6/7 February 2024
At the end of October, Swissmedic published a document on the interpretation of Annex 1, which should make it easier for users to understand the new Annex 1.
Swissmedic defines: "This technical interpretation focuses on some of the most important changes of the 2022 revision of Annex 1 and also covers aspects that were already included in the previous version of this guidance document and that have repeatedly raised questions. This technical interpretation is intended to reflect the general opinion of the Swiss Inspectorates on these issues and to assist in the inspection of manufacturers of sterile medicinal products."
The document is a list of questions on various chapters of Annex 1 and the corresponding answers as interpreted by Swissmedic. It includes the following sections:
1 Purpose and scope
3 Definitions and abbreviations
4 Interpretation: Questions and Answers
4.1 Scope (Annex 1, Chapter 1)
4.2 Premises (Annex 1, Chapter 4)
4.3 Utilities (Annex 1, Chapter 6)
4.4 Personnel/Training (Annex 1, Chapter 7)
4.5 Production and Specific Technologies (Annex 1, Chapter 8)
4.6 Environmental & Process monitoring (Annex 1, Chapter 9)
4.7 Quality Control (QC) (Annex 1, Chapter 10)
5 Changes to the previous version
It should be noted that the document references Annex 1 of the PIC/S, i.e. the revised Annex 1 of the PIC/S GMP Guideline (PE 009) on the manufacture of sterile medicinal products. This was adopted by the PIC/S Committee on September 9, 2022 and came into force on August 25, 2023 (with the exception of point 8.123, which will become binding from August 25, 2024). This in turn is based on the revised Annex 1 of the EU GMP Guideline, which also came into force on August 25th.
Below are two examples from the document that have already been discussed in various other places, e.g. at the ECA Annex 1 conferences and in the ECA Commenting Task Force:
Question: Does Annex 1 apply without restriction also to ATMPs or are only defined aspects of Annex 1 to be followed for some specific product types, such as for example the allogeneic and autologous cell therapy products?
Answer: It is recognised that ATMPs cover a very heterogeneous range of products and that for some of these products, due to their nature and manufacturing technology, specific considerations are required. This certainly applies, for example, to the allogeneic and autologous cell therapy pro-ducts, which are to be manufactured under conditions suitable to avoid microbial contaminations, but which usually cannot be terminally sterilised or sterile filtered. In addition, such products are made from unsterile patient material. Specifically with regard to cellular therapy, Annex 2A, paragraph 5.29(b), requires that aseptic processing be maintained from the time of procurement of cells through manufacturing and administration back into the patient. Annex 2A refers to Annex 1 several times (e.g., in connection with the requirements for the provision of systems for closed processing), but implies the possibility of exceptions from applying the requirements of Annex 1. It must also be taken into account that Annex 2A became valid in May 2021, i.e., more than one year before the publication of the new Annex 1 version. It is expected that ATMP manufacturers, based on the knowledge of their manufacturing processes and the execution of detailed risk analyses covering all process steps, materials and systems, develop and implement Contamination Control Strategies suitable to avoid or largely minimise risks of product contaminations. Justification must be given for any exceptions to the requirements of Annex 1.
Question: Is a pre-use / post-sterilisation integrity testing ("PUPSIT") of sterilising grade filters used in aseptically processes mandatory?
Answer: The expectation is that PUPSIT be applied to verify the integrity of the sterilized filter assembly. However, paragraph 8.87 allows some flexibility in justified cases supported by risk analysis and covered in the CCS..
The total of 46 questions and the corresponding answers can be found directly on the Swissmedic website in the published document entitled "Interpretation of GMP Annex 1 2022 (Rev. 1)"