Aseptic Vial Filling
Ideally, injectable drugs are sterilized in their final containers by a foolproof method like autoclaving. This is not possible for biologicals like monoclonal antibodies (mAbs), so they must be manufactured aseptically, sterilized by filtration and then
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23 Aseptic Vial Filling Kuldip Bhamra, Patrick Harrison, Jenny Phillips, and Geoff Hale 1. Introduction Ideally, injectable drugs are sterilized in their final containers by a foolproof method like autoclaving. This is not possible for biologicals like monoclonal antibodies (mAbs), so they must be manufactured aseptically, sterilized by filtration and then filled into sterile vials or ampoules. The final filling procedure is the most critical aseptic process and should be done in a very clean environment. Automatic machines are used for large production processes and eliminate the risk of contamination associated with manual processes. However, preparing material for early clinical trials can be problematic because the batch size is normally too small for a filling machine (e.g., 500–1000 vials). Normal practice is to fill this number of vials by hand, but the vials and closures have to be washed, depyrogenated (by baking in an oven), and sterilized, and the filling has to be carried out in a very strictly controlled environment, because the vials are open throughout the process and are only stoppered and sealed in a second step. We have developed a procedure that we believe is much simpler and safer (see Note 1). Vials are purchased ready washed, sterilized, and assembled with closure and a crimp top. They are filled using a standard pharmaceutical dispensing syringe system in a Class 100 environment. There are several advantages: 1. Costs and controls associated with washing, baking, and sterilization are eliminated; 2. Vials are always sealed, so the risk of introducing contaminants is reduced; 3. The hand sealing and crimping step is eliminated (instead this has been done by machine, which is more reliable); and 4. The filled vials are pressurized so loss of seal integrity would be evident to the user. From: Methods in Molecular Medicine, Vol. 40: Diagnostic and Therapeutic Antibodies Edited by: A. J. T. George and C. E. Urch © Humana Press Inc., Totowa, NJ
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Bhamra et al.
There are some potential drawbacks: the closure is punctured and it is not possible to fill the vials more than about 40% because of the pressure buildup. Over the past 7 yr we have used this method to fill 105 batches of therapeutic antibodies, a total of over 46,000 vials. Samples from every batch were tested for sterility by aerobic and anaerobic cultures by independent laboratories. Organisms were found on only one occasion, and the testing laboratory ascribed this to contamination during the test (extensive repeats tested negative). Over the same period we have also filled more than 2000 vials with nutrient broth and exposed them to a variety of storage conditions (see Note 2). None have shown any evidence of microbial growth. 2. Materials 1. Sterile transfer bags (We use 1–5 L Bio-Pharm recovery bags from Stedim (Aubagne, France). Similar bags can be obtained from other suppliers. 2. Connector for coupling bag to syringe. Prepare a short length (approx 7 cm) of new silicone tubing (e.g., Cole Parmer H-06411-03) with a ca
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