- EU GMP Annex 1: Manufacture of Sterile Medicinal Products (Draft)
- Quality Risk Management (QRM) principles apply to the entire document
- Any specific limits or frequencies are minimum requirements
- Draft started in 2017 includes over 6,200 comments from 140 organizations 1
What’s New with Annex 1?
The newest version of Annex 1 that was proposed in December 2017 and updated in 2020 is an entirely rebuilt guidance document based on the original version from 1971 and partial revisions in 1996, 2003, and 2007. Thus, there is a lot of new information and updated language to unpack in this 52-page document.
We have chosen several key details from the document to highlight below. While the updated guidance is written for increased clarity, some points are still open to interpretation. If you have specific questions about these or any other components of Annex 1, please reach out to one of our CQV experts to learn how these changes may impact your organization.
Increased Scope Includes Non-Sterile Products (Section 1)
“The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates but where the control and reduction of microbial, particulate and pyrogen contamination is considered important.” 2
Introduction of a Contamination Control Strategy (Section 2)
“A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks associated with contamination. The CCS should be actively updated and should drive continuous improvement of the manufacturing and control methods.” 2
Introduction of a Pharmaceutical Quality System (Section 3)
“The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that microbial, particulate and pyrogen contamination is minimized in sterile products.” 2
RABS as Part of the CCS (Section 4)
“Restricted Access Barrier Systems (RABS) and isolators are beneficial in assuring the required conditions and minimizing the microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.” 2
Detailed Airlock Measures (Section 4)
“Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate contamination of the different areas, and should be present for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, time-based separation of movement (personnel / material) by procedure should be considered. Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and non viable) as the cleanroom into which it leads. The use of separate changing rooms for entering and leaving Grade B cleanrooms is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of cross-contamination is high, separate changing rooms for entering and leaving production areas should be considered.” 2
Continuous Monitoring Systems for WFI (Section 6)
“WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, (unless justified otherwise) as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk and the outcome of qualification.” 2
Personnel Requirements (Section 7)
“The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained and experienced in the manufacture and testing of sterile products, and any of the specific manufacturing technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the manufacture and handling of sterile products.” 2
PUPSIT Requirements (Section 8)
“The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. Test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of non-sterility.” 2
New Section for Closed Systems (Section 8)
“It is critical to ensure the sterility of all product contact surfaces of closed systems used for aseptic processing. The design and selection of any closed system used for aseptic processing should ensure maintenance of sterility. Connection of sterile equipment (e.g. tubing / pipework) to the sterilized product pathway after the final sterilizing filter should be designed to be connected aseptically (e.g. by intrinsic aseptic connectors or fusion systems).” 2
New Section for Single Use Systems (Section 8)
“SUS should be designed to maintain integrity throughout processing under the intended operational conditions. Attention to the structural integrity of the single use components is necessary where these may be exposed to more extreme conditions (e.g. freezing and thawing processes) either during routine processing or transportation. This should include verification that intrinsic aseptic connections (both heat sealed and mechanically sealed) remain integral under these conditions.” 2
The second targeted consultation period ended in July 2020 and the finalized version is anticipated by many to come in early 2021.
Although Annex 1 was developed and is maintained by the EU, it is mandatory that U.S.-based manufacturers comply with these standards to sell products in Europe. Several international and U.S. organizations contributed to the Annex 1 revisions to ensure its global applicability, including WHO, PICS, FDA, ISPE, and PDA.
Questions about qualifying your facilities to meet the new EU GMP Annex 1 standards?