Cleanrooms are basically controlled spaces where particulate counts, temperature, relative humidity and pressure are controlled and monitored. While movies and the sci-fi genre may make these spaces seem very high-tech, they are actually quite basic in design and function. In fact, you can transform almost any existing space into a cleanroom, although the cost of doing so be quite high.
For companies who plan on completing short-term projects or production runs with specific products who do not have a working cleanroom, using a modular cleanroom, also known as a “portable cleanroom” can be a viable alternative.
Modular Cleanroom Benefits
A modular cleanroom can provide many benefits. The primary benefit is cost with flexibility and portability of processes following as a secondary benefit. Below are just a few of the possible benefits of choosing a modular cleanroom over a “built-in” option.
Versatility: Most modular cleanrooms can be assembled on-demand, and be ready to use in a couple of days. These are generally complete solutions requiring no ancillary expenses.
Flexibility: With portable cleanrooms, the customer can benefit from nearly unlimited floor-plans and layout options; adhering to what makes the most sense for a particular process. Alternatively, re configuring a built-in cleanroom to change the layout or design would require stopping processes and heavy construction costs.
Cost-efficient: A modular cleanroom is manufactured offsite; and can be custom built. They often cost a fraction of what permanent cleanroom construction would cost.
Renting and leasing: Most portable cleanroom builders have options to lease or rent the portable cleanroom. This makes sense for companies that know they have a short-term project. They can rent or lease a cleanroom for a short term and then return it if they need something different for the next project.
Tax break: Since a modular cleanroom can be easily disassembled and is completely portable, and moved to a different location within the company, it is considered a piece of capital equipment; benefiting from the same tax regulations as other machinery and capital equipment.
Cleanliness: For cleanroom classification requirements of ISO 6 and above, a modular/portable cleanroom can be the better option; the materials used in modular cleanrooms do not face the same material degradation challenges faced with permanent cleanroom construction.
Types of Modular Cleanrooms
Hard wall Modular Cleanrooms: These portable cleanrooms are typically designed and built to customer specifications. They are delivered on-site and installed/assembled by a manufacturer representative. Hard wall modular cleanrooms are typically built using vinyl, aluminum, fiberglass or a combination of these materials. They can be configured with windows and doors placed according to the buyers specification. They typically come complete with monitoring solutions for particle counts, temperature, pressure, and relative humidity. It is important to note, however, the monitoring instruments included in modular hardwall cleanrooms may not always be top-of-the-line, so it is important to consider using a third party, stand-alone solution for more accurate monitoring. Also included are HEPA filtration units that can be configured to meet ISO 5 – ISO 9 standards, in most cases.
Soft-wall Modular Cleanrooms: These are the most portable of all modular cleanroom designs. Customers can typically select the thickness of the plastic sheeting/enclosure, the level of filtration (and in some cases they can be outfitted to tie in to existing HVAC systems). The plastic sheeting is usually mounted on steel or aluminum frames complete with casters. While soft-wall modular cleanrooms offer the highest in portability factor, they may not reach the same cleanliness levels that hard-wall modular cleanrooms can. It all depends on the manufacturer and the cost the buyer is willing to bear.
Perhaps the greatest challenge with any cleanroom, but particularity with a modular cleanroom, is maintaining mandated cleanliness and keeping the overall environment consistent. The best way to avoid contamination is to have an accurate particle counter on site, or to have your modular cleanroom bench tested regularly. Just as important as particulate counts and air exchange rates is maintaining air quality. This generally means pressure, temperature and humidity. To monitor and maintain air pressure, temperature and relative humidity, a stand-alone cleanroom differential pressure, temperature and relative humidity monitor is essential. Differential pressure is what keeps pollutants out of a standard cleanroom (or keeps caustic chemical fumes and particles in when using a negative pressure isolation room). These highly precise cleanroom monitors are relatively inexpensive, and can be easily attached to your portable modular cleanroom. A number of these are available, each of which have different features. Always check if the instrument you choose can alert local staff, as well as provide advanced alerts via SMS, email and/or automated phone calls.
Early detection in air quality issues will save a great deal of potentially lost time, money and contamination remediation.
|Aerospace||ISO Class 5-7|
|Assembly of Touch Screen||ISO Class 7|
|Composite Materials||ISO Class 8|
|General Industrial||ISO Class 8|
|Injection Molded Parts||ISO Class 7-8|
|Optical||ISO Class 5-7|
|Semiconductor||ISO Class 5|
|SMT Assembly||ISO Class 7-8|
|Solar||ISO Class 5-7|
|Wafer Board||ISO Class 5|
|Consumables and Pharmaceuticals|
|E-Liquid||ISO Class 7-8|
|Food Packaging||No Classification|
|Nutraceutical Packaging||ISO Class 7-8|
|Pharmaceutical Compounding||ISO Class 7|
|Pharmaceutical Packaging||ISO Class 8|
|Sterile Compounding||ISO Class 5|
|Device Reprocessing||ISO Class 7|
|Inplantable Devices||ISO Class 5|
|Medical Device Packaging||ISO Class 7-8|
Building and designing a cleanroom requires proper planning, and a thorough understanding of the equipment and technology in the controlled environment that will ensure it’s correct and safe operation. Clean room design will be heavily dependent on the type of process that will be carried out in the space chosen.
Many companies prefer to consult with an engineer, an architect, an HVAC specialist and a general contractor before moving forward with a particular clean room design.
For the purposes of this article, we’ll get right down to the basics of best practices for optimal clean room design.
|ISO 14644-1 Cleanroom Standards|
|Classification||Maximum Particles/m3||FED STD 209E Equivalent|
|ISO 3||1,000||237||102||35||8.3||0.029||Class 1|
|ISO 4||10,000||2,370||1,020||352||83||2.9||Class 10|
|ISO 5||100,000||23,700||10,200||3,520||832||29||Class 100|
|ISO 6||1.0 x 106||237,000||102,000||35,200||8,320||293||Class 1,000|
|ISO 7||1.0 x 107||2.37 x 106||1,020,000||352,000||83,200||2,930||Class 10,000|
|ISO 8||1.0 x 108||2.37 x 107||1.02 x 107||3,520,000||832,000||29,300||Class 100,000|
|ISO 9||1.0 x 109||2.37 x 108||1.02 x 108||35,200,000||8,320,000||293,000||Room Air|
In May 2019, Seattle Children’s Hospital faced an emergency situation where 14 surgical rooms were forced to cease operations, with over 3,000 families potentially affected by deadly Aspergillus mold exposure. The Seattle Children’s hospital was forced to move or reschedule over 1,000 surgeries. Unfortunately, one patient recently died in 2018 after developing an infection as a result of exposure to this type of mold. Many more could face ongoing health complications.
How this could happen in this modern age of technology, to a hospital which, in 2019, U.S. News & World Report named one of the 10 best children’s hospitals in the country? In fact, U.S. News & World Report has recognized Seattle Children’s as a top children’s hospital every year since it began ranking medical facilities more than 25 years ago.
The looming question is “Was this tragedy preventable, and, if so, what should have been done?”
Who’s at fault?
According to the Centers for Disease Control and Prevention, Aspergillus is a common mold found both indoors and outdoors. Unless you live in a cleanroom or isolation room, you have most likely inhaled millions of it’s spores into your lungs every day since your birth.
While most people breathe in these spores every day without getting sick, the mold poses a real risk to those with compromised immune systems or lung disease. Mold growth can be accelerated and concentrated in man-made surroundings whereas in natural environments, the concentrations are diluted to just a few parts per million by global atmospheric conditions. The way to prevent these spores inside closed spaces like operating rooms and patient rooms inside hospitals is to carefully monitor pressure, temperature and humidity. As long as temperature and humidity are maintained a proper levels mold can not grow and if positive pressure is maintained the spores will, for the most part, be kept outside the area.
Aspergillus, and mold in general, can cause allergic reactions and infections in the lungs and other organs in the body. This is precisely why hospitals must monitor and manage mold growth of any type – patients in the hospital (children and elderly) are already at a greater risk for adverse effects of mold growth; even more so if they have existing health complications and compromised immune systems.
With that said, the Seattle Children’s Hospital had known deficiencies in room air purification systems. The patient who recently died (2019) contracted the Aspergillus mold infection a year ago. That was known at the time and should have been a wake-up call to install equipment to monitor conditions to prevent a re-occurrence. It is unclear which, if any, preventative or remediation processes were put in place after the first known incident. It is known, however, that they were largely ineffective in preventing further growth; the mold was still present a year later.
Ultimately, the Seattle Children’s Hospital is at fault – mold and other potentially harmful pollutants, of natural or synthetic origin, must be controlled no matter the cost.
What could have been done
There are dozens of monitoring systems available to hospitals, and some even provide advanced alerts when relative humidity and temperature levels become ideal for mold growth. These systems can allow for immediate correction of dangerous conditions. An alert delivered in a timely manner can help maintenance personnel make adjustments to the HVAC systems and initiate clean-up measures to get rid of the mold. Carefully monitoring potentially contaminated areas is a must for every health care provider.
Experts agree that having multiple environmental monitoring systems in place is a good idea; one tied in with a building management system, and another stand-alone as a fail safe. It is also important to note that any system which requires an employee to physically view a monitor or screen can only be as effective as the person viewing it. A better alternative is a system which includes a digital display of current values, offers a room or local alarm system when level are outside set ranges, and has the ability to notify key personnel via SMS, email and/or automated phone calls when issues of air quality occur. Many of these systems are specifically designed for hospitals, and include options to monitor both negative and positive pressure isolation rooms – helping to reduce exposure to mold and cross contamination.
Although there are only a handful of manufacturers that offer such comprehensive systems, they do exist, and are a fraction of the cost of having an incident like the one at Seattle Children’s Hospital. In fact, if you look at the math, a hospital could buy a comprehensive monitor for about the same cost it takes to operate a surgical room – for 7 minutes.
Bottom line, there are no excuses. Hospitals operate on a tight budget, and have ongoing issues with accounts receivables from patients and insurance carriers. There are huge fees to surgeons, malpractice insurance, and other costs to operate a modern and efficient hospital. However this is no excuse for overlooking something as basic as providing a mold free environment. A piece of equipment as inexpensive as a modern advanced monitoring system to prevent mold growth and provide critical data on the health of the environment. This solution does and will continue to have a huge impact of patient health and the ability to recover from surgery and the issues that brought the patient to the hospital in the first place.
Three easy steps for getting a temperature sensor into a refrigerator.
All refrigerators have a temperature probe which is connected to the compressor to regulate the internal temperature of the refrigerator. However, the need exists for a second temperature sensor to trigger an alarm or keep a record of the internal temperature. These temperature sensors can be either wired or wireless. But whether they communicate with another piece of equipment via a wired or wireless connection the need to be positioned inside the refrigerator. These sensors almost always have a wire which goes to a display or a transmitter.
So, how do you get the sensor inside the cold cavity with the wire leading to the display or a transmitter and not have the wire create an air gap as it is threaded between the gasket and the door frame. The challenge is to get the probe inside the refrigerator and still maintain a good seal, so the refrigerator stays cold.
If you have large walk-in refrigerators you can drill a hole through the side or top of the unit, insert the wire and then fill the hole with some sort of thermal sealant. You can do the same thing with smaller refrigerators. There is no reason you can not drill a hole in the refrigerator wall. The only danger is that you could puncture a coil. But the coils should all be located on the back of the unit. Your drill bit will go through the outer metal shell, an inch or so of insulation and the inner plastic shell. There are no cooling coils in the walls of a normal stand up refrigerator. But, do check first to verify that the cooling coils are on the back of the unit.
Some smaller refrigerators, particularly scientific refrigerators, have a port through which the wire can be threaded. If a port exists it will be filled with some sort of filler; molding clay, Styrofoam, plastic, etc… Generally, the port will be on the back of the refrigerator but look at the back and the sides for a hole filled with some easily removed filler. Once you have identified the port:
- Remove the filler from the port;
- Thread the wire through the port, positioning the sensor near the center of the fridge;
- Reinsert the filler, pressing it around the wire.
If your refrigerator does not have a port through which the sensor can be threaded:
- Open the refrigerator door and thread the sensor wire between the gasket and the door frame near the upper hinge. Draping the wire over the top of the door hinge will help keep the sensor wire from moving around;
- Position the sensor near the center of the fridge. Numerous studies have shown that the temperature near the walls or front or back of a refrigerator is much warmer than the air in the center of the refrigerator;
- Tape the wire against the door frame so that it stays in place. Duct tape is best because it will adhere to the wire and door even given the cold temperatures of the refrigerator.
A small gap may be left between the door and the door frame, but it should be small enough that only a tiny bit of air can escape from the fridge into the outside air and the internal temperature should not be affected. If you are worried about the resulting gap you could drill a hole in the gasket. Refrigerator gaskets generally have an expandable bellows below an internal magnet which ‘snap onto’ the metal door frame to provide a seal against outside air. Drill a hole in the bellows, underneath the magnet, and thread the sensor through the hole. Then squirt some silicon in the hole so that it fills the hole in the gasket. You can get a tube of silicon from any hardware store.
Annex 1 of the EU GMP is a guideline and set of specific rules describing the European Union’s requirements for the manufacture of sterile medicinal products, including what we refer in the USA as “compounding pharmacies.” EU MP Annex 1 guidelines are applicable to all EU nation states in regards to pharmaceuticals bought, sold and manufactured – including those imported from non-member nations. The latest revision will be released in 2019, and is expected to have a greater reaching impact on QA/QC and all laboratory activities in the EU and abroad.
So, what exactly is Annex 1 of the EU GMP, and what does it mean for pharmaceutical companies operating in the USA? For the most part, USP regulations in conjunction with 21 CFR 11 dependencies satisfy EU GMP, especially Annex 1, however, it is important to ensure manufacturing processes are not simply performed within standards and regulations, but monitored thoroughly throughout the process as well.
On 20 December 2017, the European Commission published the long-awaited draft of Annex 1 “Manufacture of Sterile Medicinal Products.” In fact, it was published nearly three years after it was first announced. Many see the change over the previous (technologically outdated) versions as having a focus on Quality Risk Management (QRM)
A key driver for the change, the concept of risk management is hard to miss in the new document:
- 92 instances of the word “risk” (only mentioned 20 times in previous version) total times mentioned is 600, so “risk” is huge.
- 15 references to QRM specifically
The 2018 (and presumably 2019) update contains substantial additional detail on virtually every topic in the 2007 version. In addition to those noted above as potential game-changers, compliance personnel can look forward to new levels of detail on such subjects as: Trending of environmental monitoring results (meaning the existence of a dependable chart recorder/data logger of pressure differential, temperature, and relative humidity)
Two key areas of focus should be viable and non-viable environmental and process monitoring and environmental control of pharmaceutical clean rooms as the essential part of the manufacture of a quality product. Simply adhering to standards without documented, digital storage of ongoing process controls is an exercise in futility.
We are somewhat partial since we engineer and develop instruments to monitor environmental conditions in cleanrooms, and for monitoring and logging data of control processes during pharmaceutical manufacturing. However, this partiality comes form countless instances of customers, and manufacturers reporting occasions where they assumed a process control was operating within optimal standards, only to find out later in log reports there was an anomaly which compromised the process. If end-use retail products are being manufactured – there is an acceptable risk for these incursions, and worst case scenario is a product mail fail or operate undesirably. In the case of a pharmaceutical product, it may be a person’s health and wellness which is ultimately compromised.
While there is no specific language to dictate specifics on “annex compliant” negative and positive pressure monitoring, as there is for acceptable micron size in particulate monitoring, it is important to note that the language does reference the requirement to maintain environmental control process monitoring, logging data throughout the manufacturing process.
There are many instruments on the market; some specialize in monitoring temperature. others focus on humidity. Some are standalone room air differential pressure monitors. The TV2 Cleanroom Monitor is the only instrument to perform all three actions with specifications which exceed EU GMP requirements, USP 787 requirements and provides data storage for one full year.
We are happy to consult with you regarding your temperature, relative humidity and room pressure monitoring needs – whether you re in the USA or adhering to new EU GMP Annex 1 compliance guidelines. We are here to help.
Here is a PDF of the EU GMP Annex 1
Not too long ago we were asked by a pharmaceutical manufacture why our TV2 pressure monitor showed a negative pressure indication on the Max/Min display.
We investigated and found that if you quickly open the door into the room the pressure drops down into the negative range. This had always been the case but he had never noticed it since he was using analog pressure monitors. They did show the jump to negative pressure but you had to look quick since the needle swings happened fast. The TV2 monitor, being digital, records and updates the high and low pressure, showing each in red if it is below the safety level. So even if the room experienced negative pressure for a few seconds it is written to the display where it is very obvious. In fact it jumps right out at anyone walking by. That is, of course, the whole point, but this manufacturer was worried that an inspector would balk if the minimum pressure reading showed up in red. Explaining that it was probably negative for a few seconds would not be enough to avoid ‘ding’ on the report. Any indication of a negative pressure was a problem. It was a problem easily fixed. We simply set the display to not show the Max/Min.
However, this fix ignores the real problem. Anytime the door of a positive pressurized room is opened, all of that positive pressure air can and often does spill out into the hall where it is instantly mixed with the outside air and then sucked back into the room. And, of course, it brings with it any and all suspended particles so that now the cleanroom is no longer clean. Or at least as clean as it needs to be.
There are actually three solutions to this problem: 1. Open the door verrrry slowly; 2. Install large capacity blowers that turn on any time a door is opened to maintain positive pressure; and 3. Install a pressurized air lock so that pressure can return to positive before the door to the clean area is opened. Each solution has its own drawback. Option one is impractical and probably impossible to enforce. Option two is expensive to install and may lead to increased maintenance costs. Option three is the best solution. In order to be effective personnel must pause in the air lock until it is re-pressurized and the in-rushing air has had time to be evacuated. It is also important that the two doors not be opened at the same time.
Cleanrooms are essentially an area or room dedicated to a particular process, and wherein such processes are required to be carried out in an ultra-clean environment. Traditionally, these “rooms” are kept clean by high-tech air filtration systems, custom HVAC systems, constant air changes and then monitored around the clock for particulate counts using expensive particle counters while simultaneously monitoring temperature, relative humidity and differential room air pressure. Particulates are a cleanroom’s worst nightmare. Particulates can include dust, dirt, viruses, bacteria, mold, allergens and a host of other contaminants – all which can be increased if any one part of the control and/or monitoring system fails.
Keeping cleanrooms clean is an ongoing exercise in futility; after all, the Earth is a dirty place, and keeping a microcosm within it clean is a very, very difficult job. On the other hand, the integration of Artificial Intelligence (AI) will one day soon take this task head-on and do it with ease and reliability never before seen – opening new doors of what’s possible in developing new breakthroughs in the fields of biotechnology, nano technology and computer processors.
Artificial Intelligence, or as it is collectively known “AI” is not something comparable to the Terminator, nor is it created in the likeness of JARVIS – the AI companion of Tony Stark in popular Iron Man movies. In fact, AI – in most cases – is not even a physical entity. Sure, AI-based algorithms can be embedded in hardware, robots, and even your refrigerator, but most commonly, AI is a specially written algorithm (computer code), created to solve a particular task. in some cases (as with deep learning) it is programmed to learn form it’s own mistakes, and develop autonomous ways to accomplish tasks with greater efficiency.
Keeping cleanrooms cleaner is one such possible task.
In order to translate theory into practice and create our “cleanroom bot”, we must first “learn” how AI “learns” – a process by which an algorithm is fed known variables, and then tasked to identify these variables with greater precision and speed. In this case, we would theoretically create the code (most likely in Python and R programming languages), and then add peripheral “senses” – like an ultra-high resolution camera and particle sensor/counter to detect particulates; and a system of identifying particulates by size and type. We would also integrate a trusted temperature, RH and differential pressure sensor system, and maybe even a biological detecting sensor system for live particulate detection.
Then we would do something quite novel – we would add sensors and learning variables for conditions existing outside of the controlled environment. We would monitor atmospheric pressure, relative humidity, differential pressure in the containing facility, geographical analysis, human bio-metrics, biofeedback, body odor, pheromone analysis, etc. Essentially, our AI-based cleanroom bot would constantly pull data from every conceivable source within and outside of the cleanroom.
We would ideally then start to train our “cleanroom bot” to identify and understand unfathomable variations of particulates. This is not as difficult as it may seem. In fact, using cameras and algorithms to identify faces, license plates, and even early detection of genetic disorder predisposition is already being used daily in the world around us. Basically, our cleanroom bot would need two distinct comparative models to start – a ultra-clean ISO-1 cleanroom with the baseline ISO-9 cleanroom, and then add the interval cleanroom types. In fact, in its simplest form, we could readily accomplish this using the TensorFlow platform, adding in some custom tweaks to the TensorFlow Image training/retraining code, add in analysis differential for areas in and outside the room, develop a baseline clean and dirty classification and voila! We have a working (infantile-level) cleanroom bot.
Up until this point, we have been focused on the process of the why’s and how’s regarding creating a cleanroom bot, or for better description, an AI-based algorithm for identifying whether or not a particular controlled environment is clean or dirty – and if it is – just how clean or dirt it is. This alone would be great, especially since it would cut the current time it takes to verify such data by thousands of times less! However, it is the predictive analysis we are really after.
Knowing is only half the battle. It is far better to speculate conditions with flawless precision and ultimate accuracy, than to know at a particular moment in time what a controlled environment can be classified as. To explain a bit further, imagine a scenario where our cleanroom bot can predict with near 100% accuracy the most ideal times and conditions by which to carry out specific processes in that cleanroom. Imagine a bit further that the rendered data collected by our cleanroom bot will enable us to know not only when a cleanroom will be “dirty” but also what exactly is making it dirty, and why. One more step – our cleanroom bot will be capable of making recommendations for building cleanrooms at the ISO -9 level and beyond, keeping them at that level and even taking them to cleaner levels – all at a fraction of the cost of operating a current ISO-9 cleanroom.
This is no longer science fiction. It is a reality, and only a matter of time before the expansive capabilities of AI-based deep learning infiltrates and enhances almost all aspects of our daily lives. Cleaner cleanrooms and controlled environments means better vaccines, better medications, more advances in biotechnology, greater capacity for maximizing processing power in chipsets, potential to identify causes for disease (and cures) and so much more. These things would not otherwise be possible without the integration of AI-based algorithms in cleanrooms and controlled environments.
JCAHO temperature standards, JCAHO tissue standards, tissue storage temperatures
The Joint Commission of Accreditation of Healthcare Organizations, issued a new standardized procedures on storing tissue samples. This new standard, PC.17.10 applies to organizations that store or issue tissue, which may include areas outside of the clinical laboratory, for example, surgery and outpatient centers and tissue banks.
Examples of tissue specimens that might be found in an organization include bone, cornea, skin, heart valves/conduits, tendons, fascia, dura, bone marrow, veins, arteries, cartilage, sperm, embryos, eggs, stem cells, cord blood, synthetic tissue (artificially prepared, human and nonhuman based), and other cellular- and tissue-based transplant or implant products.
It says in part that the organization must:
B 6. Maintain continuous temperature monitoring for storage refrigerators and freezers.
C 7. Maintain daily records to show that tissues were stored at the required temperatures.
Note: Main types of tissue storage used are: “ambient” room temperature (for example, freeze-dried bone), refrigerated, frozen (for example, deep freezing colder than –40°C), and liquid nitrogen.
B 8. Storage equipment has functional alarms and emergency back-up.
How to comply?
The easiest way to comply with this standard, without purchasing a commercial laboratory freezer with a built-in monitoring system, is by adding on a standalone temperature system that is capable of monitoring, documenting and alarming.
One such system is the Master Thermometer, manufactured by 2di. It uses a probe to sample temperature every few minutes and draws an electronic chart on its display which complies with provision B6 and C6 of the standard. It also has a built-in relay that triggers an auto dialer or strobe/siren alarm, which complies with B8 of the JCAHO standard. It stores over 1.5 years of temperature history and can be downloaded into a computer to generate a paper copy of the graph or an archived copy. An added benefit of this device is that its chart is constantly being updated and always displayed so that each person in the vicinity of the freezer is always
aware of the temperature.