Basic Clean Room Requirements | Designs for GMP Clean Rooms

What is a make clean room?

A cleanroom (GMP cleanroom), in my mind, is a combination of engineering design, fabrication, finish and operational controls (control strategy) that are required to convert a "normal" room to a "clean room". This blog will attempt to explain the necessary characteristics of a regulated company make clean room not producing potent chemicals or active or hazardous biologicals. If there are significant containment requirements, the requirements would be exterior the scope of a "simplistic" web log similar this. In a pharmaceutical sense, clean rooms are those rooms that run into the code of GMP requirements as defined in the sterile lawmaking of GMP, i.e. Annex one of both the EU and Moving picture/S Guides to GMP and other standards and guidance equally required by local health authorities.

So why do I need a clean room?

In that location is no GMP requirement in the European union and Picture/S (i.e. TGA) GMP guidance's for the manufacture of not-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, clean rooms are mandatory for the manufacture of sterile medicinal products, every bit defined in Addendum one of the EU and PIC/S GMPs. This Addendum defines many additional requirements besides the airborne particulate concentration limits used to classify make clean rooms.

In a nutshell, if you lot industry a non-sterile medicinal product, you lot should exist very careful most classifying or grading your clean areas, for example, classifying a room as "Grade D". Whilst non a code requirement, many regulators, similar the Australian TGA will expect you to fully comply with all of the requirements for a Class D room as defined in Annex i, even if it'southward non a GMP code requirement. Therefore, if you accept classified the room every bit Course D, yous will need to live with the consequences and costs of maintaining this level of cleanroom cleanliness during operation.

What blazon of clean room do I need?

If y'all are a manufacturer of not-sterile medicinal products, you should define your own cleanroom/area standards using national and international standards. Usually manufacturers volition ascertain an airborne particulate concentration standard course such as ISO 14644-1 ISO viii (at rest), outline gowning and a force per unit area pour authorities, defining a "clean corridor" design or a "dirty corridor" design.

If you are a manufacturer of sterile medicinal products, you must follow the European union or PIC/S GMPs, namely Annex ane.

"Clean corridor" or a "Dirty corridor"?

When considering pressures cascades, pharmaceutical engineers should consider a design philosophy to take a "clean corridor" or a Clean Room Pressure cascades "dirty corridor" design, which nosotros will at present explain through an instance. Typically, low moisture medicinal products such as tablets or capsules are dry and dusty, therefore more likely to exist a significant cantankerous-contagion risk. If the "clean" surface area pressure differential were positive to the corridor, the pulverization would escape out of the room and enter the corridor and will probable be transferred into the next-door cleanroom. Thankfully, almost dry formulations practice not readily support microbial growth. Therefore, every bit a full general rule, tablets and powders are made in "clean corridor" facilities, every bit opportunistic microorganisms floating in the corridor don't find environments to thrive. Unfortunately, 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 volition 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 typically designed with "dingy corridors" as you want to keep potential organisms out of the cleanroom. As well, unlike powders, droplets of liquid don't mostly "jump up" and float around the facility.

Designs can become complicated if the products or raw materials are highly strong, which cause occupational health and safety issues or a need for biological containment. These are exterior the scope of cleanroom basics, reading this blog on dedicated facilities could assist. If you want to know more, our clean room designers can assistance.

Which mode should my cleanroom doors swing?

Unless you take power-assisted doors, all doors should open up into the room with 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 betwixt rooms at levels outside the design parameters.

Annex 1, Clause 47 specifically states that sliding doors are not permitted in sterile plants every bit they typically create uncleanable recesses, projecting ledges and recesses. For these reasons, they should non be used in non-sterile facilities either.

What are the sources of contamination in a cleanroom?

It should be noted that cleanrooms do not eliminate contagion; they control it to an acceptable level.

Our 18-carat business is microbial contagion in most cases. Traditionally the technology did not exist to measure microbial contagion in real-time straight, so the "all airborne particulates" limits were used and extrapo

lated /assumed to represent possible airborne microbial contamination risk.

So the GMP'south set out defining and controlling sources of particulates to forestall possible "microbial contamination".

Personnel present in a cleanroom normally are the highest source of airborne particulates, and microbial contagion risk, and so proper gowning and limiting the number of staff into a room must exist advisedly controlled to be within the cleanroom design.

And so what makes a make clean room a "clean room"?

Cleanrooms and clean areas are defined in the GMP's every bit having the post-obit characteristics.

At that place are three things that continue a cleanroom "clean":

  1. Pharmaceutical clean roomThe internal surfaces of the clean room and the equipment within them;
  2. The control and quality of air through the clean room;
  3. The style the make clean room is operated (i.eastward. the number of staff).

Each of the three items in a higher place is equally important. Let's look at them in more particular:

1. The internal surface

For GMP compliance and to achieve the cleanliness specification, all surfaces in a cleanroom should be "smoothen and impervious", and:

  • not generate their contamination, i.east., don't create dust, or peel, flake, corrode or provide a place for microorganisms to proliferate
  • are piece of cake 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, fissure, shatter or dent easily.

There are a wide multifariousness of suitable material choices, ranging from the more expensive Dagard panelling, equally shown in the photo beneath, with sliding doors (not recommended as mentioned earlier), or the all-time and most aesthetically pleasing option is glass, i.due east., equally at the end of the corridor. Among the cheapest options tin be plaster-board with a two-pot epoxy coating,  and there is a range of other options available.

ii. Make clean room airflow

Clean rooms need a lot of air and ordinarily at a controlled temperature and humidity. This means that the cleanrooms Air Handling Units (AHU) typically consumes over lx% of all the site ability in most facilities. As a full general rule of thumb, the cleaner the cleanroom needs, the more than air information technology will demand to use. To reduce the expense of modifying the ambient temperature or humidity, AHU or systems are designed to recirculate (if production characteristics permit) about 80% air through the room, removing particulate contamination as is information technology generated and keeping the temperature-humidity stable.

Particles (contamination) in the air tend to either float around. About airborne particles volition 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 and so that it flushes the particles from the room. Depending on the nature of the operations, the air taken out of the room is commonly recirculated through the air treatment system, where filters remove the particulates. All the same, high levels of moisture, harmful vapours or gases from processes, raw materials or products cannot exist recirculated back into the room, so the air in these cleanrooms is oftentimes wearied to the atmosphere. Then 100% fresh air is introduced into the atmosphere of the facility.

Rooms occasionally experience high airborne particulates during routine operation, such equally in a sampling room or dispensary. In these cases, the room needs to be cleaned rapidly betwixt procedures to prevent cantankerous-contamination.

The volume of air introduced into a cleanroom is tightly controlled, and and then is the volume of air removed. This is considering about cleanrooms are operated at a higher pressure level to the temper, which is achieved past having a higher supply book 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 pollex, the room you need to be the cleanest operates at the highest or the lowest pressure inside a facility.

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

Supply air and frazzle (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. For case, if the operator needs to be protected from a high authorisation product, the menses should be away from the operator.

For sterile or aseptic processes that need Grade A air, the airflow typically mimics a plug flow from top to bottom and is unidirectional or "laminar". Therefore, careful consideration should ensure that the "commencement air" is never contaminated before information technology comes into contact with the product.

Operating a clean room

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

This involves:

  • minimising the amount of potential contagion that escapes from your manufacturing operations
  • strictly controlling access to the cleanroom to merely trained personnel and limiting the number, equally fifty-fifty trained operators are the nigh 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 the next conversation with your pharmaceutical engineering colleagues are provided below.

Air change charge per unit

This refers to the number of times the air is inverse within a cleanroom. It is calculated by taking the total book of air introduced into the cleanroom over an hour and dividing it by the volume of the room. Information technology is expressed equally air changes per hour (ACH), and for cleanrooms, this is normally betwixt 20 and 40 air changes per hr.

Table

Micron

A micron (or micrometre) is a millionth of a metre. A human being hair is around 100 microns thick—particles less than 50 microns. Leaner measure 1 or 2 microns.

HEPA filters

HEPA stands for loftier-efficiency particulate air. HEPA filters are 1 of the most disquisitional elements of a cleanroom. They consist of a big, box-shaped filter that removes airborne particles of specific sizes very efficiently. They must likewise exist monitored and tested regularly to make sure they are still integral.

HEPA filters are equanimous of a mat of randomly bundled fibres, typically composed of fibreglass with diameters between 0.5 and 2.0 microns. Key factors affecting role are fibre diameter, filter thickness, and filter face velocity.

Dispersed oil particle testing / Integrity Testing

Dispersed oil particle 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 tin 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 nomenclature – ISO Grade

This refers to the level of cleanroom particulate cleanliness based on many airborne particles of a specific size per cubic metre. ISO 8 is the starting cleanroom level. For example, a sterile cleanroom for the pharmaceutical industry volition need to achieve ISO 5. Classes meliorate than ISO v, ISO 4 are generally just required for the electronics industry.

Make clean room classification – Annex one or ISO?

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

The classification of 100, 10,000, and 100,000 particulates per cubic foot refer to the withdrawn FED-STD-209 E Airborne Particulate Cleanliness Classes in Cleanrooms and Clean zones cancelled on 29 Nov 2001 U.Due south. General Services Assistants (GSA).

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

Room recovery rate

The time information technology takes from a contagion event to the room regaining its designed cleanliness level as per the GMP requirements.

Particle count

A test that samples a fixed book of air and captures, filters and counts airborne particles by their size. This is performed when the cleanroom is "at rest" or "in operation". Both airborne viable (alive) and non-viable (non alive) particle counts are performed for pharmaceutical operations. This is performed equally part of the certification of a cleanroom and during regular environmental monitoring.

Cleanroom certification

Cleanroom certification is a series of tests performed to prove that a cleanroom is operating at its required course or Grade, and you have a document issued by a competent tester.

More clean room jargon

PharmOut are registered Pharmaceutical Architects in many of the countries in which nosotros operate, combined with our in firm pharmaceutical engineering team can offering a nifty solution if yous are building a single ane room cleanroom or a mega-complex.

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

A clean room explained in simple terms, xv things you should never encounter in a make clean room, 12 deadly clean room sins, what is your make clean room costing you, optimising your clean room, getting QA buy in, at present you lot know it all, have the clean room quiz.

Eudralex Vol iv: https://ec.europa.eu/health/documents/eudralex/vol-4_en

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

WHO Annex 3: https://apps.who.int:lxxx/medicinedocs/documents/s18679en/s18679en.pdf

WHO Annex five: https://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex5.pdf

WHO Annex six: https://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPSterilePharmaceuticalProductsTRS961Annex6.pdf

Page last updated 5 October 2022