混合取样的问题

beiwei5du

各位蒲友：

针对于原料药的混合，大家的取样方法一般是怎么样的呢？？（针对于单锥，双锥），非常感谢？？下文的被取消的指南虽然是针对的是制剂的，但是其中涉及到取样策略（比如取≥10个sample locations并在每个取样点取3个replicate samples）不知道是否能用到API过程中，本人没有找到相关的API混合的相关的指南，求指导。

15. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment. What were the Agency’s major concerns with this guidance?

FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.

Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least 3 replicate samples be taken from at least 10 locations in the powder blender, but that only 1 of the 3 replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. （原先的按照决策树的是取至少10个点，每个点取三个样，然后测定3个样中的一个样用于评价，其他两个样用于调查，agency现在推荐所有的取样均进行测定评估混合有效性）This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis.  （这种3replicate sampless检测能够证明取样位置的差异性not significant,但是关于每个点的取样数以及取样位置数需要使用统计的方法确定）

Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in General Chapter <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release.  Currently, there are several standard statistical practices that, if used correctly, can help to ensure compliance with CGMP regulations, including 21 CFR 211.110, 21 CFR 211.160, and 21 CFR 211.165.

References:

• 21 CFR 211.110: Sampling and testing of in-process materials and drug products
• 21 CFR 211.160: General requirements [Laboratory Controls]
• 21 CFR 211.165: Testing and release [of the finished drug product] for distribution
  

beiwei5du

其中的另一个21cfr part211 Q&A中有提到这个问题：说明必须进行within-location variability确认，那么如此一来，单点的取样位置的多个取样也是必须的要求了！

16.  Why is FDA concerned about proper sampling of powder blends?

The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110). Between- and within-location variability （这个就说明单点多个replicate samples的要求）in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors. However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance).  If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.（powder-thief取样方法的可靠性评估具体如何进行？？）

References:

• FDA Guidance for Industry, 2004, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance
  

生锈的马达

以前搞过欧盟的认证，负责硬件部分，购买过API的取样器，一次单点可以取物料不同深度的多点样品，普通取样器做不到的

beiwei5du

songxun66 发表于 2016-10-2 20:19
以前搞过欧盟的认证，负责硬件部分，购买过API的取样器，一次单点可以取物料不同深度的多点样品，普通取样 ...

这个是thief samling device，但是我问的不是这个问题呢

julia朱玉姣

针对于原料药的混合，大家的取样方法一般是怎么样的呢？？（针对于单锥，双锥），非常感谢？？下文的被取消的指南虽然是针对的是制剂的，但是其中涉及到取样策略（比如取≥10个sample locations并在每个取样点取3个replicate samples）不知道是否能用到API过程中，本人没有找到相关的API混合的相关的指南，求指导。

原料药未见相关规定。原料药相对制剂要求应该低一点，个人以为原因有：一制剂生产过程还有混合，二原料药批间和批内自身差异较小。
原料药双锥不一定采用这个指南的方法，按照双锥45度斜角停顿时取样，假定物料表面当时水平，可以将水平面以横竖2条中分线划分为4个区域，每个区域的中位点作为取样点。使用3个滑块的活动取样棒，在4个取样点将取样棒与粉料平面成30-45度左右角向下取样。假定三个滑块将取样深度四等分，取得12个样品。如果各取三次，则取样有36个样品。但是否有必要重复取样三次，可以自行讨论。
至于样品检测，一般是选择一到两个代表性指标，如水分或含量，一般不应该将样品混合后检测。