In August 2022, the European Commission published the revised edition of Annex 1 “Manufacture of sterile medicinal products” in EudraLex – Volume 4 – Good Manufacturing Practices (GMP) guidelines. This document will have a significant impact on manufacturers of sterile medicines who intend to market their products in the EU regardless of the country where they are manufactured. The new Annex 1 also applies to the United Kingdom, which continues to acknowledge European GMPs as a pharmaceutical manufacturing guideline. Manufacturers must comply with these new regulations by August 2023.
Annex 1 “Manufacture of sterile medicinal products” forms a part of European Union GMP guidelines and was originally published in 1989. Prior to 2022, the most recent revision was in 2008. The 2022 version is a significant one and gives rise to guidelines that differ substantially from previous ones.
The European Commission explains that this document intends to provide technical guidance on GMP principles and guidelines for medicinal products as set out in Directive (EU) 2017/1572 issued by the Committee for Medicinal Products for Human Use, Directive 91/412/EEC for veterinary use and by Commission Delegated Regulation (EU) 2017/1569 on experimental medicinal products for human use and inspection methods that supplement regulation (EU) n. 536/2014 on clinical trials.
What updates are included in the revised Annex 1?
Updates to Annex 1 include international-level harmonisation of quality risk management principles, plus regulations on controls related to sterility assurance. Some of the changes will require substantial economic investment and could lead to disruptions in the supply of medicines. In some respects, the new Annex 1 appears to be stricter than US requirements; this could hinder the long-standing efforts to improve harmonisation of regulatory requirements between the EU and the US.
Key changes include the inclusion of quality risk management (QRM) principles throughout the document. Pharmaceutical quality systems (PQS) now include QRM principles for the production of sterile drugs. The QRM is described in ICH Q9 (November 2005). While QRM is rarely mentioned directly throughout the document, Annex 1 states: “Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality”. Alternative approaches should be supported by adequate rationale, risk assessment and mitigation.
Annex 1 also introduces the concept of Contamination Control Strategy (CCS), which should be implemented throughout the plant in order to identify all critical control points and assess the effectiveness of controls and monitoring measures intended to manage product quality and safety risks. Manufacturers must provide comprehensive documentation that allows regulatory bodies to verify the robustness and reliability of the adopted measures. Annex 1 contains a list of the elements to be considered in the CCS and invites manufacturers not to limit themselves to these.
Here are some of the elements to consider within the CCS:
Below we list some new EU regulatory expectations that will have a significant impact on manufacturers of sterile medicines around the world:
Containment system requisites
RABS and isolators. Annex 1 indicates the use of Restricted Access Barrier Systems (RABS) or isolators as a minimum measure for secure maintenance of the conditions envisaged for grade A areas. Section 4.3 indicates that their use should be considered in CCS and any alternative approach should be justified. Annex 1 contains no elements justifying the maintenance of existing filling lines or the construction of new plants with alternative systems to RABS or isolators.
New aseptic processing criteria
Grade A = “no growth”. The 2008 version of Annex 1 required air and surface sample microbial growth in Grade A areas to be less than 1 CFU. Since a Colony Forming Unit (CFU) is necessarily an integer value, one could conclude that the requirement was effectively zero (0) CFU. However, Annex 1 described the values as averages, taking into account the rare excursion into a grade A area. The new version (2022) sets the upper limit for microbiological contamination in grade A areas at “No growth” and indicates that “any growth should result in an investigation”.