Complying with Annex 1: Things to bear in mind

The European Commission published its proposed revisions to Annex 1, Manufacture of Sterile Products, the EU’s good manufacturing practice (GMP) guide for sterile products, in February 2020. Following a second consultation period, which ended in July, the guidance has now been comprehensively updated to reflect the industry’s changing needs and challenges. 

The changes to Annex 1 continues to pose challenges to pharma company operations that will need to be overcome both technically and organisationally.

The updated Annex 1 includes a number of changes that will have an impact on the pharmaceutical developers and manufacturers. Some of these pose challenges that will need to be overcome – here’s our summary of what’s changed and how pharma companies can ensure they continue to comply with legislation. 

What’s changed?

Annex 1 has been reorganised into 10 specific sections and its scope has been enlarged to included non-sterile products where principles of contamination control could apply. 

The principal changes in the updated guidance include:

  • Quality management through the introduction of a contamination control strategy (CCS) concept combined with quality risk management (QRM) principles and a pharmaceutical quality system (PQS). Additional QRM principles have been included that have been specially adapted to the needs of the newly introduced non-sterile product category.
  • The introduction of restricted access barrier systems (RABS) and isolators, along with other new technologies in the CCS requirements.
  • The creation of new sections for form fills and seal, closed systems, and single use systems (SUS).
  • Reinforcement of 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, airlock or changing rooms, 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, combined with reinforced monitoring requirements.

On top of all this, extra stipulations about production and specific technologies have been added. Among these are pre-use post sterilisation integrity tests (PUPSIT), specific process holding times, container closure integrity, and visual inspection. The guidance mandates reinforced sterility test sampling after each critical intervention as well.

Challenges to implementation

These changes pose challenges to pharma companies and their operations that will need to be overcome both technically and organisationally. 

From a technical point of view, the guidance emphasises the need to update equipment or premises design to minimise contamination risk. Integrating new equipment, such as barrier technologies, into a CCS containing older systems using QRM principles can be an issue, both practically and financially. 

From an organisational perspective, the guidance stipulates that sterility assurance is based on the CCS and the PQS is based on both QRM and continuous improvement. This new approach means that a regular review of each risk assessment is required. Companies must also implement a new review of data and trends generated by critical CCS equipment. All of this increases the time companies must spend monitoring their systems and processes. 

Impact of CCS

A principal challenge posed by the updated Annex 1 is compliance with the revised CCS principles it contains. 

The new approach is designed to provide a global tool for companies to implement in order to ensure acceptable sterility assurance levels. Under the new requirement, each process and product should be assessed to define all critical control points, covering the following areas of contamination risks: 

  • viable (microbial) 
  • non-viable (pyrogen as well as other potential particulate matter such as glass, visible and sub‑visible)

For manufacturers, the biggest impact will be finding the time and resource required to make the link between the new measures and quality systems already in place. They will also have to update existing risk assessments periodically based on data from all critical control points, check efficiency and devise and introduce new preventative actions if the reviews reveal changes are needed.

Bringing harmony to pharma regulations

While complying with the new guidance will require companies to spend time and resource, the updated approach brings with it a number of benefits.

The new Annex 1 was updated with reference not just from the European Medicines Agency (EMA), but 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). More than 70 countries also provided comments for the guidance, and the pharmaceutical industry was consulted on the changes. 

The result is greater harmonisation of safety and anti-contamination guidelines across global borders. In the long run, this will simplify safety procedures and compliance for businesses operating internationally, all while boosting product quality and safety for patients. 

For more information on how the updates to Annex 1 will affect your operations, read this PharmTech article, Unlocking the Key Changes to Annex 1.