Aseptic Blow-Fill-Seal Technology vs. Traditional Aseptic Processing
Acknowledged by the FDA as an advanced aseptic process for the packaging of sterile pharmaceutical liquids, blow-fill-seal technology is gaining increasing acceptance by providing a high assurance of product sterility, eliminating the need for human intervention, improving flexibility in container design and increasing process uptime.
By Chuck Reed, B.Sc/MS Director, Sales & Marketing, Weiler Engineering, Inc.
Since its introduction into the North American pharmaceutical market more than 40 years ago, blow-fill-seal (BFS) aseptic processing has established itself as a highly efficient and safe system for the filling and packaging of sterile pharmaceutical liquids and other healthcare products, such as creams and ointments. BFS product usage has been widely established in the ophthalmic and respiratory therapy markets for some time, and lately BFS technology has been gaining increasing worldwide acceptance in the parenteral drug marketplace, replacing traditional glass vial processing in a growing number of applications.
BFS enables a container to be molded from plastic, aseptically filled and hermetically sealed in one continuous, integrated and automatic operation, without human manipulation. The process provides flexibility in container design and system changeovers, high volume product output, low operational costs and a high assurance of product sterility. The inherent safety of the process – packaging sterile products under aseptic conditions without human intervention – has led the FDA, and the United States Pharmacopoeia, to characterize BFS technology as an "advanced aseptic process", indicating its use as a preferred technology.
New advances in drug delivery, the desire to improve convenience in handling pharmaceutical products, growing emphasis on combination products, the increasing focus on protein-based drugs and other biologics, and tighter regulatory criteria on product safety, have focused more attention on BFS technology over traditional aseptic methods as a better solution for the sterile, aseptic processing of pharmaceutical liquids.
Traditional Aseptic Processing and Sterility of Pharmaceutical Liquids
Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria like Salmonella, E. coli
and Staphylococcus, microbes that have been found in various liquid drug products. A supposedly sterile, but contaminated product may result in deterioration of the drug and loss of potency, pyrogenic reactions after administration to a patient – particularly in parenterals, infection of the patient and colonization of microorganisms in the patient with the risk of a secondary infection. Any microorganism, pathogen or nonpathogenic, found in a supposedly sterile pharmaceutical product is dangerous.
Drug manufacturers have pursued various methods of sterilizing packaging components, product ingredients and equipment in order to achieve a sterile product in its final form. One system used is traditional processing, followed by terminal sterilization, which involves initially filling and sealing product containers within a cleanroom environment. The environment is set up to minimize the microbial content of the product while it is being manufactured. Each component of the process – the product, container and closure – have a low bioburden, but may or may not be sterile. The product, in the final container, is subjected to a “terminal” sterilization process, such as heat or radiation. The most common method uses autoclaving with saturated steam under pressure.
Traditional aseptic processing allows a final sterile drug product to be achieved by individually sterilizing the containers, material and equipment in-process, resulting in a unified sterilized product. In traditional aseptic processing, the containers are either supplied cleaned and sterilized to the filling line, or they are cleaned and sterilized within the aseptic filling line. Plastic containers are usually washed, dried, sterilized and cooled before filling. Glassware containers, which have been the dominating packaging material for terminally sterilized and traditionally sterilized pharmaceutical liquids, are usually sterilized in-line, exposed to hot air at 350 degrees C while being passed through a Class 100 tunnel. A glass container temperature of 180 to 200 degrees C is adequate for achieving sterility.
Methods of sterilization used in aseptic processing include filtering the solution by dissolving it in a solvent, such as Water For Injection (WFI), where the solution is passed through a sterilizing filter or membrane. Filter sterilization is used where the component is soluble and likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (Lyophilization) of the component as a sterile powder. Dry heat sterilization is another effective method for sterilizing components that are heat stable and insoluble. Irradiation can also be used to sterilize some components.
Aseptic processing handles components, materials and equipment in such a manner that foreign microbial and endotoxin contaminents that exceed pre-determined acceptable levels, are not introduced to the product stream. To this end, it is critical that all storage, conveying, filling and container sealing stages be carefully controlled at each step of the process to maintain sterility of the product. Traditional aseptic processing, involving filling open glass bottles or vials, requires that the manufacturer maintain aseptic conditions in critical processing areas at all times. Unfortunately, the majority of liquid drug product contamination over the past several decades has come about from products produced in traditional aseptic processing facilities. Personnel Intervention in Traditional Aseptic Critical Areas
Traditional aseptic sterilization involves handling and manipulation of the material, containers, and sterilization filling processes with human intervention, and therefore has a higher potential for contamination during processing. The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing
states that the design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment.