Terminal sterilization concludes the pharmaceutical fill-finish process. The more sensitive the drugs and their primary packaging materials are, the more important this process is. This applies in particular to pre-sterilized syringes. This white paper by Thomas Ofenböck and Christian Dallner of Syntegon describes which requirements must be considered regarding products and methods and how risks can be avoided effectively.
Many factors need to be taken into account when terminally sterilizing liquid pharmaceuticals. To ensure smooth application and exact dosing, neither the drug nor its packaging should be changed through thermal treatment. Due to the complex interaction between drugs, packaging material and physical laws, terminal sterilization of prefilled syringes is very demanding for the product as well as the sterilization process – and presents pharmaceutical manufacturers with numerous challenges.
The first challenge consists in selecting the appropriate sterilization method. While the hot water shower process, which is often used for closed containers in different batch sizes, is not suitable for dry unloading, the steam/air mixture is the method of choice for prefilled syringes. It was developed in the early 1970s by Syntegon’s subsidiary Schoeller-Bleckmann Medizintechnik (SBM) and has been an integral part of the portfolio ever since.
The core of the steam/air mixture method is a special combination of sterile-filtered compressed air and pure steam, which is circulated over and around the sterilization loads during the entire sterilization cycle by powerful radial fans and corresponding air baffles. The atmosphere of the steam/air mixture outside of the container allows maintaining pressure equilibrium between the inner and outer environment. The sterilization cycle essentially consists of three distinct phases:
• Phase 1: Heating
Once the sterilizer chamber is loaded with the syringes and the doors of the pressure vessel are closed, the heating phase begins. Pure steam and sterile filtered compressed air are released into the chamber, where fans ensure they are circulated and mixed. As soon as the required temperature has been reached, the sterilization phase is ready to start.
• Phase 2: Sterilizing
The product is typically kept at a temperature of 121 °C or 250 °F and sterilized over a period of at least 15 minutes. Other applications are also possible, for example, if the product requires sterilization at higher or lower temperatures. The latter mainly applies to temperature-sensitive products or primary packaging that depend on a lower temperature to maintain their integrity. In this case, the duration of the sterilization process is adjusted accordingly.
• Phase 3: Cooling
In the final phase, the entire load of the sterilizer is re-cooled until it reaches the required unloading temperature. This process uses heat exchanger packages, which are also located in the sterilizer chamber and are supplied with cooling water. During the cooling phase, the steam/air mixture increasingly dries out and ultimately results in the desired dry unloading of the entire sterilization batch.
The importance of supporting pressure
A key component of any terminal sterilization process is the ability to implement a pressure overlay during the different phases using sterile-filtered compressed air. The necessity of creating the so-called supporting pressure arises from the isochoric change of state in the sterilization loads.
Although the primary packaging material expands thermally, the volume of the container hardly changes. This adds energy in the form of temperature and increases the pressure inside the syringe. Adequate supporting pressure is required to ensure the integrity and dimensional stability of the container. This pressure can be adjusted individually and prevents deformation, container breakage, and stopper movement – one of the most important challenges in terminal sterilization of prefilled syringes.
Challenge one: stopper movement
Terminal sterilization of prefilled syringes is unique in that the inserted stoppers are not mechanically fixed with an aluminum cap, as is the case with vials. Hence, inaccurate supporting pressure settings lead to uncontrollable stopper movement – and, in the worst case, to loss of integrity. If a stopper is not repositioned correctly or if it twists (which in turn can lead to a loss of seal integrity of the sealing rings), the syringe is no longer sterile. As a general principle, the smaller the air bubble in the syringe, the higher the internal pressure. In this case it is recommended to realize a higher pressure design of the pressure vessel to increase the supporting pressure on the product.
Further factors that influence stopper movement include the stability of the syringe itself, the material, size and height of the stopper, the siliconization rate of the stoppers and syringes, as well as the filling volume. Sterilization tests with a small number of syringes provide the opportunity to consider all influencing factors for a particular combination of product and syringe. If the syringes are visually recorded during the test run, the footage and any negative influences can subsequently be examined for the entire process.
Challenge two: the loading pattern
An appropriate loading pattern is essential for a successful terminal sterilization process. The syringes can be aligned and positioned in different ways. Whether they are sorted individually or in bulk, in wire baskets or already packaged in blisters or cartons – sterilizer loading strongly depends on the specific customer philosophy, based on the geometry of the syringes as key factor. Some pharmaceutical manufacturers also use prepared mounts for loading. Against this background, the overall conditions and restrictions of each manufacturer must be considered in the increasingly automated handling of syringe loading.
Despite the remaining flexibility, there is one essential point that needs to be considered when defining the loading pattern: the flow of the steam/air mixture must be maintained at all times and all requirements for efficient and safe sterilization as well as the desired degree of drying must be met.
Experience and expertise are key
Both the recipes for terminal sterilization of prefilled syringes and the configuration of the sterilizer should be precisely adapted to each specific container. This requires precise knowledge of the sterilization process. Preliminary tests are recommended, especially for new products or new combinations of product and syringe. For these cases, the Syntegon subsidiary SBM offers highly flexible research sterilizers to develop recipes and to configure the appropriate sterilization equipment. Numerous international companies already rely on the long-standing experience of the SBM experts to identify the ideal sterilization conditions for their products – first and foremost with the steam/air mixture method.
The success story of SBM started in 1972 with the patent for the steam/air mixture process and the production of large-volume sterilizers in Ternitz, Austria. Since then, SBM has developed into one of the leading suppliers of vacuum-steam, steam/air mixture or hot water shower sterilization. This extensive experience in autoclaving technology led the company to expand into freeze drying equipment in 2018, leveraging its competencies in process and GMP know-how, as well as quality of design.