In the latest post in our series P.E.R.F.E.C.T.-ing the Pharmaceutical Packaging Selection Process, we evaluate Functionality, an important measure of a container closure systems’ operability. Although Container Closure Integrity is an important functionality of every system, it will not be handled in this blog; rather, an upcoming blog will take an in-depth look at CCI.
An Introduction to Functionality
Pharmaceutical elastomers do not operate by themselves (though some may work in a vacuum – pun intended). Rather, they operate within a system of components, typically including a glass or polymer container. Three common configurations include vials, syringes, and cartridges.
As these systems are triggered to dispense or release drug product, certain measures of functionality can impact their operation. Functionality can generally be defined as the quality of being well-suited to a given purpose. In this way, we must evaluate whether a given container closure system (CCS) is well-suited in each context. This is dependent upon the closures within the system, the drug product, how they work together, and the conditions in which the system will be used.
Introduction to Systems
As stated above, three common CCS configurations include vials, syringes, and cartridges. Each system is assembled in a different way, and functions uniquely. Many factors affect functionality, pertaining to the elastomeric components, the glass or polymer components, the drug product, the administer of the drug product, and how all of these factors work together to perform as a system. Below, each of these configurations is depicted.
Looking to the regulatory landscape, there are some changes upcoming. The new chapter, USP <382> Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems, will become effective on December 1, 2025. This will update the functionality tests for elastomers, whereas the functionality testing portion of USP <381> will be omitted. Under the new chapter, it will be the drug manufacturer’s responsibility to meet the functionality requirements on the final system. This is a change from USP <381> in that the whole container-closure system must be certified for functionality rather than simply the individual component. The USP describes this type of holistic testing as “fitness-for-intended-use functional suitability.”
Vial Systems
A vial system is composed of three main components:
- Vial, typically made from glass or a hard polymer.
- Stopper, typically made from rubber.
- Seal, typically made from aluminum and/or plastic.
During fill/finish, the vial is filled with drug product. Then, a rubber stopper is placed on top of the vial. An aluminum seal is then crimped around the top of the vial, pressing the stopper tightly to the lip of the vial.
One common style of aluminum seal includes an aluminum skirt covered by a flat plastic circle. The plastic circle can come in many colors and is usually “flipped off” of the aluminum ring during use. This exposes a hole in the aluminum seal, which reveals an area of the rubber stopper underneath. A needle can then puncture the soft rubber to access the drug product inside of the vial.
Throughout this process, functionality can be evaluated in the following areas:
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- Definition: The tendency of a stopper to allow chunks of itself to be cut out by a needle (referred to as “cores”), or to allow chunks of itself to be dislodged into the vial (referred to as “fragments”).
- Goal: Ideally, coring and fragmentation will be reduced as much as possible for a given application.
- Self-Sealing
- Definition: The ability of a stopper to maintain container closure integrity (CCI) after a puncture.
- Goal: Ideally, a stopper will be able to reseal after each puncture, up to the limit of the number of punctures appropriate for a given application.
- Multipuncture
- Definition: The ability of a stopper to be punctured multiple times without creating significant numbers of cores or fragments, and while maintaining resealability.
- Goal: Ideally, a stopper will be able to be punctured at least 10 times, and up to the limit of the number of punctures appropriate for a given application.
- Penetration Force
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- Definition: The amount of force required to insert a retrieval device – typically either a needle or a closed system transfer device (CSTD) – through a stopper.
- Goal: Ideally, the insertion force will be minimized to allow for easy insertion of retrieval devices, not to exceed 10N.
- Push-in
- Definition: The tendency of a stopper to be driven into a vial when a CSTD is applied.
- Goal: Ideally, push-in will not occur during standard use.
- Spike Retention
- Definition: A measure of a closed package’s ability to be fully penetrated by a spike and to retain the spike during the product dosing time period.
- Goal: The spike is retained within the container closure system during the entirety of the product dosing period without leakage.
The rubber compound, coating, and design of the stopper each have a significant impact on the performance of the system.
- Stopper formulation hardness: Formulations with softer durometers may tend to have fewer fragments during piercing, show better resealability, are better for multipuncture application, and require lower penetration force
- Stopper films and coatings: Films sometimes cause different performance and must be tested with this in mind. For example, when a thick film is applied on the top of a soft formulation, it will result in increased insertion forces. This can even lead to stopper push-in when using a CSTD, as the film can be difficult to pierce with a CSTD.
- Piercing thickness: the thicker the area to pierce, the higher the insertion force.
Other contributing factors:
- Needle Gauge: Smaller needle gauges tend to yield less fragmentation and better resealability.
- Size and Geometry of Spike: A spike’s geometry can contribute to whether it is able to be retained without leaking. Some spikes have “claws” that wrap around the neck of the vial to promote retention. If these “claws” are too small or too short, they might push the spike off of the CCS. If they are too large, they might not be helpful in holding the spike to the CCS.
- Number of Punctures: The number of fragments tends to increase with the number of punctures. Additionally, resealability is put at risk with too many punctures.
- Method of Puncture (angle, force, etc.): Proper training for drug administers can result in fewer fragments and better resealability.
- Method of Insertion of CSTD (angle, force, etc.): An inopportune method of insertion can result in stopper push-in. Proper training is required to avoid this.
Syringe Systems
A syringe system is composed of four main components:
- Plunger Rod, typically made from plastic.
- Plunger, typically made from rubber.
- Syringe Barrel, typically made from glass or a hard polymer.
- Needle, typically made from metal.
During fill/finish, a syringe barrel is often preassembled with a staked needle. In this case, a needle shield (not depicted above) may be used to ensure the needle is not bent (and does not hurt anyone) during processing. Alternatively, a “Luer Lock” finish may be utilized, in which a needle will not be screwed on to the end of the syringe until the point of drug administration. Luer Locks may require rubber tip caps (not depicted above) to ensure their quality and sterility.
Drug product is filled into the empty syringe barrel (with either a staked needle or a Luer Lock tip on the end). A plunger is placed in the syringe to seal the system, and a plunger rod is then placed behind the plunger. Often, the tip of a plunger rod will have a thread that corresponds to internal threading in the plunger; in this case, the two will be screwed together or plugged in.
Throughout this process, functionality can be evaluated in the following areas:
- Break-Loose Force (BLF)
- Definition: The force required for a plunger to move, after beginning in a motionless state
- Goal: Ideal BLF is highly dependent upon application. The BLF should be high enough that unintended motion does not occur (especially during transport) but low enough not to inhibit intentional motion.
- Glide Force (GF) or Extrusion Force
- Definition: The force required for a plunger to maintain movement once it is in motion. This is often measured as a force over time, in which consistent glide force is key.
- Goal: Ideal GF is low and consistent. Glide forces should be much lower than their respective break-loose forces.
- Plunger movement during transport
- Definition: The largest displacement from its original position experienced by a plunger during transport (or in conditions that simulate transport)
- Goal: To minimize displacement of the plunger during transport, especially not beyond a “safety zone” measured as the distance between two ribs
- Needle Shield (or Tip Cap) removal force
- Definition: The force required to remove the needle shield (or tip cap) from the syringe. This can be an axial pull-off force in case of a needle shield or tip cap and a torque force in case of a Luer Lock rigid tip cap.
- Goal: Convenient removal without accidental loss of needle shield (or tip cap) during storage or transit, through the life cycle of product.
The following plunger characteristics have a significant impact on the performance of the system.
- Plunger Rubber Formulation: Each rubber formulation can have different levels of hardness and compressibility. These factors can make it easier or more difficult for a plunger to begin movement. Also the interaction between plastic materials used for barrels and halobutyl rubber can result in increase of BLF.
- Plunger Films and/or Coatings: Films and coatings often provide lubricity, decreasing BLF and GF.
- Interference Fit between Plunger and Syringe Barrel: The interference fit between the plunger and syringe barrel is a measure of how much the plunger must be compressed to fit inside of the syringe barrel. This is commonly targeted as 3-5%. A higher interference fit (larger plunger or smaller barrel) can result in higher BLF and GF.
- Plunger design: the radius of the rills, the size of the trimming edge as well as the design of the inside of the cavity can all have an influence on the BLF and GF.
Other contributing factors:
- Syringe Siliconization: Most syringes are provided with silicone lubricating the inside of the barrels. This is intended to avoid that the plunger sticks to the barrel resulting in high break loose forces and to ensure proper gliding of the plunger during injection. The silicone can be sprayed-on (in this case the silicone can move inside the barrel during storage), baked-on, or cross linked by other methods. In contradiction to what many people believe, the plunger siliconization has no significant impact on the BLF and GF.
- Needle Gauge: A larger needle gauge allows for more product to flow through the syringe in less time, resulting in a lower glide force.
- Drug Viscosity: High viscosity of the drug product can impede the flow of product through the needle, resulting in higher glide forces.
- Headspace in the barrel: This is the distance between the plunger and the drug product when the syringe is filled. The air bubble will expand when the pressure drops during air transport. The larger the air bubble, the more impact will be seen from the decreasing pressure on the plunger movement.
- Storage time and temperature: Storage can impact stopper dimensions. Additionally, the silicone of the syringe will behave differently in different storage conditions, impacting the BLF and GF. It can also have an effect on the expansion of the air bubble impacting the plunger movement.
Cartridge Systems
A cartridge system is composed of three main components:
- Plunger, typically made from rubber.
- Cartridge Barrel, typically made from glass or a hard polymer.
- CombiSeal, typically made from a rubber component and a metal component.
During fill/finish, a cartridge barrel is often preassembled with a CombiSeal on one end. The CombiSeal is made of a metal skirt with a hole in its top. This hole exposes the center of a flat disc of rubber, which can be punctured upon administration of the drug product to gain access to the medicine inside the cartridge. The cartridge barrel is filled with drug product before being sealed with a plunger in its open end.
Most often, cartridges are loaded into medical devices for administration. A needle pierces the rubber part of the CombiSeal to access the drug product, allowing it to flow through to the patient. Most devices are handheld, although on-body wearables are also upcoming. Some are disposable, and some reusable. The variety of drug administering devices on the market is vast; a commonality among many is the use of cartridges as primary packaging containers.
Cartridge systems may be considered to have the plunger from a syringe and the septum from a vial. Plunger functionality can be evaluated similarly to the functionality of a syringe plunger (BLF, GF and plunger movement during transport). Additionally, fragmentation and resealability will be evaluated for the CombiSeal similarly to the functionality of a vial stopper (fragmentation and self-sealing). See above for the detailed description.
Compendia
As referenced above, the following compendia are useful in understanding functionality requirements:
- USP <382> “Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems”
- EP 3.2.9 “Rubber Closures for Containers”
- ISO8871-5 “Elastomeric parts for parenterals and for devices for pharmaceutical use - Part 5: Functional requirements and testing”
- ISO 11040-8 “Prefilled Syringes – Part 8: Requirements and Test Methods for Finished Prefilled Syringes”
- ISO 11608-3 “Needle-Based Injection Systems for Medical Use – Requirements and Test Methods – Part 3: Containers and Integrated Fluid Paths”
- ISO13926-2 “Pen systems - Part 2: Plunger stoppers for pen-injectors for medical use”
- ISO13926-3 “Pen systems - Part 3: Seals for pen-injectors for medical use”
- ISO11040-2 “Prefilled syringes - Part 2: Plunger stoppers for dental local anaesthetic cartridges”
- ISO11040-3 “Prefilled syringes - Part 3: Seals for dental local anaesthetic cartridges”
Conclusions
Overall, Functionality needs are imperative to understand when choosing an elastomeric closure for a pharmaceutical injectable. Container closure systems must be well-suited to their given purposes, and able to perform appropriately. In the creation of life-saving drugs, life-threatening risks must be mitigated. Though choosing appropriate elastomeric components can be difficult, Datwyler is available to help guide our clients through the selection process.
Look for the next post in the PERFECTing series, in which Engineering Capabilities will be addressed.
Sources:
https://www.futuremarketinsights.com/reports/injectable-drugs-market