Why choose robotic processing for small batch aseptic filling

Aseptic filling is changing.

Many modern therapies require smaller batch sizes, more flexibility, and faster timelines than traditional filling operations were designed to support. Early-stage clinical programs, cell and gene therapies, personalized medicines, and CDMO operations often need to manage frequent product changes while maintaining the same expectations for sterility, quality, and regulatory compliance.

For these applications, manual filling approaches may appear practical, particularly when production volumes are low. However, manual processes can introduce contamination risk, increase operational complexity, and make it more difficult to scale as manufacturing needs evolve. As manufacturers evaluate options for small-batch aseptic filling, many are considering whether automated processing can provide a more repeatable, flexible, and sustainable approach.

This article explores several key considerations when evaluating automated aseptic processing for small-batch applications.

Industry trends are driving demand for smaller, more flexible filling operations

Aseptic filling is the final step in manufacturing injectable drug products and plays a critical role in preventing contamination between sterile filtration and final container closure. For products that cannot undergo terminal sterilization, maintaining aseptic conditions throughout filling is especially important. At the same time, the industry is seeing a growing number of applications that require smaller batch sizes. Early-stage clinical trials may involve limited patient populations, while personalized therapies can require very small production runs. CDMOs must also be prepared to support multiple customers with different products, formats, and production schedules.

We’ve seen an increasing number of pharmaceutical manufacturing applications that require batch sizes of 30 000 units or less – specifically, early-stage clinical trials based on 50 to 100 patients and personalized cell and gene therapies focused on a single patient that require batch sizes of 1000 units or less. We conducted market research that demonstrates this trend (Fig 1) (1) with small-mid sized batches defined as those with batch sizes of 30 000 units or less.

Fig 1. Market research data shows a trend toward smaller batch sizes and personalized therapies (4).

This shift is changing how manufacturers think about aseptic filling. Equipment and processes designed primarily for large-scale production are not always well suited to small, variable batches that require greater flexibility.

Why manufacturers are moving toward automation

Regulatory authorities and industry experts have consistently emphasized reducing operator intervention in aseptic processing.

As FDA guidance states:

“A well-designed aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases.” (2)

Similarly, experts James Akers, Jim Agalloco, and Russell Madsen described advanced aseptic processing as an approach in which direct intervention with open product containers or exposed product contact surfaces is not required and never permitted (3).

These perspectives reflect a broader industry direction: reducing dependence on manual intervention while increasing process control and consistency.

For manufacturers evaluating their aseptic filling strategy, the question is not simply whether manual filling can work. The more important question is whether manual filling can continue to support the contamination control, repeatability, and operational flexibility modern manufacturing demands.

Gaining speed to GMP filling without creating long-term risk

Operator error and the risk of contamination

Agalloco and Akers reviewed sources of contamination in cleanrooms between 1986 and 2001, and identified personnel, human error, and non-routine activity as the top three sources (4).

While it is widely understood that humans are the highest source of contamination in a cleanroom, it needs to be said that the risks of human error and non-routine activity is especially high in the aforementioned applications. Facilities focused on development of these applications often have different drug products being produced into different containers, each with their own unique requirements. Having operators trained to deal with this level of variation is difficult, and the chances of making mistakes increases.

The repeatability and safety of manual processing have increasingly come under scrutiny as manufacturers seek to reduce sources of variability and contamination risk. These challenges can become even more significant in applications with frequent product changes and complex production requirements.

The same problem of human error exists in manufacturing cell and gene therapies. Patients receiving these therapies have often received alternative treatments without success, so their condition is usually much more fragile and administration cannot be delayed. That’s why shortest manufacturing time is so critical. In cell and gene therapy manufacturing, where therapies are often patient-specific and time-sensitive, minimizing the risk of batch loss is especially important.

The difficulty and cost of integrating and validating aseptic barriers and filling machines from many manufacturers

Having barrier systems and multiple pieces of filling equipment coming from different suppliers creates exponential effort and cost in the procurement, acceptance, qualification, and validation of the overall system. There are multiple parties to chase if something goes wrong, especially in the longer term when service and spare parts will be needed. Manual filling in a biological safety cabinet (BSC) or laminar flow hood (LFH) might seem an easier point of entry for an innovator company or contract development and manufacturing organization (CDMO) establishing aseptic filling capacity. These options would have lower upfront capital costs, but higher longer term operating costs. They add cost, as well as complexity—higher cleanroom classifications, plus more personnel, training, monitoring, and cleaning. Organizations may discover later that lower upfront investment can be offset by additional operational complexity, validation effort, and long-term maintenance requirements.

Evaluating investment costs and operational costs when building out your capabilities is critical prior to taking on this burden.

Manual operations raise the cost and failure rate of personalized medicines

Aside from investment recovery, one of the main reasons autologous cell and gene therapies cost so much is that manufacturing them can be highly manual. Lopes, Sinclair, and Frohlich modelled autologous cell and gene therapy production costs, examining how different approaches to manufacturing divided expenses (5,6). They also looked at whether these approaches could impact the efficacy of the therapy. Their model found that highly manual operations would have labor costs up to 50% of the cost of goods sold (COGS), whereas partially automated or automated operations range between 18% to 26%. Simultaneously, their models predicted failure rates of 10% for manual processes and only 3% for automated models, due to the 3.3-fold reduction in the number of manual interventions in the process. The authors’ suggestion was that automated systems needed to exist that would remove bottlenecks via parallel processing. This suggestion points to the need for equipment standardization as a path to reducing manufacturing costs of personalized medicines.

What does automated small-batch filling look like?

Manufacturers are responding to the challenges of small-batch aseptic filling in different ways, but many are evaluating technologies that reduce manual intervention, improve process consistency, and simplify contamination control.

For small-batch applications, this often means looking for solutions that combine:

• Automated operation
• Closed processing environments
• Rapid changeovers
• Flexibility across products and formats
• Simplified cleaning and decontamination
• Scalability as manufacturing needs evolve

These capabilities can help manufacturers maintain flexibility while reducing some of the operational complexity associated with manual filling approaches.

Gloveless isolators enable automated aseptic processing

The challenges associated with manual aseptic filling have led many manufacturers to evaluate automated approaches that reduce dependence on operator interventions while maintaining the flexibility required for small-batch production.

One example is the Microcell™ vial filler from Cytiva. The system was developed specifically for small-batch aseptic filling applications and was designed as an alternative to manual filling approaches performed in biological safety cabinets (BSCs), laminar flow hoods (LFHs), or conventional isolators.

Request a Microcell demo

The Microcell vial filler combines automation, single-use flow paths, rapid decontamination, and simplified format changeovers to support flexible GMP manufacturing.

The system was designed to support the manufacture of multiple products with rapid turnaround times. Features such as recipe-driven automation, tool-less format changes, single-use product-contact materials, and a fast vapor-phase hydrogen peroxide decontamination cycle help support efficient operation across different products and campaigns.

Each Microcell vial filler is also built as a standardized platform, allowing organizations to add capacity through scale-out as demand grows. This can be particularly beneficial for emerging therapies that may begin with limited production requirements but require expansion over time.

Conclusion

Small-batch aseptic filling presents a unique set of challenges. While manual approaches may appear practical initially, they can introduce contamination risk, increase operational burden, and make future growth more difficult to manage.

At the same time, industry expectations are evolving. Regulators and industry experts increasingly emphasize reducing human intervention, improving process control, and adopting technologies that strengthen contamination control and consistency.

As therapies become more specialized and batch sizes continue to shrink, manufacturers need filling strategies that provide both flexibility and control.

Automated aseptic processing offers one approach to achieving that balance. By reducing reliance on manual intervention and supporting more repeatable execution, automated systems can help organizations build aseptic filling operations that are prepared not only for today's requirements, but also for tomorrow's opportunities.

REFERENCES

1. Aseptic filling market assessment, for Cytiva. Boston Consulting Group. December 8, 2023.
2. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice. US Food and Drug Administration (FDA). September 2004. Accessed November 2024. https://www.fda.gov/media/71026/download
3. Akers J, Agalloco J, Madsen R. What is Advanced Aseptic Processing? Pharm. Manuf. 2006;4(2):25-27. N
4. Agalloco J, Akers J. Aseptic processing: A vision of the future. Pharm. Tech. 2005;29:s16-s23.
5. Lopes AG, Sinclair A, Frohlich B. Cost Analysis of Cell Therapy Manufacture: Autologous Cell Therapies, Part 1. BioProcess International. https://www.bioprocessintl.com/cell-therapies/cost-analysis-of-cell-therapy-manufacture-autologous-cell-therapies-part-1. Published March 27, 2018. Accessed November 2024.
6. Lopes AG, Sinclair A, Frohlich B. Cost Analysis of Cell Therapy Manufacture: Autologous Cell Therapies, Part 2. BioProcess International. https://www.bioprocessintl.com/cell-therapies/cost-analysis-of-cell-therapy-manufacture-autologous-cell-therapies-part-2. Published April 20, 2018. Accessed November 2024.

Explore other relevant articles

• Gain speed to GMP filling
• Standardization and flexibility in aseptic filling
• Key topics and trends in aseptic filling
• CDMO uses robotic gloveless isolator for advanced therapeutics
• Economic advantage of robotic gloveless pharmaceutical isolators
• How robotic isolator technology aligns to Annex 1 principles
• Biofluorescent particle counters are gaining momentum