The compliance and science of Blend Uniformity Analysis

According to 21CFR section 211.110(a) pharmaceutical manufacturers are legally required to demonstrate the adequacy of their mixing operations. The CFR, however, is intentionally silent on how this should be accomplished. The situation changed dramatically in 1993 as a consequence of The US vs. Barr Laboratories when Judge Alfred Wolin ruled for the government that the appropriate sample size for Blend Uniformity Analysis (BUA) is, at most, three times the weight of the final dosage unit. This ruling defined the Current Good Manufacturing Practices (cGMPs) for BUA in greater detail than is specified in 21CFR section 211.110(a). It also established a precedent that has been the focus of an almost decade long controversy between pharmaceutical manufacturers and the FDA. At the heart of the matter is the inability of current sampling technology to consistently and reliably provide small representative samples from significantly larger static powder blends. The sample thief is the state-of-the-art powder sampling technology used by the pharmaceutical industry today for purposes of BUA. Unfortunately, sample thieves are intrusive devices that are prone to sampling error. Sampling error can lead to powder samples that are not representative of the bulk blend from which they were collected. In general, sampling error increases as the concentration of the drug substance and the size of the sample decrease. Since Judge Wolin's ruling, sampling error has made it difficult, if not impossible, to validate the manufacturing processes for some acceptably uniform pharmaceutical products. This article reviews the compliance history of BUA as well as the associated scientific literature.