This next article in our series is about section 8, which is the largest section of Annex 1. As such, I intend to review it in 3 parts with this article focused mainly on the processes and part two covering Blow and Form fill Seal and the last part of section 8 covering Sterilization.
There is a fundamental split between terminal sterilized and aseptically fill products. Not much has changed for terminally sterilized products apart from additions to scope to include a validated cleaning of primary packing container and closures. Products should also be filter sterilized where possible prior to filling and maximum hold times defined.
The aseptic process should be clearly defined and assessed for risk. Precautions against contamination extend from preparation of the aseptic environment until product sealed in final container. Isolators, RABS etc. are recommended to reduce Grade A interventions, while automation is suggested to eliminate human intervention. The four grades A to D are unchanged except for expanding the activities performed at each grade.
There is now also specific guidance on using Grade A in B background such as for unwrapping sterilized items, assembly, and preparation of sterilized items for direct or indirect product contact.
While aseptic connections need to be assessed, Annex 1 stresses good engineering design principles be applied e.g. using pre-assembled and sterilized equipment, any product contact piping and equipment be pre-assembled, and sterilized in place, where possible.
Setting maximum hold times and minimizing delays is an important part of contamination control and includes, for example, decontamination of isolators as well as for the different stage of manufacture to the end of filling.
In any case aseptic operations should be regularly observed by competent personnel with specific expertise in aseptic processing to ensure inappropriate practices are avoided.
From filling, the annex moves to the finishing stage including container closure integrity (CCI) testing. 100% seal integrity testing of fusion seals now includes BFS units, small and large volume parenterals. Risk based approach are used for other closure systems. Capping/crimping needs to be at grade A in at least Grade D area unless a manual process, whereby grade A in Grade B is a minimum. Appropriately qualified, automated methods for stopper height detection should be in place. The CCI validation should account transportation requirements.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this, he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.
Our 2-day course is updated for Annex 1 changes
To see all of the articles on Annex 1 2022 select the button below:
The final stage is inspection for extraneous contamination and defects. Defect types should be categorized and evaluated, and a defect library should be maintained. Inspection rates should be appropriately controlled and qualified using the defect library sets and consideration worst case scenarios. Inspection results need trending with appropriate actions taken for adverse trends.
After filling, many products need lyophilizing and as such is a critical extension to the aseptic process. As the container is considered unsealed until the cap is secure, containers must be protected from contamination ingress, typically by use of grade A air. Loading and unloading, for example, required grade A protection combined with automation. Alternatively, trays closed in grade A and not reopened in the grade B area can be used if supported by validation.
It is essential to minimize operator intervention. In any case lyophilizers need to be sterilized frequently for every load if a manual process but an alternative frequency can be justified for automated loading/unloading or when protected by closed barrier systems. This is essentially clause 8.123 that does not come into effect until Aug 2024 probably because it is implying a significant change for those companies wish to change what they do. Sterility after lyophilization must be maintained hence the need for vent filter sterilization and integrity testing and chamber leak tests.
Section 8 closes by providing guidance on closed and single use systems. Closed systems can reduce contamination risk from the adjacent environment. The expectation is that contact surfaces for terminally sterilized products are clean while they need to be sterile for aseptic use. Connections to closed systems should be designed to be aseptic. System integrity tests are needed to check for leaks. Single use systems are closed systems and are alternatives to reusable equipment such as vessels, filters, tubing, valves, bulk tanks and even sensors. They can be individual components such as filters or multi components of bags, filters, tubing, connectors, valves etc. For aseptic use they must be sterile (usually supplied gamma irradiated) for which the process is suitably validated include demonstration of no impact on performance of the item. Suppliers are critical requiring visual inspection, outer pack integrity checks, labelling etc. on delivery. Extractables and leachables assessment is also required. They are not without risk for example concerns with product interaction, fragility, potential complexity of the assembly and risk of particle contamination.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.
