The long and winding Road of the Annex 1 Revision
The Key Note presentation during the 2020 PharmaCongress was provided by Dr Bernd Renger, Expert Member of the EU GMP Annex 1 Task Force of ECA and Past Chairman of the European QP Association.
Dr Renger described the Annex 1 Revision process as a long and winding road. Initially issued in 1992, the document was revised five times, in 1996, 2003, 2005, 2007 and 2009. There has been no complete review of the document since its first publication. Also, the Annex 1 is not harmonised with the FDA Aseptic Guide, which was issued 2004.
The first draft of the current revision was published for comments on 20 December 2017. The document was heavily discussed with app. 6,200 individual comments. The main concern from industry was that the document defines new requirements which could result in drug shortages. They could also lead to a cost increase for some important lifesaving drugs.
During the revision process the ECA Task Force on Annex 1, which was set up specifically for commenting, developed a 30 page document. Similarly comprehensive comments also came from other interest groups. The main criticism of the ECA Task Force referred to the inconsistent use of references and terminology. The document furthermore presents a view of sterile product manufacture inconsistent with other requirements - e.g. those in the major Pharmcopoeias.
In November 2019, the 96th meeting of GMDP Inspectors Working Group adopted version 10 of the draft Annex 1. The following second targeted consultation focused on specific sections and/or significantly modified paragraphs that raised most concerns by stakeholders. These concerns become particularly evident when comparing the scope of the current version with that of the second draft revision: The current version is comprised of 127 sections on 16 pages - versus 291 sections on 52 pages in the second draft.
The Guide is structured in the following 11 chapters:
1. Scope
2. Principles
3. Pharmaceutical Quality System (PQS)
4. Premises
5. Equipment
6. Utilities
7. Personnel
8. Production and Specific Technologies
9. Viable and Non- viable Environmental and Process Monitoring
10. Quality Control
11. Glossary
However, several of these chapters overlap at numerous points with corresponding chapters of the EU GMP Guide, Part I, specifically in the chapters Principles, Pharmaceutical Quality System (PQS) and Personnel.
Recommendation
Bernried, Germany18/19 March 2025
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The section on Contamination Control Strategy (CCS) must be considered "the" core element of the revised Annex 1. Chapter 2 "Principles" defines CCS as a "planned set of controls for microorganisms, pyrogens and particulates, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient and drug product materials as well as components, facility and equipment operating conditions, in process controls, finished product specifications, and the associated methods and frequency of monitoring and control. The expectation is a formal document which reflects the site-wide strategy for minimising contamination control with respect to sterile manufacturing. Each organisation needs to fully understand and review design, procedures, technical and organisational controls. The companies need to assess "isolated" contamination events holistically and should be capable of defining and implementing appropriate corrective and preventive actions (CAPA)."
Chapter 3 details the Pharmaceutical Quality System requirements for sterile product manufacture, exceeding those described in chapter 1 of EU GMP Part I, including but not limited to:
- Proactive use of Quality Risk Management principles for early detection and
- addressing any risks
- Regular review of Quality Risk Assessments
- Structured ways of addressing different levels of risk arising from Quality Risk assessments
- Staff with sufficient expertise to perform Quality Risk assessments
- Effective ways to perform root cause investigations and implementing appropriate CAPAs
- Individuals responsible for the quality release of sterile products with adequate product and process knowledge and experience in the manufacture of sterile products
The chapter "Premises" has been expanded to define requirements for the use of Barrier technologies (Isolator or Restricted Access Barrier Systems [RABS]). The second version of the draft Annex keeps the requirement to count airborne particles ( ≥ 0.5 μm and ≥ 5.0 μm). This is not in line with the FDA aseptic processing guidance, which refers to particles of ≥ 0.5 μm only.
With regard to "non-viable monitoring" the new draft Annex 1 also contains the requirement to count airborne particles ≥ 0.5 μm and ≥ 5.0 μm. Also the wording with regard to microbiological monitoring is more precise (9.27): "Continuous viable air monitoring in the Grade A zone (e.g. air sampling or settle plates) should be undertaken for the full duration of critical processing, including equipment (aseptic set-up) assembly and filling operations. A similar approach should be considered for Grade B cleanrooms based on the risk of impact on the aseptic processing. The monitoring should be performed in such a way that all interventions, transient events and any system deterioration would be captured and any risk caused by interventions of the monitoring operations is avoided."
Aseptic Process Simulation (Media Fill) is outlined in a separate section and covers non-filterable formulations, sterile powders, lyophilized products and production campaigns. Aseptic process simulation needs to cover:
- Inherent interventions representative for the routine process at the maximum accepted frequency per number of filled units.
- Corrective interventions that occur frequently during routine production, in a representative number and with the highest degree of acceptable intrusion (e.g. correcting jammed stoppers).
Recommendation
Bernried, Germany20/21 March 2025
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The topic of lyophilisation has been a heavily discussed requirement in the first consultation draft. The new wording now represents industry practice: "Lyophilizers that are manually loaded or unloaded should normally 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."
- The integrity test of filters before and after sterilization (PUPSIT) is a topic that also receives a lot of attention. Although it is already a requirement in the current Annex 1, the wording in the new draft is more precise:
- The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check for damage and loss of integrity caused by the filter preparation prior to use.
- A sterilizing grade filter should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. ….
- It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible after sterilization due to process constraints (e.g. the filtration of very small volumes of solution).
- In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of non-sterility.
The presentation of Dr Renger provided a comprehensive overview about the current status of the Annex 1 Revision. The EU Commission will now review the comments received from the stakeholders like ECA and will most likely need another year before the final document will be released.
Author:
Oliver Schmidt
... is Managing Director of CONCEPT HEIDELBERG
