Introduction
This guidance addresses changes within the edition (Feb 2008) of European Commission Union EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use -Annex 1: Manufacture of Sterile Medicinal Products (EU GMP Annex 1) effective on March 1, 2009 with a notable exception for the capping of freeze-dried vials effective on March 1, 2010 for those sites that market and/or manufacture for locations subject to EU GMP Annex 1.
This guidance applies to capping operations performed as an aseptic process using sterilized caps or as a “clean process” that is performed outside the aseptic core using clean non-sterilized caps. It is important to note that there may be other additional regional/local area requirements or expectations for capping operations that supersedes the information specified within EU GMP Annex 1 that must be considered (e.g. Irish Medicines Board (IMB) or the Medicines and Healthcare Products Regulatory Agency (MHRA).
Summary & Recommendations: “Clean Process” Capping Operations
This guidance may be considered for GMP sites where aseptic processing operations as part of sterile medicinal product manufacture occur. The EU GMP Annex 1 includes the following statements:
“The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore be performed as soon as possible after stopper insertion”. (Paragraph 118)
“Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.” (Paragraph 120).
These texts are additions to the previous version of the document that was published in May 2003. There are no requirements that the adjacent background area to the “clean process” area have any defined classification as long as the conditions of this area do not negatively impact the capping operation. What constitutes an acceptable operational environment or “clean process” for capping operations outside of an aseptic processing environment?
To address this question in the context of EU GMP Annex 1, the following general principle examples may be considered:
The following are possible design/process elements that may define a “clean process” for a capping process outside of an aseptic area:
- Barriers (e.g.flexible, rigid, doors, glove ports, etc.)
- Grade A air supply over the upstream area where vials are not yet fully crimped (i.e. not downstream)
- Interventions)
- Documentation (e.g.SOPs)
- Change control
- HEPA filter maintenance/testing
- Cleaning and sanitization
Verification of the “clean process” may include:
- Monitoring for non-viable particulates, which is performed only “at rest” due to inherent particulate generation from the capper operation.
- Minimum sampling location(s) may be defined according to a risk assessment.
- Minimum monitoring frequency should not be less than semi-annually (e.g. routine HEPA integrity testing frequency)
- The use of other physical parameter data including continuous HVAC plenum box fan alarms and differential pressure testing across HEPA filter elements should be in place for added assurance that this critical system remains operational.
A Documented rationale to define the frequency of testing to demonstrate continued acceptability of the Grade A air supply may include:
- Assessing product risk.
- Historical integrity data of the HEPA air handler.
- The amount/degree of supportive protective systems.
- Routine HEPA integrity testing (e.g. performed semi-annually5).
The principles that define the intent of a “Grade A air supply” may include:
- The air handler over the part of the capping operation where vials exit the aseptic area to the point of capping meet ISO 5 requirements for non-viable particulates.
- The immediate capping environment where the uncapped stoppered vials are located is supplied with unidirectional air that meets ISO 5 specifications immediately downstream of the HEPA filter face.
- Assessment of acceptable operation may be performed by routinely monitoring the physical parameters of the air handling system to supply Grade A quality air as outlined within EU GMP Annex 1.
In summary, the routine monitoring program may be designed to monitor both the physical parameters of the air handler and empirical data (i.e. non-viable particulates) in order to provide information on the air source to the capping operation since this ensures that the monitoring is focused on verification of air quality being supplied to the capping process versus the process itself.