UNIT DOSE SAMPLING - A TALE OF 2 THIEVES

As a consequence of the United States vs. Barr Laboratories decision, pharmaceutical companies are now compelled to demonstrate the uniformi ty of unit dose samples of final powder blends. This investigation was initiated in response to a previously reported failed attempt to vali date a process for lower strengths of a currently marketed product. Th is process has a long history of providing high-quality commercial tab lets at the higher strength. The failure occurred because the unit dos e samples of the final powder blend were indisputably subpotent. Inter estingly, during the validation effort, 799 tablets of various strengt hs were assayed and exhibited outstanding content uniformity and poten cy. It was hypothesized that this failure was due to sampling bias whi ch occurred when small (unit dose) samples were extracted with a thief from a static powder bed that was 7 orders of magnitude greater in si ze. The purpose of this two-part investigation was to test this hypoth esis. In both of these studies, sieve analyses were conducted on sampl es collected from 100 kg of the final commercial blend. From these dat a the ratio of the coarse to fine fractions was calculated. This ratio is directly proportional to particle size and, for this product, rela ted to the concentration of drug in the sample. Two different thieves (A and B) and a variety of sampling conditions were compared in Study 1 and the results suggest that the coarse-to-fine ratio: (a) decreases with sampling depth, (b) is generally larger for samples extracted wi th thief B than thief A, and (c) is larger for samples collected with a thief that is maintained in the vertical position than one held at a n acute angle. The intent of Study 2, which focused exclusively on thi ef B, was to determine if the pronounced effect of sampling depth on t he coarse-to-fine ratio was due to sampling bias or product segregatio n. The results of Study 2 demonstrated that coarser material was prefe rentially sampled from the top of the bed than from the bottom. These studies indicated that one thief used under different conditions and t wo thieves used under similar conditions can extract samples of differ ent particle size from the same population. This implicates sampling b ias and confirms that a thief is far from an ideal sampling device. We believe that the unit dose sampling requirement is more likely to imp ede the delivery of innovative pharmaceutical products to the marketpl ace than it is to enhance the quality of these products.