FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.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