FAQ
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A clean room (GMP cleanroom), 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.
- Maintenance – ask them what will need to be maintained and how it will be done.
- IT – ask them to think of the worst-case needs for the future and build those in from the start.
- Production – ask them what their needs are. What space will they need and what are the process requirements? What about cleaning?
- QC – are any microbiological sampling points required? How much media will they need to bring in at one time?
So that it’s not over-specified for the processes that will be housed in it (and not under specified so that it can’t be used for any future processes)? This is critical – consult everyone and get it right.
- Lights
- Smoke detectors (they won’t work anyway, get rid of them)
- Power points
- Sprinklers
- Fire doors
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.
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.
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.
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.
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).
ISO 14644-1 and ISO 14698 are non-governmental standards developed by the International Organization for Standardization (ISO).[22] The former applies to clean rooms in general (see table below); the latter to cleanrooms where biocontamination may be an issue.
ISO 14644-1 defines the maximum concentration of particles per class and per particle size with the following formula[23]
Where is the maximum concentration of particles in a volume of 1m of airborne particles that are equal to, or larger, than the considered particle size which is rounded to the nearest whole number, using no more than three significant figures, is the ISO class number, is the size of the particle in m and 0.1 is a constant expressed in m. The result for standard particle sizes is expressed in the following table.
| Class | Maximum particles/m3 a | FED STD 209E equivalent |
|||||
| ≥0.1 μm | ≥0.2 μm | ≥0.3 μm | ≥0.5 μm | ≥1 μm | ≥5 μm | ||
| ISO 1 | 10b | d | d | d | d | e | |
| ISO 2 | 100 | 24b | 10b | d | d | e | |
| ISO 3 | 1,000 | 237 | 102 | 35b | d | e | Class 1 |
| ISO 4 | 10,000 | 2,370 | 1,020 | 352 | 83b | e | Class 10 |
| ISO 5 | 100,000 | 23,700 | 10,200 | 3,520 | 832 | d,e,f | Class 100 |
| ISO 6 | 1,000,000 | 237,000 | 102,000 | 35,200 | 8,320 | 293 | Class 1,000 |
| ISO 7 | c | c | c | 352,000 | 83,200 | 2,930 | Class 10,000 |
| ISO 8 | c | c | c | 3,520,000 | 832,000 | 29,300 | Class 100,000 |
| ISO 9 | c | c | c | 35,200,000 | 8,320,000 | 293,000 | Room air |
|
a All concentrations in the table are cumulative, e.g. for ISO Class 5, the 10 200 particles shown at 0,3 μm include all particles equal to and greater than this size. b These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D. |
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US FED-STD-209E was a United States federal standard. It was officially cancelled by the General Services Administration on November 29, 2001,[24][25] but is still widely used.[26]
| Class | Maximum particles/ft3 | ISO equivalent |
||||
| ≥0.1 μm | ≥0.2 μm | ≥0.3 μm | ≥0.5 μm | ≥5 μm | ||
| 1 | 35 | 7.5 | 3 | 1 | 0.007 | ISO 3 |
| 10 | 350 | 75 | 30 | 10 | 0.07 | ISO 4 |
| 100 | 3,500 | 750 | 300 | 100 | 0.7 | ISO 5 |
| 1,000 | 35,000 | 7,500 | 3000 | 1,000 | 7 | ISO 6 |
| 10,000 | 350,000 | 75,000 | 30,000 | 10,000 | 70 | ISO 7 |
| 100,000 | 3.5×106 | 750,000 | 300,000 | 100,000 | 830 | ISO 8 |
Current regulating bodies include: ISO, USP 800, US FED STD 209E (previous standard, still used)
- Drug Quality and Security Act (DQSA) created in Nov. 2013 in response to drug compounding deaths and serious adverse events.
- The Federal Food, Drug, and Cosmetic Act (FD&C Act) created specific guidelines and policies for human compounding.
- 503A addresses compounding by state or federally licensed facility by licensed personnel (pharmacist/ physicians)
- 503B pertaining to outsourcing facilities need direct supervision from a licensed pharmacist and do not need to be a licensed pharmacy. Facility is licensed through the Food and Drug Administration (FDA)
EU GMP guidelines are more stringent than others, requiring cleanrooms to meet particle counts at operation (during manufacturing process) and at rest (when manufacturing process is not carried out, but room AHU is on).
| Class | Maximum particles/m3[28] | |||
| At Rest | In Operation | |||
| 0.5 μm | 5 μm | 0.5 μm | 5 μm | |
| Grade A | 3,520 | 20 | 3,520 | 20 |
| Grade B | 3,520 | 29 | 352,000 | 2,900 |
| Grade C | 352,000 | 2,900 | 3,520,000 | 29,000 |
| Grade D | 3,520,000 | 29,000 | Not defined | Not defined |
BS 5295
BS 5295 is a British Standard.
| Class | Maximum particles/m3 | |||||
| ≥0.5 μm | ≥1 μm | ≥5 μm | ≥10 μm | ≥25 μm | ||
| Class 1 | 3,000 | 0 | 0 | 0 | ||
| Class 2 | 300,000 | 2,000 | 30 | |||
| Class 3 | 1,000,000 | 20,000 | 4,000 | 300 | ||
| Class 4 | 200,000 | 40,000 | 4,000 | |||
BS 5295 Class 1 also requires that the greatest particle present in any sample can not exceed 5 μm.[29] BS 5295 has been superseded, withdrawn since the year 2007 and replaced with “BS EN ISO 14644-6:2007”.[30]
Cleaning validation is the methodology used to assure that a cleaning process removes chemical and microbial residues of the active, inactive or detergent ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes.[1][2] All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by waste from the previous product and the quality of future products using the equipment, to prevent cross-contamination and as a good manufacturing practice requirement.
The U.S. Food and Drug Administration (FDA) has strict regulation about the cleaning validation. For example, FDA requires firms to have written general procedures on how cleaning processes will be validated. Also, FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required. FDA also require firms to conduct the validation studies in accordance with the protocols and to document the results of studies. The valuation of cleaning validation is also regulated strictly, which usually mainly covers the aspects of equipment design, cleaning process written, analytical methods and sampling. Each of these processes has their related strict rules and requirements. Regarding to the establishment of limits, FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. But some limits that have been mentioned by industry include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose and organoleptic levels.
Now that you have your clean room plan in place and have received the green light from the board, you are ready to start the installation phase. Here are some key things to consider during installation.
Classification
At the heart of the clean room planning process is its classification. This is the industry-standard measure of the control of airborne particles in the clean room. Your research team will be able to let you know the level of cleanliness required for their work, and this will be translated into ISO classification from ISO 1 (the cleanest) to ISO 9.
The following table will help you and your supplier understand the classification your clean room needs to meet:
| ISO Class | Air Changes Per Hour | Maximum Particles/Cubic Meter | |||||
| 0.1 Micron | 0.2 Micron | 0.3 Micron | 0.5 Micron | 1 Micron | 5 Microns | ||
| ISO 1 | N/A | 10 | 2 | N/A | N/A | N/A | N/A |
| ISO 2 | N/A | 100 | 24 | 10 | 4 | N/A | N/A |
| ISO 3 | 360-540 | 1,000 | 237 | 102 | 35 | 8 | N/A |
| ISO 4 | 300-540 | 10,000 | 2,370 | 1,020 | 352 | 83 | N/A |
| ISO 5 | 240-480 | 100,000 | 23,700 | 10,200 | 3,520 | 832 | 29 |
| ISO 6 | 150-240 | 1,000,000 | 237,000 | 102,000 | 35,200 | 8,320 | 293 |
| ISO 7 | 60-90 | N/A | N/A | N/A | 352,000 | 83,200 | 2,930 |
| ISO 8 | 5-48 | N/A | N/A | N/A | 3,520,000 | 832,000 | 29,300 |
| ISO 9 | N/A | N/A | N/A | N/A | 35,320,000 | 8,320,000 | 293,000 |
Type of air pressure
Perhaps the most important factor in installing a clean room is identifying and understanding the type of airflow that you require. Using an air filter, it is possible to control the pressure, and subsequently the contamination level in the room.
The vast majority of clean rooms use the positive pressure method, in which the clean room has a higher pressure than surrounding rooms, which forces contaminated air away. However, some clean rooms are negatively pressured, which prohibits the air from leaving the room. Negatively-pressured clean rooms are usually reserved for labs dealing with some form of contaminant, such as infectious diseases, that cannot leave the room.