In recent years, there have been a significant number of news headlines arising from the challenges of aseptic manufacturing. The challenges inherent to traditional aseptic manufacturing of injectable products, especially into glass vials, can result in foreign particulate, glass particles and microbial contamination. The consequences of these contaminations reaching the market can be extremely serious to the patient and when a risk of contamination is identified, may result in product recalls. Couple these challenges with an apparent systemic issue in quality management systems and the aging U.S. aseptic manufacturing infrastructure, and these factors have contributed to nearly 30% of the U.S. manufacturing capacity being taken offline,¹ and has led to a strain on the U.S. supply of injectable drug products.

Historically, the pharmaceutical industry has relied heavily on inspection processes to identify and contain these challenges prior to products entering the market. However, as a part of the FDA’s movement to a science- and risk-based approach to manufacturing,² there has been a significant amount of activity in recent years to address potential problems in pharmaceutical manufacture by developing a sound and thorough knowledge of the process and product to prevent problems before they occur. These ideals are enshrined in the principles of Quality by Design (QbD).

This systematic approach to pharmaceutical development and manufacturing begins with pre-defined objectives being determined for the manufacturing process. It emphasizes product and process understanding with the knowledge of the critical process controls that are based on sound science and quality risk management. In essence, QbD converts the reactive nature of the traditional approach to pharmaceutical quality into a proactive product process and performance quality management system. This is furthered through the ICH Q10 Pharmaceutical Quality System guidelines that provide for a more proactive approach to manufacturing. The balance is tilted in favor of the implementation and operation of product performance and monitoring systems, with the aim to design out potential quality issues. Ultimately, this will enable the identification and control of the critical process parameters over the product’s lifecycle to be achieved.

The aseptic filling of parenteral products is a process that requires careful control because of the multitude of variables that contain risk to the product becoming contaminated. In a traditional vial filling line, there are many points at which contaminants might be introduced. For example, everything within the filling suite needs to be cleaned and sterilized, including the containers and stoppers prior to the production run. Human intervention is also required throughout the run, from assembling the filling components to ensuring the components are fed into the system properly. Human operators have been proven to be the most likely source of contamination in an otherwise sterile environment, regardless of how careful they are, the gowning procedures, and the training and other procedures that are in place. Additionally, the time during which the primary containers are exposed to the environment, potentially for hours prior to filling, increases the risk for contamination.

The Blow/Fill/Seal Alternative
An alternative technology to traditional aseptic manufacturing is blow/fill/seal, or BFS. This technology is based around an automated aseptic filling technique that is fundamentally rooted in the principles of QbD. Unlike traditional filling, BFS has been designated as an advanced aseptic process by the industry.³ This designation is based on its equipment design, process and operational controls, as well as the results of numerous microbial challenge tests proving its ongoing aseptic nature during processing.

The BFS technology forms, fills and seals the primary sterile container, typically in less than 15 seconds in a Class A (ISO 4.8) environment. The aseptic filling machine starts with raw plastic pellets, which it uses to create the container immediately before it is filled. Virgin plastic pellets are fed into a hot melt extruder, where the polymer is melted at high temperature and pressure; the typical temperature is 180°C and pressure 200 atm. The pathway for the polymer is closed, and significantly reduces the opportunity for microbial or particulate ingress as the container is formed.

This molten plastic is extruded into parisons, which are long plastic tubes extending from the extrusion head directly into the contained Class A environment. Next, a two-stage mold closes around these parisons and the first stage of the mold creates the container body. The mold then shuttles into an isolated fill zone. At this point, fill nozzles are automatically inserted into the open container and the product is filled. For vial applications, a sterilized stopper is used as the closure, with the insertion process utilizing vacuum tubes for placement. After this occurs, the second stage of the mold closes and seals the contents into a fully integral container. The product then leaves the machine through conveyors and is ready for secondary packaging.

Perhaps the greatest advantage in terms of inherent safety is that the container is automatically formed, filled, a sterilized stopper inserted, and the seal is completed within just 15 seconds, under Class A aseptic conditions. This vastly reduces the potential for the product to become contaminated. The primary container closure simply does not exist before it is formed, and the temperature and pressure at which it is formed are sufficiently high to inactivate microbial contamination that might be present in the plastic resin. The machine can be installed in a compact footprint and the class A filling conditions are maintained within the footprint of the machine.

Compare this to a typical traditional glass vial filling line. Both the vials and the stoppers must be separately loaded, washed using injection-quality water, siliconized and sterilized. The vials move into an isolator or restricted-access barrier system area, where they are cooled and treated with vaporized hydrogen peroxide before filling. The glass vials are then fed into a filler and the stoppers are introduced and applied to the vials after the filling is complete. These containers are then capped by crimping before they move out of the isolator for inspection, labelling and secondary packaging. Typically, this will require a significant amount of controlled and Class A space to handle the complexity and variables associated with traditional vial filling.

Challenging the System: Reducing Foreign Particulates
Through automated aseptic processing with BFS technology, the risk of contamination from both microbial and foreign particulates is drastically reduced. When measuring foreign particulates the BFS technology can provide a drastic reduction of particulates compared to both the industry standards measured by USP ⁴ and the industry average.⁵ The USP states that there should be no more than 6,000 particles larger than 10µm and no more than 600 larger than 25µm. In 2004, a study was conducted and published to indicate that these standards were too high and needed to be tightened. This study reviewed 406 drug lots across 295 ANDAs, and the average numbers across these lots were 219 particles greater than 10µm, and 15 greater than 25µm.

This is in contrast to Catalent’s filling technology employing BFS. A design experiment was conducted to review the specific processing conditions within the BFS process. This study reviewed 32 different conditions within the process and yielded an average of 5.0 particles greater than 10µm, and just 0.9 greater than 25µm on average. This represented a reduction of more than 95% in foreign particulates compared to the industry average.

Proof of Aseptic Processing and Critical Control Parameters
The microbial challenge of the system was pivotal to the designation of BFS as an advanced aseptic filling process. To carry out these challenge tests, a self-contained area and room were built to house a commercial BFS machine. This had separate air handling systems and full environmental monitoring control. This facility within a facility hosted a series of different experiments challenging the parameters of the system and how that impacted the sterility of the finished containers. Over the course of the studies the three critical areas were determined: the room, the fill zone, and the resin.

To challenge the room, it was continuously aerosolized with a 106 aerosolized Bacillus subtilis suspension throughout the media fill processing.⁵ A number of fills and processing conditions were carried out. The experiments proved that as long as the nozzle shroud was in operation and the fill shroud was closed, the process had the potential to provide 10-6 reduction of microbial contamination. To challenge the fill zone, the surfaces of the BFS machine were loaded with 106B. subtilis spore suspension.⁶ Again a series of tests were conducted to explore the critical parameters and it was revealed that proper air flow around the nozzles and the fill nozzles being free of contamination, the process yielded zero contaminated media samples. Finally, to challenge the polymer resin used to make the containers, it too was loaded with a 106 spore suspension of B. subtilis.⁷ After this was used in a standard BFS media fill run, the temperature and pressure revealed a 10–3 bioburden reduction. This study verified the assumption that the high temperature and pressure at which the resin is extruded is sufficient to inactivate the introduced spores.

These series of microbial challenge tests identified a series of critical control parameters. These include, but are not limited to, the sterilization of components in situ, the need for proper airflow in the nozzle shroud area, that the HEPA filtered area in the parison areas is running, and fill shroud doors remained closed. As an additional precaution the air around the fill zone is continuously monitored for both viable and non-viable particulates throughout the run to monitor the in process conditions.

Another significant difference between traditional vial filling and BFS, if on a rare occasion there is an excursion and the sterile boundary is breached, the line must be shut down to prevent product contamination. However, during this time no product or container is being exposed during that period of time. This provides a higher level of control and minimizes waste and risk in the process.

Risk Reduction Through Automation and Simplification
Fundamentally, BFS equipment has been designed to provide significant advantages for ensuring a high level of sterility assurance. Additionally, through decades of studying the process, the critical control parameters have been defined. Akers and Agallaco, leading aseptic manufacturing industry experts, consider that advanced aseptic filling via BFS reduces the risk 100-fold compared to traditional glass vial filling.⁶  The technology drives to eliminate the root cause of the contamination issues that are being seen in the injectables market today. The reduction of variables, automation of the process, and elimination of human intervention, drives at a more robust supply of products into the industry based on the reduction of risk in the manufacturing process.

The advanced aseptic processing represented by BFS technology is well understood and widely accepted in the sterile manufacturing of respiratory and ophthalmic products. In these markets, BFS has provided innovative primary packaging solutions for decades, and has helped those markets convert from glass to plastic many years ago. In addition, the technology is widely accepted and commonly used to fill parenteral pharmaceutical products in the EU and Japan, as well as in the developing regions of South America and Asia. Yet the penetration of BFS into the U.S. injectables market remains surprisingly low. With the FDA having accepted the advanced aseptic nature of BFS, the time is more than ripe for U.S. biopharmaceutical manufacturers to embrace the technology. There is a significant amount of data to back up its safety and reliability, and replacing traditional glass vial filling will only serve to potentially improve product safety and enhance the reliability of supply. 

References

1. House of Representatives Committee on Oversight and Government Reform Report: FDA’s Contribution to the Drug Shortage Crisis.  112th Cong. (2012)
2. Food and Drug Administration.  (2004). Pharmaceutical cGMPs for the 21st Century-A Risk Based Approach. 
3. United States Pharmacopeial Convention. (2014). General Chapter , Microbiological Control and Monitoring of Aseptic Processing Environments.  In USP 37, pp. 931-942.
4. United States Pharmacopeial Convention. (2014).General Chapter , Particulate Matter in Injections. In USP 37, pp. 398-401.
5. Presenter Shabushnig, John. (November, 2010).Regulatory and Compendial Considerations for Particles in Parenteral Products. Presented at AAPS, New Orleans, LA.
6. Bradley, A., Probert, S.P., Sinclair, C.S., &Tallentire, A. (1990). Airborne Microbial Challenges of Blow/Fill/Seal Equipment: A Case Study. PDA Journal of Parenteral Science and Technology, July/August 1990
7. Catalent Internal Report – MCF-022 –Air Dispersions, LTD C. Sinclair, 11/2002
8. Leo, F., Poisson, P., Sinclair, C.S., Tallentire, A. (2004). Evaluation of Blow Flow Seal Extrusion through Processing Polymer Contaminated with Bacterial Spores and Endotoxin.PDA Journal of Pharmaceutical Science and Technology, Volume 58 (3), May-June 2004
9. Akers, J., &Agalloco, J. (2006). The Simplified Akers-Agalloco for Aseptic Processing Risk Analysis. Pharmaceutical Technology, July 2006.