By Michael Song, Ph.D., AstraZeneca
At the heart of any combination product and biopharmaceutical products is the drug container. Drug containers can be vials, ampules, prefilled syringes, or cartridges. Each type of primary container has its unique attributes, nuances, and areas of consideration. Understanding the technology behind each is an essential element for the development of a biopharmaceutical product.
Today, with more and more biological drug products in development, prefilled syringe (PFS) usage has grown. This growth has also spurred advancements in prefilled syringe science, manufacturing, and design, from minimizing glass stressing during manufacturing to better control over tungsten residuals. While these technological improvements have dramatically advanced prefilled syringe quality, there are still areas to consider when selecting and fitting your drug product in a prefilled syringe.
The two most common types of prefilled syringes are the needle-free PFS and needled PFS (PFS with integrated / staked-in needle). In general, needle-free prefilled syringes are more commonly used for vaccine products, while the staked-in needle PFSs are typically used with biologic and pharmaceutical drug products. The geometries of these two types of PFS are common and follow ISO standards. In addition, there are also other types of PFSs, such as dual-chamber syringes designed for co-delivery of two drugs or for ease of use with lyophilized injectable drug products. In recent years, several novel dual-chamber syringe designs have also emerged with unique attributes to provide pharmaceutical companies with additional flexibility and advantages.
This two-part article provides an introduction to these three general PFS types and will share important factors to take into consideration for your drug product. In this first part, we discuss the needle-free PFS and the dual-chamber system. Part 2 covers prefilled syringes with staked-in needles and will provide some thoughts on partner selection for PFS development.
Needle-Free Prefilled Syringe
To start off, let’s examine the needle-free prefilled syringes. These syringes usually include an attachment that acts both as a sterile barrier cap and a Luer lock attachment. The attachment is plastic and secured on the syringe nozzle. PFSs intended for Luer lock attachment are typically manufactured with a circular band groove on the nozzle. This band is what engages with and locks the Luer lock attachment in place. The Luer lock attachment also includes a cap element with a breakable tamper prevention design, somewhat similar to that of soda bottle caps. To remove the cap, one usually must twist the cap to break the tamper design, freeing the cap from the rest of the attachment. To maintain a sterile barrier, the nozzle of the syringe is capped with an elastomer plug. Prior to use, the pressure from the cap is what holds the plug in place and maintains the seal at the syringe nozzle.
If you are using a needle-free prefilled syringe, the usability of the Luer lock cap attachment and cap separation should be assessed in relation to your therapeutic area (TA) and patient demographics.
In addition, you must also consider the Luer lock geometry, because, unless your product is co-packaged with a compatible supplied needle, the end user will choose the needle to be used with your PFS device. This can pose a challenge, as there are a number of different needle manufacturers and brands to choose from. For this reason, most Luer lock attachment needles conform with ISO standards to ensure interchangeability and cross-brand compatibility. That said, you should nevertheless pay attention to ensure your PFS Luer lock attachment conforms with ISO standards.
Furthermore, the Luer lock attachment is what helps maintain the pressure on the elastomeric plug against the syringe nozzle in creating the seal. You should always check and test the sealing capability/performance of the syringe’s Luer lock attachment in relation to the elastomeric plug during evaluation to minimize container closure integrity challenges down the road. This can be achieved through a number of leakage detection and/or container closure integrity test methods.
When selecting prefilled syringes, it is essential to also consider your drug product and any potential immediate and long-term drug product-syringe material interactions. These interactions can take many forms, from delamination of the syringe glass barrel to protein aggregation. In addition, needle-free PFSs have two elastomers that come in contact with the drug product, the syringe plunger, and the syringe nozzle plug. The formulation and material composition of both components should be looked at closely in terms of potential leachables and their potential interaction with your drug product.
Many vendors oftentimes will have done some form of forced extraction study on the elastomer, which can be a good source of data in initial assessment of the suitability of the plug or plunger. Elements with higher zinc extractables are known to potentially interact with some drug formulations, resulting in aggregates. When leveraging vendor data, attention should be paid to the type of solvents used, test components and their source location (more important for elastomers), and extraction conditions.
Similarly, tungsten residual is another area to pay attention to. Tungsten residual comes from the tungsten pin used during the syringe forming process to create the channel on the syringe nozzle (to be discussed in detail in Part 2). With manufacturing and technology improvements, syringe manufacturers have managed to better control and reduce tungsten residual. Nonetheless, this is an area to be aware of when evaluating and selecting a PFS for use with your drug product.
Because the needle-free PFS does not have an integrated needle, in most cases syringe barrel siliconization is through baked on. This is quite different from a staked-in needle PFS and is more reminiscent of insulin cartridges. The baked-on siliconization process typically uses silicone emulsion as opposed to pure liquid silicone. As such, attention should be paid to the silicone type and grade used, as well as how the emulsion is made, the silicon dilution ratio, etc. Silicone should always be medical grade and of appropriate purity and centipoise (cP). This information is essential in designing the appropriate silicone spiking study as part of drug product compatibility assessment.
As with all prefilled syringes, plunger/stopper selection can have a significant impact on your final product performance. Today there are a number of differing plunger design available. Depending on the plunger selected, it should be assessed from a number of perspectives, such as container closure, performance, and filling machine compatibility, to name a few. One area often overlooked from a primary container or device engineering perspective — and even more so from a process engineering standpoint — is the amount of siliconization on the plunger. Plungers come in ready-to-use bags that are poured into a stoppering bowl during filling operations. Through vibration, the stoppering bowl sorts and orients the plungers and loads them into feed tracks for stoppering of drug-filled PFSs. The silicone left behind in the stoppering bowl will need to be cleaned via a validated cleaning method. Cleaning silicone is typically a challenge for both pharmaceuticals and medical devices, and the potential direct impact on drug product quality significantly limits the available cleaning agents that can be used. (We will discuss cleaning and cleaning validation in more detail in future articles.)
Finally, as most needle-free PFSs will not be fitted with a needle safety device, decisions will need to be made on the type of PFS flange to adopt. If you are planning to add a finger flange accessory to your PFS as part of your device offering to aid in the user experience, then your choice between a cut flange and a type C small round flange will be dependent on your filling operation as well as, potentially, on your syringe platform status. Most filling operations can handle the small round flange as easily as the more traditional cut flange, but using the same syringe across programs will achieve the best economies of scale and minimize the need for multiple stock keeping units (SKUs). One area where the choice of syringe finger flange type will become important is if you intend to only incorporate a plunger rod in your PFS without any additional finger flange accessories. In such a case, the choice of a cut flange may be more appropriate, as it provides an inherent anti-rolling feature to your PFS.
In recent years there has been an increase in the number of dual-chamber technologies available. Whether you are considering the traditional dual-chamber syringe or the newer dual-chamber technologies — such as those that use standard ISO syringe designs — reliability, usability, and performance are essential areas to assess when selecting the right technology for your product.
Dual-chamber syringes are unique in that they have two partitioned chambers, where the front chamber can be filled with lyophilized drug product and the back chamber with its diluent, or both chambers can be filled with drug products intended for co-delivery.
There are a number of unique differences between dual-chamber syringes and standard prefilled syringes. For one, at the start of use, the cap or needle shield of a dual-chamber syringe should not be removed. Instead, the user should first push the plunger rod forward, forcing the content of the back chamber into the front chamber. This mechanism does not support the rare cases where medication is intended to be delivered sequentially.
The introduction of the back-chamber content into the front chamber builds up pressure within the syringe. To prevent the pressure from pushing the plunger/plunger rod back out, the plunger rod often either has an intermediate lock that keeps the plunger rod in position after the contents of the back chamber are introduced into the front chamber, or the front half of the plunger rod is threaded to both improve the user experience and prevent the plunger/plunger rod from being forced back by the pressure buildup within the syringe.
In addition, with dual-chamber syringes, the standard break loose and extrusion force test method does not apply. This is because there are a number of additive force variables when using a chamber. In the case of a traditional dual-chamber syringe, when the plunger rod is pushed forward, this motion induces pressure within the back chamber that drives the middle plunger forward until a channel between the two chambers is formed. This has a very different force profile than that of a standard prefilled syringe, due to multiple moving pieces and competing forces. Careful attention should be paid to examining the force profile in its entirety.
With dual-chamber syringes, the filling operation can also be challenging. This is an area that should be carefully considered, as you may need to modify your current fill line equipment, purchase new filling equipment, or restrict filling sites. Other factors to weigh include the manufacturing process, media fill approach, etc.
In addition, dual-chamber syringes pose more complexity for the user. For instance, a dual-chamber syringe requires the user to take more preparation steps prior to injection — and conduct them in the proper order. If the user removes the cap prior to mixing the two chambers, for example, there is high risk of drug loss. Or, if the user orients the syringe slightly downward and away from their body when removing the cap after mixing the content of the two chamber (similar to how they would remove the needle shield cap on a traditional prefilled syringe), it can also lead to drug loss due to the buildup pressure within the syringe.
For those whose companies are moving toward or have adopted deterministic container closure integrity testing (CCIT) methods, such as high voltage leak detection (HVLD) CCIT, dual-chamber syringes with bypass will pose a challenge, even when both chambers are filled with sufficient conductive liquid. This is because the HVLD tester utilizes a traveling probe and rotates the syringe to achieve full coverage, and bypass on traditional dual-chamber syringes will interfere with both. (CCIT will be discussed further in future articles.)
These are just some of the factors to consider in dual-chamber and needle-free PFS designs. In Part 2, we turn our attention to prefilled syringes with staked-in needles and to considerations for selecting a good partner for PFS development.
Disclaimer: Opinions expressed in this article are those of the author and do not necessarily represent those of the author’s employer.
About The Author:
Michael Song, Ph.D., leads the biological device functionality, safety, and digital connectivity group within AstraZeneca’s biologic device development. In his current role, he oversees device functionality and safety, primary container science and technology, biocompatibility, container closure integrity strategy and testing, and digital connectivity development. Prior to his current role, Song was head of the Device, Packaging, and Process Engineering Department at Adello Biologics (part of Amneal Pharmaceuticals). He has held key technical positions at Stryker, Amgen, and Kavlico Corporation and has led the development of both combination products as well as 510(k) medical devices. He received his postdoctoral training at Barrow Neurological Institute / St. Joseph Hospital and Medical Center (part of Dignity Health) and holds a B.S. in electrical engineering from Purdue University and Ph.D. in neuroscience and Toxicology from Iowa State University.