Issue link: https://www.e-digitaleditions.com/i/377863
The instrument also allows you to measure, using a hand- held force meter (photo), the detachment force (punch take-off force). That information is especially useful when studying lubrication processes. The benchtop unit can also measure tablet tensile strength. By quickly testing a wide range of formulations—using small amounts of material—you can gain the insight Woods sought more than a century ago: "[T]he proper manipulation of the medicinal ingredients, and the choice, proportioning, and manipulation of excipients best suited to use with the different formulas require a considerable degree of skill, as well as an intimate knowl- edge of the physical and chemical properties of the ingre- dients" [6]. That summarizes the value of using a properly instrumented system: You gain the knowledge required in a consistent way, enabling you to formulate and manufac- ture good tablets. Simulation and production equivalence Tabletting simulation also enables you to understand what occurs in a production environment. Indeed our work has shown that data from our benchtop tablet press simulate data generated on a production tablet press operating under actual production conditions. Specifically, we compared how two products—one a wet granulation and one a direct-compression granulation— performed on a Fette 2090 production tablet press and on our benchtop tablet press. The data showed an equiva- lence, which illustrated an important but seldom recog- nized fact: Over a wide range of tablet sizes and com- paction pressures, the tensile fracture stress of a tablet is independent of tablet size and is determined solely by the compaction pressure. Indeed, the study showed an equivalence between an 800-milligram capsule-shaped tablet and a flat-faced circu- lar 100-milligram tablet 6 millimeters in diameter. The ten- sile fracture stresses of the capsule-shaped tablets—tested in longitudinal compression—were calculated using an analysis [7] that can determine the tensile fracture stress of tablets of almost any shape. We subsequently extended that analytic method to apply to cylindrical tablets as small as 2 millimeters in diameter. In so doing, we learned that tensile fracture stress is size-independent in tablet diame- ters of 2 to 12 millimeters, at least for the materials we have tested to date, including lactose, startch 1500, micro- crystalline cellulose, and many other proprietary formula- tions at pressures as high as 200 MPa. Improving process development The FDA's QbD initiative correctly states that it is safer, more efficient, and more cost-effective to get a for- mulation right the first time and monitor its performance than it is to troubleshoot it or discard defective or poorly performing formulations. This is especially true once for- mulations are at an advanced stage. If not caught early, the problems only compound once poor formulations reach the manufacturing site. To prevent problems, your formulation development process should include these steps: Identify your company's preferred manufacturing method. Seldom do companies decide which process they would prefer to use, but that should be done early in the developmental stage. After all, manufacturing costs increase significantly as a project moves from direct com- pression to dry granulation and, finally, to wet granula- tion. Unfortunately, the ability of the process to with- stand variations in API or excipient properties follows the same order. That is, changes to direct-compression processes are most susceptible to upsets; dry-granulated formulations are a little more robust; and wet granulations cope with wide variation in properties. Find the right bal- ance between the cost and robustness of your process and formulation. Evaluate the process and formulation variables. This is now a regulatory expectation (and essential for an ANDA submission), but many companies still struggle with it. This is due partly to the difficulty of evaluating processed materials prepared on a small scale and partly to our lack of understanding of the key elements that underpin formulation science. For example, if a powder blend suffers from poor content uniformity, we cannot predict the effect on blend quality when we replace one excipient with another that is either more or less free flowing. In some cases, using a more free-flowing material will improve the product; other times it makes powder flow worse. Develop a manufacturing control strategy. Document all development work and all prior knowledge about the formulation and process during development and manu- facturing. No formulation is developed in a vacuum, and most companies have volumes of data about their manu- facturing processes. Few, however, use these data to guide product development toward processes that will be both robust and low cost. It would be very useful, for example, to receive management updates about the performance of dry granulation processes (as a group) versus wet granula- tion processes. Which are in better control? Use that data to guide your selection of processes for future products. 12 September 2014 Tablets & Capsules Using a handheld gauge to measure detachment (take-off) force on a benchtop tablet press and material tester