9/10 November 2021
On 20 February, the Directorate for Health and Food Safety of the European Commission published a further draft for the revision of Annex 1 of the EU GMP Guide to Good Manufacturing Practice. This document enters a 3-month phase of commenting by concerned organisations and stakeholders.
Annex 1 "Manufacturing of sterile medicinal products" was first published in 1971. In the following years it was updated several times, e.g. to adapt the classification table of cleanrooms to include guidelines on media simulation and biological stress monitoring in 2005 and 2007 as well as the guidelines on vial sealing in 2010.
At the end of 2017, the first draft of a fundamental revision was published, which was intended to focus on a more structured guidance, including state-of-the-art principles such as quality risk management and consideration of new technologies and innovative processes. At that time, the draft contained new sections, e.g. for utilities, and extended sections on topics such as production and specific technologies or on the requirements of Aseptic Process Simulation (APS).
During the following public consultation over 6000 comments were submitted to EMA, which then had to be processed in parallel with the challenge of moving to Amsterdam.
The current document contains a large number of changes compared to the 2017 draft and 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 sterilization 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.
In detail, we will present the changes in a series of articles on this website arranged by topic or section to be published soon. At this point, we would like to present only a few selected, partly comprehensive changes to give you a first impression.
A first significant difference to the currently valid Annex 1 and also to the draft of 2017 can already be seen in the title or the table of contents. Annex 1: Manufacture of Sterile Medicinal Products has become Annex 1: Manufacture of Sterile Products, i.e. the range of products covered by Annex 1 is significantly extended. This is also made clear in the scope by the sentence "Includes additional areas (other than sterile products) where the general principles of the annex can be applied". It further continues: "The manufacture of sterile products covers a wide range of sterile product types (active substance, sterile excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing and closed systems)."
The importance of Quality Risk Management (QRM) is also emphasized in greater detail than in the 2017 version, which of course includes a general evaluation of the existing processes according to criticality as shown in the scope: "This Annex provides general guidance that should be used for the manufacture of all sterile products using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination is prevented in the final product." On the other hand, QRM is also seen as the basis for justifying any necessary deviation from the specified requirements. This is stated in the current draft: "Where alternative approaches are used, these should be supported by appropriate rational and risk assessment and should meet the intent of this Annex. QRM priorities should include good design of the facility, equipment and process in the first instance, then implementation of well-designed procedures, with monitoring systems as the final element that demonstrate that the design and procedures have been correctly implemented and continue to perform in line with expectations. Exclusively monitoring or testing does not give assurance of sterility."
With regard to contamination control, an area which is generally mainly attached to quality assurance, the term "Contamination Control Strategy (CCS)", which appeared in the draft of 2017, is emphasized even more strongly. The principle of a coherent concept across the entire manufacturing process and all related areas ("...across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks associated with contamination") is clearly required. It is also emphasised that this must be a dynamic system that requires continuous updating.
In the context of CCS consideration, it is also possible to build a bridge to the topic of insulators and RABS. These are already supplemented with a sub-item in Premises which emphasises that they are "useful in ensuring the necessary conditions and minimisation of microbial contamination associated with direct human intervention" and should be considered in a CCS.
It is also new 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 latter is related to this in terms of content and has undergone a number of supplements compared with the previous Annex, particularly with regard to one-way concepts and anchoring in CCS. In the chapter on the qualification of cleanrooms, reference is made to ISO 14644, as before. However, as before, reference is made to the measurement of particle sizes 0.5 and 5 ?m: "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 current difference to ISO 14644, which only refers to one of the two sizes, is therefore still maintained.
In today's News, we have only addressed a few topics of interest. More detailed analyses will follow in the next Newsletters, especially as the revision will raise further questions, e.g. what will happen with the Guidance for Industry "Sterile Drug Products Produced by Aseptic Processing" dated 2004. Particularly, the question arises whether it still represents the current state-of-the-art in science and technology, and how to assess this when manufacturing for both the US market and the European market.
On the website of the European Commission you will find the complete draft of Annex 1: Manufacture of Sterile Products.