【求助】医疗器械细菌内毒素方法学验证

zhulikou431

如题，现在做类似聚乳酸材料的骨内固定螺钉，但是细菌内毒素方法学验证不知道怎么做，限值确定以及依据找不到。希望各位大神能不吝赐教。

zhulikou431

如果在社会主义国家找不到依据，我往往把目光投向垂死挣扎的美帝国主义。

2012年6月，FDA发布了内毒素测试问答，答复如下：



11. What are the endotoxinslimits for medical devices?

医疗器械的内毒素限度是什么？

The Center for Devices andRadiological Health (CDRH) has adopted the USP Endotoxin Reference Standard andlimits for medical device extracts expressed in EU/mL. USP Chapter <161>Transfusion and Infusion Assemblies and Similar Medical Devices provides thelimits for medical devices within its scope. The endotoxins limit for a medicaldevice is dependent on the intended use of the device and what the devicecontacts (e.g., blood, the cardiovascular system, cerebrospinal fluid,intrathecal routes of administration, permanently implanted devices, anddevices implanted subcutaneously).27

CDRH已经采用USP内毒素标准品和限度用于医疗器械提取物，表示单位是EU/ml。USP161章《Transfusion andInfusion Assemblies and Similar Medical Devices》在这个范围内为医疗器械提供了内毒素限度。医疗器械的内毒素限度和器械的用途以及器械接触的物品（例如，血液、心血管系统、脑脊髓液、鞘内给药、永久植入医疗器械和皮下植入器械）相独立。

For medicaldevices, using the extraction volume recommendations described below, the limitis 0.5 EU/mL or 20 EU/device for products that directly or indirectly contactthe cardiovascular system and lymphatic system. For devices in contact withcerebrospinal fluid, the limit is 0.06 EU/mL or 2.15 EU/device. For devicesthat are in direct or indirect contact with the intraocular environment, alower endotoxins limit may apply. Please contact the appropriate reviewdivision for specific recommendations.

对于医疗器械，采用下面推荐的提取体积，对于直接或者间接接触心血管系统和淋巴系统的产品，限度是0.5EU/ml或者20EU/每个器械。对于接触脑脊液的器械，限度是0.06 EU/mL 或者2.15 EU/每器械。对于直接或者间接接触眼内环境的器械，一个更低的内毒素限度可能是合适的。请联系恰当的审核部门来获得具体建议。

The processof preparing an eluate/extract for testing may vary from device to device. Somemedical devices can be flushed, some may have to be immersed, while others mayneed disassembly. Unless otherwise directed by another compendial standard, ourrecommended rinse volumes include the following: (1) each of the 10 test unitsshould be rinsed with 40 mL of non-pyrogenic water; (2) for unusually small orlarge devices, the surface area of the device that contacts the patient may beused as an adjustment factor in selecting the rinse or extract volume. Theendotoxins limit can be adjusted accordingly. In any case, the rinse/extractprocedure should not result in a greater dilution of endotoxin than recommendedin USP <85>. For inhibition/enhancement testing, both the rinse/extractsolution and the device eluate/extract should be tested.

制备测试使用的淋洗液或者萃取液的流程对于不同的器械是不同的。一些器械可以冲洗，一些器械必须被浸泡，而其他器械可能需要拆卸。除非其他药典方法给出另外的说明，我们建议联系体积包括：

1-每10个测试样品应该用40ml无热原水来淋洗；

2-对于异常的小体积或者大体积器械，在选择淋洗液或者萃取液体积时，器械接触患者的表面积应该做为一个调节因素。

内毒素限度可以相应的做调整。在任何情况下，淋洗/萃取规程不应该产生比USP85章建议的更大程度的内毒素稀释程度。对于抑制/增强测试，淋洗液/萃取液和器械的淋洗物/萃取物都应该进行测试。

27 USP,2011, Chapter <161>, Transfusion and Infusion Assemblies and SimilarMedical Devices.

注释27：USP2011,161章，Transfusion and Infusion Assemblies andSimilar Medical Devices《输液和输液组合产品以及类似的医疗器械》.

Examples ofmedical devices with testing or interference challenges include devices thatare coated with anticoagulant, contain heavy metals, or that have particulates.In these situations, treatments for interferences can include digestion,dilution, and addition of buffers, centrifugation, or filtration.

用于测试或者干扰挑战的医疗器械的例子，包括包封抗凝剂、包含重金属或者粒子的器械。在这些情况下，干扰的处理措施可以包括消解、稀释和缓冲物的添加，离心或者过滤。

During the same surgicalprocedure or placement in the same surgical site, multiple units of the samedevice from one manufacturer should generally meet the same endotoxins limit asa single device administered during the procedure. In instances where multipleunits of the same device are known or intended for use in a single procedure,manufacturers should justify any deviation from the overall endotoxins limitidentified in this guidance.

在相同的外科规程中，或者在相同的外科位置处置中，来自一个制造商的相同器械的多个单元应该符合相同的内毒素限度，在手术中作为一个器械来使用。在这样例子中，相同器械的多个单元是已知的，或者目的用途就是用于一个单个的手术规程中，制造商应该论证偏离本指南确定的内毒素限度的任何偏差。

When a manufacturer of medicaldevices plans to use LAL testing that deviates significantly from this guidanceor recognized standard, a premarket notification (510(k)) under section 510(k)of the Federal Food, Drug, and Cosmetic Act (the Act) or a premarket approvalapplication (PMA) supplement under section 515 of the Act should be submitted.Significant deviations include, but are not necessarily limited to: higherendotoxin concentration release criteria, sampling from fewer than three (3)lots for inhibition/enhancement testing, lesser sensitivity to endotoxins, anda device rinsing protocol resulting in greater dilution of endotoxins than thatrecommended in this guidance.

当一个医疗器械制造商决定采用LAL测试，显著偏离本指南或者确定标准的偏差，应该根据FDCA的510（k）条款递交上市前的通知（510（K）），或者根据FDCA的515条款递交上市前批准申请（PMA）补充申请。显著偏差包括，但是没必要限定于：较高的内毒素浓度放行标准，用于抑制/增强测试的样品少于3批次，较低的内毒素灵敏度，器械淋洗方案导致内毒素比本指南建议的更大程度的稀释。

xiaoshuo101

【求助】医疗器械细菌内毒素方法学验证  

modestybruce

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如题，现在做类似聚乳酸材料的骨内固定螺钉，但是细菌内毒素方法学验证不知道怎么做，限值确定以及依据找不到。希望各位大神能不吝赐教。  

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&#8226; 【共享】肾脏病理--电镜—膜性肾病 【讨论】冷藏罐内壁变形【讨论】GMP检查几个特殊案例-比较狠【信息】FDA减少本土企业检查40%以增加海外检查

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这个我也不很清楚，不也蛮好奇想知道答案。



帮楼主顶一下，希望早日有人来解答。  

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modestybruce wrote:

如题，现在做类似聚乳酸材料的骨内固定螺钉，但是细菌内毒素方法学验证不知道怎么做，限值确定以及依据找不到。希望各位大神能不吝赐教。



如果在社会主义国家找不到依据，我往往把目光投向垂死挣扎的美帝国主义。

2012年6月，FDA发布了内毒素测试问答，答复如下：



11. What are the endotoxinslimits for medical devices?

医疗器械的内毒素限度是什么？

The Center for Devices andRadiological Health (CDRH) has adopted the USP Endotoxin Reference Standard andlimits for medical device extracts expressed in EU/mL. USP Chapter <161>Transfusion and Infusion Assemblies and Similar Medical Devices provides thelimits for medical devices within its scope. The endotoxins limit for a medicaldevice is dependent on the intended use of the device and what the devicecontacts (e.g., blood, the cardiovascular system, cerebrospinal fluid,intrathecal routes of administration, permanently implanted devices, anddevices implanted subcutaneously).27

CDRH已经采用USP内毒素标准品和限度用于医疗器械提取物，表示单位是EU/ml。USP161章《Transfusion andInfusion Assemblies and Similar Medical Devices》在这个范围内为医疗器械提供了内毒素限度。医疗器械的内毒素限度和器械的用途以及器械接触的物品（例如，血液、心血管系统、脑脊髓液、鞘内给药、永久植入医疗器械和皮下植入器械）相独立。

For medicaldevices, using the extraction volume recommendations described below, the limitis 0.5 EU/mL or 20 EU/device for products that directly or indirectly contactthe cardiovascular system and lymphatic system. For devices in contact withcerebrospinal fluid, the limit is 0.06 EU/mL or 2.15 EU/device. For devicesthat are in direct or indirect contact with the intraocular environment, alower endotoxins limit may apply. Please contact the appropriate reviewdivision for specific recommendations.

对于医疗器械，采用下面推荐的提取体积，对于直接或者间接接触心血管系统和淋巴系统的产品，限度是0.5EU/ml或者20EU/每个器械。对于接触脑脊液的器械，限度是0.06 EU/mL 或者2.15 EU/每器械。对于直接或者间接接触眼内环境的器械，一个更低的内毒素限度可能是合适的。请联系恰当的审核部门来获得具体建议。

The processof preparing an eluate/extract for testing may vary from device to device. Somemedical devices can be flushed, some may have to be immersed, while others mayneed disassembly. Unless otherwise directed by another compendial standard, ourrecommended rinse volumes include the following: (1) each of the 10 test unitsshould be rinsed with 40 mL of non-pyrogenic water; (2) for unusually small orlarge devices, the surface area of the device that contacts the patient may beused as an adjustment factor in selecting the rinse or extract volume. Theendotoxins limit can be adjusted accordingly. In any case, the rinse/extractprocedure should not result in a greater dilution of endotoxin than recommendedin USP <85>. For inhibition/enhancement testing, both the rinse/extractsolution and the device eluate/extract should be tested.

制备测试使用的淋洗液或者萃取液的流程对于不同的器械是不同的。一些器械可以冲洗，一些器械必须被浸泡，而其他器械可能需要拆卸。除非其他药典方法给出另外的说明，我们建议联系体积包括：

1-每10个测试样品应该用40ml无热原水来淋洗；

2-对于异常的小体积或者大体积器械，在选择淋洗液或者萃取液体积时，器械接触患者的表面积应该做为一个调节因素。

内毒素限度可以相应的做调整。在任何情况下，淋洗/萃取规程不应该产生比USP85章建议的更大程度的内毒素稀释程度。对于抑制/增强测试，淋洗液/萃取液和器械的淋洗物/萃取物都应该进行测试。

27 USP,2011, Chapter <161>, Transfusion and Infusion Assemblies and SimilarMedical Devices.

注释27：USP2011,161章，Transfusion and Infusion Assemblies andSimilar Medical Devices《输液和输液组合产品以及类似的医疗器械》.

Examples ofmedical devices with testing or interference challenges include devices thatare coated with anticoagulant, contain heavy metals, or that have particulates.In these situations, treatments for interferences can include digestion,dilution, and addition of buffers, centrifugation, or filtration.

用于测试或者干扰挑战的医疗器械的例子，包括包封抗凝剂、包含重金属或者粒子的器械。在这些情况下，干扰的处理措施可以包括消解、稀释和缓冲物的添加，离心或者过滤。

During the same surgicalprocedure or placement in the same surgical site, multiple units of the samedevice from one manufacturer should generally meet the same endotoxins limit asa single device administered during the procedure. In instances where multipleunits of the same device are known or intended for use in a single procedure,manufacturers should justify any deviation from the overall endotoxins limitidentified in this guidance.

在相同的外科规程中，或者在相同的外科位置处置中，来自一个制造商的相同器械的多个单元应该符合相同的内毒素限度，在手术中作为一个器械来使用。在这样例子中，相同器械的多个单元是已知的，或者目的用途就是用于一个单个的手术规程中，制造商应该论证偏离本指南确定的内毒素限度的任何偏差。

When a manufacturer of medicaldevices plans to use LAL testing that deviates significantly from this guidanceor recognized standard, a premarket notification (510(k)) under section 510(k)of the Federal Food, Drug, and Cosmetic Act (the Act) or a premarket approvalapplication (PMA) supplement under section 515 of the Act should be submitted.Significant deviations include, but are not necessarily limited to: higherendotoxin concentration release criteria, sampling from fewer than three (3)lots for inhibition/enhancement testing, lesser sensitivity to endotoxins, anda device rinsing protocol resulting in greater dilution of endotoxins than thatrecommended in this guidance.

当一个医疗器械制造商决定采用LAL测试，显著偏离本指南或者确定标准的偏差，应该根据FDCA的510（k）条款递交上市前的通知（510（K）），或者根据FDCA的515条款递交上市前批准申请（PMA）补充申请。显著偏差包括，但是没必要限定于：较高的内毒素浓度放行标准，用于抑制/增强测试的样品少于3批次，较低的内毒素灵敏度，器械淋洗方案导致内毒素比本指南建议的更大程度的稀释。


版主kinginsun留言:

感谢回复！  

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kinginsun edited on 2014-04-01 13:37 举报


zhulikou431

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如果在丁香园检索zhulikou431+内毒素，将给你展示一个不同的天地。  

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整体抄袭，无耻！

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个人觉得：不同的论坛，可以拿来引用，这里有不是出版个人专著的地方。zhulikou431，在丁香园论坛是很不错的一个老师。zhulikou431，我顶你！！！

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大家 交流学习的地方，这个有什么无耻的 又不是写书发论文

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