粒度方法验证

1、1. 通则1. General 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

2、 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被验证。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，可以有一个单独的验证方案。2. 目的2. purpose2.1 To define the typical analytical parameters that should be considered when a validation of an an

3、alytical method is performed.2.1 当执行一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 parameters2.2 描述按照这些参数进行方法验证的方法。2.3 To establish acceptance criteria for acceptance / rejection of drug substances, finished products or other materials.2.3 建立原料药，成品

4、或其它原料的放行/拒绝标准。3. 范围3. Range4. 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 regulation

5、s and this SOP. 4.2.2 Approval of validation protocol (when applicable) and validation report. 4.3 QC Laboratory manager (only if an interlaboratory 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

6、protocol. 4.3.2 To perform the Interlaboratory 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 PARAMETERSIn order to prove the analytical cap

7、ability 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，下面三个主要的分析参数是比较重要的：Precision 精密度Accuracy 准确度Robustness 耐用性5.1 精密度5.1 Precision The precision expresses the closeness of agreement betwe

8、en a series of measurements obtained from multiple sampling of a homogeneous sample. 精密度是指同一样品进行多次取样测试后的一致程度。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 an

9、alyst with the same equipment. 重复性指的是同一分析人员用同一台仪器在间隔很短的时间内使用同一分析方法分析样品。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一实验室内，不同天，不同分析人员使用不同仪器分析样品。Interlaboratory study (reprodu

10、cibility or technical transfer) refers to the use of the analytical procedure in different laboratories 重现性是指不同实验室之间的研究。5.2 准确度5.3 AccuracyThe 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 p

11、reparation 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 p

12、rovides 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意发生微小变化时分析方法的灵敏度，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 deviation

13、s, this SOP can serve as the validation protocol.6.1 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，方案中任何主要的变更应反映在方案的修正案中。7 方法验证的一般程序7 Ge

14、neran procedure for validation of a methodValidation 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 will not be available, the validation should be c

15、ompleted when additional representative sample/s will be available (as an amendment to validation).如果没有附加的样品测试，可以测试一批或者两批样品，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：a Intermediate precision

16、test is not required when interlaboratory study performed by QC (or other lab).A- 当测试了重现性的时候，中间精密度可以不做b- When interlaboratory study is not performed, intermediate precision can be done instead. The method cannot be transferred to another laboratory until that technical transfer is performed. Values

17、like d(0.1), d(0.5), d(0.9), undersize/oversize percent or other relevant values will be recorded and will be evaluated according to the tables in each section.B- 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了技术转移。类似d(0.1), d(0.5), d(0.9),尺寸过小/尺寸过大比例或其他相关的数值应被记录并且评估。Note: In case the results fall between two

18、levels categories, take the lower level as acceptance criteria.注意如果结果介于两个限度，选择低的限度作为可接受标准。Note: For special methods in which more replicates are required use appendix 1.注意对于专属性方法，用按照附录1做更多的重复性。注意- Any change done in the process at the step where the API molecule already produced (from crude step) sh

19、ould 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 analytical method is considered appropriate to use after the change, and the change in

20、particle size distribution is concluded not significant, only verification of the method is required (repeatability and accuracy should be checked on one batch). In case that the change is evaluated to be not relevant to the PSD results, no additional validation activity is required and the current

21、validated method is applied.8 方法验证程序8 Detailed procedure for validation of a method8.1 Method repeatability8.1 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1，该样品应进行6次重复的分析，RSD应符合下表规定。d(0.1), d(0.5) and d(0.9)的可接受标准：结果RSDd(0.

22、1)和d(0.9) 10umNMT 15%d(0.1)和d(0.9) 10umNMT 30%d(0.5) 10umNMT 10%d(0.5) 10umNMT 20%Note: If the measured value is smaller than 1.0 micron the SD (Standard deviation) should be NMT 0.5 micron for acceptance criteria.注意如果结果小于1.0um，SD应NMT0.5um。Acceptance criteria for under size oversize percent:尺寸过小或过大比

23、例的可接受标准:结果RSD 过大/过小尺寸 70%NMT 15%30%过小尺寸/过大尺寸 70%NMT 20% 5%过小尺寸/过大尺寸30%NMT 30% 过大/过小尺寸5%NMT 1%（SD）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RSDd(X)d(0.3)或d(0.7) 10umNMT 15%d(X)d(0.3)或d(0.7) 10umNMT 30%d(0.3)d(X)d(0.7) 10umNMT 10%d(0.3)

24、d(X)d(0.7) 10umNMT 20%Note: If the measured value is smaller than 1.0 micron the SD (Standard deviation) should be NMT 0.5 micron for acceptance criteria注意如果测试结果小于1.0um，SD应NMT0.5um。8.2 中间精密度测试 Intermediate Precision Test Analyst #2 will analyse the sample according to method or Analyst #1 will analy

25、ze 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在另外一天分析样品。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 av

26、erage =(average from first measurement + average from the second measurement)/2 总平均值=（第一次分析的平均值+第二次分析的平均值）/2% Difference = (average from first measurement average from the second measurement)*100 / total average;偏差=（第一次分析的平均值-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

27、 d(0.1), d(0.5) and d(0.9) values:结果RSDd(0.1)和d(0.9) 10umNMT 30%d(0.1)和d(0.9) 10umNMT 60%d(0.5) 10umNMT20%d(0.5) 10umNMT 40%Note: If the measured value is smaller than 1.0 micron the absolute difference for acceptance criteria should be NMT 1 micron.注意如果测试结果小于1.0um，绝对偏差不得大于1um。Acceptance criteria fo

28、r under size oversize percent:尺寸过小或过大比例的可接受标准：结果RSD 过大/过小尺寸 70%NMT 25%30%过小尺寸/过大尺寸 70%NMT 40% 5%过小尺寸/过大尺寸30%NMT 60% 过大/过小尺寸5%NMT 2%（绝对偏差）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RSDd(X)d(0.3)或d(0.7) 10umNMT 30%d(X)d(0.3)或d(0.7) 10um

29、NMT 60%d(0.3)d(X)d(0.7) 10umNMT 20%d(0.3)d(X)d(0.7) 10umNMT40%Note: If the measured value is smaller than 1.0 micron the absolute difference for acceptance criteria should be NMT 1 micron.注意如果测试结果小于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 acce

30、ptance 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 StudyThe 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一方法进行测试。The difference between the average result and the average repeatability result (or duplicate

31、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 avera

32、ge;总平均值=（实验室一的平均值+实验室二的平均值）/2% Difference = (average from first laboratory average from the second laboratory)*100 / total average;偏差=（实验室一的平均值-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8.28.4 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 将相关参数改变大约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一个参数的改变都应被测量一次。应计算耐用性测试的结果与重复性测试结果平均