EU GMP Annex 1 revision to be released mid-year

Regulatory NewsRegulatory News | 15 March 2022 |  By 

The EU’s pending revision of Annex 1 covering good manufacturing practice (GMP) for sterile drug products is a “significant improvement” over the previous version and emphasizes the importance of risk management in preventing microbiological contamination of products, said Paul Gustafson, chair of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The final version also retains the controversial provision calling for testing filters in the cleanroom.
Gustafson provided an update on the long-awaited Annex 1 revision on 14 March at the ISPE Aseptic Conference, held virtually and in Bethesda, MD by the International Society for Pharmaceutical Engineering (ISPE). Gustafson is a senior corporate regulatory compliance and enforcement advisor with Health Canada. He said there are plans to issue the widely anticipated Annex 1 in mid-year 2022.
Regulators in the EU drafted the revision, with input from PIC/S and the World Health Organization (WHO).
Gustafson said the revision is “much more comprehensive” than the current Annex 1, which was last revised in 2008. In addition, the revision is a “significant improvement over the current version and highlights the tremendous collaborations between PIC/S, EMA and WHO.” He said that annex will have a “wonderful impact on aseptic processing and protection of patients.”
The revision consists of 57 pages, with a revised chapter layout, while the 2008 version was 16 pages. The revision has 10 sections covering scope, principles, pharmaceutical quality system (PQS), premises, equipment, utilities, personnel, production and specific technologies, environmental and process monitoring and quality controls.
The second 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)
Revisions explained
Gustafson said the revised annex “builds on the pharmaceutical quality system requirements detailed in Chapter 1 of the PIC/S GMP guide and helps ensure that an effective quality risk management is integrated into all areas of the product life cycle, with the aim to minimize microbial contamination and ensure the quality of sterile products that are manufactured.”
There is also new content on barrier technologies designed to prevent contamination, such as restricted access barrier systems (RABS) and isolators to address the ambiguities of the previous guidelines.
The revision also aligns with the European Pharmacopoeia (EP) in the water for injection (WFI) section by “allowing distillation or an equivalent purification process, such as reverse osmosis when coupled with other appropriate techniques.”
There is also new content on closed systems and single-use systems used for aseptic processing. This content, said Gustafson “is really playing catch up with content that isn’t present in the current guide, which simply highlighted the need for an update.”
PUPSIT testing retained
The revision also retains a provision calling for testing filters used in the sterilization process, called pre-use, post-sterilization integrity testing (PUPSIT). The PUPSIT provision “has driven a substantial amount of discussion and has resulted in a number of papers being drafted,” said Gustafson.
A number of industry groups, including the Parenteral Drug Association, argued in comments on the revision that the risk of filter testing, or testing filters used in the sterilization process, could introduce the contamination that it is designed to prevent.
The one change is a “carve-out” exempting radiopharmaceutical manufacturers from performing PUPSIT testing, said Gustafson.
Looking forward
Gustafson said a working group consisting of regulators from EMA, PIC/S and WHO endorsed a revised version in mid-February. The annex is now being reviewed by EU legal services as well as by PIC/S and WHO.
“There are a lot of moving parts here and we are working in collaboration with separate approval processes within PIC/S, WHO and the European Commission. The target date is to have a revision in mid-2022,” Gustafson said.
There are plans underway to develop an aide memoire to ensure the document is implemented in a harmonized way.
Gustafson said that even though a revision has not yet been published, regulators are already thinking long-term and planning an update. “There are many technological advances that will follow in the years ahead.”
ISPE meeting


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