EU issues long-awaited GMP Annex 1 revision

The EU’s eagerly anticipated revision of its good manufacturing practice (GMP) Annex 1 for sterile drug products was released on Thursday after 14 years of development. The revised requirements, which are set to take effect 25 August 2023, govern the manufacturing of sterile drugs made in the EU, as well as imported products.

The revised Annex comes after hints earlier this year that it be out in mid-2022. (RELATED: EU GMP Annex 1 revision to be released mid-year, Regulatory Focus 15 March 2022)

The existing Annex I has been in effect since 2008 and has undergone several proposed revisions since then. The latest proposed revision of the Annex was released for consultation in early 2020 and generated over 2,000 comments. (RELATED: EU begins second consultation to revise Annex 1 of EU GMP guide on sterile drug manufacturing, Regulatory Focus 6 March 2020)

The Annex has been revised to “reflect changes in regulatory and manufacturing environments. The new guideline should clarify how manufacturers can take advantage of new possibilities deriving from the application of an enhanced process understanding by using innovative tools as described in the ICH Q9 and Q 10 guidelines,” the Annex states.

The final Annex I is a wholesale rewrite of the original 2008 version; the final version contains 59 pages, while the 2008 version had 16 pages. The Annex includes 10 sections covering scope, principles, pharmaceutical quality system (PQS), premises, equipment, utilities, personnel, production and specific technologies, environmental and process monitoring and quality controls.

There is a new section on the pharmaceutical quality systems, which incorporates the principles of quality risk management (QRM) into sterile drug manufacturing. References to QRM are also sprinkled throughout the document. There is also a new section addressing the concept of a contamination control strategy (CCS) in reducing contamination, as well as new sections which adopt recent advances in sterile processing technology in manufacturing, such as restricted access barrier systems (RABS) and isolators.

Lastly, the revision harmonizes sterile drug manufacturing principles with those of the World Health Organization (WHO) and Pharmaceutical Inspection Cooperation Scheme (PIC/S) standards of sterile drug manufacturing, as well as better align with the US Food and Drug Administration’s (FDA) 2004 guidance on sterile drug products manufactured by aseptic processing.

The Annex states that while it aims to provide guidance for the manufacture of sterile products, “some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, 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 endotoxin/pyrogen contamination is considered important.”

The Annex will take effect on 25 August 2023, except for section 8.123 on lyophilizer sterilization, which takes effect one year later on 25 August 2024.

Annex 1

EU issues long-awaited GMP Annex 1 revision

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