Podcast: How the EU’s New Revised Annex 1, Eudralex Volume 4 (GMP), Will Affect the Manufacturing of Sterile Medicinal Products in the EU and U.S.

Jay Jariwala in Washington, D.C. and Josefine Sommer in Brussels talk to Raj Pai about how they expect the EU’s new revised Annex 1, EudraLex Volume 4 (GMP), to affect the manufacturing of sterile medicinal products. They discuss how the update reflects changes in the manufacturing environment and how the new Annex 1 is likely to be considered within the U.S. regulatory framework. Prior to joining Sidley, Jay worked for the Office of Compliance at the Center for Drug Evaluation and Research, a branch of the U.S. Food and Drug Administration, and he brings this experience to bear in considering the impact of Annex 1.

Key Takeaways

• Sterile injectables have been a key enforcement focus for FDA for years because of the risks of patient harm if they are solid.
• The publication of the revised EU Annex 1 (the Annex) has been in the works for a substantial period of time. It reflects a significant update that will have far reaching impacts.
• The new Annex was published on August 25, and the EU is giving about one year for its implementation.
• The new Annex reflects changes in the regulatory and manufacturing environment. It takes a more holistic approach to product quality, and this approach will ultimately reduce the quality issues that may result in significant actions, such as a recall.
• The Annex integrates very well with the existing regulatory frameworks across the world in areas such as quality, risk management and pharmaceutical quality systems.
• What we’ve ended up with is much more modern guidance, which takes into account some of the modernizations which have taken place at ICH level over the past couple of years, particularly with respect to risk management.
• Manufacturing sites should not wait until August 2023 to engage with the guidance, this work must begin now. They should go through the Annex carefully and identify the gaps within their quality systems that will be affected. Every change will need to be carefully evaluated. Due to ongoing production, manufacturing sites will need to take time to plan.
• One thing that pharma companies need to do right now relates to a new requirement about Contamination Control Strategy (CCS). Many facilities will already have CCS in place, but the Annex makes this a codified requirement; facilities are now required to have a CCS in place. Companies should define and identify all the critical control points of a facility and assess the effectiveness of these controls. Once these critical controls have been identified, the expectation in the Annex is that the facility will then implement a monitoring plan or measures to manage these risks.
• The Annex also contains new content on barrier technology that is designed to prevent contamination. This doesn’t go as far as mandating what to use, but talks about robust risk assessment and asks the manufacturer to look at carefully at whether what they are implementing is suitable for their existing needs and controls.
• The Annex will cover all manufacturers who manufacture products for the European market, regardless of where the facility is located. It will of course affect facilities located in Europe, but also those in India or the US, if those facilities manufacture for the European market.
• The Annex aligns extremely well with other regulatory authorities worldwide.
• With the revised Annex, there will be much more information available for FDA in a decision making, as EU investigators start visiting facilities post August 2023.
• This alignment will help FDA to consider an inspection carried out in the EU to be equivalent with its own standards, because it will give FDA more detailed information. FDA is likely to use this information in a risk-based manner to prioritise facilities for inspection.

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