This article looks at section 4, Premises where we find reference to clean rooms, Isolators and RABS. We see qualification of clean rooms and clean air equipment requirements and requirements for disinfection.
The materials used in cleanrooms and clean air equipment construction and use should minimize particle generation and permit disinfection. Strong emphasis is on using barrier technology (Isolators and RABS) particularly for aseptic processing. Although not mandated their extensive reference in Annex 1 suggests that they are very much the preferred option.
The early clauses introduce general requirements enhanced from the original requirements. Consideration is given to the flow of people and materials through the process. For example, Annex 1 now requires a unidirectional flow of materials through A/B areas, a sensible approach although procedural alternatives are still permitted. Practicalities of this include sterilizing items in or allowing entry via a validated aseptic transfer if sterilization is not possible. A linear or time-based approach should also be used for product and waste exit. An approved list of items permitted into the cleanroom is now specified. Interlocks are needed for A/B area airlocks with a visual or audible warning for C/D airlocks. Transfer hatches to have filtered air. Facilities should be designed to permit observation from outside A/B areas to reduce entry of personnel.
The 2008 Annex 1 hardly mentioned barrier technology but now there is much more detail. Isolators and RABS are given specific definitions. The glossary defines an isolator as an enclosure capable of reproducible interior bio-decontamination and an internal Grade A work zone that provides uncompromised, continuous isolation from the external environment i.e., a closed systems to remove human interventions. To account for technological advances two types of isolators are now considered. Firstly, closed isolator systems which exclude external contamination of the isolator’s interior and remain closed throughout operations albeit using aseptic transfer equipment allowing operation in Grade D. The second type are “Open” isolator systems designed for continuous entry and exit of materials during operations. Although operated by continuous overpressure, these are riskier so need a minimum of grade C. Isolator validation should include internal and external air quality, sanitisation, and transfer processes. Glove systems should have appropriate chemical and mechanical resistance with regular glove integrity testing being performed. Sanitisation should be an automated, controlled, and validated process to render surfaces free of viable organisms.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this, he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
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RABS were mentioned once in the 2008 Annex 1, now there is extensive coverage. They are typically enclosures that are not intended to be fully sealed. A positive flow from critical zone is needed. They offer certain operational advantages over isolators but as RABS not considered sealed, they need grade B background. Integrity testing validation is similar to isolators. There should be a validated sporicidal disinfection to ensure a suitable environment for aseptic processing. Gloves should be sterilized before fitting or subject to validated decontamination process. They should also be examined with each use.
Reference is now made to Annex 15 regarding the qualification of clean rooms and clean air equipment. These for example include filter system leakage and integrity testing, air pressure difference tests and air pattern visualisation. Classification is still to ISO 14644 but the link between ISO classes and GMP grades has gone. The particle and microbiological limits have been separated for Qualification (this section) and routine monitoring purposes (section 9). In both sections the 5.0mm particle size are no longer specified for Grade A or at rest for Grade B. The remaining 5.0mm particle limits have been increased to better reflect the calculations from ISO 14644. Microbiological limits for Grade A are now set at “no growth” in both sections.
The final part of section 4 is on disinfection. Additional requirements include prior cleaning to remove surface contamination, effective removal of disinfectant residues and the periodic use of a sporicidal agent. The disinfection process should be validated typically to account for usage, different surfaces, and in-use expiry support. Effectiveness of fumigation or vapors disinfection dispersion system should be included. Approved supplier C of A’s acceptable if “ready-made”.
About the author
Andy Martin
Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.
Training courses on Annex 1
There are a number of half-day workshops organised to take you through the changes in more detail and to look at how they relate to your organisation.