Physical tests performed for release purposes need to be validated. The physical test that is comprised in this validation procedure is Particle Size Distribution by Laser Diffraction Instruments. This SOP can serve as the validation protocol for validating a method for particle size distribution. A separate validation protocol is necessary in case of an exception from this SOP.
当物理测试作为放行目的的时候应彼验证。本验证程序中包含的物理测试是通过激光粒度仪测试 样品的粒度分布。该SOP可以作为验证粒度分布方法的协议。若有异议，可以有•个单独的验 证方案。
2. 目的 2. purpose
2.1 To define the typical analytical parameters that should be considered when a validation of an analytical method is performed.
2.1当执行•个分析方法验证的时候，应考虑典型分析参数的定义。
2.2 To describe the way in which a method is validated according to these parameters 2.2描述按照这些参数进行方法验证的方法。
2.3 To establish acceptance criteria for acceptanee / reject)on of drug substances, finished products or other materials.
2.3建立原料药，成品或其它原料的放行/拒绝标准。 3. 范围 3. Range 4•责任
4. Responsibility
4.1 Physical R&D laboratory analyst - performance of all laboratories studies required for method validation according to this SOP. 4.2 Physical R&D Laboratory manager -
4.2.1 Verification to compliance of this Physical R&D laboratory with GMP regulations and this SOP.
4.2.2 Approval of validation protocol (when applicable) and validation report.
4.3 QC Laboratory manager (only if an in terlaboratory study is performed in the QC laboratory): 4.3.1 Verification of compliance of the QC laboratory, with GMP regulations with this SOP and the validation protocol.
4.3.2 To perform the In terlaboratory study.
4.3.3 Approval of validation protocol (when applicable) and validation report.
4.4 QA manager - approval of validation protocol (when applicable) and validation report.
5. 分析参数的定义
DEFINITION OF ANALYTICAL PARAMETERS
In order to prove the analytical capability of a method that assesses physical properties of powder or other solid materials, three main analytical parameters are relevant:
为了证明分析方法的可行性，评估粉末或其它固体原料的物理性质，下而三个主要的分析参数是 比较重要的：
Precision 精密度 Accuracy 准确度 Robust ness 耐用性
5.1精密度 5.1 Precisio n
The precision expresses the closeness of agreement between a series of measurements obtained from multiple sampling of a homogeneous sample.
精密度是指同-样品进行多次取样测试后的•致程度。
The method precision should be assessed in three levels:
方法精密度应评估下列三个方面
Repeatability refers to the use of analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment.
重复性指的是同•分析人员用同•台仪器在间隔很短的时间内使用同•分析方法分析样品。 Intermediate
precision (ruggedness) express within laboratory variation, as on different days, or with different analysts or equipment within the same laboratory.
中间精密度是指在同•实验室内，不同夭，不同分析人员使用不同仪器分析样品。
In terlaboratory study (reproducibility or technical transfer) refers to the use of the an alytical procedure in d iff ere nt laboratories
重现性是指不同实验室之间的研究。
5.2准确度 Accuracy 5.3
The accuracy of the particle size method is defined as the closeness of test results obtained by the analytical procedure to the true value. Accuracy of sample preparation is achieved when the results includes all the particles as they are presented by an independent method - microscope.
粒度方法的准确度是指通过分析方法测得的粒度值与真实值的接近程度。
5.4耐用性 5.5 Robustness
The robustness expresses the sensitivity of the method to small, but deliberate variations in the method parameters and provides an indication of its reliability during normal use and stability of the suspension during the measurement.
耐用性是指分析参数故盘发生微小变化时分析方法的灵敬度，为正常使用时的重复性和在测试阶 段悬浮液的稳定性提供指示。
6验证方案
6. Validation protocol
6.1 Any deviation from the SOP should be specified in a validation protocol. If there are no deviations, this SOP can serve as the validation protocol.
6」任何偏离本SOP的偏差应在方案中被指出。如果没有偏差，本SOP可以作为验证方案。
6.2 Any major change in the protocol, due to difficulties encountered in the method development work, should be reflected in amendment to the protocol.
6.2由于在方法开发阶段遭遇的困难，方案中任何主妥的变更应反映在方案的修正案中。 7方法验证的-般程序
7 Generan procedure for validation of a method
Validation of PSD methods is performed on three representative samples. PSD的方法验证应选取三批样品。
It is possible to perform validation on one or two representative samples in case that additional representative sample/s w川 not be available, the validation should be completed when additional representative sample/s will be available (as an amendment to validation).
如果没有附加的样品测试，可以测试•批或者两批样品，如果有附加的样品测试(作为验证修正 案)，验证应被完成。
The validation experiments to be performed in the validation procedure are summarized in the following table.
在验证阶段，下列项目应涉及：
In termediate precisi on test is not required when interlaboratory study performed - a by QC (or other lab).
当测试了重现性的时候，中间持密度可以不做A-
b- When in terlaboratory study is not performed, i ntermediate precision can be done instead. The method cannot be transferred to another laboratory until that technicml transfer is performed.
Values like d(0.1), d(0.5), d(0.9), undersize/oversize perce nt or other releva nt values will be recorded and will be evaluated according to the tables in each section.
当没做重现性时，可以做中间精密度代替。方法不得转移给其他实验室直到完成r B- 技术转移。 尺寸过大比例或其他和关的数值应彼记录并且尺寸过小/类似d(0.1), d(0.5), d(0.9),评估。In case the
results fall between two levels categories, take the lower level Note: as acceptanee criteria.
如果结果介于两个限度，选择低的限度作为可接受标准。注意一 .Note: For special methods in which
more replicates are required use appendix 1做更多的重复性°对于专属性力•法，用按照 附录 1 注意
一molecule API step where the process change 注恿-Any done in the at the already produced (from
crude step) should be evaluated by physical R&D if may affect the physical properties of the material (such as : solubility , PSD etc.). A full validation may be required if the change was evaluated as significant. If the same the change, after to considered method analytical is appropriate use the and cha nge in particle size distribution is con eluded not significa nt, only verification of the method is required (repeatability and accuracy should be checked on one batch). I n case that the change is evaluated to be not releva nt to the PSD results, no additional validation activity is required and the current validated method is applied.
8方法验证程序
8 Detailed procedure for validation of a method 8.1 Method repeatability 8.1方法重复性
Analyst #1 will analyze sample 1 in six replicate measurements according to table. RSD will be calculated.
分析员1将分析样品仁该样品应进行6次重复的分析，RSD应符合下衣规定。
d(0.1), d(0.5) and d(0.9)的可接受标准:
结果RSD
NMT 15% >10um 和 d(0.1)d(0.9) NMT 30% NMT 20%
^10um d(0.5)
Note: If the measured value is smaller than 1.0 micron the SD (Standard deviation) should be NMT 0.5 micron for acceptance criteria.
注恿一如果结果小于1.0um, SD应NMT0.5um。
^10umd(0.1)和 d(0.9)
d(0.5)
NMT 10% >10um
Acceptance criteria for under size oversize percent:
尺寸过小或过人比例的可接受标准：
结果RSD
NMT 15% 过小尺寸M 70%/过大NMT 20% 70% 30%<过小尺寸/过大尺寸 NMT1% (SD) 过小尺寸/过大 W5% Acceptance criteria for other values than d(0.1), d(0.5), d(0.9): d(0.1), d(0.5) and d(0.9)为其它结果的可接受标准： 结果测试值RSD NMT 15% Md(0.7) d(X)Wd(0.3)或结果 RSD 10um > 或 d(X)Wd(0.3)Md(0.7) ^10um 25% N 70%过大/过小尺寸 d(0.3)Vd(X)VV过 小尺寸/30% NMT NMT 30% NMT 10% NMT 20% d(0.7) NMT 40% 70%过大尺寸V d(0.7) NMT 60% W30% 10um > W10um d(0.3) Intermediate Precision Test Analyst #2 will analyse the sample according to method o「Analyst #1 will analyze the same sample on another day according to table. 分析员2应根据方法分析样品或分析员1在另外-天分析样品。 The difference between the average result and the average repeatability result (or duplicate result in case of amendement to validation) will be calculated according to formula: 平均结果的偏差以及平均重复性结果(或修正案中的重复结果)按下式计算： Total average =(average from first measurement + average from the second measurements 总平均值二(第一次分析的平均值+第二次分析的平均值)/2 % Differenee = (average from first measurement - average from the second measurement)*100 / total average; 偏差二(第•次分析的平均值-第二次分析的平均值)*100/总平均值 d(0.1), d(0.5) and d(0.9)的可接受标准: Acceptance criteria for d(0.1), d(0.5) and d(0.9) values: II Number of tests for ainenclement to validation (oil one or t\\ Precision Ittteimediate precision test3 Int^iiaboratoiy stuch II Paragraph 8.2 II Paragraph S3 结果RSD NMT 30% > 10um 和 d(0.9) d(0.1)NMT 60% d(0.9) ^10umd(0.1)和 NMT20% > 10um NMT 40% W10um d(0.5) Note: If the measured value is smaller than 1.0 micron the absolute differenee for acceptance criteria should be NMT 1 micron. 。1um,绝对偏差不得大于1.0um如果测试结果小于一注意 d(0.5) Acceptance criteria for under size oversize percent: 尺寸过小或过人比例的可接受标准： NMT 2% (绝对偏差) d(0.1), d(0.5), d(0.9): 过小尺寸 W5% 过人/Acceptance criteria for other values than d(0.1), d(0.5) and d(0.9)为其它结果的可接受标准: 结果测试值RSD NMT 30% NMT 60% d(X)Wd(0.3)或衣d(0.7) 10um > 或^d(0.7) d(X)Wd(0.3) ^10um NMT 20% d(X)d(0.3)< Note: If the measured value is smaller than 1.0 micron the absolute differenee for acceptanee criteria should be NMT 1 micron. 注意一如果测试结果小于1.0um,绝对偏差不得大于1um, In case the results fall between two levels categories, take the lower level as acceptanee criteria (see table). 如果结果介于两个限度，选择低的限度作为可接受标准。 8.3重现性 8.3 Interlaboratory Study The sample will be tested according to method in another laboratory (generally QC) according to table. 样品应在另外的实验室用同•方法进行测试。 The difference between the average result and the average repeatability result (or duplicate result in case of amendement to validation) will be calculated according to formula: 平均结果的偏差以及平均重复性结果(或修正案中的重复结果)按下式计算： Total average =( average from first laboratory + average from second laboratory)/2 % Difference = (average from first laboratory - average from the second laboratory)* 100 / total average; 总平均值二(实验室•的平均值+实验室二的平均值)12 % Differenee = (average from first laboratory - average from the second laboratory)*100 / total average; 偏差二(实验室•的平均值-实验室二的平均值)*100/总平均值 Use the acceptance criteria of section 8.2・ 可接受标准同8.2 8.4准确度（通过显微镜） 样品应用显微镜进行测试并拍照。 比较粒度分布法和显微法测得的结果并解释/校正结果。 8.5耐用性测试 8.5.1将和关参数改变大约±10%,如： 样品质量 样品池的转速 超声时间 压力 加样速度 其它参数 每•个参数的改变都应彼测量•次。应计算耐用性测试的结果与重复性测试结果平均值之间的偏 差。 偏差％二（耐用性测试结果-重复性测试结果的平均值）700/重复性测试结果的平均值 可接受标准同8.2 如果结果超出可接受标准，调小耐用性参数的范围，重复测试。 8.5.2 循环时间 作为耐用性测试的•部分，应测试方法（湿法）的稳定性。样品应按照方法测试•次，不取出样 品，继续循环10%的循环时间（不得小于5秒）后测试-次。 第•次测试的结果与第二次测量的结果偏差按下式计算： 偏差%=（第二次测试结果-第•次测试结果）^00/第•次测试结果 可接受标准同8.2 Note: --In cases that the time of readi ng for the measureme nt is Ion ger tha n the difference between the two times of recirculations, two aliquots are needed. 注意: 9. 将方法从•个实验室转移到另•个实验室的技术转移程序 分析方法的转移是通过分析方法的转出实验室和接受实验室检测同样的样品。通常转出实验室和 接受实验室都是QC实验室。 三批样品将彼测试，测试方法为转出方的方法。 两个实验室的结果的平均值的偏差按下而的公式计算： 总平均值二（转出方实验室结果的平均值+接受方实验室结果的平均值）/2 偏差％二（接受方实验室结果的平均值-转出方实验室结果的平均值）700/总平均值 可接受标准同8.2 10. 交叉程序一两个不同方法的验证 当有•个不同的方法，单独于现行的方法，下而两点应实行： 两个方法都应被验证，按照8 证明新的方法和现行方法检测的结果是相同的。这样，按照现行的方法至少妥检测三批样品。这 三批样品 应按新的方法检测。 应计算两个方法结果的平均值的偏差 %偏差二（线性方法结果的平均值-新方法结果的平均值）*100/总平均值 可接受标准同8.2 9参考资料 11.1 11.2 11.3 11.4 11.5 USP34<1225>:方法验证程序的概述，2011 ICH分析程序验证指南：定义和技术实验性，第8部分，1995年3月1日 ICH原料药良好生产指南Q7,卷4,第12部分，2000年10月11日 Barr Laboratories Inc., MTH-05 version 3: General Test Method - Particle Size. USP34<429>：粒度的光衍射测试，2011 Determination Using the Malvern Mastersizer. Effective date: 09.02.2009. 1 附录. 因篇幅问题不能全部显示，请点此查看更多更全内容