Editorial | Open Access | Published 25th July 2023

GUEST EDITORIAL : Implementation of Revised Annex 1

Author : Simon McEwen

Abstract

If we cast our minds back to those bright sunny uplands of pre-Brexit 2014, the editorial in this journal (issue 19 no. 4) expressed hope, excitement and great anticipation at the news of a root and branch revision of Annex 1. Previous attempts to modify this section of the regulatory guidance had been perceived as largely tinkering at the edges, and this revision was clearly viewed as long overdue.

Key words: Annex 1, European Pharmacopoeia, ATMP, pupsit 

Nine years later, and I am certain that there are few managers within our ranks who are so enthused, rather looking with trepidation at the new and unexplored impacts that the changes will have on their working practices, and certainly the first recipients of inspections once these changes will come into effect on 25th August will be pounced upon to give presentations about their successes and failures to the wider industry.

Some parts of the revision (such as the alignment with the European Pharmacopoeia in regard to the production of water for injection) appear to be uncontroversial, however the relative inexperience of personnel who are less knowledgeable with the different technologies involved may still pose challenges for companies which adopt methodologies other than distillation.

With regard to emerging technologies, I recall a conversation with a European regulator regarding a closed, single-use system for the manipulation of cells for an ATMP, in which they stated that they regard such a system as requiring a grade B or even a grade A background, in contrast to an opinion expressed to me by a regulator from a different country who suggested that grade C was sufficient. The new revision now includes sections on closed systems and restricted access barrier systems (RABS) and this should clarify expectations and remove some subjectivity from the inspection process for both the inspectors and the companies.

Perhaps the single most controversial element of the new revision remains the requirement for pre-use, post-sterilization integrity testing of filters (PUPSIT). The debate around this requirement is interesting, as the arguments brought forth on both sides are centered around risk to patient safety. Over time, different process development departments will presumably start to demonstrate when PUPSIT is appropriate and when (if ever) it could increase risk to patients. No doubt, evidence one way or the other will trigger a further revision to the annex.

There has been considerable discussion over the new requirement for a Contamination Control Strategy document. Even though this document will contain no new information, the organization of this information into a new format has caused considerable work for all quality departments, and the industry is still learning what such a strategy document should look like.

Seven years, a UK regulator now outside of the EU and an expansion from 16 to 59 pages: The root and branch revision has surely been thorough. My sincere hope is that we as an industry will reflect on these much-needed clarifications of the standards to which we must operate and aim to develop them further as we work to increase the safety and quality of our products.