Aseptic filling for viral vector therapies
With recent FDA approvals, gene therapies and other personalized medicines delivered using viral vectors are a hot topic.
Viral therapies use viruses (retroviruses, adenoviruses, herpes simplex, lentiviruses, etc.) to deliver nucleic acid to specific cell types. Viruses have the ability to reach cells without detection and enabling the therapeutic “payload” to pass through the cell’s walls. These are targeted therapies, sometimes described as “cruise missiles for (insert disease name here).”
Viral vectors are applicable in gene therapy, chimeric antigen receptor T-cells (CAR-T) in immuno-oncology, and in vaccinations to proactively treat genetic diseases. Here’s a widely cited article on the different viral vectors and their applications.
The development of viral vectors has held the Vanrx team’s interest since the mid-2000s, when while working for a previous employer, we evaluated the manufacturing aspects of early immuno-oncology companies. Viral vector therapies showed promise, but needed advances in genomic sequencing, cell culture and single-use systems to propel development and commercialization.
Fast forward and today we see Spark Therapeutics’ manufacturing approach to Luxturna—its adeno-associated virus (AAV) delivered gene therapy—cited as a factor in the product’s speed in achieving FDA approval.
How can your company have the same type of success, and accelerate viral vector-based products to market? Let’s talk specifically about how aseptic filling can help.
Test and repeat for improved potency and stability
Drug development for viral vectors is an iterative process in which scientists progressively improve the potency and stability of their therapy. Potency comes from identifying the best virus for reaching the cells and having the genes replicate themselves over time for an ongoing therapeutic effect.
Experts have described aseptic filling for viral vectors as “a low-volume, low-speed operation, and is typically performed using isolator filling systems.” This can also mean manual filling under biosafety cabinets housed in Class A or B cleanrooms. Traditional isolator-based systems lack the ability to perform repeated filling cycles in a relatively short period of time, because they cannot decontaminate and change over fast enough. Manual filling poses risks for human error or contamination. In either scenario, if it takes a day to run one small batch, decontaminate the biosafety cabinet or isolator and aerate it, the company has lost valuable development time.
In contrast, viral vector development and manufacturing needs an isolator-based filling machine that can quickly cycle between small batches of a few hundred units or less. More development cycles equals an optimized vector, especially in the typical rush into formulation after the first proof of concept succeeds. That’s the role of the Microcell Vial Filler, which straddles development, clinical and commercial production. The Microcell is a gloveless robotic isolator—a technology currently only offered by Vanrx. For larger batches, customers would use the SA25 Aseptic Filling Workcell, which uses the same gloveless robotic isolator technology as the Microcell.
The Microcell fulfills the fast cycling requirements of developing viral vectors by allowing at least 4 separate loads of 300 units to be filled in an 8-hour shift. For batches smaller than 300 units, the number of therapies per shift could increase, owing to the machine’s 15-minute decontamination and aeration cycle, and single-use product contact materials.
A robotic filling and closing process, using nested, ready-to-use vials and press-fit closures with integrated stoppers, is highly repeatable. One operator can load the machine and start the decontamination sequence, which is followed by the filling sequence. Filling is performed by a peristaltic pump, which is highly accurate and capable of handling delicate drug products. Press-fit closures with integrated, industry standard stoppers are used to avoid the multi-step closing process and particle contamination issues of aluminum crimp caps. Vials and closures can both be sourced in materials that can undergo cryogenic freezing.
As will be described in greater detail below, with gloveless robotic systems, the sources of operator interventions have been designed out of the system. While no production process is “set it and forget it,” this is the closest anyone has come in aseptic filling.
Deactivation, containment and operator interventions
All drugs for injection need to be safe and pure, but those criteria take on extra importance with viral vectors. Speed to market, clinical efficacy and operational efficiency are all affected by the downsides of using biosafety cabinets for manual filling, or the use of traditional fillers under isolators. The key point here is that companies should make their work easier, not harder, since therapies using viral vectors are difficult enough.
Viruses replicate easily, so if they survive in the isolator, on the vial’s exterior, or in an improperly autoclaved flow path, there is a significant risk of cross-contamination between fill batches. Cross-contamination could delay or mislead development efforts and ultimately create a health risk for the patient. A loss of containment could cause operator exposure and a risk to their health.
Between batches, it is important to deactivate any viruses. Vapour-phase hydrogen peroxide (VPHP) is a very effective virus killer. Deactivation is best achieved via a concentrated exposure of the isolator to VPHP before the filling cycle, and then another before the closed vials are removed from the isolator. A fully validated, single-use product flow path, filling needle and product bag—which can be equipped with custom filters—is used with each batch.
The ideal filling machine for viral vectors should avoid any sources of operator interventions, because of the heightened risk of losing the batch. A gloveless robotic isolator provides a highly repeatable filling process where the sources of operator interventions (jams, glass breakage, etc.) have been designed out of the system. In addition, going gloveless prevents the loss of containment through leaks in the glove ports, and saves the time and expense of glove testing.
The Microcell Vial Filler
The new Microcell Vial Filler can help companies making viral vector-based therapies bring products to market faster. A highly repeatable and completely closed filling process within a gloveless isolator will help you to improve the stability and potency of your viral therapies. With a highly effective and fast decontamination and changeover time that uses single-use product contact materials, complete viral deactivation is achieved and the risk of cross-contamination is minimized. It can function as a machine for clinical trials, or scale out to commercial with multiple cost-effective machines providing agility to the manufacturer.
How the Microcell Works
The Microcell is designed to make aseptic filling for personalized medicines simple. The operator only needs to set up the machine and remove finished product. The Microcell handles all other tasks robotically. The filling and closing process is completely automated and highly repeatable
Step 1 – The operator sets up the Microcell:
- Installs the flow path and filling needle
- Loads the nested vials and press fit closures
Step 2 – The operator selects the recipe.
Step 3 – The Microcell performs the filling and closing process:
- Performs VPHP decontamination and aeration
- Removes tub covers
- Fills the vials
- Performs in process weight checking
- Closes the vials
- Post-filling VPHP cycle for viral deactivation
Step 4 – The operator removes the finished vials.
For more information on gloveless robotic isolators, please download the white paper “A New Paradigm for Manufacturing Injectable Medicines.”
van der Loo, JC, Wright, JF. Progress and challenges in viral vector manufacturing. Hum Mol Genet. 2016 Apr 15;25(R1):R42-52. doi: 10.1093/hmg/ddv451. Epub 2015 Oct 30.
Walters, P. Facility design considerations for gene therapy manufacturing. Bioprocess International. URL: https://www.bioprocessonline.com/doc/facility-design-considerations-for-gene-therapy-manufacturing-0001 Accessed: November 30, 2017.
Robbins PD, Ghivizzani SC. Viral vectors for gene therapy. Pharmacol Ther. 1998 Oct;80(1):35-47.