Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

RTD-based material tracking in a fully-continuous dry granulation tableting line.

Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control strategy. In this work the residence time distributions (RTD) of single unit operations (blender, roller compactor and tablet press) of a continuous dry granulation tableting line were captured with NIR based methods at selected mass flow rates to create training data. RTD models for continuous operated unit operations and the entire line were developed based on transfer functions. For semi-continuously operated bucket conveyor and pneumatic transport an assumption based the operation frequency was used. For validation of the parametrized process model, a pre-defined API step change and its propagation through the manufacturing line was computed and compared to multi-scale experimental runs conducted with the fully assembled continuous operated manufacturing line. This novel approach showed a very good prediction power at the selected mass flow rates for a complete continuous dry granulation line. Furthermore, it shows and proves the capabilities of process simulation as a tool to support development and control of pharmaceutical manufacturing processes.

Continuous monitoring of API content, API distribution and crushing strength after tableting via near-infrared chemical imaging.

Near-infrared chemical imaging (NIR-CI) with high-speed cameras based on the push-broom acquisition principle is a rapidly-evolving and can be used for a variety of purposes, from classification (and sorting) of products to mapping spatial distribution of materials. The present study examined if NIR-CI is suitable for tablet manufacturing. To that end, the tablets were introduced into the CI system via a flat belt conveyor. A formulation, which consisted of 4wt.%-6wt.% caffeine, 5wt.% crospovidone as a disintegrant, 88wt.%-90wt.% lactose as a filler and 1wt.% magnesium stearate as a lubricator, was tableted at compression forces ranging from 5kN to 30kN. The intra- and inter-tablet homogeneity of caffeine and the tablet's hardness were analyzed via NIR-CI. For the homogeneity evaluation, two methods were applied: standard deviation (SD) and distributional homogeneity index (DHI). The results showed that the SD of caffeine in a single tablet increased with an increase in the caffeine content. This was attributed to natural variations in a binary mixture of caffeine and excipients. Overall, the chosen NIR-CI setup has strong potential to be transferred to the production scale to monitor all tablets in a production stream.

Economies of scope in physicians' work: the performance of multiple surgery.

While the fees for the large majority of physicians' services in the new Medicare Fee Schedule (MFS) are derived directly from studies of the resource costs involved, payments for one class of procedures, multiple surgery, are based instead on existing policies and conventions. Using surveys of physicians, we measured the work and time involved in performing 146 multiple surgeries. We found economies of scope exist in performing these services, particularly during the preoperative and postoperative periods. We also found some differences in economies across procedures. Based on our findings, we propose payment policies for multiple surgery.

The resource-based relative value scale: methods, results and impacts on urology.

Increased concern for rising health care costs in the United States has led to the passage of legislation to reform physician payment for Medicare services based on resource inputs. In January 1992 the Health Care Financing Administration began implementing the new law, which replaces the existing Medicare system of physician payment with a fee schedule based on the resource-based relative value scale (RBRVS). We summarize the methods and data used to derive the RBRVS for urology. A national random sample of 115 practicing urologists completed structured telephone surveys to provide ratings of physician time and work required before, during and after most frequently performed urological services. Subsequent survey cycles with urologists provided further refinement. Urologists then participated in a cross-specialty physician panel to link services from all specialties onto a common scale. This common scale was adjusted for geographic differences in practice overhead costs and malpractice insurance premiums. A monetary conversion factor, determined by the Health Care Financing Administration, was then applied to convert the RBRVS into a Medicare fee schedule. The merits and demerits of the scientific process used to develop and maintain the relative value scale are extensive. While statistically valid and reproducible, the study results have been altered in the political arena. The results and impacts of the new Medicare payment system on urology will be significant, although it is not yet clear how urological practice will be affected. Although faring better than most surgical specialties, urologists stand to lose approximately 8% of their Medicare income when the new fee schedule is fully implemented. There will be relative gains for evaluation and management services and losses for most invasive procedures.