Between the start of 2022 and the end of 2024, GlobalData鈥檚 Drugs database recorded 160 US approvals for currently marketed drugs with one of the following parenteral packaging formats: vial, pre-filled syringe (single chamber), prefilled device (auto-injector), or cartridge. In 2024, several of these have achieved 鈥� or maintained 鈥� blockbuster status for global sales, including Eli Lilly鈥檚 auto injector-based GLP-1 receptor agonists Mounjaro and Zepbound, and Genentech鈥檚 Vabysmo, a bi-specific antibody intravitreal injection indicated for three different causes of vision loss. In 2024, Vabysmo became the first syringe prefilled with an FDA-approved bispecific antibody to treat these retinal conditions.[i]
Injectable drugs are often life-changing therapies, and primary packaging components are critical for maintaining their sterility, stability, and safety. The process of sourcing and validating packaging components involves several critical steps necessary to ensure that the packaging maintains the integrity of the drug product while meeting regulatory standards.
As a leading provider of elastomeric packaging components to the pharmaceutical industry, Datwyler has compiled a complete and aptly-acronymed checklist of considerations to help companies 鈥楶.E.R.F.E.C.T.鈥� this meticulous decision-making process. As outlined in this article, the seven steps in the 鈥楶.E.R.F.E.C.T.鈥� packaging selection process include: Particulate, Extractables and Leachables, Regulatory, Functionality, Engineering Capabilities, Container Closure Integrity, and Total Quality.
Particulate
According to an analysis of FDA recall data, contamination is the leading cause of drug recalls. Some level of particulate is unavoidable in pharmaceutical manufacturing, but it must be controlled and mitigated as much as possible. For pharmaceutical manufacturers, this may involve selecting parenteral packaging components that have been manufactured in ultra-modern cleanroom environments featuring a high level of automated technologies, sophisticated particulate monitoring systems, and smart approaches to personnel and material flow. As outlined in USP <788>, microscopic particle count tests and light obscuration tests can be deployed to check for particles.
Extractables & Leachables
The potential for extractables and leachables (or E&L) to migrate from a primary packaging component is a serious safety concern in the world of parenteral drugs. Extractables are inherent to the ingredients used in the creation of a component and should be evaluated during the selection process; these compounds can be extracted from a material under extreme conditions. Leachables are specific to interactions between the components and the packaged drug product, and must therefore be evaluated for every individual combination of product and packaging. Leachables occur under normal conditions within a product鈥檚 lifecycle.
Any risk of leachables should be multiplied by the product鈥檚 dosage, meaning a daily injection such as insulin could be a much higher cause for concern compared to a one-time vaccination for an infectious disease. Other factors to consider when evaluating E&L risks include the patient population, route of administration, and the sensitivity level of the drug substance. Depending on the determined risks, the packaging provider may recommend applying a spray or film coating to the component to decrease interactions between the surface and the drug product.
Regulatory
The pharmaceutical industry is heavily regulated, and scrutiny has only gotten stronger in recent years. From 2020 to 2023, the pharmaceutical industry has seen an increase in FDA 483 warning letters, a notice given by the FDA which warns that deficiencies were observed in quality systems or conditions that violate the U.S. Food, Drug and Cosmetic Act. This makes it imperative for drug manufacturers to work with trusted packaging providers whose manufacturing environments comply with (or even exceed) regulatory standards like ISO 14644-1. By choosing a supplier that aligns with and prioritises core regulations, pharmaceutical companies ensure that their products meet the highest standards required.
Functionality
A complete parenteral packaging solution is comprised of individual components; it is compatibility between these parts which ensures the functional performance of the final system. For vials, this includes a glass or polymer container alongside a rubber stopper and aluminium seal. When choosing the rubber stopper for a vial, manufacturers must consider factors such as its propensity for coring and fragmentation, its self-sealing capabilities, and the penetration force required to insert a retrieval device through the component.
When it comes to syringe systems, which are comprised of a glass or polymer barrel, rubber plunger, plastic plunger rod, and needle, functionality can be evaluated by considering break-loose force, glide force, and plunger movement during transport. The same is true for cartridge systems, which are comprised of a cartridge barrel, plunger, and CombiSeal.
Engineering Capabilities
While the ambition to create a high-quality product that will benefit patients always drives drug development, the manufacturability of the product cannot be overlooked. This is where the engineering capabilities of a packaging component becomes crucial. During fill-finish activities, there are many common issues to look for across a wide range of component types. These include stickiness, stopper twinning, and problematic friction during plunger placement.
For an optimal fill/finish experience, component manufacturers can provide clients with varying levels of siliconization, a wide array of packaging formats, and various processing options (such as washed or sterilized components).
Container Closure Integrity
Container Closure Integrity (CCI) is essential for a packaging system. When good CCI is maintained across a product鈥檚 shelf life, potential contaminants cannot enter the packaging system and pharmacological material is unable to leak out. When it comes to syringe and cartridge systems, plunger diameter relative to barrel diameter is one of the most important considerations. Too small and CCI may not be achieved, but too large and the component may exceed break-loose force limits or simply not fit inside the barrel.
Where vials are concerned, sealed caps are often added on top of stoppers for the purpose of ensuring CCI at the land seal. However, if this capping step occurs later in the packaging process, manufacturers should evaluate the CCI of the stoppered vial at the valve seal. To do so, they must compare the dimensions of the stopper plug and the inner vial neck to determine how much the stopper will need to compress to fit into the vial. With the addition of the seal on top, further calculations are needed to determine the dimensional compatibility of all three components. As per USP <1207>, companies should perform deterministic leak test methods such as vacuum decay tests or helium leak tests to evaluate the full effectiveness of their final system.
Total Quality
In this context, Total Quality refers to multiple measures of a product鈥檚 physical, chemical, or biological state that are previously agreed upon by manufacturer and recipient. The size and geometry of the component should be detailed in a product drawing; particulate and sterility expectations should be set; and defect classification and acceptance levels should be detailed in a quality agreement.
Each component company will have a slightly different process for communicating quality standards. Similarly, each drug manufacturer will have a slightly different incoming inspection process. It is important for these entities to communicate well prior to exchanging product, to ensure everyone has the same understanding of the quality of products to be received.
Enhance your knowledge on the critical obstacles involved in packaging injectable drugs. Download the white paper below to gain clarity on evaluating and assessing the highest-quality solutions for your needs.
[i] https://www.gene.com/media/press-releases/15030/2024-07-04/fda-approves-genentechs-vabysmo-prefille
