Batch manufacturing is inherently difficult due to the stop, rebuild, and restart nature of the processes involved. Toss in real, potentially lethal, risks due to process inconsistencies, and its easy to see why the pharma manufacturing space is riddled with expensive and time-consuming QA/QC testing. With little or no on-line instrumentation to guide them, pharmaceutical manufacturing unit operators rely on SOP recipes to tell them how to process the step and the QA/QC lab to tell them if theyve done it right.
The FDAs Process Analytical Technology (PAT) initiative is an enabling directive to move the manufacturing end of the pharmaceutical business into a more on-line analytics model as typified by todays modern hydrocarbon processing or semiconductor manufacturing facility. The availability of near real-time measurements allows the operator to streamline the process or correct processing errors as they occur. The logical result of the use of on-line analytics is to automate the process itself by using collected data from any number of sources to model a good day in order to be able to predict, or fix, a day that has gone, or is rapidly going, bad. In this case, while the QA/QC lab may be necessary to do spot-checking from batch to batch, it will be the information coming from the on-line instrumentation that will trigger the release of the product or initiate the next step in the process.
While the ultimate end game hasnt yet been reached in pharmaceutical manufacturing, there is no doubt that the PAT initiative has spurred the use of on-line analytics in the sector. Even the tentative use of these instruments will begin to reveal the inner workings of the various unit operations with previously unseen levels of detail.
Bulk Product Drying
One of the, if not the, most time consuming of any of the unit operations is the bulk drying of either intermediates or APIs. There are generally large amounts of solvent-laden product involved and these solvents must be removed to a certain level prior to moving the product to the next step in the operation.
There are any number of dryer configurations available to accomplish the task. Vacuum dryers working down to 10 mbar absolute are very common as are combination dryers that use both pressure and vacuum to facilitate the drying process. The dryers can be equipped with various mechanical enhancements (stirring paddles; centrifuging action) designed to assist the process. Inert gas purging may also be performed to provide a measure of explosive protection or to keep filters and pumping paths cleared of product.
Without the benefit of on-line analytical data, this important production step has historically been done by using a time-temperature-pressure recipe with periodic QA/QC testing to chart the progress of the process. Of course there are variations to this recipe depending on the site and the product, but the path to a dry product has traditionally been a fairly simple affair. Simple, perhaps, because of the perceived simplicity of the process itself.
But what if the simple approach leads to a failure in the process that isnt as simple as the product not being dry enough but a failure that leads to the questioning of the quality of the drying process itself?
A Case Study
Process mass spectrometry has proven to be a remarkably effective way to monitor and streamline the drying process. With multiple point sampling, construction geared towards the industrial environment, and very high sensitivity when working with common pharmaceutical solvents, process MS can cut drying times by 50% or more, and can provide a wealth of information abut the drying process itself.
While the majority of these instruments are being used in API production and R&D/Pilot facilities, we were recently approached by Pfizer, Inc., which needed to investigate a possible drying problem that was leading to a failure of the product (a coated pill) during dissolution testing. While the product was in fact dry (with acetone as the primary residual solvent) it was beginning to appear to the group that not only was dry an important parameter, but how it got that way was equally as important.
Fig 1. Front view of walk-in tray dryers
In this case, the dryer in question was a tray type with an internal volume of roughly 480 cubic feet and there were three such dryers in operation (Figure 1). Each dryer could accommodate two carts carrying the pills on perforated trays. The carts were a very tight fit in the dryer leaving little space on either side of the cart.
The dryers were operated at slightly above atmospheric pressure and were of the flow-through type. Air from an outside handler/conditioner entered (~1000 cfm) from the top of the dryer and was pushed through a perforated side wall. From this wall, the heated air flowed over and through the trays on the cart and exited through another perforated wall on the opposite side of the dryer.
While these dryers had been characterized with regard to temperature distribution, it was felt that there was an uneven drying taking place due to possible stratification of the airflow as it moved through the trays. An Ametek Promaxion process mass spectrometer was used to determine whether there was any stratification taking place and, furthermore, whether this stratification was involved in the finished product non-uniformities.
Each dryer was equipped with eight sampling pointsone each in the dryer inlet and exhaust plenums, and six points in the dryer volume separated equidistantly from top to bottom and front to back in the dryer (Figure 2).The sample tubes were 1/8 SS and were routed behind the perforated panels and up and out through the plenums as part of a multiple tube heated bundle that was maintained at 100°C to guarantee solvent mobility (Figure 2). This sampling arrangement provided a spatially differentiated look at each dryer along with totalized dryer input and output solvent levels by using the inlet and outlet sample points.