Mixing with the experts
The world of cGMP pharmaceutical mixing systems

In the pharmaceutical industry, a
mixer is not just a mixer. This
introduction emphasizes the importance of choosing a vendor who
understands pharmaceutical manufacturing standards and cleaning
methods.

Amixer can be seen as a vessel in which mixing takes places, and in many process plants it’s as simple as that. In applications such as pharmaceuticals, however, the mixing vessel is surrounded by auxiliary items that are as essential to the process as the vessel itself. Also special to the pharmaceutical industry is the requirement to record and validate data during the mixing process. These special requirements mean that when you deal with a mixer manufacturer, you expect
people who deal with pharmaceuticals as part of their daily business. That is why Hosokawa Micron has founded a special Pharma Team bringing together all the different disciplines, from sales to project management, engineering, manufacturing and service. Whether collaborating with pharmaceutical end-users or engineering companies, the Pharma Team offers unique capabilities.
In the last few years, buyers of mixing equipment have become more demanding in the process guarantees they expect from their suppliers. As well as mixing performance, production cycle time, cleaning time, cross-contamination levels and operator exposure levels have all become important criteria when choosing a mixer.
Turnkey pharmaceuticalmixing systems
Validation and project management requirements have also changed. Mixer vendors need to understand the latest FDA requirements for documentation, validation protocols, control validation, batch identification and electronic history registration—and for that they need good people and good training. Hosokawa Micron understands these trends, and since the late 1990s the company has supplied turnkey pharmaceutical mixing systems including:
-Raw materials charging: containment technologies such as isolators and downflow booths are used when charging mixers or dryers to protect the product, the environment and the operator from active substances.
-Control systems: Hosokawa Micron has handled complex projects requiring implementation of the latest FDA requirements like GAMP 4 and 21 CFR 11. Compliance can be achieved in several ways; one is to use industrial PCs with special software such as Intouch, in combination with a main control cabinet equipped with a PLC. Another solution is to use I/O modules and a suitable Scada system for the whole plant. The first part of the job is to work with the customer to design and source a suitable control and data acquisition system. This followed by site installation, commissioning and functional testing (SAT, IQ and OQ). The validation paperwork is a big part of the job, and here Hosokawa Micron can be of great benefit to customers by relieving them of much of this workload.
-Cleaning-in-place systems: customer’s requirements for CIP have also changed. A few years ago, CIP was seen as the business of the operating company, not the equipment vendor. Now, customers often ask vendors to supply cleaning solutions as well as mechanical devices like cleaning balls and nozzles.
Depending on the customer’s facilities, there are several options for cleaning. If the existing CIP network has adequate capacity (both volume and pressure), all the utilities can be supplied directly from the network. If the network does not have enough capacity to meet instantaneous demands, or an intermediate step such as heating or adding cleaning materials is required, then one or more break tanks can be added. One break tank is usually needed for pre-washing and recirculation, and another tank to store the final rinse liquid.
Cleaning is either mechanical, with direct and indirect liquid impact, or chemical, with detergent solutions or solvents. Either method can be carried out as a single pass or by recirculation through a break tank, or in some cases through the mixer itself. To facilitate recirculation and draining, Hosokawa Micron has developed a special conical discharge valve with a hinged drain.

To identify the bestCIP solution
Customer requests for cleaning performance guarantees led Hosokawa Micron to invest in CIP test capabilities in the existing test station. This helps identify the best CIP solution for each application, and once the tests are complete, the company can supply guarantees on cleaning time and residual contamination. The test station at Doetinchem, the Netherlands, with CIP possibilities has various Hosokawa Micron mixers and dryers, the latter in sizes of 300 l and 800 l. The cleaning equipment includes the revolutionary Cyberjet robotic CIP system and a range of cleaning solutions.
Cleaning tests are backed up by laboratory analysis to ensure that the cleaning process meets the customer’s requirements without being over-designed. The plant can test the effectiveness of dry gas cleaning as a way to recover valuable product before the wet cleaning cycle, and can check the performance of metallic filters with the product in question.
To save time and eliminate residual
moisture, Hosokawa Micron can supply drying skids. These are used to dry the vessel by introducing hot gas through the drain point. The drying skid can usually be mounted in a utilities area.
Validation and documentation is one of the most critical aspects in avoiding time overruns in projects. Experience, good project management skills and detailed discussion with the customer are the keys to getting it right. The GAMP 4 guidelines and the customer’s Validation Master Plan are the starting points when planning the documentation. The most important documents are:
-functional specification and QPP;
-mechanical drawings and equipment datasheets;
-PI&Ds and the PI&D list;
-graphtec, software and hardware specification;
-manufacturing reports;
-FAT protocols for static and dynamic
testing;
-SAT protocols for static and dynamic testing;
-installation qualification protocols; and
-operation qualification protocols.
In the last few years Hosokawa Micron has supplied the secondary pharmaceutical industry with several complete mixing systems based on the renowned Vrieco Nauta screw cone mixer to supply tablet presses. Large batches of wet granulated powders from fluidized-bed granulators, or dry granulated powders from compactors, are mixed with additives and lubricants before being fed to the tablet presses. These pharmaceutical mixing systems are available in sizes from 5l up to more than 10 m3.