Draft Annex 1: New Requirements for Lyophilization?

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.

Production and Specific Technologies

Chapter 8 "Production and specific technologies" discusses approaches to sterilization of products, equipment and packaging components. The chapter now also discusses different technologies such as lyophilization, Form-Fill-Seal and Single Use Systems (SUS) where specific requirements apply. Some of the relating aspects for lyophilization are presented below:

• Grade A is proposed for loading of a lyophilizer.
• All control measures in place should be determined by the CCS (Contamination Control Strategy).
• Validation: Sterilization of lyophilizers and associated equipment should be validated and holding times between sterilization cycles appropriately challenged during aseptic process simulations (Media Fill). The lyophilizer should be sterilized regularly, based on system design. Resterilization should be performed following maintenance or cleaning.
• Sterilized lyophilizers and associated equipment should be protected from contamination after sterilization.
• Lyophilizers that are manually loaded or unloaded should be sterilized before each load. For lyophilizers loaded by automated closed systems or located within systems that exclude operator intervention, the frequency of sterilization should be justified and documented as part of the CCS.
• CCIT: Samples of containers closed by other methods than by fusion (e.g. stoppered vials) should be taken and checked for container closure integrity (CCI) using validated methods. The frequency of testing should be based on the knowledge and experience of the container closure system being used. A scientifically valid sampling plan should be utilized. The sample size should be based on information such as supplier approval, packaging component specifications and process knowledge. Visual inspection alone is not considered as an acceptable integrity test method.

Media Fill

The process simulation procedure for lyophilized products should

• represent the entire aseptic processing chain including filling, transport, loading, chamber dwell, unloading and sealing under specified, documented and justified conditions representing worst case operating parameters.
• duplicate all aspects of the process, except those that may affect the viability or recovery of contaminants.
• take into account various aseptic manipulations and interventions known to occur during normal production as well as worst case situations (e.g. loading of vials).

Quality Control

Sterility Test: For products that are lyophilized, samples are taken from different lyophilization loads.

For more detailed information please visit the website of the European Commission: Revision of Annex 1 Manufacture of Sterile Products.