How Active Freeze Drying simplifies validation for pharmaceuticals

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.

At freeze drying or 'lyophilization' events around the world, the topic of validation is always a key talking point. 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.


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. 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

The Active Freeze Drying 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

The Active Freeze Drying technology produces a powder with a very small particle size and an open, porous structure, facilitating effortless dissolution in water. This obviates the necessity for subsequent processing steps such as crushing or milling. Consequently, this one-step approach not only avoids delicately structured products and living organisms being damaged, but it 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)


Moreover, Hosokawa Micron's single-vessel solution is a fully contained system that has been designed with aseptic processing in mind. The Active Freeze Drying system operates as a 'one-pot' process that keeps the product sterile at all times. 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 conceived the Active Freeze Drying solution about a decade ago, prompting a surge in customer inquiries. Collaborative efforts with customers leveraged the company's extensive experience in vacuum drying and powder processing technology, particularly in the pharmaceutical sector. Extensive testing, both with small-scale lab systems in customers' R&D facilities and at the Hosokawa Micron Test Centre, contributed to the gradual refinement and upscaling of the process.


At the Hosokawa Micron Test Centre in the Netherlands, various unit sizes (1-litre, 5-litre, 60-litre, and 800-litre) are available for customer testing, to assess scalability and conduct trials. The company offers a 'try before you buy' option for all its technologies, including Active Freeze Drying, supporting customers in initial product testing, development, and trials. This approach facilitates the collection of valuable feedback and collaborative efforts aimed at optimizing solutions for individual requirements.

Pharmaceutical customers not only appreciate the product quality, by many of them described as 'revolutionary,' but also the reduced handling and easy validation of this enclosed system. Hosokawa Micron is encouraged to witness a growing number of pharmaceutical manufacturers worldwide recognizing these advantages and considering their Active Freeze Drying technology as a more efficient alternative to traditional tray-type freeze drying.


Hosokawa Micron B.V. is certified according to ISO 14001. Our certification covers all environmental themes of ISO 14001: air, soil, energy, waste, water, noise and hazardous substances. In addition, Hosawa Micron was awarded an EcoVadis Silver Medal for its sustainability achievements. EcoVadis determined that the company was among the top 7% of companies rated by EcoVadis in the special machinery industry.

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