In a previous post I briefly identified the two primary methods (terminal sterilization and aseptic processing) for producing a sterile pharmaceutical product, such as a vaccine injection. In this post I will contrast the two methods.
A sterile product contains no living organisms. This means the sterilization process must kill any present organisms, including disease-causing microorganisms called pathogens. The only two methods used to manufacture sterile products are terminal sterilization and aseptic processing.
Terminal sterilization is a traditional method going back to the 19th century canning industry. For this method, most drug products are produced by mixing the ingredients to form the bulk drug product solution. Which is then:
filled into a container such as a vial or syringe;
tightly sealed with a rubber-type stopper or syringe plunger; and
then sterilized the sealed container, usually with high heat in a chamber called a steam autoclave.
The sterilization process is very well controlled through well-defined conditions of time, pressure, and temperature. The items in the chamber are arranged to ensure sterilization of each.
Terminal sterilization is widely used in other industries. Pasteurization of milk is a similar but lower temperature process to kill pathogens. Autoclaves are widely used to sterilize materials in hospitals, dentists’ offices, and tattoo parlors.
Other types of terminal sterilization include: ethylene oxide gas for surgical garments; hydrogen peroxide vapor for items not suitable for high heat; or gamma-ray irradiation.
The first two only sterilize the outside surface of the container. Only radiation and steam (indirectly) can sterilize the interior.
Terminal sterilization has several advantages that make its use the default method for pharma:
The sterilization cycle can be tightly controlled with typical temperatures varying by less than 1 °C and timed to the second. Steam is ideal as it disperses throughout the camber quickly while pressure controls temperature. It also holds a unique chemistry that makes it more lethal to living cells at lower temperatures than dry heat alone such as in a hot-air oven.
Thus, the sterilization process is highly predictable and repeatable and provides a very high level of statistical assurance that the filled containers are sterile. Although there is never a 100% assurance of sterility, the minimum standard is typically that the chance of a non-sterile unit is less than one in a million.
Since the container is fully sealed prior to terminal sterilization, there is very little risk of contamination afterwards.
Because terminal sterilization occurs after the formulation and filling process, these manufacturing steps can occur in more relaxed environment. This lowers the cost and complexity of maintaining and operating such a manufacturing space.
As a general rule, regulatory agencies such as the FDA regard terminal sterilization as the preferred method of sterilization, due to the high level of sterility assurance it provides. So, why would drug manufacturers use any other method?
Unfortunately, less robust medications, including many newer biologic drugs such as proteins, mRNA, hormones, and monoclonal antibodies will quickly deteriorate at the extreme conditions of terminal sterilization. While the end product might be sterile, but the drug will not work!
Luckily, most products can be sterilized by filtering the clear bulk solution through filters so fine that even the smallest microbes cannot pass. But that leaves the problem of how to get the now sterile solution into the vial and sealed without recontamination. This is where aseptic processing is required.
When terminal sterilization is not an option, aseptic processing is used. Each component (drug, container, closure, etc.) is individually sterilized first, then carefully assembled in a clean room to make the finished drug product in a manner that prevents contamination.
Aseptic processing cannot provide the same quantitative level of sterility assurance as terminal sterilization, but it features several layers of control to minimize the risk of contamination:
Containers, closures, and filling materials go through their own validated sterilization cycles.
The filtration of the formulated drug product is also validated – manufacturers will demonstrate repeatedly that passing the product through the selected filter will remove a particular microorganism. For this validation a bacterium of very small size (even compared to other bacteria), which is therefore more likely to pass through a filter, is used.
The clean room environment in which the filling takes place is much more strictly controlled than the environment for non-aseptic processing.
Operator gowning in an aseptic processing area typically consists of full coverage – no skin or hair is exposed – with sterilized coveralls, hoods, boots, goggles, and gloves. Operators are highly trained from how to put these gowns on to using proper aseptic techniques to avoid contamination. Each operator must pass certification testing before they are allowed to participate in aseptic activities.
The entire aseptic process is routinely simulated in a challenge is designed to detect the potential for contamination in the finished drug product. A single unit positive for growth is a sign that somewhere the process has failed and would be thoroughly investigated – zero positives is the norm for this challenge.
There are several variations on aseptic processing. In addition to the traditional clean room, some facilities use barriers to separate operator from the actual filling area. These can be full isolators completely closed to the surrounding environment, or less enclosed systems such as RABS (“remote access barrier systems”). Both require operators to interact with the filling area only through special glove ports, further minimizing the potential for contamination of the drug product.
Whether a product is sterilized via terminal sterilization or aseptic processing, it is very important to prove that there is no degradation of the product over time. This is shown through extensive stability testing, which is a long-term evaluation of the container/closure system and the product itself.
When possible, terminal sterilization is the expected method of sterilization for drug products. Since terminal sterilization is destructive to some products, aseptic processing is used as a proven safe and effective method to sterilize medications. As new products are developed and manufactured, both methods will continue to be used to ensure that they are safe for patients.