The updates to Annex 1 include internationally harmonized quality risk management principles, but the revisions also significantly expand regulatory expectations for contamination controls related to sterility assurance. Some of the changes will require substantial capital investments and might lead to supply disruptions. The updated Annex 1 also appears to be more stringent than current U.S. requirements in certain respects, which may impede longstanding efforts to improve harmonization of regulatory requirements and to enhance collaboration between U.S. and EU regulators.

Effectively, the EU GMP guidelines are understood as the minimum standard that manufacturers must meet, although regulatory authorities can allow a differing approach to meeting the goals of the standard if the different approach is justified under a sound scientific rationale that is fully demonstrated with data.

Background

Annex 1, “Manufacture of Sterile Medicinal Products,” is part of the European Union GMP guidelines and was originally published in 1989. Prior to 2022, the most recent revisions were published in 2008. The 2022 revision is a significant update, increasing the content of the document from 16 to 50 pages.

The European Commission explains that the document provides technical guidance on GMP principles and guidelines for medicinal products as laid down in Commission Directive (EU) 2017/1572 for medicinal products for human use, Directive 91/412/EEC for veterinary use, and Commission Delegated Regulation (EU) 2017/1569 for investigational medicinal products for human use and arrangements for inspections supplementing Regulation (EU) No 536/2014 on clinical trials.

The new document indicates that the revised guideline should (1) 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; (2) take into account related changes in other GMP chapters and annexes as well as in other regulatory documents; and (3) seek to remove ambiguity and inconsistencies and will take account of advances in technologies.

Notable changes

One general improvement to Annex 1 is the incorporation of quality risk management principles into the entire document. Pharmaceutical Quality Systems (PQS) now includes the principles of Quality Risk Management (QRM) for sterile drug manufacturing. QRM is described in ICH Q9 (November 2005). Although QRM is infrequently referenced directly throughout the document, Annex 1 indicates, “Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality.” Alternative approaches should be supported by appropriate rationale, risk assessment and mitigation. See Annex 1, §2.2.

Annex 1 also introduces the concept of a Containment Control Strategy (CCS), which is not a significant departure from prior basic requirements for contamination control. However, Annex 1 now recommends a more comprehensive, coordinated and documented compilation of measures that a facility takes to control contamination related to sterility assurance. Organizations will need to consolidate and augment their documentation to assure regulatory authorities that the non-exhaustive list of seventeen CCS elements in Annex 1 were adequately considered and implemented. The following are among the elements listed in Annex 1 for consideration within the CCS:

1. Design of both the plant and processes including the associated documentation.
2. Premises and equipment.
3. Personnel.
4. Utilities.
5. Raw material controls.
6. Product containers and closures.
7. Process and sterilization validations.
8. Preventative maintenance.
9. Cleaning and disinfection.
10. Monitoring systems.

Other specific requirements are likely to require capital investment or potentially increase the frequency of drug shortages or both. Here are just a few examples of the new EU regulatory expectations that will have a significant impact on sterile drug manufacturers around the world:

New facilities requirements

• RABS and isolators. Annex 1 appears to establish the use of Restricted Access Barrier Systems (RABS) or isolators as the expected minimal approach to aseptic processing. Section 4.3 indicates that their use should be considered in the CCS and any alternative approaches should be justified. Annex 1 does not explain what factors would justify the continued use of existing filling lines or whether newly constructed installations could justify alternative approaches to RABS or isolators.

New criteria for aseptic processing

• Grade A = “no growth.” The 2008 version of Annex 1 required that microbial growth for air and surfaces samples in Grade A areas must be less than 1 CFU. Because a colony forming unit (CFU) is necessarily an integer value, one could conclude that the requirement was actually zero (0) CFU. But Annex 1 described the values as averages, allowing for the rare excursion in an otherwise controlled Grade A area.

  • The revised Annex 1 (2022) sets the maximum action limit for viable particle contamination in Grade A areas at “No growth,” and indicates that “any growth should result in an investigation.” See § 9.30.

• Stricter success criteria for Aseptic Process Simulations (APSs). Annex 1 (2008) was aligned with FDA’s guidance, “Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice” (September 2004) (“FDA’s Guidance”) in that the target for each APS was no media contamination in any filled vial. However, both FDA’s Guidance and Annex 1 (2008) required an investigation and consideration of repeating the APS if one contaminated unit was found for a simulation with more than 5,000 units.

  • The revised Annex 1 (2022) indicates that any contaminated unit should result in a failed APS, followed by an investigation, determination and implementation of corrective measures, and the successful completion of three consecutive APSs to demonstrate that the process has been returned to a state of control.

  • Many manufacturers currently resume commercial manufacturing “at risk” immediately after a semi-annual APS and while the APS results are pending during the 14 day media incubation period; if the APS fails, then “at risk” batches are rejected. Manufacturers will need to consider how an APS failure followed by three consecutive APSs will impact line capacity and the benefits of manufacturing at risk.

Annex I will take effect on 25 August 2023, except for section 8.123 on lyophilizer sterilization, which will take effect one year later on 25 August 2024. Public consultations issued by local authorities may take place for the local language versions of Annex I at EU Member State Level. Due to some of the language issues in Annex I, it may be worthwhile for industry players to consider contributing to such consultations when they will be published. We recommend staying alert on such consultations.

If you are a manufacturer who has questions about the new Annex 1 requirements or concerns about how regulatory authorities may enforce the requirements, or you wish to be involved in any consultation process, for technical and legal support feel free to contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Ted Lis, David Horowitz, Mikael Salmela, Joerg Schickert, Giuseppe Aminzade, Fabien Roy, and Jane Summerfield