Monitoring and Understanding Pharmaceutical Cleanrooms

Published by Mikaela Fernandez on

medical cleanroom

When people look at the items around their homes, oftentimes, they do not realize how many processes it took to produce one product. Nanochips of gadgets are built in strictly closed spaces with environment control measures, otherwise known as cleanrooms. They are also used in the pharmaceutical industry during the manufacturing process.

What are pharmaceutical cleanrooms?

Cleanrooms are specific controlled areas used to process bio/pharmaceuticals, where micro-organisms and contaminants are regulated through various methods. It is a curated environment with a low level of pollutants like airborne microbes, dust, chemical vapors, and airborne particulates. They do not completely eradicate contamination, but they control it to an allowable level. Specific provisions are set within a cleanroom to reduce particle contamination and regulate environmental conditions such as temperature, pressure, and humidity.

Example of a cleanroom design

Due to the proliferation of diseases, there is a consistent growth in the demand for pharmaceutical cleanrooms. Almost every facility that produces pharmaceuticals has one cleanroom. Along with the increasing number of cleanrooms, demand is rising for technological innovations for cleanroom construction and design. Due to contaminating construction materials, regulatory concerns, operational deficiencies, and a heightened need for faster modular and prefabricated modular building.

In the healthcare sector, cleanrooms can be categorized based on the following applications:

  1. Drugs
  2. Biopharmaceuticals
  3. Cellular/ gene therapies

Cleanrooms are distinguished by the cleanliness of the air or the size or number of particles allowed per air volume. The cleanroom classification standards FS 209E and ISO 14644-1 classify the cleanliness level through particle count measurements and calculations. Meanwhile, the UK uses British Standard 5295 for cleanroom classification. Domestically, Federal Standard 209E is used. Large numbers like “class 100” or “class 1000” use FED_STD-209E. Small numbers use the ISO 14644-1 standard.

Clean Air Technology, inc. What is a Clean room?

In the ISO 5-9 range, there is an estimated 8,000 total number of installed bio/pharmaceutical cleanrooms worldwide. This number is expected to grow at 11,000 in 2025 and 15,000 in 2030.

Drug manufacturers rely on pharmaceutical cleanrooms to consistently ensure a contaminant-free environment since even small amounts of pollutants, or other irregularities can cause dire repercussions on the development of essential pharmaceuticals.

There are two types of contaminants in a cleanroom: viable particulates and non-viable particulates. Viable particulates are micro-organisms like bacteria, yeast, and molds. They often come from outside air, water, people, equipment, tools, excipients, and active ingredients. Meanwhile, non-viable particulates like metal specks and fiber from clothing are brought by equipment, people, and tools.

The highest source of possible contaminants inside a cleanroom is the personnel. They bring around 80% of particles in cleanroom inspections by bringing particles such as skin, hair, oil, and bacteria. Additionally, they also bring about external particles from cosmetics, lotions, perfume, deodorants, and lint and fibers from clothing.

How are environmental contaminants controlled in a cleanroom?

Effective air filtration is one of the most important factors to ensure a correctly functioning cleanroom. Air can spread contamination in a cleanroom, which is why several features of the cleanroom have been designed to control airborne particles.

The main component is the High Efficiency Particulate Air (HEPA) filter that is that are able to eliminate 99.9% of micro-organisms through a continuous filtration process and air with high-velocity speed through the filter. It traps particles that are size 0.3 micron and larger. All air that flows to a cleanroom passes through the HEPA filter. When more stringent cleanliness levels are needed, the Ultra Low Particular Air (ULPA) filters are used.

Personal Protective Clothing (PPC)

Protective Personal Clothing are the clothes worn by the personnel to lessen the likelihood of contaminants infiltrating the cleanroom. The apparel often includes scrubs, lab coats, gloves, masks, sleeves, hoods, goggles, etc.

It is also important to wash hands thoroughly. All jewelry should be removed, and personnel should immediately wear gloves after washing. Gloves also need to be sanitized using 70% alcohol.

Continuous inspection

The work area, clothing, IV bags, equipment, and needles need to undergo continuous inspection to guarantee that the items are free from debris, clutter, and defect.

If an item has been discovered to have been compromised, it should be immediately removed. After its removal, the area should be re-sanitized.

Regular sanitation of cleanrooms

It is essential that the cleanrooms are sanitized daily. The cleaning process should be properly documented in data sheets to easily check whether standards are being followed. 70% isopropyl alcohol can be used during this sanitization process because it can effectively combat most grambacteria. A second sanitizer such as hydrogen peroxide, quaternary ammonium, peracetic acid can also be used to further ensure a highly effective sanitization process.

Procedural Manipulation

Procedural manipulation indicates the meticulousness in conducting compounding procedures in a cleanroom. These manipulations minimize interaction with product surfaces such as septums and needles. Should an interaction or contact be made, the surface needs to be disinfected with 70% Isopropyl Alcohol. When a procedure is precise, movement is limited, which in turn reduces the possibility for particle generation and contamination. It is best executed through repetition and media proficiency testing demonstration.

Disposal and cleanup

Immediate cleanup should be done in the work area after the admixture is completed in order to ensure that the cleanroom is well-maintained. Spillage and other potential hazards should be taken care of immediately to mitigate possible risks and contamination. Once personnel moves out of the sterile area, they need to be re-sanitized before entering the cleanroom. The materials used should be properly discarded, and the area should be sanitized after every activity.

Monitoring pharmaceutical cleanrooms

Monitoring is essential in the production and quality control of pharmaceuticals. Since the manufacturing environment needs to be controlled at all times, monitoring ensures that contamination is limited during the process since final drug products need to be sterile and safe.

Routine monitoring allows better insight regarding the microbiological profile of a controlled environment. It enables systems to continue providing consistency in terms of environmental quality. An initiated monitoring program ensures that performance degradation will be immediately identified upon its occurrence.

Many applications monitor the environmental conditions inside a cleanroom to demonstrate capability for regulatory compliance. Aseptic processes are consistently monitored to demonstrate that the environment is conducive to producing safe and quality products.

The conversion of environmental data into information is crucial for effective monitoring like real-time data visualization, alarm notifications, and trend reports. Through this, identifying issues that are made easier, and staff will be able to proactively attend to them as they arise. Employing a data-driven approach for monitoring cleanrooms leads to reduced product waste, less segregated product, and fewer manufacturing disruptions, which ultimately results in overall operational savings.

Particle concentration is highly correlated with cleanroom monitoring since it determines the cleanroom class, which needs to be first demonstrated during qualification and reiterated during re-qualification. Turbulent steamed rooms are required to adhere to ISO 14644-1 (2015) since it is a mandatory GMP regulation for sterile manufacturing. It shows a table listing the measuring points depending on the room size with cleanroom measurements for qualification/re-qualification concerning particle concentration. Temperature and humidity need to be monitored as well, but there is no binding specification regarding their specific measuring points.

Sterile medicinal drugs often have strict requirements for cleanroom monitoring, while non-sterile forms have fewer restrictions. However, this greater flexibility often leads to uncertainties since each zone has a separate monitoring concept.

Cleanrooms that refer to USP797 and USP800 do not usually integrate centralized cleanroom monitoring in their designs. Small cleanrooms also tend to deviate from investing in smart FFU centralized airflow controls. The installer or certifier manually adjusts the air-exchanges or exhaust in order to meet compliance. Compliance with USP797 and USP800 requires continuous certification updates to existing facilities.

Installing non-invasive sensors in cleanrooms will notify the staff if the facility is about to border on non-compliance. These sensors make it easier to determine when a cleanroom needs to be adjusted or rebalanced.

Sensors often provide the following features:

  1. Measurement data
  2. Alerts and notification if the measurements go beyond the allowable range
  3. Recording and storing data for future study and review

Depending on the needs of a cleanroom, individual sensors, or a centralized sensor monitoring system can be installed. A centralized monitoring system records the cleanroom measurements and sends notifications if the cleanroom has been compromised.

Facilities are better assisted by centralized systems that allow Fan Filter Unit (FFU) control, environment monitoring, and exhaust adjustments. These monitoring/control systems are often cost-effective since they enable airflow FFU optimization, ease the burden regarding balancing and certification, reduce energy consumption, and extend filter media life. They allow for better cleanroom monitoring in-between certification visits to ensure stable performance.



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