EudraLex Volume 4, Annex 1 Update: What You Need to Know: 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 now. The objective of the upcoming revision is 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. Read about this revision below, or contact our experts for additional guidance.
This major update is 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 20 December 2017 to 20 March 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 20 February 2020 to 20 July 2020. It is expected that the revised EU GMP Annex 1 will be published at the end of 2021 and will come into operation six months after publication.
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 the 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.
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:
The new Annex 1 additions give detailed guidance for the 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.
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.
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.
The best way to implement the new version of Annex 1 may be to start with a high-level gap assessment to identify potential contamination risks that are not yet covered by a QRM approach. The next step would be setting up the required CCS, thereby assessing newly identified risks, re-assessing previously identified contamination risks, and assessing compliance with the Annex.
For newly identified contamination risks, appropriate control measures and monitoring systems should be designed and implemented. The control and monitoring of known contamination risks should also be verified for meeting the expectations in accordance with Annex 1.
If you need support as you prepare to align with the revisions in Annex 1, connect with the experts at ProPharma Group. Our team is here to help, whether you need an independent gap assessment, or full support implementing the necessary controls.
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