Sterile manufacturing Annex 1 amendments: what, why and how explained

In January 2020 the European Commission published some proposed significant revisions to Annex 1, the EU’s good manufacturing practice (GMP) guide for the manufacture of sterile products. In the following three-month consultation period, affected organisations and stakeholders from over 70 different countries submitted more than 2,000 comments to the proposed update. 

In this article Dr. Thomas Becker, Director Quality at Recipharm in Wasserburg, discusses the key changes to the guide and the impact it will have on companies responsible for the manufacture of sterile products as the industry continues to work to meet the industry’s changing requirements and overcome reoccurring challenges in the supply chain.   

The changes saw the scope of Annex 1 enlarged to include guidance to non-sterile product manufacturers, where contamination control is relevant, and its format was reorganised into 10 distinct sections. Beyond this, the main changes include: 

• Introduction of a contamination control strategy (CCS) concept, quality risk management (QRM) principles and a pharmaceutical quality system (PQS). 

• Additional QRM principles included to support non-sterile product category. 

• Introduction of restricted access barrier systems (RABS) and isolators, as well as some additional new technologies as part of the CCS requirements.

• The creation of new sections for form fill and seal, closed systems, and single use systems (SUS).

• Reinforced recommendations for area classification and qualification, including microbial airborne and surface contamination.

• The introduction of detailed measures and specifications to prevent any contamination (for example, unidirectional material flow, continuous monitoring systems for total organic carbon and conductivity on water for injection loops, validated disinfection and decontamination programme including a focus on vacuum, cooling systems, and dry heat tunnels).

• The introduction of specific personnel requirements, including training and gowning, combined with reinforced monitoring requirements.

• Stipulations about production and the use of specific technologies including, pre-use post sterilisation integrity tests (PUPSIT), specific process holding times, container closure integrity, and visual inspection. 

• Mandatory reinforced sterility test sampling after each critical intervention.

• Additional aseptic process simulation runs before shut down periods are to be taken into consideration.

• Trending dating for environmental monitoring and visual inspection results are to be taken into consideration for batch release.  

Overall, these new additions to the guidelines could potentially pose significant challenges to pharma companies both technically and organisationally;  Key examples would be updating equipment or premises design to minimise contamination risk, integrating new equipment, such as barrier technologies, into a CCS containing older systems using QRM principles, ensuring an approach that guarantees regular reviews of each risk assessment and the review of data and trends generated by critical CCS equipment. 

That being said, successfully implementing these new rules could bring about improved safety and anti-contamination measures. In addition, the growing involvement of other regulatory organisations and stakeholders such as the International Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), the World Health Organisation (WHO) and the US Food and Drug Administration (FDA) could mean harmonised compliance requirements across the global market. 

At Recipharm we have worked to successfully implement the required measures to ensure continued compliance during the manufacture and handling of sterile and non-sterile products requiring contamination control. By taking a proactive approach to meeting the changing demands of Annex 1 we will be able to continue to provide seamless sterile project solutions for out customers.