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Primary packaging and container design reflects a move to patient-friendly formulations and delivery systems.
Biopharmaceutical packaging is changing. As pharmaceutical manufacturers embrace more flexible processes that limit the risk of product contamination, packaging and containment systems are being designed to facilitate manufacturing of smaller product lots and batches. Some fill/finish operations are moving to fully enclosed, automated operation, requiring the use of not only nested syringes and closures, but also nested vials and caps, and manufacturers are working to standardize these components.
Examples of flexible filling lines may be found at Boehriger Ingelheim’s Fremont, CA facility or Mithra Pharmaceuticals’ line in Belgium. The contract manufacturer, Singota, recently bought contained and fully automated filling technology from Vanrx Pharmasystems.
But agile manufacturing is only part of the picture. As pharmaceutical manufacturers develop more convenient formulations to improve patient compliance, designers of primary packaging and delivery system components have had to change their approach to product development. West Pharmaceutical Services, for example, teamed up with specialists in ergonomics and human factors to develop components for novel packaging and delivery systems (1).
Large molecules, which, in the past, could only be taken via infusion or repeated injection, requiring visits to the hospital or clinic, can now be taken with autoinjectors and new delivery systems, but the move to more patient-centered approaches has presented technical challenges.“The monoclonal antibodies and other biologics that are now being produced are highly concentrated and therefore the solutions are more viscous and may require higher dosing volumes,” says Fran DeGrazio, vice-president of scientific affairs and technical services at West.
These changes in dosing have driven recent improvements in packaging components. Earlier this year, for example, West introduced a 1-3mL plunger for use in 2.25-mL syringes, designed to deliver higher volumes of drug product--especially biopharmaceuticals. The new plunger was developed using the same principles that drive quality-by-design (QbD) practices in drug development. This controlled approach wound up revealing the need for a different design and shape, says DeGrazio. “These differences allowed us to optimize functionality and improve control,” she says.
Improved component designs come together in West’s SmartDose platform, which uses a cartridge system made from Daikyo Crystal Zenith (CZ) polymer, a cyclic polyolefin material. When coupled with the Daikyo Flurotec plunger the system is silicone oil-free. The West Smartdose delivery device adheres to the patient and can deliver more than 3 mL of drug in several minutes.
In July 2016, FDA approved Amgen’s monoclonal antibody, Repatha (evolocumab)--not only the drug, but using the SmartDose delivery system and primary container. Five months earlier, Amgen had opted for CZ vials and a closure system based on West’s FluroTec stoppers, to contain its drug Imlygic (talimogene laherparepvec). The vial was designed to minimize extractables from entering product, says DeGrazio.
CZ’s ability to withstand lower cold-chain storage and transport temperatures, even down to the dry nitrogen level required for some gene and cell therapies, has been another benefit, says DeGrazio. In addition, when used as part of a syringe system it does not contain silicone oil or tungsten, which has led to particulate contamination. This has been found to cause some proteins to aggregate in prefilled syringes (2). A number of companies are working on alternatives to silicone-treated glass containers, including W.L.Gore, which received a patent in 2014 for a silicone-free syringe stopper.
Maintaining system integrity and preventing contamination is crucial for product integrity and patient safety, says DeGrazio, and manufacturers accomplish this in different ways, through improved facility and workflow design, use of machine vision inspection and continuous monitoring on the plant floor, and the use of higher quality elastomers and barrier systems. Improved integrity testing is also crucial.
In August, 2016, the United States Pharmacopeial Convention (USP) released updated its recommendations for container closure integrity testing. The revised USP Chapter <1207> outlines the analytical tests that should be performed to show integral product safety, for instance, leak detection for vial and syringe systems, says DeGrazio. Before the chapter was published, she says, methylene blue dye testing was used in vacuum to find leaks. Now, regulators realize that such methods are more probabilistic than determinant, she says, and subject to error. Among the methods that West uses and offers is helium leak detection, which allows testing and validation down to -120 °C to -140 °C.
A small but growing part of the components and packaging business is pre-sterilized and ready- to-use-nested components.This approach was inspired by the semiconductor industry’s Front Opening Unified Pod, a box of silicon disks that could easily be picked up and manipulated by a robot without operator intervention. These tubs of nested containers and closures allowed for a greater level of automation in fill-finish operations, explains Greg Speakman, vice president of sales and marketing for Vanrx, whose automated approach to fill-and-finish was inspired by the workcells of the electronics industry. Becton-Dickinson came out with the first nested systems nearly 30 years ago, he says.
Ompi entered the market in 2007 with EZ-fill nested syringes, introducing vials and cartridges two years later, and nested closures for vials, developed together with Daikyo Seiko, in 2015, says product manager Alessandro Massignani.
Nesting syringes, cartridges, vials and closures in standardized nest or tub packaging allows maximum flexibility from fill/finish equipment, says Gregor Deutschle, business development manager at SCHOTT AG, since fill/finish operations are performed with the containers remaining in the nest. He points to Schott’s adaptiQ vials, which allow all process steps to take place inside the nest, including checkweighing, freeze-drying as well as closure of the vials with press fit caps, as an example.
The trend to nested systems began with prefilled syringes, so they have been standardized to the highest level so far, says Deutschle. Nested vials and cartridges are just emerging on the market, he says, and are being standardized.Massignani adds that there is a specific work group led by Ompi’s regulatory affairs manager that is entitled to redact the ISO Standard for Ready-To-Use Vials and Ready- To-Use Cartridges.
Vanrx’s system requires that containers and closures be placed in a nest to allow for robotic handling. Packaging component vendors,including Daikyo Seiko, Datwyler, SCHOTT, SCHOTT KAISHA, Ompi, ARaymond and Vanrx established the Matrix Alliance in 2016, to work on standardization and ensuring interoperability of containers and closures. The key goal is ensuring that a container from one vendor will work with a closure system from another vendor, without requiring extensive retesting and integration by the end-user,” says Speakman.
Alliance members recently shared test results involving vials and press-fit caps with their shared biopharma customers, and plan to release findings publicly during the first quarter of 2017. But the move to nested vials and caps reflects trends that are not going away any time soon: a shift from blockbusters to smaller niches of high-value drugs; more frequent/fast product changeovers in multi-product facilities, and a move from large facilities in developed markets to smaller facilities in more remote parts of the world, says Speakman.
Another important shift is that component packaging suppliers are taking over services once handled by pharma companies, says Deutschle. “In using ready-to-use nested components, our customers want to eliminate the need for preparation of the containers prior to filling. Therefore, we take care of depyrogenation, washing, and packaging as well as sterilization.”
Flexible filling represents a major change from standard fill finish equipment, which is geared toward high-speed, large production volumes, and often dedicated to a single container type or drug, Deutschle explains. Changeover from one container format to the next can take a long time in a bulk filling plant, because all containers must be handled individually and thus require a large number of spare parts. In addition, he notes, classic bulk lines can be very large and require a lot of expensive clean room space.
Using nested components in a flexible line reduces the need to invest in washing, water for injection, and utilities, and also reduces maintenance and validation costs, says Massignani. “The containers travel in packaging that prevents glass-to-glass contact, reducing rejection rate. This approach adds value, not only by improving product quality but because it shifts responsibility for the sterility and cleanliness of primary packaging from the pharma manufacturer to the packaging components supplier,” he says.
1. C. Evans, “The Critical Role of Human Factors and Usability in Improving medication Adherence,” IPIMediaWorld.com, June 22, 2016.
2. A. Siew, BioPharm International, 29 (11), p. 38 (November 2016).
Vol. 30, No. 1
When referring to this article, please cite it as A. Shanley, "Packaging’s Flexible, Patient-Centered Future,” BioPharm International 30 (1) 2017.