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How Ready Are You? Annex 1 and the Impact of Primary Packaging

Written by: Niamh Bissett, Director, Operations, PMO, West Pharmaceutical Services.

While it officially applies to the manufacture of sterile medicinal products in the European Union, the revised EU Good Manufacturing Practice (GMP) Annex 1 effectively reset the benchmark for quality standards across the globe when it came into force on 25 August 2023.

At this point, entire supply chains entered a new era defined by a raft of updated rules, all of which are ultimately focused on enhancing levels of public health protection. Indeed, a key aspect of EU GMP Annex 1 is the requirement for pharmaceutical manufacturers to develop a comprehensive Contamination Control Strategy (CCS) that documents their approach to assuring the sterile drug product’s high quality and patient safety.

The holistic approach to CCS required by EU GMP Annex 1 makes consideration of primary packaging components and the wider supply chain vital to compliance. As well as contributing to Container Closure Integrity (CCI) and reducing the potential for microbial ingress and particulate matter, components must also be manufactured in environments where sterility is controlled and assured.

At an operational, equipment and process level, this means ensuring that systems are geared towards continual improvement of contamination-limiting measures. At the same time, it is also essential to consider contamination risks from a behavioural perspective since the sterility of cleanroom environments has the potential to be compromised by human activity: equipping staff with a ‘contamination-control mindset’ through continual education and communication is fundamental if quality measures are to be upheld and enhanced over time.

For a pharmaceutical company to meet their CCS responsibilities, therefore, they must rely on the support of a supply partner capable of addressing both aspects of process and people. Only then can they receive full assurance that primary packaging components do not only comply with the specific rigorous demands of EU GMP Annex 1 but are managed via a holistic approach that supports continual improvement into the future.

What is Annex 1?

Annex 1 provides technical guidance on the principles and guidelines of good manufacturing practice (GMP) for medicinal products for human use and veterinary use. A deliberate and well-documented contamination control strategy is one of the new focuses in the EU GMP Annex I revision. The 2023 GMP   Annex 1 revision is causing a seismic shift in drug manufacturing. The regulations have more than tripled in length with this revision, and they contain over 30 references to primary packaging material alone.   

What are the implications for primary packaging?

Specifically, section 8.2 in Annex 1 defines “Primary packaging containers and components should be cleaned using validated processes to ensure that particulate, pyrogen and bioburden contamination is appropriately controlled.” The evolving regulatory landscape requires pharma and biotech companies to partner with a true expert who can help them navigate the new regulations successfully. Supplier   components may be part of the overarching sterile manufacturing process and contamination control strategy; however, it is the responsibility of the finished product (drug/biologic) manufacturer to comply with the regulation.  

What does a good CCS look like?

The holistic approach to CCS required by EU GMP Annex 1 makes consideration of primary packaging components and the wider supply chain vital to compliance. West has a comprehensive contamination control strategy for limiting biological, loose, and embedded contamination throughout the stages of design, installation, testing, and manufacturing at our sites. We also have an ongoing internal initiative to assess the manufacturing controls within our facilities along with our current manufacturing process, facility, equipment, and workflows against the requirements of EU GMP Annex 1. It is our goal to continually evaluate and evolve our contamination control strategy.  

What are the key considerations for assessing components in Annex 1?

There are four key considerations to consider for Annex 1 readiness:

Product: Analysing the current quality level of packaging components, understanding the specifications for particulate, bioburden, and endotoxins, and if a tighter specification is required.

  1. Process (manufacturing design)- where is the product sterilised- is in house or with the component supplier?  How will components be introduced on the fill/finish line? Will sealing occur in an aseptic environment?
  2. Protection (CCI)- Is there a robust understanding of the factors that will impact the CCI? Is there a monitoring and testing plan in place over the life of the drug product? and finally, 
  3.  Does your supplier have a Contamination Control Strategy (CCS); and are they focused on continual improvement? What documentation is available to support your CCS? 

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