-Christophe Cordary

Synthesis of APIs/HAPIs requires mostly several steps, which are either in liquid or in solid phases. One step is the exact interface between both faces: the solid liquid separation. This is a very critical step during the process where the total batch time can be drastically reduced or increased, and where the quality of the product can be strongly influenced. Most of the time this is also a step where the product has already a high added value - and therefore high costs, especially for final steps.
One equipment, which is used more and more to realize this critical process is the Agitated Nutsche Filter Dryer  (so called ANFD). This equipment provides the advantages of combining the mechanical solid /liquid separation phase as well as the thermal drying phase. These two steps are processed in a fully contained way, giving reproducible results and in a fully safe way for both the environment and the product. The Rosenmund product line of the company De Dietrich Process Systems was the finder of this technology and has become over the year the leading brand in this field, especially when it comes to high value product.
 
Planning, Designing and Integrating Complete Engineered System under cGMP and FDA Guidelines
The competence center Rosenmund based in Switzerland is the ideal partner when it comes to ANFD and environment of ANFD. Manufacturing and delivery of the machine is important for Rosenmund. Skilled & dedicated process engineers plant design the equipment for industry applications Based on experience in the field of API and experience of the product, company can optimize the design with regards to the ANFD and also

• All direct ancillary equipments (Heating/cooling skid, vacuum units, filling stations...)
• Containment devices (isolators, filling liners, soft bag containment...)
• Post ANFD system for powder API (mill, powder transfer device, blender, packing station)
• The control system for the all installation and ancillaries mentioned above

All these equipments are designed according to the latest cGMP and FDA guidelines. That way, you are not only technical risk is minimized but this also drops the regulation conformity risk to almost zero level. In the same time the team does not have to manage all the interfaces between the different suppliers and can focus on more critical aspects of the project. This provides an improved delivery time of the equipment, improved time for commissioning and ultimately an optimal time to market the drug!

Decreasing the Batch Time and Humidity in Final Product.
The company has already installed more than 3000 units so far and some of the very first ones are still functional. The design details reflect the experience and account for the unique features of the equipment.
 

• Agitator and Drive Unit
  This is the heart of the equipment. The "S blade" Rosenmund® agitator ensures perfect mixing of the powder, even at very low filing rates (The former Guedu company which belongs to Rosenmund since 1995  started its activities with manufacturing of pure mixers. Rosenmund implemented this know-how in the design of the agitator) This also ensures an optimal heat transfer. This is possible because of the specially machines grooves for heating/cooling media along the shaft and the agitator. The heat transfer is not only a matter of high exchange surfaces but also a matter for the kind of flow for the circulation of the thermal fluid. The combined actions of a very good mixing of the powder with a constant turbulent flow for the thermal fluid allow the  agitator to reach the shortest drying time of the market for ANFD and thus low residual humidity.
  The special way how the shaft is transmitting the torque to the agitator blades offers major advantage even for difficult products.
• Vacuum Dust Filter
  The use of a vacuum pump is mandatory for the contact drying process. Because this kind of pump needs to be protected from solid particles, Rosenmund® integrates dust filters directly on the top of the ANFD. These are designed in a way that these are big enough to allow an optimized use of the vacuum pump capacity and compact enough so that there is no compromise for the nozzles on top of the ANFD required. The uses of filter cartridges (synthetic or metallic) as well as integrated automated choking by N2 and CIP are realized in most of the cases.
• Side Discharge Valve
  This is yet another sensitive component of an ANFD. From a process point of view, the side discharge valve should be able in a fully automated way to discharge all amount of powder without obstructing the falling tube. This must be done also in case of difficult product without losing the tightness of this discharge valve. Rosenmund solves this by using very special metallic sealing seats.
  From the safety point of view and since the plug of this side discharge valve also needs to withstand the process pressure, any kind of risk of "bang opening" or deformation of the drive of the plug must be avoided. Safety is a constant worry and is the main focus of design of  the side discharge valve.

Innovation is the Key Driver
Innovation has always been the main drive for Rosenmund and the company can propose the most technically advanced features to enhance product quality, operator's safety and reduce batch time. Two of the products that are actually booming in the field of API synthesis are 

• Gas Knife
  The safety space between the agitator and the filter media is required to protect the filtration media (synthetic and metallic) from mechanical damages. The main drawback of this is the remaining product, which is impossible to discharge in a traditional mechanical way. Rosenmund has innovated Gas Knife System with a major pharmaceutical company that allows to blow nitrogen through the shaft up to the nozzles welded on one blade of the agitator. This device enables to to mechanically blow the residual product heel up to the side discharge valve. Achievement and efficiency depend on the product. Out of the numerous systems that have already been installed some achieve removal of more than 90 percent of the heel. Machine does not require to be opened for these steps and containment does not break. FDA has validated this system for sterile applications in few cases as required.

Easy Clean
When it comes to sticky powders, the metallic seats of the side discharge valve might lose their tightness with the time and the "open/close" sequences. In order to avoid a delicate opening of the side discharge valve housing (including loss of containment, loss of time, risk of product contamination, risk for the operator...), Rosenmund has developed Easy Clean system. Easy Clean is a special side discharge valve that includes two gloves and additional sight glass. The operator can easily put his hand into the glove (hand hole fitted with a safety switch) and manually clean the dirty metallic seat by checking visually the all operation.

Handling Hazardous Products
Even if the ANFD provides 100 percent containment for the mechanical separation and thermal drying steps, APIs are mostly still very active and/or very toxic in their dried form. Therefore the requirement for a high level of containment is still there for the discharge steps of the API powder out if the ANFD and the following process (milling, blending, filling and packing).
Depending on the Operator Exposure Level (OEL) value that is given by the user, there are different solutions, which might be applicable to reach the requirements. This field of solutions is going from a very simple filling directly in container (via double butterfly valve or liner) up to a more sophisticated globe-box or flexible glove-bag. Rosenmund® can help to define the best suitable solution for applications and design as per cGMP and FDA guidelines. These containment solutions can be developed and integrated directly by Rosenmund including mechanical tests during FAT for the following process steps:

• Product filling in the ANFD
• Product discharge
• Product sampling
• Safe change of items on the ANFD (dust filter cartridges, filter media...)

Mastering the Regulations
Quality of equipment and processes are of utmost importance for the drugs that are exported to the US and European markets.  Another essential point of the installation which are subject to strong and detailed inspection from FDA authorities are all kind of documentation that include user manual to maintenance manual and manufacturer data books.  Rosenmund is the world reference in mastering these aspects of a proper and compliant documentation.  Rosenmund's long experience with all the major pharmaceutical companies as well as the major engineering offices reflects clearly in the quality of this documentation. The company emphasizes on regular training of engineers with the help of organizations like International Society for Pharmaceutical Engineering (ISPE). 
The quality of the Rosenmund documentation is reflected in the following master pieces for a proper FDA conform API manufacturing process:

• Users' manual
• Maintenances' manual
• Manufacturer data book (material certificates, calibration certificates, ATEX certificates...). This gives you a full traceability of the material and components used for manufacturing of the equipment.
• FAT/SAT protocols
• Qualification documents: DQ/IQ/OQ is integral part of the Rosenmund® capabilities. These documents can be used as a great support for the validation of the full installation on site.

The Best Equipment is Nothing Without Best Service
Rosenmund is not only a machine manufacturer but also a solution provider, hence particular care is given to the quality of services during the all life cycle of equipment supplied.  The pilot plant in Liestal (CH) for drying comparison trials as well as the rental fleet for filter/dryers helps Rosenmund team to design together the best equipment for actual purpose.
Company also carries out revamps, upgrade and service contract to upgrade the process to match cGMP / FDA guidelines, Improvement of process performance of existing unit by integrating one of the unique Rosenmund technical features or change the equipment design as per the new process.
With the philosophy of " Think Global and Act Local" Rosenmund has set up in Mumbai with 12 employees that includes 3 service engineers well trained and equipped with knowledge about product lines and dedicated to specific projects.

Conclusion
Manufacturing sterile APIs and/or drugs according to cGMP and FDA guidelines for the export to US and European market is always a challenge linked to high investments for which the return of investment must be as short as possible. Time to market of the drug is therefore of the essence and most of the time each day is crucial. One process step where days and weeks can be easily won or lost are the mechanical separation and drying. A few points are here which can influence this timing and at the end the ROI:

• Reducing the interfaces during the project: this is key to avoid heavy and time costly discussions by coordinating different equipment suppliers. The supplier of one stream like mechanical separation and drying should have the proper engineering capacities and know how to manage all interfaces
• Reducing batch time: this is a key parameter to be retained for the choice of the right partner. A proper heat transfer, mixing, heel removal and CIP are essential there.
• Reactivity for service during and after the project: skilled people should be available within few hours or days. This can be easily achieved with a local setup.
• Professional documentation and traceability, which is mandatory when it comes to regulated markets.
• Experts in the field of processes are required when it comes to equipment optimization, start up and trouble shooting.