Recalls and warning letters are littering the news and don’t help those pharma and biopharm companies engaged in producing sterile dose forms. The issues that lead to unacceptable products may have a direct impact on product availability, and even patient safety, if they go undetected. Many of the negative headlines arise from problems that occurred in the aseptic parenteral filling process, and frequently they involve microbial contamination or contamination by foreign particulates.
Aseptic filling is a complex business, with the potential for contamination throughout the process of preparation, storage, handling, filling, and sealing injectable products in traditional vials. Blow-Fill-Seal (BFS) technology is an advanced aseptic technique, and can significantly reduce the potential for microbial and particulate contamination, as it permits much greater control of the critical parameters, such as the continuous monitoring of both viable and non-viable air in the fill zone and eliminating the preparation and handling of preformed vials. In addition, the combination and automation of the container forming and filling processes eliminate human intervention from the critical filling areas, which is always regarded as a major source of contamination.
Advanced Aseptic Processing is no mere marketing term, but a regulatory one, with the FDA having set out what is required. There is no direct regulatory definition; however, a working definition is that an advanced aseptic process is one in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required and never permitted. So, to be declared advanced aseptic, a process should offer a fast, automated, controlled environment, with controlled parameters that can be machine-set and monitored. It applies to areas such as isolators, BFS equipment, and restricted access barrier systems.
There are many reasons why the industry and the FDA have designated BFS as an advanced aseptic process in the FDA’s 2004 Guidance [1]. Three of the main ones are: the design of the equipment, process and operational controls, and the results of extensive microbial challenges to the system.
A good deal of published information and microbial challenge data are behind this designation, which has led to increased expectations from both the regulators and the market. A comprehensive set of data were generated from the microbial challenges of the BFS process, including the air in the filling suite, the surfaces of the equipment, and the plastic resin that forms the primary container.
Despite this data and regulatory guidance, BFS was considered a niche technique, with only a handful of experts in the biopharma industry fully understanding the process, equipment, and design parameters that form the basis of the “advanced aseptic” categorization. However, the technology has been a mainstay within ophthalmic and respiratory markets for more than three decades, where it is the primary method used to create sterile primary container closures. This represents an area of opportunity for the parenteral sector to garner further knowledge from the experiences set forth in the ophthalmic and respiratory markets.
The design of BFS equipment is rooted in the Quality by Design principles. It produces the primary container, fills the product, and then seals it in a single, continuous, automated process. The filling takes place in a Class A (ISO 4.8) environment and is completed in less than 15 seconds. There are two main BFS equipment technologies, rotary and shuttle. While the machines share many basic principles, the set-ups of the container molding processes differ. However, both machine types are designated as advanced aseptic, and maintain the same closed system principles.
The closed system design of equipment ensures a high level of control. There are two primary pathways into the equipment for the polymer and the product. Both are closed and require no human intervention. In addition, by the temperature and melt processing of the resin at high heat and pressure the process renders the material microbe and endotoxin free.
Closed Polymer Pathway
The polymer is used to form the primary container, and the process for forming this has several significant advantages over more traditional methods. The closed polymer pathway uses a vacuum source to feed virgin polymer pellets into a standard plastic hot melt extrusion process, which exposes the polymer to temperatures in excess of 180°C, and pressures in excess of 200 atm. The temperature and pressure act as a first level of defense against adventitious microbial contamination as it will inactivate them. The heat and pressure in the extruder are more than sufficient to kill the flora commonly found in facilities.
Once the plastic resin is extruded; it forms long plastic tubes called parisons that extend from the extrusion head within an ISO 4.8 viable air space. This is air in which the maximum permitted number of particles per cubic meter is 3,520 for 0.5μm particles, and 20 for 5.0μm particles. A two-stage mold closes around the parisons to form the body of the primary container. In the BFS shuttle technology, the mold then “shuttles” forward, where nozzles extend and fill the container. After the fill is completed a rubber stopper is placed in the mold through vacuum tubes and then, in the final step, the second stage of the mold closes to seal the container. The entire cycle takes less than 15 seconds.
The air around the nozzle shroud is continuously monitored and controlled for both viable and non-viable air. If the permitted levels of particulates are exceeded, the equipment will automatically shut down, ensuring the container is never exposed to out-of-spec air conditions. Therefore, the primary container is only ever exposed to ISO 4.8 air for less than the 15 seconds it takes to form, fill, and seal it and because the process is automatically shut down if the air quality is measured to be out of specification, there is no container or product exposure during this excursion.
In contrast, in a traditional filling line, the primary container and components may be exposed to the environment for several hours, as the glass vials are open to the air as they rotate on a turntable. During these extended periods of exposure, a non-viable particulate incursion could occur, requiring an investigation, but the components and containers would still have been exposed.
A further risk arises from the presence of humans within the filling area, who may be walking around, righting bottles that have tipped over, and dislodging stoppers. In addition, the traditional filling process has a series of processing points for the primary container, including washing, depyrogenation or autoclaving, and storage that occur prior to the loading of the containers and components into the processing suite. All of these points represent a potential access point for contamination. BFS removes all of these as the vials simply do not exist before they are formed so cannot be exposed to the environment, and no human intervention occurs.
Closed Product Pathway
The product pathway in BFS is an inherently safe design. Again, it is completely closed, and the tank, hoses, filter housings, and fill system are all cleaned and sterilized in place before production begins. A traditional filling line requires these components to be sterilized and stored before they are assembled and aseptically connected in the processing suite. These procedures require human interaction, and thus there is an increased opportunity for error and/or contamination.
Such risks are eliminated in BFS, with the product only ever being exposed to equipment that has been sterilized in place within a closed system, with no further human intervention. In addition, the ISO 4.8 space around the filling nozzle is never breached by humans during processing. If an operator does need to enter the area while the filling is under way, the run will be stopped, and the entire system re-cleaned and re-sterilized in place before production starts up once more.
Proving Advanced Aseptic Conditions
While the design and control of the BFS process provide the basic premise for the advanced aseptic designation, a deeper analysis of the data used to establish its inherent aseptic nature offers further confirmation. In the early 1990s, a series of comprehensive studies were performed and published by industry experts. These detailed the capabilities of the BFS process, and many were carried out by Automatic Liquid Packaging, Inc., now part of Catalent Pharma Solutions. The studies were performed in a specially designed microbial challenge facility, inside a “room within a room,” with dedicated HVAC and exhaust systems. This allowed introduced microbial loads to be measured, the room to be fogged, and equipment with known microbial loads of an aerosolized spore suspension to be introduced.
Although many studies were carried out, three studies in particular provide reassurance to pharmaceutical quality professionals. These studies address airborne, equipment, and polymer microbial challenges, with a series of media fills in accordance with normal processing parameters being carried out after microbial challenges were introduced.
The first of these was an airborne challenge study [2]. The BFS room was fogged with 102 to >107 m3 of a Bacillus subtilis aerosolized suspension. Aerosolization occurred throughout the challenge. Multiple media fills were performed under a series of different conditions, including challenging the activity of the HEPA air shower in the ISO 4.8 space. The contamination fraction was found to be 10–3, indicating a significant reduction from the high levels that had been introduced, which was also directly proportional to the microbial load applied. There was also a direct relationship to the operational activities and incidents of contamination. The authors of the published study concluded that, “Responses to controlled microbial challenges provide the opportunity to define operating and environmental conditions under which BFS machinery can meet a sterility assurance level comparable to that targeted for terminal sterilisation, i.e. 10–6.”
The second study was designed to evaluate a microbial challenge to the equipment [3]. All surfaces of the BFS line except the filling nozzle were coated with a 107 spore suspension of Bacillus subtilis. Again, aerosolization occurred throughout the challenge. The equipment was set up, sterilized in place, and the media fills performed in the usual way. None of the filled vials were found to contain contaminated product. The equipment itself, therefore, can be highly contaminated, yet the filled product will remain uncontaminated. This further highlights the value of a closed processing system.
The final pivotal study [4] was a microbial challenge on the polymer raw material, with a series of organisms being introduced to the virgin plastic resin. When the resin was loaded with a 107 spore suspension of Bacillus subtilis, the contamination fraction within the plastic forming the vials was shown to be 10–3, establishing a bioburden acceptance level for the resin at an extreme level of microbial challenge. The study authors concluded, “The frequency of product contamination resulting from microbial levels found routinely on the virgin polymer is low, and acceptable (<106).”
The real value of these studies—and their results—becomes evident when one contemplates challenging a traditional pharmaceutical processing suite, equipment, or primary containers with an aerosolized107 spore suspension. The stopper bowl, open containers, forceps, equipment, and all material being handled would likely be riddled with contamination. Even if the aerosolization did not continue throughout the filling process, the rate of product contamination would be unacceptable, with common sense indicating that every single vial would be contaminated. Yet in the studies carried out on BFS lines, there was a zero rate of contamination on coated equipment, and low incidentrates in contamination in both aerosolization and polymer studies.
These studies also give a profound insight into the critical parameters that, together with the basic elements of equipment design, ensure that the routine operation of a BFS line achieves the sterility assurance levels demanded of terminal sterilization.
Future Perspectives
The equipment design, process controls, and studies described above provide the basis for the advanced aseptic designation afforded to BFS technology. Industry must continually challenge its current process dogmas if it is to find improved ways of manufacturing high-quality products in a reliable and reproducible manner. Advanced aseptic processes have already been established via regulatory guidance and other published studies. It is surprising how few FDA-approved parenteral products are manufactured on a BFS line, especially bearing in mind the prevalenceof BFS injectables in Europe, Asia, and South America. In light of numerous recent problems with traditional glass filling operations that have led to product recalls and drug shortages, implementing an advanced aseptic technology such as BFS may reduce the risks and ensure patients can rely on a sustainable supply of high-qualityproducts.
References
1. US FDA: Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice (2004).
2. Bradley, P.; Sinclair, C.S.; and Tallentire, A. Parenteral Science and Technology July/August1990.
3. Sinclair, C. MCF/2—Effect of Changes in Key BFS Process Variables on Frequency of Vial Contamination.
4. Sinclair, C.S. and Tallentire, A. Predictive Sterility Assurance for Aseptic Processing. In: Sterilization of Medical Products, Volume VI, Polyscience Publications, Montreal (1993).
Author Biographies
Bill Hartzel is the Director of Strategic Execution at Catalent Pharma Solutions, a global leader in development solutions and advanced drug delivery technologies. In this role he is responsible for the implementation of a full suite of advanced aseptic processing solutions for biologic and complex pharmaceutical liquid products. Mr. Hartzel provides a strong background in advanced aseptic processing in Blow-Fill-Seal and plastics in which he has numerous publications and presentations on the topics. Additionally, he has been a leader in the single use “disposables” industry since 2006 for his background in materials of construction. Mr. Hartzel is on the Board of Directors for BPSA, a technical author for the PDA–TRon Single Use Manufacturing, and the former Chairman of the ASME BPETask Group for Single Use. He has an undergraduate degree in Chemical Engineering and an MBA from Villanova University.
Hope Mueller is Director of Quality and Regulatory Affairs at Catalent Pharma Solutions. Ms. Mueller has more than 17 years of quality and operational excellence experience in the pharmaceutical industry. The majority of her experience is in the parenteral and contract manufacturing space for major pharmaceutical companies including Eli Lilly, Baxter, and Catalent Pharma Solutions. A microbiologist with Six Sigma Black Belt certification, Ms. Mueller has progressed through various global continuous improvement activities and quality management roles. In 2009, she joined the Catalent team as the Director of Analytical Services at the Woodstock site and is now the site’s head of Quality.