Part 2: Selection of appropriate Production Technology

Typical batch process tableting line

• Dispensing of API and Excipients
• Milling of Raw materials in order to destroy lumps
• (Wet) Granulation with subsequent Drying
• Dry Milling
• Addition of Lubricants
• Tablet Compression
• Coating
• Primary and secondary packing

The selection of the overall material handling system for potent APIs is of paramount importance as it determines more than any other aspects the containment performance of the entire installation. There are fundamentally two choices: systems based on stainless steel or disposable systems.

IBCs (Intermediate Bulk Containers) with 'split' butterfly valves are the most commonly used material handling systems for dealing with potent APIs: the entire material required for a batch is loaded, e.g. under a laminar flow booth, into the IBC in the dispensing area. This IBC is then moved into the granulation area where it is docked using a 'split' butterfly valve connection to e.g. a discharge station. The raw material is loaded either by gravity (if the room height allows) or via vacuum conveying into the granulator. A mill for breaking lumps should be integrated in between.

Split Butterfly Valves
Split butterfly valves offer a proven solution for make and break connections. They are available in different performance levels. An overview can be found here.

As a disposable solution Hicoflex® the excipients to be handled in a conventional way, can be used. The API can be weighed inside a glovebox and, via a funnel, be transferred into a Hicoflex™ bag below. Afterwards both containers are connected via an integrated mill to the granulator infeed.

Granulation
For granulation various options exist (for more information please follow the link to comparison paper). If potent APIs are used typically only a small percentage of the formulation is API. These low dose recipes are not well suited for dry methods, such as roller compaction, as first these machines are very difficult to build in a contained way and there are quite often problems achieving an even distribution of the API. Therefore wet granulation methods should be preferred.

Here there are four main options:

1. Integrated line consisting of a high shear granulator and a fluid bed
2. Fluid bed spray granulator
3. Continuous granulation and drying
4. Single Pot processing

The advantage of option 1 is to combine the most efficient granulator with the most efficient dryer to achieve high throughput can be realized. Additionally the high shear granulation process avoids any issues with material separation which can be challenging when micronized APIs are used. Another advantage is the robustness of the granulation process which allows, for example, the opportunity of compensating for fluctuations in raw material quality by adjusting the process parameters. The downside of course is the configuration of the equipment which, during product changeover will demand a longer downtime than other. This option also requires the use of a high quality, high-shear granulator. For example systems with good impellers ensure a fast and even distribution of the granulation liquid. This avoids subsequent problems with uneven drying and extended  time needed for the milling of the granules after drying.

Fluid Bed spray granulation is a single pot operation which is a huge advantage when handling potent substances. The process also creates material with high inter-granular porosity that demonstrates excellent compression behavior. Using the FlexStream™ system developed by GEA Pharma Systems, granules also show excellent flow properties that are most important for a homogenious filling of the dies during compression. For cleaning the filters can be wetted down and taken out with minimal risk of contaminating operators or environment. The remaining part of the processor can be cleaned in place.

Continuous lines such as GEA’s Consigma™ offer a good alternative to conventional batch systems. The only potentially problems are: 1) that the majority of existing recipes have been developed for batch machines, and;  that for the existing continuous systems an automatic cleaning system is not yet proven . Continuous systems do, however, offer significant advantages so these should be closely watched for future developments.

The ideal solution for the granulation of potent API is offered by the Single Pot Processor. It combines the process advantages of a high-shear granulator with a minimal surface area and the built-in possibility of cleaning in place to offer an extremely fast change-over.

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 homogeneous mix is achieved by tumbling the IBC in a container blender. This IBC can also be used to feed the tablet press.

Tablet Compression
When dealing with highly potent substances, compression is probably the most challenging stage of the tablet manufacturing process.

The main reasons are:

• The complex mechanical design and construction of the inside of a tablet press.
• The continuous flow of materials into and out of the press.
• The need to clean a very complex system in case of product change-over, including upstream and downstream equipment.
• The multiple interfaces between the tablet press and its environment (air inlet, tablet outlet, powder inlet, dust extraction), each requiring a contained interconnection.
• The need for frequent tablet sampling for IPC – either manually or automatically.

For compression of potent materials GEA’s MODUL™ tablet press offers an unbeaten solution. The key feature of the MODUL™ concept is the Exchangeable Compression Module (ECM). The ECM is a completely sealed box; it contains all product-contact parts and is easy to remove from the press.

Case Studies
Over recent years several companies in India have used the experience and technical excellence of GEA Pharma Systems when installing containment systems for highly potent compounds.

These include:

Zydus Cadila - Oncology solid dosage formulations

Single Pot Processor - UltimaPro™ 75 & UP 10 (for R&D)

Material Handling Solution: includes IBCs with Buck® MC 100 valve, Vibroflow™ & blending prism, Hicoflex® for discharging API from Isolator & charging into Single Pot Processor, IBC filling station at discharge of Single Pot Processor, Post Hoist Blender and Buck® MC Valve on Courtoy™ Tablet compression, IBC wash station, WIP drain frame.

Tablet compression machine MODUL™ P with HC-ECM

Conclusion
The design of a line able to handle potent APIs in a safe way requires an in depth understanding of the required level of protection. Here the specifics of the API, the dilution with excipients, the containment performance of the equipment and the frequency of operation are the key parameters which are linked by complex interrelations.