GMP Sources of Particulate Contamination in Cleanroom
The inert or non-viable particles originate from manufacturing process or equipment supplying air to the manufacturing areas(AHUs), garment fibers. The viable organisms require support to sustain in the environment, which is provided by such type of particles. Therefore microbial spores, bacteria, and viruses by clinging on to the surface of the non-viable particles gain access into the exposed product and contaminates it. So, it becomes extremely important to contain non-viable particles in order to protect the product from contamination. As far as particles for air supply is concerned, these can be effectively removed by HEPA filters with an efficiency of 99.97% down to 0.3 µm, but most important is to focus on containing other sources of particle generation. The sources of particulate generation is classified into two broad categories i.e. internal and external.
These are the sources which are present inside the classified rooms or clean spaces.
1.0 Area Personnel
2.0 Manufacturing Process
3.0 The complexity of processing equipment
4.0 AHU duct-work after terminal HEPA filters
5.0 Items which are transferred into the clean space may harbor contaminants
6.0 Utility Service lines (especially insulated ones)
Personnel are the greatest source of contamination in a clean space. There are lot of variables associated with the personnel, which result in dispersion of different levels of particles from them. These include:
1. The type and level of garments a person is donning.
2.. Personnel comfort w.r.t. the area humidity and temperature.
3. The type of activity undertaken and way of performing that activity.
4. No. and type of manual interventions in an aseptic processing.
5. Level of training received.
The combination of all of these variables produce different results of particle emission from a person. The nature of particles emitted from personnel can either be non-viable or viable. Therefore to restrict these particles from entering into the exposed sterile product, the practice of using a barrier technology i.e. RABS or isolators has proven to be exceedingly useful.
The processing machinery releases mostly non-viable particulate matter if consistently stored and maintained under the clean conditions post validated cleaning. However the cleaning activity, being a demanding in nature, may release large quantities of particles during cleaning. There are some manufacturing processes in which processing equipment have an inherent tendency to generate particles, such as Centrifuges used in Biological Product Processing.
The generation of particles from the process, is dependent on the nature of the product being processing, e.g. especially sterile powder processing. In such cases airborne product itself becomes a source for cross-contamination of another product. So, the product spread should be restricted using combination of segregation philosophy and contained reverse laminar flows. If the nature of the product is liquid, then it should not be allowed to dry, as on drying it forms aerosols and facilitates cross-contamination of other product. Area work surfaces should always be kept clean, where the activity has a potential to dislodge particles deposited on the surface. Consideration should be given to the airflow patterns during the designing stage to ensure that airflow does not move from such areas towards critical areas.
Particles generated within the HVAC system are eliminated high efficiency particulate air filters. The location of HEPA filter is most critical as it shall ensure the cleanest air is supplied in the area. Therefore, the final HEPA filters should not be placed either in an AHU or in a supply duct, but should be placed at terminal supplies to the area.
It is important to understand the source of particulate contamination with respect to the material transfer. Both viable and non-viable particles get transferred to the cleanrooms alongwith the transfer of materials. If sterility is the only concern, then sterile materials should be supplied using double or triple bagging. However, care should be taken when removing the outer packaging to ensure it does not pose a threat to the inner packaging. Transferring bulky materials is particularly difficult so such items may have to be wheeled into the cleanroom on trolleys due to the weight or size of the material. These trolleys should be thoroughly cleaned and disinfected before entering the cleanroom, in particular the wheels. Use of Sticky mats may help to remove excess contamination from the floor area.
The insulation typically open-celled polyethylene foam used in cleanrooms is prone to the performance problems. The standard open-celled insulation can also shed particulate due to everyday contact from workers who need to gain access through tight spaces. The insulation in some chilled-water applications are susceptible to condensate formation, due to crevices or cracks resulting from impact damage or normal wear and tear from worker contact. Condensate formations therefore can provide a huge breeding ground for microbial growth, a highly undesirable intruder to any cleanroom environment. It is recommended to use PVDF based self adhering insulation tapes in order to avoid conditions as mentioned above.
Room pressures play a major role in spread of particulate contamination. So a room maintained at a positive differential pressure, stops the infiltration of contaminated air from less cleaner adjoining areas. The rooms of different cleanroom classifications should be segregated by means of placing an airlock with interlocked doors, to assure that one door always remains closed, to avoid direct infiltration of air to the cleaner spaces. The differential pressure greater than that of the lesser cleaner area and lesser than that of the cleaner spaces should be maintained in the airlock. It depends upon the nature of product handled and intent behind putting the airlock, as to whether the airlock shall remain a bubble type or a sink type.
So if a cleanroom is maintained at positive differential pressure then airborne particulate contamination shall depend on quantity of particles generated inside the room or particles carried into the room and on cleanliness of air supplied and degree of air dilution achieved.