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Volume 30, Issue 11
Siliconization is a key process step in the manufacturing of prefilled syringe systems.
Biologics are fast becoming the driving force of the pharmaceutical industry. Because the primary route of administration for most biologics is still by injection, there is a demand for advanced drug-delivery systems that offer convenience and ease of administration. Prefilled syringes have gained strong acceptance as delivery systems for injectable drugs, especially in the treatment of chronic conditions that require repeated administration of the medication.
“Prefilled syringes make injection easier and safer for both doctors and patients by ensuring the patient always receives the right dosage,” says Fabian Stöcker, head of Strategic Marketing & Innovation, Schott. “Additionally, prefilled syringes work well with increasingly popular safety devices and auto-injection systems, making injections easy, safe, and convenient.” He notes that pharmaceutical companies also stand to benefit from prefilled syringes. “Compared to vials, they can reduce overfill, which can be particularly costly in biopharmaceuticals. Also, customized delivery systems and prefilled syringes are helping pharmaceutical companies in the biotech industry deliver personalized drugs tailored to smaller patient populations,” Stöcker says.
Prefilled syringes can potentially offer better patient experiences than traditional means, observes Graham Reynolds, vice-president and general manager, Global Biologics at West Pharmaceutical Services, Inc. “There is some degree of variability when removing a drug product from a vial with a conventional disposable needle and syringe. With a prefilled syringe system, the very nature of its design eliminates the withdrawal step and delivers the drug product directly to the patient, which can result in a more accurate dose of the drug with less exposure to needles,”
Reynolds adds that because some biologic drug products are in short supply and can be very costly to produce, manufacturers are seeking innovations to minimize waste. “Prefilled syringes, with their premeasured dosage, have the potential to reduce dosing errors and increase patient compliance while potentially saving manufacturers money,” he says. “Unlike single- or multi-dose vials that may require drug product overfill by as much as 30% to ensure adequate withdrawal, a prefilled syringe can virtually eliminate the need for excess overfill, thus conserving expensive drug products. This is important where manufacturing and product costs are high and bulk manufacturing capacity is limited.”
Glass prefilled syringes continue to dominate the market, but there is a shift toward the increasing use of plastic as an alternative material for prefilled syringes because of its robustness against breakability while delivering consistent stability and performance for many drug products. The two types of polymers mainly used to make plastic syringes are cyclo olefin polymer (COP) and cyclo olefin co-polymer (COC).
Stöcker acknowledges that glass and polymer both have their strengths. “The right material for a syringe depends on the application,” he says. “The excellent barrier properties of glass and regulatory ease make it the first choice for drug manufacturers, but the polymer’s stability and inert properties, as well as its wide design options, make it an attractive choice as well.” Stöcker cites the example of the anticoagulant heparin, which has been stored in glass prefilled syringes for decades without any major recalls or drug contamination cases, making glass an easy choice. Dermal fillers, on the other hand, are typically highly viscous substances that need to be stored in packaging that allows for consistent gliding force and a robust luer lock, which is integrated in a polymer syringe. In this case, polymer is the material of choice, according to him.
Stöcker recommends a holistic evaluation along the three Ps--product, process, and patient--to find the best solution. He explains that a number of aspects needs to be considered, such as:
Reynolds adds that the selection of the drug container starts with an understanding of the potential interactions between the drug and the system. He points out that certain biologics may be sensitive to silicone oil or tungsten, which are found in many glass syringes. “Certain polymer syringe systems, such as West’s Daikyo Crystal Zenith syringe system, provide container systems free from silicone oil, tungsten, and other extractables,” he says.
For the majority of drugs, glass remains the preferred material; however, Reynolds notes that in certain circumstances, a polymer syringe may offer unique advantages. “Evaluation of both options at an early stage can help to identify the pros and cons of both,” he highlights. “In addition, the selection of either glass or polymer syringes can be influenced by other factors such as storage temperatures (polymer systems offer advantages at extremely low temperatures), potential risks of breakage, and, in cases where a device is used, precision. Functionality and dimensional tolerances can also be key factors in order to reduce the risk from incorrect function of the injection system.”
The development of biologic drug products in prefilled syringes has attracted a lot of interest within the bio/pharmaceutical industry because of the win-win situation for both end-users and manufacturers. But besides formulation considerations and compatibility between the drug product and its primary packaging, there are other technical challenges that have to be addressed such as functionality issues and syringe siliconization.
“A drug product’s formulation is comprised of multiple raw materials, as are the components of prefilled syringes. It is ultimately the compatibility of these systems that will help to qualify the system for its intended use,” says Reynolds. “Components of prefilled systems typically include pistons, syringe barrels, needles, and needle shields--all of which must be compatible as a system and with the drug product.”
According to Reynolds, the prefilled syringe component with the maximum drug product contact area is the syringe barrel, which can have a major influence on drug product quality. The compatibility of the drug product with the barrel’s contact surface is crucial to the drug product quality, he explains, while the break loose and glide forces are key to the administration of the drug.
Siliconization is a key process step in the manufacturing of prefilled syringe systems, highlights Tillmann Burghardt, team manager, Manufacturing Science and Process Development, Vetter Pharma-Fertigung GmbH & Co. KG. “It involves not only the coating of syringe barrels, but also any rubber parts and the needle itself with a thin layer of pure silicone oil or distinct silicone oil/water emulsions, respectively. This process facilitates the assembly of the syringe parts and promotes ease of use and injection,” he says. Burghardt explains that the silicone oil acts as a lubricant that provides certain properties crucial for drug administration. “The silicone layer forms a hydrophobic surface so that the solution within the syringe drains better and supports recovery rate accuracy. The oil layer also has a barrier function--it prevents absorption of the compound by the container. The drug formulation is, therefore, protected from reactive surface mediated chemical modifications,” he says.
According to Bernd Zeiss, manager, Technical Support Medical Systems, Gerresheimer, all prefilled glass syringes today are siliconized in some way. Siliconization is essential to process capability. “Without silicone oil as a lubricant, prefilled syringe systems based on glass do not work because the plunger stopper would not move properly,” he notes. “Extremely high gliding forces would prevent the emptying and make it impossible to carry out a smooth and comfortable injection. The plunger stopper could get stuck in the middle of the injection because direct contact between glass and the currently used elastomers causes very high friction forces. Only appropriate siliconization can overcome this friction.”
Burghardt points out that silicone itself is non-toxic, biocompatible, and insoluble in water; therefore, it has limited impact on the formulation. “As an integral component of prefilled syringes, the use of silicone oil in drug-delivery systems has been clinically tested for decades and commercially proven in billions of patients,” he says.
Zeiss, however, cautions that a few biologics may react to the silicone oil, but adds that not all biologics react this way. For this reason, dedicated stability studies of any newly developed formulation with the intended syringe need to be carried out, he highlights. According to Zeiss, in rare cases where too much protein binds to the siliconized glass surface, or if silicone oil-protein aggregates are formed in the liquid itself, the efficacy of the injectable formulation may be compromised. “In such cases, immunogenic effects cannot be excluded,” he says. “And the safety of the drug could be impaired.”
One modern tool to measure silicone oil-induced protein aggregation is microflow imaging (MFI), notes Zeiss. “The amount of particles found in the formulation provides an indicator of the sensitivity of the protein toward silicone oil. By applying MFI, the amount and shape of particles in the formulation can be determined. Free silicone oil will form round droplets while any odd shapes seen indicate protein aggregation,” he explains.
Burghardt highlights that siliconization involves introducing supplementary material into the prefilled syringe system, in addition to the actual injected compound. “Therefore, before choosing a siliconization technology, companies have to consider various factors,” he says. “As the silicone coating is not covalently bonded to its substrate, it is susceptible to change over time. Storage conditions and transport stress, in particular, temperature and agitation, can affect the layer and its interaction with the syringe surface over time. Silicone layers can also interfere with analytical assays because they might release subvisible particles to the liquid phase. The migration of such silicone oil droplets at parts per million (ppm) level into the compound is a known phenomenon. Therefore, each new compound requires individual compatibility and stability assessments.”
Siliconization methods use either pure silicone oil or distinct silicone oil emulsions. Burghardt notes that pure silicone oil is still the most commonly used technology for a prefilled syringe. “It can be applied by wipe down or dynamic spraying processes and can also be used for glass and polymer systems,” he says. “This medium allows for various types of sterilization procedures such as autoclaving, ethylene oxide treatment, or gamma irradiation. It is also used for rubber components, needles, and the syringe barrel itself.”
Zeiss concurs that the standard approach used until today is the spray siliconization method with silicone oil. “Medical-grade oil is sprayed into the barrel using special diving nozzles that distribute the coating inside the syringe. If required, different siliconization levels can be applied, depending on the customer needs,” Zeiss explains. Burghardt adds that this process supports layer uniformity from the cone toward the flange of the barrel. However, he notes that temperature-sensitive polymer systems in general, as well as glass syringes with diameters less than 0.5 cm, are restricted to the conventional static spray process, which involves spraying from outside the barrel to avoid nozzle to glass contact within the syringe.
The second method is baked-on siliconization. Zeiss explains that in this process, an oil-water emulsion is sprayed into the barrel and subsequently baked on the inner barrel surface in a dedicated heat chamber. “Water is evaporated, and the silicone oil is fixed to the glass surface,” Zeiss says.
According to Burghardt, the use of silicone oil emulsions is gaining growing importance, but he points out that this method is only indicated for glass barrel systems because it requires a dry heat sterilization step. “The syringe is heated to more than 300 °C to evaporate the water of the emulsion and help bond the silicone oil to the sterilized syringe. These silicone oil emulsions can be applied by either static or dynamic spraying nozzles to the glass barrel.”
Zeiss highlights that baked-on siliconization leads to dramatically lower residual-free silicone in the prefilled syringe. The method was originally developed for ophthalmic applications, according to him, but turns out to be well suited for sensitive biologics.
Insufficient or excessive siliconization can cause issues in the functional performance of the prefilled syringe. “It is crucial to evaluate the ideal siliconizing process on the basis of the given compound and the anticipated fill and finish steps with regard to possible post-fill treatments,” Burghardt stresses. “The topology of the initial silicone coating is determined by which siliconization technology is used. However, the impact of pH and ionic strength of the filled compound formulation, as well as storage temperature and transport stress or potential lyophilization processes, should not be underestimated during process development. Thorough analytical testing has to be considered to elicit the amount and distribution of the silicone oil on the syringe body surfaces both prior to and after filling.”
Burghardt explains that various analytical methods can be used to examine the amount and distribution of silicone inside the system. “For example, one can measure total extracts of silicone oil from empty barrels by Fourier transform infrared spectrometry, or optically assess the uniformity and thickness of the layer by reflectometry,” he says. “The overall functionality of the entire system can be evaluated by tensile force measurements on both empty and filled units, thus, simulating the later application process. Simple flow microscopy technology is applied for detecting subvisible particles in liquid solutions after incubation in the desired prefilled syringe, allowing for particle classification by count, size, and shape.”
Zeiss notes that siliconization can be optimized in many ways. “Over the past 10 years, the use of diving nozzles in spray siliconization have led to much lower amounts of silicone in the syringes. Manufacturers have also constantly improved and optimized the baked-on process,” Zeiss says. “The lower the lubrication levels in a syringe, the more critical the interface between barrel and elastomer stopper becomes. Finally, choosing a modern plunger stopper makes a good syringe system complete.” According to Zeiss, Gerresheimer has carried out a comprehensive test campaign comparing all kinds of available plunger stoppers in combination with spray-siliconized and baked-on siliconized syringes. He adds that it is not only important to lower and optimize siliconization itself, but also apply a system approach to evaluate which syringe plunger combination is the best. “In addition, the amount of product to be filled into the syringe and the plunger stopper placement method are part of this equation. Today, low silicone syringe systems with very good gliding behavior of the stopper can be offered,” Zeiss says.
Volume 30, Number 11
When referring to this article, please cite it as A. Siew, “Delivering Biologics in Prefilled Syringes," BioPharm International 30 (11) 2017.