The CGMPs address the issue of sample compositing directly but only in the context of individual container sampling. Section 21 CFR 211.84(c)(4) explicitly prohibits compositing samples taken the top, middle, and bottom of a single container when such stratified sampling is considered necessary (as might be the case when moisture content needs to be controlled, particularly when only a portion of a container may be used in a drug product batch). The preamble for 21 CFR 211.84(c)(4) explains further that there "is no general prohibition... on compositing samples [ single containers] where such compositing would not mask subdivisions of the sample that do not meet specifications" (see 1978 preamble7, par. 231).
Testing individual samples multiple containers provides a high level of assurance and is consistent with CGMP. Testing a composite sample for identity could satisfy the CGMP regulations (21 CFR 211.84 and 21 CFR 211.160) but only if a manufacturer demonstrates either that the detection of a single non-conforming container is not masked by compositing or that an additional test(s) routinely performed on the composite sample assures that all containers sampled contain the same
material. Thus, a purity assay on a composite sample prepared by mixing equal aliquots each container may be acceptable provided such a test is sufficiently sensitive to reveal the presence of a single non-conforming container.
