Second targeted stakeholders’ consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of Eudralex volume 4

Period of consultation : From 20 February 2020 to 20 May 2020.

Objective of the consultation

Annex 1 was first published in 1971, to ensure sterility of medicinal products placed on the market for the benefits of patients.

Since then it has undergone a number of targeted updates but, until now it has not undergone a full review. This revision is intended to add clarity, introduce the principles of Quality Risk Management to allow for the inclusion of new technologies and innovative processes and to change the structure to a more logical flow. Key changes are:

  • Introduction of new sections;
  • Introduction of QRM Principles;
  • Restructured to give more logical flow;
  • Added detail to a number of the previous sections to provide further clarity.

A first targeted consultation conducted from 20 December 2017 to 20 March 2018 allowed about 140 companies and/or organizations to comment. The drafting group processed more than 6200 lines of comments.

Due to widespread interest from industry following the first targeted consultation, and because of substantial modifications introduced in several sections, it was agreed to engage with stakeholders a second targeted consultation on the updated draft guidance (version 12) focused on the sections and/or significantly modified paragraphs that raised most concerns by stakeholders.

The second targeted consultation aims at collecting experience from the sectors on certain manufacturing steps. The European Commission therefore expect to receive contribution from the European associations representing the sectors.

The current document contains a large number of changes compared with the 2017 draft.

  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.

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