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Annex 1 (2022) – The Brave New World of Regulatory Compliance

After six years in draft form and through various consultations with Industry, the revision to Annex 1 was finally released in August 2022 and will become effective in August 2023. It is the greatest single change to the regulatory approach in decades.

Those following the journey of the draft Annex 1 through to fruition have already identified and largely anticipated the changes to the previous Annex 1. Indeed for many pharmaceutical manufacturers, Annex 1 now aligns closely with the technologies and processes they have already built into their manufacturing facilities over the last few years.

For others who waiting for Annex 1 to become live has been the modus operandi: now is the time to act. Of course, you will need to quickly identify and assess the gaps you may have to comply with Annex 1, but there is no need to panic just yet…

Annex 1 provides a remarkably level-headed regulatory approach to Contamination Control Strategy (CCS) and Quality Risk Management (QRM) that will reinforce current best practices. Where the CCS nor QRM is not specifically called out in each of the clauses, then the intent of these underpinning foundations within Annex 1 is implicit. The spirit or purpose of these facets remains unyielding throughout the entire document.

While Annex 1 is a European Union regulatory focus, any drug entering the EU also needs to meet Annex 1 expectations (in conjunction with any mutual recognition understandings). Many international and US organisations contributed to the Annex 1 revisions, including FDA, WHO, PIC/S, PDA, and ISPE. Annex 1, therefore, is truly a global standard. It is highly likely that the groundbreaking work of Annex 1 will be adopted by these key regulatory bodies - PIC/s was the first to harmonize and be updated on 09 Sep 2022.

Annex 1 provides a detailed list of precise expectations to reduce areas of ambiguity, yet, more importantly, it also seeks to drive a shift of regulatory focus to a more risk-centric approach and responsibility within your organisation.

Architectural and engineering design companies have already introduced the key facets of Draft Annex 1 into new greenfield designs and those brownfield sites where changes were being introduced as part of ongoing programs. In recent years, we have worked with several sites to identify potential Annex 1 shortfalls, and we can say firsthand that there is little broken that sound engineering practices cannot fix.

Major Changes and Considerations

Side-by-side, the 2022 Annex 1 document physically dwarfs its 2008 predecessor at about four times the page count. The changes in Annex 1 represent a deeper dive into contamination control commensurate with the industry's evolution to a more risk-centric approach.

We are in a new era of injectable biologics, which includes our historic ability to develop and administer many millions of Pandemic vaccines. This highlights the need to protect each and every one of these patients from the possibility of any adventitious contamination making it’s way into the product. Our drive is to ensure the highest possible Sterility Assurance Levels (SAL) of these products, by developing mechanisms of protecting the product from sources of contamination, including of course the biggest source of contamination in a cleanroom – the people who make them.

The most significant changes to Annex 1 are:

  • Development of the Contamination Control Strategy (CCS). This now has a broader context, covering sixteen major points ranging from facility and process design to continuous improvement planning.
  • Focus on quality risk management (QRM), which permeates the entire document, explicitly stated initially and then implicit for the remainder of the document
  • Detailed requirements for technologies used to keep operators away from the product
  • Widening of the scope of Annex 1 to cover sterile products and allow for adaptation of its regulations for other products not intended to be sterile.

Although the new Annex 1 regulations contain many specific compliance points, the ones outlined above best represent the overall theme of Annex 1 changes. Each of these significant changes is discussed in more detail below:

1. Contamination Control Strategy

The CCS is largely existing within many organisations and is a high-level document that explains the organisation of the documentation comprising the CCS. The CCS is a document entirely specific to your facility and, indeed often to your process within the facility. The CCS represents your approach to minimizing contamination at every manufacturing process step. This includes the aspects of the facility design and process engineering. Still, it extends to every element in contact with your process, from preventative maintenance to sourcing quality vendors of sterile components.

Your CCS is a tool for Pharma companies to have an understanding and knowledge of their processes and know how the contamination control processes align. It demonstrates that you have thoroughly and scientifically identified and assessed potential risks and where necessary corrected them. The document should explore your options and define how you will prevent contamination in your facility. In no small measure, the CCS must be a "live" document that continuously grows and updates in line with the increasingly available technologies that ensure the product is fit for purpose.

The CCS is mentioned no less than fifty times in the Annex 1 document. The CCS is increasingly seen as the primary tool to mitigate potential contamination issues before they become a problem. Your facility CCS is the forcing mechanism that will drive a culture that adheres to reducing contamination and improving best practices.

2. Quality Risk Management

If the CCS drives every aspect of your facility's contamination risk approach, the QRM should scientifically justify your decisions. The principles of ICH Q9: Quality Risk Management and ICH Q10: Pharmaceutical Quality Systems underpin Annex 1 and provide a framework to ensure current Good Manufacturing Practice (cGMP) applies throughout.

As stated, the QRM is the heart of Annex 1 changes and is explicit even when not mentioned. Your Quality Risk Management practices ensure that you have a robust and scientifically defendable Contamination Control Strategy.

3. Approach to barrier technology – keeping people away from the product

Annex 1 is fundamentally about the control of sterile products. The problem, however, is that your facility workers are fundamentally not aseptic. Humans continuously slough off cells and hairs. Your sterile operators contain and shed microbes that can cause harm if found in the product – despite your best efforts to mask and gown them into cleanliness.

The most prescriptive aspects of Annex 1 revolve around excluding direct human involvement from your manufacturing process. Fortunately, existing and emerging technologies, such as barrier isolators and advanced automation design, have made this goal more attainable since the last Annex 1 revision. Much has changed since 2008, and Annex 1 embraces the advent and use of new technologies to ensure people and products do not mix.

4. Widening the regulatory scope

Annex 1 represents an achievement in a common regulatory sense. Whereas a merely prescriptive set of regulations would probably be obsolete before they were even approved, Annex 1 encourages companies to apply and justify their approach to reducing contamination across the manufacturing process to protect human life.

Do not get us wrong, however. There are many prescriptive components to Annex 1, and you must justify why a specific regulation may not apply to your process. In addition, you must define, explain and defend your choices with scientifically sound supporting data.

In the end, the regulators want your product to get to patients and be used safely. The regulators, like all of us, have a duty of care to ensure the general population has both ample supplies of their prescribed medicine, but also of good quality to ensure the individual quality of life is not unduly affected.

What are the next steps to achieve Annex 1 Regulatory compliance?

Engineering design houses have a pivotal part to play in helping you achieve Annex 1 readiness. The best Annex 1 subject matter experts have both the technical knowledge and hands-on practical experience of running aseptic facilities - to aid in identifying and assessing those gaps in the compliance armory. But, best of all, not only do they know how to fix the gaps, but can also help you engineer those Gaps into robust fixes.

As of the writing of this article, you have eight months to enact your changes. Many pharmaceutical companies will shortly be vying for the same resources to enable those gap analyses and fixes. The time for complacency is over. Use your time wisely and bring expertise where needed; reach out and see how we can help.

This article originally appeared in Pharmaceutical Engineer.

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