The basics of aseptic processing
Susan J. Schniepp, Distinguished Fellow of Regulatory Compliance Associates, answers some frequently asked questions about aseptic processing.
Q. What is aseptic processing?
A. Aseptic processing is a manufacturing method that can produce a bacteria-free product without subjecting the product to terminal sterilization processes. Many products degrade and become ineffective when subjected to the harsh conditions of terminal sterilization. The aseptic manufacturing allows these products to be manufactured in a sterile environment, allowing them to maintain their effectiveness while being safe for injection to patients.
Q. What is the difference between aseptic processing and terminal sterilization?
A. The main difference between aseptic processing and terminal sterilization is when the sterilization step takes place in the process. In terminal sterilization, sterilization is performed after the API, excipients, containers and caps have been assembled. The assembled product is then subjected to high heat and / or radiation which renders the final product sterile. Terminal sterilization processes are severe and can have negative effects on the effectiveness of the product. For products that do not withstand terminal sterilization, manufacturers use aseptic manufacturing. The aseptic manufacturing process requires that the drug product and all excipients, container and caps are individually sterilized before being introduced into the clean room or sterile manufacturing core where the end product is manufactured in a constantly highly controlled environment. monitored for air quality and potential microbial penetration.
Q. Why do manufacturers need to establish environmental controls for aseptic processes?
A. Let’s be clear, all drug manufacturing, including solid oral dosage forms and terminal sterilization manufacturing, must have established environmental controls. This requirement is reflected in current Global Good Manufacturing Practices (cGMP). The purpose of these controls is to prevent product contamination due to unsanitary conditions. Environmental controls to monitor include, but are not limited to, air quality, including particulates, ventilation, temperature, humidity, atmospheric pressure, and microbial contamination. Environmental control limits are, as expected, more stringent for aseptic processors due to the nature of their business.
Q. What does PUPSIT mean and why is it mandatory?
A. PUPSIT is a term used in aseptic processing operations and stands for post-sterilization integrity test before use. This test is carried out on the sterilizing filter after its installation before the manufacture of the product, then again after the manufacture of the product is completed. The purpose of the pre-test is to make sure that the sterilization and installation process has not damaged your filter before filtering your product. The purpose of the post-test is to demonstrate that the filter has remained intact and undamaged during the actual filtration of the product.
An article published by the Parenteral Drug Association (PDA) states: “Since 1998, the EU Guidelines for Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or ‘Annex 1 ‘contain the requirements for verifying the integrity of a sterilizing grade filter before use and after sterilization. The requirement remained in the 2008 revision and in the 2017 draft revision of Annex 1. Although it is not a requirement of the United States FDA, inspectors of the EMA and some PIC / S inspectors have expressed increasing expectations that companies will use this test procedure ”(1). The article goes on to explain the concerns that led to the PUPSIT requirement: “Concerns have been expressed that a sterilizing filter could develop certain defects that would allow microbiological contamination to pass during filtration. The key is that defects can be blocked or clogged with liquid contaminants or components during the filtration process and not be discovered during integrity testing after use. This phenomenon is sometimes called “filter defect masking” (1).
Additionally, the article explores the rationale for not using PUPSIT due to the fear “that the risk of product contamination / deterioration associated with running PUPSIT may significantly outweigh the risk of product contamination due to masking effect. To test a filter that has been sterilized by current means, the sterile filtrate side of the sterilized filter must be at atmospheric pressure, which requires a passage of fluid to remove any wetting agent. Exposure of the downstream parts of the sterile product transport line presents a risk for maintaining the sterility of the filtered product. This, along with other risks, including additional interventions in the aseptic space, increased complexity of the filtration system, performing these additional tests, failure of PUPSIT assembly components, and stress on the filter. sterilized to perform the test, is greater than the low probability of microbiological contamination from a defect that may be masked when using the filter and not subsequently detected ”(1).
As noted above, the PUPSIT concept is actively debated. The best way to combat the use / non-use of PUPSIT in your organization is to make sure that you have an appropriate risk assessment to defend your position.
Q. What makes manufacturing aseptic drugs so difficult?
A. Aseptic manufacturing requires highly skilled and experienced people to perform operations, special equipment and cleaning procedures, as well as constant monitoring of the environment, even when the manufacturing area is not in use. The risk to the product and to patients is significant if the aseptic process is compromised.
1. T. Morris et al., “PUPSIT and the Revision of Annex 1”, PDA letterr, August 29, 2019.
About the Author
Susan J. Schniepp is a Distinguished Fellow of Regulatory Compliance Associates.
Book 45, Number 10
Pages: 58, 57
When you refer to this article, please place it under the name of S. Schniepp, “The Basics of Aseptic Processing, Pharmaceutical technology 45 (10) 2021.