Directly compressing a dry blend of pharmaceutical ingredients into tablets has the benefits of requiring minimal powder handling and reducing processing costs. Maintaining content uniformity of the dry blend, especially for low-dose therapeutics, throughout the process poses significant challenges. But personnel can modify the manufacturing equipment and process to help ensure content uniformity of low-dose tablets.
The authors produced a low-dosage tablet (i.e., one containing < 2% active ingredient) using a direct-compression process. The process included screening the drug along with the excipients, blending the ingredients in a V-blender, transferring the blend from the V-blender to an intermediate bin, and compressing the tablets using a 51-station D-Hata tablet press (Elizabeth-Hata International, North Huntingdon, PA).
Based on the process, an initial demonstration batch was manufactured at 787.5-kg scale. The proprietary composition comprised a low-dose drug, a carbonate buffer system, and coprocessed sugars as filler. Additional common excipients were included to aid in the tableting process. Given the low dose of the active ingredient, samples were collected and analyzed for blend uniformity (BU) and content uniformity (CU) per FDA's draft guidance for stratified in-process dosage-unit sampling (1, 2). The uniformity data were collected during various transfer steps and during compression. For the first demonstration batch, the BU data met the specification, but the CU results did not meet the specification: a location average exceeded 110% of the label-claim limit at the end of compressionTo understand the lack of CU during the tableting process, the authors conducted several tests at the bench scale to elucidate the segregation mechanism and flow properties of the formulation blend. The authors hypothesized that fluidization during the transfer of the blend from the blender to the intermediate bin, and subsequently from the bin to the tablet press, could result in segregation of the active in the formulation.
Based upon the test results described in this article, corrective process and equipment modifications were implemented for a second demonstration batch. These modifications successfully reduced the segregation during the blender-to-press transfer steps, so that the CU data passed FDA's draft guidance for the second demonstration batch (1). These modifications were incorporated into the commercial process and successfully validated. The details of the root-cause analysis and process and equipment modifications are discussed in the following sections.
Root-cause assessment and confirmation
A root-cause analysis of the CU variation for the first demonstration batch was conducted using established troubleshooting methods (3). The BU data collected from the blender and bin had minimal variation and was within specification as described in FDA's guidance. The BU samples were obtained using a sampling thief from 10 locations within the V-blender and 12 locations within the bin. These samples weighed 1–2 times as much as the tablet. On the other hand, the CU data had higher variation (RSD = 3.2%, n = 60 samples) due to a distinct upward trend at the end of compression (average = 112% label claim, n = 3 samples).
During an analysis of variance of the CU data, the authors observed that more than 90% of the variation occurred between locations, as opposed to a variation of individuals at a single location. Samples collected from the intermediate bin also exhibited higher variation (RSD = 2%, n = 12 samples) than the blender samples. Based on these results, the authors hypothesized that segregation during the postblending steps (i.e., the blender-to-bin or bin-to-press transfer steps), in combination with the flow pattern from the intermediate bin, resulted in the upward CU trending at the end of compression. In particular, fluidization with or without dusting segregation during the transfer steps can result in a concentration of active-rich fines at the periphery or top of the bin. When the segregated blend discharged in funnel flow (i.e., a first-in-last-out flow pattern), the drug-rich blend would be present in the tablets obtained toward the end of compression. The authors discussed changes in material flow patterns (i.e., mass flow versus funnel flow) and the effect they can have on CU trending in a previous article (4).