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发表于 2017-4-30 17:59:31
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Questions and Answers on Current Good Manufacturing Practices—Production and Process Controls
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 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.
补充内容 (2017-5-2 22:35):
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 FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment.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FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.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. 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.
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. |
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发表于 2017-4-28 13:03:11
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