灯检可见异物分类方法标准化！
由辉瑞、阿斯利康、拜耳等17家单位组成的课题小组发布了《注射剂可见异物分类方法标准化白皮书》（AN INDUSTRY-WIDE STANDARDIZED METHODOLOGY AND RISK CLASSIFICATION TOOL FOR PARTICLE CLASSIFICATION IN BIOPHARMACEUTICAL PARENTERAL PRODUCTS），白皮书中表示尽管很多制药公司对颗粒异物进行分类，但很少基于科学或风险。白皮书给出一种标准化方法以帮助制药企业客观基于风险对颗粒异物进行合理分类。
解读如下：
根据异物对患者安全的影响可将可见异物划分为关键缺陷、主要缺陷和微小缺陷。
关键缺陷为可能导致无菌不良，影响容器完整性或对病人造成危害的异物。应不得出现关键缺陷。
主要和微小缺陷对患者的风险较小，允许大于0个。
关于不同缺陷等级设定的AQL，给出如下标准：
根据颗粒来源，可将颗粒分为外来颗粒、内部颗粒、固有颗粒
外来颗粒包括头发、非工艺相关的纤维、昆虫部位和无机/有机材料。这些颗粒可能会增加微生物或可萃取污染的风险。可能存在产品相容性问题或 GMP 问题。
内部颗粒为与工艺相关颗粒，可能来自加工设备或内包装材料, 这些材料要么是在加工过程中引入的, 要么是在容器准备过程中未能清除的。这些主要产品接触材料可能包括不锈钢、密封件、垫片、包装玻璃和橡胶、管材和有机硅润滑剂。
应梳理罗列出工艺过程中所有的接触材料，以帮助颗粒的分类、解决偏差问题或调查。
内部颗粒仍然构成异物的风险, 但一般来自无菌或已消毒的材料, 并且其在与产品接触时的相互作用了解更多。这些与工艺相关的固有颗粒应建立控制。
固有颗粒为与产品相关的颗粒，在产品开发过程中, 应评估产品固有颗粒的生成 , 包括聚集或沉淀物。应评估对产品稳定性、有效性和安全性的潜在影响。应确定其是否被视为缺陷。
报告列出了可见异物风险评估需要考虑的因素
针对各风险因素给出风险评估的赋分原则：
摘译如下：
Particle classifcations
颗粒分级
critical defects, which may cause a lack ofsterility, impact on container integrity or cause harm to patients9. Criticaldefects (those that pose the greatest risk to the patient) should be assignedan AQL with a low value. Often, the accept number (the number of defectiveunits allowed in the sample) for a critical defect is zero.
关键缺陷：可能导致无菌不良，影响容器完整性或对病人造成危害。关键缺陷应分配一个较低的AQL。通常，关键缺陷的接受数量（样品中允许的有缺陷的单位数量）为0.
major and minor defects, which pose less risk to the patient, will have increasing (lessstringent) AQL values and accept numbers greaterthan zero11. Major defects are described as those that may alterthe content or the function of the product12. Minor defects donot affect patient health or productfunctionality13. It is expected that particulate matter will be classifed as atleast a major defect.
主要和微小缺陷：对患者的风险较小, 可以分配一个较大的 (不太严格) AQL 值, 并允许数量大于0个。主要缺陷被描述为可能改变产品内容或功能的缺陷。微小缺陷为不影响患者健康或产品功能。要求颗粒物的分类至少为主要缺陷。
Particle knowledge
颗粒知识
product-related particles – the generation of particles within a product (typically describedas inherent), including aggregates orprecipitates, should be assessed during productdevelopment. The presence of visible product-related elements, such as precipitates of the active ingredient or excipient (native or degraded) mustbe assessed for the potential impact on product stability,effcacy and safety. This assessment should determinewhether the visible product element isconsidered a defect or not, or be used to inform potential downstream investigations.
与产品相关的颗粒——在产品开发过程中, 应评估产品内颗粒的生成 (通常称为固有颗粒), 包括聚集或沉淀物。必须评估是否存在可见的产品相关元素, 如活性成分或辅料的沉淀 (本身或降解), 以确定对产品稳定性、有效性和安全性的潜在影响。这一评估应确定可见产品元素是否被视为缺陷, 或用于为潜在的下游调查提供信息。
mapping all contact materials throughout theprocess – to assist classifcation of particles, e.g.as being intrinsic (to the manufacturingtrain), the whole manufacturingprocess and the contact materials could bemapped and listed. This can facilitate resolution of deviations or investigations.
找到工艺过程中所有的接触材料——以帮助颗粒的分类, 例如, 内部的 (生产过程), 可以对整个生产过程和接触材料进行梳理和罗列。这有助于解决偏差问题或调查。
origin of particulates – particles may be related to the product or process (typically describedas inherent or intrinsic, respectively) and those particles might reasonably be expected to be found because of the process or the contact material parts such as glass, stainless steel,rubber stopper and tubing- or process related fbers. Particles might also befound that are unrelated to the product orprocess (typically described as extrinsic).These include hair, non-process-related fbers,insect parts and inorganic/organic materials. Theseparticles may represent an increased risk of microbiologicalor extractable contamination because less is known about their origins or path prior to ingress into the product container.
颗粒物的来源——颗粒可能与产品或工艺有关 (通常分别描述为固有的或内部的), 并且由于该工艺或接触材料部件 (如玻璃、不锈钢、胶塞和管材或工艺相关纤维), 出现这些颗粒也是情理之中。此外，还可能会发现与产品或工艺无关的颗粒 (通常称为外来颗粒)，包括头发、非工艺相关的纤维、昆虫部位和无机/有机材料。这些颗粒可能会增加微生物或可萃取污染的风险, 因为在进入产品容器之前, 对其来源或路径了解较少。
site dependent – the type of particle that should be included in the test kits is site-dependent because every site is a unique environment, e.g. a unique manufacturing process with specifc materials that will result in aspecifc particle portfolio for that site
工厂——测试样品中应包括的颗粒类型取决于工厂, 因为每个工厂都是一个独特的环境, 例如, 具有特殊材料的特殊生产工艺, 这将导致该工厂的特殊颗粒组合。
test kits – for training purposes, different test kits need to be used for qualifcation and automated VI set-up. The defects used in thetest kits can be gathered from typical particles from process rejects or may be artifciallyprepared (if their appearance and behavior aresimilar to process rejects). These materials, or production defects, are preferred for inspector training and qualifcation as well as machine validation as they better represent actual inspection performance. Spherical standard particles may be utilized as surrogates for naturally occurring particulates;however, these are best used for routine machine calibration rather than validation or inspector qualifcation, as they donot move or look like actual production defects
测试样品——为了培训目的, 需要使用不同的测试样品进行确认和自动灯检设置。测试样品中使用的缺陷可以从过程不合格品中的典型颗粒中收集, 也可以是人工准备的 (如果它们的外观和行为类似于过程不合格品)。这些材料或生产缺陷, 是灯检人员培训和确认, 以及设备验证的首选, 因为它们更好地代表了实际的检测性能。球状标准颗粒可用作天然颗粒的代料；然而, 这些最好用于设备日常校准, 而不是验证或灯检人员确认，因为它们不移动或看起来像实际的生产缺陷。
Particle source
颗粒来源
Extrinsic particles
外来颗粒
Particles that are foreign to the manufacturing process are consideredto be exogenous or ‘extrinsic’ in origin; these include hair,non-process-related fibers, starch, minerals, insect parts and similarin organic and organice materials. Some fbers may also be included under theintrinsic defnition, depending on their source. These particles may carry anincreased risk of microbiological or extractable contamination. Extrinsicparticles may have product compatibility issues or GMP concerns.
与制造过程无关的颗粒被认为是外源性的或 '外来的';这包括头发, 非工艺相关的纤维, 淀粉, 矿物质, 昆虫和类似的无机和有机材料。一些纤维也可能是固有的缺陷, 这取决于它们的来源。这些颗粒可能会增加微生物或可萃取污染的风险。外来颗粒可能存在产品相容性问题或 GMP 问题。
Common to all defnitions of this category is that the source of the particle isoutside of the normal product contact material. Extrinsic particles areunderstood to present a greater risk to sterility assurance as their bioburdenis unknown and uncontrolled.
此类别的所有缺陷的常见之处在于, 颗粒不是来源于正常的产品接触材料。据了解, 外来颗粒对无菌保证构成更大的风险, 因为它们的生物负荷是未知的, 也是不受控制的。
Intrinsic particles
内部颗粒
Other particles are considered ‘intrinsic’ or from within. Thesemay come from processing equipment or primary packaging materials that wereeither added during processing or not removed during container preparation. Theseprimaryproduct-contact materials may include stainless steel, seals,gaskets, packaging glass and rubber, tubing and silicone lubricant. Some fbersmay also be included under the intrinsic defnition, depending on their source.Such particles still pose the risk of a foreign body, but generally come fromsterile or sanitized materials and more is known about their interactions whenin contact with the product. These process-related intrinsic particles shouldhave controls established.
一些颗粒被认为是 '内部的' 或内源性的。这可能来自加工设备或内包装材料, 这些材料要么是在加工过程中引入的, 要么是在容器准备过程中未能清除的。这些主要产品接触材料可能包括不锈钢、密封件、垫片、包装玻璃和橡胶、管材和有机硅润滑剂。一些纤维也可能是固有的缺陷, 这取决于它们的来源。这些颗粒仍然构成异物的风险, 但一般来自无菌或已消毒的材料, 并且其在与产品接触时的相互作用了解更多。这些与工艺相关的固有颗粒应建立控制。
Inherent particles
固有颗粒
The third category of particles is the ‘inherent’ particles, whichare known to be or intended to be associated with specifc product formulations.Every container with a particle, extrinsic or not should be rejected. Thephysical form or nature of the inherent particles varies from product toproduct and includes solutions, suspensions, emulsions and other drug deliverysystems that are designed as particle assemblies (agglomerates, aggregates,etc.). For protein-based products in which the aggregates may form longerchains or protein strands, the protein species may become visibly detectable ashazeor individual particles during changes over the shelf-life of the product.Product formulation-related suspensions or particulate formations should bestudied in the development phase and in samples placed on stability todetermine the normal characteristics and time-based changes that can occur.Inherent particles should have a defned allowable profle over the shelf-life ofthe product. Where applicable, the inherent particle profle may be covered inproduct-submission documentation or productspecifc monographs.
第三类颗粒是 '固有的' 颗粒, 这些颗粒与特定产品配方有关。固有颗粒的物理形式或性质因产品而异。对于基于蛋白质的产品, 在这些产品中, 聚集体可能形成更长的链或蛋白质链, 蛋白质在产品有效期内发生变化时, 可能会明显地检测到絮或颗粒。应在开发阶段和样品中研究与产品配方相关的悬浮液或颗粒形成, 以确定正常特性和可能发生的基于时间的变化。固有颗粒在产品的保质期内应具有可允许的概述。适当时, 固有颗粒可能需要包括在产品提交文档或产品标准专论中。
课题小组成员包括：艾伯维、亚力兄制药、阿斯利康、拜耳、渤健、百时美施贵宝、康泰伦特、礼来、葛兰素史克、易普森、杨森、默克、辉瑞、再生原、罗氏、夏尔、BioPhorum