The overall materials handling concept for potent APIs is the controlling factor in determining the containment performance of the entire installation. There are two basic choices: stainless steel or disposable systems.
Selecting Appropriate Production Technology
Part 1 of this article (Containment Fundamentals) explained that more than half of all new APIs are classified as potent (OEL <10 μg/m3), and that health and safety authorities around the world are strengthening protection for operators who work with these substances. The article showed why effective containment is always better than personal protective equipment or systems that rely on human behaviour, and showed how to calculate the degree of containment required based on occupational exposure limits (OELs), acceptable daily intakes (ADIs) and cross-contamination limits.
In this second article we look at how to choose containment solutions from the huge variety on the market. A typical tablet process has the following steps:
- dispensing of API and excipients
- milling of raw materials to destroy lumps
- (wet) granulation with subsequent drying
- dry milling
- addition of lubricants
- tablet compression
- primary and secondary packing.
IBCs (intermediate bulk containers) with split butterfly valves are the material handling systems most commonly used for potent APIs. Split butterfly valves offer a proven solution for make-and-break connections. They are available in different performance levels.
In this case the entire material required for a batch is loaded into an IBC in the dispensing area, typically under a laminar-flow booth. The IBC is moved into the granulation area where it is docked using a split butterfly valve connection to, say, a discharge station. The raw material is then loaded into the granulator by either gravity (if the room height allows) or a vacuum conveyor, with a mill to remove lumps in between.
If a disposable solution is preferred, one answer is the Hicoflex® flexible container system from GEA. Excipients are handled in a conventional container, while the API is weighed inside a glove box and then transferred via a funnel into a Hicoflex® bag below. Both containers are connected via an integrated mill to the granulator inlet.
Granulator and Tablet Press
Various options exist for the granulation stage, but the use of potent APIs restricts the choice somewhat. Potent APIs generally mean that only a small percentage of the formulation is API, and such recipes are not well suited to dry methods such as roller compaction; the machines are difficult to build in a contained way, and there are often problems achieving an even distribution of the API. As a result, wet granulation is preferred. There are four main options:
- an integrated line consisting of a high-shear granulator and a fluid bed
- fluid bed spray granulator
- continuous granulation and drying
- single-pot processing.
The advantage of option 1 is that it allows the most efficient granulator to be combined with the most efficient dryer to achieve high throughput. High-shear granulation also avoids any issues with material separation, which can be challenging when micronized APIs are used. Another advantage is the robustness of the granulation process that provides, for example, the ability to compensate for fluctuations in raw material quality by adjusting the process parameters.
A downside is the fact that this configuration typically involves a relatively long downtime during product changeover. It also requires a high-quality granulator. Systems with good impellers, for example, ensure rapid and even distribution of the granulation liquid. This avoids subsequent problems with uneven drying and extended time needed to mill the granules after drying.
Fluid bed spray granulation (option 2) is a single-pot operation, which is a huge advantage when handling potent substances. This process also creates material with high inter-granular porosity and excellent compression behaviour. Using the FlexStream™ system developed by GEA, granules also show excellent flow properties, ensuring homogenous filling of the dies during compression. For cleaning, the filters can be wetted down and taken out with minimal risk of contaminating operators or the environment. The remaining part of the processor can be cleaned-in-place.
Continuous lines such as GEA’s ConsiGma™ (option 3) offer a good alternative to conventional batch systems. The only potential problems are, first, that most existing recipes have been developed for batch machines and, second, that automatic cleaning for existing continuous granulation and drying systems is not yet a proven technology. Connected continuous systems do offer significant advantages, however, so it is a good idea to watch for future developments. The ideal solution for the granulation of potent API is offered by the single pot (option 4). This combines the process advantages of a high-shear granulator with minimal surface area and a built-in opportunity for CIP to provide extremely fast changeover.
After granulation, the outer phase needs to be added. This is easiest if the dry granules are discharged via an integrated dry mill into an IBC. After the addition of the outer phase, a homogenous mix is achieved by tumbling the IBC in a container blender. This IBC can also be used to feed the tablet press. For the compression of potent materials, GEA’s MODUL™ range of tablet presses offers an unbeaten solution.