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[原料药] APIC 201405原料药厂清洁验证指南:8.0残留量检测(中英文)

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APIC 201405原料药厂清洁验证指南:8.0残留量检测(中英文)  



8.0 Determination of the Amount of Residue 残留量的检测
8.1 Introduction 介绍
This section provides a practical guidance for the determination of the amount of residue in cleaned equipment based on the requirements from regulatory authorities[1] and current guidelines on analytical validation.[2] Specific requirements for the validation of analytical and sampling methods for cleaning validation purposes are provided in this section, in addition to examples of sampling methods and the appropriate use of analytical methods.
本部分根据药监当局的要求和现行分析方法验证指南,提供了检测已清洁设备中残留物数量的实用指南。在本部分中给出了清洁验证中所用分析方法和取样方法的验证要求,以及取样方法和适当使用分析方法的例子。
The carryover acceptance limit (Mper) is a calculated figure that represents the specification limit for the equipment cleanliness (see Section 4.0, Acceptance Limits), however, the determination of the actual amount of residue (M) remaining in the equipment following cleaning must be achieved using appropriate methods i.e. for both the sampling method and the quantitation of the contaminant in the sample.
允许残留限度(Mper)是一个计算出的数值,代表设备清洁程度的质量标准限度(参见4.0部分,可接受限度),但是,对清洁后设备中残留物(M)实际数量的检测必须使用适当的方法来获得,即,针对取样方法和样品中污染物的定量。
Since the decision on the acceptable cleanliness of the equipment bears a potential risk to product quality, the method(s) used for the determination of M must be validated1 and the specificity, sensitivity and recovery of the method(s) should be determined as a minimum.
由于对设备可接受清洁度的决定会对产品质量有潜在风险,因此用于M检测的方法必须进行验证,必须至少验证方法的专属性、灵敏度和回收率。
8.2 Validation Requirements 验证要求
8.2.1 General 通则
The requirements for analytical method validation are defined in ICH Q2(R1), Validation of Analytical Procedures: Text and Methodology, November 2005. There are four types of analytical methods with principally different validation requirements; these are identification tests, tests for impurities (both quantitative and limit tests) and assay tests. The validation requirements for each method type are shown Table 1.
分析方法验证的要求在ICH Q2(R1)“分析方法验证:检验和方法学,2005年11月”中已给出。其中列出了四种不同类型的分析方法,各适用不同的验证要求,它们分别是:鉴别测试、杂质检验(定量和限度测试)和含量测试。每种类型方法的验证要求在表1中列出。
The list should be considered typical for the aforementioned analytical procedures, however, exceptions should be dealt with on a case-by-case basis. It should be noted that robustness is not listed in the table and should be considered at an appropriate stage in the development of the analytical procedure.
在上述的分析方法中必须考虑该清单,但是,要根据各案处理例外情况。要注意耐用性在表中并未列出,但在方法的研发过程中适当阶段需要进行考虑。
In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance; specificity, linearity, range, accuracy and precision.
在实际应用中,通常可以设计一个试验性工作,使得在方法设计时可以同步考虑方法的验证特性,例如,专属性、线性、范围、准确度和精密度。
The validation of an analytical method should occur in compliance with pre-established acceptance criteria that should be documented in a written general policy or Validation Plan. However, there should be one validation report per validated method that summarises the specific results.
分析方法验证必须符合预定的可接受限度。可接受限度应记录在书面的通用方针或验证中。但是,对每个验证过的方法必须有一个验证报告,总结验证结果。
TABLE 1 Requirement List for Analytical Validation
Characteristic
Type of Analytical Procedure
Identification
Testing for Impurities
Assay
Quantitative
Limit
Accuracy
+
+
Precision
Repeatability
+
+
Intermediate Precision
+1
+
Specificity2
+
+
+
+
Detection Limit
—3
+
+
Quantitation Limit
+
Linearity
+
+
Range
+
+
Key
—       Signifies that this characteristic is not normally evaluated.
+   Signifies that this characteristic is normally evaluated.
1          In cases where reproducibility has been performed, intermediate precision is not needed.
2          Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s).
3          May be needed in some cases.
表1 方法验证需求清单
特性
分析方法类型
鉴别
杂质检测
含量
定量测试
限度测试
准确度
+
+
精密度
重复性
+
+
中间精密度
+1
+
专属性2
+
+
+
+
检测限
—3
+
+
定量限
+
线性
+
+
范围
+
+
说明
—       表示该特性一般不需要评估。
+   表示该特性一般要进行评估。
1          如果做了重复性测试,则不需要做中间精密度。
2          如果一个方法缺乏专属性,则可以用另一个支持性分析方法进行补偿。
3          有时需要。
The requirements for ‘Testing for Impurities’ are typically employed for the validation of analytical methods specific to cleaning validation.
在清洁验证专用分析方法验证中,一般应用“杂质检测”的要求。
The requirements for ‘Quantitative Testing for Impurities’ can apply, for example, in cases where a method should be suitable for several possible acceptance limits and therefore quantitation of the residue over a certain range may be necessarye.g. the measured amount of residue M must be compared with acceptance limits between 5 and 750 g/equipment. This is possible when the method will be used for several changeovers.
有时可以应用“杂质定量检测”要求,例如,如果一个方法适用于几个可能的可接受限度,因此可能需要对一定水平范围内的残留物进行定量检测,例如,残留物M的测得量必须与可接受标准5-750g/设备相比较。如果方法要用于几个产品更换情况下的检测,则可以使用上述方法。
The requirements for ‘Limit Testing for Impurities’ can apply, for example, in cases where the method should be suitable for one specific acceptance limit e.g. the measured M must be compared with Mper ≤ 105 g/equipment.
有时可以应用“杂质限度检测”要求,例如,如果方法需要符合一个特定的可接受限度,例如,对M的测量必须与Mper ≤ 105 g/设备进行比较。
8.2.2 Analytical Method Validation for Cleaning Validation 清洁验证所用分析方法验证
In the following sections, aspects of analytical method validation specific to cleaning validation are emphasised. For further details refer to ICH Q2 (R1).
在以下部分强调了清洁验证专用的分析方法要点。更详细的要求参见ICH Q2(R1)。
Specificity is a basic requirement for all analytical methods (see Table 1), however, in the case of cleaning validation it may occur, that not all potential impurities are clearly specified. It is important to note that in such a situation a specific method may not always detect all impurities. Studies should be performed to characterise the unknown impurities, develop and validate suitable analytical methods. However, this can be an unacceptably time consuming task. In this case a method that detects all potential impurities together can be suitable, even when it is not specific for each of the impurities. For example, in a situation where only non-volatile impurities occur, a dry residue determination method that is specific for the sum of non-volatile impurities could be used, provided that the validation requirements according to Table 1 are satisfied. In order to consider the equipment acceptable for use it must be assumed that the dry residue consists of the worst case impurity (most toxic, most active etc.). In some cases a combination of several methods can achieve the necessary specificity.
专属性是所有分析方法(见表1)都适用的基本要求,但是,在清洁验证中,可能并不是所有潜在杂质都能被明确,在这种情况下要重点注意即使是专属的方法,也并不一定能检测出所有杂质。可以研究未知杂质的特性,建立适当的检验方法并验证,但这样做所耗费的时间可能是无法接受的。这时,可能会适当的办法是采用一个能检出所有潜在杂质的方法,即使该方法对有些杂质不具有专属性。例如,如果只有不挥发性杂质产生,只要验证结果符合表1的要求,可以使用非专属性方法蒸发残渣来检测所有不挥发性杂质的总和。考虑到要使设备清洁程度可以接受,必须假定蒸发残渣结果中会包括最差情形的杂质(毒性最强、活性最强等)。有时,可以联合使用几个方法来达到必需的专属性要求。
After the completion of a cleaning validation study an unspecific method (e.g. dry residue) may be used for the routine verification of equipment cleaned by the validated cleaning procedure provided that it is shown that the unspecific method is suitable for the intended purpose. If possible, the sensitivity of impurity detection for cleaning validation should be determined for both the sampling and analytical methods together (see Section 7.2.4).
在清洁验证完成后,可以使用非专属性方法(例如,蒸发残渣)对按验证过的清洁程序清洁后的设备进行日常检测,只要该方法适合其既定用途。可能的情况下,清洁验证所用检验方法对杂质检测的灵敏度应与取样方法和分析方法一起测试(参见7.2.4部分)。
8.2.3 Detection and Quantitation Limits 定量限和检测限
Measured values below limit of quantification (LOQ) should be reported as the LOQ value (worst case approach). For example if the LOQ is 10 mg/l, the measured blank is 7 mg/l and the measured residue amount is 3 mg/l, the reported value for the sample should be equal to the LOQ i.e. 10 mg/l.
低于定量限(LOQ)应报告为定量限值(最差情况法)。例如,如果LOQ为10mg/L,测得空白结果为7mg/L,测得残留值为3mg/L,则该样品的残留值应报告为LOQ,即10mg/L。
Usually it can be assumed that, for quantitative impurity determination, the LOQ should approximately be 0.5 of the specification i.e. for cleaning validation 0.5 of the acceptance limit or lower. LOQ should never be higher than the acceptance limit. In the following sections three methods of LOQ/LOD determination are outlined:
一般可以假定,在杂质定量检测时,LOQ应为质量标准的约0.5倍,即对于清洁验证来说,可接受限度的0.5或更低。LOD不得高于可接受限度。在以下部分,列出了三种确定LOQ/LOD的方法:
? Based on Visual Evaluation 目视评估
Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. Frequently this approach is used for TLC.
目视评估可以用于非仪器方法,但也可用于仪器分析方法。这种方法经常用于TLC。
? Based on Signal-to-Noise Approach 信噪比方法
This approach can only be applied to analytical procedures which exhibit baseline noise (e.g. GC, HPLC). A signal-to-noise ratio (S/N) between 3 or 2:1 is generally considered acceptable for estimating the detection limit (LOD) and a typical ratio for acceptable quantitation limit is 10:1 (LOQ). The value for S/N can be calculated according to Equation 1 and Figure 1:
本方法只能用于产生基线噪声的分析方法(例如,GC、HPLC)。信噪比(S/N)为2-3:1时,一般可以作为估计的检测限(LOD),10:1可以作为定量限(LOQ)。信噪比值可以根据公式1和图1计算:


where: H is the height of the peak from the mean baseline.
hn is the maximum deviation of the baseline within the range of 5 to 20 fold width of peak at half height.
其中:H为基线平均值的峰高
hn是基线在5-20部半峰高时峰宽范围内最大偏差


? Based on the Standard Deviation of the Response and the Slope
根据响应和斜率的标准偏差
The detection limit may be expressed by Equation 2 and the quantitation limit by Equation 3.
检查限可以采用公式2表示,定量限可以用公式3表示。


8.2.4 Determination of Recovery 回收率测定
If possible, the recovery of impurity detection for cleaning validation should be determined for the sampling and analytical methods together at least for recovery and sensitivity (Limit of Quantitation - LOQ, or Limit of Detection - LOD). This can be achieved, for example, by spiking a surface equivalent to the equipment surface (e.g. material, polish grade) with different known amounts of the impurity. The impurity can then be recovered and analysed using the same sampling and analytical methods that will be used for the cleaning validation study. The overall results from this procedure are then compared to criteria for detection or quantitation limits as defined in ICH Q2 (R1). Validation of the limits may be achieved by the analysis of samples known to be near at the limits.
可能的话,可以针对取样方法和检验方法同时进行清洁验证中杂质检测的回收率和灵敏度(定量限-LOQ,或检测限-LOD)。例如,可以采用与设备表面材质相同的表面材料(例如,材质、粗糙度),在上面加不同已知数量的杂质,然后采用与清洁验证研究相同的方法取样并分析。再将使用该方法所得的总体结果与ICH Q2(R1)中定义的检测限或定量限标准进行比较。可对接近限度的已知样品进行分析来验证分析方法的检测限和定量限。
The measured results are then compared to the actual amount applied to the surface. The recovery is typically determined during the accuracy determination and should be reported as a percentage of the known applied amount of the impurity.
将检测结果与实际数量进行比较,用于表面残留计算。回收率一般是在准确性测试中确定,应报告为已知杂质数量的百分比。
As an example, quantitative impurity determination recoveries of ≥ 90 % are usually regarded acceptable. For cleaning validation, recoveries of ≥ 90 % do not need to be taken into account for the calculation of the true value for M. Recoveries of < 90 % must be included in the calculation for M (see Equation 4) and recoveries of < 50 % should be omitted.
例如在杂质定量测试中,回收率≥ 90 %时一般认为是可以接受的。在清洁验证中,如果回收率≥ 90 %,在M残留量真值计算中可以不需要考虑回收率;如果回收率< 90 %,则需要在M计算时加以考虑(参见公式4),如果回收率<50%,则该方法不适用。


Where: M: True value for the amount of residue remaining in the equipment after cleaning;
Mres: The measured amount of residue (sampling and then analytical measurement);
R Recovery in % divided by 100 (e.g. for 75%, 75/100 = 0.75).
公式4:
其中M:清洁后设备上残留物的数量真值
Mres:测得残留量(取样后分析测量)
R:回收率除以100(例如,对于75%即为75/100=0.75)
8.2.5 Validation Requirements for Quantitative Testing of Impurities 杂质定量测试的验证要求
The requirements for the validation of quantitative testing of impurities according to ICH Q2 (R1) are shown in Table 2, including proposed acceptance criteria (as an example only). Alternative acceptance criteria may be established based on sound scientific rationale.
根据ICH Q2(R1),杂质定量检测方法的验证要求在表2中列出,包括制订的可接受标准(只是举例)。可以根据科学合理的原则制订适当的可接受标准。
It is important to note, that the summarised requirements should be used for the validation of quantitative testing for impurities during cleaning validation studies. Validation of quantitative testing for impurities is usually applied when the analytical method will be used for several specifications of the residue amount in the equipment.
重点要注意的是,在清洁验证研究中,定量检测方法验证应满足所有要求。如果分析方法将用于设备中残留量有不同的几个质量标准,则一般采用杂质定量方法验证要求。
The lowest foreseen acceptance limit is referred to as MperMin and the highest limit as MperMax in Table 2. For only one specific acceptance limit normally limit testing for impurities and the corresponding validation of the analytical method is sufficient. If the validation of quantitative testing for impurities will be used for one specific acceptance limit, then MperMin = MperMax = Mper.
最低预期可接受限度,在表2中称为MperMin,和最高限度,称为MperMax。对于只有一个特定的可接受限度,一般可以使用杂质限度测试方法,对方法只要做相应的验证即可。如果要将杂质定量方法的验证用于单一可接受限度,则MperMin = MperMax = Mper。
For the experimental work described in Table 2, the samples can be spiked with appropriate levels of the impurities (when standards are available) or compared with another well-characterised procedure (when standards are not available) to obtain the true value of the analyte concentration.
表2中试验里,可以采用杂质(如果可以获得标准品的话)加入样品中至适当的浓度水平,或与另一个经过确认的检验方法进行对比(如果不能得到标准品的话),以得到被分析物的真实浓度值。
TABLE 2 Validation Requirements
Experiments
Possible Acceptance Criteria
Accuracy:
Perform a minimum of 9 determinations over a minimum of 3 concentration levels covering the specific range (e.g. 3 concentrations/3 replicates each of the total analytical procedure). Determine analyte with respect to the total amount of residue in the sample (e.g. weight/weight). Report:
□ Accuracy as percent recovery or
90.00-110.00%
□ Difference between the mean and the accepted true value.
≤10.00% (P=95%)
□ Confidence intervals.
Precision:
Investigate using homogenous, authentic samples or (if not possible) artificially prepared sample. Perform a minimum of 9 determinations covering the specified range for the procedure (e.g. 3 concentrations/3 replicates each) or a minimum of 6 determinations at 100% of the test concentration.
Repeatability (intra-assay precision):
Establish precision under the same operating conditions over a short interval of time.
Report:
□ Standard deviation (interdependent with S)
See S
□ Overall relative standard deviation over the whole range of the method
≤10.00%
□ Relative standard deviation within one concentration level
≤20.00%
□ Confidence interval
Intermediate Precision (may include robustness, ruggedness):
establish precision on different days, for different analysts, on different equipment and after variation of method parameters (= robustness, e.g. stability of solutions, variations of pH, of mobile phase composition, of flow rate, of temperature, of columns etc.). It is not necessary to study these effects individually. Experimental design (matrix) may be applied.
Report:
□ Standard deviation (interdependent with relative standard deviation)
See S
□ Relative standard deviation
3×S from repeatability or 10% whichever is greater
□ Confidence interval
Specificity:
Demonstrate the discrimination of analyte in the presence of the other impurities:
□ Test samples containing the analyte and other impurities. Obtain positive and correct results for the analyte.
Specify acceptable deviation
□ Test samples without the analyte.
Negative results
□ For chromatographic procedures use representative chromatograms to document specificity. Label individual components appropriately.
Specify acceptable resolution of peaks
Linearity:
Measure a minimum of 5 concentrations across the range of the procedure (dilute standard stock solution or prepared synthetic mixtures). Plot the signals as function of concentration. Evaluate the plot:
□ Visually
Linear
□ Statistically (e.g. regression line by the method of least squares)
Correlation coefficient
≥0.99000
y-intercept
Confidence band (P = 95%) contains 0
Slope of the regression line
Residual sum of squares
Range:
Confirm that the analytical procedure provides an acceptable degree of linearity, accuracy and precision within or at the extremes of the specified range. Minimum specified ranges:
□ From the reporting level to 120% of MperMax. The reporting level for cleaning validation reasonably will be the LOQ. However, the reporting level must be below MperMin and should be below or at 80% of MperMin.
From LOQ or 80% of MperMin to 120% of MperMax.
表2 验证要求
测试项目
可能的可接受标准
准确度
在指定的浓度范围内对3个浓度进行至少9次检测(例如,3个浓度各按完整的分析方法检测3次)。测试残留物在样品中的总量(例如重量/重量)。
报告:
□ 精密度,表达为回收率百分比或
90.00-110.00%
□ 平均值与所接受的真值之间的差异.
≤10.00% (P=95%)
□ 置信区间
精密度:
使用均匀的具有标准值的样品或(如果没有标准样品的话)人为制备的样品,在指定范围内采用指定方法(例如,3个浓度各3次重复检测)检测至少9次,或在检测浓度100%水平测试至少6次。
重复性(含量精密度)
建立相同操作条件下较短时间内的精密度
报告::
□ 标准偏差(与S相互依存)
参见 S
□ 整个方法浓度范围内的总体相对标准偏差
≤10.00%
□ 一个浓度水平的相对标准偏差
≤20.00%
□ 置信区间
中间精密度(可以包括耐用性)
在不同天、不同化验员采用不同设备对方法参数进行变动(=耐用性,例如,溶液稳定性、pH值变化、流动相比例、流速、温度、柱子等)检测方法精密度。不需要单独研究各因素的影响,可以使用试验设计(矩阵)。
报告:
□ 标准偏差(依赖于相对标准偏差)
参见S
□ 相对标准偏差
重复性中的S值乘3或10%,取大者
□ 置信区间
专属性
证明被分析物与其它杂质的分离度
□ 检验含有被测试物和杂质的样品,得到被分析物的符合的正确结果。
指定可接受偏差
□ 检测不含被分析物的样品。
测试结果不含被分析物
□ 对于色谱方法,采用代表性图谱记录专属性。对各化合物进行恰当标识。
指定各峰间的可接受分离度
线性
检验方法范围内最少5个浓度检测(稀释标准贮备液或制备的合成混合物)。画出浓度-信号点,评估:
□ 目视
线性
□ 统计数据(例如,最小平方法回归线)
相关系数
≥0.99000
Y轴截距
置信区间 (P = 95%) contains 0
回归线斜率
残差平方和
范围:
确认检验方法的线性可以接受,精密度和准确度在指定的范围内或在范围极值。最小指定范围:
□     报告限至最大样品浓度的120%。合理的清洁验证的报告水平应在定量限,但是报告水平必须低于最小样品浓度,低于或等于最小样品浓度的80%。
从定量限或最小浓度的80%到最大浓度的120%。
8.3 Sampling Methods 取样方法
In order to demonstrate that the plant equipment is verified clean and meets the pre-defined acceptance criteria, sampling and analysis should be carried out using the methods described in the following sections. Justification should be provided for the selection of the appropriate verification technique on a case by case basis. A combination of the two methods is generally the most desirable. For all methods the sampling points should be fixed in a manner such that the true contamination of the equipment will be reflected.
为了证明工厂设备是清洁的,且符合预定的可接受标准,应采用以下部分所述的方法进行取样和分析。应各案论述对选择技术的恰当性。一般最好采用同时采用两种取样方法。对所取样方法,取样点应以一定方式固定,以反映设备中的真实污染情况。
8.3.1 Swab sampling (Direct Surface Sampling) 擦拭取样(表面直接取样)
Swab sampling of the direct surface is designed to test small sections of the equipment surface for the presence of residues. Samples should be taken from all main equipment items and since swab sampling does not cover the entire equipment surface area, justification should be provided for the choice of the area for swabbing.
对设备表面进行直接擦拭取样设计用于检测设备上小面积上残留物。样品应从所有主要设备上取样,由于擦拭取样并不覆盖整个设备表面,因此要对于取样部位的选择做出论述。
Typically a small area of the cleaned equipment is swabbed with a material according to a pre-defined method i.e. swab material, solvent and technique. The swab sample can then be extracted and examined using a suitable analytical method.
一般来说,对已清洁设备的一个较小面积采用预定的方法,例如擦拭材料、溶剂和方法,进行擦拭取样。对擦拭样品进行提取,采用适当的分析方法进行检测。
The quantified residue obtained from the sample is then extrapolated to the whole equipment (see Equation 6).
将样品测试所得的残留量值外推至整个设备(参见公式6)。
It is important: 以下内容应重视
l         That the validation of the swab sampling is performed on the same surface (material, polish grade, area in dm2) and with the same materials as the routine sampling of the equipment.
l         擦拭取样方法验证应采用相同表面(材质、光洁度、面积以dm2为单位),以及设备常规取样时相同的取样棒
l         That the choice of swabbing material considers extractable materials that could interfere with the expected residue.
l         选择擦拭材料时,要考虑可萃出物料可能对预期的残留物产生影响
l         To ensure that the sampling points represent the worst case areas of the equipment.
l         要保证取样点代表设备的最差面积
The disadvantage of this sampling method for often complex API equipment is that difficult to reach areas (e.g. sealings, condensers, transfer pipework) may not be accessible by swabbing. Nevertheless these areas may be the critical areas for the determination of the amount of residue in the equipment.
该取样方法的缺点是有些原料药设备比较复杂,有些部分难以取到擦拭样品(例如,密封处、冷凝器、转移用管道),而这些面积可能对于设备残留量的测定比较关键。


M
Amount of residue in the cleaned equipment in mg.
已清洁设备中残留量mg
WF
Recovery rate for the whole chain swab/analytical method (e.g. 0.8 for 80%).
整个设备链的擦拭/分析方法回收率(例如0.8代表80%)
Ftot
The entire inner surface of the equipment in dm2
设备整个内表面积,平方分米
Mi
Amount of residue (e.g. previous product) in the sample i in mg.
样品中的残留量(例如,上一产品)mg
Ci
Gross amount of residue in the sample i in mg.
样品 i 中残留总量mg
CBi
Blank of the sample i in mg. To establish the blank, a swab (or several swabs) can be treated in the similar way as a sampling swab except swabbing of the contaminated surface. Usually one and the same blank can be used for all N sampling swabs.
空白样品 i 重量mg
为建立空白,可以将一个(或几个)取样用空白棉签采用与样品同等方法处理。一般一个相同的空白可以用于所有N个取样棉签。
Fi
Area swabbed by the swab i in dm2.
擦拭取样的面积,平方分米
N
Number of swab samples.
样品数量
i
Sample identifier (current number from 1 to N).
样品识别号(现在编号为1至N)
The first production batch of the following product may be sampled and analysed for impurities (for preceding product) since chromatographic analytical methods will typically be used (e.g. HPLC, GC, TLC).
由于现在普遍使用色谱分析方法(例如HPLC、GC、TLC),可以对下一产品的第一个生产批号取样,分析其中(上一产品)杂质。
8.3.2 Rinse or Wash Solvent Sampling 淋洗或冲洗取样
In cases where swabbing is not possible, for example restricted access, swabbing may be substituted by the analysis of final rinse solutions. Rinse samples can be used to determine the carryover of residues over a large surface area and cover all main process items including transfer pipework. In cases where swab sampling is not practical, it is acceptable to analyse only rinse samples, however this should be justified as part of the validation study.
如果没办法进行擦拭取样,例如不能入口受限,可以对最终淋洗液进行检测来替代擦拭样品。淋洗样品可以用于确定一个很大表面积上的残留量,并覆盖所有主要工艺设备,包括物料管道。如果擦拭取样不实际,可以接受只对淋洗样品进行检测,但应作为验证研究的一部分进行论述。
This section outlines the quantitation of the amount of residue remaining in the equipment after cleaning based on the amount of residue in the last rinse of the routinely used cleaning procedure.
本章列出了根据清洁程序中最后一次淋洗液中残留量,计算清洁后设备中残留量的定量方法。
The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash or rinse solvent portion. The assumption is based on the worst case consideration that a further rinse (or any reaction) would not remove more than the same amount of residue present in the analysed rinse sample.
可以假定设备中残留量等于最后冲洗或淋洗溶剂中的总量。该假设是基于最差情形考虑,即进一步淋洗(或任何反应)将无法得到比分析用淋洗样品结果更高的残留物。
The advantage of the rinse sampling method is the whole equipment will be reached by the solvent, including difficult to reach locations that cannot be disassembled. Therefore, if appropriately designed, this method will give the best indication of the amount of residue remaining in the equipment.
淋洗取样方法的优点是整个设备都会被溶剂洗到,包括最难触及且不能拆卸的部位。因此,如果对淋洗方法进行了适当的设计,该方法能最好地显示设备中残留量。
For quantitation, a solvent sample (e.g. 1 litre) is removed and the residue in the sample is determined by a suitable analytical method, which can then be extrapolated to the whole equipment according toEquation 5.
在定量检测时,取一个溶剂的样品(例如1L),对样品中的残留采用适当的分析方法进行检测,然后根据公式5外推至整个设备。
Equation 5: M = V × (C – CB)
Where 其中
M
Amount of residue in the cleaned equipment in mg.
清洁后的设备中的残留量mg
V
Volume of the last rinse or wash solvent portion in litres.
最后淋洗或冲洗溶剂体积,L
C
Concentration of impurities in the sample in mg/l.
样品中杂质浓度,mg/l
CB
Blank of the cleaning or rinsing solvent in mg/l. If several samples are taken during one run, one and the same blank can be used for all samples provided the same solvent lot was used for the whole run.
清洁或淋洗溶剂空白水平,mg/l
如果在一个轮次中取了几个样品,并且在整个轮次中使用的溶剂是同一个批号,则可以在所有样品计算中使用同一个空白。
8.3.3 Stamps 邮戳法
In this exceptionally used sampling method, “coins” (or stamps) are placed on appropriate sampling points in the equipment during the manufacture of the previous product and during cleaning. After cleaning, the contamination on the coins can be analysed and the overall contamination can be calculated by extrapolation to the whole equipment. For quantitation, the coins may be firstly swabbed followed by further analysis of the samples.
这是一种在例外情况下使用的取样方法。取一个“圆片”(或邮票),置于设备中适当的取样点上,进行上一产品的生产清洁。在清洁后,对硬币上的污染物进行检测,采用外推法计算整个设备的全部污染。如果是要进行定量分析,则对圆片进行擦拭取样,然后对样品进行进一步分析。
8.4 Analytical Methods 分析方法
A sample isolated by either of the sampling methods discussed in Section 8.3 should be analysed by a suitable analytical method (e.g. HPLC, GC, GC-MS, TLC, dry residue, TOC, UV, titration, conductivity or pH). The suitability of the method can be documented by appropriate validation as detailed inSection 8.2.
按第8.3部分所讨论的取样方法之一所获得的样品应采用适当的分析方法(例如,HPLC、GC、GC-MS、TLC、蒸发残渣、TOC、UV、滴定、电导率或pH值)进行检测。方法的适用性可以依据8.2部分指导进行适当的验证并记录。
A combination of analytical methods can be used if appropriate. For example evaporation of the solvent sample and analysis of the dry residue by another method (e.g. HPLC) can enhance the sensitivity of the final analytical method by a factor 106. Alternatively, the use of several methods (e.g. titration, HPLC) can provide the required specificity.
适当时,可以合并使用几个分析方法。例如,将溶剂样品蒸发,采用另一个方法(例如HPLC)分析残渣。这样可以增加最后分析方法的灵敏度到100万倍;而采用几个方法(例如,滴定、HPLC)可以达到所需的专属性。


[1] FDA Guide to Inspections Validation of Cleaning Processes,http://www.fda.gov/ICECI/Inspect ... uides/ucm074922.htm

[2] ICH Q2 (R1), Validation of Analytical Procedures: Text and Methodology, November 2005




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药徒
发表于 2014-10-15 14:24:52 | 显示全部楼层
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药徒
发表于 2014-10-15 14:33:32 | 显示全部楼层
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药徒
发表于 2016-8-23 16:38:56 | 显示全部楼层
谢谢分享!
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药徒
发表于 2016-8-24 11:27:27 | 显示全部楼层
关于邮戳法,上次做离心袋的时候用过一次,坏的离心袋上剪了两块后缝在验证的离心袋上,一块做化学残留,一块做微生物,结果,取下来一看,离心后,离心袋上好大几个针眼,直接不能用了
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药徒
发表于 2017-1-19 10:36:21 | 显示全部楼层
谢谢楼主分享,可惜图片打不开了
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发表于 2017-1-22 13:02:44 | 显示全部楼层

谢谢分享,学习一下!
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药徒
发表于 2017-6-8 16:35:51 | 显示全部楼层
先马后看  
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药徒
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发表于 2018-8-24 08:03:12 | 显示全部楼层
正需要,感谢楼主
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药徒
发表于 2020-12-24 10:02:58 | 显示全部楼层
谢谢楼主提供
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药仙
发表于 2023-5-2 10:27:23 | 显示全部楼层
辛苦了,谢谢分享。
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发表于 2023-7-27 15:32:01 | 显示全部楼层
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