In recent years, the growing number of drug shortages for injectable drugs has highlighted some of the challenges of traditional aseptic manufacturing of injectable products in glass vials, including the ingress of foreign or glass particulates, and microbial contamination. With the increasing number of biologic based drug products advancing through the clinic and to the market, the number of injectable doses is increasing, leading to a strain on traditional manufacturing processes and further highlighting these manufacturing challenges.
There is a growing need to look for innovative solutions to address these issues. One such alternative to traditional aseptic glass vial filling is Blow-Fill-Seal (BFS), an automated aseptic filling technique based on the principles and practices of Quality by Design (QbD), and that addresses the main issues of contamination in aseptic manufacturing. The very nature of the technology eliminates the sources by removing people and glass management from the process.
The BFS technology creates, fills and seals the primary sterile container in less than 15 seconds. The aseptic filling machine effectively contains and maintains the class A filling conditions within the machine, reducing the amount of controlled space required and minimising process variables whilst simultaneously eliminating human intervention. The BFS process is wholly automated and starts with virgin plastic pellets that are fed into a hot melt extruder, where the polymer is melted at high temperature and pressure. These extreme physical conditions act as an effective barrier because they can inactivate microbial contaminants. Additional, the process creates the primary container before immediately filling the body of the vial and sealing it. The container therefore is only exposed to the class A environment for a few seconds; drastically reducing the risk of foreign particulate contamination.
This is in contrast to a glass vial filling line, where the vials are loaded, undergo multiple washing, treatment and depyrogenating steps. After filling, the stoppers are introduced and capped by crimping. The majority of the stages take place in barrier-control conditions and then all products are inspected, labelled and contained in secondary packaging. Human intervention is required throughout, and with it, the risks of microbial contamination, regardless of how much care and training is undertaken. Additionally, the time during which the components and products are exposed to the environment, potentially for hours prior to filling, increases the risk of contamination.
When measuring foreign particulates, BFS technology can provide a drastic reduction in particulates compared to both the industry standards measured by USP <788>1 and the reported industry average. In 2004, a study was conducted and published2 indicating that the acceptable levels within USP <788> 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 patent-pending BFS filling technology, ADVASEPT. When an experiment was conducted to review the specific processing conditions within its BFS process, it 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.
The QbD principles behind the technology aim 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, provides a more robust supply of products, based on the reduction of risk in the manufacturing process.
BFS technology is used widely in the sterile manufacturing of respiratory and ophthalmic products where the sectors were early adopters of the technology and have benefited from innovative primary packaging solutions. Because of the challenges with traditional glass vial manufacturing, more companies are being exposed to the benefits that BFS advanced aseptic processing can have on the production, and an extensive compendium of data has been generated to support the use of BFS for biologics products. Safety and quality are still the most important factors in drug product manufacture and with more data available on the reliability of BFS, this innovative technology may help provide more reliable supply of products for the injectable drugs market.
References
- United States Pharmacopeial Convention. (2014).General Chapter <788>, Particulate Matter in Injections. In USP 37, pp. 398-401.
- Presenter Shabushnig, John. (November, 2010).Regulatory and Compendial Considerations for Particles in Parenteral Products. Presented at AAPS, New Orleans, LA.