The deadline to comply with the revised EudraLex Volume 4, Annex 1 is August 25th, 2013. Only for a sole point (point 8.123: "product transfer/loading/unloading areas for lyophilizers“) a later deadline (Aug 2024) exists.
With the deadline fast approaching, completing your comprehensive review of all changes to the Annex 1 guideline has become crucial for your business. However, it may not be as straightforward as it seems. After all, this is a major revision: Annex 1 has grown from 16 pages in the 2008 version to 52 pages.
To counteract this challenge with concrete measures, ProPharma has analyzed the New Annex 1 and created a proprietary questionnaire. This questionnaire divides the New Annex 1 requirements into multiple questions. It has been designed to facilitate an efficient and well-structured step-by-step assessment on all aspects of the New Annex 1.
The new Annex 1 requires the implementation of a Contamination Control Strategy (CCS). This strategy is expected to play a central role in the Documentation System of every manufacturer of sterile products. When it comes to implementing your CCS, you can benefit from ProPharma's extensive experience in this field. A well-designed CCS is seamlessly integrated into your QMS and is tailored to your specific manufacturing situation. The New Annex 1 outlines numerous requirements for your CCS, and ProPharma offers a proprietary CCS template that aligns with these requirements. This template serves as an excellent starting point for creating or reviewing this key document.
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 was not carried out until August 2022. The objective of the revision was to enhance clarity, introduce the principles of Quality Risk Management (QRM), accommodate the inclusion of new technologies and innovative processes, and improve the structure to a more logical flow.
This significant update was a collaborative effort involving European health authorities, the World Health Organization (WHO), and the Pharmaceutical Inspection Convention/Pharmaceutical Co-Operation Scheme. The first draft underwent targeted consultation involving 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.
The updated version of Annex 1 emphasizes the application of QRM principles throughout the entire process of sterile manufacturing. The objective is to proactively and continuously identify, evaluate, address, control, and monitor potential risks related of microbial, particulate, and pyrogen contamination.. This comprehensive approach encompasses 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 cannot rely solely on monitoring and sterility testing; instead, it should adopt a holistic approach. The new Annex 1, therefore, requires the implementation of a Contamination Control Strategy (CCS). The CCS will serve as a high-level document describing the application of QRM in controlling contamination risks in compliance with Annex 1's regulations. It should identify potential contamination risks to the final product and include references to risk assessments and policies for controlling those risks. Furthermore, it should incorporate references to monitoring systems that ensure ongoing 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 provides comprehensive guidance to premises, equipment, utilities, personnel, production and technologies, viable and non-viable environmental monitoring, and aseptic process simulation This new version has expanded significantly toto 52 pages, compared to the previous 16-page version from 2008. Each chapter emphasizes the importance of implementing QRM principles. he updated requirements cover a wide range of areas and include the following examples:
The new Annex 1 additions provide detailed guidance on the production of Water for Injection (WFI). This includes the options of utilizing methods other than distillation. However, it is important to note that these alternative methods, such asnanofiltration, ultra-filtration, and electrodeionization are considered in conjunction with reverse osmosis membranes.
Compared to the 2008 version, the updated Annex 1 places significantly more emphasis on the requirements related to personnel behavior, hygiene, training, qualification, and disqualification. In addition, it mandates both the validation of the maximum number of operators permitted in a cleanroom and the qualification of the cleanroom garment cleaning process.
In relation to this crucial aspect, the revisions offer more comprehensive guidance on the risk-based development and execution of Aseptic Processing Simulation (APS). According to the updated guidelines any contaminated unit should result in a failed process simulation and necessitate an investigation. To revalidate the process, a minimum of three consecutive successful repeat process simulations should be conducted.
The use of Restricted Access Barrier Systems (RABS) or isolators is highly recommended in the new Annex 1 which outlines specific requirements for this technology.
One of the main objectives is to minimize microbial contamination that may occur due to direct human interventions in the critical zone. Therefore, the implementation of RABS or isolators should be carefully considered in the CCS. It is important to note that any alternative approaches to the use of RABS or isolators must be thoroughly justified.
Partner with ProPharma to ensure future Annex 1 compliance and benefit from our expertise and tools for an effective review of your situation.
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