Last August 2022, the EMA published the new version of Annex 1 of the EU GMP on the manufacture of sterile medicinal products. This version will be mandatory as of August 2023 (except for clause 8.123, which will be implemented one year later). This forces laboratories to update quickly in order to remain compliant after summer.
The new version of Annex 1, compared to its previous version in 2008, is much longer, with almost four times as many pages. This increased length is, in large part, taken up to develop two of the main focuses of this version:
- Contamination Control Strategy (CCS)
- Quality Risk Management (QRM)
CCS and QRM have been the changes that have received the most attention in the document, as they represent an important leap for the management of risks that impact product quality. But in this article we want to focus on some less explored aspects of the new regulation: the implications it will have on the design of pharmaceutical equipment and facilities. Both new and existing.
The key: identifying risks
The new standard, unlike its previous version, goes into detail on the different technologies for manufacturing and monitoring sterile products. As mentioned above, it also puts the focus on risk management and contamination control.
“There should be no panic among manufacturers that their existing plants may not comply with the new regulations, nor should projects planned under the umbrella of the previous regulations be scrapped.”
The key is to:
- identify the parts of the process that are critical, i.e. that have a substantial effecton product quality based on scientific knowledge and knowledge of the process itself, and
- influence these parts with measures to reduce the risk. These measures can be design modifications, additional control measures, and/or changes in manufacturing procedures.
Proper risk identification is essential both for redesigning existing facilities and equipment, and for the design of new facilities that aim to minimise the risk to the product from the outset. The standard is intended to ensure that these decisions are made in a rational manner based on risk and science.
Technology as a tool to prevent contamination
The new Annex 1 touches upon several technologies that can help reduce the risk of product contamination, and which should be considered during the design/redesign of facilities and equipment. The most relevant considerations of these technologies are detailed below:
- Restricted access barriers and isolators: the new regulation stresses the importance of minimising direct operator interventions (without gloves or barriers) on the critical process. For this reason, the use of restricted access barriers (RABS) or isolators with unidirectional air flow is recommended. These technologies are now almost indispensable in aseptic manufacturing plants.
Regulations also state that interventions that affect critical process segregation or airflow must be validated and recorded when they occur, so this is an aspect that manufacturers of such equipment must consider in their alarm logging systems and manual actions.
- Ventilation system: room ventilation is a fundamental tool to prevent product contamination. Three points in the new Annex 1 introduce important changes compared to the previous version:
- The importance of ensuring that air flows do not pass through “dirty” areas or equipment or personnel who can then transfer contamination to critical areas is emphasised. It may be beneficial to consider this point from the design phase, through airflow simulation studies, and thus avoid mishaps in visualisation tests during qualification.
- The pressure difference between rooms remains a basic tool for contamination control. In addition, it is stated that pressures that are critical for the process must be defined and the time delay of the alarms (between the moment when the pressure difference is lower than required and the moment when the alarm is triggered) must be justified.
- The focus is on the bio-decontamination of equipment and rooms. This bio-decontamination is normally carried out with hydrogen peroxide, and allows for an automated, validatable and repeatable decontamination process. Air movement patterns greatly influence the distribution of decontamination agents, as well as the use of doors and mouse holes to prevent the spread of these agents to unwanted areas. The selection of room and equipment materials should consider the use of bio-decontaminants, to choose suitable and resistant materials.
- Single-use systems: the requirements for single-use systems are regulated as a tool to avoid contamination. These pre-cleaned and pre-sterilised systems avoid the risks associated with cross-contamination, incorrect cleaning or sterilisation of reusable equipment. However, these systems imply an additional degree of control over these items, as well as a greater number of manual actions by the operators. In addition, the compatibility of the polymers that make up these materials with the manufactured products must be considered and their integrity must be ensured throughout the process.
- Closed systems: Closed systems are a good approach to reduce the risk of environmental contamination. These systems avoid contact of the product with the environment, reducing the use of very restrictive sorting rooms (with high operational costs). These systems must be able to clean and sterilise all components in contact with the critical product, in a controllable and repeatable manner, and must be able to demonstrate that they remain intact by pressure testing.
- Filtration: Filtration is, for many products, the only way to achieve an aseptic product without compromising product quality. In the new Annex 1, it is defined that the integrity of sterilising filters must be verified before and after use by in-place integrity testing. Similarly, the integrity of gas filters in contact with the product and vent filters must also be verified.
- Monitoring: the new Annex 1 defines a large amount of data to be included as part of the batch record: environmental monitoring, filter integrity testing, sterilisation data, closed system integrity testing, process data (filtration, filling, sealing, etc.), interventions and shutdowns in the aseptic zone, alarms during the different processes, etc.
Additionally, monitoring should detect negative trends (even if the defined alert limits are not exceeded). Gathering and analysing all this data can be time-consuming for operators, so centralising data can save operators a great deal of time, even if it requires a greater initial validation effort.
As seen from the above examples, the new version of Annex 1 aims to streamline decision-making to protect product quality. And while there are notable changes, there should be no panic in plants where sterile medicines are produced.
At Klinea, we have made sure that we are aware and updated with all the changes to continue to offer the best services to our customers. If you are interested in finding out more about the changes to Annex 1 and how we can help you, please contact us: klinea@klinea.eu
