In the first article I summarised the background to the latest update to Annex 1. In this article I want to focus on sections 1, “Scope”.
The scope of a document is usually intended to outline the range of application of the document. It can be used to summarise areas that are excluded from the document. The outgoing Annex 1 did not have a formal scope although the first line of the principle statement suggested a limited scope to sterile products, “The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination”. Even such a basic statement can, in hindsight appear unclear, for example what is meant by a product? Traditionally it would be a final dose form such a sterile solution in a glass vial. We would not immediately think of a sterile API, or sterile excipient or even a sterile container closure system. Yet, to the manufacturer of these materials, they are their products. The final part of the statement suggested that the scope of the outgoing annex should include specifically microbiological, physical (particulate) and pyrogenic (implying endotoxin) contamination. The point being that the applicability of the outgoing Annex 1 left the reader to draw their own conclusions. It was left to other documents to create a link back to Annex 1. For example, it is wording in Part II GMP for APIs, that Part II applied to the manufacture of sterile active substances only up to the point immediately prior to the active substance being rendered sterile.” and “The sterilisation and aseptic processing covered but active substances are not covered, but should be performed in accordance with… Annex 1.” that adds to the scope for the outgoing annex 1.
The 2022 Annex 1 attempts to create a clearer direction. It states that “The manufacture of sterile products covers a wide range of sterile product types” and explicitly includes active substances, excipients, primary packaging material, and the finished dosage form.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this, he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
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It suggests coverage of packaging types such as single dose units to multiple does units. It also suggests a range of manufacturing processes from manual to highly automated processes technologies including biotechnology, classical small molecule manufacturing systems and closed systems to name just a few.
Contrary to belief, the outgoing annex 1 did refer a lot to risk although risk management was mentioned only once. The new annex 1 it much more focused on Quality Risk Management (QRM) and the processes of assessing risk and is clear that QRM applies to the whole of annex 1 even if not explicitly mentioned. It now clarifies that QRM, is there to ensure that microbial, particulate and endotoxin/pyrogen contamination is minimized or even prevented in the final product.
The Scope also refers to the interpretation of limits, frequencies etc. where the expectation is that these should be considered as a minimum requirement given that they are based on regulatory experience that have impacted patient safety.
The final part of the scope of Annex 1 is quite powerful. To date organisations of non-sterile products have elected to apply elements of Annex 1 as good practice usually in the absence of any other guidance. Organisations may for example already opt for grade D conditions for manufacturing and limit setting, for the design and use of clean room clothing and even for a strategy on control of contamination. While Annex 1 clearly states that its intent is to offer guidance for sterile products, it now formally extends the guidance to other dosage forms where the general expectation to control contamination is deemed important. This is not saying that Annex 1 has to apply to these dosage forms, but that certain guidance may be relevant. For example, the scope identifies the contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring, and personnel gowning as being potentially relevant. Dosage forms that can be particularly at risk of contamination include certain liquids, creams, ointments as well as low bioburden biological intermediates. The caveat is that where annex 1 guidance is applied to a non-sterile dosage form, it should be clearly documented and that compliance with the guidance needs to be demonstrated.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.
