Annex 1 Revision

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A look back

The aseptic filling of a sterile medicinal product must be carried out in a controlled environment. (Grade A). The relevant part of the EU GMP Guidelines for this type of manufacturing is the document's Annex 1 . After a long revision period of the previously valid version of 2008 and two rounds of comments, the long-awaited revised Annex 1 on the manufacture of sterile medicinal products was finally published by the European Commission on 25 August 2022 (1). The main reason for the update was to reflect changes in the regulatory environment and in manufacturing, which includes a significant shift towards the application of quality risk management principles. The new Annex 1 will enter into force on 25 August 2023.

The European Commission published a first draft in 2017 for public comment. This resulted in over 6000 submitted comments from industry, stakeholder organisations and others. A second comment period on the revised draft in 2020, which included a targeted consultation period by recognised stakeholders from industry and organisations such as ECA and EQPA, received over 2000 comments. The intense debates, e.g. on the prominent PUPSIT (Pre- Use Post Sterilisation Integrity Test), were no surprise as there were significant revisions, additions and much more detail, resulting in an expansion of the document from 16 to now 58 pages.

We should acknowledge here the efforts of both industry and regulatory bodies, including the WHO (World Health Organisation) and the PIC/S (Pharmaceutical Inspection Co-Operation Scheme), in issuing a much more modern guide to the manufacture of sterile products. They have thus also succeeded in creating an agreed document between the three institutions EMA, WHO and PIC/S. The FDA also contributed to the revision. Accordingly, the revised PIC/S Annex 1, which is now identical to the EU Annex 1, was published at the end of September. Although the final version will only come into force after a transitional period of one year, it is expected that the current version will form the basis for the inspection of sterile products and components intended for the manufacture of sterile medicinal products.

Relevance for the production of many modern active substances and therapies

Although the title in both drafts no longer referred exclusively to sterile medicinal products, it was not changed in the end and remains "Manufacture of sterile medicinal products". Presumably also in order to minimise global effects on the basis of a European guideline and not to force discussions about the validity and controllability outside the EU too much, especially since a corresponding control by the inspecting European authorities would hardly be possible. Nevertheless, one aim of Annex 1 is to also provide a guideline for the manufacture of sterile products in general. Active ingredients, excipients, primary packaging materials and finished dosage forms are explicitly listed as sterile product types. In addition, some of the principles and guidance in Annex 1 can also be applied to other products that are not intended to be sterile, such as biological intermediates with low biological load. Overall, the aim is to prevent any microbial, particulate or endotoxin contamination of the final product. To emphasise one of the key principles of the previous and new Annex 1: "Sterility or other quality aspects should not be determined solely by a test of the final process or product."

As a result, the new Annex 1 is now of greater importance to many suppliers of packaging materials, starting materials, active ingredients and CDMOs. Although there is a separate complete GMP guideline for advanced therapy medicinal products (ATMP) with Eudralex Vol. 4, Annex 1 certainly also concerns modern active ingredients or therapeutic approaches such as mRNA and viral vectors if these are not used for ATMP but e.g. for vaccines. Often, these products are not released with the indication "sterile", but are sterile-filtered and then aseptically filled into previously sterilised containers or bags. Given the potential variability in filtration performance of these products, the overall contamination control strategy becomes increasingly important.

No way around it: Contamination Control Strategy

The "Contamination Control Strategy" (CCS) is a frequently discussed topic in all debates on Annex 1. Already in the draft versions it was stated:

"Contamination Control Strategy (CCS) - A planned set of controls for microorganisms, pyrogens and particulates derived from current product and process understanding that ensures process performance and product quality. Controls may include parameters and attributes related to active ingredient, excipient and drug materials and components, facility and equipment operating conditions, in-process controls, final product specifications and associated methods and frequency of monitoring and control."

Various support documents and templates have already been published for this purpose (2, 3) to assist pharmaceutical manufacturers in creating their own CCS, which will be a must in the future, more precisely by 25 August 2023! The aim of a holistic CCS is to move away from sterility based only on an audit of the final process or product, towards detailed process knowledge and all potential sources of contamination. There is a long list of elements that need to be considered, from equipment and process design to corrective and preventive actions. Different areas of responsibility play a role, as contamination control measures may reside in different departments, from production to engineering to quality assurance or quality control. While it is acknowledged that the manufacturer may already have control systems in place that do not need to be replaced, these need to be referred to in the CCS, or to make the CCS a coordinated whole and take into account any interactions. It should also provide a better opportunity to identify any gaps in the existing system.

The guideline of the ECA Contamination Control Strategy Task Force listed at the references will be updated shortly after the publication of the final Annex 1. It has the following structure:

The ECA Guide contains a 3-stage-approach to achieve "CCS-readiness."

  • Stage 1: Development (or review and refinement/improvement) of the CCS
  • State 2: Compilation of the CCS documents
  • Stage 3: Evaluation of the CCS

This document is intended to provide guidance for two possible cases:

1. For a new plant, new equipment, e.g., for:

  • Mapping of the manufacturing processes to identify possible sources of contamination.
  • Carrying out a risk assessment to evaluate the risk of contamination.
  • Establishing preventive measures and their controls in a holistic system (including the definition of responsibilities).
  • Assessing and managing the residual risk of contamination.

2. For an existing facility that has already carried out a risk assessment, e.g., for:

  • Evaluation of existing contamination control measures
  • Analysis and overview of possible gaps
  • Risk assessment and, if necessary, the addition of further measures and integration into the overall system (including determination of responsibilities)
  • Managing the residual risk of contamination

The Single Use Issue:

The new Annex 1 recognises the use of single-use systems (SUS) in the manufacture of sterile products and includes a separate paragraph listing "some specific risks associated with SUS that should be assessed in the context of the CCS": Drug Interaction (e.g. Leachables and Extractables play a role in SUS), Integrity ("risk of holes and leaks") and Particle Contamination. Expectations such as supplier qualification, extractables assessment, integrity verification throughout the process, incoming inspection, operator training and more are listed. Another new and interesting chapter deals with "closed systems", which includes considerations on how to design and use a closed system and what measures should be taken to ensure the integrity of the system, especially when a closed system is used in an area with a classification lower than Grade A. Closed reprocessing considerations also include the use of a sterile connection device, which is now referred to throughout the Annex 1 document as an 'intrinsic sterile connection device'.

This is intended to address only some of the relevant issues at this point. A separate article could be dedicated to the topic of quality risk management alone, and more "trivial" topics such as "cleanroom socks", which can become a challenge for the manufacturer but also for the reprocessing cleanroom laundry (or disposable socks? Is that sustainable?) remain undiscussed here. The subchapter "Barrier Technologies" in the chapter "Premises" has also been extensively expanded, almost doubling in size. The topics of background environment, gloves and decontamination methods have been dealt with separately for both isolators and RABS. The subchapters "Form-Fill-Seal (FFS)" and "Blow-Fill-Seal" in the chapter "Production and Specific Technologies" have almost tripled in size and go into much more detail.

As mentioned, the implementation period for Annex 1 ends on 25 August 2023, i.e. exactly one year after publication in Eudralex Volume 4, only for one section, Chapter 8.123 "Product transfer/ loading/unloading areas for freeze dryers" the deadline is two years, i.e. until 25 August 2024. At this point, the objections of the industry for longer deadlines for some sections have probably been listened to.

More detailed information and examples of the Authority's expectations and industry implementations can be expected at the ECA Live Online Annex 1 Conference on 14 and 15 December 2022.


About the Author
Dipl. Biol. Axel H. Schroeder has been working at CONCEPT HEIDELBERG since 2008 and is head of the microbiology department.

1 European Commission (2022), EU GMP Annex 1 (assessed 29 Aug 2022).
2 ECA Foundation (2022), Contamination Control Strategy – A New Guideline from ECA, (assessed 29 Aug 2022).
3 El Azab W (2021), Contamination Control Strategy: Implementation Road Map. PDA J Pharm Sci Technol., 75(5):445-453.

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