶料的正硫化时 间,经实验证明,取 90%转矩上 升对应的时间 MHML 硫化程度交链的疏密度,作为正硫化时间,是因 为从统计规律看,这个区域 所体现的硫化胶性能最 好;从工艺角度来考虑,需有一定的保险系数，以防 止过硫或欠硫，还因 为胶料硫化的化学反应在此 区域已足够完全。 欠硫阶段：指硫化起步与正硫化之间的阶段，此 时交联密度低，橡胶制品应具有的能大多不明 显。 过硫阶段：指正硫化阶段后继续硫化进入的阶段， 此时硫化胶的各项物理机械性能基本上保持 稳定， 当平坦期过后，天然橡胶和丁基橡胶由于断链多 于交链而出现硫化返原现象而变软，合 成橡胶则 因交联继续占优势和环化结构的增多而变硬，且 伸长率也随之降低，橡胶性能到损害。 橡胶的交链程度影响其弹性、气密性、热 稳定性和抗溶胀性等性能。 硫化条件：压力、时间、温度是构成硫化 硫化条件：压力、时间、 工艺的主要条件，通常称为 “ 工艺的主要条件，通常称为“硫化三要 素”。 通常性况下，硫化温度高、速度快、时间 短；另外还与制品的厚度有关，影响因素 主要有：胶 种、硫化体系、硫化方法。硫 化时方式一般有加热和辐射等方法。
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橡胶的相关知识 橡胶的概念
根据有关定义，可把橡胶的定义归结为： 橡胶是一种高分子材料；橡胶可以被改性， 即硫化； 橡胶在大的变形下能够迅速而有 力地恢复其形变。
橡胶的分类 按来源分 天然橡胶 NR 合成橡胶 通用橡胶：丁苯 SBR,顺丁 BR,异戊 IR，丁 腈 NBR，丁基 IIR,氯丁 CR，乙丙 EPM,EPDM 特种橡胶：氟橡胶 FRM,丙烯酸酯胶 ACM,聚 硫 T，硅橡胶 Q，氯化聚乙烯 CPE 等
ISO8536 目前的行业标准是 目前的行业标准是 YBB00052005、 、 YBB00042005 在国际标准，行业标准的基础上我公司又 出了<<内控标准>>、<<检验规程>>等相关 标准来保 证胶塞的质量。 下面介绍一下上述标准的内容： 胶塞所采用的标准及内容
尺寸标准 YY0169.1-94 丁基橡胶输液瓶塞 YY0169.2-94 丁基橡胶抗生素瓶塞 ISO8362-5 冻干注射瓶塞 ISO8536-2 输液瓶塞 ISO8362-2 注射瓶塞 ISO8536-6 冻干输液瓶塞 依据客户要求设计制作
胶塞配方的注意事项 ①不使用含有铅、汞、砷、钡等物质的原材料。 ②少用或尽量不用软化剂、防老剂。 ③硫化剂不采用含硫、含锌的化合物。
④胶料流动性好，产品表面应光滑，不得有裂缝。 ⑤选择一些气密性好，弹性好的胶种。 ⑥选择杂质少的原材料。
硫化 硫化的基础知识 橡胶只有经过硫化之后才能显示出优异的性能， 什么叫硫化呢？ 硫化是指在加热或者辐射的条件下，混炼胶中的生胶与硫化剂发生化学反应，由线型结构的大分 子交链成立体网状结构的大分子，并使胶料的物 理机械性能及其它性能随之发生根本变化的过 程。 生产上总希望焦烧时间长一些，硫化速度快一些， 以保证操作安全和提高生产效率，这可以通 过调 整配方来实现。