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How automated monitoring systems can increase contamination protection and save you time and money.

MOST OF US HAVE EXPERIENCED being in a barn on a sunny day with the sun penetrating the wooden slats and the small light speckles reflecting the sunlight and moving all around us. Looking at the shaded areas the small light speckles are not visible. The reason is that the particles in the shade are unable to reflect the sunlight penetrating the slats and for that reason we do not see them. We breathe in millions of particles everyday. Our immune system is able to combat 99% of the particles we inhale with the exception of some bacteria and viruses.

Inside a cleanroom, the environment is controlled using high efficiency particle air filters, more commonly known as HEPA filters. Depending on the classification of the cleanroom, the number of air changes per hour increases or decreases. That environment is tested and classified based on the validation work carried out.

So when a cleanroom is built, it reaches its highest classification before the process equipment or operators are introduced. With the introduction of process equipment and operators, the levels of particles entering the cleanroom rise. Gowning up and the use of smooth surfaces on process equipment reduce the build up of particles but equipment with moving parts and the operators still generate a considerable amount of particles. Independent tests show that the average human generates about 500,000 particles/minute. That figure reduces by gowning up but particles are still generated. Sources of contamination may include; dead skin and hair, cosmetics and clothing, bacteria, an addition of a new contaminated product, or ingression from operating environment.

It is critical that sterile environments are particle free. Consider a drug manufacturer whose product is administered to patients intravenously. The most critical point during the process of the final product is the filling and capping. Viable particles should be non-existent in these areas; otherwise the patient’s health is at risk as his or her already low immune system may not be able to effectively combat contaminated medicine. Also, if the particle is big enough it may block veins or capillaries. These are just some of the reasons why this type of industry and product are heavily regulated by bodies such as the FDA (Food and Drug Administration) and the EC (European Commission).

How do we fight a battle when we cannot see what we are trying to eliminate? Particle counters and air samplers are used to monitor cleanrooms. Particle counters detect the size and concentration of particles present. Air samplers detect what types of particles are present.

There are two types of particles 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. Grade A sterile environments monitor continuously during production using facility monitoring systems (FMS) and biological monitoring systems (BMS).

Map of cleanroom with FMS software. Monitoring locations are
clearly identified and sample data for 0.5µm and 5.0µm displayed.

Table outlining cleanroom classification and
maximum viable and non-viable particles per m3of air sampled

A FMS contains particle sensors mounted in critical areas along the filling machine that detect non-viable particles. The data is sent back using a SCADA software system that is controlled and monitored by the operator. 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. Before the process begins, the sampling heads are loaded with 90 mm Petri dishes containing a media. One system on the market cleverly uses bar coding 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 again 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 FMS software must be 21CFR11 compliant after validation.

The advantages of using automated systems for particle monitoring outweigh any manual labor system, 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 labor 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 are also used in the same manner.

The following are some of the advantages when monitoring with FMS and BMS.

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 thus 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.

Labor: Using a FMS/BMS saves labor costs as the systems are automated and can generally be run and supervised by one operator significantly reducing labor costs.

Reliability: FMS/BMS by nature of their design, are more reliable and in the case of breakdown, plug-and-play can be utilized 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. Labor costs are also significantly reduced.

Summary
All drug manufacturers must comply with current Good Manufacturing Practice (cGMPS) regulation. Compliance must be demonstrated at every stage before a drug can be released to market. Facility monitoring and biological monitoring systems are the most effective and reliable methods for monitoring of viable and non-viable particles in Grade A/B Cleanrooms.

Jason Kelly is Director of Optical Sciences at OptiCal Sciences (Ireland) Ltd.Pembroke, Carlow, Co.Carlow, Ireland.He has been in the cleanroom industry for nearly 10 years working in the semiconductor industry at Intel before moving over to the pharmaceutical industry where he has managed projects and FMS installations at many pharmaceutical, medical device, and biotech companies in Ireland.He can be reached at +353 (0)59 91 82948 or jason.kelly@optical-sciences.ie.