Minimizing Drug Contamination through Blow-Fill-Seal Processing
Contamination has led to product recalls of several parenteral drugs over the last year or two. Glass, metal, and rubber particulates have been found in vials and syringes; several drugs have also been recalled because of concerns for nonsterility. FDA states that such contamination can threaten patient health. In one recent recall involving visible particulates, FDA stated that “potential adverse events after intravenous administration of solutions containing particulates may include disruption of blood flow within small blood vessels in the lung, localized inflammation (swelling and redness due to accumulation of inflammatory cells), and granuloma formation.”
Aseptic blow-fill-seal processing presents an alternative packaging technology. Chuck Reed, director, sales and marketing, Weiler Engineering Inc., suggests that it could be a better solution for certain sterile aseptic liquid processing. “Plastic ampoules produced through blow-fill-seal processing offer an advantage over glass vials with rubber stoppers. These plastic ampoules are not subject to breakage as are glass vials,” Reed wrote in a press release provided to PMP News. And the rubber closures used on the glass containers could fall victim to mold contamination, he added in the release. The process itself is designed so that it produces very low levels of particulate matter, Reed added. Further, “based on information supplied by FDA, there has never been a recall linked to the operational failure of a blow-fill-seal machine,” Reed told PMP News.
According to Reed, manufacturers of liquid pharmaceuticals, in particular, face the challenge of microbial contamination. While the drug product, container, and closure can each be sterilized prior to traditional aseptic processing, parenteral liquid drugs typically are not subject to terminal sterilization. Maintaining an ultrahigh-quality environment is therefore critical for ongoing sterility.
Aseptic blow-fill-seal technology, on the other hand, integrates blow molding, sterile filling, and hermetic sealing in one continuous operation, Reed noted. And today’s aseptic blow-fill-seal systems are often automated in order to minimize human activity, which can pose a threat to product integrity.
Sophisticated blow-fill-seal machinery incorporates controls for container weight, fill weight, wall thickness, visual defects, and particulates, explained Reed. For instance, Weiler’s KleenKut parison cut-off technology features an automated cold-knife instead of oft-used heated high-resistance wire. Using ultrasonics, KleenKut does not generate smoke and can reduce particulate generation at the source by more than 99%. “The KleenKut mechanism ensures that nonviable particles 0.3 µm to 10 µm in size are significantly reduced in quantity when compared with the volume of particles produced during the use of a hot-knife cut-off mechanism,” stated Reed in the press release.
In addition, filling is conducted under a continuous flow of positive-pressure sterile filtered air. “Systems protect the product by moving particles outward and preventing any inflow from the adjacent environment,” Reed added in the release. An air-shower device can supply HEPA-filtered air that meets Class 100 (ISO 5) microbiological standards during operations.
Even processes that introduce secondary closures for special dispensing features can be controlled to reduce contamination. “Isolation/insertion is a proven adjunct technology with BFS, permitting the addition of a secondary component with special dispensing features,” Reed told PMP News. “The secondary component must undergo a separate terminal sterilization process prior to introduction into a remote, sterile isolator for subsequent insertion into the BFS container prior to sealing. The entire insertion/BFS process takes place under Class 100 conditions and has been considered a secure, advanced aseptic process for several years.”
Extractable or leachables presented by direct labeling has been a concern of potential users of blow-fill-seal packaging, however. Reed told PMP News that labeling or printing directly onto the body of a blow-fill-seal container “is generally not accepted by FDA or other international regulatory authorities.”
However, “the blow-fill-seal process is uniquely suited to the embossing of specific product details directly onto the container by engraving the mold cavities,” Reed told PMP News. “This not only completely removes the risk of introducing extractables or leachables, but also provides an added measure of anticounterfeiting security.”
A few years ago, Weiler Engineering Inc. participated in a study with Cardinal Health Inc. and Air Dispersions to determine the effect that the extrusion process had on the quality of blow-fill-seal product. Reed reported that the challenge study demonstrates a uniform capability of achieving high sterility assurance levels (10-6 SAL) throughout the entire process.
Drug products with viscosities of less than 15,000 centipoise and suspension products can be processed by blow-fill-seal machines with specially designed product fill systems, Reed stated in the press release.
In particular, “Weiler BFS machines have been used successfully for more than a decade to process heat-sensitive drugs such as protein-based and biologic products,” Reed told PMP News. He claims that some other BFS machines may have design limitations that preclude the packaging of heat-sensitive materials.
There are some restrictions on the types of barrier materials that could be used for packaging sensitive drugs. “The resins typically used for blow-fill-seal packaging include low-density and high-density polyethylene and polypropylene. Secondary methodologies are typically employed for products that are sensitive to vapor transmission such as the use of nitrogen blanketing during the blow-fill-seal process or foil overwrapping post blow-fill-seal,” he told PMP News.
Many generic formulations of ethical drugs have been moved into BFS from glass in the international marketplace to enable cost advantages to the producers, Reed told PMP News.