Basic clean room requirements

What is a clean room?

Clean rooms, 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 cleanroom / 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 cleanroom basics.

Which way should my 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”:

1. The internal surfaces of the clean room and the equipment within them;
2. The control and quality of air through the clean room;
3. The way the clean room is operated (i.e. the number of staff).

Each of the three items above are equally important. Let’s look at them in more detail.

The internal surface

For GMP compliance and to achieve the cleanliness specification, all surfaces in a cleanroom should be “smooth and impervious”, and:

• not generate their own contamination i.e., don’t create dust, or peel, flake, corrode or provide a place for microorganisms to proliferate
• are easy to clean i.e., all surfaces are easily accessible, there should not be any ledges or recesses
• are rigid and robust and won’t crease, crack, shatter or dent easily.

There are a wide variety of suitable material choices, ranging from the more expensive Dagard paneling, as shown in the photo below, with sliding doors (not recommended as mentioned earlier), or the best and most aesthetically pleasing option is glass, i.e., as at the end of the corridor. Among the cheapest options, can be plaster-board with a two pot epoxy coating,  and there are a range of other options available.

Airflow

Cleanrooms need a lot of air and usually at a controlled temperature and humidity. This means that in most facilities the cleanrooms Air Handling Units (AHU) consume over 60% of all the site power. As a general rule of thumb, the cleaner the cleanroom needs to be, the more air it will need to use. To reduce the expense of modifying the ambient temperature or humidity, AHU or systems are designed to recirculate (if product characteristics permit) about 80% air through the room, removing particulate contamination as is it generated and whilst keeping the temperature and humidity stable.

Particles (contamination) in the air tend to either float around. Most airborne particles will slowly settle, with the settling rate dependent on their size.

A well-designed air handling system should deliver both “fresh” and “recirculated” filtered clean air into the cleanroom in such a way and at a rate so that it flushes the particles from the room. Depending on the nature of the operations, the air taken out of the room is usually recirculated through the air handling system where filters remove the particulates. High levels of moisture, noxious vapours or gases from processes, raw materials or products cannot be recirculated back into the room, so the air in these cleanrooms is often exhausted to atmosphere and then 100% fresh air is introduced into the facility.

Rooms occasionally experience high levels of airborne particulates during routine operation, such as in a sampling room or dispensary. In these cases, the room needs to be cleaned quickly between operations to prevent cross-contamination.

The volume of air introduced into a cleanroom is tightly controlled and so is the volume of air that is removed. Most cleanrooms are operated at a higher pressure to the atmosphere, which is achieved by hiving a higher supply volume of air into the cleanroom than the supply of air being removed from the room. The higher pressure then causes air to leak out under the door or through the tiny cracks or gaps that are inevitably in any cleanroom.

As a rule of thumb, within a facility the room you need to be the cleanest operates at the highest or the lowest pressure.

A good air handling system makes sure that air is kept moving throughout the cleanroom. The key to good cleanroom design is the appropriate location of where the air is brought in (supply) and taken out (exhaust).

Supply air and exhaust (return) air

The location of the supply and exhaust (return) air grilles should take the highest priority when laying out the cleanroom. The supply (from the ceiling) and return air grilles (at a low level) should be at the opposite sides of the cleanroom, to facilitate a “plug” flow effect. If the operator needs to be protected from a high potency product, for example, the flow should be away from the operator.

For sterile or aseptic process that need Grade A air, the airflow typically mimics a plug flow from top to bottom and is unidirectional or “laminar”. Careful consideration should be made to ensure that the “first air” is never contaminated before it comes into contact with the product.

Operating a clean room

The most effective way of maintaining the air quality in a cleanroom is to operate and maintain it correctly.

This involves:

• minimising the amount of potential contamination that escapes from your manufacturing operations
• strictly controlling access to the cleanroom to only trained personnel and limiting the number, as even trained operators are the most significant source of cleanroom contamination
• regularly cleaning your facility to strictly controlled procedures
• regular maintenance of the facility and equipment
• regular monitoring of the air filters and air flows and frequent recertification of the cleanroom.

Some cleanroom jargon

Some basic cleanroom jargon, acronyms and technical aspects for next conversation with your pharmaceutical engineering colleagues are provided below.

Air Change Rate

This refers to the number of times the air is changed within a cleanroom. It is simply calculated by taking the total volume of air introduced into the cleanroom over an hour and dividing it by the volume of the room. It is expressed as air changes per hour (ACH) and for cleanrooms, this is normally between 20 and 40 air changes per hour.

Room type	ACH
Commercial kitchens & Toilets	15–30
Smoking rooms	10–15
Laboratories	6–12
Classrooms	3–4
Warehousing	1–2

Micron

A micron (or micrometre) is a millionth of a metre. A human hair is around 100 microns thick. Particles less than 50 microns cannot be seen by a naked eye. Bacteria measure 1 or 2 microns.

HEPA Filters

HEPA stands for High-efficiency particulate air. HEPA filters are one of the most important elements of a cleanroom. They consist of a large, box shaped filter that removes airborne particles of specific sizes very efficiently. They must also be monitored and tested regularly to make sure they are still integral.

HEPA filters are composed of a mat of randomly arranged fibres, which are typically composed of fiberglass with diameters between 0.5 and 2.0 microns. Key factors affecting function are fibre diameter, filter thickness, and filter face velocity.

Dispersed oil particle (DOP) Testing / Integrity Testing

DOP testing or integrity testing is a testing procedure to ensure that a HEPA filter meets its efficiency specification and is properly seated and sealed in its frame.

Airlock

An airlock is a room where personnel, materials or equipment are transferred into or out of a cleaner environment. It can be the size of a small “cupboard”, or a large room where personnel change into and out of cleanroom garments, or where a forklift can enter.

Clean room classification – ISO Class

This refers to the level of cleanroom particulate cleanliness based on a number of airborne particles of a certain size per cubic metre. ISO 8 is the starting cleanroom level. A sterile cleanroom for the pharmaceutical industry will need to achieve ISO 5. Classes better than ISO 5, that is ISO 4 are generally only required for the electronics industry.

Clean room classification – Annex 1 or ISO?

Grades A through to D refer to cleanroom cleanliness for sterile products only, these Grades can be related to the ISO Classes, but they are not the same.

The classification of 100, 10,000, and 100,000 normally refers to the withdrawn FED-STD-209 E Airborne Particulate Cleanliness Classes in Cleanrooms and Clean zones which was cancelled on November 29, 2001 by the U.S. General Services Administration (GSA).

This was superseded by International Standard ISO 14644, Cleanrooms and controlled environments-Part 1: Classification of air cleanliness, and Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1.

Room Recovery Rate

The time it takes from a contamination event to the room regaining its designed cleanliness level as per the GMP requirements.

Particle Count

A test that samples a fixed volume of air and captures, filters and counts airborne particles by their size. This is performed when the cleanroom is “at rest” or “in operation”. For pharmaceutical operations, both airborne viable (alive) and non-viable (not alive) particle counts are performed. This is performed as part of the certification of a cleanroom and during regular environmental monitoring.

Room Certification

A series of tests that are performed to show that a cleanroom is operating at to its required class or grade.

More cleanroom jargon

If you would like to know more, you can follow the links below.

Eudralex Vol 4: http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

FED-STD-209E: https://en.wikipedia.org/wiki/FED-STD-209E

WHO Annex 3:http://web.archive.org/web/20151106050031/http://apps.who.int:80/medicinedocs/documents/s18679en/s18679en.pdf

WHO Annex 5: http://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex5.pdf

WHO Annex 6: http://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex6.pdf