Controlling controlled and sterile environments

All licensed drug manufacturers must comply with current Good Manufacturing Practice regulation. Cell and tissue, radiopharmacy and cytotoxic manufacturers also fall under the same scrutiny as do some research facilities. Compliance must be demonstrated at every stage before a drug or human medicinal product can be released to market. Automated environmental monitoring and biological monitoring systems provide effective and reliable methods for monitoring of viable and non-viable particles in Grade A/B cleanrooms along with other critical environmental conditions such as pressure, relative humidity and temperature.

However, keeping a cleanroom clean is not easy. It will be at its zenith of ‘cleanliness’ before any equipment or operators are introduced into it -  but let’s face it, even though the environment may be sterile, without equipment and workers it will be useless.

As people and equipment enter the cleanroom they bring particulate matter with them. Gowning up and the use of smooth surfaces on process equipment will help reduce the build-up of particles but equipment with moving parts and the operators still generate considerable quantities of particles.

Sources of contamination may include dead skin and hair, cosmetics and clothing, and bacteria. Independent tests have shown that the average human generates around 500,000 particles/minute. That figure reduces by use of suitable attire, gowns, masks, gloves, and hair and beard coverings, but particles are still generated and an addition of a new contaminated product or ingression from an operating environment can further increase the particulate contamination.

There are two types of particle representations present in our environment - viable and non-viable particles. Viable particles are the ones that are feared most in pharmaceutical, medical device and biotech cleanrooms as they contain living organisms.

Along with other critical environmental conditions such as pressure, relative humidity and temperature control, automated environmental monitoring (EMS) and biological monitoring systems (BMS) can provide an effective and reliable method for the monitoring of viable and non-viable particles in Grade A/B cleanrooms.

An environmental monitoring system (EMS) contains particle sensors mounted in critical areas such as along a filling machine or inside a biological safety cabinet that detect non-viable particles. Other environmental sensors can be included in the EMS monitoring such as room pressure, humidity and temperature. The data is sent back to a software system that is controlled and monitored by the operator. Any out-of-specification alarms will trigger an email/SMS notification or activate local alarms and flashing indicators within the cleanrooms.

Inside a cleanroom, the particulate contamination in the environment can be controlled using HEPA filters - high-efficiency particle air filters. Depending on the classification of the cleanroom, the number of air changes per hour can be configured. That environment is tested and classified based on the validation work carried out.

Particle counters and air samplers are used to monitor cleanrooms and sterile controlled environments. Particle counters detect the size and concentration of particles present. Air samplers detect what types of particles are present by capturing them on a media plate.

Grade A sterile environments monitor continuously during production using environmental monitoring systems combined with automated or real-time biological monitoring systems.

The control room can be located off the cleanroom, which keeps the monitoring operator out of the sterile area. The BMS also has sampling heads located along the filling machine or inside LAF or biological safety cabinets. Before the process begins, the sampling heads are loaded with 90 mm Petri dishes containing a media - the most common media being TSA. One system on the market cleverly uses barcoding so the BMS software knows the 4 Ws - Who, What, When and Where. The 4 Ws ask: WHO loads the Petri dish; WHAT dish is loaded; WHEN is the dish loaded; and WHERE is the dish loaded. After processing, the 4 Ws are stored in the software: WHO unloads the sample; WHAT sample is unloaded; WHEN was the sample unloaded; and WHERE is the sample unloaded. The sample is then incubated and the colony forming units (CFUs) counted, and the data is downloaded into the software so a complete history of the sample is available. All the data can be stored securely. Note that the BMS and EMS software must be 21CFR11 compliant after validation.

There are some software package on the market that combine the EMS and the biological monitoring onto one complete package allowing for real-time monitoring of viable and non-viable particles.

The advantages of using an automated system for particle monitoring outweighs any manual labour systems, which are prone to error and slower. This type of system keeps monitoring operators outside Grade A/B environments and, as previously mentioned, is located off the main cleanroom, thus reducing particle contamination levels and significantly reducing labour costs. Process data can be easily retrieved and reviewed by the quality manager. These systems have become cost effective compared to purchasing portable units.

The portable particle counter is usually used for spot checks or monitoring background counts in lower-grade cleanrooms. Portable air samplers can be used in the same manner.

The following are some of the advantages when monitoring with EMS and biological monitoring systems.

• Collection of data: The amount of data collected by FMS and BMS is vast compared to portable units. Trending of this data is achieved easily using the software applications. Events can be seen in advance, allowing for corrective action before they effect production.
• Storage of data: The FMS/BMS store all sample data on a dedicated secure server. The software can be validated to comply to Code of Federal Regulations section 21 part 11 (21CFR11). Data is easily and securely reviewed.
• Labour: Using a FMS/BMS saves labour costs as the systems are automated and can generally be run and supervised by one operator, significantly reducing labour costs.
• Reliability: EMS/BMS by nature of their design are more reliable and, in the case of breakdown, plug-and-play can be utilised with spare calibrated units available allowing production to continue as scheduled.
• Alertness: Alarm limits can be programmed into the software. This gives the operator time to react and, with the right action, can prevent contamination before it has an impact on production.
• Cost: FMS/BMS has become a more cost-effective and efficient way to continuously monitor. Labour costs are also significantly reduced.