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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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.
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.
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.
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.
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.
Cleanrooms and clean areas are defined in the GMP&#;s as having the following characteristics.
There are three things that keep a cleanroom &#;clean&#;:
Each of the three items above is equally important. Let&#;s look at them in more detail:
For GMP compliance and to achieve the cleanliness specification, all surfaces in a cleanroom should be &#;smooth and impervious&#;, and:
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.
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).
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.
The most effective way of maintaining the air quality in a cleanroom is to operate and maintain it correctly.
This involves:
Some basic cleanroom jargon, acronyms and technical aspects for the next conversation with your pharmaceutical engineering colleagues are provided below.
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.
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 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 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.
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.
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.
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.
The time it takes from a contamination event to the room regaining its designed cleanliness level as per the GMP requirements.
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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 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.
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
By Jeffery Gloyer
When designing a cleanroom, there are many aspects to take into consideration. While regulations and guidelines such as USP chapters outline the minimum requirements for cleanroom design, they do not address all important elements. Many compounding pharmacies use the requirements stated in USP chapters <797> and <800> as the template for designing their cleanroom&#;often at the expense of a workflow that is operationally efficient and designed to minimize contamination risk. To help compounding pharmacies stay compliant and reduce risk without sacrificing efficiency, here are some of the aspects to consider when designing a cleanroom, as well as some recommendations that we at Eagle consider best practices.
Three-Room Design
The fundamental purpose of a cleanroom is to minimize the risk of contamination of compounded sterile preparations. In order to best achieve this goal, design considerations should address the number of personnel, the movements of personnel and supplies, and the activities that need to be performed in the classified areas. When all of these considerations are taken into account, best practices for cleanroom design often become more involved than the minimum requirements prescribed by USP regulations.
For example, while USP <797> only requires an ISO 7 buffer room adjacent to an ISO 8 ante room, many pharmacies do not consider the amount of space they will need for all activities and equipment in this area. Therefore, cleanrooms don&#;t always have sufficient space for pre-sterilization activities, such as weighing non-sterile powders, or for the placement of equipment, such as autoclaves, convection ovens and powder-containment enclosures. We typically recommend using a three-room design, which allows the segregation of aseptic processing, pre-sterilization procedures, and handwashing and gowning activities.
When employing a three-room design, we typically recommend a buffer area and two ante rooms. The ante room that is adjacent to unclassified areas serves as a gowning room, should contain a sink for handwashing, and should be a positive-pressure ISO 7 or 8 area. This room can be shared between hazardous and non-hazardous cleanroom suites, though if it is shared with the hazardous suite, it must meet the ISO 7 classification. The second ante room can be used for prep, such as weighing of powders and sterilization or depyrogenation of supplies and compounded sterile preparations.
Finally, there is the ISO 7 buffer area that contains the ISO 5 primary engineering control, such as a laminar-airflow workstation. This room should be adequate in size to accommodate the size of the primary engineering control. It is important to carefully consider the placement of equipment and supplies in this area as well, and the impact that they have on the ISO classification and on the HEPA-filtered airflow supplied by the primary engineering control. You can see an example of three-room design in Figure 1 below.
Negative- and Positive-Pressure Areas
When designing a cleanroom suite that meets USP <800> requirements for handling hazardous drugs, it is especially important to consider the activities that personnel will perform in these areas. USP <800> requires a negative pressure ISO 7 buffer room that is adjacent to a positive pressure ISO 7 ante area. Since the buffer room will maintain negative pressure relative to the ante room, the ante room must maintain ISO 7 air quality to prevent the influx of lower quality air into the buffer room. Similarly, the ante room must be positive pressure relative to adjacent, unclassified areas in order to prevent the influx of lesser quality air into the sterile suite.
However, pharmacies must also consider where they will perform pre-sterilization weighing of hazardous APIs. Personnel must handle hazardous drugs under negative pressure, so we strongly recommend a second ante room that is under negative pressure and has a containment primary engineering control, such as a powder-containment enclosure, that can be used for weighing non-sterile ingredients. This design results in an ISO 7 buffer room that is negative pressure relative to the adjacent ISO 7 prep area, which is negative pressure relative to the ISO 7 gowning room, which is positive pressure relative to unclassified areas. Figure 1 below shows an example of this.
Figure 1. An example of a cleanroom suite that uses three-room design with appropriate negative- and positive-pressure areas.
Maintaining Sanitary Conditions
The USP chapters also do not address all design considerations that are discussed in the FDA guidance document &#;Insanitary Conditions at Compounding Facilities.&#; This guidance document describes conditions&#;including cleanroom design elements&#;observed at compounding facilities that the FDA considers to be insanitary. Regardless of whether a facility qualifies for 503A or 503B exemptions from federal requirements, if they prepare compounded drugs under conditions that the FDA considers insanitary, then the compounded drugs are considered adulterated, and the facility may be subjected to regulatory actions or asked to recall their products.
Some of the insanitary conditions discussed in the FDA document that relate to cleanroom design are as follows:
These are just a few of the aspects that compounders should consider when designing a cleanroom facility. If you have any questions about cleanroom design, the Eagle engineering team can provide a range of consulting services. Please feel free to contact us at 800.745..
Jeff Gloyer joined the Eagle team as an Engineer I in . He has experience in working with multidisciplinary teams to implement the engineering design process, and he has led projects in many different sectors, including energy, automotive, semiconductor, aerospace, robotics and pharmaceutical industries. He also brings experience from working with cleanroom spaces for both the satellite and semiconductor manufacturing industries.
Pictured in banner: cleanroom facility by Nicos Group Inc. For more information about Nicos cleanrooms, contact your PCCA sales representative at 800.331..
A version of this article was originally published in the winter issue of the Apothagram, PCCA&#;s members-only magazine
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