New biopharmaceutical products are high-value and complex to manufacture. Many are targeted at smaller patient populations. At the most extreme, personalised medicines such as cell and gene therapies are made for a patient population of only one person. Most of these drugs are injectables that need to be aseptically produced in different vial, syringe and cartridge containers. Manufacturers are challenged to make a greater number of more complex products in smaller batches, so production flexibility is crucial.
In this environment, conventional aseptic filling technologies are not well-suited for small batch manufacturing. Time-consuming glove testing and decontamination cycles rob manufacturers of their agility to switch between drug products and container types quickly. Complex electro-mechanical components mean container changeover processes last at least several hours, if not days. Most of these systems, if not all, are custom-designed, so installation and validation are unique each time a filling facility is constructed. Plus, conventional systems routinely require many operators at a time when regulators, such as the US Food and Drug Administration, have long stated the need for aseptic filling systems to use robotics and reduce human interaction with drug manufacturing.
Chris Procyshyn and Ross Gold, Vanrx Pharmasystems’ founders, know this well. Earlier in their careers, when managing and operating biologic fill-finish facilities, they had their own painful experiences with restricted access barriers (RABs) and isolators. They set up Vanrx to do things differently. They looked at examples from other industries and designed a new type of gloveless robotic isolator, first commercialised in 2013. A gloveless isolator redesigns the aseptic filling process to improve containment and provide flexibility for multi-product manufacturing.
Productivity gain
The gloveless robotic isolator for biopharma has strong roots in semiconductor manufacturing. In the 1990s, semiconductor wafer manufacturers realised tremendous gains in productivity and quality by using robotic “workcells”. These are completely closed robotic systems that could operate at extremely low particle levels. These productivity gains are now being seen in pharma.
The isolator is called “gloveless” because it does not have glove ports through which operators can intervene in the production process. Robotics perform all operations within these systems. A gloveless isolator can be installed into a grade C or D cleanroom, depending on the regulatory authority.
Conventional systems need glove ports because problems occur that can only be corrected by operators. With gloveless isolators and robotics, not only do the majority of operational issues send in conventional systems simply not happen, but issues that do occur can be solved through robotic manipulation.
There are two key design parameters of a gloveless isolator. First, the sources of interventions through glove ports are designed out of the machines. If there are no conveyors, vibratory bowls, star wheels and other moving parts, at least 95% of the possible interventions no longer exist. Designing these parts out simplifies the interior of the isolator, boosting decontamination speed and effectiveness. Vibratory bowls and conveyors are particle generators, so their removal reduces the risk of particle introduction into the drug product.
Second, containers and closures are never handled individually and are only handled by robots. This concept was learned from semiconductor manufacturing, which uses a front-opening unified pod (FOUP) to move wafers between machines. In an aseptic filling workcell, the FOUP’s equivalent is pre-sterilised, nested ready-to-use (RTU) containers and closures. Handling nests of containers significantly reduces the possibility of an intervention and eliminates particles from glass-to-glass contact.
By integrating filling and handling robotics within a gloveless isolator, there is far lower risk to the product through particulate generation or human intervention. Vision systems and automated environmental monitoring support a repeatable, error-free process with strong assurance that the product is safe.
The role of the operator changes with the workcell. Only one operator is required, versus several for a conventional system. This operator loads the machines with containers and closures, attaches a fill vessel containing the drug, installs a single-use flow path, and initiates the recipe sequence. The operator observes the sequence and removes finished product from the machine.
The combination of RTU components and robots unifies the material handling method across different container types, which means fewer change parts and faster changeover times.
The handling and filling of the containers are identical whether the container is a vial, syringe or cartridge, providing a highly repeatable process. Press-fit vial closures with integrated, industry standard stoppers are also used. These closures generate fewer particles than conventional aluminium crimp caps reducing the risk of contaminating the drug product.
Vanrx Aseptic Workcells provide a common platform of integrated robotic filling systems within gloveless isolators
Faster to market
The Vanrx gloveless robotic isolator standard product with the built-in flexibility to fill and close multiple container types. With low downtime between batches, it can be effective at both clinical and commercial quantities.
The Aseptic Filling Workcell supports pharma companies to bring their products to market faster. Because the Workcell is a standard product, new drug product process development can occur earlier in a product’s lifecycle, and filling capacity can be built and validated in 15 months or less. Its compact design takes 60% less cleanroom space than a conventional isolator alternative, reducing build costs. Furthermore, as drug product demand grows, pharma companies can quickly add additional Aseptic Filling Workcells, cloning existing processes and recipes.
Global adoption
Due to the need for small batch, multi-container flexibility and improved aseptic assurance, Aseptic Filling Workcells are experiencing wider global adoption. As drug products become more personalised, Aseptic Filling Workcells represent a manufacturing model that can help to scale up or scale down the process while improving product safety and the economics of biologics and cell and gene therapies.
Four contract manufacturing organisations (CMOs) – AB Biotechnologies, Fujifilm Diosynth, Patheon and Singota Solutions – have publicly announced their use of Vanrx’s SA25 Aseptic Filling Workcell. A host of innovator drug companies are also using the SA25 for drug development, and clinical or commercial drug product manufacturing into vials, syringes and cartridges.
In late 2017, Vanrx introduced the Microcell Vial Filler for the production of personalised medicines (cell and gene therapies, mRNA, and liposomal formulations), clinical trial supplies, and drug development. The Microcell won the 2018 ‘Best in Show’ award at Interphex, North America’s largest pharmaceutical manufacturing trade show.
Safety is an important part of commercialising new therapies. If we can separate the operator from the production process, the number one source of possible drug contamination is taken out of the equation. Many new drug categories—antibody drug conjugates (ADCs), and the viral vectors that carry cell and gene therapies—also pose production safety risks that are more easily dealt with by using gloveless robotic systems.
At Vanrx, we believe that cutting-edge drugs should be available to the largest number of patients possible. To achieve that goal, we are developing aseptic filling technologies that can help biopharmaceutical companies bring drug products to market faster, and make their production more cost-effective.
The future is gloveless for aseptic filling of biopharmaceuticals.
This article appeared in the October issue of Cleanroom Technology.
