ANNEX 1 - CLARIFICATION NEEDED
On 20th December 2017, the draft version of the update of Annex 1 "Manufacture of Sterile Medicinal Products" has been published by the European Commission. The draft version of this important regulatory document, being roughly three times longer than its current version, was open for public consultation until 20th March 2018. - Thus, in May 2018, it was time to get together and speak about this document and discuss it with and among regulators, inspectors, as well as industry and supplier representatives.
More than 200 participants from over 35 countries took this opportunity and joined the Annex 1 Conference in May 2018 in Berlin. The regulatory document was comprehensively reflected: 15 speakers covered many different aspects and reflected all possible perspectives - from the regulatory, industry and the supplier side.
Andrew Hopkins, who is in charge of the Annex 1 update at the British MHRA, led into a contemplation of the changes in sterile manufacturing: enhanced automation, allowing to keep the operator away from the product and the opportunities and challenges of real time and rapid monitoring microbiological test methods. He dared to raise the question whether these changes possibly present an insurmountable challenge; not only for the industry, who may be reluctant to broadly invest in new technology and consecutively apply for regulatory updates, but also for regulators and with regard to international harmonization.
We heard that the public consultation phase for the Annex 1 update resulted in 140 sets of comments with over 7,000 lines, which EMA received from pharmaceutical manufacturers, individuals, committees and organisations, grouping the comments of different pharmaceutical companies. Andrew Hopkins shared the complexity which had to be taken into account for the update: Not only is the new document relevant for the EU, but also for other regulatory bodies all over the world, e.g. PIC/S and WHO. Not only is the document supposed to provide guidance for sterile drug products, for products with classical small molecules and large molecules, but also for sterile APIs. Not only for terminally sterilized, but also for aseptically manufactured products. He emphasized that the update is meant to clarify existing requirements and is not meant as a step into more stringent requirements. The update reinforces and for some areas introduces the concept of Quality Risk Management (QRM) which conversely means that the document must not be too prescriptive.
Recommendation
Berlin, Germany5-8 November 2024
Contamination Control Strategies & Workshop Risk Assessment in Contamination Control
At this point, industry representatives shared the concern that the increased level of descriptive detail conveys the impression that the new document is both, highly prescriptive while introducing the concept of QRM, which is regarded as a conflict.
Dr Beate Reutter, GMP-Inspector from the German Inspectorate in Schleswig Holstein, familiarised the audience with the areas of applicability of the QRM principles which e.g. are an essential element for process understanding and consecutive continuous improvement, and allow a holistic approach to define an individual contamination control strategy. To avoid any misunderstandings she pointed out the specific and explicit requirements - such as that the Clean Room Grades as defined in Annex 1 are binding and not subject to "discussion" via QRM.
All speakers, no matter whether industry or regulator's representatives, shared the conviction that QRM is a very valuable element strengthened in the update of Annex 1, if it is based on the principles of ICH Q9 "Quality Risk Management", i.e. done in a systematic, data-driven and multidisciplinary approach. Arjan Langen presented a case study, where his company had applied different QRM techniques in context with the revision of a comprehensive contamination control concept. The concept included e.g. QRM-based decisions on replacement of technology from traditional LAF to Isolators, definition of criticality factors and subsequent determination of monitoring frequency. One of the QRM techniques applied in this contamination control case study was the HACCP concept: a multi-step approach from identification of hazards or contamination risks, the determination of Critical Control Points (CCPs), establishing limits, and a system to control and monitor the CCPs.
The section regarding Aseptic Process Simulations (APS; "process simulation" in the current version) is more explicit and also includes some additional requirements which can be seen easily by the fact that the current version explains the APS in 6 points (half page), whereas the draft version mentions 16 points on four pages! Andrew Hopkins familiarized the participants with the importance of QRM for designing an adequate process for specific circumstances and with the more extensive expectations regarding the investigation in case of growth detection during APS and subsequent initiation of CAPAs.
A corresponding presentation was held by Julia Allgaier and Franziska Petershagen, both representing Vetter Pharma, Germany, outlining the impact of the APS-requirements in a step-by-step comparison of the current and the drafted, increased requirements. Just to mention one example: All products manufactured on a line subsequent to the process simulation performed on the same line should be quarantined until the APS has been successfully completed. This requirement did not exist until now and will have a direct impact on the operations as more batches will have to wait for release. However, there was doubt whether this demand is reasonable.
A scientific approach to the possibilities and limitations of automated media fill inspections has been developed and was presented by Dr David Brückner (F. Hoffmann-La Roche Ltd.).
Other presentations held by Dr Christina Meissner (BASG / AGES, the Austrian Inspectorate) and Stefan Löw (CSL Behring) dealt with requirements for facilities and utilities. Appreciation was given to the fact that water and utilities play a more important role now. Regarding clean rooms and facilities, there are no entirely new requirements. However, the introduction of the QRM concept obliges pharmaceutical manufacturers to go deeper and to take more responsibility for the entirety of the individual contamination control strategy.
There was need to go deeper into the wording of the draft version. Dr Friedrich Haefele (Boehringer) and also other speakers revealed weaknesses, a lack of clarity and therefore uncertainty: Urgent need is seen e.g. for clarification of the terms around "decontamination" "bio-decontamination", "sanitization", "disinfection", "SIP" - where it is left open in the document whether it is "Steam-in-Place" or "Sterilization-in-Place"; both long versions are used - or could it as well be "Sanitization-in-Place", which is widely used in industry, but not mentioned in the document? And although the glossary has 18 additional definitions, it appears to be widely adopted from the US-FDA "Aseptic Guide". Thus, it does not fully match the terminology used in the draft Annex 1.
Jean-Dennis Mallet (NNE and an ECA Advisory Board Member) made the effort and profoundly compared the USFDA's "Aseptic Guide" (2004) with the draft updated Annex 1. Although the documents have the vast majority of requirements in common which is of course no surprise - there are some differences. The requirements and approaches matured in the course of the years: The EU-document (2017), having the QRM concept as a basis, encompassing a higher level of individual responsibility, allows and requires to profoundly reflect the specific processes and define customized contamination control measures. The use of Single-Use-Systems (SUS) has of course increased in the previous decades and has thus become a more important subject in the more recent EU-regulatory document.
In the past years, isolators and RABS-systems have become the state-of-the- art technology for aseptic manufacturing which is reflected in the updated Annex 1. Dr Daniel Müller, GMP-Inspectorate, RP Tübingen, Germany, elucidated the much more distinct requirements regarding these technologies.
Recommendation
Berlin, Germany5-7 November 2024
Contamination Control Strategies
Container Closure Integrity Testing (CCIT), another subject of increasing interest and enhanced requirements, was presented by Matthias Schaar (Novartis), who gave an in-depth comparison of the current and updated version of Annex 1. Among many others, a major conclusion was that visual inspection is not considered sufficient for proving CCIT - and, of course, QRM plays an important role, e.g. when defining inspection rates.
An update of a guideline which has substantial relevance and high importance has a fundamental impact on a company's operations and its Pharmaceutical Quality System. Dr Tilman Rock (Roche ) gave an insight into the steps for reliable and thorough implementation of the modified requirements, starting with a comprehensive gap-assessment to provide the basis for necessary actions.
During both days, participants asked numerous questions, challenging speakers to provide interpretation of the drafted guideline and initiating high-level technical discussions, during which it became clear that, although the draft version provides many more details than the current version, there is still a lot of room for interpretation.
Thus, participants - both, speakers as well the audience - shared the hope and expectation that the final version will provide a more unequivocal terminology, with an adapted glossary which will help to avoid uncertainties and potential misinterpretation on the regulators' as well as on the industry's side.
Notwithstanding the request for further clarification, it can be concluded that the pharmaceutical industry will have to assume even more responsibility as the update of Annex 1 will strengthen the importance of Quality Risk Management.
Author:
Dr Ingrid Walther
... is running her own business as GMP Compliance Consultant since 2009.
