Sterile Isolator With 100% Airflow Velocity Distribution
- by Zener Engineering Services Ltd
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- 18 Nov, 2021
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GxP Supplier Management
As part of a maintenance review, a ZES consultant realised that the individual airflow velocity sample point values had not been quoted in the maintenance documentation, but an average airflow velocity had been calculated and documented.
Realising that GMP raw data had potentially been lost, the ZES consultant reviewed the qualification performed two years earlier. For the benefit of the reader, below are the applicable regulatory requirements and industry-accepted guidance referenced in this case, with the most important information in bold and underlined.
Regulatory Requirements For Sterile Isolators
EudraLex: The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products.
‘Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s
(guidance value) at the working position in open clean room applications.
The maintenance of laminarity should be demonstrated and validated.
A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.’
Sterile Isolator Air Flow Guidance
Gerpac Guide: Isolators Qualification and Maintenance March 2017
This industry guidance quotes additional accepted performance criteria, of an average airflow velocity of 0.45 m/s +/- 20% (distribution from average). This can be seen quoted in the guidance below, available to download below. Here is a direct quote from the guidance:
‘In the case of a pharmaceutical Grade A filling line isolator at rest and in activity,air flow is unidirectional flow
(average air velocity 0.45 m/s ± 20 %).’
Download The Gerpac Guidance from the case study page:
Isolator Principle of Operations
A laminar airflow should be present to provide a protective air curtain with laminar air flow from the top, down, past and away from the ascetic high risk area, via a 'false bottom'.
The Sterile Isolator in this case had been qualified and accepted by the pharmaceutical company's Quality Department with a documented 100% air flow distribution from the average. A minimum airflow was recorded near the gloves fitted to the chamber of 0.1m/s and at the back of the chamber a 0.7 m/s velocity was recorded.
Upon a design review, the ‘Sterile Isolator’ in question had a single extract vent, along the base of the back of the chamber. Supplier smoke studies showed that the airflow was not laminar and with a velocity of 0.1 m/s, (near stagnant air) was recorded at the front of the chamber, in the facility of the gloves. Smoke studies performed by the Supplier, recorded with a fast-moving smoke source, did not provide a clear picture.
The following diagram shows the principles of operation and the differences between a Sterile Aseptic Isolator, and a Microbiological Safety Cabinet and the 'Sterile' Isolator in question, on the right.
Note: the Aseptic Isolator false bottom should be perforated, not shown in the basic diagram below.
In the above diagrams, size and direction of the arrows indicate size and direction of airflow.
When ZES spoke to the Supplier of the Isolator, with airflow velocity distribution concerns, the Supplier offered the following justifications:
- 'As the ‘Sterile Isolator’ chamber is cleaned and sterilised before every batch, there is no impact to the product.'
- 'The design is ‘fine’ as we [the Supplier] have sold hundreds of these and there isn’t a problem’ (although later in the conversation they admitted they have modified a small number).'
It can be seen from the airflow direction for the Supplier's 'Sterile Isolator' on the right in the diagram above, that airflow is being drawn slowly over the high risk area, depicted as the orange area in the diagram, towards the extract at the back of the chamber.
Using the Supplier's justifications for their design immediately above and applying the Supplier's logic, (with which ZES totally disagrees), could be used to justify the total removal of the downward laminar airflow as it would be no longer required.
ZES Director David Easton is quoted as saying to the Supplier ‘Selling hundreds doesn’t mean that there isn’t a problem. Hundreds of high rise tower blocks were covered in cladding, this didn’t mean there wasn’t a problem.'
Later David commented 'I strongly recommend that all Life Science organisations using Aseptic Isolators for Sterile filling review their qualification packages for suitable laminar airflow distribution of +/- 20% from average and fundamental operational design. The recording of individual sample airflows around the chamber should be documented during maintenance activities on a routine basis.'
In the opinion of ZES, the design of the Isolator in question was based on a Microbiological Safety Cabinet, which had been sealed at the front and a pair of gloves installed. The actual design of the Isolator in question can be seen as the third figure on the right above. Here only the chamber airflows are shown, as ZES did not investigate the air supply construction behind the chamber supply filter (at the top of the chamber), or behind the extract.
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