【美国药典】

早在1975年提出对大体积单剂量的液体进行不溶性微粒检查,采用滤膜过滤后用显微镜和测微尺进行微粒大小的测量并计数, 计算出每1mL中所含大于10μm和25μm粒子的数量。后来美国药典把不溶性微粒检查方法逐步扩大了应用范围,其中包括大体积多剂量制剂、小体积单剂量制剂乃至非水溶性制剂、粉针制剂等。

直到1995年出版的美国药典,在原有显微镜法的基础上增加了光阻法由于这种方法智能化程度高,应用范围广泛,所以具有非常良好的发展前景,美国药典并把这种方法摆在了首要位置上。又由于仪器分析的相对性和对仪器校正的复杂性,美国药典也非常明确的规定了在采用光阻法检验不合格的样品应用显微镜进行复验,最终的判断结果应以显微镜法的结果为准。

【英国药典】

同样很早就收载了不溶性微粒检查的方法,最早见于1973年版药典采用显微镜法,规定对500mL以上输液必须有微粒控制项目,每mL液体≥2μm微粒少于1000个、≥5μm微粒少于100个。

直到1980年收载了电阻法,并提出如电阻法的仪器不能够解决问题的时,也可以采用光阻法仪器进行检查。但是在新出版的英国药典1998年版此项检查却发生了巨大的变化,使用了近25年的电阻法被光阻法替代,光阻法成了新版英国药典唯一的检查方法。

【日本药典】

最早见于1980年版药典,采用显微镜法,直到1995年版药典引入光阻法并作为首选,方法和限度与美国药典相同,并规定符合光阻法条件检品的检测结果可仲裁。显微镜法则用于光阻法不能检测的部分检品和小剂量注射液(小于25mL)。

【欧共体药典】

随着欧洲一体化的建设,力求协调统一的原因,其规定与英、美药典相同。

【中国药典】从1985年版至1995年版均采用显微镜法检查注射液中的不溶性微粒。检查≥10μm与≥25μm两档,与美国药典标准基本相同。

在2000年版【中国药典】显微镜法检查注射液中不溶性微粒的基础上增加了第二法----光阻法。

在2005年版【中国药典】中增加了对小剂量注射液的检测。

【中国药典】2005年版初稿对注射液中不溶性微粒污染的监控作了修订,将光阻法修订为第一法,显微镜法为第二法。 修订后的结果判定也与美、英、欧共体、日本基本一致。

不溶性微粒检测及标准

光阻法

1.1 标示装量为100mL或100mL以上的静脉注射液 除另有规定外,每1mL中含10μm以上的微粒不超过25粒,含25μm以上的微粒不超过3粒,判为符合规定。 如果每1mL中含10μm以上的微粒数超过25粒;或虽未超过25粒,但其中含25μm以上的微粒超过3粒时;均判为不符合规定。

1.2 标示装量为100mL以下的静脉注射液、静脉注射液用无菌粉末及注射用浓溶液除另有规定外,每个供试品容器中含10μm以上的微粒不得过 6000粒,含25μm以上的微粒不得过600粒,判为符合规定。

如果每个容器中含10μm以上的微粒数超过6000粒,或虽未超过6000粒,但其中含25μm以上的微粒超过600粒时;均判为不符合规定。

显微计数法

1.标示装量为100mL或100mL以上的静脉注射液 除另有规定外,每1mL中含10μm以上的微粒不超过12粒,含25μm以上的微粒不超过2粒,均为符合规定。

如果每1mL中含10μm以上的微粒数超过12粒;或虽未超过12粒,但其中含25μm以上的微粒超过2粒时;均判为不符合规定。

2.标示装量为100mL以下的静脉注射液、静脉注射用无菌粉末及注射用浓溶液除另有规定外,每个供试品容器中含10μm以上的微粒不超过3000粒,含25μm以上的微粒不超过300粒,判为符合规定。

如果每个容器中含10μm以上的微粒数超过3000粒;或虽未超过3000粒,但其中含25μm以上的微粒超过300粒;均判为不符合规定。

光阻法
LIGHT OBSCURATION PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 1.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 1.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 1.B. [NOTE—Test 1.Ais used in the Japanese Pharmacopoeia.]

If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test.

Test 1.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per mL equal to or greater than 10 μm and does not exceed 3 per mL equal to or greater than 25 μm.

Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 μm and does not exceed 600 per container equal to or greater than 25 μm.

显微计数法
MICROSCOPIC PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of test 2.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of test 2.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of test 2.B.

Test 2.A – Solutions for infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 12 per millilitre equal to or greater than 10 μm and does not exceed 2 per millilitre equal to or greater than 25 μm.

Test 2.B – Solutions for infusion or solutions for injection supplied in containers with a nominalcontent of less than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 3000 per container equal to or greater than 10 μm and does not exceed 300 per container equal to or greater than 25 μm.

光阻法
LIGHT OBSCURATION PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 1.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 1.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 1.B. [NOTE—Test 1.Ais used in the Japanese Pharmacopoeia.]

If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test.

Test 1.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per mL equal to or greater than 10 μm and does not exceed 3 per mL equal to or greater than 25 μm.

Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 μm and does not exceed 600 per container equal to or greater than 25 μm.

显微计数法
MICROSCOPIC PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of test 2.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of test 2.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of test 2.B.

Test 2.A – Solutions for infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 12 per millilitre equal to or greater than 10 μm and does not exceed 2 per millilitre equal to or greater than 25 μm.

Test 2.B – Solutions for infusion or solutions for injection supplied in containers with a nominalcontent of less than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 3000 per container equal to or greater than 10 μm and does not exceed 300 per container equal to or greater than 25 μm.

光阻法
LIGHT OBSCURATION PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 1.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 1.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 1.B. [NOTE—Test 1.Ais used in the Japanese Pharmacopoeia.]

If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test.

Test 1.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per mL equal to or greater than 10 μm and does not exceed 3 per mL equal to or greater than 25 μm.

Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 μm and does not exceed 600 per container equal to or greater than 25 μm.

显微计数法
MICROSCOPIC PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of test 2.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of test 2.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of test 2.B.

Test 2.A – Solutions for infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 12 per millilitre equal to or greater than 10 μm and does not exceed 2 per millilitre equal to or greater than 25 μm.

Test 2.B – Solutions for infusion or solutions for injection supplied in containers with a nominalcontent of less than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 3000 per container equal to or greater than 10 μm and does not exceed 300 per container equal to or greater than 25 μm.

光阻法
LIGHT OBSCURATION PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of Test 1.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of Test 1.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of Test 1.B. [NOTE—Test 1.Ais used in the Japanese Pharmacopoeia.]

If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle Count Test.

Test 1.A (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 25 per mL equal to or greater than 10 μm and does not exceed 3 per mL equal to or greater than 25 μm.

Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL)—The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 μm and does not exceed 600 per container equal to or greater than 25 μm.

显微计数法
MICROSCOPIC PARTICLE COUNT TEST

For preparations supplied in containers with a nominal volume of more than 100 mL, apply the criteria of test 2.A.

For preparations supplied in containers with a nominal volume of less than 100 mL, apply the criteria of test 2.B.

For preparations supplied in containers with a nominal volume of 100 mL, apply the criteria of test 2.B.

Test 2.A – Solutions for infusion or solutions for injection supplied in containers with a nominal content of more than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 12 per millilitre equal to or greater than 10 μm and does not exceed 2 per millilitre equal to or greater than 25 μm.

Test 2.B – Solutions for infusion or solutions for injection supplied in containers with a nominalcontent of less than 100 mL. The preparation complies with the test if the average number of particles present in the units tested does not exceed 3000 per container equal to or greater than 10 μm and does not exceed 300 per container equal to or greater than 25 μm.

基本上所有的药典都规定了光阻法为第一法,显微计数法法为第二法。一般先采用光阻法;当光阻法测定结果不符合规定或供试品不适用于光阻法测定时,应采用显微计数法进行测定,并以显微计数法的测定结果为最终判定依据。

美国PSS粒度仪公司不溶性微粒检测专用仪器介绍

  • AccuSizer 780SIS 系列仪器是美国PSS粒度仪公司专为对定量样品作精确的粒径分析设计的一款产品,其使用最简洁易用的系统和操作可对样品进行精确计数和粒度分布计算。其拥有高达 512 个的高分辨率检测通道,用户只需通过简单的单击鼠标操作,即可完成检测。

  • 带有注射量在 0.5mL 到 25 mL 的注射器和精确的进样泵装置的 780 SIS 进样器是模块化装置家庭中的一个完美的模块

  • 特别适用于制药工业,例如中小剂量和大剂量的注射剂。而且拥有符合 21CFR Part 11 法规的软件和配套文件,可为企业建立一个符合cGMP标准的操作规程(SOP)。

780SIS的特点
USP-788美国药典<788>推介
高达512个检测通道
精确体积,采样体积精确度 +/- 1 %
自动采样分析时间小于60s
水相,有机相均可测试
适于超大样品量分析
最高用户可自定义32个标准通道
应用领域: 医用不溶性微粒检测, 污染物,纯水等
AccuSizerSIS工作模式
技术参数以及配置要求
传感器选配
LE400-0.5 (检测范围0.5 – 400 μm)
LE1000-2 (检测范围 2 – 1000 μm)
样品流速5 – 60 mL/min
机械搅拌(可选)
解析度低于10 %
重复性低于 10 % 计数; 2 % 粒径
专门针对粒子数稀少的样品
分析时间小于60s
采样体积精确度 +/- 1 %
最新单粒子光阻法计数器
512 个数据通道; 最高用户可定义32个标准通道
21 CFR Part 11法规软件 (可选)
水相和有机相样品均可测试

AccuSizerSIS相对于其他仪器的优点

512个数据通道——为研发分析工作提供强有力的数据支持。

研发过程中,工作人员越了解产品或原料的实际情况,越能帮助他们设计思路和改进方案。

AccuSizer 780SIS 通道数高达512个,这样给出的数据将非常详细具体。通道数越多,辨析率相应越高,可以清晰地呈现出每一段粒径通道下的粒子数目。

21CRF法规软件——符合cGMP要求。

AccuSizer 780 SIS配备了符合美国联邦法规21章第11款(21 CFR PART11)要求的软件。这是FDA认可的符合cGMP要求的软件。

中国CFDA有政策趋势将对医药研发企业实施规范的GLP 管理。毫无疑问,符合21 CFR PART 11法规的软件是实施GLP/GMP必要因素之一。

医药企业自身定位——需选择高标准科学仪器

定位于高端市场,这需要与国际紧密接轨,精确而又高端的仪器向来是从事研发实验的首选。AccuSizer 系列通过了FDA,欧盟认证。

操作简便——大大减少人工和时间成本

PSS 一直推崇UE (User Easy )的操作界面以及使用方法。以达到测试方便,快速的效果,SIS整机采用模块化设计,便于产品后期的维护和跟新升级。

AccuSizerSIS在研发和质控中的案例

  • Bayer Healthcare
  • Merck
  • Bausch & Lomb
  • Novartis Vaccines
  • Designer RX Pharmaceuticals

常见问题与解答

Q1、是否需要把仪器放置在无菌环境中测试样品?

由于各种菌的直径都比较小,处于纳米和亚微米级别,而不溶性微粒是针对微米级以上的粒子进行检测,所以在对不溶性微粒检测时不需要将仪器780SIS放置在无菌环境中测试样品;但是对空气质量有要求,如下。

实验室研究:

针对于一般的实验室研究,不需要将仪器PSS 780SIS放置在无菌的环境中进行测试样品,但是需要确保实验室中没有明显的粉尘漂浮,不然会对样品测试结果又影响。

GMP生产线:

针对于GMP生产线上的成品检测,需要确保在其符合GMP生产要求的实验室中进行检测,即空气洁净度要保证,以排除空气中的粒子对其测试结果的影响。

Q2、小容量剂型比如5mL针剂如何测试?

针对小容量的样品(每支<5mL),需要将几支样品混合在一起后进行测试;如测试容量为2mL注射用样品时,需要将同一批号的12支样品进行混合在一起,测试4次,每次检测5mL样品,舍弃第一次数据,最后得到样品测试结果。

Q3、各国药典的标准有无不同?

中国药典和美国药典保持一致,测试的项目和规定的标准一致。

Q4、什么是21CFR PART 11标准的软件?

21 CFR Part 11是指联邦法规21章第11款中的规定,主要内容涉及电子记录和电子签名;在此标准之下FDA将认为电子记录、电子签名和在电子记录上的手签名是可信赖的、可靠的,其作用等同于纸质记录和在纸上的手写签名;

Q5、仪器是否需要校准?校准的周期多长?

需要校准:仪器使用的原理是光阻法,凡是利用光阻法进行测试的仪器均需要校准;

校准周期:校准周期视仪器使用的频率而定,每周使用时间超出20小时的校准周期为6个月,每周使用时间不足10小时的校准周期为12个月


 

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