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Small & micro batch filling with Versynta microBatch: setting new gloveless standards
While the production of drugs in large quantities used to be the benchmark for decades, today individual therapies are playing an increasingly important role in the fight against diseases. These usually very costly drugs require a high level of commitment in research and development. In addition, new machine concepts that can process small and very small batches are required – a task that Syntegon and development partner Vetter have now brought to a successful close.
The official market launch of the new Versynta microBatch1 from Syntegon at CPHI Barcelona in October 2023 quickly turned out to be a crowd puller. The fully automated gloveless production cell surprised visitors with its numerous technological innovations as well as its first sale to development partner Vetter, a globally leading CDMO. “There was already a lively exchange between the experts on both sides during the development phase,” says Vetter Managing Director Thomas Otto. “Versynta microBatch enables us to achieve the desired flexibility, regulatory compliance, and high level of automation that we, as one of the leading service providers for the fill and finish sector, want to offer our customers,” Otto says.
From small to micro batch
More and more novel and often personalized medications are now available to cure or at least delay some life-threatening illnesses. Cellular and molecular biotechnology has been accompanied by a revolution in pharmaceutical manufacturing: while high-speed, high-throughput lines used to be in greatest demand, more and more pharmaceutical companies are now investing in the development and commercialization of small-volume medicines, which have very different production and filling requirements. The increasing prevalence of advanced therapy medicinal products (ATMPs), such as cell and gene therapies and bioengineered tissue products, shows that the industry is specializing steadily. These drugs are not manufactured on huge lines. Instead, the focus is on what is commonly known as small batch production.
A precise definition of the term “small batch” is not specified in the ICH guidelines. The U.S. FDA, however, provides an answer for generic parenterals. Following the “Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers”, small batches consist of at least ten percent of the proposed maximum commercial batch size, or less than 15,000 to 60,000 containers based on fill volumes2. The batch size shrinks to a few thousand containers for parenterals used in clinical trials. For highly specialized treatments such as autologous cell therapy, batches are even smaller. On average, a patient needs about five to ten containers. The new fully automated production cell Versynta microBatch fills between 120 and 500 syringes, cartridges, or vials made of glass or plastic per hour with virtually no product loss.
The highest flexibility at the lowest possible reject rates
The growing number of cell and gene therapies in the development phase underlines the importance of ATMPs. Conventional high-speed machines can no longer meet the requirements of these new products. But how to produce these small or even very small batches economically? What must a filling line do to satisfy both pharmaceutical companies and patients? Flexibility is at the top of the list of requirements.
A wide variety of products must be filled into different container sizes and types. Single-use technologies are particularly popular for handling and processing these biotech drugs in a flexible manner since they eliminate the effort and costs involved in cleaning validation. Another criterion for flexibility is the reduced number of format parts, which removes the need for lengthy format changes. In addition, these very small drug product quantities require maximum product yield and low rejects. In a nutshell, any product loss must be avoided.
Automation for even higher safety
Human intervention is still the main reason for contaminated pharmaceuticals. Automation is essential to reduce or eliminate these interventions. For example, as far back as 2004, the FDA required that “the design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.” In addition, the FDA states that “automation of other process steps, including the use of technologies such as robotics, can further reduce risk to the product.”3
The new Annex 1 “Manufacture of Sterile Medicinal Products” of the EU GMP guidelines4, which came into effect on August 25, 2023, also focusses on preventing product contamination. One rationale of the new Annex 1 is the separation of the aseptic process area from the operator environment. For the first time, the document clearly recommends the use of appropriate barrier technologies – isolators and RABS (Restricted Access Barrier Systems) are considered equal. Pharmaceutical manufacturers will therefore require at least RABS for the approval of new products; new approval on existing cleanroom lines will only be possible in exceptional cases. In the long run, aseptic filling will evolve from human-centered to fully automated production with the use of appropriate technologies.
“Annex 1-ready” from the start
This change is already in full swing. For example, if containers within the isolator are conveyed to the filling station and on to the crimping station by a robotic arm, the risk of contamination is significantly reduced. Robots can also decrease the number of format parts and eliminate any glass-to-glass contact.
Newly developed systems, such as Syntegon's Versynta FFP (Flexible Filling Platform)5, also feature a laminar flow-optimized design to make sure that the air flow can reach the containers and flow around them without obstruction. One hundred percent in-process control (IPC) during the filling process reduces product loss to a minimum and ensures that almost every milliliter of the high-quality product is filled.
The newest member to the Versynta family was developed with Annex 1 in view right from the start. Although the exact wording of the document was still in discussion when the project kicked off, the most important points were already known – and a key prerequisite from Vetter for the joint development. Hence, the production cell with integrated air handling sets new standards, particularly in terms of sterility and automation. For conventional RABS filling lines, Annex 1 requires high level disinfection as soon as the gloves have been exposed to the RABS environment for interventions. A switch to gloveless systems with robotics that handle these manipulations represents the ideal solution. Manual intervention is no longer required with Versynta microBatch; steam-sterilized parts are fed via port systems and installed by the robot. Optional network cameras facilitate continuous remote production monitoring in the isolator.
An award-winning cooperation
The fully automated gloveless production cell fills between 120 and 500 syringes, cartridges, and vials made of glass or plastic per hour with virtually no product loss and with 100 percent in-process control. The dimensions of the machine are just as small as its output. With a length of barely 3.5 meters, a width of around 2 meters, and a height of 3 meters, the machine can easily be integrated into existing production environments. The isolator cell itself measures just 1.6 x 1.5 meters. It houses tub opening, the filling station including one hundred percent in-process control, and the combined stoppering and crimping station. Thanks to the integrated air handling system, hardly any interfaces to the building or technical ceiling installations are required.
The development partnership was honored with the PDA Drug Delivery Award in the category “Partnership Innovation” in 2021, followed by the German Packaging Award in 2022, and was nominated for the CPHI Pharma Award in the “Packaging and Machinery” category. The combination of regulatory, market, and technology expertise was the key to success: systems that ensure flawless processing for pharmaceutical manufacturers and the highest level of product and operator safety can only be developed if both partners not only react to trends, but proactively shape them together from the outset.
Author
Dr. Laura Moody
Director Product Management Pharma North America
Syntegon Technology
E-Mail: laura.moody@syntegon.com
About Syntegon
Processing and packaging for a better life – this is what 5,800 Syntegon employees work for every day. Be it with individual machines, systems, or services, Syntegon helps its customers in the global pharmaceutical and food industries to improve people's lives. The company, which is headquartered in Waiblingen, Germany, looks back on more than 160 years of experience and achieved annual sales of 1.4 billion EUR in 2022. In the pharma sector, the company’s intelligent solutions enable the safe and high-quality production, processing, filling, inspection, and packaging of liquid and solid pharmaceuticals. In the food industry, Syntegon’s flexible and reliable technologies produce and pack confectionery, dry food, frozen food, and dairy products. With 1,100 service experts and a comprehensive service portfolio throughout the entire machine lifecycle from spare parts management to digital line optimization, Syntegon lays the foundation for smooth production processes for all customers. More than 35 sites in almost 20 countries keep a firm eye on Syntegon’s impact on the environment and society. Syntegon is a leader in the development of sustainable packaging solutions, reduces the energy consumption of its machines and pursues ambitious goals to lower its emissions. www.syntegon.com
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