How Active Freeze Drying simplifies validation for pharmaceutical companies

Validation of their testing and manufacturing activities is a major challenge for pharmaceutical manufacturers, and the freeze drying process is no exception. Hosokawa Micron B.V. has developed a unique Active Freeze Drying technique that makes validation of pharmaceutical ingredients easier, faster and more cost effective by producing fully homogeneous batches of sterile material. André Hermsen, Manager Team Pharma at Hosokawa Micron, explains more.

"As part of my job, I regularly attend freeze drying or 'lyophilization' industry events around the world, and the topic of validation is always a key talking point," explains André Hermsen. He is Manager Team Pharma at Hosokawa Micron B.V., a powder processing equipment specialist based in Doetinchem, the Netherlands. "In order to export their products, manufacturers of active pharmaceutical ingredients (APIs) have to comply with lots of very strict standards, such as EMA, FDA, cGMP and GAMP. Therefore, they are continuously looking for ways to document and demonstrate that their testing and production activities consistently produce the expected results."

Single, closed-vessel system

In the traditional tray/shelf-type freeze-drying approach which is still common in the industry today, the material is frozen in the individual vials on the plate. "This makes it very difficult for the manufacturer to guarantee that all those vials have undergone the exact same process and have been exposed to the same temperature, the same pressure and so on. It usually involves lots of temperature probes and time-consuming measurements," he continues. "But in our Active Freeze Drying technology, the material is frozen and dried aseptically in a single, closed vessel. In effect, it produces 'sterile bulk API' – although in this case 'bulk' can mean as little as a few hundred grams of product. This makes it much easier to monitor, confirm and demonstrate that the product quality of the complete batch is 100% homogeneous."

Active Freeze Drying process

Hosokawa Micron's Active Freeze Drying (AFD) system is capable of drying solutions, dispersions, pastes and wet solids. Successful applications include APIs and parenteral formulations, probiotics and large-molecule products like PLGA and hyaluronic acid. The technology incorporates the use of a jacketed and stirred dryer and collection filter. The material is frozen quickly inside the vessel under agitation. The energy needed for sublimation is applied through the jacket and distributed efficiently throughout the product by the stirrer, which results in a fine, loose, free-flowing powder.

Freeze dried powder

"Our technology produces a powder with a very small particle size with an open, porous structure so the solids dissolve in water easily afterwards," explains Hermsen. "This eliminates the need for post-treatment such as crushing or milling. So our one-step solution not only avoids delicately structured products and living organisms becoming damaged, but also saves pharma manufacturers time and money – and that's definitely a bonus in today's competitive market."

API, milled, after tray freeze drying      API after Active Freeze Drying

Microscopic photos of API, milled, after tray freeze drying (left) and API after Active Freeze Drying (right)

Aseptic design

Moreover, Hosokawa Micron's single-vessel solution is a fully contained system that has been designed with aseptic processing in mind. "Our Active Freeze Drying solution is a 'one-pot' process that keeps the product sterile at all times," he adds. "The equipment is completely smooth, with no edges or crevices that could harbour bacteria. The material can be charged into the vessel via sterile valves. When the vacuum is broken with sterile gas on cycle completion, the finished dry powder can be aseptically discharged into a sterilized container which can be docked onto a vial-filling machine. And the system is cleaned easily, quickly and effectively thanks to cleaning in place (CIP) and sterilization in place (SIP)." This is based on spray nozzles inside the drying chamber which start the cleaning and sterilization process as the first step of the batch process. SIP is achieved by pressurized steam.

Hosokawa Micron in the Netherlands originally thought up the idea of the Active Freeze Drying solution around ten years ago, and it generated a growing number of enquiries from customers. "We worked very closely with those customers to combine our many decades of experience in vacuum drying and powder process technology – including in the pharmaceutical industry – with their own product expertise," recalls Hermsen. "It involved a lot of testing, both with small-scale lab systems in customers' R&D centres and at our own in-house test centre in Doetinchem. We gradually evolved and fine-tuned the process from there to develop larger-scale industrial systems."

Try before you buy

Customers can make use of the 1-litre, 5-litre, 60-litre and 800-litre units at the Hosokawa Micron test centre for testing purposes and to explore scale-up potential. "We offer our customers a 'try before you buy' opportunity for all our solutions, including Active Freeze Drying, so that they can do initial product testing, product development and trials. That approach enables us to get the right feedback and work together with them to optimize the solution for their specific situation," comments Hermsen. "Our pharma customers are not only happy with the product quality, which many of them describe as 'revolutionary', but also with the reduced handling and easy validation of this completely closed system. We're pleased to see that a growing number of pharmaceutical manufacturers around the world are discovering all these benefits, and are considering our Active Freeze Drying solution as a more effective alternative to the traditional tray-type freeze drying method."