The EU Annex 1: Lyophilization

Finally, on 22 August 2022, the new Annex 1 of the EU GMPs was published.

Manufacturers do not need to panic though, the new standards from the European Commission will not come into effect until August 2023. And if you are focused on the frequency of sterilisation of lyophilisers, there is an extra year on top of that.

Here we summarize the points related to lyophilization from the original text:

  • Lyophilization is a critical process step and all activities that can affect the sterility of the product or material need to be regarded as extensions of the aseptic processing of the sterilised product. The lyophilization equipment and its processes should be designed to ensure that product or material sterility is maintained during lyophilization by preventing microbial and particle contamination between the filling of products for lyophilization, and completion of lyophilization process. All control measures in place should be determined by the site’s CCS.

  • The sterilisation of the lyophilizer and associated equipment (e.g. trays, vial support rings) should be validated and the holding time between the sterilisation cycle and use appropriately challenged during APS. The lyophilizer should be sterilised regularly, based on system design. Re-sterilisation should be performed following maintenance or cleaning. Sterilised lyophilizers and associated equipment should be protected from contamination after sterilisation.

  • Lyophilizers and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as far as possible. The frequency of lyophilizer sterilisation 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 sterilised before each load. For lyophilizers loaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilisation should be justified and documented as part of the CCS.

  • The integrity of the lyophilizer should be maintained following sterilisation and during lyophilization. The filter used to maintain lyophilizer integrity should be sterilised before each use of the system and its integrity testing results should be part of the batch certification/release. The frequency of vacuum/leak integrity testing of the chamber should be documented and the maximum permitted leakage of air into the lyophilizer should be specified and checked at the start of every cycle.

  • Lyophilization trays should be checked regularly to ensure that they are not misshapen or damaged.

  • Points to consider for the design of loading (and unloading, where the lyophilised material is still unsealed and exposed), include but are not limited to:

  1. The loading pattern within the lyophilizer should be specified and documented.

  2. The transfer of partially closed containers to a lyophilizer should be undertaken under grade A conditions at all times and handled in a manner designed to minimize direct operator intervention. Technologies such as conveyor systems or portable transfer systems (e.g. clean air transfer carts, portable unidirectional airflow workstations) should be used to ensure that the cleanliness of the system used to transfer the partially closed containers is maintained. Alternatively, where supported by validation, trays closed in grade A and not reopened whilst in the grade B area may be used to protect partially stoppered vials (e.g. appropriately closed boxes).

  3. Airflow patterns should not be adversely affected by transport devices and venting of the loading zone.

  4. Unsealed containers (such as partially stoppered vials) should be maintained under grade A conditions and should normally be separated from operators by physical barrier technology or any other appropriate measures.

  5. Where seating of the stoppers is not completed prior to opening the lyophilizer chamber, product removed from the lyophilizer should remain under grade A conditions during subsequent handling.

  6. Utensils used during loading and unloading of the lyophilizer (e.g. trays, bags, placing devices, tweezers) should be sterile.