Aseptic filling is a crucial step in drug manufacturing, as it safely seals a medicine into its final container before it’s administered to patients. Although critically important, this step is often riddled with outdated technology and hearsay guiding processes and equipment selection. It’s time to bring science and data into the conversation, as needs, technology, and regulatory scrutiny have evolved. Read on to discover what’s topical with insights from two subject matter experts that have decades of industry experience under their belts – plus feet on the ground at conferences, inspections, and audits across the globe.
Where we started with aseptic filling
Automated filling, which started mostly with beverages but expanded to food and medicines, traces back to the mid-1800s. While hand filling was common for small-scale needs like clinical trial batches, automated processes have been in place for a very long time. Aseptic practices started to change in the mid-20th century with the introduction of cleanroom classifications, high-efficiency particulate air (HEPA) filtration, and environmental monitoring. But the core challenge remained: humans are the main source of contamination. With this realization came the development of barrier technologies such as restricted access barrier systems (RABS) and isolators, which physically separate operators from the product to varying degrees.
Despite the use of isolator technology in other industries since the mid-1900s, pharma didn’t start to look seriously at isolators until the 1990s. Although drug development progressed, aseptic filling adoption remained slow – until recently, when that began to shift.
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What’s driving the need for change
Personalized medicine and smaller patient numbers
The rise of targeted treatments for highly specific patient populations has reshaped the landscape of aseptic filling. Advanced therapy medicinal products (ATMPs)—including cell therapies, gene therapies, and nucleic acid therapeutics—are often produced in small batches to treat a small number of seriously ill people. Despite the low volume, these therapies demand a high level of purity, rapid turnaround, and minimal product loss, especially given their high cost and limited shelf life.
Another factor leading to smaller batch sizes is the trend of onshoring domestic supply, which started with the 2020 pandemic and continues today. Adds Scott Harper, Director of Global Sales for Aseptic Filling at Cytiva, “What we can witness from that is you need smaller manufacturing footprints because you're not producing for a global population.”
Advances in technology
To meet the demands of modern therapeutics, new technologies have emerged over the past few decades. On this list are advances to automate operations in isolators, remove the need for operator interventions, improve the connectivity, and design systems that can continuously monitor viable particles in real time. Though adoption was slow at first, these innovations are gaining traction.
Today’s aseptic filling isolators offer fully enclosed systems with decontamination cycles. They’re available open or closed, with or without glove ports for operator access. Gloveless isolators eliminate human intervention in the critical zone. Some systems are fully automated and can integrate with modern methods of environmental monitoring (EM).
Read about how BFPCs are gaining momentum
Though they don’t take full advantage of recent advances, RABS (restricted access barrier systems) are a move forward from manual filling. They provide a physical barrier between operators and product, typically with glove ports for manual intervention. Open and closed configurations are available.
Each technology has trade-offs in terms of cost, flexibility, and sterility assurance, among other factors.
Heightened regulatory scrutiny
Regulatory bodies have sharpened their focus on contamination control and sterility assurance. The 2022 revision of EU GMP Annex 1: Manufacture of sterile medicine products emphasizes quality risk management (QRM), contamination control strategies (CCS), and the use of advanced technologies to minimize human intervention.
According to Brent Lieffers, Sr. Director of Innovation Advocacy at Cytiva, regulatory scrutiny is increasing around system design, EM, and material transfer methods. Interpretation of guidance on these topics varies across geographies and even within agencies. This has led to a more conservative industry stance, with manufacturers often exceeding baseline requirements to hedge their bets on acceptance in all intended markets.
Global harmonization challenges
Brent suggests that this conservatism continues to hinder the progress on alignment and adds that the ultimate goal of a simplified global approval process based on mutual recognition seems very far off. Despite efforts by the European Medicines Agency (EMA), World Health Organization (WHO), and Pharmaceutical Inspection Co-operation Scheme (PIC/S) to harmonize standards, regional differences persist. These nuances pose challenges for manufacturers to design and implement aseptic filling processes that will support approvals in all regions where they intend to provide their drugs.
Hot topics in aseptic filling
Regulatory interpretation and Annex 1
Annex 1 promotes risk-based approaches and modern technologies but leaves room for interpretation. As a result, its principles haven’t been applied consistently. Scott notes that some people are looking at it as a prescriptive document, to be followed letter by letter. He clarifies, “The intent of Annex 1 is very clearly stated in the introduction, and it's to ensure contamination—microbial, particulate, and endotoxin—is prevented in the final product. Everyone has an opinion on it, which isn’t always based on good data or sound rationale.” This sentiment applies especially to new technology that can be used to speed up the process and give better results.
First air
In the 2008 version of United States Pharmacopeia (USP) <797> Pharmaceutical Compounding - Sterile Preparations, "first air" is defined as “the air exiting the HEPA filter in a unidirectional airstream that is essentially particle free”. In the 2024 revision, this was simplified to the “air exiting the HEPA filter in a undirectional airstream”. It’s interesting to note that USP <797> is the chapter describing the minimum standards to be followed for compounding sterile preparations rather than for the manufacture of sterile medicinal products. Compounding is mainly done by hand for small volumes; good aseptic technique is crucial to prevent contamination.
The term “first air” was added to Annex 1 in the 2022 revision. The definition was expanded to “the filtered air that has not been interrupted prior to contacting exposed product and product contact surfaces with the potential to add contamination to the air prior to reaching the critical zone”. This definition is interpreted in various ways and continues to be a hot topic at conferences. Some have focused on the aspect of airflow interruption, even stating that first air can’t be interrupted. But it's not physically possible to move a needle over an open container to fill it without interrupting the airflow to some extent. Rather, the inherent interruption of the airflow shouldn’t be with something that could add contamination. Again, it makes sense that this idea came from compounding where the most common interruption of the manual filling process is the human operator – the biggest source of contamination. Ultimately, systems should be designed to effectively use airflow to prevent contamination of the final product, using computational fluid dynamics and airflow visualization to demonstrate effectiveness.
Material transfers into a Grade A cleanroom
Material transfer remains a critical challenge that spurs much debate. Somehow, materials and components must make their way into the critical zone in a way that protects both them and the environment from contamination. Common methods include vapor-phase hydrogen peroxide (VPHP), E-beam, UV pulsed light, and no-touch transfer (NTT) systems, each with unique pros and cons. The key is to select an approach that makes sense for your system, then validate the implemented method and document it within the CCS.
Stopper bowls
Stopper bowls are a persistent source of risk mostly because of their size and weight, which makes them difficult to handle in a way that prevents the potential for contamination. Some equipment manufacturers have eliminated them by using ready-to-use (RTU), single-step closures, thereby simplifying setup and reducing aseptic risk.
Brent adds some color stating, “There are plenty of disagreements on how you clean, prep, sterilize, and install such parts. Cytiva simply got rid of the stopper bowls. Our design eliminated all the indirect product contact parts, such as stopper bowls, hoppers, vibratory tracks, syringe stoppering tubes, etc., drastically reducing the risks those common hazards otherwise present.”
Environmental monitoring
Traditional methods for detecting microbial contamination have all relied on the use of growth media. This means results are never real-time, as the media must be incubated and then checked to see if any microorganisms have grown sufficiently to be seen. Newer technology, specifically biofluorescent particle counters (BFPCs), offers real-time monitoring of both viable and nonviable particles, making it possible to immediately identify contamination concerns and react accordingly. These technologies are referenced more and more in regulatory guidance, including Annex 1. Whatever the method, it’s critical to demonstrate control through robust CCS and validated data.
The path to modernizing operations
Understand your options
Modernizing aseptic filling begins with understanding your choices. Each technology—manual, RABS, and isolators—has its place depending on sterility assurance, batch size, training requirements, and other factors.
Brent notes that it’s important not to just consider your needs today; instead, think about how they might evolve in the future. Speaking about automated, gloveless isolators he shares his experience, “Anyone who's lived the pain of running a small-batch aseptic filling operation doesn’t take long to recognize the benefits.”
Engage all stakeholders
Successful implementation shouldn’t be left to chance. It requires input from all stakeholders, including operators, quality assurance (QA) personnel, and clients – ideally even before you make a purchase. Too often, the day-to-day users and QA staff are overlooked in these early stages. CDMOs must balance their interests with the expectations of different clients.
Collect and document compelling evidence
Data-driven decision-making is essential to choosing the technology that best matches your needs and will stand the test of time. From a regulatory perspective, it’s important to collect and present compelling evidence to support your choices, especially when you’re looking beyond historical options. Brent, who has been at regulatory meetings, adds that this evidence should be well-documented in the CCS.
Learn from others
You don’t have to travel this journey alone. Case studies offer valuable insights. For example, look at organizations that have already achieved what you’re aiming for.
For example:
- NorthX Biologics achieved GMP compliance within 15 months of acquiring a Microcell™ vial filler.
- White Raven secured EMA Annex 1 certification in just 18 months using the SA25 aseptic filling workcell, enabling rapid changeovers and flexible batch sizes.
- Emergent BioSolutions implemented an SA25 to bring new products to market faster.
View infographic to see how NorthX and White Raven achieved Annex 1 GMP certification
These examples demonstrate how thoughtful planning and collaboration with vendors can trim the time from purchase order to fully operational.
Other places to look for guidance are publications and user groups where companies are willing to share their experiences using the equipment you’re considering.
Insist on high-quality vendor support
From installation and training to regulatory alignment, you will set yourself up for success with vendors that go beyond simply making a sale. One point to consider is how the vendor design their technology – do they truly have your best interests in mind? Scott and Brent concur that standardized systems designed according to QRM principles can minimize project risk and accelerate time to clinic. Regulatory support and qualification services are especially helpful for smaller companies that lack in-house expertise in those areas.
Involve regulators early
Early engagement with regulators can preempt misunderstandings and streamline approvals. Sharing risk assessments, design rationales, and validation plans upfront fosters transparency and builds trust. As Brent notes, proactive dialog is essential to overcoming skepticism and aligning expectations.
The path forward
Aseptic filling is undergoing a profound transformation driven by personalized medicine, a rapid pace of innovation, and evolving regulatory landscapes. While challenges remain—particularly around regulatory interpretation and harmonization—the path forward is clear: prioritize risk-based design and foster collaboration across the value chain.
Whether you’re considering RABS, gloved isolators, or gloveless systems, the key is to align your technology choice with your product needs, regulatory strategy, and operational goals. By embracing innovation and involving key stakeholders, manufacturers are well on their way to delivering safe, effective treatments to patients quickly and reliably. Ultimately, that’s the most important goal of all.
Brent Lieffers biography
With more than 30 years in the parenteral pharmaceutical industry, Brent is a seasoned leader who’s walked the walk – from API manufacturing to aseptic filling and final drug product packaging. As Sr. Director of Innovation Advocacy at Cytiva, he channels that deep experience at both biotechs and CDMOs into helping customers bring life-changing medicines to patients quickly and efficiently. Prior to his current role, Brent served as general manager of the company’s aseptic filling business, joining from CDMO Singota Solutions where he was one of the first to implement and realize the advantages of Cytiva’s gloveless aseptic filling workcell. Passion for innovation and customer success continues to drive his work.
Scott Harper biography
As Director of Global Sales for Aseptic Filling at Cytiva, Scott leads strategic initiatives that drive innovation in pharmaceutical manufacturing. With over 20 years of experience in sales and business development, he has cultivated strong partnerships with C-suite leaders and industry stakeholders. Since joining Vanrx Pharmasystems (now part of Cytiva) in 2017, Scott has witnessed how standardization can transform industries – just as it did in dental labs earlier in his career. That same shift is now reshaping pharma, albeit at a more measured pace. Scott is passionate about delivering scalable, efficient solutions that meet the evolving demands of modern drug production.
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