Flexibility Provides Solutions to Small-Batch Manufacturing Challenges

Personalized therapies have become a focus of the pharmaceutical industry with the advancement of cell and gene therapies, creating a need for specialized manufacturing processes and infrastructures. This new market of personalized treatments is also increasing the need for small batch sizes.

“Point-of-care production or hub-and-spoke models could become the norm,” David Phasey, Innovation Director at 3P innovation, said in an interview with BioPharm International® (1). “The automation of patient and manufacturing data will be key to this. The real question is whether the pharmaceutical industry is ready to adopt and accept this level of automation into a very slow-to-change industry. Can regulations keep up with technology and the opportunities it presents?”

Complexity often comes along with innovation. And the aspects of small-batch manufacturing for personalized medicine are no different. Processing speed, flexibility, and product yield are among these complex challenges.

“Every drop counts for high-value drugs, since even the slightest product loss has significant consequences related to the number of patients treated, as well as economic impacts, and must be avoided,” says Laura Moody, director of Product Management Pharma North America, Syntegon.

The challenges of small-batch manufacturing

Small-batch manufacturing comes with a distinct set of challenges, according to
Dr. Jitendra Amrutkar, Head–Process Technology & Support, ACG Engineering. Small batch means fewer doses and, therefore, a high cost per unit, Amrutkar adds, and these costs can be reduced by using modular systems and single-use technologies. The frequent changeover of products can also hit costs by creating downtime.

“There is clearly a trend toward smaller batch sizes of sterile product,” says Hanns-Christian Mahler, CEO, ten23 health. “This, of course, raises key questions on ‘yield’, as maximizing yield translates directly into the cost-of-goods for a given product. This is particularly important for such costly APIs as biologics.”

The manufacturing facility and processes must be adequately designed for small batches, stresses Mahler. “Specifically, ready-to-use (RTU) containers are convenient to avoid the need for large washing machines or sterilizing tunnels. However, formulation development and stability data are required to allow selection of an RTU container a priori,” he states.

There are also unique complexity considerations with personalized treatments, such as specialized materials and unique regulatory approvals, according to Dr. Amrutkar. “AI [artificial intelligence] and blockchain can help to overcome this issue by improving visibility and coordination,” he offers as a solution to supply chain concerns. For regulatory compliance issues, he recommends using digital records and adaptive pathways.

Automation has been an increasing tool for pharmaceutical manufacturing, but Dr. Amrutkar cautions that traditional automation systems are not suited for small batches. He recommends smart, modular automation and cobots, which offer flexibility.

Process development for small batches

A variety of process development approaches can help with the challenges of small-batch manufacturing, according to Dr. Amrutkar. He points to modular process design for flexible, scalable setups of products to support faster changeover and reduced downtime. A modular design may also make expansion easier. Virtual testing of processes before they are implemented can be facilitated by digital twins and simulation, Dr. Amrutkar says, which can reduce risk and improve efficiency. Continuous manufacturing can also streamline production by causing fewer interruptions and increasing turnaround times. Lastly, optimal process conditions can be identified by utilizing design of experiments.

“On the process side, suitable processing materials, such as tubing and filters, help to maximize extraction of the product,” Mahler explains. “Pharmaceutical manufacturers must consider ‘flush volumes’ that are required for the setup (e.g., to saturate sterile filters); how much volume other in-process controls (IPCs) require; and how the sampling volume may be reduced. Understanding the scale and batch size capabilities of a facility, including the lowest compounding volume that can be used, are key considerations.”

The evolution of human-centered to fully automated production in aseptic filling is increasing, according to Moody, with the use of “robotics for container transfer, fill/finish operations, and format part exchange within the isolator. A shift to gloveless systems further reduces the need for manual intervention,” she says.

“To avoid product loss, 100% IPC during the filling process ensures that almost every drop of product is filled,” Moody continues. “Moreover, new small- or even micro-batch solutions can support scale-up from manual clinical trial operations to automated production scale.”

Small-batch manufacturing equipment

Isolators and restricted access barrier systems can provide high contamination control and cost-efficiency for small-batch manufacturing by ensuring sterility in aseptic environments, says Dr. Amrutkar. To minimize product loss and ensure dosing accuracy, he points to micro fillers that can provide precision filling for low-volume, high-value biologics. Digital management of manufacturing and batch records can be achieved through manufacturing execution systems and electronic batch records. “They improve traceability, compliance, and data integrity, which is especially important for personalized medicine,” Dr. Amrutkar says. In addition, “ACG’s capsule filling and inspection systems are high-precision systems tailored for clinical and personalized applications. They are tailored for low-volume needs with integrated inspection to ensure quality assurance,” Amrutkar offers.

Flexible filling platforms are available for small- and micro-batch operations. Syntegon offers platforms that can process between 120 and 500 containers per hour and batches up to 3600 containers per hour. The company’s Versynta microBatch platform is a fully automated gloveless production cell with integrated air handling that was developed in partnership with Vetter, according to Moody.

ten23 uses ready-to-use (RTU) containers to operate at different sterile filling scales. In July 2025, the company announced it had joined the “Alliance for RTU” partnership, which intends to advance knowledge around sterile manufacture of RTU containers. The company’s role will be to contribute its own experience in development, sterile fill/finish, and testing of sterile drug products using RTU containers (2).

Fill/finish of small batches

When it comes to fill/finish of small batches, scale related to unit operations needs to be appropriate, says Mahler, who says manufacturers should consider the following questions. “How do you mix and homogenize 1 liter of material for a commercial product? Is that in place? Which disposables do you use, and how can you minimize residual volumes on the line? Where and why do you pull samples for in-process testing or extended characterization, and how can these volumes be reduced?”

He adds, “One great example is the choice of adequate sterile filters: some filter materials tend to adsorb critical components of a biologics formulation and may require 1 or more liters of flush volume. Other filters will be saturated with 10 mL. That can be a huge cost driver, or saver.”

Targeted solutions can address challenges associated with the fill/finish of small batches, says Dr. Amrutkar. For sterility assurance, isolators and automated aseptic systems are key for managing contamination risk, he says.

Safeguarding the aseptic environment is key in fill/finish of small batches of biopharmaceutical products, Moody agrees. “Humans pose the greatest risk for product contamination, so operator intervention must be reduced to an absolute minimum or even completely avoided to reduce this risk,” she says. Annex 1 of the European Union’s good manufacturing practice guidelines (3) recommends the use of these barrier technologies.

Precision filling technologies and single-use systems can combat product loss. Adopting a risk-based digital validation approach can streamline repeated validation.

Fill/finish systems that are traditionally used in pharmaceutical manufacturing are often too large for filling small batches of product. Scaling down to miniaturized, single-use equipment can combat this, according to Amrutkar.

Small batches of products may require different container formats that complicate the setup of machines. “Implementing modular lines and quick-change tools can help simplify the process, increase flexibility and adaptability, and help eliminate bottlenecks,” Amrutkar says.

Design and flexibility are key

Small-batch manufacturing should be performed holistically with development, manufacturing, and testing approaches integrated, says Mahler, and the combination of formulation and primary packing should be done ‘wisely.’

“Think about potential failure modes and assess your process in development labs, assessing the choice of materials, failure modes and acceptable ranges for your operating parameters, to ensure there is no (relevant) impact on your product’s critical quality attributes,” Mahler concludes.

References

1. Haigney, S. New Modalities in Biopharmaceutical Development Transform Industry. BioPharm International 2025 38 (5).
2. Lavery, P. ten23 health Joins Gerresheimer, SCHOTT, Stevanato Group in ‘Alliance for RTU’. PharmTech.com. July 1, 2025.
3. EC. Annex 1: Manufacture of Sterile Medicinal Products. EudraLex–Volume 4. Aug. 25, 2024.

About the author

Susan Haigney is lead editor for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 6
July/August 2025
Pages: 16–17

Citation

When referring to this article, please cite it as Haigney, S. Flexibility Provides Solutions to Small-Batch Manufacturing Challenges. Pharmaceutical Technology 2025 49 (6).