With Plasma, There?s No Immunity From Challenges - Lyop...

With Plasma, There?s No Immunity From Challenges

With Plasma, There?s No Immunity From Challenges
July 2005
by Pan Demetrakakes
Food & Drug Packaging
The immunoglobulin therapies packaged at the main Talecris plant are among the most demanding of pharmaceuticals.
Talecris Biotherapeutics? Plasma Fractionation facility in Clayton, N.C., processes 53,000 liters of frozen blood plasma a week. The purpose is to isolate proteins from the plasma and process them into intravenous therapeutic solutions. Among those therapies is the immunoglobulin intravenous (IGIV) Gamunex, a treatment for patients with compromised immune systems.
The Gamunex (IGIV-C) production facility, which was mechanically complete in 1999, is dedicated solely to the production of this IGIV solution. The process is totally enclosed and highly automated, using distributed control systems with clean-in-place technology for all process equipment and piping. The facility produces IGIV solutions for patients with compromised immune systems. Using this new process for Gamunex production reduces the cycle time from 120 hours to 39, with increased yields, says Jerry Sellers, director of manufacturing. A key improvement in the new process involves the gentle handling of a target protein in the plasma. The old process extracted, or ?precipitated,? it from the plasma multiple times, which led to loss or damage of the fragile protein. The current process allows the IgG molecule to remain in solution from beginning to end, reducing the risk of damage.
The facility layout includes two identical production lines, called ?trains,? that can process two batches of Gamunex independently. The complex process, roughly speaking, involves a series of filtrations in different forms. A substance called caprylate is used in the process as a viral inactivation step. Filter presses and ion-exchange chromatography columns remove the caprylate and any unwanted proteins, then a subsequent ultrafiltration/diafiltration step in the process increases the protein concentration to the goal of 10%.
Once the formulation process is complete, the product is sterile filtered into a filling bulk tank. A forklift truck transports the tank to the Sterile Filling Facility, a separate building where primary aseptic filling is done on four filling lines. These lines handle syringes and glass vials ranging from 3 to 250 milliliters.
Heavy regs
Blood plasma products come with rigorous regulatory requirements. ?Human biologics is the most heavily regulated industry monitored by the FDA,? says Larry Bagwell, director of filling, packaging and freeze-drying.
One of the most important requirements is maintaining a sterile environment in the filling areas. That starts with the people in the plant. Workers, supervisors, visitors and everyone else who enters the Sterile Filling Facility?s primary filling area must go through an elaborate gowning procedure that involves doffing street clothes and putting on scrubs, a jumpsuit over the scrubs, two sets of shoe coverings, a face mask, a hairnet and gloves. Operators have to be trained in this procedure before their key cards will permit access to the sterile area.
Once the fill tanks arrive from the processing building, they are hooked up to the fillers through a ?product bulk connection,? a set-up of valves and tubes that maintains sterility.
Glass vials come from several suppliers, including The Glass Group, Kimble Glass and Saint-Gobain Desjonqu?res. They are removed from their pallet skids and pass through a lighted, mirrored visual inspection station. Operators cull those with cracks, chips or other flaws. The vials are collected in an accumulation area from Garvey Corp., then travel into a rinser, where they are turned upside down inside a domed chamber and sprayed with sterile water.
From the rinser downstream, the packaging system is a Calumatic turnkey system supplied by BOC Edwards. An air blast dries the vials, and they enter a hot air sterilizer tunnel, where dry radiant heat lamps sterilize them at 350? C. A cool-down zone, with HEPA-filtered air, takes the vials back to ambient temperature?a vital step, because heat might denature the proteins in the product.
Like almost all glass containers, the vials Talecris uses come with minute variations in weight. To compensate for these differences, Talecris employs a volumetric fill-by-weight system. The carousels in the fillers have load cells that register the tare of the empty container, then keep track of the weight change as needle-style nozzles descend and fill the vials.
A second turret in the filler holds the vials as rubber stoppers are applied to fully seal the vial. An aluminum snap-on overseal is then applied. Some Talecris products are prepared as freeze dried dosages. For these products the stoppers are only half-tamped. Vials to be freeze-dried are collected on tables and transferred to an auto load-unload system for transfer into a freeze dryer. Vials are stoppered in the freeze dryer under vacuum.
When a vial of freeze-dried product is ready to be used, a health professional (or the patient) plugs one end of a small tube into a vial of sterile water and the other end into the vial of product; the vacuum in the latter sucks in the water, reconstituting the product.
Constant monitoring
Maintaining a sterile environment in the filling area is crucial. To help monitor contaminants, small culture dishes are left open inside the aseptic core to capture any microbes that might be in the air. The dishes are incubated to detect any microbiological contamination. In addition, a small cup-shaped probe collects inorganic contaminants like dust particles?called ?non-viable particulates.?
After the portable fill tank is emptied?completing what plant personnel call a ?fill event??change parts in the filling system must be completely sterilized. The filler nozzles and other change parts are taken to the equipment preparation area and washed in an ultrasonic bath from Sonicor Instrument Corp. They then are wrapped in Tyvek and sterilized in a pass-through autoclave at 120? C. The tape holding the Tyvek in place has ink markings that turn black to indicate exposure to high temperatures.
Two of the products produced at Clayton, Plasbumin and Plasmanate, have to be pasteurized after bottling. The vials build up in rows, and each row is pushed onto a perforated slip sheet. As the slip sheets build up, they are lowered into a large cage with perforated sides. When the cage is full, it is removed and submerged in a hot-water bath.
Tamper-evident packaging is supplied either by shrink bands over the stoppers, or by seals on the paperboard cartons that some of the vials are packed into. Product is hand-packed into cases, and the cases into a variety of shipping containers, ranging from insulated corrugated shippers for domestic distribution to Envirotainer skid-mounted units for overseas shipment.