Introduction
The EU Rules for Manufacture of Medicinal Products GMP, published in 1989, contained an annex on the manufacture of sterile medicinal products to ensure the sterility of medicinal products. A version of this annex, “Annex 1”, issued according to its document history in May 2003, underwent several targeted updates in the interim period until 2009, but now Annex 1 has undergone, for the first time, a complete revision.1
The new version of Annex 1, released on 22 Aug 2022, is a comprehensive revision to the previous Guideline, which covers all aspects related to the facilities, utilities, equipment, and systems and controls used for the production of sterile medicinal products. This includes sections on aseptic preparation and processing, and Aseptic Process Simulation (APS), and media fill. There is much interest regarding additions to this latest revision of Annex 1, which has much more detail compared to previous versions. In this article, we have reviewed the section on Aseptic Process Simulation (APS), which previously consisted of five brief paragraphs, and now consists of four pages– approximately a 300% increase in the content related to APS. Drawing on our recent publications regarding the application of media simulations in the validation of aseptic processes,2,3 this article aims to assess the changes and additional requirements related to APS.
Aseptic Process Simulation (APS): Process Design
In the updated Annex 1, Section 9 “Environmental and Process Monitoring” paragraphs 9.32 to 9.49 discuss Aseptic Process Simulation (APS) commonly known as media fill. Paragraph 9.32 stresses the importance of process design, adherence to pharmaceutical quality systems, process controls, training, and evaluation of monitoring data to ensure an effective aseptic manufacturing process. If the actual processing conditions during APS affect the viability of potential microbial contaminants, alternative procedures that function as closely as possible to the actual operation should be used. Paragraph 9.32 also mentions “surrogate materials”, or substitute materials such as buffer solutions that may be used in parts of the APS. If used, it is important to ensure they do not inhibit the growth of microorganisms. (“Surrogate” is not defined in the glossary.)
In paragraph 9.33, Annex 1 states that the APS should imitate the routine aseptic manufacturing process as closely as possible and include all the critical manufacturing steps. While this is not a new requirement, the following steps are new:
The scope of the APS should include all aseptic operations after the sterilization and decontamination of materials to the point where the containers are sealed.
Non-filterable products should have additional or other aseptic steps considered.
Process air should be used instead of inert gas to promote the growth of microorganisms. An exception to this is when anaerobes have been isolated from these systems, and APS is performed specifically to detect anaerobes in these systems.
Surrogate materials can be used in place of sterile powders in the same containers.
Individual simulation for unit operations should be avoided unless supported by documented justification, ensuring all the unit operations APS add up to cover the whole process.
Lyophilization
The APS requirement for lyophilization is also introduced in this new Annex 1. The main consideration is to simulate all aspects of the lyophilization process including filling and transport of vials. There are some exceptions where the simulation process may have an impact on the recovery of the microorganisms, such as using process air instead of nitrogen during vacuum break or causing boiling-over or freezing of the media. Elements to consider in APS design include the maximum sterile hold time, i.e., duration from the end of sterilization to use of lyophilizer, and the maximum hold time from filtration to lyophilization.
Some examples of worst-case challenges are also mentioned. These include loading the largest number of trays, and the maximum duration of chamber door opening where the chamber interior is exposed to the clean-room environment.
An important requirement in the new Annex 1 is 8.123. “Lyophilizers and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as far as possible. The frequency of lyophilizer sterilization should be determined based on the design and risks related to system contamination during use. Lyophilizers that are manually loaded or unloaded with no barrier technology separation should be sterilized before each load. For lyophilizers loaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilization should be justified and documented as part of the CCS [Contamination Control Strategy].”
This requirement seems to indicate a preference for automated loading and unloading, and/or with the loading/unloading equipment protected with barrier isolation, under which situations the frequency of lyophilizer sterilization can be justified and documented, as opposed to manual loading/unloading situations where the lyophilizers must be sterilized before each use. The additional delay permitted for the introduction of this requirement (25 August 2024) seems to indicate that mechanical modification within the clean room and re-validation via media simulation is expected (which may be incorporated during an annual shutdown).
Source from:
plastic pharmaceutical packaging
Polymer Vial for cell and gene therapies
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