Baxter Cytotoxic Contract Manufacturing Facility, Germany

Baxter Biopharma Solutions is expanding its cytotoxic manufacturing facility in Halle in Westfalen, Germany. It is one of the most advanced cytotoxic facilities in the world and has over 20 years of experience in lyophilisation, process development, aseptic filling and sterile crystallisation in clinical and commercial batch sizes. The facility, operational since 1978, was redesigned for isolator technology in 2002. Two phases of capacity expansion have been carried out at the facility since then.

The third phase of expansion to further boost capacity was initiated in 2010. Designed in compliance with international manufacturing and regulatory standards, the expansion is expected to be complete by mid 2010. It will be followed by an additional phase of expansion scheduled for completion in 2012.

Cytotoxic manufacturing facility expansion

The third phase of capacity expansion will boost the facility's resources that support processes from early-stage drug formulation to commercial scale-up, introduction and lifecycle management. To increase manufacturing capacity of cytotoxic and other oncology therapies, a number of specialised capabilities at the facility were upgraded during the expansion. A large-scale lyophilisation unit was installed to increase the overall freeze-drying capacity of the facility. Freeze-drying supports a substantial part of the manufacturing business conducted at Halle.

As part of the expansion, new technology will be installed in place of the existing filling system at the facility. The new technology will boost commercial cytotoxic manufacturing capacity by over 50%. It will accommodate the growing demand for commercially marketed oncology drug products.

The facility extends over 1,100ft² and accommodates four large-scale lyophilisation units.

There is an advanced loading cart that transports products from one isolator to another. The fully automatic cart that travels around the facility with the help of sensors transports the cytotoxic vials from filling and loads the freeze driers automatically, without any human assistance. There is also a manually operative transfer system from LaCalhene that offers greater flexibility within the facility.

All the transfer systems, isolators and filling systems at the facility are custom designed for individual processes by suppliers that include German-based firms Bausch & Strobel and Metal + Plastic.

A hand-fill suite supports small-scale production of clinical cytotoxic batches, and a nanoparticle suite is available for the production of cytotoxic emulsions, liposomes and suspensions on commercial scales. A high-pressure homogeniser is installed within the nanoparticle suite.

Production

The facility manufactures parental products in liquid, crystallite, dry powder and lyophilised dosage form. It primarily develops cytotoxic agents that are highly sensitive drugs to manage and produce. Process development for scale up, clinical and large-scale contract manufacturing of advanced drugs is also undertaken at the facility. Lyophilisation and filling capabilities at the facility include aseptic filling of highly potent, cytotoxic and non-cytotoxic liquid and dry-powder vials, sterile crystallisation of cytotoxic active pharmaceutical ingredients and lyophilisation cycle development.

Integrated support services can also be provided that include stability storage, validation and documentation, technology transfer, analytical and microbiological services, and packaging / kitting.

Barrier isolator technology

The facility operates with barrier isolator technology that provides complete containment. Known as cRABS (closed restricted access barrier system), the state-of-the-art technology offers operator safety and better product sterility. It avoids human exposure to the cytotoxics, which keeps the process contaminant free.

To perform all the mixing, formulation and compounding activities, negative-pressure isolators are used. Products from the lyophilisation equipment are shifted to negative or positive pressure isolators for further processing. Positive-pressure isolators are used during sterile filtration and filling.

The filling isolators are equipped with controllers that check the temperature, difference in pressure and humidity. The facility is also equipped with an in-process quality analysis technology.