CONTROVERSIAL DISCUSSION: REQUIREMENTS OF ANNEX 1 CRIMPING / CAPPING
Although the revised version of Annex 1 of the EU GMP Guide was issued in 2008 the parameters for crimping / capping of vials are still being discussed extensively as the requirement definitions in Annex 1 are partly imprecise. Therefore, companies affected by the regulation need to individually interpret the Annex. Now, a document entitled PI 032 "GMP Annex 1 Revision 2008, Interpretation of most important changes for the manufacture of sterile medicinal products" by PIC/S, a pool of inspectors from different countries, may help companies to interpret the parameters of Annex 1.
The subject was also discussed comprehensively during the Pharma Congress 2010 in Duesseldorf, Germany, in early March. The central questions basically are "When can vials provided with stoppers be seen as closed and how does the specification "Class A air supply" have to be interpreted?"
A case study demonstrated the chosen approach for the interpretation and implementation of the Annex 1-Specifications:
(Section 120: Vial capping can be undertaken … as a clean process outside the aseptic core. Where this later approach is adopted, …, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped). The way the company interpreted "Class A air supply" showed that in its understanding it does definitely not mean the complete specifications relative to clean room class A of the EU GMP Guide, e.g. Class B as background for Class A or the microbiological specifications. Instead, "Class A air supply" was interpreted in a way that at the point of air release the air quality has to comply with the particular specifications of Class A.
(Section 121: Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials to minimise microbial contamination). To fulfil this requirement a camera system was installed to detect misplaced stoppers before the capping. Due to the room conditions and the process stability the vials are not automatically separated before capping. In the case a misplaced stopper is detected the machine is stopped completely and the operator intervenes at the vial using tweezers. The collected microbiological monitoring data up to this day do not show anything abnormal in this procedure. In addition sedimentation boards are routinely laid out and evaluated.
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(Section 122: Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation). These specifications were interpreted in a way that a RABS (restricted access barrier system with gloves) is not mandatory. The facility is cabinetised and access is hence restricted - it cannot be accessed by using gloves, though. Access by employees is rather organisationally and technically limited to a minimum and is controlled microbiologically by the sedimentation boards.
Altogether this approach is a very practical. It is still being compared with the interpretations of the PIC/S documents.
Author:
Dr Andreas Mangel
CONCEPT HEIDELBERG
