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Pharmaceutical Manufacturing and Packing Sourcer

BFS Explained

Blow-fill-seal (BFS) technology is not new in the sterile manufacturing of drug products, but far too often the true value of this automated advanced aseptic filling method is overlooked. For decades, BFS has provided innovative primary packaging solutions for sterile respiratory and ophthalmic products, and helped these markets shift from filled glass containers to plastic.

Europe and Japan, as well as developing markets such as Asia and South America, have accepted BFS technology for parenteral packaging. However, the US injectables market has been slow to adopt what the industry has deemed to be advanced aseptic technology (1).

The market dynamics for global injectables have changed dramatically in recent times, due to challenges in sterile manufacturing and, in some instances, the subsequent recalls that have led to significant drug shortages in the market. This has forced the industry and regulatory agencies to explore alternative technologies to improve supply. The advanced aseptic processing of BFS drives at many of the root causes of these manufacturing issues, providing automated aseptic filling of a glass-free alternative for primary container closures.

PROCESS RISKS


A typical glass vial filling line requires a significant amount of controlled and Class A space in which to contain the process and associated machinery. All the contents of the filling suite must be cleaned and sterilised – for example, the vials and stoppers are loaded separately and undergo numerous washing and pre-treatment steps. Once the filling of the vials is complete, stoppers are introduced and capped by crimping, before inspection, labelling and secondary packaging. Human intervention is necessary throughout the run, including while assembling the components and feeding them into the system. These process steps can each bring delays, adding up to a considerable amount of time where the open vials are exposed to the risk of potential contamination.

Contamination risks within the process are predominantly from microorganisms or particulates – either glass fragments from the primary packaging, or foreign objects. Human operators have been proven to be the most likely source of contamination in an otherwise sterile environment, regardless of how careful they may be, the gowning procedures undertaken, and the training and other systems in place. Again, the time during which the products are exposed to the environment – potentially for hours prior to filling – increases the risk of contaminates being introduced.

QUALITY BY DESIGN

Post-processing inspection protocols have long been relied upon by the pharmaceutical industry to identify and contain problems before products enter the market. However, as part of the FDA’s goal of a science- and risk-based approach to manufacturing, there has been a significant amount of activity in recent years to address, and prevent, potential problems by developing a sound and thorough knowledge of the process (2).

These ideals are enshrined in the principles of Quality by Design (QbD), which drives a systematic approach to pharmaceutical manufacturing and development, identifying and defining proactive objectives for processes. Scientific actualities and quality risk management combine to ensure a full understanding of both the product and process. Critical controls are established to ensure product quality – bringing a proactive performance quality management approach to what was traditionally a reactive process. This is furthered through the ICH Q10 Pharmaceutical Quality System Guidelines, which also provide for a more proactive approach to manufacturing.

The end result is a system that ultimately enables the identification and control of the critical process parameters throughout the product’s lifecycle, designing out potential quality risks before issues occur, and promoting an environment for continuous improvement.

SETTING THE PARAMETERS

BFS is an alternative technology to traditional aseptic manufacturing, and has its roots fundamentally within the principles of QbD. It is an automated filling technique that has been designated as an advanced aseptic process, based on its equipment design, process and operational controls. Research experiments have been undertaken to microbially challenge the system, to identify the critical control parameters and provide the industry with the data needed to support this approach (3).

In comparison to the laborious, multi-step process for traditional glass vial filling, BFS technology forms, fills and seals the primary sterile container, typically in less than 15 seconds. The aseptic filling machine effectively acts like an isolator and contains the Class A filling conditions within its footprint – reducing both the amount of controlled space needed and the number of process variables involved. The automated BFS process is sterilised in situ and the sterile boundary is not breached, virtually eliminating the risks associated with human intervention.

The BFS process starts with pellets of virgin plastic, which are fed into a hot melt extruder where the polymer is melted at high temperature and pressure, usually 180°C/200atm. This molten plastic forms tubes, called parisons, that are fed into the body of the BFS machine. The first phase of a two-stage mould closes around the parison to form the container. At the same time, the body of the container efficiently dissipates the heat and takes form, while the top of the container remains molten. The seal mould then enters the Class A fill zone, and nozzles fill the newly formed body of the vial with product. Then, depending on the container design, any stoppers are inserted via vacuum tubes, and the container is sealed in a matter of seconds.

The harsh, physical conditions under which the resin is processed effectively inactivate any potential microbial contamination, and the exposure of the container to the Class A environment is only for a few seconds, which significantly reduces the risk of ingress of foreign particle contaminants. Again, compare the process to filling glass vials, and the minimisation of risks becomes apparent.

ASSESSING THE TECHNOLOGY


When measuring foreign particulates, BFS technology has shown it can provide a considerable reduction, compared to both the industry standards measured by the US Pharmacopeial Convention (USP) 788 and the reported industry average (4). In 2004, a published study indicated that the acceptable levels within USP 788 were too high and needed to be tightened (5). The research reviewed 406 drug lots across 295 abbreviated new drug applications: the average numbers across these lots were 219 particles greater than 10µm, and 15 greater than 25µm. This is in contrast to a patent-pending BFS technology, optimised specifically for the manufacture of sterile injectable products. An experiment evaluating the unique processing conditions of this system 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, under the same USP 788 testing. This represented a reduction in the averages of more than 95% in foreign particulates, compared to the industry average.

Research has also been carried out into the stability of biologics undergoing the BFS process, to assess any potential compatibility issues it may have on the molecule or differences in the BFS container compared to glass – for example, the use of high temperatures in the plastic moulding or leachables from the polymer container.

A comprehensive study was conducted by Catalent using a model monoclonal antibody formulation within the process of its BFS technology, with glass vials with uncoated stoppers used as controls. Several parameters of a monoclonal antibody’s physical properties, as well as stability, potency and observable leachables, were tested and measured over a nine-month period. The stability data – such as aggregation, chemical degradation, affinity and leachables – indicated no significant differences between glass and the BFS technology container systems over that time. Even though it is difficult to extrapolate from protein to protein, the study demonstrated that BFS is a viable and cost-effective method for producing aseptically-filled biologic formulations.

STERILITY ASSURANCE

BFS has been designed to offer significant advantages in the provision of a high level of sterility assurance. The process has been studied intensively over decades and, as the foundations of QbD require, the critical control parameters have been identified, defined and optimised. Akers and Agallaco, leading aseptic manufacturing industry experts, consider the risk to be reduced 100-fold by utilising advanced aseptic filling via BFS, compared to traditional glass vial filling (6).

Ultimately, BFS works to eliminate the root cause of the contamination issues that are being seen in today's injectables market. By reducing the number of variables and eliminating human intervention, this technology creates the possibility of a more robust supply of products, based on lower risk in the manufacturing process. The FDA and industry acknowledge the advanced aseptic nature of BFS, and there is a growing amount of data to back up its safety and reliability. Replacing old-fashioned glass vial filling in this way has the potential to improve product safety, enhance the reliability of supply, and benefit drug developers, manufacturers, practitioners and – most importantly – patients.

References

  1. United States Pharmacopeial Convention, General Chapter 1,116: Microbiological control and monitoring of aseptic processing environments, USP 37: pp931-942, 2014
  2. FDA, Pharmaceutical cGMPs for the 21st Century – A risk-based approach, 2004
  3. Leo F, Poison P, Sinclair CS and Tallentire A, Impact of blow/fill/seal process variables in determining rate of vial contamination by air dispersed microorganisms, PDA Journal of Parenteral Science and Technology, September-October 2005
  4. United States Pharmacopeial Convention, General Chapter 788: Particulate matter in injections, USP 37: pp398-401, 2014
  5. Shabushnig J, Regulatory and compendial considerations for particles in parenteral products, presentation at the American Association of Pharmaceutical Scientists meeting, November 2010
  6. Akers J and Agalloco J, The simplified Akers-Agalloco method for aseptic processing risk analysis, Pharmaceutical Technology, July 2006

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Bill Hartzel is Director of Strategic Execution at Catalent Pharma Solutions. He is responsible for the implementation of a full suite of advanced aseptic processing solutions for biologic and complex pharmaceutical liquid products. Bill has a strong background in aseptic processing in BFS and plastics, as well as being a leader in the single-use disposables industry since 2006. He has an undergraduate degree in Chemical Engineering and an MBA from Villanova University.
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Bill Hartzel at Catalent Pharma Solutions
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