Annex 1 of the European Good Manufacturing Practice (GMP) for sterile products is a key piece of legislation for pharmaceutical manufacturers looking to operate or trade within the European Union (EU).1 It is the primary document governing the manufacture, control and release of sterile pharmaceutical products (both terminally sterilised and aseptically filled medicines) for European markets.
The document is currently undergoing a significant revision process, further complicated by the fact that the original publication date for the revised version was postponed in 2020. It’s expected to be made public later in 2022. We do not yet know what will be in the finished draft.
Nevertheless, we can be sure that the amendments will significantly impact ways of working for pharmaceutical companies and their contract development and manufacturing organisation (CDMO) partners when producing sterile drug products.
The lack of certainty surrounding the contents of the final revision is of deep concern to many pharmaceutical companies. Many feel deterred from investing in their internal infrastructure as they are unsure whether it will continue to meet the new standards when they come into effect.
Understanding the key updates to Annex 1
Despite these concerns, there are a number of changes to the Annex 1 recommendations that we can be confident will appear in the new draft. By understanding what these are, drug developers and their CDMO partners can begin to implement measures to ensure that both their new and existing lines and facilities are prepared to meet Annex 1 requirements when they finally come into force.
The key updates that pharmaceutical companies need to be aware of include the following:
The introduction of contamination control strategies (CCSs): It is certain that pharmaceutical companies will need to implement a comprehensive and overarching CCS in cleanroom zones where sterile products are manufactured and handled.
This requires a documented approach to contamination control that’s designed to minimise the complexity of separate technical, organisational and procedural contamination control measures. A comprehensive risk assessment must also be performed and steps must be taken to monitor integrity across production lines.
Permission for transfers to be done in lower class environments, provided certain conditions are met: Under current Annex 1 guidelines, connections for sterile processing must be performed under highly classified Grade A aseptic environments.2
However, we know from previous announcements that the latest Annex 1 revision will acknowledge the advancement of sterile processing technology, which has the potential to further reduce potential contamination risk in the surrounding environment.
As a result, the updated document will permit transfers to take place in lower classified environments, provided that the connection device has been validated to show no ingress of microbial contamination and a CCS review has been conducted.
This means that the use of transfer technologies such as specially designed bio or sterile processing equipment will allow manufacturers to declassify the surrounding environment whilst still providing an acceptable and high-quality aseptic transfer.
The challenge of meeting new Annex 1 requirements
It’s a positive step that the new guidelines consider the enhanced sterility benefits of the latest production line technologies, potentially reducing the burden of compliance for many drug developers and CDMOs in the future. However, this may not be the case for every organisation right now.
Some companies may not yet have the new generation of sterile processing technologies in place within their manufacturing facilities. Such organisations must still ensure that their lines and internal processes comply with the previous generation of Annex 1 guidance, with product transfers taking place in higher classification environments.
The implementation of a detailed CCS for the first time also poses challenges for certain organisations. Companies must plan their documentation update procedures well in advance of the date when Annex 1 is due to come into effect. Leaving this too late could lead to a significant loss of productivity.
In addition, pharmaceutical companies should consider the time required to find and implement solutions that close any sterility gaps identified by their CCS.
The sourcing, delivery and installation of any new equipment as part of this could be impacted by the current supply chain disruption resulting from COVID-19. Any delays in delivery could result in additional costs and reduced productivity.
When sourcing these new technologies, pharmaceutical companies opting for equipment with reusable production line components must also factor in the cleaning and verification processes needed between each transfer to confirm sterility in line with Annex 1 requirements. Washdowns and verification can both take a significant amount of time, impacting on manufacturing efficiency.
Solutions to reconcile compliance and efficiency
Single use technology (SUT) can support pharmaceutical companies to ensure compliance with new Annex 1 requirements while optimising manufacturing efficiency. There are several key advantages to SUT equipment in sterile pharmaceutical production that have the potential to streamline adherence with new requirements under the revised Annex 1 for manufacturers:
- Streamlined cleaning and validation: As they are designed to be used once prior to disposal, cleaning and validation procedures needed to maintain sterility can be reduced, optimising integrity while minimising production downtime.
- Enhanced usability: SUTs are generally easy to use, with minimal training or production line upgrades required.
- Sterile transit options: In addition, they can ensure the aseptic integrity of products during transit as well as within manufacturing facilities.
The impact of SUTs
SUTs have the potential to enable drug developers to meet the new requirements of Annex 1. One key example is the split butterfly valve (SBV). These enable the sterile transfer of powders, including drug substance and drug product, into and out of process equipment.
SBVs consist of an active component, which connects to the production line equipment, and a passive half, which attaches to the filling container. When fitted together, these components allow product to flow from the line into the container without it coming into contact with the surrounding environment and ensuring sterility.
Next generation hybrid SBVs incorporate a disposable version of the passive component, which can help to achieve the same stringent level of aseptic processing while significantly enhancing efficiency. The passive half doesn’t need to be cleaned after use as it can simply be disposed of between fillings, increasing productivity.
These disposable SBV variants are manufactured within an ISO 6 cleanroom environment and are sterilised by gamma radiation prior to use, ensuring compliance with current and future Annex 1 guidelines.
Time to act
There are plenty of measures that pharmaceutical companies can take now to ensure that they remain compliant when Annex 1 comes into effect. Failure to be proactive could mean that companies don’t leave themselves enough time to update their infrastructure and processes to meet the new requirements, with costly repercussions for their productivity. Those that act sooner rather than later will be in a good position to continue business-as-usual while ensuring optimum product safety for the well-being of users and patients.
References
- www.gmp-compliance.org/guidelines/gmp-guideline/eu-gmp-annex-1-revision-manufacture-of-sterile-medicinal-products-draft.
- https://ec.europa.eu/health/sites/default/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf.
