胶塞标准USP、EP、YBB对比
关于医用丁基胶塞的保质期问题
江阴市海华橡塑有限公司-吴锋
关于医用丁基胶塞的保质期问题
针对医用丁基胶塞的保质期问题，我国于1994年发布的国家医药行业标准《丁基橡胶抗生素瓶塞》（YY0169.2-94标准）中7.4（贮存）条款规定：“瓶塞应贮存在干燥、通风、无化学污染物的仓库内，贮存温度应在30℃以下，瓶塞保质期为7年。
瓶塞贮存超过6个月须进行复验，合格方可出厂、使用”。
我国现行的YBB标准和国外同类产品标准均无此项规定。
我公司曾经做过试验，通过对胶塞产品留样观察试验，发现在公司留样室存放了1年、2年、3年以及5年的留样胶塞，按照国家标准（YBB）进行全项检验，其各项性能与刚生产时对比没有明显变化。
同时关于橡胶制品的保质期问题，受到较多因素的影响，比如原材料选用、配方、生产工艺、贮存条件等方面的影响，不可一概而论，要根据不同厂家的产品而定。
我公司生产的卤化丁基胶塞在常温、避光状态下可以保证在3年内使用的安全性。
江阴市海华橡塑有限公司
2011-7-11。
胶塞的质量标准
1.目的
建立丁基胶塞的质量标准。
2.适用范围
质量管理部、生产管理部。
3.职责
生产管理部人员、质检人员、库管人员
4.定义
无
5.引用标准
YBB00042002
6.材料及设备
6.1无
7.流程图
无
8.内容
8.1. 穿刺落屑：按YBB00042002第二法对照法测定，落屑数≤5粒。
8.2 胶塞与容器密合性：取本品10个，置烧杯中，加水5分钟，取出，在70℃干
燥1小时，备用，另取10个与之配套的瓶加水至标示容量，用待测胶塞塞
紧，再加上与之配套的铝盖，压盖，放入高压蒸汽灭菌器中，121℃保持30分
钟，冷却至室温，放置24小时。
将瓶倒置，放入含10%亚甲兰溶液的容器
中，置于带抽气装置的容器中，抽真空至真空度为25kPa，维持30分钟，真
空装置恢复至常压，再放置30分钟，取出，用水冲洗瓶外壁，观察，亚甲兰
溶液不得渗入瓶内。
8.2.1 灰分遗留残渣＜ 50%
8.2.2 自密封性：取胶塞与容器密合性项下样品，采用穿剌力测定法YBB00042002
第二法中注射针，向胶塞不同部位穿剌，每个胶塞穿剌3次，每穿剌10次后
更换注射针，将样品倒置，放入含10%亚甲兰溶液的容器中，置于带抽气装置
的容器中，抽真空至真空度为25kPa，维持30分钟，真空装置恢复至常压，
再放置30分钟，取出，用水冲洗瓶外壁，观察，亚甲兰溶液不得渗入瓶内。
9.注意事项
无
10.附录及派生记录
无
11.相关文件
无
12.修订记录。
卤化丁基橡胶塞标准与外观常见异物缺陷
卤化丁基橡胶塞标准与外观常见异物缺陷
王备战韩治军
(郑州翱翔医药科技股份有限公司，河 南 郑 州 452483)
摘 要 ：结合2015年颁布的《国家药包材标准》，对卤化丁基橡胶塞的外观常见异物进行了分类，并分析了 胶塞常见外观缺陷产生的原因及解决方法。
关 键 词 ：卤化丁基橡胶塞;外观;异物;标准;原因
1 国家标准
塞外观 异 物 按 是 否 可 掉 落 分 类 ，可 分 为 可 掉 、不可
掉两类；
2015年 我 国 颁 布 了 《国家药包材标准》1"，简称
按是否属于胶塞本体材料分类，可分为外来
YBB标 准 。其 中 ，卤化丁基橡胶塞（以下简称胶塞) 异 物 和 自 身 产 生 两 类 ；
的，
加
类缺陷应该通过加强对设备的有效管理来解决问 强，
中的 物
题 ，定 期 进 行 设 备 检 修 、巡 查 、清 洁 等 工 作 ，并按照 注 。 目前，不论是国际标准、国家标准，还是行业标
，
药物
见异物
2 胶塞常见外观异物的分类
根 据 笔 者 以 往 工 作 经 验 ，卤 化 丁 基 橡 胶 塞 的 胶
3 胶塞外观异物检验方法
药品生产企业常用的胶塞外观异物检验方法 检验法
光 照 强 度 ：300 Lx (局 部 可 以 放 大 ）； 光 源 距 胶 塞 15 cm左 右 ，人眼距胶塞20〜25 cm 左右。
因此，只有严格按照GMP要求对人员、设 施 、洁 净 区 等 进 行 管 理 ，才 能 有 效 避 免 毛 发 和 纤 维 等 异 物 的产生。
有 可 能 是 在 胶 塞 硫 化 时 产 生 ，因 此 ，应在胶塞冲切
YBB药包材标准
YBB00342003药用玻璃成份分类及其试验方法
YBB00352003低硼硅玻璃管制药瓶
YBB00362003钠钙玻璃管制药瓶
YBB00372003抗生素瓶用铝塑组合盖
YBB00382003口服液瓶撕拉铝盖
YBB00392003外用液体药用高密度聚乙烯瓶
YBB00402003输液瓶用铝塑组合盖
YBB00142004笔式注射器用铝盖
YBB00152004笔式注射器用氯化丁基橡胶活塞和垫片
YBB00162004笔式注射器用溴化丁基橡胶活塞和垫片
YBB00172004口服固体药用低密度聚乙烯防潮组合瓶盖
YBB00182004铝/聚乙烯冷成型固体药用复合硬片
YBB00192004双向拉伸聚丙烯/真空镀铝流延聚丙烯药品包装用复合膜、袋
YBB00332003钠钙玻璃管制注射剂瓶
YBB00342003药用玻璃成份分类及其试验方法
YBB00352003低硼硅玻璃管制药瓶
YBB00362003钠钙Байду номын сангаас璃管制药瓶
YBB00372003抗生素瓶用铝塑组合盖
YBB00382003口服液瓶撕拉铝盖
YBB00392003外用液体药用高密度聚乙烯瓶
YBB00402003输液瓶用铝塑组合盖
YBB00242003121℃内表面耐水性测定法和分级
YBB00262003硼硅玻璃药用管
YBB00272003低硼硅玻璃药用管
YBB00282003钠钙玻璃药用管
YBB00292003硼硅玻璃输液瓶
YBB00302003低硼硅玻璃模制药瓶
YBB00312003硼硅玻璃模制注射剂瓶
YBB00322003低硼硅玻璃模制注射剂瓶
胶塞标准USP、EP、YBB对比
/
/
USP、EP、YBB标准对比
项目
标准（USP381）
标准（EP3.2.9）
YBB00052005
外观
符合规定
符合规定
针刺圈内或与内容物接触面有污点、杂质，针刺圈内或密封面有气泡、裂纹;表面有污点、杂质、胶丝、胶屑、海绵状、毛边，塞颈部分粗糙，明显缺胶;除边造成的残缺和锯齿，由模具造成的痕迹，色泽明显不均匀
鉴别
红外图谱与典型样品图谱一致
在220-360nm波长范围内，溶液的吸收度应≤（I类）；（II类）
≤
易氧化物
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
≤
溶液澄清度
≤18 NTU
≤Ⅲ号浊度标准液(II类)；≤II号（I类）
≤2号浊度标准液
溶液颜色
符合规定
≤5号黄绿标准比色液
≤5号黄绿色标准比色液
重金属
≤2ppm
≤2ppm
≤1ppm
铵盐
≤2ppm
≤2ppm
≤％
穿刺落屑
≤5粒/48针
≤5粒/48针
≤5粒/48针
灰分
在鉴别中
≤％
可溶性锌
≤5 ug/ml
≤5ug/ml
≤％
挥发性硫化物
供试液试纸上产生的黑斑点不得深于对照溶液
供试液试纸上产生的黑斑点不得深于对照溶液
≤50ug/20cm2
A:弹力符合规定B:红外鉴别与典型样品符合规定C:总灰分为典型样品±10％
（1）呈正反应(化学鉴别－卤离子)
（2）样品的红外吸收图谱应与对照图谱基本一致
注射用橡胶塞欧洲药典标准
欧洲药典-摘自《欧洲医药精粹》之欧洲药业标准第50节注射用橡胶塞非肠道药用瓶塞非肠道药用瓶塞由大分子弹性有机物经硬化而成。
本标准同样适用于粉针及冻干胶塞，但对于硅氧烷胶塞、层状胶塞或漆层胶塞却不适用。
胶塞是由天然橡胶及各种添加物通过聚合、缩聚反应而成。
胶塞中含有的天然成分及添加物的含量根据需要而定。
胶塞按等级分为Ⅰ类和Ⅱ类。
Ⅰ类胶塞符合高的要求，并优先选用；Ⅱ类胶塞的机械性能则适合于某些特定的用途（如：多次穿刺），由于其化学成分，Ⅱ类胶塞不被优先选用。
胶塞选用原则- 不吸收、渗透制剂，不影响制剂的成分。
- 不受制剂反作用改变稳定性及产生毒性。
- 胶塞在整个密封过程中需与制剂相容。
- 胶塞供应商必须提供胶塞成分给制剂生产商，以配合配伍性测试。
- 一旦胶塞成分有变，则应及时通知药品生产商，并重做配伍性测试。
因为配伍性部分或全部取决于化学成分的改变。
特点胶塞具有弹性，为半透明或不透明体，没有特定的颜色，最终颜色需由添加物决定。
这些添加物实际是大量的可逆膨胀产生的四氢呋喃。
它们是同源质的，不受闪蒸及偶发性物质的影响（比如纤维异粒，废橡胶）。
对于胶塞中橡胶类型的签定说明不在本标准范围内。
因此以下所举各种分析方法中，弹性胶塞及非弹性胶塞的签定没有作橡胶类型的区分。
每批胶塞在使用前都必须做配伍性测试。
多种方法可用于配伍性的测试。
如在萃取物中相对浓度测定，硫酸盐的测定及硫磺的测定，干馏物的红外吸光度测定及紫外吸光度测定。
规定取一横截面为1毫米2 -5毫米2 范围的弹性物，用手拉伸至原长的2倍，并保持1分钟，然后松开，该弹性物在30秒内可收缩至原长的1.2倍。
实验试验液S制备：用水清洗总面积约为100厘米2 的未经切割过的胶塞，然后放入一适当的玻璃容器中，加水浸没。
煮沸5分钟，用水反复洗涤5次。
将清洗后的胶塞放入一宽口三角杯中，加200ml水并称重。
用铝箔或硼硅玻璃烧杯盖住瓶口，在20分钟至30分钟内升温至121℃±2℃保持30分钟，30分钟内冷却至室温。
高硼硅玻璃管制注射剂瓶 ybb标准
高硼硅玻璃管制注射剂瓶 ybb标准高硼硅玻璃管制注射剂瓶 ybb标准一、引言在医学和药品行业中，注射剂瓶的质量和安全性至关重要。
为了确保药品的有效性和安全性，选择合适的注射剂瓶材料和符合标准的生产工艺显得尤为重要。
高硼硅玻璃管制注射剂瓶 ybb标准就是其中一种重要的标准，本文将围绕这一主题展开讨论。
二、高硼硅玻璃管制注射剂瓶 ybb标准的定义和作用1. 高硼硅玻璃管制注射剂瓶的定义高硼硅玻璃管制注射剂瓶是指采用特殊的高硼硅玻璃材料制造的用于装载注射剂的瓶子。
这种玻璃材料具有优异的化学稳定性和耐热性，能够有效保护药品免受外界污染和氧化影响，保证药品的质量和有效期。
2. ybb标准的作用YBB标准是指《药典玻璃容器标准规范》，是日本医药品和医疗器械等产品的包装容器标准。
这一标准规定了高硼硅玻璃管制注射剂瓶在制造和使用过程中的各项要求，包括材料选取、生产工艺、包装、运输等环节。
符合YBB标准的注射剂瓶能够确保药品的安全性和稳定性，是医药行业中被广泛认可的标准之一。
三、高硼硅玻璃管制注射剂瓶 ybb标准的生产流程1. 高硼硅玻璃的选材高硼硅玻璃是一种特殊的玻璃材料，含有较高比例的硼氧化物，具有优异的耐热性和化学稳定性。
在生产高硼硅玻璃管制注射剂瓶时，首先需要选择高质量的高硼硅玻璃原料，确保产品的品质和稳定性。
2. 生产工艺在高硼硅玻璃管制注射剂瓶的生产过程中，需要严格控制各项制造工艺，包括玻璃成型、热处理、表面处理等环节。
只有严格按照YBB标准要求的工艺流程，才能确保注射剂瓶的质量和安全性。
3. 检测和包装生产完成的高硼硅玻璃管制注射剂瓶需要经过严格的检测和质量控制，保证产品符合YBB标准的各项要求。
之后再进行包装和运输，以确保产品在运输过程中不受损坏。
四、高硼硅玻璃管制注射剂瓶 ybb标准的优势1. 比传统玻璃瓶更安全相比传统的玻璃材料，高硼硅玻璃具有更好的化学稳定性和耐热性，能够更好地保护药品免受外界污染和氧化影响。
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
胶塞和瓶口尺寸及公差对比
• YY0169.1-94《丁基橡胶输液瓶塞》1994-07-02发 布 1994-11-01实施 本标准等效采用国际标准 ISO8536-2—1992《医用输液器具—第二部分：输 液瓶塞》
• 塞颈直径
32型 28型 26型
•
23.6 18.0 15.4
•
±0.2
15.0 ±0.15
• 对应的瓶口内径 22.5 16.5 14.5
• YBB00032005
±0.3 ±0.5 14.0 ±0.5
• YBB00022005-2
胶塞和瓶口尺寸及公差对比
• YY0169.2-94《丁基橡胶抗生素瓶塞》1994-07-02 发布 1994-11-01实施 本标准等效采用国际标准 ISO8362-2—1998《医用注射器具—第二部分：注 射瓶瓶塞》
胶塞质量标准对比
抗生素胶塞
输液胶塞
功能特性：穿刺力
10N
75N、80N
穿刺落屑 密封性与穿刺器保持性
5粒/100针
20粒/10针
--
4h/0.5Kg不拔出
无泄漏
自密封性 25kPa真空30分钟
--
密合性
亚甲蓝溶液不得渗入
同上
胶塞质量标准对比
生物特性：溶血 热源
急性全身毒性
抗生素胶塞 溶血率﹤5% 符合规定 符合规定
胶塞质量控制与常见质 量问题
2024年2月5日星期一
胶塞质量控制及常见质量问题
李立军
丁基胶塞政策背景
• 药包材质量控制有章可循
• 我国新修订的《药品法》规定，药包材标准可纳入药品管 理体系。《药品法》五十二条对药包材的监管方式有明确 的规定:不符合标准的药包材由药品监督管理部门监督停 止使用。如果使用未经批准的直接接触药品的药包材包装 药品，按照《药品管理法》第四十九条的规定，该药品将 按劣药论处。
胶塞资料(1)知识讲解
一、抗生素粉针与药用丁基胶塞的相容性研究及潜在质量风险分析… 胶塞概述z 药品包装材料与药物相容性试验指导原则z 药用丁基胶塞与头孢曲松钠相容性研究z 药用丁基胶塞与药物相容性试验总结z 相容性试验常用手段及试验条件z 2009胶塞抽验和十一五课题研究工作‹ 胶塞是药品包装中瓶装密封材料的重要组成部分，主要包括天然胶塞和丁基胶塞。
‹ 在我国的制药史上，长期一来一直采用的都是加垫涤纶膜的翻口天然胶塞。
天然橡胶胶塞虽然具有优秀的物理性能和耐落屑性能，但是，天然胶塞主要存在以下几个弊端：首先，生物安全性较差。
其次，化学性质比较活跃，易与药品发生相互反应。
第三，气密性较差。
第四，使用工艺复杂。
‹ 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。
‹ 日、美、欧等发达国家均已在20世纪六七十年代实现了医药用胶塞的丁基化，而中国目前天然胶塞仍在大批量的使用，这也就是我国许多制剂产品不高和不能出口外销的原因之一。
药用胶塞丁基化已势在必行。
‹ 我国已经全面停止使用天然胶塞。
丁基胶塞存在的主要问题z 药用丁基胶塞直接与药物接触，虽然丁基橡胶具有良好的气密性、能够耐热、耐酸碱，但在使用过程中，仍然存在与药物的相互作用，甚至影响药物的物化性质和药理作用。
存在与药物的相互作用，甚至影响药物的物化性质和药理作用。
z 胶塞发展至今，由于胶塞质量可能导致的使用安全始终是该产品的关注热点。
总起来说，只要存在以下四方面的问题：z 1、吸附的问题：即是药物先被吸附于瓶塞的表面，然后是药物在瓶塞的基体内扩散。
尽管这种扩散是极度轻微的，有时甚至是无法测定的，但是，终究这种交互作用是在缓慢地进行中。
蛋白质被吸附也是一个较大的难题，很多由生物技术制备的含蛋白质的药物被瓶塞大量吸附，会导致药物迅速失效。
z 2、浊度问题：z （1）浸出物问题：尽管丁基胶塞的化学稳定性是很好的，而且配方中所用的材料也是精细的，但是，毕竟加入了大量的其它材料，由于浓度梯度的关系，实际上也在缓缓地向外渗出，污染或破坏被包装药物，以至降低药效。
《国家药包材标准》的反馈意见处理结果
7
YBB00162002--2015
铝制药用软高管
8
YBB00162002--2015
铝制药用软高管
第 1 页，共 15 页
序 号
9
标准号
YBB00162002--2015
名称
铝制药用软高管
原标准内容
Φ25为0.55± 0.15
存在问题
修订建议
修订理由
建议单位
处理意见
暂不修订。YBB标准提高 西安德宝药用包装有限公 时可以通过调研，酌情考虑 司 。 暂不修订。YBB标准提高 西安德宝药用包装有限公 时可以通过调研，酌情考虑 司 。 暂不修订。YBB标准提高 西安德宝药用包装有限公 时可以通过调研，酌情考虑 司 。 GB/192-1981 普通螺纹基本牙型标 准及GB/196-1981普通螺纹基本尺 寸标准中均没有M7*1.25这一尺 西安德宝药用包装有限公 暂不修订，YBB标准提高时 寸，且目前国内主流铝管供应商 司 可以通过调研，酌情考虑。 生产Φ13.5规格产品时均以 M7*1.00作为口外径标准。
20
YBB00292005-1-2015 高硼硅玻璃管制注 垂直轴偏差 射剂瓶
1.垂直轴偏差与瓶子的肩部造型没 判定指标不要再区分端肩瓶和 有关系，主要与瓶身高度、瓶身 端肩瓶和溜肩瓶采用了不同的判定指 溜肩瓶，采用统一的判定指标 外径、瓶头与瓶底造型有关。 标。 即可。 2.ISO标准中也没有区分不同的肩 部造型。
19
YBB00292005-1-2015 高硼硅玻璃管制注 耐冷冻性 射剂瓶
1.检测方法中没有详细规定检测设备 和检测步骤。 2.目前的耐冷性检测方法的冷冻原理 与药厂的冻干设备及生产方法的冷冻 原理完全不匹配，没有起到指导生产 的作用。 3.在实际检验中，存在着小规格产品 检验合格几率较高，大规格产品检验 建议取消“耐冷冻性”项目 合格几率较低的情况，而在药厂使用 中则很少出现冻干破损。 4.同样用于冻干产品，高硼硅玻璃瓶 的膨胀系数较小要检测“耐冷冻性”， 而低硼硅玻璃瓶的膨胀系数大，却不 用检测“耐冷冻性”，标准设计的检测 项目不合理。
洗胶塞机新标准发布，胶塞清洗灭菌要求变化！
洗胶塞机新标准发布，胶塞清洗灭菌要求变化！近⽇，中国制药装备⾏业协会发布了《药⽤胶塞清洗机》的标准草案，解读如下：修改了胶塞⽔分的要求（见5.6.1，2007版5.6.2）；修改了不溶性微粒的要求（见5.6.2，2007版5.6.3）；修改了澄清度的要求（见5.6.2，2007版5.6.4）；修改了胶塞灭菌的要求（见5.6.1，2007版5.6.5）；修改了热源的要求（见5.6.2，2007版5.6.6）；修改了胶塞含⽔量的检测⽅法（见6.6.4，2007版6.6.3）；修改了⽆菌检测⽅法（见6.6.5，2007版6.6.6）；修改了澄清度检测⽅法（见6.6.7，2007版6.6.5）；修改了热源检测⽅法（见6.6.8，2007版6.6.7）；增加了补风过滤器在线/离线灭菌的要求（见5.4.2，2007版 5.4）；增加了总排⽔防倒灌的要求（见5.4.10，2007版 5.4）；增加了真空检漏的要求（见5.4.11，2007版 5.4）；增加了在线清洗的要求（见5.4.12，2007版 5.4）；增加了⾃控系统的要求（见5.4.13，2007版 5.4）；增加了真空检漏的性能检测⽅法（见6.4.12，2007版 6.4）；增加了在线清洗的性能检测⽅法（见6.4.13，2007版 6.4）；增加了⾃控系统的性能检测⽅法（见6.4.14，2007版 6.4）；增加了可见异物要求（见5.6.2，2007版 5.6）；增加了可见异物测试⽅法（见6.6.9，2007版 6.6）；删除附录A（见2007版附录A）。
关于表⾯粗糙度，要求清洗机应符合要⽤胶塞灭菌⼯艺的要求，清洗机箱体和清洗筒的内表⾯应光滑、平整。
所有转⾓应圆滑过渡，易于清洗，其表⾯粗糙度Ra值应不⼤于0.8µm，外表⾯粗糙度Ra值应不⼤于1.6µm。
规定了核黄素检测喷淋头清洗死⾓的⽅法：模拟对箱体内壁喷核黄素，通过设备在线清洗功能查验在线清洗的效果，⽤荧光紫外灯检查内表⾯，没有荧光反应为合格。
胶塞质量控制及常见质量问题[1]
![胶塞质量控制及常见质量问题[1]](https://img.taocdn.com/s3/m/b42509f29e3143323968935d.png)
胶塞常见质量问题
·微粒： 微粒超标是经常困扰输液生产质量的难
题，微粒超标的原因较多，有胶丝、胶屑、杂质、控制 悬浮物、纤维、毛边等，按形成原因分为内源性微粒污 染、外源性污染、摩擦产生的微粒污染和生物微粒污染 四方面。要减少胶塞微粒污染，生产胶塞的配方应考虑 内源性不溶性微粒要少；加强生产过程控制及符合规范 的环境；优异的清洗工艺；生产环境必须通过GMP认证。 在具备以上条件后，胶塞微粒才可以得到很好的控制
生物特性：溶血 热源 急性全身毒性
胶塞与药物相容性试验
• 胶塞与药物相互作用的方式 吸收—药物分散在胶塞内 吸附—药物被吸附在胶塞的表面 浸出—胶塞内可萃取物浸入药剂内 渗透—水分、空气以渗透方式从胶塞传输至药剂内
胶塞与药物相容性试验
• 胶塞与药物相容性出现问题的基本迹象 药液PH值变化 药液产生沉淀或浑浊 药液颜色改变 药物有效成分降解、含量降低 辅料（如防腐剂等）含量降低 胶塞膨胀变形
加速
长期
考察包装对药物 有效期的支持
5 - 8 个 ， 0 、 3、 6、9、12、18、 12、18、 24、36月 24、36月
胶塞与药物相容性试验
丁基胶塞与头孢粉针剂相容性简易试验
国食药监办【2008】 号文件（2008.12）要求： SFDA 国食药监办【2008】7号文件（2008.12）要求： 注射用头孢曲松钠，用丁基胶塞的，每批成品出厂前， 做相容性简易试验，合格后方可出厂；其他头孢类注射剂参 照此法，建立适宜试验方法 。
胶塞和瓶口尺寸及公差对比
• YY0169.2-94《丁基橡胶抗生素瓶塞》1994-07-02 丁基橡胶抗生素瓶塞》 丁基橡胶抗生素瓶塞 发布 1994-11-01实施 本标准等效采用国际标准 ISO8362-2—1998《医用注射器具—第二部分：注 射瓶瓶塞》 • 塞颈直径 A型 B1型 B2型 • 13.2 13.0 13.0±0.1 • 对应的瓶口内径 12.6 12.5 12.5±0.2 • YBB00062005-2 YBB00292005-1 YBB00292005-2
胶塞标准USP、EP、YBB对比
≤
易氧化物
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
≤
溶液澄清度
≤18 NTU
≤Ⅲ号浊度标准液(II类)；≤II号（I类）≤ Nhomakorabea号浊度标准液
溶液颜色
符合规定
≤5号黄绿标准比色液
A:弹力符合规定B:红外鉴别与典型样品符合规定C:总灰分为典型样品±10％
（1）呈正反应(化学鉴别－卤离子)
（2）样品的红外吸收图谱应与对照图谱基本一致
酸碱度
消耗L氢氧化钠不超过或消耗L盐酸不超过
消耗L氢氧化钠不超过或消耗L盐酸不超过
PH变化值≤
吸收度
在220-360nm波长范围内，溶液的吸收度应≤（I类）；（II类）
项目
标准（USP381）
标准（EP3.2.9）
YBB00052005
外观
符合规定
符合规定
针刺圈内或与内容物接触面有污点、杂质，针刺圈内或密封面有气泡、裂纹;表面有污点、杂质、胶丝、胶屑、海绵状、毛边，塞颈部分粗糙，明显缺胶;除边造成的残缺和锯齿，由模具造成的痕迹，色泽明显不均匀
鉴别
红外图谱与典型样品图谱一致
胶塞与容器密合性
符合规定
不溶性微粒
≤60粒/ml（≥10um）
≤6 粒/ml （≥25um）
电导率
≤μS/cm
密封性
任一瓶内溶液不得发蓝
任一瓶内溶液不得发蓝
符合规定
蒸发残渣
/
≤（II类）
≤（I类）
≤
穿透能
≤10N
≤10N
药包材标准中丁基胶塞质量要求及测试方法介绍
药包材标准中丁基胶塞质量要求及测试方法介绍药包材标准中丁基胶塞质量要求及测试方法介绍丁基橡胶塞在洁净度、化学稳定性、气密性等方面的性能都非常好，所以广泛应用于输液、口服液等药品包装中。
由于丁基胶塞在药品行业应用广泛，而且胶塞产品直接接触药品，所以国家出台了很多相关标准来控制丁基胶塞的产品质量。
以下我们结合国家药包材标准的要求来介绍丁基胶塞产品的性能要求和测试方法。
一、参考标准（部分）：YBB00042005-2015注射液用卤化丁基橡胶塞YBB00052005-2015注射用无菌粉末用卤化丁基橡胶塞YBB00322004-2015注射剂用胶塞垫片穿刺力测定法YBB00332004-2015注射用胶塞垫片穿刺落屑测定法1.穿刺落屑取样品10个，照注射剂用胶塞、垫片穿刺落屑测定法YBB00332004-2015测定，落屑数应不得过20粒。
测定法：选择20个注射剂瓶，每个瓶内加1/2公称容量的水。
取10个被测胶塞和10个已知穿刺落屑胶塞分别装在注射剂瓶上，盖上铝盖或铝塑组合盖，封口后进行预处理。
预处理完成后用丙酮或其他适当的有机溶剂擦拭金属穿刺器，然后手持穿刺器，垂直穿刺被测试胶塞上的标记部位，刺入后晃动注射剂瓶数秒后拔出穿刺器。
将注射剂瓶中水全部通过一张滤纸过滤，在人眼距离滤纸20cm 的位置，用肉眼观察滤纸上的落屑数，必要时可以通过显微镜进一步证实落屑大小和数量。
附金属穿刺器标准要求1.穿刺力取样品10个。
照注射剂用胶塞、垫片穿刺力测定法YBB00322004-2015第二法测定，穿刺瓶塞所需的力均不得超过10N。
测定法：依据标准要求对胶塞样品进行预处理。
取10个胶塞配套的注射剂瓶，分别加入公称容量的水，装上预处理过的被测胶塞，加上铝盖或者铝塑组合盖，封口。
将一只注射针置于材料试验机上固定，将注射剂瓶放入材料试验机，打开铝盖或铝塑组合盖，漏出胶塞标记部位，穿刺器以200mm/min的速度进行垂直穿刺，记录胶塞穿刺所施加的最大力值。
中国医药包装协会标准
中国医药包装协会标准中国医药包装协会标准中国医药包装协会标准YBX-2002-2018药⽤玻璃输液瓶规格尺⼨与外观Glass Infusion Bottles specifications and standard size 2018-xx-xx公布2018-xx-xx实施中国医药包装协会发布前⾔本标准参照ISO8536-1：2000《医⽤输液器具》第1部分《玻璃输液瓶》GB2639-90《玻璃输液瓶》和YBB00032002《钠钙玻璃输液瓶》本标准作为贸易供货签约使⽤本标准将YBB标准与GB2639-90标准进⾏整合，要紧规定了规格尺⼨和外观质量，材质要求按YBB 标准本标准由中国医药包装协会提出本标准起草单位：南通耀荣玻璃股份有限公司本标准要紧起草⼈：董孝兴、吉志华本标准⾸次公布药⽤玻璃输液瓶的规格尺⼨与外观1 范畴本标准规定了玻璃输液瓶的产品分类、规格尺⼨、外观质量、抽样试验⽅法及标志、包装、运输、贮存。
其它要求应符合YBB 标准。
本标准适⽤于⼀次性使⽤的注射⽤玻璃输液瓶。
2 规范性引⽤⽂件下列⽂件中的条款通过本标准的引⽤⽽成为本标准的条款。
此标准引⽤⽂件，其随后所有的修改单(不包括勘误的内容)或修订版不适⽤于本标准。
⿎舞依照本部分达成协议的各⽅研究是否可使⽤这些⽂件的最新版本。
GB2639-90 玻璃输液瓶YBB00032005 钠钙玻璃输液瓶ISO8536-1：2000 医⽤输液器具第1部分：玻璃输液瓶YBB00192003 垂直轴偏差测定法GB191 包装储运图⽰标志GB6543 ⽡楞纸GB/T2828.1 逐批检查计数抽样程序及抽样表(适⽤于连续批的检查)3 产品分类3.1 产品按玻璃类型分为Ⅰ型和Ⅱ型，并应标记在瓶⼦底部。
3.2 产品按瓶型分为A型与C型。
4 规格尺⼨4.1 A型瓶的规格尺⼨应符合图1和表1的规定4.2 C型瓶的规格尺⼨应符合图2和表2的规定5 外观质量5.1 输液瓶内、外不应有玻璃搭丝、飞翅尖刺。
胶塞标准USP、EP、YBB对比
胶塞标准USP 、EP 、YBB 对照1 / 1USP 、 EP 、 YBB 标准对照项目标准（ USP381）标准（ EP3.2.9 ）YBB00052005针刺圈内或与内容物接触面有污点、杂质，针刺圈内或密封面有气泡、 裂纹 ;表面外观切合规定切合规定有污点、杂质、胶丝、胶屑、海绵状、毛边，塞颈部分粗拙，显然缺胶; 除边造成的残破和锯齿， 由模具造成的印迹， 色彩显然不平均鉴识红外图谱与典型样品图谱一 A:弹力切合规定 B:红外鉴识 （ 1）呈正反响 (化学鉴识－卤离子 )与典型样品切合规定C:总灰 （ 2）样品的红外汲取图谱应与比较图谱致分为典型样品± 10％基本一致酸碱度耗费 L 氢氧化钠不超出或耗费耗费 L 氢氧化钠不超出或耗费 PH 变化值≤L 盐酸不超出L 盐酸不超出汲取度在 220-360nm 波长范围内，溶 在 220-360nm 波长范围内，溶液的汲取度应≤（ I 类）；（ II 液的汲取度应≤（ I 类）；（II ≤类）类）易氧化物样品液与空白液耗费滴定液 样品液与空白液耗费滴定液≤的体积差应≤（ II ） ;（I 类）的体积差应≤（ II ）;（ I 类）溶液澄清度≤ 18 NTU≤Ⅲ号浊度标准液 (II 类 )；≤II≤ 2 号浊度标准液号（I 类）溶液颜色 切合规定 ≤5 号黄绿标准比色液 ≤ 5 号黄绿色标准比色液重金属 ≤ 2ppm ≤2ppm ≤ 1ppm铵盐 ≤ 2ppm ≤2ppm ≤％穿刺落屑 ≤5 粒/48 针≤5 粒/48 针 ≤5 粒/48 针灰分在鉴识中≤％可溶性锌≤ 5 ug/ml ≤5ug/ml≤％挥 发 性 硫化 供试液试纸上产生的黑斑点 供试液试纸上产生的黑斑点 ≤ 50ug/20cm2物不得深于比较溶液不得深于比较溶液胶塞与容器切合规定密合性不溶性微粒≤ 60 粒/ml （ ≥10um ）≤ 6 粒 /ml （ ≥25um ）电导率 ≤ μS/cm密封性任一瓶内溶液不得发蓝 任一瓶内溶液不得发蓝 切合规定蒸发残渣/ ≤（ II 类）≤≤（I 类）穿透能 ≤ 10N ≤10N ≤ 10N细菌内毒素 / / 切合规定（热原）溶血 / / 溶血率＜ 5％急性毒性 // 切合规定生物毒性试USP<87> USP<88>//验。
免洗胶塞质量标准
免洗胶塞质量标准
免洗胶塞质量标准是指对免洗胶塞产品进行质量评估和监督的一系列规定和约定。
免洗胶塞的质量标准通常包括以下方面：
1. 外观质量：免洗胶塞应具有光滑、无明显划痕、毛刺等缺陷，颜色均匀一致，不得有色差、漏色等问题。
2. 尺寸和容差：免洗胶塞的尺寸应符合相应的标准，包括长度、直径、圆度等指标，并且容许范围内的偏差应在规定的范围内。
3. 物理性能：免洗胶塞应具有一定的物理性能，如耐磨、耐老化、耐酸碱等特性。
4. 功能性能：免洗胶塞应能够达到相应的密封性能要求，不得有渗漏、滴漏等问题。
5. 包装和标识：免洗胶塞的包装应符合相关的规定，包括包装材料的质量和防护性能等。
同时，产品上应标明相关的信息，如品牌、规格、批次号等。
以上是一般免洗胶塞质量标准的基本要求，实际的标准还根据不同的产品和行业可能有所差异。
具体的质量标准应该根据生产和行业标准进行制定和执行。
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标准（USP381）
标准（EP3.2.9）
YBB00052005
外观
符合规定
符合规定
针刺圈内或与内容物接触面有污点、杂质，针刺圈内或密封面有气泡、裂纹;表面有污点、杂质、胶丝、胶屑、海绵状、毛边，塞颈部分粗糙，明显缺胶;除边造成的残缺和锯齿，由模具造成的痕迹，色泽明显不均匀
鉴别红外图谱与典型样品图来自一致≤5号黄绿色标准比色液
重金属
≤2ppm
≤2ppm
≤1ppm
铵盐
≤2ppm
≤2ppm
≤％
穿刺落屑
≤5粒/48针
≤5粒/48针
≤5粒/48针
灰分
在鉴别中
≤％
可溶性锌
≤5 ug/ml
≤5ug/ml
≤％
挥发性硫化物
供试液试纸上产生的黑斑点不得深于对照溶液
供试液试纸上产生的黑斑点不得深于对照溶液
≤50ug/20cm2
胶塞与容器密合性
符合规定
不溶性微粒
≤60粒/ml（≥10um）
≤6 粒/ml （≥25um）
电导率
≤μS/cm
密封性
任一瓶内溶液不得发蓝
任一瓶内溶液不得发蓝
符合规定
蒸发残渣
/
≤（II类）
≤（I类）
≤
穿透能
≤10N
≤10N
≤10N
细菌内毒素
/
/
符合规定（热原）
溶血
/
/
溶血率＜5％
急性毒性
/
/
符合规定
生物毒性试验
USP<87> USP<88>
/
/
USP、EP、YBB标准对比
A:弹力符合规定B:红外鉴别与典型样品符合规定C:总灰分为典型样品±10％
（1）呈正反应(化学鉴别－卤离子)
（2）样品的红外吸收图谱应与对照图谱基本一致
酸碱度
消耗L氢氧化钠不超过或消耗L盐酸不超过
消耗L氢氧化钠不超过或消耗L盐酸不超过
PH变化值≤
吸收度
在220-360nm波长范围内，溶液的吸收度应≤（I类）；（II类）
在220-360nm波长范围内，溶液的吸收度应≤（I类）；（II类）
≤
易氧化物
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
样品液与空白液消耗滴定液的体积差应≤（II）;（I类）
≤
溶液澄清度
≤18 NTU
≤Ⅲ号浊度标准液(II类)；≤II号（I类）
≤2号浊度标准液
溶液颜色
符合规定
≤5号黄绿标准比色液