INTERNATIONAL. STANDARD. ISO. First edition this PDF file can be found in the General Info relative to the file; the PDF-creation. The ISO Standards features two International Standards on biocontamination control for . Create a book · Download as PDF · Printable version. Impaction Technology and ISO Selection of Portable and Automated. Air Sampler Systems to meet cGMP by Jason Kelly. Rev
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ISO (E). PDF disclaimer. This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file. Details of the software products used to create this PDF file can be . This part of ISO specifies the methods required for monitoring. This part of ISO is the first general International Standard for biocontamination control. However, many factors besides cleanliness must be considered in.
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Although often overlooked by some laboratories, the international standard on biocontamination control, ISO , is an important resource for the development of a biocontamination strategy. There are two parts to this standard: Part 1 covers general principles and methods of biocontamination control; Part 2 covers the evaluation and interpretation of biocontamination data.
Both parts of ISO are currently undergoing revision. ISO is a part cleanroom certificate standard that is focused on airborne particulates. This standard covers cleanroom design, HEPA filter specification, pressures, and how to monitor a cleanroom in order to assess the cleanroom class. ISO focuses on the ongoing assessment of cleanrooms for viable contamination. Overview: Despite good design and the available guidance, cleanrooms are at risk for several sources of contamination, of which people are the greatest source.
Second to people, water is a key source of contamination. The challenge with water is that it not only allows contamination to spread, but it also helps microorganisms to grow.
Microorganisms are carried in air streams until they are deposited on a surface. Unless they have recently been disinfected, most surfaces will have contamination on them.
The fourth limitation is the residual agar transferred onto the surface being sampled; media residue on the surface must be promptly removed as media residue could serve as a nutrient source for microbial proliferation.
Prior to their implementation the type of media and incubation conditions must be qualified. If you decide to use both methods in the same area make sure the data is analyzed independently. This is because it has been reported that RODAC plates are superior to the swab technique for the detection of Gram-positive cocci, whereas Gramnegative rods can be detected more often by the swab technique.
Microorganisms are likely to be found in air and surface forming clusters of one or distinct strains, associated to dead skin scalp, soils or inorganic material. In addition, metabolic active microorganisms normally are found in different stages of cell cycle.
When conditions become unfavorable for growth bacteria stop replicating and viability starts to decrease.
A high initial bacterial load increases the likelihood to be recovered and identified. Once isolation of the microorganism is achieved, microbial characterization and identification is performed. Identification platforms may vary between pharmaceuticals. Genotypic and Phenotypic automated systems are commercially available.
The system chosen must be validated.
Characterizations can reveal useful clues as to the possible source of isolates. Routine characterization of isolates should continue to determine whether isolates are part of the normal microflora or represent something atypical.
Meanwhile, the level of identification of microorganisms from ISO 7 and ISO 8 class could be determined based on a risk assessment analysis. For example, for non-sterile class ISO 8 manufacturing or support areas it may be sufficient to identify isolates to morphology level by gram staining on a routine basis.
Higher level of identification is recommended for microbes isolated from aseptic processing areas and may require identification to species level. The key concern is to determine the state of control for the facility with some relative level of confidence. Indeed, there is regulatory guidance that suggests the requirement to identify isolates to strain level when investigating microbial excursions or sterility failure. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation.
The Gram stain method is prone to a significant level of operator error, which has encouraged the development of alternate methods for showing the difference in cell structures.
Nowadays, automated gram staining systems have provided some level of reproducibility. Most pharmaceutical companies identify isolates recovered from samples that have exceeded their alert and actions levels. Other pharmaceutical companies have designed a grid for randomly identified isolates. Less often others may identify the morphology of representative colonies captured.
Most aseptic pharmaceutical laboratories identify microorganisms at the species level. Most Pharmaceutical companies identify filamentous fungi isolates to at least the genus level if the colony counts reach action level, but I would recommend that it be done sooner at the alert level to remediate a potential fungal plum within critical control manufacturing work spaces.
Fast growing microorganisms should be identified at the species level, if possible. Such fast growing phenotype is a potential threat to the manufacturing environment and the product.
Some species of Bacillus tend to form spreaders on moist semisolid media. Early read of test samples before the end of incubation or test plates transfer to the following incubation temperature is recommended to get an accurate count if spreaders are present.
A final word of advice is to be consistent with the microbial identification platform used to identify isolates from different sources like EM samplings or finished product because the same strain tested using two different microbial identification platforms may give the laboratory results two different species names. This discrepancy may make it difficult to correlate matching microbes found in the finished product test with microbes recovered from the manufacturing area or specific raw materials used for product compounding.
Microorganism Prevalence in Cleanrooms The low density of aerosolized particulates within cleanrooms should reduce the amount of both inorganic and biological contamination on and within the assembled products.
The nutrient-deprived i. With a careful study of the EM data one may confidently predict this origin of microbial influx and ultimately design a mitigation step to prevent it from becoming a continued source of contamination for the controlled facilities. The identification of these entry sources is essential to improve microbial contamination prevention. There is no such thing as endogenous microflora for a constructed manufacturing facility.
The establishment of any microorganism within the cleanroom shall be considered as a control breach and must be investigated and eradicated.
Bacteria can adapt to distinct environmental conditions. These include adaptations to changes in temperature, pH, concentrations of ions such as sodium, and the nature of the surrounding available nutrients.
Bacteria react to a sudden change in their environment by expressing or repressing of various sets of genetic operons that control the expression of inducible proteins and other critical cellular components.
These responses change the properties of both the interior of the microorganism and its surface chemistry. A well-known example of this adaptation is the so-called heat shock response also known as stress shock response. The name derives from the fact that the response was first observed in bacteria suddenly shifted to a higher growth temperature. The engineering controls as well as frequent cleaning and disinfection of clean rooms is the major challenge for the minimizing the establishment of any microbial entity.
For rapid growth in different environments, bacteria need to adjust their enzyme levels to rapidly benefit from the nutrient mix that is currently available in the surrounding.
The opportunity for growth of bacteria is determined not only by the organic composition of their surroundings but also by sudden changes in the living environment. Therefore, this microbial phenotype type s must be available prior to the environmental change. Vegetative cells form spores under adverse conditions as a means of survival. Spore formation protects the bacteria from starvation, drying, freezing, harsh chemicals, and extreme heat. When conditions become favorable, the spores germinate, allowing each spore to once again become a vegetative cell with the ability to reproduce.
Among the bacteria, sporulation is not a means of reproduction since each cell forms a single spore which later germinates into a single cell again.
Most sporulating bacteria that grow in the presence of air belong to the Genus Bacillus, and those microbes that grow only in the absence of air belong to the Genus Clostridium. The endospores of several Bacillus species isolated from spacecraft assembly facilities have previously exhibited various levels of resistance to H2 O2 treatment.
Most human source microflora are mesophilic. The occurrence of thermophiles Geobacillus spp. Due to the described limitations of the EM methods currently available for pharmaceutical manufacturing monitoring, it is unlikely to obtain all the microorganisms that may occur in the clean rooms that employ the need for human intervention.
When manufacturing is performed in the presence of people, most likely the microorganisms recovered will be human source Gram positive, mesophilic aerobic or facultative aerobic bacteria. The current commercial growth media allows for the recovery and enumeration of these human and terrestrial microflora within a 7-day incubation period.
Although, as stated in the introduction the need for microbial environmental monitoring is a global regulatory and compendia expectation and should not be taken lightly. The frustration and caveats with the available commercial methods to perform these tasks is that their recovery capability of natural microorganisms is not optimal. Acknowledgments I would like to thank Dennis E. Guilfoyle, Ph. References 21 Code of Federal Regulations Good Manufacturing Practice for Finished Pharmaceuticals.
Cleanrooms and associated controlled environments—part I: classification of air cleanliness. ISO Sterilization of health care products — Radiation — Part 2: Establishing the sterilization dose ISO Cleanrooms and associated controlled environments — Biocontamination control. Part 1: General principles and methods. UNI; pp—1.
Brandes, R. Cundell AM Risk based approach to pharmaceutical microbiology. In: Miller MJ, ed. Encyclopedia of Rapid Microbiology Methods.