The CGMPs address the issue of sample compositing directly but only in the context of individual container sampling. Section 211.84(c)(4) explicitly prohibits compositing samples taken from 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 § 211.84(c)(4) explains further that there “is no general prohibition… on compositing samples [from single containers] where such compositing would not mask subdivisions of the sample that do not meet specifications” (see 1978 preambleExternal Link Disclaimer, paragraph 231).

Testing individual samples from multiple containers provide a high level of assurance and are consistent with CGMP. Testing a composite model for identity could satisfy the CGMP regulations (§§ 211.84 and 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 ensures that all containers sampled contain the same material. Thus, a purity assay on a composite sample prepared by mixing equal aliquots from each container may be acceptable, provided such a test is sufficiently sensitive to reveal the presence of a single non-conforming container.

References:

The preamble to the Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding regulations (43 FR 45014, Sept 29, 1978)

21 CFR 211.82: Receipt and storage of untested components, drug product containers, and closures

21 CFR 211.84: Testing and approval or rejection of components, drug product containers, and closures

21 CFR 211.160: General requirements (Laboratory Controls)

FDA Guidance for Industry, 2000, ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances [Text or PDF]

FDA Guidance for Industry, 1999, ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products [PDF]