The aseptic blow-fill-seal (B/F/S) process has proven to be an ideal system for the creation of a wide variety of container shapes and sizes used for packaging sterile pharmaceutical liquids. B/F/S is well suited to producing closed aseptic containers, like injectable products, that need to be opened under critically sterile conditions within a clinical environment such as a hospital, as well as sterile products opened by individuals in work-a-day environments, such as 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 with no loss of product integrity.

Advances in insertion technology have facilitated the more recent improvements in aseptic B/F/S processing. The latest generation of aseptic B/F/S 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 B/F/S unit through a transfer tunnel. The isolator and tunnel are typically sterilized with vaporized hydrogen peroxide and the Class 100 environment within it is maintained by HEPA filtration. This new addition to the aseptic B/F/S system has not only streamlined the insertion process, but has provided a higher level of sterility assurance for products with tip-and-caps and rubber/silicone stoppers inserted under aseptic conditions.

Insertion Applications in Advanced Aseptic B/F/S

Although glass has been the traditional choice for packaging sterile pharmaceutical liquid products, B/F/S-produced plastic containers have emerged as a viable alternative during the past few decades, and particularly with the recognition by the FDA of B/F/S as an advanced aseptic process, indicating it as a preferred technology over other aseptic systems.

Unlike glass, plastic containers are shatter-proof. Glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters, such as with small volume parenterals, where glass ampoules can generate a fine array of small glass particles during opening.

A critical aspect of B/F/S technology is its pyrogen-free molding of containers and ampoules. B/F/S processing resins, polyethylene and polypropylene, which are 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 B/F/S processing have received international acceptance as suitable for pharmaceutical liquids applications. These inert materials do not contain additives, have low water vapor 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 B/F/S machines, providing a level of enhanced sterility assurance.

For these reasons, the interest in B/F/S-produced plastic containers, and particularly injectable product containers, is continuing to grow within the pharmaceutical industry.

Along with increased interest in B/F/S plastic containers, the application of aseptically-produced B/F/S containers with inserts has also grown popular. Advanced B/F/S machine designs allow operators to incorporate the addition of pre-molded, 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 eyedrop containers (used to deliver a calibrated drop), are inserted into the container after the blowing and filling process, prior to the final sealing step. The application of inserts has allowed B/F/S technology to advance and expand into product markets that were previously unavailable, such as IV drug administration, irrigation solutions and ophthalmic dropper units.

With ophthalmics, the B/F/S 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 B/F/S-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. 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 B/F/S-produced small-volume parenterals (SVP), such as those used for local anesthetics, vitamins, vaccines and other standard injectable products, 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. Luer locks or luer-slip fits can also be provided for making leak-free connections. For 2 to 20 mL small-volume parenterals, syringes can be connected directly to the ampoules without a needle, creating an inherently safer packaging solution.

Advanced B/F/S insertion processes can also incorporate tamper-evident features for multi-dose container closures, offering added security.

Advanced Insertion Isolation Technology

The latest generation of B/F/S machines use a modular design, integrating duo Class 100-environment manufacturing processes, and utilizing servo-drive controls with system-integrated programmable logic controllers (PLCs). These B/F/S 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 isolation chamber located outside of the B/F/S unit, but integrated with the B/F/S 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 B/F/S filling shroud.

Sterile inserts are loaded into the isolator through a double-locking, sterile rapid transfer port. The inserts are indexed into a special track mechanism that transfers them from the isolator into the nozzle shroud of the B/F/S. The filling of the container and the placement of the insert into the container both take place in sequential operations within the Class 100 nozzle shroud. Each component is inserted into a molded container before the final top closure is formed. The container-insert combination package is then sealed, having given the B/F/S product the intended drug delivery features. The entire operation takes place under Class 100 controlled environment conditions with no human intervention, providing a high level of sterility assurance for the final product.

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 B/F/S container are enclosed within a Class 100 environment. A servo-controlled fill and insertion system eliminates the need for hydraulics above the mold. Servo-drives deliver the inserts, so belt and chain mechanisms, which typically require lubrication and can generate non-viable particles, are eliminated. High-speed PLCs provide integrated control architecture for the entire B/F/S machine. All modular functionalities, such as with the insertion isolator, the insert-delivery track system and the B/F/S filling processes, are totally integrated for speed and optimum performance. The PLCs receive continuous communication from the B/F/S-isolator system, continually monitoring the differential air pressure in the B/F/S and isolation systems, as well as ensuring that particle counts are under control.

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 B/F/S 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 B/F/S and insertion isolation technology offer distinct advantages over earlier systems. This includes maintaining precise control over differential air pressure between the isolator, the insert transport and the B/F/S nozzle shroud. Both the isolator and the B/F/S system are equipped with HEPA air showers to assure a Class 100 environment under dynamic conditions in the isolator, tunnel and nozzle shroud area.

It has been well documented that in the B/F/S process, non-viable 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 B/F/S process. The more advanced B/F/S systems use additional technology in response to FDA concern over particulate contamination during B/F/S fabrication.

Expanding Use of B/F/S Insertion Technology

Advanced aseptic B/F/S 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 B/F/S 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 B/F/S technology, particularly into injectable product areas and biologics, where proteins and other complex solutions have brought B/F/S technology to the forefront.
As the use of advanced aseptic blow-fill-seal processes broaden, insertion technology will become more important as drug producers continue to seek new delivery methods for breakthrough drugs.

Andrew W. Goll is technical sales manager at Weiler Engineering, Inc., a provider of aseptic B/S/F custom packaging machinery for pharmaceutical and healthcare applications. He can be reached at solutions@weilerengineering.com or 847-697-4900.