Revised Annex 1, EudraLex Volume 4: Deadline to Comply: August 2023

April 24, 2023

August 25th, 2023 is the deadline to comply with the revised EudraLex Volume 4, Annex 1. Only for a sole point (point 8.123: "product transfer/loading/unloading areas for lyophilizers“) a later deadline (Aug 2024) exists.

Are you prepared for the changes to the Annex 1 Guideline?

With the deadline approaching, the need to complete your comprehensive review of all changes to the Annex 1 guideline becomes critical to your business. When doing so, it may not seem straight forward. After all, we are talking about a major revision: Annex 1 has grown to 52 pages compared to just 16 pages from the 2008 version.

To counteract this challenge with concrete measures, ProPharma has analyzed the New Annex 1 and created a proprietary questionnaire. This questionnaire segregates the New Annex 1 requirements into multiple questions. It has been designed to enable an efficient, well-structured, step-by-step assessment on all aspects of the New Annex 1.

Contact us today to can gain access to our New Annex 1 Questionnaire.

Need Help Implementing a Contamination Control Strategy for Annex 1?

The new Annex 1 requires the implementation of a Contamination Control Strategy (CCS). The CCS is supposed to take a central role in the Documentation System of each manufacturer of sterile products. You can now leverage ProPharma's profound experience, when implementing your CCS. A good CCS is effectively tailored into your QMS. In consequence, it will always reflect the respective situation of a manufacturer. Nevertheless, the New Annex 1 describes numerous requirements for your CCS. ProPharma has designed a proprietary CCS template, which reflects these requirements and thus constitutes an excellent starting point to create or review this key document.

What Do You Need to Know About the New Annex 1, EudraLex Volume 4?

EudraLex Volume 4, Annex 1 provides guidance for the manufacturing of sterile medicinal products that are intended for the European market. It has been updated several times, with the latest revision in 2008, but a fundamental review has not been carried out until August 2022. The objective of the revision was to add clarity, introduce the principles of Quality Risk Management (QRM), to allow for the inclusion of new technologies and innovative processes, and to change the structure to a more logical flow.

This major update was a joint effort by European health authorities, World Health Organization (WHO), and Pharmaceutical Inspection Convention/Pharmaceutical Co-Operation Scheme. A first draft was submitted for targeted consultation among 140 companies and organizations from December 20th, 2017 to March 20th, 2018. This consultation round resulted in more than 6,200 lines of comments. An updated draft was submitted for a second targeted consultation among a limited number of stakeholders from February 20th, 2020 to July 20th, 2020. Finally, the revised EU GMP Annex 1 was published in August 2022.

What do the Changes in EudraLex Volume 4, Annex 1 Mean for You?

The updated version of Annex 1 emphasizes the application of QRM principles throughout the process of sterile manufacturing. This is to proactively and continuously identify, evaluate, address, control, and monitor potential risks of microbial, particulate, and pyrogen contamination. This includes the design, qualification, and operation of facilities, utilities, equipment, and validated processes using well-designed procedures, and finally, the utilization of monitoring systems to demonstrate continuous performance in line with expectations.

Contamination control should not be based on monitoring and sterility testing alone but should follow a holistic approach. The new Annex 1, therefore, requires the implementation of a Contamination Control Strategy (CCS). The CCS will be a high-level document describing the way in which QRM is applied in the control of contamination risks in accordance with Annex 1's regulations. It should identify potential contamination risks to the final product, contain references to risk assessments and policies to control those contamination risks and contain references to monitoring systems to verify continued compliance. The CCS should proactively be reviewed to continuously assess and address potential risks of microbial, particulate, and pyrogen contamination.

What are some of the changes in EudraLex Volume 4, Annex 1?

In general, the updated Annex 1 contains more extensive guidance to premises, equipment, utilities, personnel, production and technologies, viable and non-viable environmental monitoring, and aseptic process simulation. In the new document, which has grown to 52 pages compared to just 16 pages from the 2008 version, each chapter conveys the importance of implementing QRM principles. Examples of updated requirements include the following:

1. Water for Injection

The new Annex 1 additions give detailed guidance for production of Water for Injection (WFI). This includes the possibility to produce WFI by methods other than distillation, provided that further techniques such as nanofiltration, ultra-filtration, and electrodeionization are considered in conjunction with reverse osmosis membranes.

2. Personnel

Compared to the 2008 version, the updated Annex 1 draws much more emphasis to the requirements for personnel behavior, hygiene, training, qualification, and disqualification. In addition, it requires both the validation of the maximum number of operators in a cleanroom, and the qualification of the cleanroom garment cleaning process.

3. Aseptic Process Monitoring

Related to this key area, the revisions provide more extensive guidance in the risk-based development and performance of Aseptic Processing Simulation (APS). Any contaminated unit should result in a failed process simulation and require an investigation. A sufficient number of – at a minimum – three successful, consecutive repeat process simulations should be conducted to revalidate the process.

4. Use of Barrier Technologies (RABS or Isolators)

The use of Restricted Access Barrier Systems (RABS) or isolators is advocated in the new Annex 1. At length, the respective requirements for this technology are now included. The use of RABS or isolators to minimize microbial contamination associated with direct human interventions in the critical zone is to be considered in the CCS. And furthermore, any alternative approaches to the use of RABS or isolators should be justified.

Benefit from ProPharma Expertise and Tools to Ensure Your Future Annex 1 Compliance

Partner with ProPharma to ensure future Annex 1 compliance and benefit from our expertise and tools to enable an effective review of your situation.

We offer the following approach supported by our experts:

  1. Use ProPharma’s proprietary questionnaire together in an expert scrum. During this efficient session compliance with the New Annex 1 will be reviewed. This comprehensive and structured exercise will identify any gap ahead of the August 2023 deadline.
  2. CCS review using ProPharma’s proprietary CCS template as starting point.
  3. CAPA resolution including amendments of CCS for CAPA completion.

Contact Us

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