White Paper EU GMP Annex 1

Abstract: 

The new version of EU GMP Annex 1 was issued on August 22, 2022, addressing the manufacture of sterile products for human and veterinary use and was developed by the European Medicine Agency (EMA).  It is a legally binding document as EU GMP Guideline is integrated into EU Legislation, in specific into Directive 2001/83/EC of the European Parliament. In Chapter 47 is stated that the European Commission shall adopt, the principles and guidelines of good manufacturing practice (for active substances). The purpose of this white paper is to highlight the impact of the revised Annex on inspection tasks in general and on integrity testing of blow-fill-seal containers in specific.

EU GMP Annex 1 of the European Medicines Agency (EMA) is the governing regulatory document related to “Manufacture of Sterile Medicinal Products” and was originally published in 1989. Prior to 2022, the most recent revisions were published in 2008. The 2022 revision is a significant update, it has been expanded considerably from 16 to 50 pages. 

With the publication, it became clear that companies need to comply with the requirements no later than August 25, 2023. An exception was made for one section (8.123) - Companies are expected to have them implemented no later than August 25, 2024, two years following publication. 

EU GMP Annex 1 (2022) now contains a stronger focus on Risk Management and the implementation of a Contamination Control Strategy. 

In particular, the integration of ICH Guidelines Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) as well as the inclusion of new technological developments made the revision of Annex 1 imperative. 

1. Quality Risk Management (QRM) is the systematic process and review of risks to the quality of the drug product across the product lifecycle. 
   
   According to ICH 9 two main principles of quality risk management are:
   ▪ “The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient “; and 
   ▪ “The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.” 
   
   It is evident that the revised Annex 1 document has considerably raised the bar in terms of applying QRM strategies in the Pharmaceutical Industry. Providing data is the basis for the systematic review of the risk while fulfilling the scientific requirements.
2. A substantial part of the Annex is dedicated to each organization requiring a detailed, comprehensive Contamination Control Strategy (CCS) - the expectation is a formal document reflecting the site-wide strategy to prevent contamination of finished products. It is obvious that for confirming the effectiveness of this strategy a rigorous testing scheme is required. The concept of a CCS is much more developed in the newly revised Annex 1, compared to the version previously in force. 

Among other methods Container Closure Integrity Testing (CCIT) and Process Analytical Technologies (PAT) can be used for confirming the effectiveness of contamination prevention and as such a part, if not a corner stone of the contamination control strategy.

3.1.1 Fusion sealed containers

Annex 1 states the requirement of 100% Container Closure Integrity Testing of units that are closed by fusion, e.g. BFS cards or bottle, glass or plastic ampoule. In draft versions of the latest Annex 1 revision a 100% integrity testing of containers independent of the volume using a validated method was discussed, the f inal version was changed to include containers up to a volume of 100 mL (SVP - Small Volume Parenterals) and BFS units (it is arguable if the volume limit is also applicable to blow fill seal products). This discussion about testing every product independent of size or volume, which could be taken up again in the future, is another example of the fact that the legal framework is becoming increasingly strict. 

For larger volumes, the test frequency may be reduced and, if so, it must be scientifically justified and based on data. Visual inspection is not considered anymore as an acceptable integrity test method. 

3.1.2 Containers sealed by methods other than fusion

Containers not sealed by fusion shall be checked for integrity using validated methods. The frequency of testing should be based on the knowledge and experience of the container and closure systems being used. A scientifically justified sampling plan should be used. 

It shall be noted that the integrity testing must consider storage conditions (e.g. deep cold storage at -80°C) as well as transportation conditions (e.g. air freight or truck transport at high altitudes) that may negatively impact the integrity (e.g. by decompression or extreme temperatures), which is a new requirement compared to the previous version of the Annex.

3.1.3 Containers sealed under vacuum

For containers sealed under vacuum with oxygen sensitive drugs the frequency of integrity testing has been specified in more detail in latest revision: while in Annex 1 (2008) an appropriate, pre-determined period between test was sufficient, the latest revision demands testing prior to certification/release and during shelf life. 

3.2.1 Aseptic Process Simulations (APS ) / Media Fill Inspection

More extensive guidance on the risk-based development and performance of aseptic processing simulation (APS) or media fill inspection, a measure to confirm the sterility of the aseptic filling system, is being provided. The target should be zero growth. Any contaminated unit should result in a failed APS. Consequence is, after an investigation and the implementation of corrective action, that minimum three (3) consecutive repeat APS have to be performed to demonstrate that the process has been returned to a state of control. 

Moreover Annex 1 demands an APS: 

• At initial validation of the filling line, with at least three consecutive satisfactory simulation tests that cover all working shifts where the aseptic process may occur
• After any significant modification of the equipment
• Repetition twice a year for each aseptic process, each filling line and each shift
• After the last batch prior to shut down, before long periods of inactivity or before decommissioning or relocation of a line
• In case of failed APS minimum three (3) consecutive repeat APS are required  
• Regarding no. of containers a full batch size is mentioned, typically 5’000 to 10’000 units 

With the revised Annex 1 (2022) the effort in time and resources for APS has significantly increased. While today the traditional manual visual inspection is being used for media fill inspection, new, data driven PAT are on the horizon that have presented in various conferences. These offer interesting alternatives with advantage regarding time, resources and quality supporting the scientific approach demanded by Annex 1 (2022). 

The scope of Annex 1 relates to pharmaceutical companies who manufacture products within the European Union (EU), and those importing into the European Union. 

While it is specific to the EU, its principles and standards are often recognized and used as a reference by regulatory authorities in other countries, including the United States. Although each country has its own specific regulatory framework and requirements these can be linked to the EU GMP guidelines through: 

• Harmonization of Standards
• International Collaboration
• Cross-Referencing and Adoption
• Global Regulatory Trends
• Regulatory Convergence
• International Compliance 

As such, they are applied to a greater or lesser extent in regions outside the EU. 

It is worth noting that almost simultaneously with the EU Commission, the Pharmaceutical Inspection Cooperation Scheme (PIC/S), an instrument to improve co-operation in the field GMP between regulatory authorities and the pharmaceutical industry on a global level (52 member states), also published the revised Annex 1 on September 9, 2022. 

• The GMP Guideline Annex 1 is significant update of the previous version:
  • More specific about which fusion sealed containers require 100% testing, validated methods required and VI only is not accepted anymore (compared to rev. from 2009)
  • Test for maintenance of vacuum during shelf-life (New)
  • Transport studies requested (New)
  • Significant effort for APS / media fill inspection required (New chapter)
  • BFS filling machines need additional check beside APS (New chapter)
• Special focus on Quality Risk Management and Contamination Control Strategy
• Far-reaching global influence on the integrity testing of pharmaceuticals
• More stringent regulation expected in the future
• There are solutions for CCI and PAT testing available for laboratory and production
• There are possibilities to combine CCIT and automated visual inspection on one machine 

Matthias Hiddemann - WILCO AG

EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines: https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

Pictures: WILCO AG