GETTY IMAGES/CHRISTINE BALDERAS
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Regulations governing the manufacture of sterile pharmaceuticals in the US and Europe have been significantly revised over
the past few years. The first milestone was set by the FDA's Guidance for Industry Sterile Drug Products Produced by Aseptic Processing" — "Aseptic Guide in 2004. In 2008, four parts of the EU GMP Guide Annex 1 Manufacture of Sterile Medicinal Products were extensively revised. Annex 1 became fully effective on 3 January 2010.
Another important document that often receives little attention is the PIC/S (Pharmaceutical Inspection Cooperation Scheme;
http://www.picscheme.org/) recommendation PI 0075 "Validation of Aseptic Processes". Primarily aimed at pharmaceutical inspectors, this document also
aids the pharmaceutical user in the interpretation and implementation of the new Annex 1 standards. In the course of the Annex
1 revision, the PIC/S document underwent several revisions and now corresponds with the current guideline.
The revised version of EU GMP Guide Annex 1 Manufacture of Sterile Medicinal Products
The revised version of Annex 1 primarily applies to four partial aspects:
- Clean room and clean air device classification
- Process simulation / media fill
- Bioburden monitoring
- Finishing of sterile products
Clean room and clean air device classification has been developed to be harmonised with the standard EN ISO 14644. For Process simulation / media fill the requirements were harmonised with the standards of the FDA Aseptic Guide. These standards were also adopted in the PIC/S document PI 007-5. The specifications for Finishing of sterile products generated a much higher need for text interpretation. The new specifications, particularly for capping vials, have also caused
uncertainty for inspectors in the pharmaceutical industry.
To eliminate this uncertainty, the PIC/S published another document in January 2010, introducing the changes in Annex 1 and
interpreting the new specifications. The document PIC/S recommendation PI 0322 GMP Annex 1 revision 2008, interpretation of most important changes for the manufacture of sterile medicinal products was prepared under the leadership of Swiss inspectors from Swissmedic.
The most controversial changes made to Annex 1 were found in the section for Finishing of sterile products and related to the capping of vials. Some statements in Annex 1 concerning this matter were clarified in the PIC/S document
and are presented here in more detail. The PIC/S interpretations are supplemented with two case studies from pharmaceutical
companies.
The author says...
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Interpretations1. "Grade A air supply" — definition, qualification and monitoring requirements (Annex 1 Section 120)
"Grade A air supply" was listed again in Annex 1 but not defined. PIC/S clearly explains the need to discern between Grade
A air supply and Grade A area and defines the terms as follows:
"Grade A air supply is specifically used to describe a supply of air which is HEPA filtered, and at the point of supply meets,
when tested, the non-viable particulate requirements of a Grade A area."
It is important to differentiate between the terms Grade A air supply and Grade A area. According to PIC/S, a Grade A air
supply should be qualified and monitored; the qualification is to be performed in an "at rest" state. For the capping machine
the "at rest" state is achieved when the air intake is switched on, the machine is operating (but without vials being fed
and needing to be capped), and there is no user operation. For the transport tunnel the "at-rest" state is reached when the
air intake and the conveyer are switched on and there is no user operation.
The requirements for nonliving particles are to meet Grade A area requirements. The sample is to be taken from beneath the
air outlet and smoke studies are to be performed. A unidirectional air flow is not required. However, an efficient protection
for the vial is to be proven, particularly an absence of ambient air entering. Rational air speed limitations should exist.
Companies must determine monitoring requirements for nonliving particles and microbiological contaminations in line with a
risk analysis.
