Unlocking the Key Changes to Annex 1

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Annex 1, the European Union’s good manufacturing practice (GMP) guide for sterile products, has undergone several updates since its original publication in 1971. The latest revised document, the proposed draft of which was published in February 2020 and has undergone a second consultation period (1), has been comprehensively updated and builds on a significant number of comments submitted to the European Medicines Agency (EMA) by companies and organizations from the pharmaceutical industry.

To find out more about the key revisions to Annex 1 and the impact the changes will have on industry, Pharmaceutical Technology Europe spoke with Vincent Quiles-Pelletier, director, quality management and head of steriles at Recipharm.

Key revisions

PTE: Could you highlight the key changes of the Annex 1 2020 revision?

Quiles-Pelletier (Recipharm): The Annex 1, Manufacture of Sterile Products guideline, was proposed as a new draft in February 2020 for a second consultation period, which ended in July 2020. This document was completely rewritten to organize and describe detailed and comprehensive requirements in 10 specific sections. The scope was enlarged to include non-sterile products where principles of contamination control could apply, using quality risk management (QRM) principles adapted to these products.

The key changes in this new version include: quality management through the introduction of the contamination control strategy (CCS) concept combined with QRM and pharmaceutical quality system (PQS); introduction of new barrier technologies such as restricted access barrier systems (RABS) and isolators, which should be considered as part of the CCS; creation of new sections for form fill and seal, closed systems, and single use systems (SUS); reinforcement of some requirements around areas classification and qualification, including microbial airborne and surface contamination; introduction of detailed measures and/or specifications to prevent any contamination (for example, airlock/changing rooms, continuous monitoring systems for total organic carbon and conductivity on water for injection loops, validated disinfection/decontamination programme including a focus on vacuum, cooling systems, and dry heat tunnels); and introduction of specific requirements regarding personnel, including a strong knowledge and expertise through adapted training, combined with reinforced monitoring and gowning requirements.

Additional requirements have also been introduced regarding production and specific technologies, including pre-use post sterilization integrity test (PUPSIT), specific process holding times, container closure integrity, and visual inspection. Further, reinforced sterility test sampling after each critical intervention is also mandatory.

Reasons for change

PTE: What were the reasons behind the revisions to the Annex 1 guidance and why has the revised document taken so long to prepare?

Quiles-Pelletier (Recipharm): Since the first version was published in 1971, several updates with partial revisions were issued in 1996, 2003, and 2007 to align classification of cleanrooms, to include guidance on media simulations, bioburden monitoring and capping of vials. In 2012, German authorities started to require a complete revision to be handled by the Inspectors Working Group (IWG) from EMA, involving EMA, the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and World Health Organization (WHO) experts. The work began in 2014 and a concept paper was raised on 8 Jan. 2015 (2). Consideration was given to the fact that that the initial document was never completely reviewed despite significant changes in technologies, practices, and in GMP (e.g., International Council for Harmonization [ICH] Q9 and Q10 guidelines adoption).

A first draft of the new Annex 1 was proposed in December 2017 for review until March 2018, and about 6200 comments were received from 140 companies and organizations, showing a significant interest from all actors involved in sterile manufacturing. As a result, this new Annex 1 proposed in 2017 and updated in 2020 is a completely rebuilt document of 50 pages (16 pages for the current version) answering to the concept paper objective from 2015.

Important challenges

PTE: Are there specific changes in the newly revised guidance document that will significantly impact industry?

Quiles-Pelletier (Recipharm): Absolutely, the most important challenges will be technical and organizational. From a technical perspective, we have seen that a big prominence was placed on any equipment or premises design that can minimize the risks of potential contamination. If new equipment is completely integrated into the CCS using QRM principles, this can be a challenge, both technically and financially, for old equipment and premises. A good example of this issue is new barrier technologies, which should be considered in the CCS as it offers significant improvements in terms of contamination control.

At an organizational level, the sterility assurance level is based on CCS and PQS is based on QRM principles and continuous improvement. This new concept demands a periodic review of each risk assessment initially raised, and the implementation of a new review of data and trends generated by systems or equipment considered as critical in the CCS.

Principle of CCS

PTE: Could you describe the principle of a CCS in more detail and how the revised Annex 1 approach to CCS will impact manufacturers?

Quiles-Pelletier (Recipharm): The principle of the CCS is to provide a global tool, allowing companies to implement, follow, and maintain an acceptable sterility assurance level. This required level of quality assurance in sterile operations means that each process and product should be assessed to define all critical control points, covering the following areas of contamination risks: viable (microbial) and non-viable (pyrogen as well as other potential particulate matter such as glass, visible and sub‑visible).

The impact for manufacturers will most probably be a significant effort in making a link between measures and the quality systems in place, and to reopen and reassess existing risk assessments periodically based on data generated by all critical control points, checking efficiency, and deciding new adapted preventive actions if justified by these reviews.

Harmonization of approaches

PTE: Does the newly revised EU guidance offer a more harmonized approach with other global regulatory requirements?

Quiles-Pelletier (Recipharm): Definitively, as EMA, PIC/S, and WHO experts were all involved in the revision process, as well as there being some input from the United States Food and Drug Administration, to provide a more comprehensive document, there is harmonization of approaches. Overall, more than 70 countries provided comments for the revised guidance.

Some reference documents were taken in consideration for the review, such as current monograph of the relevant pharmacopoeia for water (3) or ISO 14644 for cleanroom qualification (4). However, some significant differences remain between US and EU regulations, for example PUPSIT or cleanroom requirements.

The new Annex 1 version, proposed for review and comments, has been the opportunity for targeted stakeholders to give a valuable input in terms of technical feasibility, alignment, and consistency with other guidance, precision and clarity on some of the requirements, and disagreement on specific requirements. This revised document is a good example of what a harmonized approach can achieve, making a link with the mutual recognition process in progress between the US and EU.

References

1. EC, “Second Targeted Stakeholders’ Consultation on the Revision of Annex 1 on Manufacturing of Sterile Medicinal Products, of Eudralex Volume 4,” ec.europa.eu [Accessed 24 Sept. 2020].
2. EMA, “Concept Paper on the Revision of Annex 1 of the Guidelines on Good Manufacturing Practice—Manufacture of Sterile Medicinal Products,” ema.europa.eu, 8 Jan. 2015.
3. EMA, Guideline on the Quality of Water for Pharmaceutical Use (London, UK, November 2018).
4. ISO, ISO 14644-1:2015, “Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness by Particle Concentration” (Geneva, 2016).

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology Europe
Vol. 32, No. 10
October 2020
Pages: 42–43

Citation

When referring to this article, please cite it as F. Thomas, “Unlocking the Key Changes to Annex 1,” Pharmaceutical Technology Europe 32 (10) 2020.