Did you know that aseptic (or sterile) processing in pharmaceutical manufacturing is relatively new? Sterility requirements were established in the 1920s. Later, during World War II, requirements were created around large scale biological manufacturing of plasma and blood products. Previously, some blood products required post-fill pasteurization, where they underwent the low heat treatment of 60°C for 10 hours. While this does sterilize, pasteurization does not reduce fungi contamination.
Over the years, discoveries like the inadequacy of pasteurization have been found and the requirements have become more stringent. Now, biopharmaceutical manufacturing is a highly regulated industry to protect the end user. In fact, many of the pharmaceutical recalls over the last several years were due to gaps in process documentation - not actual errors in the aseptic filling process. That is how careful they are about the process.
So what exactly is the aseptic filling process? The Food And Drug Administration's (FDA) 1987 guidance for septic filling (or sterile filling), defines it nicely, “In aseptic processing, the drug product, container and closure are subjected to sterilization processes separately and then brought together. Because there is no further processing to sterilize the product after it is in its final container; it is critical to the maintenance of product sterility that containers be filled and closed in an environment of extremely high quality”.
In this article, we are going to walk through the basics of aseptic filling.
Sterile drugs are finished in molded glass bottles, glass vials, glass syringes, and, sometimes, glass ampoules. They can be just about any solution, powder, or suspension, as long as they are able to be terminally sterilized before they go through the aseptic fill process.
To complete the process, start by sanitizing the people working with the drug, the filling components, equipment and parts, and the cleanroom and its equipment. You will also need to terminally sanitize the product. Essentially, this is ensuring that the product is free of harmful germs. Once everything is sanitized, including the drug product, bring it all together to fill the container in a sterile process: the aseptic filling process.
Before the aseptic filling process, we will need to sterilize the product via filtration. Usually, we see bulk drug sterilization is done by a depth filter. Whatever filtration process you use, you will need one that is compatible with your aseptic fill process. You can pre-sterile filter products with one size of filter and follow it with a series of two or more sterile filters at a smaller size. From the filtration process, the sterile drugs are passed to the fill equipment. This is done best if the fill equipment is connected to protect the drug from any intervening contamination. Your sterile system should be a close system from sterilization to filling equipment.
After your drug has been filtered, it passes into your filling components. It is required that whatever components and supplies you use during the aseptic fill process are sterilized. Components should first be washed to rid them of any endotoxins. Then you can pass them through steam autoclaves, dry-heat ovens, and sanitized cleanroom airlocks.
Different production requirements and drugs use varying types of filling components. Small Volume Parenterals (SVPs) often use Tubular Type 1 glass vials. Whereas Large Volume Parenterals (LVPs) often use sterile lyophilization (which we will discuss further in this article) and blown Type II glass bottles.
Once the drug is put into its container, it is sealed. This seal is what keeps the sterile interior of the container and the sterile drug from being contaminated as well as shelf stability. Once the drug is passed off to the healthcare staff in charge of distributing it, they should handle it with sterile procedures onsite to prevent contamination.
The FDA defines lyophilization as “a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase.” It is also called freeze drying.
Typically, the load and unload process for sterile lyophilization is often automated, like the other steps in the aseptic filling process. This is just one more way to decrease contamination opportunities.
It is loaded into the chamber after the product is filtered and loaded into its container. But the difference is that the product is left only partially sealed. You do run this risk: the product is exposed to the environment longer because it is only partially sealed.
There are usually two steps in sterile lyophilization: freezing and crimping.
Using either liquid nitrogen or a sterile shelf, the drug is then frozen. This is normally done twice for good measure. It is usually done near a vacuum at -35°C or colder. After the freezing process, the container is moved to the crimping process. This is where the product is finished being sealed.
Two weeks (14 days) after the aseptic fill, you should complete a visual inspection of the drug. This time would allow for the growth of microorganisms. You should use a white and black background viewing areas. This is around 85% effective, so many companies have implemented a double inspection with tight criteria.
How do you know your aseptic filling process worked? Your liquid will be free of particles and contamination. To determine if your process is working, you will need a liquid particle counter.
We recommend the Liquid Batch Sampler LS-60 (LS-20). With a high accuracy syringe pump flow control system and high sample volume sensor, this is designed to be the perfect tool for multiple batch sampling applications.
If you want to see if the LS-20 is right for you, contact us to schedule a hassle-free consultation.