Prefilled syringe manufacturing can be accomplished in a variety of ways. Syringes can be filled with or without a vacuum. The difference in filling of syringes exists primarily in the stoppering and filling method. These include: online filling followed by online stopper placement; online vacuum filling followed by offline vacuum stoppering; and online vacuum filling followed by online vacuum stoppering.
Recently, Hyaluron Contract Manufacturing (HCM), a leading provider of aseptic manufacturing services, introduced another method which uses online vacuum filling and vacuum stoppering coupled with additional, proprietary technology to eliminate the bubble inside a syringe for non-viscous fluids, which further enhances the benefits of prefilled syringes.
A study by HCM suggests that choosing the best filling and stoppering method for a given drug product can be as important as choosing the right container. Choosing a process that reduces or eliminates the bubble inside a syringe can further enhance the benefits of a prefilled syringe and eliminate: (1) stopper movement during transport; (2) dosing precision variances; (3) dripping after needle shield removal; and (4) problems with product and air interface.
The most common filling process uses high-speed filling equipment and online stopper insertion. In this process, stoppers are placed inside a filled syringe via an insertion tube – which compresses the stopper so it is narrower than the syringe – followed by an insertion rod which uses force to expel the stopper into the syringe. The advantages of this method include minimal operator intervention and high throughput, making it less costly and more time-efficient. A significant disadvantage is the large air bubble-minimally 2.5mm – which is left in the syringe. This bubble can increase the risk of stopper movement during shipping and cause loss of product during expulsion activities prior to administration. It can also cause stability issues for some proteins and oxygen-sensitive compounds. Additionally, online stopper placement does not work well with coated stoppers since the compression of the stopper in the insertion tube and the force of the insertion rod can cause the coating to wrinkle and tear.
Online high-speed filling followed by offline vacuum stoppering is the second most common method for filling and stoppering syringes. With this method, syringes that have been filled online are manually moved from the filling machine and placed into a vacuum chamber. The advantage of this method is that it is effective in removing above 99percent of the air bubble, resulting in a bubble that is significantly smaller than that left by traditional online stoppering methods. One disadvantage to this method is that it requires additional operator handling and significantly reduces throughput.
Online vacuum filling followed by online vacuum stoppering was recently introduced by fill equipment manufacturers and is becoming increasingly popular. In this method, a vacuum is applied both before and after filling and vacuum stoppering is done online. The primary advantage of this method is reduced operator handling and the ability to obtain bubble free filling of viscous liquids. Online vacuum stoppering also works well with coated stoppers, as there is no compression of the stopper via the insertion rod.
The latest innovation in filling and stoppering syringes uses online vacuum filling and online vacuum stoppering in conjunction with other proprietary technology to produce a syringe that is bubble-free. This method, Bubble-free filling, is well-suited to non-viscous products as viscous products can be filled without bubbles using online vacuum filling and online vacuum stoppering.
The advantages of Bubble-free filling include:
- The elimination of stopper movement during shipping. Many drugs are shipped several times before reaching the end-user. Reducing stopper movement which results from the expansion of the gas bubble when the syringe is exposed to changes in atmospheric pressure decreases the potential for harmful contaminants and/or silicon oil from the barrel to be pulled into the drug product.
- A decrease in product hold-up when a syringe is oriented incorrectly. This ensures that the patient receives the entire dose desired regardless of syringe orientation. Given the low concentration of protein drugs as well as the increased number of non-clinical uses for prefilled syringes, this is an important consideration.
- The elimination of a drip when the needle shield is removed. The expansion and contraction of a gas bubble inside a prefilled syringe can cause product to leak from the needle when the needle shield is removed. Eliminating the drip reduces the potential for administrator exposure to cytotoxic compounds and decreases waste.
- The elimination of the gas/liquid interface inside a prefilled syringe. Protein and peptide based products are sensitive to their packaging and can precipitate due to the liquid/gas interface.
Understanding the options available prior to filling a product into a syringe is important to the overall drug development process. Advancements in filling technologies by manufacturers and contract filling houses have added benefits that were not available before. The advent of bubble elimination offers many advantages which may be worth exploring prior to deciding how a product is to be packaged for commercial distribution.
Andrea Wagner is Vice President of Business Development, Hyaluron Contract Manufacturing located in Burlington, MA. USA. www.hyaluron.com
