Basic cleanroom requirements
A clean room, in my mind are a combination of engineering design, fabrication, finish and operational controls (control strategy) that are required to convert a “normal” room to a “clean room”. In this blog I will attempt to explain the necessary characteristics of a regulated company clean room not producing potent chemicals or active or hazardous biologicals. If there are significant containment requirements, the requirements would be outside the scope of a “simplistic” blog like this. In a pharmaceutical sense, clean rooms are those rooms that meet the code of GMP requirements as defined in the sterile code of GMP, i.e. Annex 1 of both the EU and PIC/S Guides to GMP and other standards and guidance as required by local health authorities.
So why do I need a clean room?
There is no GMP requirement in the EU and PIC/S (i.e. TGA) GMP guidance’s for the manufacture of non-sterile medicinal products in a “clean room”, but we do use clean areas that are effectively ventilated with filtered air where the products or open clean containers are exposed. On the other hand, for the manufacture of sterile medicinal products, clean rooms are mandatory, as defined in Annex 1 of the EU and PIC/S GMPs. This Annex defines a number of additional requirements besides the airborne particulate concentration limits used to classify clean rooms.
In a nutshell, if you manufacture a non-sterile medicinal product, you should be very careful about classifying or grading your clean areas, for example, classifying a room as “Grade D”. Whilst not a code requirement, many regulators, like the Australian TGA will expect you to fully comply with all of the requirements for a Grade D room as defined in Annex 1, even if it’s not a GMP code requirement. If you have classified the room as Grade D, you will need to live with the consequences and costs of maintaining this level of clean room cleanliness during operation.
What type of clean room do I need?
If you are a manufacturer of non-sterile medicinal products, you should define your own clean room / area standards using national and international standards. Usually manufacturers will define an airborne particulate concentration standard class such as ISO 14644-1 ISO 8 (at rest), outline gowning and a pressure cascade regime, defining a “clean corridor” design or a “dirty corridor” design.
If you are a manufacturer of sterile medicinal products, you must follow the EU or PIC/S GMPs, namely Annex 1.
“Clean corridor” or a “Dirty corridor”?
When considering pressures cascades, the pharmaceutical engineers should consider a design philosophy to have a “clean corridor” or a “dirty corridor” design, which we will now explain through an example. Typically, low moisture medicinal products such as tablets or capsules are dry and dusty, therefore more likely to be a significant cross-contamination risk. If the “clean” area pressure differential was positive to the corridor, the powder would escape out of the room and enter the corridor, and is likely then to be transferred into the next door cleanroom. Thankfully, most dry formulations do not readily support microbial growth, so as a general rule, tablets and powders are made in “clean corridor” facilities, as opportunistic microorganisms floating in the corridor don’t find environments in which to thrive. This means that the rooms are negatively pressurised to the corridor.
For aseptic (processed), sterile, or low bio-burden and liquid medicinal products, the opportunistic microorganisms usually will find supportive media in which to flourish, or in the case of an aseptically processed product, a single microorganism could be catastrophic. So these facilities are normally designed with “dirty corridors” as you want to keep potential microorganisms out of the cleanroom. Unlike powders, droplets of liquid don’t generally “leap up” and float around the facility.
Designs can become complicated if the products or raw materials are highly potent, which cause occupational health and safety issues, or if there is a need for biological containment. These are outside the scope of clean room basics, reading this blog on dedicated facilities could assist. If you want to know more, our clean room designers can help.
Which way should my clean room doors swing?
Unless you have power-assisted doors, all doors should open into the room with the higher pressure. Double-leafed doors are notorious for causing the pressure differential balancing of rooms to drift off as the door springs gradually weaken and the doors leak air between rooms at levels outside of the design parameters.
Annex 1, Clause 47 specifically states that sliding doors are not permitted in sterile plants as they typically create uncleanable recesses, projecting ledges and recesses. For these reasons they should not be used in non-sterile facilities either.
What are the sources of contamination in a clean room?
It should be noted that cleanrooms do not eliminate contamination altogether, they control it to an acceptable level.
Our real concern is actually microbial contamination in most cases. Traditionally the technology did not exist to directly measure microbial contamination in real-time, so the “all airborne particulates” limits were used and extrapolated /assumed to be representative of possible airborne microbial contamination risk.
So the GMP’s set out defining and controlling sources of particulates in an attempt to control possible “microbial contamination”.
Personnel present in a cleanroom are normally the highest source of the airborne particulates and/or microbial contamination risk, so proper gowning and limiting the number of staff into a room must be carefully controlled to be within the cleanroom design.
So what makes a clean room a “clean room”?
Cleanrooms and clean areas are defined in the GMP’s as having the following characteristics.
There are three things that keep a cleanroom “clean”:
- The internal surfaces of the clean room and the equipment within them;
- The control and quality of air through the clean room;
- The way the clean room is operated (i.e. the number of staff).