5/6 October 2022
On 20 February, the Directorate for Health and Food Safety of the European Commission published a second draft for the revision of Annex 1 of the EU GMP Guide. The document enters a 3-month phase of commenting by concerned organizations and stakeholders.
Following the Q&As on what data is required for sterilization processes of primary packaging (published in 2016) the European Medicines Agency, EMA, released a new Guideline on the sterilization of the medicinal product, active substance, excipient and primary container. The guideline came into effect on October 1, 2019.
For containers required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site where sterilization of the containers takes place may not have undergone inspection by an EU authority. Consequently it may not hold an EU GMP certificate in relation to this activity. Sites located in the EU which perform sterilization of primary containers only are not required to hold a Manufacturer’s/Importer’s Authorization (MIA), whereas sites, which carry out sterilization of medicinal products, are required to hold a MIA in relation to these activities.
However, this possibly changes if the new Annex 1 enters into force. The second draft of Annex 1 entitled "Manufacture of Sterile Products" states under "Scope": "This Annex provides general guidance that should be used for the manufacture of all sterile products (including primary packaging material) using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination is prevented in the final product."
Chapter 8 "Production and specific technologies" discusses approaches to sterilization of products, equipment and packaging components. The chapter also discusses different technologies such as lyophilization, Form-Fill-Seal and Single Use Systems (SUS) where specific requirements apply. Some of the relating aspects are presented below:
Terminally sterilized products: Primary packaging containers and components should be cleaned using validated processes to ensure that particulate, pyrogen and bioburden contamination is appropriately controlled.
Aseptic preparation and processing operations: Grade A is proposed for staging and conveying of sterile primary packaging components.
Sterilization: All sterilization processes should be validated. Validation studies should take into account (amongst others) the composition of the material and the storage conditions. Before any sterilization process is adopted, its suitability, and its efficacy in consistently achieving the desired sterilizing conditions in all parts of each type of load to be processed should be validated notably by physical measurements and where appropriate by biological indicators (BI). According to the document, dry heat ovens are typically employed to sterilize or depyrogenate primary packaging components. Critical Process Parameters (CPPs) that should be considered in qualification and / or routine processing should include (but may not be limited to):
Sterilization with ethylene oxide (EO) should only be used when no other method is practicable. During process validation, it should be shown that there is no damaging effect on the product and that the conditions and time allowed for degassing result in the reduction of any residual EO gas and reaction products to defined acceptable limits for the given material. CPPs include, for example, EO gas concentration, EO gas pressure, amount of EO gas used, relative humidity, temperature, and exposure time. In addition, the aeration phase should be validated as part of the overall EO sterilization process validation.
Form-Fill-Seal: Form-Fill-Seal (FFS) units include blow moulding from thermoplastic granulate and thermoforming from thermoplastic film, typically known as Blow-Fill-Seal (BFS) and Vertical-Form-Fill-Seal (VFFS). All such containers are considered to be closed through sealing by fusion and, therefore, fall under the requirement to perform 100% integrity testing. Visual inspection alone is not considered as an acceptable integrity test method.
Single use systems (SUS): The extractable and leachable profile of the SUS and any impact on the quality of the product especially where the system is made from polymer-based materials should be evaluated. An assessment should be carried out for each component to evaluate the applicability of the extractable profile data. For components considered to be at high risk from leachables, including those that may absorb processed materials or those with extended material contact times, an assessment of leachable profile studies, including safety concerns, should be taken into consideration. If applying simulated processing conditions, these should accurately reflect the actual processing conditions and be based on a scientific rationale.
For more detailed information please visit the website of the European Commission: Revision of Annex 1 Manufacture of Sterile Products.