Annex 1 and the New Revision — Setting New Expectations

If you work in areas related to the manufacture of sterile drug products, you are by now very aware of the ongoing effort to revise "Annex 1 Manufacturing of Sterile Medicinal Products" of the EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use.

The European Medicines Agency has been working diligently on the revision for some time and, at this writing, we believe they are in the process of finishing their work. The size of the latest draft (v.12), published in 2020, provides a good indication as to the significance of the revision. EMA has expanded the current Annex from 16 pages to more than 50.

This is the first complete revision of Annex 1 since its initial publication in 1971. The significant effort required by the EMA in moving this document forward and addressing the many comments received must be commended. The draft brings the document up to date in many areas. Among the many improvements are the inclusion of the central themes of incorporating quality risk management (QRM) and having a documented contamination control strategy across the facility to define critical control points and the monitoring measures employed.

The impact of revised Annex 1 when published should not be underestimated. It will be a very important document for the global sterile manufacturing community. Just as the 2004 update to the U.S. FDA’s 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing changed expectations going forward well beyond product produced within and for the United States. The same is expected for the Annex 1 revision when issued. The principles in the revised Annex, when released, are expected to appear in many other regions outside of the European Union as guidance documents are revised or where the Annex is adopted in its entirety.

To assist in the revision process, the European Commission (EC) initiated in February 2020 a second targeted stakeholders’ consultation on the latest published draft. The comment period, which was extended due to COVID-19, provided a significant amount of time for industry to comment through the stakeholder organizations. Many thanks to the EC for providing the extension as it afforded the time needed by many of the stakeholder organizations to complete their commenting processes.

In addition to each stakeholder organization having the opportunity to comment, a rare decision was made among associations to also comment jointly through a letter outlining significant concerns industry had on the draft. 

While much of the draft is viewed as improvements, some of the new requirements proposed, while aspirational, may create significant issues for industry and its ability to produce product. In some cases, the technology to meet those requirements is not yet available, in others, the changes required would be so significant that entire filling lines and areas would need to be redesigned.

In addition to the joint comments the associations provided on the draft, a request was made to provide joint input related to the implementation timing of the Annex 1 draft as written. This was a very important request as industry will need time to implement specific changes in Annex 1 once it is issued. 

This concept of including longer implementation times in Annex 1 for specific requirements is not new and has precedent as seen in the 2008 revision of Annex 1, where a new requirement was introduced to perform the capping of vials under a Grade A air supply. In that revision, an extended timeline was provided for industry to come into compliance with the new requirement based on the changes to the manufacturing process/area required. In March of 2021, the associations responded with a second joint letter that addressed the timing issue and provided general examples of implementation timing.

Based on conversations with colleagues, it is apparent that industry continues to willingly offer assistance to the EMA in the development of the revised Annex 1 where needed. The mutual goal is a revised Annex 1 that continues to drive the industry forward in regard to continuous improvement while ensuring that the product supply to patients is not impacted. We appreciate having been included in the process thus far and, as the revision enters its final phase, we stand ready to assist in any way we can.

As I was writing this article, I thought about the 2004 revision to the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice and what, in part, made that activity so successful. There was a point in that process where the ideas of industry and the FDA differed on several key points. In an effort to resolve these points of disagreement, a team of experts from the Agency, industry, and academia was created to provide science-based recommendations to the FDA within a very short, specified timeframe. Many of these recommendations were ultimately reflected in the final guidance. If there remain key points of disagreement in the revision to Annex 1, one might wonder if such an approach could be used again successfully.

If you have not already, I would encourage you to begin looking at the revised Annex 1 draft. While changes between the draft and the final version are expected, the draft provides good insight into the concepts and expectations that are being considered for the new revision.