For some time, it seemed as if the vaccine market of the typical pediatric and flu vaccines had matured. Recently, however, the segment has been revived due largely to advances in research into the human immune system and pathogenicity. Also, the successful introduction of several new and highly effective vaccines has boosted confidence. Industry analysts like RNCOS expect continuous growth in the coming years. In fact, the RNCOS 2011 Global Vaccine Market Forecast predicts sales growth of almost 20% to about $33 billion by 2013. The best opportunities for drug manufacturers will be in areas such as nosocomial infections, therapeutic vaccines and pandemics.
But while the outlook is positive, there continue to be a number of challenges ahead. Modern substances that stem from biotechnological processes have more challenging requirements when it comes to production, manufacturing, and administration. Until recently, the main players had made only limited investment in future technologies in these particular areas. Therefore, to help bridge the technology gap, many pharma firms in the vaccine space are looking into contract manufacturing to take full advantage of the comprehensive know-how and high capacities of leading CDMOs. With their innovative manufacturing facilities, such service providers can realize potential solutions for this emerging growth segment.
Setting Up a New Premise
While the established markets for pediatric vaccines and influenza have become increasingly saturated, new biotechnological methods for producing vaccines for complex pathogens like meningitis, hepatitis C, cancer, and HIV are providing new sales growth. The specifications for these substances and their areas of application are giving rise to entirely new packaging and manufacturing processes. Sensitive substances, for example, require extremely high quality and safety standards in production. However, because of the high value of the substances, the trend is to shift away from vials and move towards prefilled syringes. In today’s global world, the risk of pandemics is omnipresent and thus, public vaccination programs are increasingly demanding prefilled syringe use.
The outbreak of H1N1 in 2009 demonstrated quite well how the lack of speed in vaccine filling could be a potential weak point in effective combat against dangers. In the case of a pandemic, as many as 300 million people in the U.S. alone would need a jab. For the health authorities and emergency management organizations, such numbers represent an enormous challenge. Multi-dose vials need more time and trained personnel for administering the vaccine if accidental “stick” injuries are to be avoided. As such, many emergency agencies prefer prefilled syringes as an option for vaccinating large numbers of people in a short period of time.
Looking to the immediate future, vaccine manufacturing plants must be able to produce large quantities within a few weeks while maintaining high quality and safety standards. And because the “blockbuster model” of drug manufacturing is largely in the past, the old monoplant model is no longer relevant or economically feasible. Therefore, today’s CDMOs must be flexible, allowing for a simple product changeover.
For the pharma company, avoiding loss of expensive antigen is another important issue. Because they are already meeting stringent requirements to work safely and efficiently for their customers in other areas, CDMOs are in an excellent position to provide answers to this challenge. By collaborating with a top engineering firm, a CDMO can develop a high-speed filling line conceived specifically to meet the complex demands of vaccines.
A Special Approach for Vaccines
As the prefilled syringe market becomes more established, pre-sterilized injection systems have now become an accepted alternative to bulk systems. However, the entire process has to be maintained at a high aseptic level — never a simple task. The decisive question is how to introduce the tubs and the syringes into the critical area for filling. For an illustration of what a solution for vaccine filling should look like, let’s look at our newly built high-speed filling line.
Because the line utilizes pre-sterilized syringes, the time needed for making preparations at the filling location is considerably lessened. When delivered, the syringes are already washed, siliconized, sterilized and validated and are, therefore, ready for processing. The syringes are nested in magazines and sterile packed in tubs for transportation. The tubs themselves are wrapped in a sterile protective plastic film. Some suppliers even require a second sterile protective film wrap of the tubs.
To meet quality and safety demands, the line has been equipped with a comprehensive tub-handling concept involving such technical innovations as an automatic disinfection tunnel. To respond to the economic needs, the plant can also perform a number of different filling processes that allow for rapid product changeover. High efficiency is provided thanks to automated processes, optimized paths and a lean operating concept.
Safe Tub Processing
The handling of the tubs is the decisive factor in maintaining a high level of quality and safety. That is why tub-maneuvering steps such as unpacking and transportation are performed mechanically and is program-controlled and reproducible. The tubs begin
their journey in a hygienic and logistics area still wrapped in their protective foil. They are then placed on a conveyor belt that transports them to a class C cleanroom. If the tubs are wrapped in two films, the outer wrapping is removed as the tub passes from the logistics zone to the classified area. While a cutter performs this task automatically, a special tool keeps the film shut until the transfer is completed. Before entering class A, the protective bag is automatically removed and disposed.
For tubs with a single wrapping, transportation is directly to the class C room. Thus, all tubs in the classified area are wrapped in a plastic film.
The packaging is then disinfected in an especially developed automatic spraying tunnel. The wrapping is sprayed with a disinfectant on all sides by means of jets. Any number of products can be used for this step, but alcohol and a sporocide are the preferred method. After spraying, the tubs remain in the tunnel until all the disinfectant has dried. They are then transferred to the crossing point into the filling zone, which is a class A cleanroom. The disinfected wrapping is cut open, but kept closed until the tubs can be introduced so that no contact is made with the remaining wrapping upon entering the higher-classification cleanroom. Only when it reaches the class A environment is the protective lid removed by machine. The automated process was designed to respond to the issue of how to introduce tubs and syringes aseptically into the classified area.
Innovative in-process controls also help contribute to the avoidance of defective filling and ultimately, to greater safety and efficiency. A primary example is the 100% monitoring of all syringes. Prior to filling, each syringe is tested for having the necessary closure parts. An in-line 3-D scanner automatically scans the systems and registers any potential defects. Syringes lacking a closure part are identified and automatically left unfilled. This monitoring system is based on an end-to-end, track-and-trace system with testing and documentation features. Cameras are used to pick up starting data on the number of nested syringes and their formats, and the data is then printed on the tubs. Problems such as the absence of closure parts are automatically noted. The data is assigned directly to the particular syringe in the tub. An inline printer then notes the data on the tub. At the end of the line, a robotic arm automatically removes the syringes from the tub. This process not only prevents loss of substance, but also ensures the sterility of the machine itself by avoiding contamination due to substance leakage from a syringe lacking closure parts.
Processes That Meet Various Requirements
Aseptic safe handling of tubs meets one of the main requirements for filling innovative biologics and vaccines. Modern filling plants also have to meet new requirements regarding economic efficiency. This includes creating conditions for manufacturing a variety of substances. Quick and efficient product changeover is necessary because, as mentioned earlier, the blockbuster model is rapidly becoming obsolete and monoplants are no longer economically viable.
The production facilities should be able to apply the appropriate processing method for each type of substance. Basically, a line should also be able to fill various syringe systems and formats. Suitable packaging and volumes have to be available to meet differing demands. The line described above allows for the use of tubs with a single or double protective film as well as the pre-sterilized systems that may come from different manufacturers. The plant also has a filling station with as many as 16 filling heads for a variety of formats and quantities of syringes per tub. Tubs with as many as 160 nested syringes can be processed in this manner. The ability to use the appropriate format part for varying sizes also allows for a great deal of flexibility. Different procedures can be selected to install stoppers, so syringes with various silicon layers can be processed as well.
Furthermore, this plant was designed to integrate several pumping systems in order to meet the demands of various substances. For suspensions, permanent recirculation of the substance in solution is also possible. Thus, one facility offers various options and production conditions for a wide range of different substances.
The Key to Flexibility
One of the decisive issues in selecting a manufacturer is how flexible and quick it is in product changeover. In the case described, this plant uses a restricted access barrier system (RABS), which allows for fast production changes with a high degree of safety. RABS essentially implies stringent separation of user and areas that are in contact with the product. Plastic walls and doors create a physical barrier around the critical zones of the filling area. Ports for gloves are integrated into the barriers to perform the entire manual steps needed for product changeover. The area inside the walls is maintained under cleanroom class A conditions. Laminar flow air travels downward from the ceiling, surrounding the filling machine. The air then leaves the class A area by flowing underneath the barrier into the operating area, which is under class B conditions. From there it is filtered and directed back into the ventilation system.
During format change and filling, the separating walls must be kept closed. The barrier doors are only opened for cleaning purposes following manufacturing and microbiological monitoring. Line clearance can only be given after a high-level disinfection process is completed with the use of a sporocide. Once these procedures are completed, the gloves are removed and tested for integrity. If they are airtight, they can be sterilized, packed up, autoclaved, and then mounted back into the glove ports in the barriers. Prior to the next production cycle, the change of format can be initiated using the gloves, and without tools. Rapid locks allow for a fast change of parts that can be installed easily through strategically placed glove ports. All the sterilized format parts are brought into the machine using a SteriSet® container. And all parts of the machine or format parts are made of resistant materials that can be autoclaved like stainless steel (316L), PEEK, or silicon. Depending on the product to be filled and conditions on the line, clearance and setup of the line can be achieved within four hours.
An Efficient Plant
Short preparation times mean that even in the absence of blockbuster products, modern plants can achieve high capacity utilization. Lines like the one described above can fill several products a day using a 24-hour shift model. Depending on the syringe format and the substance being filled, some products can be manufactured for as long as 20 hours a day. With as many as 16 filling heads, translating to 50,000 syringes per hour, full production output can reach 1 million systems per day. By automatically avoiding filling syringes without closures, the system increases production reliability.
The plant is especially efficient thanks to its lean servicing concept. Because many processes have been automated, only three staff members are needed to run the line (depending on the situation and momentary requirements). Naturally, the system itself is not the only contributor to high efficiency. The design of the building around the line was also important to enable short paths between various processes such as the compound area and the filling station, permitting the greatest possible utilization of available substance supplies. In sum, reduced preparation times, higher capacity utilization, and leaner servicing resources are conducive to greater optimization of operating and unit costs.
Overall, the facility described offers the reader in detail how a modern manufacturing line can support the changing demands in prefilled syringe production. They must be flexible and allow for high safety and more efficient production. If these criteria are met, then commercial manufacturing plants will be able to respond to the current and future challenges like cost and competitive pressures, as well as meet the increased regulatory demands in the manufacturing of vaccines and other high-volume products. They will also support drug companies in their efforts to develop innovative therapies and enter growing market segments like vaccines.
Dr. David Brett is product & service manager at Vetter Pharma International GmbH. He can be reached at 49 751 3700-0.