Issue link: http://www.e-digitaleditions.com/i/769284
The high-shear granulation process comprises three basic phases: pre-mixing, wet massing, and drying. In most cases, drying is performed on trays in an oven or fluidized-bed processor. Most research has focused on the wet massing portion of the process, and correctly so because the overall result can change quickly if it's not well controlled. To gain better process understanding, pharmaceutical manufacturers use different probes, cameras, calculations, and theories. A common approach to determining the end- point of the wet massing phase is to track how much resis- tance the impeller encounters. Typically, this involves moni- toring the increase in the amperage drawn or in the hydraulic force required. These kind of techniques are use- ful, but they don't explain or prevent two perplexing process results: 1) After the process endpoint is said to be reached, a large portion of the granulating liquid may remain, and 2) the process endpoint is not achieved even after making incremental additions of the granulating liquid. In fact, both situations can occur, even when the same API, formula, vendor lot, and process vessel are used in a multiple-batch campaign. Some manufacturers accommo- date these unexplained results by specifying an acceptable range of endpoints. Sometimes that works, and a final value within that range is completely predictive of the granulation's performance on the tablet press. In other cases, the outcome is less certain and that unpredictability has led some manufacturers to abandon wet granulation in favor of roller compaction or other alternatives. Over the years, I've heard a lot of grumbling about high-shear granulation. Do the following complaints sound familiar? Maybe you've even made them yourself: • With some products I achieve the desired amp/power reading before I use all of the granulating solution. • With some products I never achieve the desired amp/power reading no matter how much solution I add. • With some products, the amp/power reading never reg- isters because it's so small. • I see different results on the tablet press even when I use the same granulation procedure. In short, progress has been slow and uneven and con- trolling the process remains something of an art. As a result, some pharmaceutical companies are moving away from relying on probes and fixed liquid additions as a means to reach the endpoint. In fact, some of the generic companies I work with are abandoning the resistance- based model in favor of adding restrictive instructions to the master batch record to give operators more say in the process. While that may sound potentially arbitrary, there is science that supports the practice. Pre-mixing From my review of the research, it appears that many studies take the pre-mixing cycle for granted. In fact, I haven't seen any articles or studies that focus on it or give it much scrutiny. Yet in the manufacturing setting, many operators understand its importance quite well. They've noticed that in some cases—in granulators that use a top- or bottom-driven impeller—the dry powder only gets partially blended and can splatter across the sides and lid of the process vessel. In other cases, the formulation leaves no residue. If the powder splatters, it should be removed from the walls and lid and reintroduced into the main bed or the wet massing phase will suffer. In operations where scraping is frequent, some manufacturers made two changes: 1) Adding a separate pre-blending step before introducing the powder into the granulator, and 2) instructing opera- tors to stop the process and scrape any splattered powder and return it to the product bed before starting the wet massing phase (photos). If there's no separate pre-blending step, I recommend operators set the impeller at low speed in addition to scraping off the dry powder. Physical standardization The many problems that arise with high-shear granula- tion have led some firms to conclude that probes are an unreliable way to track and quantify the process and to determine the endpoint. Some generic manufacturers have abandoned probes altogether and embraced what I call "physical standardization" because, in some cases, it gives more reproducible results on the manufacturing floor and hence a more validation-friendly process. The concept of physical standardization grew from observing—at multiple sites—two behaviors of granula- tions processed in top- and bottom-driven high-shear granulators, but especially in bottom-driven machines. The first, as noted above, is that powder often splatters during pre-mixing. (It can also happen during wet massing.) The second is the failure to standardize the quantity of granu- lating solution to the length of the mixing period after the solution is added. With most formulations and in most top- and bottom- driven granulators, powder splattering is unavoidable. The splattering pattern, however, varies and is a function of the quantity of powder in the vessel, the nature and quantity of the API, the impeller type, the vessel configu- ration, and the impeller speed. 34 January 2017 Tablets & Capsules If powder splatters on the walls and lid during the pre-mixing phase, operators should be allowed to reintroduce it powder into the main bed before starting the wet massing phase. Don't rely solely on amperage readings or fixed rates of liquid addition to determine a granulation's endpoint.