European Commission publishes revised Annex 1

New document enters a three-month consultation period

The Directorate for Health and Food Safety of the European Commission has published a new draft for the revision of Annex 1 of the EU GMP Guide to Good Manufacturing Practice, the ECA Academy has reported.

Organisations and stakeholders can submit their comments to the revised document within the three-month consultation period.

The Annex 1 of the "Manufacturing of sterile medicinal products" was first published in 1971, and has been updated several times over the years. Amends have been around the classification table of cleanrooms to include guidelines on media simulation and biological stress monitoring, and the guidelines on vial sealing in 2010.

The current review dates back to 2017 when the first draft of a fundamental revision was published. It was intended to focus on structured guidance, incorporating contemporary principles such as quality risk management and consideration of new technologies and innovative processes.

The 2017 revision featured new sections for utilities and extended sections on topics such as production and specific technologies on the requirements of Aseptic Process Simulation (APS).

The current revision builds on more than 6,000 comments submitted to the European Medicines Agency.

The 2020 revision

The current document contains a large number of changes compared with the 2017 draft. It now comprises just over 50 pages divided into 11 sections:

  1. Scope - Includes additional areas (other than sterile products) where the general principles of the annex can be applied.
  2. Principle - General principles as applied to the manufacture of sterile products.
  3. Pharmaceutical Quality System (PQS) - Highlights the specific requirements of the PQS when applied to sterile products.
  4. Premises - General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of Barrier Technology.
  5. Equipment - General guidance on the design and operation of equipment.
  6. Utilities - Guidance with regards to the special requirements of utilities such as water, gas and vacuum.
  7. Personnel - Guidance on the requirements for specific training, knowledge and skills. Also gives guidance to the qualification of personnel.
  8. Production and specific technologies - Discusses the approaches to be taken with regard to aseptic and terminal sterilization processes. Discusses approaches to sterilisation of products, equipment and packaging components. It also discusses different technologies such as lyophilization and Form-Fill-Seal where specific requirements apply.
  9. Viable and non-viable environmental and process monitoring - This section differs from guidance given in section 4 in that the guidance here applies to ongoing routine monitoring with regard to the design of systems and setting of action limits alert levels and reviewing trend data. The section also gives guidance on the requirements of Aseptic Process Simulation (APS).
  10. Quality control (QC) - Gives guidance on some of the specific Quality Control requirements relating to sterile products.
  11. Glossary - Explanation of specific terminology.

ECA Academy analysis

The ECA Academy has announced a series of articles arranged by topic will be published on its website in due course.

Below is an excerpt of ECA's first analysis on the Premises and Qualification considered in the new draft revision.

In relation to the contamination control strategy (CCS), "it is also possible to build a bridge to the topic of insulators and RABS", concepts already present in Premises, and described as 'useful in ensuring the necessary conditions and minimisation of microbial contamination associated with direct human intervention", thus should be considered in a CCS.

The ECA notes that the topic of transfer of materials, equipment and other components is already taken into account in Premises with sub-sections 4.10 and 4.11, i.e. immediately before the section on airlocks.

The chapter concerning cleanroom qualification, reference is made to ISO 14644, yet with further focus on the measurement of particle sizes: "For cleanroom classification, the airborne particulates equal to or greater than 0.5 and 5 µm should be measured. For Grade A zone and Grade B at rest, classification should include measurement of particles equal to or greater than 0.5 µm; however, measurement using a second, larger particle size, e.g. 1 µm in accordance with ISO 14644 may be considered. This measurement should be performed both at rest and in operation."

The ECA notes that the current difference to ISO 14644, which only refers to one of the two sizes, is therefore still maintained.

The complete draft of Annex 1: Manufacture of Sterile Products is available on the European Commission website.

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