Aseptic Pharma Manufacturing

The future of aseptic pharmaceutical manufacturing is gloveless, but what might sound like a bold vision is already turning into reality today

Markus Heinz at Syntegon Technology

Regulations are becoming stricter by the day, product and packaging characteristics are changing, and cost-performance pressure is increasing exponentially. Hence, the pharmaceutical and biotech industries are overthinking their manufacturing processes. In parallel – or, in the best case, together with the manufacturers – equipment suppliers are developing new technologies and processes. The long-term goal is to eliminate human intervention in the sterile environment through gloveless processes.

The pharma industry is experiencing an era of innovation. This not only applies to new drugs in the development pipeline and new therapeutics entering the market at an astonishing pace, it is also true for technological innovations that are urgently needed to keep up with the fast-paced industry. From small to micro batches, right through to high-speed filling processes, there is a clear trend towards removing operators from the aseptic area and automating as many process steps as possible. Gloveless manufacturing is no longer just a vision; it is in fact already becoming reality today – what is pushing this development towards gloveless manufacturing?

Firstly, compliance requirements with international guidelines have become much stricter, particularly regarding sterile manufacturing. EU GMP Annex 1 is influencing the way pharma and biopharma manufacturers, as well as contract development and manufacturing organisations (CDMOs), are viewing and changing their processes.1 This results in the need for higher automation and, ultimately, reducing human intervention to an absolute minimum, or even eliminating it altogether.

Secondly, manufacturers and CDMOs are facing enormous cost pressure. They must bring new drugs to the market faster and produce existing medicines at unprecedented output rates to safeguard international supply chains and patient demands. This calls for even more automation and robotics. If all process steps are performed autonomously by the fill-finish line, glove ports are a thing of the past and performance can be increased significantly, which results in higher yield, higher outputs and a higher drug availability.

Finally, flexibility and seamless integration with existing facilities are top priorities for the industry. Fill-finish lines must be able to switch between different products in very short times. The shift from traditional bulk glass production to ready-to-use (RTU) containers is further changing the requirements. Especially for CDMOs, RTU containers make switching much easier, allowing seamless transitions between vials, syringes and cartridges.

Since the revised Annex 1 entered into force in August 2023, liquid pharma manufacturing in particular has placed greater emphasis on automation. A central objective of Annex 1 is the physical separation of the aseptic processing zone from the operator environment. For the first time, the guideline explicitly recommends the use of barrier technologies such as isolators or restricted access barrier systems. Isolator technology is expected to become the prevailing standard, as automated bio-decontamination procedures and defined pressure differentials relative to the surrounding environment provide an additional level of protection.

To establish and sustain sterility, Annex 1 explicitly addresses automation and robotic systems as ‘appropriate technologies’ that reduce or, where possible, eliminate glove-based operations and direct human intervention. At the same time, compliance with the ‘first air’ principle introduces new technical challenges. Higher levels of automation, combined with positioning robotic systems at a greater distance from critical process zones, support an unobstructed airflow. This approach helps to minimise particle presence in the aseptic core area, and thereby reduces contamination risks while preserving first air conditions.

At the outset, automated, gloveless filling lines involve higher investment costs, primarily due to increased development and engineering requirements. As adoption by pharma manufacturers and CDMOs expands, these costs are expected to decrease as a result of scale effects in production and the supply chain. Equipment suppliers can multiply their machine concepts due to standardised processes and shorten machine delivery times.

Moreover, by reducing human intervention, contamination risks will decrease and sterility assurance will rise. In addition, functions such as 100% in-process control or automated re-dosing contribute to higher yields and increased batch output, which can help compensate for the higher initial expenditure associated with gloveless systems.

Another relevant, though often less visible, aspect is sustainability. Despite the relatively high energy demand of automated systems, they can contribute to a reduced overall environmental footprint by enabling lower personnel involvement and more compact facility designs. Contactless, suspended transport systems, for example, prevent particle generation that is inherent to conventional mechanical solutions.

Furthermore, reducing the number of components within isolators shortens cleaning and maintenance processes, and will prospectively further improve the safety of operators (if at all required) when handling highly potent substances such as oncology products.

Modern fill-finish lines are expected to offer a high degree of flexibility to meet the pharma industry’s increasing demand for a broad range of liquid drug products. In practice, this requires equipment that can handle multiple container formats, including vials, cartridges and syringes, while also supporting the growing use of RTU containers. Equally important is the ability to integrate seamlessly with upstream and downstream systems, such as de- and re-nesters, freeze-dryers, capping units and inspection solutions. Beyond container compatibility, flexibility is also defined by the capacity to accommodate varying production speeds and batch sizes.

In parallel, digitalisation and connectivity are gaining significance in pharma filling environments. The integration and use of data across systems will become increasingly central, particularly as filling lines are embedded more closely within broader production and factory infrastructures. Applications such as real-time condition monitoring can provide insights into equipment performance and support faster and more reliable batch release processes. In addition, the use of artificial intelligence and digital twin technologies enables new operational and analytical capabilities, contributing to a gradual but sustained advancement of digital practices within pharma manufacturing.

As pharma companies continue to introduce new therapies, technology providers are advancing solutions that support a transition towards highly automated fill-finish operations. These efforts focus on isolator concepts that are largely gloveless, minimally occupied and partially autonomous. Strategic collaborations between manufacturers and suppliers play an important role in this process, combining pharma expertise with engineering and automation capabilities to shift production away from human-centred processes. Future-oriented filling operations will further rely on flexibility and seamlessly integrated digital systems to support operational decisions.

Aligning technical development with regulatory requirements, performance and flexibility objectives will continue to be essential to ensure reliable production while meeting increasing global demand and maintaining high patient safety standards. The vision of fully automated fill-finish processes with a virtually empty, gloveless and partly autonomous isolator is approaching at a never-expected speed. Strategic cooperations between pharma manufacturers and technology suppliers will enable the necessary shift from human-centred to fully automated and, ultimately, lights-out production.

Reference:

1. Visit: health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf