MC Oxoid P35 37 Sept 06 V3 12/15/06 9:33 AM Page 35
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MC Oxoid p35_37 Sept 06 v3 12/15/06 9:33 AM Page 35 aseptic technology AA strategystrategy forfor microbemicrobe monitoringmonitoring suits. If this process is not performed correctly, contaminants can enter the cleanroom on gowns, gloves, over- shoes, etc. The garments worn in the cleanroom must fit well, so that skin Figure 1: Typical settle particles are retained within the suit, and contact plates and be made of a material that does not shed fibres or particles. Aseptic tech- niques should be taught in order that Key to any cleanroom or aseptic operation is a planned personnel do not contaminate gloves after, for example, touching their faces. programme of monitoring. Colin Booth, vice-president Water is a potential vector of conta- mination, enabling organisms to spread science and technology at Oxoid, outlines the basis for a in ways they cannot on solid surfaces. Regulations state that there should be microbial monitoring strategy no water outlets in cleanroom areas; however, water is used in cleaning and here it is not possible to good cleanroom design; effective air is probably the most commonly used terminally sterilise, to be handling; cleaning and disinfection; raw material in manufacture. Water- confident of producing a staff training for adherence to aseptic based fluids must be sterilised before sterile product manufac- techniques; properly fitted cleanroom they are taken into the filling rooms. W turers of parenteral drugs gowns; sterilisation of materials As water is also used in cleanroom sup- must ensure that a robust environ- brought into the aseptic environment; port areas, pharmaceutical grade water mental monitoring programme is in adequate monitoring of controlled con- should be used wherever possible, and place within aseptic processing areas ditions (such as air flow and air pres- it should be microbiologically con- (cleanrooms). sure) along with alert settings that draw trolled and monitored. According to the US Food & Drug attention to a developing problem. Materials of animal, plant or natural Administration, environmental moni- There are many routes by which a mineral origin are considered to be of toring should promptly identify poten- cleanroom can become contaminated, higher risk than materials produced by tial routes of contamination, allowing personnel being one. In a well-designed chemical synthesis. However, any for implementation of corrections and controlled cleanroom, personnel materials introduced to an aseptic before product contamination occurs.1 Figure 2: Swabbing is are the most likely source of contami- processing area should be monitored It is one of the most important labora- used to monitor areas nation. This may originate in the for signs of damage and attention paid tory controls in aseptic processing, pro- that are difficult to changing room where personnel shed to the microbiological quality of the viding crucial information on the qual- access their own clothes and put on sterile material content. ity of the aseptic manufacturing envi- Disruption of airflow, air movement ronment; preventing the release of a and inadequate maintenance of HEPA potentially contaminated product; and filters could all cause contamination. preventing future contamination by HEPA filters should be free from leaks detecting adverse trends. around the sealing gaskets, frames and Ideally, a monitoring programme fabric. A high degree of air movement provides immediate feedback, allowing can pick up skin or dust particles from any problem to be rectified promptly. personnel or equipment, so cleanroom Environmental monitoring by micro- design should ensure that airflow biological means does not provide this sweeps particles away from the point- because of the incubation time required of-fill, product or other critical areas. to detect micro-organisms. Neverthe- Proper design will ensure uni-direc- less, the microbiological status of the tional airflow with no turbulence or cleanroom is a valuable tool that can stagnant air. indicate a loss of environmental control Although it is well known that the not picked up by other means. It also design and construction of the clean- serves as a reminder to personnel of the room should involve smooth surfaces importance of aseptic techniques. made of easy-to-clean materials, Environmental monitoring is only a special attention must be given to areas part of ensuring a sterile manufacturing that are difficult to clean and disinfect. environment. Other elements include: Different control measures should ᮣ www.manufacturing-chemist.info October 2006 manufacturing chemist 35 MC Oxoid p35_37 Sept 06 v3 12/15/06 9:33 AM Page 36 ᮣ be in place to minimise contamina- perforated cover through tion from these sources. which the air is drawn. The Table 1: Recommended limits for microbial contamination in The aim of an environmental moni- air impacts on the surface of clean areas levels (EU (2003) guide to GMP,Annex 1) toring programme is to detect a change the agar, along with the air- in count of colony forming units (cfu), borne particles, before being Classification of clean area Active air Settle plate Contact plate Glove print or a change of species, outside of the expelled through the rear of (cfu/m3) (90mm) (55mm) (cfu/glove) 'norm'. Minimum acceptable standards the machine. (cfu/4hr exposure) (cfu/plate) for clean areas are laid down in guid- Passive air sampling is per- Grade A (including local <1 <1 <1 <1 ance, such as the US Pharmacopoeia formed by placing agar plates (USP), the EU (2003) guide to Good (see Figure 1) in test areas, with zones for high risk Manufacturing Practice, Annex 1, Man- the agar surface exposed for a operations, eg, point of fill) ufacture of Sterile Medicinal Products, set time. In 1981, the Parenteral Grade B (background 10 5 5 5 (see table 1) and the Manufacture of Drug Association (PDA) recom- environments to Grade A Sterile Products 2002 (Therapeutic mended only 30 minutes, but zones in a cleanroom) Goods Agency, Australia). more recently other guidelines Grade C (support areas, 100 50 25 N/A The inspecting body will determine recommended that this be eg, rooms where aseptic the guidance that should be followed increased to four hours. The solutions are prepared for each site. Each site should establish logic is that longer exposure for filtration) its own alert and action levels based times increase the sensitivity of on the historical data. These must be at the method. However, care has least as strict as in the standard. If the to be taken against excessive desiccation are effective for sampling areas that are data suggests that local alert and action of the medium, since this may reduce not suitable for contact plates. For levels should be stricter, a regulatory recovery rates. either method, neutralisers may be body would expect these stricter levels Although passive air sampling is not included in the medium to counteract to be adopted. quantitative, settle plates are relatively residual sterilants and cleaning agents The most common micro-organisms inexpensive, require no extra equip- that may be present on test surfaces. isolated from aseptic processing envi- ment or technical expertise and are less The effectiveness of aseptic training ronments are bacteria from human likely to disturb the airflow in the and precautions can be measured by skin, such as Staphylococcus and cleanroom than active air sampling. periodically sampling staff clothing. Micrococcus species (gram-positive With either method, the frequency of The hands are a potential source of cocci). In addition, airborne bacterial testing should take into account the fact contamination and gloves should be spores (e.g. Bacillus species) and fungal that any human intervention intro- tested periodically – this is done by spores (e.g. Aspergillus or Penicillium duces an increased risk within critical touching the tips of all fingers and species) are found and, more infre- areas. The manufacturer must weigh thumbs onto the surface of an agar quently, gram-negative cocci (e.g. Enter- the benefits of these interventions plate, after which the gloves are obacter and Burkholderia species).2 against the disruptions created by per- replaced with a clean set. At the end of The data produced, both counts and forming them. a shift, other garments can be tested species, leads to a greater overall using contact plates or swabs. understanding of the microbial envi- surface samples The most frequently used culture ronment within the manufacturing area Regular sampling of surfaces within the media in environmental monitoring and, if performed regularly, can reveal processing environment is another are Tryptone Soya Agar (TSA) – a gen- trends or changes in established important aspect of monitoring an eral purpose medium suitable for the patterns. This information can be used aseptic environment. However, the growth of a wide range of organisms, to identify high-risk areas and to elimi- monitoring of critical surfaces during and Sabouraud Dextrose Agar (SDA) – nate potential routes of contamination. production is not recommended as this ideal for the growth of yeasts and There are two main methods for can increase the risk of contamination. moulds. Other key media used sampling air for microbial contamina- Surfaces can be sampled using contact include: R2A Agar (a minimal medium tion: active and passive. Active air sam- plates (Figure 1) or swabs (Figure 2). for testing water samples); McConkey pling is generally considered to be Contact plates are used to sample flat quantitative as it measures the number surfaces on equipment, floors, walls, Validating media performance of viable organisms in a defined countertops, etc. These specially volume of air (e.g. cfu/m3). Several designed agar plates have a domed sur- he growth promotion properties of each medium types of active air samplers are avail- face that is pressed gently onto the sur- used should be validated, according to plate size able, including sieve impactors, slit-to- face causing organisms present to be and fill volume, using a pre-defined list of organ- agar samplers, surface vacuum sam- transferred to the agar.