Basic clean room design requirements and considerations

What is a 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 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.

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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, clean rooms are mandatory for the manufacture of sterile medicinal products, as defined in Annex 1 of the EU and PIC/S GMPs. This Annex defines many 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. Therefore, if you have classified the room as Grade D, you will need to live with the consequences and costs of maintaining this level of cleanroom 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 -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, 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 were positive to the corridor, the powder would escape out of the room and enter the corridor and will likely be transferred into the next-door cleanroom. Thankfully, most dry formulations do not readily support microbial growth. Therefore, as a general rule, tablets and powders are made in &#;clean corridor&#; facilities, as 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 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 typically designed with &#;dirty corridors&#; as you want to keep potential organisms out of the cleanroom. Also, 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 a need for biological containment. These are outside the scope of cleanroom 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 cleanroom doors swing?

Unless you have power-assisted doors, all doors should open 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 between rooms at levels outside 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 cleanroom?

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

Our genuine concern is microbial contamination in most cases. Traditionally the technology did not exist to measure microbial contamination in real-time directly, so the &#;all airborne particulates&#; limits were used and extrapolated /assumed to represent possible airborne microbial contamination risk.

So the GMP&#;s set out defining and controlling sources of particulates to prevent possible &#;microbial contamination&#;.

Personnel present in a cleanroom usually are the highest source of airborne particulates, and 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 is equally important. Let&#;s look at them in more detail:

1. The internal surfaces

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

• not generate their 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 panelling, 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 is a range of other options available.

2. Clean room airflow

Clean rooms need a lot of air and usually at a controlled temperature and humidity. This means that the cleanrooms Air Handling Units (AHU) typically consumes over 60% of all the site power in most facilities. As a general rule of thumb, the cleaner the cleanroom needs, 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 keeping the temperature-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. However, high levels of moisture, harmful 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 the atmosphere. Then 100% fresh air is introduced into the atmosphere of the facility.

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

The volume of air introduced into a cleanroom is tightly controlled, and so is the volume of air removed. This is because most cleanrooms are operated at a higher pressure to the atmosphere, which is achieved by having 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, the room you need to be the cleanest operates at the highest or the lowest pressure within a facility.

A good air handling system 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 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. For example, if the operator needs to be protected from a high potency product, the flow 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 &#;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 the 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 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.

Micron

A micron (or micrometre) is a millionth of a metre. A human hair is around 100 microns thick&#;particles less than 50 microns. Bacteria measure 1 or 2 microns.

HEPA filters

HEPA stands for high-efficiency particulate air. HEPA filters are one of the most critical 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, typically composed of fibreglass 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 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 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.

The company is the world’s best pharmaceutical cleanroom panel supplier. We are your one-stop shop for all needs. Our staff are highly-specialized and will help you find the product you need.

Clean room classification &#; ISO Class

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 will need to achieve ISO 5. Classes better than ISO 5, ISO 4 are generally only required for the electronics industry.

Clean room classification &#; Annex 1 or ISO?

Grades A through 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 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 U.S. General Services Administration (GSA).

This was superseded by International Standard ISO , Cleanrooms and controlled environments-Part 1: Classification of air cleanliness, and Part 2: Specifications for testing and monitoring to prove continued compliance with ISO -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&#;. Both airborne viable (alive) and non-viable (not live) particle counts are performed for pharmaceutical operations. This is performed as part of the certification of a cleanroom and during cleanroom monitoring.

Cleanroom certification

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

More clean room jargon

PharmOut are registered Pharmaceutical Architects practice in many of the countries in which we operate, combined with our in house pharmaceutical engineering team can offer a great solution if you are building a single one room cleanroom or a mega-complex.

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

A clean room explained in simple terms, 15 things you should never see in a clean room, 12 deadly clean room sins, what is your clean room costing you, optimising your clean room, getting QA buy in, now you know it all, take the clean room quiz.

EudraLex &#; Volume 4 &#; Good Manufacturing Practice (GMP) guidelines

Airborne Particulate Cleanliness Classes in Cleanrooms &#; FED-STD-209E

World Health Organization Annex 5

If you&#;re working on a technical specification for your new cleanroom design, you&#;ve likely noticed different types of cleanroom wall materials in the market. Unless you have experience with all the different types of cleanrooms, you might not yet know which cleanroom envelope system is suitable for your project.

Well, we&#;re here to help you out as best we can. We know it can be tough to find the info you&#;re looking for when it comes to cleanroom components, so we put together this blog to help you figure out your options for cleanroom walls. First, what essential elements do you need for a successful cleanroom wall that upholds your application&#;s standards?

When it comes to cleanroom walls, you&#;re looking for two things: smooth, dust-free surfaces. But finding the perfect surface type for your operation is easier said than done. Here are some considerations to determine what wall material type is best for you:

 

FLEXIBILITY

One of the biggest concerns for any new cleanroom is deciding how flexible your cleanroom should be. If you plan on housing it in the same building for a decade or more, you can probably get by with cheaper wall options.

Drywall coated with epoxy paint was a popular way to create cleanroom walls. You would take your building&#;s existing walls and paint them with an epoxy coating rated for cleanrooms. But one of the main problems with painted drywall is that those will be the walls you&#;re stuck with now and forever. When it comes to stick-built cleanrooms, there&#;s minimal scope for rearranging or expanding the space you started with, and providing the required extraction levels is challenging.

If you think your cleanroom is likely to expand once operations get underway, then a modular cleanroom with moveable wall panels would be a much better option. The materials might cost a bit more upfront, but you&#;ll also want to consider what you&#;d be getting for that additional fee.

Modular cleanroom wall panels are typically manufactured out of scratch and damage-resistant materials. This is helpful because if something runs into one of your modular wall panels, you don&#;t have to worry about drywall particulate below an epoxy coating seeping out and contaminating your cleanroom. If a modular wall panel gets a scratch, there&#;s very little cause for concern, and in most cases, you can return to business as usual. Worst case scenario: if the damage is substantial, you can arrange for a replacement panel to be easily fit into your existing system in no time.

 

STANDARDS

SoftWall cleanroom walls are the most economical type of modular cleanroom wall construction. Clear and flexible panels are mounted onto a robust steel frame, enclosing the clean area. As the panels overlap, the walls remain an effective barrier to create an ISO class 7-8 cleanroom, but with a higher volume of air required to achieve a higher level of cleanliness, you may need a solid wall panel.

RigidWall cleanroom construction can withstand the high airflow required for ultra-clean environments such as ISO class 5-6 clean zones. But the bright and durable finish makes them an attractive option for ISO class 7-8 cleanrooms.

HardWall cleanroom panels create a flush finish to a cleanroom wall. They are perfect for high-performance cleanroom applications with a range of proprietary features, such as raceway trunking to supply services, flush glazing, doors, and wall and ceiling panels.

 

CLEANING AGENTS

Once you&#;ve decided on modular cleanroom walls, it&#;s time to consider the cleaning agents you&#;ll be using on those walls. Every cleanroom classification is different and requires different levels of cleaning and disinfection. Pharmaceutical cleanrooms, for example, must be disinfected regularly with very harsh chemicals to prevent microbial buildup. In this situation, you need a HardWall cleanroom wall finish that can hold up to those chemicals without warping, corroding, or melting. Walls made from stainless steel with a cleanroom-specific coating are typically suitable for applications that use super-strong cleaning materials.

On the other side of the coin, if you plan on cleaning your cleanroom regularly but don&#;t need to use the highest-grade disinfectants, RigidWall cleanrooms wall options like acrylic, static dissipative PVC, or polycarbonate wall panels are a more cost-effective choice. When using lower-grade cleaning materials, you need a wall panel that prevents bacteria and particulate from sticking to it. You won&#;t have to worry about harsh chemicals eating through coatings and materials, causing a lot of particulate buildup within your cleanroom.

 

DURABILITY

As mentioned before, durability can play a significant role in choosing cleanroom wall material. Depending on your application, you&#;ll need varying levels of material durability. Some materials, like lightweight vinyl modular wall panels, or epoxy-coated drywall, can easily scratch. When the protective coating is breached, the material underneath is exposed and can give off dangerous particulate that can interfere with your processes. Moreover, some wall materials not certified for cleanroom use could outgas or start to give off particulate as they age.

Cleanrooms with more intensive standards are typically best served by walls made primarily of aluminum structure. Aluminum is lightweight, durable, and, best of all, doesn&#;t give off particulate as it ages. That said, it is a more costly option. So if your cleanroom doesn&#;t need quite that level of cleanliness, you might choose a less expensive option.

 

COST

Perhaps the most significant consideration for your cleanroom wall material decision is that you have to stick to a specific budget. With cleanrooms, particulate control is the most critical factor, so it stands to reason that a large part of the investment goes into the airflow, the expensive filtration systems, and the energy you use to keep your cleanroom functioning correctly. Because of this, many cleanrooms don&#;t look as expensive as they are.

Your cleanroom walls can be one of the least costly aspects of your cleanroom as they are relatively low-tech. So, if you&#;re looking for an area of the project where you can save money, this could be it.

That said, a few companies want their cleanrooms to reflect the expense put into them, so they spend more on their walls. A high cosmetic finish can be achieved if you have extra room in the budget and want to build a cleanroom that looks like a high-tech, cutting-edge facility. But know that you don&#;t have to have the highest specification of walls to meet your cleanroom standards.

 

When designing a new cleanroom, deciding which cleanroom wall material will work best for your application and convey the image you&#;re looking for can be difficult. If you have more questions about choosing a suitable wall material for your cleanroom, call the experts at Angstrom! We&#;re here to help you, and we&#;d love to provide you with any cleanroom information you want to make the best, informed choice for your company. Call our office at 888-768-, or request a quote online today!

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