关于混合均匀性的7个问题！
Do we need blend uniformity – why is the CU testing withappropriate sampling plan not acceptable?
我们是否需要混合均匀性–为什么不接受使用适当取样计划的含量均匀性测试？
CGMP (21 CFR.211.110) requires an in-process testing of powder blends todemonstrate adequacy of mixing, but it does not state that the blend has to bedirectly assessed for uniformity. It was on this premise that the originaldraft stratified sampling guidance document allowed the use of in-processdosage unit data as a surrogate to demonstrate dosage unit uniformity duringroutine manufacture. Blend uniformity should be assessed during process design(Stage 1 Validation) and process qualification (Stage 2 Validation). Defaultingdirectly to the testing of in-process dosage units is discouraged, theexception being when blend sampling presents severe risks to the operatorstaking the samples (which should be discussed and accepted by regulators).
CGMP （21 CFR.211.110） 要求对粉末混合进行工艺测试，以证明混合是否充分，但未说明必须直接评估混合物的均匀性。正是基于这个前提，分层抽样指南的草案允许使用过程中剂量单位数据作为代替，以证明在日常生产期间的剂量单位均匀性。在工艺设计（第 1 阶段验证）和工艺确认（第 2 阶段验证）期间，应评估混合均匀性。不鼓励仅对剂量单位进行测试，除非混合取样对取样人员造成严重风险（监管机构应讨论并接受）。
Do I have to do the systematic sampling for the routinemanufacturing release testing?
我是否要为日常生产放行测试进行系统性取样？
Systematic sampling plans covering the entire compression or fillingoperation (including beginning and end of batch samples) should be used duringroutine manufacture, if the results are also to be used to demonstrate blendhomogeneity.
在日常生产过程中，应使用涵盖整个压片或灌装操作的系统性抽样计划（包括批次样品的开始和结束），如果结果也用于显示混合均匀性。
How much variability in the manufacturing process andanalytical methods should be tolerated?
在生产过程和分析方法中，可允许多少变异性（RSD相对标准偏差）？
It is in a company’s best interest to minimize variability in the processand/or analytical methods, especially for processes that have SD’s > 3%.Analytical methods should be validated in accordance with CGMP criteria(including linearity, selectivity, limit of quantitation, precision, accuracy,range, repeatability, robustness, etc.). In general the underlying precision ofanalytical methods should be better than the variability target for the product(i.e. 3%).
最大程度减少工艺和/或分析方法的变异性是符合公司的最佳利益的，尤其是对于SD＞3%的工艺。分析方法应根据CGMP标准进行验证（包括线性、选择性、定量限、准确度、精密度、范围、可重复性、稳健性等）。一般来说，分析方法的基本精度应优于产品的变异性标准（例如3%）。
Can in-process dosage units be used for batch release?
工艺中剂量单位可用于批放行吗？
The results from the in-process dosage units can also be used for batchrelease testing (non-weight corrected). If the in-process dosage units are notthe finished dosage form (e.g., tablet core vs. film coated tablet), contentuniformity data for the in-process and finished dosage forms should be comparedto demonstrate similarity.
工艺中剂量单位的结果也可用于批放行测试（非重量校正）。如果工艺中剂量单位不是成品的剂量形式（例如，素片与薄膜包衣片），则应比较过程和成品剂型的含量均匀性数据，以证明相似性。
The Agency currently recommends that all replicatesamples taken from various locations in the blender be evaluated to perform astatistically valid analysis. The Group recommends only assaying one sample perlocation if SD is < 3.0% following the analysis of one sample from eachpoint. Will this be acceptable?
FDA目前建议对从混合机不同位置采集的所有复制样品进行评估，以便进行统计上有效的分析。专家组建议，先每个位置只检测一个样本，如果SD＜3.0%，即可。这是可以接受的吗？
The ISPE BUCU Group acknowledges the FDA Q&A published in August 2013,which recommends that all replicate samples taken from various locations in theblender be evaluated to perform a statistically valid analysis. However, theISPE BUCU Group feels that this is unnecessary if after the analysis of thefirst sample from each location, the SD is <3.0. VCA performed on allsamples (including the remaining replicates) would only be assessing randomvariability and noise.
ISPE BUCU 小组知道 FDA 于 2013 年 8 月发布的问答，其中建议评估从混合机中不同位置采集的所有复制样品，以便进行有效的统计分析。但是，ISPE BUCU 小组认为，如果在每个位置分析第一个样本后，SD＜3.0，则无需这样做。对所有样本（包括其余复制）执行的 VCA 将仅评估随机变异性和噪声。
If the BU standard deviation is >5.0, is BU acceptableor not acceptable? Do you progress to analysis of the dosage units?
如果 BU 标准偏差为±5.0，则 BU 是否可以接受？是否可以继续剂量单位分析？
During Stage 2 validation (process qualification), batches with BU SDs>5.0% fail if one cannot attribute the root cause of the high SD to be dueto be non-mixing/material related (such as blend sampling bias or an analyticalerror) and supported by dosage units data. If the standard deviation for theblend is > 3.0, replicate blend samples should be analyzed and aninvestigation into the cause of the high standard deviation, in particular tosee if it is due to a non-blending related cause (such as sampling error oranalytical error). Repeatability and reproducibility tests should be conductedto assess variability in the analytical methods. VCA should be performed on theblend and dosage unit data as part of the investigation, to determine withinlocation and between location variance.
在第 2 阶段验证（工艺确认）期间，如果无法将混合均匀性SD 的根本原因归因于非混合/物料相关（如混合取样偏差或分析错误），并且受剂量单位数据支持，则 BU SD＞5.0% 的批次将失败。如果混合的标准偏差＞3.0，则应分析混合备检样本并调查标准偏差高的原因，特别是确认其是否由于非混合相关原因（如取样误差或分析误差）。应进行重复性和重现性测试，以评估分析方法的变异性。作为调查的一部分，应在混合和剂量单位数据上执行 VCA，以确定同一位置和不同位置之间的变异性。
Situations where within locationerror is high for the blend, but low for dosage units may imply sampling bias.If the within error component is high for both the blend and dosage units,micro mixing issues exist (possibly poor dispersion, segregation oragglomeration). If between location variances are high, the blend and dosageunits have poor uniformity. Regardless of the fate of the batch, scientistscompanies can use the analysis on blend and dosage unit samples to identifyunderlying causes for poor content uniformity and make process improvements.
如果同一位置误差较高，但剂量单位低，可能意味着样品偏差。如果混合和剂量单位内误差都很高，则存在微混合问题（可能存在差的分散、分离或聚集）。如果不同位置差异高，则混合和剂量单位的均匀性较差。无论批次的命运如何，科学公司都可以使用混合和剂量单位样品的分析来识别含量均匀性差的根本原因，并改进工艺。
Did you use HAZOP (Hazard and Operability Analysis) toidentify sampling locations?
是否可以使用 HAZOP（危害与操作分析）来确定采样位置？
The BUCU Group did not specify a specific approach to use during any riskassessment process to identify problematic areas to sample. Problematic areaswithin the process should be identified, and the systematic sampling schememodified to cover those events. Any extra samples and data collected aroundcritical events should be assessed separately.
BUCU小组没有具体说明在任何风险评估过程中使用的具体方法，以确定取样的问题领域。应查明工艺中的问题区域，并修改系统抽样方案以涵盖这些问题。围绕关键事件收集的任何额外样本和数据应单独评估。
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