Cell therapy final product containers must meet many Vial Packaging. “Will the product fit the container?” is obvious, but it’s rarely that simple. Choosing the best container for your product can quickly become a problem with unintended consequences.
A good final product container should protect and stabilize the product throughout its lifecycle. This affects temperature stability, light protection, particulate levels, leachable and extractable materials, and container integrity during manufacturing, storage, and shipment. The container must be scalable for commercial success. The end user must be able to use the living cell product without affecting viability or potency and with minimal effort. The manufacturing process or end user may have different testing and quality control requirements. Many products require labeling or attachment of certain information. This can cause problems with smaller containers, which can affect marketing.
When choosing a final product container, there are tradeoffs, pros, and cons. Here are the three most common biotech and cell therapy containers: Screw-top Vial Packaging, Boxes, and sealed/semi-closed vials. This article avoids glass Vial Packaging. In some cases, a lyophilized product may require a glass vial, but there is almost always a non-glass alternative with better physical properties.
This is the most common container for cryopreserving cells in cell culture applications. These vials existed before regenerative medicine and are widely available. They’re easy to implement in a manufacturing process, simple for end-users to understand, and good for testing and analysis. Many xeno-free options exist, most can withstand cryogenic temperatures for long periods, and automated or semi-automated filling processes are available.
Despite their ease of use, alternative containers may be necessary for cellular therapies. Scaling up screw top Vial Packaging filling can be labor-intensive and require as much financial and technical investment as other container technologies. The screw top cap may be the screw top vial’s biggest flaw. Screwed-on caps aren’t closed systems by nature. They must be open during the manufacturing process and when the end-user accesses their contents. This requires processing in a biological safety cabinet (BSC) or similar isolated environment and handling by well-trained, dexterous personnel.
This rarely causes problems for small-scale manufacturers or testing organizations, but it can add complexity and contamination risk at clinical sites, hospitals, and patients. Screw top Vial Packaging has limited capacity. Off-the-shelf options are plentiful for volumes up to 2 mL, but options shrink quickly for larger volumes, and there are very few screw-top vials over 5 mL. Small containers can make labeling difficult. Small curved surfaces make it difficult to print all required information on Vial Packaging and make them legible, especially after cryostorage. Expandable labels, packaging, barcodes, and product inserts can overcome space restrictions, but they add complexity and obscure the final product.
Bagged cell therapy products have been around since the industry’s earliest days. In an industry that often views the process as the product, this can be invaluable.
A bagged product can be sterile-welded to another bag or cell culture container for a closed transfer. This can reduce or eliminate the need for a BSC in a manufacturing environment. With off-the-shelf and often customizable final product Boxes, almost any volume can be accommodated. This makes bagged final products appealing for high-volume, low-number processes. Boxes can be useful for a large-scale manufacturing process that uses “single-use” materials and is otherwise closed. Bagged products often have more labeling space. Many Boxes have a pocket that can hold a label that won’t fall off in cryogenic storage and can be printed double-sided without affecting the product’s appearance.
Putting Your Final Product in A Bag Has Drawbacks.
Although many Boxes are rated for cryogenic storage, they are not as durable as rigid containers. Usually, a case or overwrap is recommended for liquid nitrogen storage. This can complicate a bag manufacturing process that is already difficult and labor-intensive. Filling a sealed bag in a single-use system is difficult. Filling involves welding tubing and using pumps or syringes to remove excess air. Sterile tubing welders can be used to assemble a filling line, but if every bag must be welded and sealed before being filled, throughput will be limited.
Simpler, faster connections or manifold systems can help with throughput. Simple solutions aren’t always preferred. Attaching and detaching a Luer lock is faster than welding and sealing, but reduces some closed system benefits. Similarly, a manifold that fills many Boxes at once increases final product loss and complicates priming and fill volume control. Despite their advantages, bagged final products are difficult to scale up, and lot sizes are usually capped at 150-200 Boxes per manufacturing run.
Vial Packaging, Sealed or Semi-Closed
In this section, we’ll discuss containers that offer the scalability of screw top Vial Packaging and the closed system benefits of Boxes. These containers are filled with needles, Luer fittings, or similar connections and have ridged elements to improve container integrity. We’ll discuss Aseptic Technologies’ AT-Closed Vials® and Sexton Biotechnologies’ CellSeal® closed-system cryogenic vials.
Filling and Dispensing From AT-Closed Vials Without Removing The Septum is a New Technology.
A special needle allows air to escape during filling, preventing overpressurization. As the needle is removed, the elastomeric septum closes around it, preventing further interaction with the environment or product release. Using a specially designed laser, the septum’s integrity is restored without affecting product quality. A plastic cap covers the stopper. Filling a small number of vials with minimal equipment can be scaled up to commercially relevant levels (e.g. 1000s per lot) with automated filling systems.
AT-vials range from 1 to 50 mL, so volume is rarely an issue. AT-Closed Vials® are compatible with cryogenic temperatures, and all but the largest vails fit upright in standard cryo boxes for storage and shipment. With the AT-AdaptTM vented Vial Packaging access device, it’s as simple as attaching a syringe to the Luer and filling it. The air vent prevents over- or under-pressure without needles. This configuration allows for Luer-connected tubing or other components.
Aseptic Technologies has validated these vials with leachable and extractable studies and FDA Drug Master Files (DMF) (FDA). AT-Closed Vials® are attractive for late-stage development and commercial applications, but they have drawbacks. Even at small scales, the initial investment in technology and equipment to work with vials is likely higher than with other container options. This is a slow and cumbersome way to fill Vial Packaging.
Without laser sealing equipment, these vials can’t be fully utilized. Filling these Vial Packaging in a manufacturing setting requires controlled equipment. Though the septum provides a relatively aseptic way to remove material, the filling needle is exposed to the environment. Basic entry-level equipment fits most standard-size BSCs, but higher throughput and automated filling require custom equipment.
CellSeal vials are sealed or semi-close containers. This 2 mL and 5 mL ridged vials have a protected septum on one end and a needleless Luer fitting on the other. A vent with a microbial barrier can prevent pressure issues or be sealed for vessel integrity. This configuration accepts syringes, pipettes, and needleless Luer fittings. Once filled, the tubing can be sealed with a radio frequency sealer, creating a secure container. Similar methods can remove a sealed product. The vial’s bottom cover can be removed to access the septum, and the vent seal can be cut to reopen it.
This allows easy product removal with a needle, but Sexton has also created a needleless Luer adaptor. This allows needle-free material removal with syringes or tubing. Sexton has also created snap-on Vial Packaging markers, freezing containers, an automated thawing device, storage boxes, and freezer racks. The manufacturer has conducted good extractable/leachable studies and has a US FDA Master File to support customers.
Cell Seal Vial Packaging
Scalability is one of CellSealbiggest ®’s advantages. Sexton Biologics has developed two automated vial-filling devices. The Signate CT-5TM can dispense up to 1.5 L of product into CellSeal® vials or compatible Boxes. A small footprint and flexible design should suit a development lab or small-scale GMP operations. AF-500 is for larger processes. This system can fill 400 vials per hour in a standard biological safety cabinet. Custom Box Printer is a newer final product container option. Some products may be limited by the limited Vial Packaging options, and the taller profile may require modifications to storage and shipping systems. Sexton Biotechnologies has thought of solutions to many of the challenges of working with these unique containers and could be an excellent solution for your product.
There are many options to consider when designing a new cell therapy product or looking for a new container. Screw top vials are the simplest and fastest to implement, single-use Boxes are good for completely closed systems, and AT-Closed Vials® and CellSeal® vials offer flexibility and scalability. Whatever your product or scale, one of these containers should work.