2023 Changes to EU Annex 1

EU Annex 1 is designed to outline the requirements for the manufacture of sterile medicinal products. Since its introduction in 1972, Annex 1 has undergone several changes and revisions. The most recent changes to the annex were made to reflect current best practices and technological advancements in the field of sterile product manufacturing.

Key takeaways:

1. A Contamination Control Strategy (CCS) is now required and should be implemented across the facility
2. Contaminants should be now removed before performing disinfecting. Sterile Wipes can be used for this task
3. More than one type of agent is now required for disinfecting activities.
4. Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use
5. Facility suits (cleanroom coveralls), covering the full length of the arms and the legs, and (cleanroom) socks covering the feet, should be worn before entry to change rooms for Grades B and C areas

Contact us to learn more about the many products we offer to help maintain compliance with Annex 1

CCS Strategy Requirement

In short, a Contamination Control Strategy (CCS) is needed to achieve Annex 1. A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks to medicinal product quality and safety.

It should establish robust assurance of contamination control which includes the prevention of contaminants such as endotoxins, microorganisms, and particulate control. Once established, CCS should be reviewed (with periodic management review) and updated where appropriate.

It should be noted that Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood.

New Requirements for Disinfecting

• Cleanrooms should be cleaned and disinfected thoroughly in accordance with a written program, as defined in the CCS.
• Wiping prior to disinfecting: Remove contaminants before performing disinfecting activities.
• Cleaning programs should effectively remove disinfectant residues.
• More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi.
• Disinfection should include the periodic use of a sporicidal agent.
• Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection program and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use).
• The disinfection process should be validated.
• Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use. Disinfectants used in grade C and D may also be required to be sterile where determined in the CCS.
• Cleaning of equipment should be validated to be able to:
  • Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.
  • Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.

Annex 1 New Apparel/Garment Requirements

Annex 1 Part 7 outlines Guidance on Cleanroom Garment, Protective Clothing & Donning Procedures. Read on to see what’s new and noteworthy:

• Annex 1 Part 7.11 says that protective clothing and its quality should be appropriate for the process and the grade of the working area
• Cleanroom garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Sterile products manufactured by High-Tech Conversions are individually inspected and double bagged in our facility to ensure the integrity and quality of the final product.
• A sterile facemask and sterile eye coverings (e.g. sterile goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles.
• Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas.
• Facility suits (cleanroom coveralls), covering the full length of the arms and the legs, and socks covering the feet, should be worn before entry to change rooms for Grades B and C areas. Facility suits and socks should not present a risk of contamination to the gowning area or processes.

Reasons for Changes

According to the European Commission, the following outlines the reason for changes:

The GMP/GDP Inspectors Working Group and the PIC/S Committee jointly recommend that the current version of annex 1, on the manufacture of sterile medicinal products, is revised to reflect changes in regulatory and manufacturing environments. The new guideline should clarify how manufacturers can take advantage of new possibilities deriving from the application of an enhanced process understanding by using innovative tools as described in the ICH Q9 and Q10 guidelines. The revision of Annex 1 should also take into account related changes in other GMP chapters and annexes as well as in other regulatory documents. The revised guideline will seek to remove ambiguity and inconsistencies and will take account of advances in technologies.

Deadline for coming into operation:

• 25 August 2023 : one year from the date of publication in Eudralex Volume 4
• 25 August 2024 : two years from the date of publication in Eudralex Volume 4 for point 8.123

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