The BFS technology which is not only used in the pharmaceutical industry, but also for a diversity of applications in adjacent areas like the cosmetics industry because of its many potential uses, user-friendly design and flexibility,is continuously growing.
BFS (blow/fill/seal) technology is the filling technology used for liquid products during which the polymer containers are manufactured, filled and sealed in a single cycle. Originally developed in Europe in the 1930s, it was introduced in the United States in the 1960s, but over the last 20 years it has become more prevalent within the pharmaceutical industry and is now widely considered to be the superior form of aseptic processing by various medicine regulatory agencies including the U.S. Food and Drug Administration (FDA) in the packaging of pharmaceutical and healthcare products.
A major advantage of BFS technology is the extremely compact high-purity space which provides an appropriate level of safety during aseptic filling.
The aseptic BFS process can create a variety of container shapes and sizes used for packaging sterile pharmaceutical liquids. The process is also suited to producing closed aseptic containers, like injectables, that need to be opened under sterile conditions within a clinical environment such as a hospital, as well as sterile products opened by individuals in environments like ophthalmic dropper units.
These products must meet the mandates of drug manufacturers and government regulators that require sterile products that will stay sterile until time of use. Manufacturers also desire the most cost-efficient packaging systems to achieve these ends without any loss of product integrity. One of the more recent improvements in aseptic BFS processing that facilitates these goals is the advance in insertion technology.
The latest generation of aseptic BFS machines incorporate dedicated isolators adapted specifically for insertion applications. These modular insertion isolators are typically located outside of the classified machine room, separate from but directly connected to the BFS unit through a transfer tunnel.
A critical aspect of BFS technology is its pyrogen-free moulding of containers and ampoules. BFS processing resins, polyethylene and polypropylene, used to produce aseptic containers for injectables, ophthalmics, biologicals, and vaccines, are generally considered inert by the FDA, and many of the blow-molding resins used in BFS processing have received international acceptance as suitable for pharmaceutical liquids applications. These inert materials do not contain additives, have low water vapour permeability, and are easy and safe to handle in critical care environments such as hospitals.
Further, temperature-sensitive biological and protein-based products can be processed in advanced BFS machines, providing a level of enhanced sterility assurance.
The application of aseptically produced BFS containers with inserts has also gained in popularity. Advanced BFS machine designs allow the capability to incorporate the addition of premolded, pre-sterilized components (inserts) into the basic container. These inserts, including items such as rubber and silicone stoppers, and tip-and-cap dropper units for eye drop containers (used to deliver a calibrated drop), are attached to the container after the blowing and filling process, prior to final sealing step. The application of inserts has allowed BFS technology to advance and expand into product markets such as intravenous drug administration, solution irrigation, and ophthalmic dropper units.
With ophthalmics, the BFS insert process enables increased efficiency and sterility control in the processing of expensive drug formations for treatment of glaucoma and other eye diseases. Other types of sterile inserts can be incorporated into the basic BFS-produced container as well, such as top geometrics for both bottles and ampoules that can include a multi-entry rubber stopper or a controlled diameter injection-molded insert, useful where multiple administration of a drug is required. The stopper would typically be an FDA-approved, rubber, or silicone insert that would be placed inside the bottle or parenteral. Then, at the point of delivery the nurse would stick a needle through the stopper and extract the fluid, or if it is a vascular flush, the nurse would insert it into the patient's IV set.
Aseptic BFS-produced small-volume parenterals (SVP), such as those used for local anesthetics, vitamins, vaccines, and other standard injectables, can be manufactured with a twist-off-opening feature. They can also be combined with a controlled-diameter form in the top to accommodate needle-less spikes.
BFS-produced, one piece, plungerless sterile syringes (designed for prefilling) for use in flushing hospital equipment such as catheters, are available for replacing traditional two-piece plunger-type syringes. The B/F/S syringe provides an offset chamber for trapping air, and preventing it from being dispensed during drug delivery.
Advanced BFS insertion processes can also incorporate tamper-evident features for multi-dose container closures.
The latest generation of BFS machines use a modular design, integrating duo Class 100-environment manufacturing processes, and utilizing servo drive controls with system-integrated PLCs (programmable logic controllers). These BFS systems address process monitoring, streamlined maintenance, and consolidated machine components for optimum performance.
They feature advanced insertion technology, incorporating the use of a Class 100 environment isolation chamber located outside of the BFS unit, but integrated with the BFS machine. This process allows the operator to present a pre-sterilized (typically with a gamma or an e-beam process) component (stopper or dropper insert) through a secure sterile pass-through into a Class 100 environment for insertion within the BFS filling shroud.
Key factors of this isolation technology include minimizing particles generated through moving components, and controlling the air pressure cascade from the isolator to the nozzle shroud, providing enhanced sterility assurance and thereby achieving regulatory compliance. All of the mechanical features required to get the inserts from the isolator into the BFS container are enclosed within a Class 100 environment. A servo-controlled fill and insertion system eliminates the need for hydraulics above the mould.
Conventional liquid aseptic manufacturing, with parenterals for example, requires filling and sealing to be carried out in a Class 100 environment and necessitates considerable validation efforts. Both the BFS machine and the insertion isolator do not need to be housed in a Class 100 area because their activities are protected within the machines themselves. This protection considerably reduces the scope of validation requirements.
Sterility and particulate matter are two of the most critical requirements for aseptically produced products, and advanced BFS and insertion isolation technology offer advantages over earlier systems. They include maintaining precise control over differential air pressure between the isolator, the insert transport, and the BFS nozzle shroud. Both the isolator and the BFS system are equipped with HEPA air showers to assure a Class 100 environment under dynamic conditions in the isolator, tunnel and nozzle shroud area.
In the BFS process, nonviable particles primarily originate from the electrically heated cut-off knife contacting the molten parison, and that better control of non-viable particulates will provide enhanced sterility assurance for the BFS process. More advanced BFS systems use additional technology in response to FDA concern over particulate contamination during B/F/S fabrication.
Advanced aseptic BFS containers and ampoules can deliver precise dosing in disposable formats. The incorporation of a sterile tip-and-cap, a rubber stopper, or a multi-entry insert into the BFS package offers added flexibility in container design and drug delivery methods, as well as enhanced sterility safety. These benefits are continuing to push the acceptance and use of advanced aseptic BFS technology, particularly into injectable product areas and biologics, where proteins and other complex solutions have brought BFS technology to the forefront.
Catalent's ADVASEPT™ technology helps to optimize the BFS process. It gives manufacturers, including those that produce biologics, another option when it comes to primary packaging applications.
ADVASEPT technology is a glass-free vial design that leverages proven Quality by Design (QbD) manufacturing techniques to optimize the BFS process.
This form of advanced aseptic processing creates a next-generation, glass-free vial that minimizes the risk of contamination through automation and process simplification. The process reduces foreign particulates, process steps, and human intervention, which lowers some of the major risks associated with aseptic filling of injectable products into glass vials.
Advanced aseptic processing of parenterals (such as intravenous or intramuscular injection) can mitigate the risk factors for sterility challenges via automation. ADVASEPT technology eliminates glass particles and de-lamination, and provides a reduction in foreign particulates.
The technology uses a medical-grade polypropylene (PP) resin that provides chemical and physical properties, simplifies opening, and reduces breakage risks.
In addition to moving from glass to plastic, the advanced aseptic processing method is based on BFS equipment that includes engineering controls and automation that help drive out variables and simplify the process.
The BFS equipment and process is set up, with cleaning and sterilizing done in place to eliminate human intervention into key processing points. During the process, liquid product is formulated in a process tank.
Depending on the product, the formulation delivered to the machine is sterile. This is accomplished through the handling of sterile ingredients with aseptic additions, bulk sterilization, or sterile filtration. This formulation then flows through a process path into the machine to be time-pressure filled. Meanwhile, molten medical-grade PP resin pellets are extruded through a parison head into two-stage moulds, where the tube-like parisons descend via gravity. When these descend to the proper length, the first stage of the mould closes around the parisons, which are then formed into the body of the container.
The mould then shuttles forward into the fill zone where filling tubes descend into the formed vials and fill the liquid product into each open vial. Sterile stoppers, also contained within the BFS process, are transferred into the BFS machine through an isolator. Vacuum tubes are employed to place stoppers into the vials. Vials are then sealed by the second stage of the mould and sealed vials are conveyed out of the machine for secondary processing.
When compared to traditional glass vial filling, automated aseptic BFS of plastic vials eliminates traditional manufacturing steps, reduces the required controlled space, and lessens the risk of contamination. The latter is possible by reducing particles, process steps, and human interaction. Air quality improvements and less exposure greatly reduce aseptic processing risks.
Another important process differentiator is the BFS system’s container closure system, which is glass-free, delivering a lower weight for shipping, is disposable, shatter-resistant, and allows for primary container design flexibility.
This aseptic process creates a new container closure system, and that means that extractables and leachables considerations differ from traditional glass vial filling. Stability matters need to be evaluated as plastic is not impervious to moisture and gases. Additionally, the BFS process requires heat to form the container; even though this heat dissipates quickly thermally sensitive products need to be evaluated.