Alivia Leon

Blow-fill-seal (BFS) technology presents several advantages over other aseptic techniques, such as flexibility in packaging design, the ability to ensure a high level of sterility assurance, and maintaining low costs (1). In addition, the use of BFS technology limits human involvement, which further improves the level of sterility assurance by removing a significant contamination factor from the process entirely. The technology enhances the ability to form the container and closure during the packaging process, which allows for a more custom design of the container. BFS technology can thus be used to meet specific needs and improve container ease-of-use (1). In order to learn more on the logistics, benefits, and potential drawbacks of BFS technology, 

spoke with Waiken Wong, PhD, manager of development engineering at Woodstock Sterile Solutions, an Illinois-based provider of sterile development and commercial solutions.

Can you please explain what BFS packaging technology is and how it applies to bio/pharmaceutical manufacturing?

 Blow-fill-seal packaging technology is a method where the container is formed, filled with product, and then sealed in a sterile environment. What comes out is a fully sterile finished product. It’s a good presentation for many drugs, including biopharmaceuticals. Sterility is critical for biologics and many other drugs because it prevents microbial contaminants in products.

 What benefits does BFS packaging technology offer, compared to traditional glass vial manufacturing?

There is far less human intervention when BFS packaging [is employed], and humans are the biggest cause of contamination. Contamination can have a negative impact on microbial sterility. Because the BFS process happens completely inside the cabinet of the machine, there is little chance for external contamination and problems with sterility. With BFS, the environment inside the cabinet of the machine is continually monitored for viable and non-viable particulate, and there is a constant, positive pressure shower of high-efficiency particulate air (HEPA)-filtered air that covers the filling section of the BFS machine. With those controls in place, along with the automation of the BFS machine, the operator doesn’t have to be in the room. It is designed to operate on its own, without any human intervention. An additional benefit is that there are fewer components compared to glass vials, so you don’t have to deal with stoppers, crimp tops, and other closures. There are no equivalent cleaning steps to the ones glass vials need to go through. There are also no equivalent treatment steps to the ones glass vials need to go through, such as depyrogenation. Raw resin is used; it goes directly into the BFS machine and is molded directly. So, there are fewer components, fewer steps in the actual manufacturing process, and there is far less human interaction.

Can you explain cold temperature BFS and its benefits compared to regular BFS?

 Cold temperature BFS requires implementing a combination of techniques all together in one manufacturing process to help control the amount of heat that is imparted onto a drug product. During the typical BFS process, there is naturally quite a bit of heat, because raw resin is being melted to make bottles. The bottles themselves also need to be warm throughout the process so that the containers can be sealed shut in the final step. There is latent heat, but Woodstock Sterile Solutions has found ways to control that heat so that biomolecules can survive with no impact through the manufacturing process. With a cold BFS process, there are additional drug products that you can package, since you do not have to worry about drugs that are thermally sensitive. Many biomolecules are heat sensitive, and there are many proteins that can denature or degrade with heat, so traditionally, the biopharma industry has stayed away from BFS and stuck with glass—a tried-and-true option. Having this collection of manufacturing steps expands what is possible for drug products in blow-fill-seal.

What are some key considerations when implementing BFS technology?

One important consideration is understanding the drug product’s compatibility/interactions with plastic. Before opting for BFS, there needs to be an understanding of how the product interacts with plastic—if there are concerns about adsorption or absorption, for example. Additionally, plastic containers are permeable in a way that glass is not, and it is critical to understand if that will have an impact on the product throughout its shelf life. That being said, there are ways to counter permeation, whether it is water vapor moving out or oxygen moving in, in order to maintain the quality of the product inside. Lastly, although BFS can be used to fill liquids that are highly viscous, if the product is more ointment-like, then it will be difficult to fill using BFS. That makes it harder to push through the piping and other parts of the system, but the technology can handle a wide range of viscosities.

What are the drawbacks of using BFS technology, if any?

The permeability mentioned earlier is one challenge, as are the material interactions I noted. Also, there are challenges with heat and thermally sensitive products, but those can be addressed using cold BFS.

What are the regulatory and compliance considerations when using BFS, if any?

 FDA considers BFS as an advanced aseptic manufacturing technique, recognizing its ability to produce sterile drug products reliably while also ensuring a high level of quality for patients. The industry is held to the same standards, as all drug packaging technologies are, to ensure product safety and quality.

Pharmaceutical Technology, Pharmaceutical Technology Europe


Vol. 46, No. 9
October 2022
Pages: 37, 51

When referring to this article, please cite it as A. Leon, "Improving Sterility Using Blow-Fill-Seal Technology," 

Articles

BFS technology can help maintain sterility during the biologics manufacturing process.

Improving Sterility Using Blow-Fill-Seal Technology

Unexpected occurrences, such as the COVID-19 pandemic, have shone a light on the already existing issue of global accessibility to medicines through traditional means of manufacturing. As technology improves, the industry looks toward how to improve the landscape of medicinal accessibility. Point-of-use manufacturing may have the potential to change the distribution and accessibility of medicines throughout the world, but not without considering some of the challenges that may arise. 

 spoke with Peter Walters, director of advanced therapies at CRB, and Maik Jornitz, president and CEO of G-CON, to explore some of the benefits, challenges, and logistics of point-of-use manufacturing.

The flaws of a new manufacturing approach

What are some of the major challenges/obstacles to consider when approaching point-of-use manufacturing of drug products?

 Point-of-use manufacturing solves the problem of patient adjacency and therapy transport logistics, but typically introduces the problem of a distributed manufacturing model. The design capacity of a point-of-care facility is most often smaller than that of a central production center, and, as a result, the cost effectiveness of having a fully effective support infrastructure must be evaluated. It is typical for functions like QC/EM [quality control/environmental monitoring] testing, warehouse, engineering support, etc. to be stripped from the building and outsourced or supplied from other sites. As a result, it can be difficult to provide and ensure the same degree of quality, consistency, and compliance in a point-of-use facility compared to a centralized manufacturer. While you have possibly solved the issue of patient access and therapy transport, you have introduced logistical issues with maintaining supply chain and support (engineering, maintenance, calibration, etc.) logistics.

: The past of point-of-use or point-of-care manufacturing has shown certain weaknesses when reviewing cGMP [current good manufacturing practice] compliance and aseptic processing safety. There were many examples which showed flaws, [such as] contamination control strategies, [where] low costs were the focus instead of high quality. These past experiences need to be overcome, [which] can only be done when the new wave of point-of-care systems are of high quality and in compliance with regulatory requirements. For example, process spaces or units still need to have the appropriate cleanroom classification, material, and personnel flows and gowning. Any cleanroom installed base at the point-of-care requires to be of sufficient quality instead of a cheap fix.

How has the COVID-19 pandemic impacted point-of-use manufacturing, in your opinion?

 Yes, it has; from mobile sample/test units to compounding and filling units to be able to fight the pandemic spread and drug shortages. The pandemic highlighted that we can be more flexible within our processing systems and bring the processing towards the point-of-use. In our experience, it has been very encouraging to see the industry, regulators, and suppliers come together to work on processing solutions, which allow much faster and more flexible capacity build-up.

The availability of COVID-19 vaccines in countries not manufacturing a vaccine directly has been challenging and has caused many countries to revisit their philosophies for providing capacity for therapy supply in-country. Some smaller countries have begun government-sponsored facilities for bringing vaccine and critical therapy innovation within their borders to manage against a repeat of the COVID-19 pandemic situation.

: How can point-of use-manufacturing facilities improve accessibility to vaccines and other drugs in certain countries?

 Many pharmaceutical therapies, especially when it comes to sterile injectables, have transport and storage logistics that involve cold chain complications. When trying to manage transport between different countries, factoring in customs and inspections timing, the effective shelf life and efficacy of a therapy can be dramatically impacted by just trying to deliver cross-border. Further, factor
in that most countries producing a
vaccine are likely going to prioritize their own citizens first. The brutal truth is that smaller countries may find themselves waiting in the queue for therapies to arrive, with reduced usability once they do. In many cases, the ability for these countries to have point-of-use manufacturing centers enables them to begin supplying patients faster and more effectively.

: How can modular facilities/point-of-use drug manufacturing impact manufacturing capacity/scalability?

: The design capacity of a point-of-care facility is typically smaller than that of centralized production facility. The facility is intended to serve a local patient population instead of a global population. Therefore, the scale of production for a point-of-use facility is going to be smaller by design. While smaller production [is] at an individual level, at a global view you can leverage a number of these distributed facilities to make an impact on patient populations.

 How can a controlled environment be maintained in a modular facility in different climates/smaller production space to ensure consistent drug quality?

: It all depends on the technology deployed. It is much more difficult to control the environment in a modular facility unit, which was meant for other purposes, for example, transport containers. Cleanrooms are purpose-built, with high quality to be assured that the injectable coming out of such unit is safe for the patient. Mobile units we delivered need to have the right robustness in containment to [ensure] that the processing of the medicinal drug is safe in any outside environment. That starts with temperature, pressure, and humidity controls, which means the air handling units needs to be appropriately scaled, [and] insulation needs [to be] correctly specified and personnel/material flows controlled so outside air cannot penetrate the processing space. This can only be done with high-quality designed and constructed cleanroom systems.

: There is, at this point, an established history of fully modular manufacturing spaces being able to provide robust cleanroom environments to support GMP processing. The design team would need to account for the site location requirements, and, if the point-of-use facility is intended to be mobile and relocatable, the span of site requirements it may encounter.

 What engineering considerations must manufacturers be aware of prior to approaching point-of-care manufacturing in a modular facility setting?

 Modular builds are fast to erect but come with their own set of design complications. Spaces must adhere to certain dimensional restrictions for shipping purposes, which can implicate how many cleanroom suites and how large they can be. Modular builds can be completely free-standing outside, but this would need to be factored in from the start of design. One prime benefit of the modular approach for point-of-care spaces is that they can be disassembled and relocated to different sites, as befits the point-of-care need.

: The processing environment requires to be protected in the same way as any other processing space. In [certain] instances, one can see a drift into low quality environments, which requires strict regulatory reviews as there may be weaknesses in containment and stable environmental conditions. That means the design and build of these modular facility settings requires detail and experience to meet the quality and regulatory demands.

 spoke with Peter Walters, director of advanced therapies at CRB, about point-of-use manufacturing for cell and gene therapy.

 How can point-of-use drug manufacturing impact the cell and gene therapy industry?

 Point-of-use manufacturing could have the potential to improve the personalized cell therapy industry. These therapies suffer from transport logistical issues in moving patient cells from the clinic to the manufacturing facility, and then back again. This transport causes delays to the delivery of the therapy to the patient, introduces cold chain and sheer sensitivity shipping hurdles, and lengthens the time the cells are forced to be stored in a non-ideal state. All of these ultimately contribute to lowering the efficacy of the therapy and the chances the patient will have a successful recovery. Moving the manufacturing activity adjacent to the patient could dramatically reduce these issues, potentially improving the therapy’s effectiveness.

: What technological
improvements have occurred that have helped to progress point-of-use
manufacturing?

: The technology improvements happened twofold; single-use process technology enabled closed processes and mobile cleanroom units to deploy such processes to different location or being cloned to a multitude of locations. In addition, the volumes processed, for example in cell therapy, are much smaller, which
allowed process intensification and the processing within single-use
assemblies within smaller footprint mobile cleanrooms. If the volumes would not have gone down and we would still live in a world of 20,000L volumes, point-of-care processing would not [be able to] happen.

 The industry push towards Pharma 4.0 and the widespread adoption of automation and digitalization helps drive toward consistent and digitally documented manufacturing. One of the biggest hurdles for a distributed manufacturing model is how to maintain and ensure quality and consistency from site to site. The use of concepts like electronic batch records, online process monitoring, and automated quality testing would go a long way to providing quality assurance and helping negate site to site nuances.

 What, in your opinion, do you foresee as being important trends that will impact point-of-use manufacturing in the near future?

: Three factors will determine the use of point-of-use manufacturing; scalability, controls, and quality. With the possibility of mass-production of mobile progressing units, we can bring costs down and therefore scale such platforms much faster. Controls are needed to keep these processes and units under the robust containment options needed, as well as potentially reduce the human contamination impact. Quality is a must and it starts with the design and construction materials used. Ultimately, the quality benefits will outweigh the cost of bad quality, and that will save patients’ lives.

: To enable point-of-use manufacturing to go from talking point to reality, facilities are going to need to utilize robust small-scale processing solutions that are automated and digitally integrated. To make the business model viable, manufactured therapies will need to be handled and produced with the same level of quality and care from site to site. Use of automated processes, testing, and digital monitoring will be essential in ensuring quality and consistency across the manufacturing network. 

When referring to this article, please cite it as A. Leon, “Advancing Accessibility through Point-of-Use Manufacturing,” 

Point-of-use manufacturing may lead to a big change in the accessibility of medicines globally. 