Statement on the new Annex 1 of the GMP Guide

Requirements in the new Annex 1 of the GMP Guide [1] regarding the use of mini-containments have raised the question of whether safety cabinets can still be used for the aseptic, patient-specific preparation of medicines.

The concerns are primarily based on the following statements:

“Restricted Access Barrier Systems (RABS) or isolators are beneficial in ensuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone.”

“Where possible, the use of equipment such as RABS, isolators, or other systems should be considered in order to reduce the need for critical interventions into grade A and to minimize the risk of contamination.”

Alternative barrier systems are not explicitly named in Annex 1. Does this mean that pharmacies and manufacturing facilities will have to switch to RABS or isolators in the future to continue meeting the requirements for the preparation of ready-to-use parenterals?

Decision Criteria

Product protection: If the preparation takes place within the framework of the so-called usual pharmacy operations, the product protection requirements from § 35 of the ApBetrO [2] must be implemented. The method of achieving the required cleanroom class A is not specified. The PIC/S Guide PE 010-4 [3] recommends the use of laminar flow cabinets (or biological safety cabinets) or pharmaceutical isolators for this purpose. According to the Federal Chamber of Pharmacists (BAK), the necessary containment should also be implemented in this form [4]. The German Hospital Pharmacists Association (ADKA) also names safety cabinets and isolators as suitable laminar airflow systems but also lists RABS in the relevant guideline [5]. When manufacturing medicines in facilities with a manufacturing license according to § 13 AMG [6], the GMP guide requirements must be comprehensively observed. However, this does not mean that the use of RABS or isolators is the only feasible option. Alternative solutions are also possible if they are adequately justified and subjected to a risk assessment. Annex 1 states: “Any alternative approaches to the use of RABS or isolators should be justified.”

Occupational safety: If parenterals with toxic properties (e.g., those with CMR potential) are to be prepared, measures to protect the manufacturing personnel as well as measures to maintain product integrity are required. The new Annex 1 allows deviations from air supply and room pressure for cleanrooms if the exhaust of hazardous materials from containment must be prevented. In this case and after applying specific risk control measures, it is permitted to use an underpressure-operated isolator. Clear requirements regarding the use of technical equipment are derived from occupational safety law: According to TRGS 525 [7], “every preparation [of CMR medicines] must be carried out in a suitable safety cabinet according to DIN 12980.” Equipment providing equivalent safety can also be used. Exhaust air return to the surrounding room is generally not permitted. These requirements are also reflected in the aforementioned pharmaceutical guidelines. RABS and isolators with openings to the environment and/or operated under positive pressure do not constitute suitable occupational safety devices.

Practicality and Ergonomics

Another important aspect in choosing the right containment is its practical suitability concerning the activities to be performed. Due to the variability of the parenterals to be manufactured, a large part of their preparation still involves manual work. A containment designed for this purpose should therefore be configured to protect product and personnel from contamination while supporting ergonomic and work-practice-oriented execution of the steps. RABS and isolators—especially those designed according to industrial procedures—are therefore only suitable with restrictions for manual production. Safety cabinets and isolators for cytostatics according to DIN 12980 [8], on the other hand, are specifically designed for this purpose. The extensive access to the preparation area of a safety cabinet requires a correspondingly adapted and validated working method to reliably prevent contamination spread (especially during material transfer).

Our Assessment

The preparation of patient-specific parenterals represents a special form of pharmaceutical manufacturing due to its high demand for manual steps. This must be considered when selecting a suitable containment. Even if safety cabinets are not explicitly listed as barrier systems in the new GMP Annex 1, they are recognized in current regulations as an accepted means to meet the specific requirements for sterile preparation of individual medicines. This is particularly true when requirements for both product protection and occupational safety (e.g., preparation of CMR parenterals) must be met. Safety cabinets offer a balanced compromise between protection and ergonomics under these manufacturing conditions, allowing—more than other containments—the manual activities to be adequately considered (see table). The specification of all performance requirements in a dedicated testing standard and the obligation for manufacturers to test their devices, offered as “safety cabinets according to DIN 12980,” according to standards, provides users with the assurance of deploying a reliable containment solution in all respects. As required by Annex 1, this can be justified based on manufacturing conditions and the demonstrably necessary level of protection. Safety cabinets according to DIN 12980 are superior to RABS and open isolators for the preparation of patient-specific medicines and thus represent a safe, proven, and often more practical alternative to closed isolators (according to DIN 12980). To maintain the protective functions, particular attention must be paid—especially when using safety cabinets—to a demonstrably suitable working method by personnel.

References

[1] European Commission: The Rules Governing Medicinal Products in the European Union. Volume 4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Annex 1. Manufacture of Sterile Medicinal Products. Status: 22.08.2022. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en.
[2] Federal Ministry of Justice and Consumer Protection: Ordinance on the Operation of Pharmacies (Pharmacy Operating Ordinance - ApBetrO). Status: 12.12.2023. https://www.gesetze-im-internet.de/apobetro_1987/.
[3] Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme: PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments. PE 010-4. Status: 01.03.2014. https://picscheme.org/en/publications.
[4] Federal Chamber of Pharmacists (BAK): Commentary on the Guideline of the Federal Chamber of Pharmacists on
Quality Assurance. Aseptic Manufacturing and Testing of Ready-to-Use Parenterals. Status: 14.05.2024. https://www.abda.de/fuer-apotheker/qualitaetssicherung/leitlinien/
guidelines-and-work aids/manufacturing/.
[5] German Hospital Pharmacists Association (ADKA): ADKA Guideline for Aseptic Preparation and Testing of Ready-to-Use Parenterals in Hospital Pharmacies. Status: 03/2025. https://www.adka.de/wissenschaft/standards-leitlinien.
[6] Federal Ministry of Justice and Consumer Protection: Law on the Traffic of Medicines (Medicines Act - AMG). Status: 23.10.2024. https://www.gesetze-im-internet.de/amg_1976/.
[7] Federal Institute for Occupational Safety and Health (BAuA): TRGS 525. Hazardous Substances in Medical Facilities. Status: 09/2024. https://www.baua.de/DE/Angebote/Regelwerk/TRGS/TRGS-525.
[8] DIN Media: DIN 12980:2017-05. Laboratory Equipment - Safety Cabinets and Isolators for Cytostatics and Other CMR Medicines. Status: 05/2017. https://www.dinmedia.de/de/norm/din-12980/272714933.