The revision of Annex 1 to the EC GMP Guide took place in 2008. The changes come into force by 1 March 2010 at the latest. Changes result in the 4 areas clean room classification, media fill, bioburden and the finishing of sterile products. In part, the changes are debatable and need to be interpreted.
The Pharmaceutical Inspection Cooperation Scheme (PIC/S), an association of inspectors from several, mainly European countries, provides such an interpretation in the form of the document "Recommendation GMP Annex 1 Revision 2008, Interpretation of the most important changes for the manufacture of sterile medicinal products", which is primarily addressed to inspectors.
The document, whose creation had been headed by the Swiss supervisory authority Swissmedic, was adopted by the PIC/S Committee at the beginning of November 2009 and came into force as version 1 on 1 December 2009 and as version 2 on 1 January 2010.
The interpretation refers primarily to 3 of the 4 modified areas. The point "Media Fill" had been harmonised with the requirements of the US Aseptic Guide and did not require any further interpretation.
The most controversial changes were made to the section "Finishing of Sterile Products" regarding the capping/crimping of vials. Some statements of Annex 1 on this topic are clarified by the PIC/S interpretation.
1. "Grade A air supply" - Definition, Qualification and Monitoring Requirements (Section 120)
"Grade A air supply" has newly been included into Annex 1, but not defined. The PIC/S defines the term as follows: HEPA-filtered air that fulfils the non-viable particulate requirements of a grade A area at the point of supply. The "grade A air supply" requirements should be qualified and monitored.
The qualification has to be carried out under "at rest" conditions. For crimping machines, the "at rest" state is defined as: The air supply is switched on; the crimping machine is running (but without the need of feeding vials for crimping); no interference by the operator. For the conveyor tunnel, "at rest" conditions are defined as: Air supply and conveyor belt are switched on; no interference by the operator.
The non-viable particulate requirements are meant to equal those defined for grade A areas. The probe should be located at the point of supply of the filtered air.
Smoke studies should be conducted. A unidirectional air stream is not considered necessary. However, an efficient protection of the vials is meant to be demonstrated, especially the absence of entrained air from the environment.
A rational limit for air velocity should be fixed.
Monitoring requirements on non-viable particles and on microbiological contamination shall be defined by the firms within the framework of a risk assessment.
2. The handling of vials with missing or displaced stoppers (Section 121)
Great emphasis is placed on the detection of missing or displaced stoppers prior to crimping. These vials should be removed from the process prior to crimping. In validated systems, a removal of rejected vials is also acceptable after crimping; however, an ejection prior to crimping is clearly to be preferred. The better the controls are for correct capping and the more reliable the proof of packaging integrity, the lower the requirements can be on the environment. If there is no such control system, the capping must be performed as an aseptic process.
3. Use of RABS or isolators (Section 122)
The use of RABS or isolators for crimping is no direct requirement. Human interventions into the process can also be ensured through other procedures.
The PIC/S interpretation of the changes to Annex 1 is an important tool for the industry in the implementation of the new requirements. It is to be hoped that all inspectors will agree to this interpretation.
We will soon inform you about the PIC/S interpretation concerning clean room classification and the bioburden monitoring of the sterilisation.
Dr Andreas Mangel
On behalf of the European Compliance Academy (ECA)