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分析方法---之专属性  

2009-12-02 14:59:45|  分类: 分析方法 |  标签: |举报 |字号 订阅

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Specificity/ Selectivity

 

ICH Q2

Specificity is the ability to assess unequivocally the analyte in the pretence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, ect.

专属性是毫不含糊地确定组分中预计可能会存在的分析物的能力。典型地,这些分析物包括杂质,降解产物,基质等。

 

Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).

分析方法缺少专属性可以通过其它支持的分析方法来补充。

 

This definition has the following implications:

专属性的定义有如下的含义:

Identification: to ensure the identity of an analyte

鉴别:为了确保分析物的同一性

Purity tests: to ensure that all analytical procedures performed allows an accurate statement of the content of the impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, ect.

纯度检测: 为了确保所做的所有的分析方法可以对分析物中杂质的含量有准确的陈述,如有关物质检测,重金属,残留溶剂,等。

 

Assay(content or potency)

To provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.

含量测定(含量或功效)

为了提供准确的结果,其对样品中分析物的含量和功效有准确的陈述、

 

An investigation of specificity should be conducted during the validation of identification tests, the determination of impurities and the assay. The procedures used to demonstrate specificity will depend on the intended objective of the analytical procedure.

专属性的调查应在鉴别试验,杂质和含量的测定中做。证明专属性采用的方法取决于分析方法的目的。

It is not always possible to demonstrate that an analytical procedure is specific for a particular analyte (complete discrimination). In this case a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination.

通常情况下,不可能证明某一分析方法特定专属于某一特定的分析物(完全区分)。在这种情况下,建议联用两种或两种以上的分析方法以达到必要程度的区分。

1.1.  Identification

鉴别

Suitable identification tests should be able to discriminate between compounds of closely related structures which are likely to be present. The discrimination of a procedure may be confirmed by obtaining positive results (perhaps by comparison with a known reference material) from samples containing the analyte, coupled with negative results from samples which do not contain the analyte. In addition, the identification test may be applied to materials structurally similar to or closely related to the analyte to confirm that a positive response is not obtained. The choice of such potentially interfering materials should be based on sound scientific judgement with a consideration of the interferences that could occur.

合理的鉴别试验应能够区分可能存在的紧密相关的结构。方法的区分可以通过从含有分析物的样品中获得阳性结果(可能会和已知的标准品比较),以及从不含分析物的样品获得阴性结果来区分。此外,鉴别试验可以应用于结构相似的物质或紧密相关的分析物,未获得阳性相应来证实。这些潜在干扰物质的选择应基于合理科学的判断,需考虑到可能存在的干扰。

1.2.  Assay and Impurity Test(s)

含量和杂质检测

For chromatographic procedures, representative chromatograms should be used to demonstrate specificity and individual components should be appropriately labelled. Similar considerations should be given to other separation techniques.

对于色谱方法,用典型图谱来证实专属性,图谱上单个组分应合理标注。其它的分离技术也应给予类似的考虑。

Critical separations in chromatography should be investigated at an appropriate level. For critical separations, specificity can be demonstrated by the resolution of the two components which elute closest to each other.

应调查色谱法的关键分离(临界分离)处于适当的水平。对于临界分离,专属性应通过相邻出峰的两个组分的分离度来证明。

In cases where a non-specific assay is used, other supporting analytical procedures should be used to demonstrate overall specificity. For example, where a titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used.

若是使用的非特定的专属含量测定,应使用其它的支撑的分析方法来证明总体的专属性。例如,采用滴定方法来测定用于放行的原料药,可以联合使用含量测定和杂质的合理检测。

The approach is similar for both assay and impurity tests:

对于含量和杂质检测,方法是类似的。

1.2.1 Impurities are available

杂质可以获得

For the assay , this should involve demonstration of the discrimination of the analyte in the presence of impurities and/or excipients; practically, this can be done by spiking pure substances (drug substance or drug product) with appropriate levels of impurities and/or excipients and demonstrating that the assay result is unaffected by the presence of these materials (by comparison with the assay result obtained on unspiked samples).

对于含量测定,这应包括杂质和、或赋形剂中分析物的区分的证明。在实践上,可以通过在纯的物质(原料药或制剂)中加入适量的杂质和赋形剂,并证明含量的结果不受这些物质存在的影响(通过和未加样的样品的含量测定结果比较)。

For the impurity test, the discrimination may be established by spiking drug substance or drug product with appropriate levels of impurities and demonstrating the separation of these impurities individually and/or from other components in the sample matrix.

对于杂质检测,通过在原料药或制剂中加入适量的杂质,并通过证明这些杂质逐个分离,和样品基质中其它组分也分离,来建立区分。

1.2.2 Impurities are not available

杂质不可得到

If impurity or degradation product standards are unavailable, specificity may be demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure e.g.: pharmacopoeial method or other validated analytical procedure (independent procedure). As appropriate, this should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis and oxidation.

如果杂质或降解产物的标准品不能够得到,专属性可以通过比较含有杂质或降解物的样品的检测结果和另外的完好的分析方法,如,药典方法或其它验证的分析方法的结果来证实。(独立程序)。适当的,这应包括在相关强降解条件下储存的样品:光,湿,酸解/碱解,以及氧化条件。

-        for the assay, the two results should be compared;

对于含量,应比较两个结果。

-        for the impurity tests, the impurity profiles should be compared. Peak purity tests may be useful to show that the analyte chromatographic peak is not attributable to more than one component (e.g., diode array, mass spectrometry).

对于杂质检测,杂质的概况应比较。峰纯度的检测对表明分析物的色谱峰不是有超过一个以上组分产生的很有用(如,二极管阵列,质谱)。

 

 

FDA reviewer guidance -- Validation of analytical procedure

Specificity/selectivity

专属性/选择性

 

The analyte should have no interference from other extraneous components and be well resolved from them. A representative HPL chromatogram or profile should be generated and submitted to show that the extraneous peaks either by addition of known compounds or samples from stress testing are baseline resolved from the parent analyte. Examples of the extraneous peaks are as follows:

分析物应不受其它无关组分的干扰,和它们有好的分离。生成并递交典型的HPLC图谱或概况以表明通过加入已知的物质或强降解样品的无关的峰和母分析物基线分离来表明。无关峰的例子如下:

For the drug substance or raw material, the related substances to consider are process impurities (which include isomeric impurities) from the synthesis process, residual pesticides, solvents, and other extraneous components from extracts of natural origin.

For the drug product, the related substances may be impurities present in the active drug, degradation products, interaction of the active drug with excipients, extraneous components, e.g., residual solvents from the excipients or manufacturing process, leachables or extractables from the container and closure system or from the manufacturing process. Submission of data from stress testing of the drug substance using acid and base hydrolysis, temperature, photolysis and oxidation according to the Guideline for Submitting Samples and Analytical Data for Methods Validation is recommended. Representative HPL chromatograms are recommended for stressed and non-stressed samples that include test methods for impurities, preservatives, etc. and placebo sample. With the impurities test method, the HPL chromatogram should indicate the presence of impurities at the level of detection/quantitation claimed. The chromatograms should be legible, labeled, and the time or time scale and attenuation should be indicated.

对于原料药或原辅料,待考虑的有关物质是来自合成工艺的工艺杂质(包括异构体杂质),残留的杀虫剂,溶剂,和其它的天然提取的无关组分。对于制剂,有关物质可能是存在于原料药中的杂质,降解物,原料药和赋形剂的相互作用,外源物质,如赋形剂中的残留溶剂,工艺中的残留溶剂,包装材料或工艺的滤取物,提取物。建议递交强降解原料药的数据,强降解条件应根据指南“Guideline for Submitting Samples and Analytical Data for Methods Validation”。建议强降解和非强降解样品的HPLC图谱,包括杂质、防腐剂的检测方法。HPLC图谱应指明高于检测限/定量限存在的杂质。图谱应是清晰可见的,标注的,注明时间。

Points to note are as follows:

注意点如下:

1. The parent peak may be expanded, e.g., by increasing the concentration, attenuation change, so that extraneous peaks can be observed at a reasonable size to evaluate stability-indicating capability. See comments in section IV.B under Limits of Detection/Quantitation.

母峰可能会变长,如增加浓度,使得可以在合理的尺度下观察到无关的峰来表明稳定指示性。见检测限定量限下的评论。

2.        The baseline should be on-scale as off-scale baseline (observed as a flat straight line) can hide minor peaks. Peak purity can be determined by the photo-diode array detector. Low level extraneous components present under the compound of interest, however, may not interfere or influence the UV spectrum of the analyte. Figures 3 and 4 illustrate the combination of UV spectroscopy and HPL chromatography by photo-diode array detection using (a) 3-dimensional plot and (b) conventional HPL chromatogram. The analyte elutes at 4.7 minutes. It should be noted that the quality of the UV spectra for the low level components is poor.

基线应在刻度以内,因为刻度范围以外会隐藏小峰。峰的纯度可以通过光电管二极管阵列检测器测定。

When stressed samples are used, an appropriate detector/integrator setting should be selected. For example, to be able to detect low levels, e.g., 0.1% degradation products, the parent peak should be of a size that at least a 0.1% detectability or area count is feasible.

当使用强降解样品,应选择适当的检测器。如,能够检测低含量的杂质,如0.1%的降解物,母峰应有合适的大小,至少可以检测0.1%或面积量可行。

Recommendations:

Representative HPL chromatograms should be submitted for stressed and non-stressed samples that include impurities test method, preservative(s), etc. with the related placebo sample. Representative HPL chromatogram(s) to show selectivity by the addition of known extraneous compounds also should be submitted.

建议

强降解和非强降解样品的典型的HPLC图谱应递交,包括杂质的检测方法。通过加入已知的无关物质表明选择性的典型图谱也应提供。

 

 

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