How to make tablets from potent APIs
Suppliers not specialists in the field often try to promote ’their containment equipment’ with claims such as “3 µg/m³”, “better than 1µg” or even worse “OEL 2 µg/m³”. All of these claims are meant to describe the containment performance of equipment such as extraction booths or containment valves. While the last claim obviously is wrong (OEL is a product-related number, it only has the same unit as the containment performance of a piece of equipment), the problem of the other claims is that the test conditions are not defined. This makes it extremely difficult to compare figures obtained by using different test materials, different samplers, different sampler positions or different analytical procedures.
After inventing the split valve technology, GEA Buck Valve again took the lead to form (under the umbrella of ISPE) an expert working group, consisting of experts from pharma companies, engineering companies and containment equipment suppliers. This group developed a guideline (see PROCESS plus) in which all of the variants discussed above are defined. The accepted test procedure uses Lactose of a defined grade (other substances are possible), uses the equipment in a defined environment (humidity, temperature, number of air changes), and places the defined samplers in specific positions. The test includes performing the intended task, and collecting air (via the filters of the samplers) for 15 minutes. Analyzing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment. As the average of 15 minutes is taken, this performance is called STTWA (Short Term Time Weighted Average). It is important to note that the total amount of powder escaping is measured. If dealing with potent APIs, often only a small percentage of a powder mixture is active, while the rest is excipient. The LTTWA (Long Term Weighted Average) is defined as the containment performance over a longer period of time, for example one shift of 8 h. Fig. 1 shows two different scenarios.
It is important to distinguish if there is an intermittent exposure as shown on the left side generated e.g. by the docking of a container with raw materials to a fluid bed with subsequent operation of the fluid bed, or a permanent exposure as shown on the right side e.g. by a tablet press which is not totally tight.
The most important numbers to describe the exposure of the operator are ROI (Real Operator Intake) and RDI (Real Daily Intake). These numbers describe the amount of API which gets into the body of the operator while being for a certain period of time in an area with a certain airborne drug concentration. If we know the breathing rate of the operator, and the dust concentration in the room, then the drug uptake can be calculated, for example shown in Fig. 2.
If the actual RDI is less than the drug specific ADE, the situation is fine. If the RDI exceeds the ADE, measures must be taken to improve the situation. In our example the most effective way would be to upgrade the granulator by a loading/unloading system with a better containment performance.
Conclusion of fundamentals
This visualisation helps the concept to be easily understood. For real situations of course, a detailed risk analysis needs to be done in order to judge the containment performance of an existing installation, or to select the appropriate equipment for an upgrade of an existing facility, or the design of a new facility. GEA Pharma Systems not only offers the largest variety of hardware solutions for contained materials transfers, but also unrivalled experience in identifying the most appropriate solution, based on a containment risk analysis.