132
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      scite_
      Version and Review History
      Preprint
      EN Translations: RU
       
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Monitoring of microbial contamination of the educational and scientific cleanroom facility Translated title: Мониторинг микробного загрязнения учебно-научного Модуля чистых помещений

      Published
      research-article
      Bookmark

            Abstract

            The production environment in the pharmaceutical industry should not be a source of microbial contamination of the product. The purpose of this study was to examine the patterns of changes in the microbial contamination level in cleanrooms. The study was conducted at the educational and scientific Cleanroom Facility of the Biotechnology Department of the Obninsk Institute of Nuclear Power Engineering (IATE NRNU MEPhI). It was shown that the level of contamination of surfaces in a production facility increases with the presence of personnel on the premises. The degree of microbial contamination in the air varies slightly depending on the type of activity and the number of personnel on the premises. The compliance of the investigated Cleanroom Facility with class D for cleanrooms was confirmed. It was concluded that it is necessary to monitor the microbial contamination of premises more often as well as to implement the sanitary treatment in order to eliminate the sources of spore-forming microflora.

            Translated abstract

            Окружающая среда при производстве лекарственных средств должна обеспечивать минимальный риск микробного загрязнения продукта. Нами были изучены закономерности изменения уровня микробного загрязнения в чистых помещениях на примере учебно-научного Модуля чистых помещений Отделения биотехнологий ИАТЭ НИЯУ «МИФИ» (Обнинск). Показано, что уровень загрязнения рабочих поверхностей увеличивается при наличии в помещениях работающего персонала. Степень микробного загрязнения воздушной среды в зависимости от вида выполняемых работ и количества персонала изменяется незначительно. Подтверждено соответствие исследуемых чистых помещений классу чистоты D по микробиологической чистоте. Сделан вывод о необходимости чаще осуществлять контроль микробного загрязнения помещений, а также усилить санитарно-гигиенические мероприятия для устранения источников спорообразующей микрофлоры.

            Main article text

            INTRODUCTION

            According to the regulatory requirements, the production environment in the pharmaceutical industry should ensure the minimal risk of microbial contamination of the product. In order to confirm compliance with these requirements, it is necessary to conduct the regular microbiological monitoring of cleanrooms [1, 2].

            The results of microbiological monitoring are used for the selection of disinfectants, identification of sources of microbial contamination as well as to assess the effectiveness of the conducted sanitary and hygienic procedures. However, compliance with the level of microbial contamination for a certain class of cleanrooms is not the only goal of microbiological monitoring. The composition of the microflora is also important, since the presence of pathogenic and some opportunistic microorganisms present risks for the personnel and the product [3, 4]. If the microorganisms that pose a danger to human health and/or are resistant to adverse environmental conditions (for example, form spores or biofilms) are found in cleanrooms, it is necessary to act in order to eliminate them [5, 6, 7, 8].

            The goal of this project was to study the changes in the microbial contamination of the educational and scientific Cleanroom Facility of the Biotechnology Department of the IATE NRNU “MEPhI” (Obninsk) depending on the number of personnel and type of activity on the premises. Despite the fact that the cleanrooms at this facility are used for educational and research activities only, which means that the drugs produced there are not intended for release on the market, they are also subject to the declared cleanroom class requirements. In addition, the observed patterns of changes in the microbial contamination at this facility can be used to improve the operations in cleanrooms at pharmaceutical enterprises.

            MATERIALS AND METHODS

            The object of this study is the Cleanroom Facility, which includes four class D cleanrooms: No. 2 – storage room for raw materials (5.2 m2), No. 3 – locker room (14.8 m2), No. 4 – production area (40.2 m2), and No. 5 – finished product room (4.0 m2) (Fig. 1). A laminar airflow is maintained in the studied facility as well as a pressure drop between the rooms of at least 10 Pa (the type of pressure drop is “Cascade”); the highest pressure is maintained in room No. 4. The supply and exhaust ventilation systems of the facility provide three-stage filtration of the supply air: the first stage – filters G4 class and F5 class, the second stage – F7 class, the third stage – H11 class. Cleaning in the investigated cleanrooms is conducted at least once a month. Germicidal lamps/UV air purifiers are not used as an additional means for the reduction of microbial contamination.

            Fig. 1.
            Plan of the educational and scientific Cleanroom Facility with an indication of sampling points for the analysis of microbial contamination of air and for contamination of working surfaces. Description: AS – aspiration air control, SP – sedimentation air control, CP – control of working surfaces by contact plates method.

            Sampling points

            2 Raw materials storage room:

            2 AS1 / 2 SP1- the central part of the room

            3 Locker room:

            3 AS1 / 3 SP1 - “clean zone”

            3 CP1 – door knob

            3 CP2 – sink

            4 Production area:

            4 AS1 / 4 SP1 – near the entrance to the Locker room

            4 AS2 / 4 SP2 – near the granulator

            4 AS3 / 4 SP3 – near the tablet press

            4 CP1 – door knob

            4 CP2 – sink

            4 CP3 – celling (near the hood, close to the entrance to the Locker room)

            4 CP4 – floor (close to the entrance to the Locker room)

            4 CP5 – drainage screen under the sink

            4 CP6 – hood above the granulator

            4 CP7 – wall (near the granulator)

            4 CP8 – laboratory workbench (near the granulator)

            4 CP9 – tablet press

            5 Finished product room:

            5 AS1 / 5 SP1 – the center of the room

            Microbiological monitoring is carried out monthly in order to assess the microbial contamination level of the investigated facilities. The data presented in the present paper were obtained during the microbiological monitoring of the investigated cleanrooms for two years. The monitoring was carried out in the most critical places for microbial contamination: 6 locations for air control and 11 locations for work surface control (Fig. 1). Microbial contamination in the production area has the greatest impact on the quality of the product and, therefore, air control was carried out at three places with the highest risk of contamination: two locations near the production equipment and one near the entrance to the locker room.

            The working surfaces in the production area were monitored by the contact plates method at 9 locations: doorknob, sink, drainage grate, ceiling, and floor near the entrance to the locker room, hood, wall, and laboratory workbench next to the granulator, tablet press. The rest of the rooms are designed for the less critical operations and, therefore, the air sampling in each of them was carried out at one location in the center of the room, and the surface control was carried out at two locations in the locker room – doorknob and sink. The sampling scheme for the cleanrooms is shown in Fig. 1. The sampling was carried out during different activities – training sessions – on the premises including the determination of the contamination background (the concentration of aerosol particles and microorganisms); the production process simulation with the number of working personnel from 5 to 12 people; after the completion of the production process simulation; during validation of premises as well as after the cleaning. Samples during operations were taken 15-20 min after the start of the training session.

            The simulation of the Solid Dosage form production includes stages of mixing, grinding, and direct pressing. During cleanroom validation, the following parameters were measured: concentration of aerosol particles, airflow rate, air temperature and humidity as well as the pressure drop for different rooms. For each operation, the sampling was performed three times, with one sample taken at each location. Air contamination was determined by means of the aspiration and sedimentation methods using Petri dishes with a diameter of 90 mm. The contamination of working surfaces was measured by an imprint method using contact plates with a 55 mm diameter. The air quality was assessed by aspirating a 1000 l sample at each location with a PU-1B microbiological sampler (Khimko, Russia).

            The sedimentation method of air quality control was used during the production process simulation, after its completion as well as during the validation of cleanrooms. Sedimentation dishes were exposed for 4 h. During the production process simulation, sedimentation dishes were exposed through two successive stages (during the production process simulation with the number of personnel being 5 people/20-30 min after its completion; during the production process simulation with the number of personnel being 8 people/production process simulation with the number of personnel being 12 people). Sampling was carried out in parallel on two nutrient media produced by CFGS LLC (Russia) with additives of neutralizers (lecithin and tween 80): trypticase-soy agar for isolating bacteria and Sabouraud agar with dextrose for isolating yeast and fungi [1, 9].

            In order to minimize the influence of personnel on the results, air sampling with the PU-1B microbiological sampler in the process of determination of the contamination background was carried out after the personnel left the cleanrooms using the sampling delay function. During the determination of the contamination background, the personnel used the following personal protective equipment (PPE): coveralls, high shoe covers, a cap, and sterile gloves. The PPE used in the other sampling steps met the corresponding requirements for class D cleanrooms and included a disposable lab coat, shoe covers, cap, and sterile gloves. The collected samples were incubated in a SI500 thermostat (Stuart, UK) for 5 days at a temperature of 30-35°C (bacteria) and 20-25°C (fungi) [1, 9, 10]. Then the species of isolated bacteria were identified using the MicrogenID test systems (Microgen Bioproducts, UK), which consists of the microtubes containing dehydrated substrates and additional biochemical tests.

            Bacteria were identified according to the following sequence of operations:

            • - description of the cultural characteristics of the isolated microorganism;

            • - obtaining a clean daily culture by inoculation on trypticase-soy agar 18-24 h before testing [1, 10];

            • - Gram Staining procedure;

            • - selection of the required test system;

            • - preparation of a bacterial suspension according to the test system instructions;

            • - filling the microtubes with bacterial suspension;

            • - recording the color change of the culture media at the end of the required incubation period.

            The final conclusions were based on the results of the above-mentioned experiments and the biochemical reactions used in the test system database.

            Determination of the isolated mold fungi species was not carried out at this stage of the study, but their cultural characteristics were described.

            The average concentration of microorganisms in the air (M) and on working surfaces as well as the corresponding standard deviation (SD) were calculated with the help of Microsoft Excel 2010 using our experimental data.

            The proportions of gram-positive cocci, gram-positive and gram-negative rods as well as mold fungi were calculated as a part of the total number of isolated microorganisms.

            RESULTS

            The results of the contamination monitoring of the air and the working surfaces (average values) during different activities in the cleanrooms are shown in Table 1 and Fig. 2. According to these data, the levels of microbial contamination of the air and working surfaces do not exceed the limits set in the Order of the Ministry of Industry and Trade of Russia (No. 916 dated June 14, 2013), namely the 200 CFU/m3 limit for air by the aspiration method, the 100 CFU/dish limit for air by the sedimentation method (per 4 h), and the 50 CFU/plate limit for working surfaces by the contact plates method.

            Table 1.
            The composition of microorganisms in the air and on work surfaces in various operating conditions of the Cleanroom Facility.
            The type of activity/number of personnelThe composition of microorganisms in the air and on work surfaces (average values)
            Gram-positive cocci, %Gram-positive rods, %Gram-negative rods, %Mold fungi, %
            1Determination of the contamination background / 0 a 25.037.5037.5
            2After the cleaning of the premises / 2 a 94.70.90.44.0
            3After the completion of the production process simulation / 2 b 80.70.94.414.0
            4cleanroom validation / 9 b 70.80.91.926.4
            5The production process simulation / 5 b 80.61.03.914.5
            6The production process simulation / 8 b 80.41.06.711.9
            7The production process simulation / 12 b 96.9003.1
            a

            Totally 51 samples collected (by AS at 6 points, by CP at 11 points; all the measurements were performed in triplicate)

            b

            Totally 69 samples collected (by AS at 6 points, by CP at 11 points and by SP at 6 points; all the measurements were performed in triplicate)

            Fig. 2.
            Analysis of the microbial contamination of air and working surfaces.

            Analysis of microbial contamination of air by the aspiration method (A), by the sedimentation method (B); analysis of microbial contamination of working surfaces (C). The type of production process (number of personnel): 1 – determination of the contamination background (0), 2 – after the cleaning of the premises (2), 3 – after the completion of the production process simulation (2), 4 – cleanroom validation (9), 5 – the production process simulation (5), 6 – the production process simulation (8), 7 – the production process simulation (12).

            The isolated microflora was dominated by gram-positive cocci, which is typical for cleanrooms in general [3, 4, 11, 12]. Gram-positive and gram-negative rods were present on the studied premises at almost all stages of sampling and made up a small fraction (less than 10%) of the total number of isolated microorganisms (except for the sampling during the determination of the contamination background, when the portion of gram-positive rods increases sharply). Mold fungi were also isolated at all stages of the sampling. The microorganisms identified in this study are shown in Table 2.

            Table 2.
            The identification results of the isolated microorganisms
            Gram Stain identification resultsGenus/speciesRoomThe type of activity/number of personnelSampling pointSampling method
            Gram positive cocci Micrococcus spp. a
            Staphylococcus spp. b
            N 2, N 3, N 4, N 5Isolated from every sample (air, working surfaces)
            Gram positive rods Bacillus firmus N 4Determination of the contamination background / 0FloorContact plate
            After the cleaning of the premises / 2
            N 2After the completion of the production process simulation / 2AirAspiration
            Bacillus lentus N 4Determination of the contamination background / 0FloorContact plate
            Bacillus megaterium N 4Determination of the contamination background / 0Sink
            Bacillus mycoides N 4The production process simulation / 5Drainage screen
            Brevibacillus laterosporus N 4The production process simulation / 8Tablet press
            Geobacillus stearothermophilus N 4The production process simulation / 8Air (near the tablet press)Aspiration
            Gram negative rods Aeromonas hydrophila N 4The production process simulation / 8Drainage screenContact plate
            Aeromonas salmonicida N 3The production process simulation / 8AirAspiration
            Mannheimia haemolytica N 4The production process simulation / 5Air (near the tablet press)
            Pantoea spp.N 4Cleanroom validation / 9SinkContact plate
            Pseudomonas stutzeri N 4Cleanroom validation / 9Air (near the granulator)Sedimentation
            Ralstonia pickettii N 4The production process simulation / 5Air (near the entrance)Aspiration
            Rhizobium radiobacter N 4After the completion of the production process simulation / 2FloorContact plate
            Serratia ficaria N 4The production process simulation / 8Drainage screen
            Vibrio alginolyticus N 5The production process simulation / 5AirSedimentation
            Mold fungiGenus/species were not identifiedN 2, N 3, N 4, N 5Isolated from every sample (air, working surfaces)
            a

            Four different species were isolated including Kocuria kristinae и Kocuria rosea.

            b

            The following species were isolated: S. capitis, S. caprae, S. chromogenes, S. epidermidis, S. hominis, S. lentus, S. lugdunensis, S. warneri and S. xylosus.

            In total, 28 species of bacteria were isolated: gram-positive cocci (13 species), gram-positive rods (6 species), and gram-negative rods (9 species).

            DISCUSSION

            Cleanrooms are a unique habitat for microorganisms. Proper design and maintenance of cleanrooms create unfavorable conditions for the growth and reproduction of microorganisms that limits the diversity of microbial colonies in this environment. The main ways for microorganisms to enter the cleanrooms are through the personnel, water, raw materials, packaging materials, and other materials brought into cleanrooms (if they are not properly treated) [6, 12].

            The results of this study confirmed the class D compliance of the Cleanroom Facility in terms of the level of microbial contamination. The values obtained for air contamination by both aspiration and sedimentation methods did not exceed the established limits for class D cleanrooms (200 CFU/m3 and 100 CFU/dish, respectively) (Fig. 2A, 2B).

            The highest level of microbial contamination of air was recorded during cleanroom validation, with mold fungi making up more than a quarter of all the isolated microorganisms. These results can probably be explained by the long (about three weeks) downtime in the Cleanroom Facility with ventilation shutdown and a lack of cleaning procedures.

            In addition, due to the specifics of the educational program, the procedure of cleanroom validation included the intensive movement of personnel that led to the enhanced release of microorganisms. The concentration of microorganisms in the air in the course of determination of the contamination background (case 1 in Fig. 2A) is significantly lower than that in the presence of personnel.

            Analysis of the air samples during the production process simulation showed that there is no correlation between the number of people on the premises and the concentration of microorganisms in the air (cases 5, 6, and 7 in Fig. 2A). In addition, no statistically significant difference was found between the levels of air contamination during the production process simulation with 12 people on the premises (case 7 in Fig. 2A), after the completion of the production process simulation (case 3 in Fig. 2A), and after the cleaning of the premises (case 2 in Fig. 2A).

            These results showed that with the proper operation of ventilation and air filtration systems the degree of microbial contamination of the air in cleanroom does not depend significantly on the type of work performed and the number of personnel on the premises.

            The main conclusions on microbial air contamination from the aspiration method data were confirmed by the analysis of the data obtained by the sedimentation method (Fig. 2B). However, a comparison of the corresponding measurements made by the two methods (Fig. 2A, 2B) shows that sedimentation is a much less sensitive method than aspiration.

            The obtained values of microbial contamination of the working surfaces were also within the established limits for class D cleanrooms at less than 50 CFU/plate (Fig. 2B). The level of microbial contamination of the working surfaces was enhanced with an increased number of personnel on the premises during the production process simulation (cases 5, 6, and 7 in Fig. 2B), but there was no statistically significant difference between the level of contamination in cases with 8 and 12 people working on the premises (cases 6 and 7 in Fig. 2B, respectively).

            The level of microbial contamination of working surfaces during the class D cleanroom validation of premises (case 4) was comparable to that after the cleaning of the premises (case 2). These results could be explained by the thorough training for the cleanrooms entry/exit procedure that the personnel received right before the class D cleanrooms validation session. In addition, this session involved less contact of the personnel with working surfaces.

            The analysis of the samples in the series of sessions “After the completion of the production process simulation” (case 3) – “After cleaning of the premises” (case 2) – “Determination of the contamination background” (case 1) showed a statistically significant reduction of the level of microbial contamination of working surfaces. The highest content of gram-positive cocci was recorded at the sessions “After cleaning of the premises” (94.7%) and “The production process simulation” with the maximum number of working personnel (96.9%) (Table 1). The results obtained at the “After cleaning of the premises” session may be related to the fact that the bulk of the microorganisms was removed from the cleanrooms as a result of the cleaning, and the detected microorganisms were probably introduced by the personnel during the sampling. The smallest number of gram-positive cocci was isolated from the samples taken during the contamination background check. These results can be explained by the maximally reduced influence of personnel at this stage.

            Our results show that the proportion of gram-positive cocci increases in the presence of personnel. This conclusion was expected due to the fact that the main source of these microorganisms in cleanrooms is the personnel [3, 4, 12]. In addition, these data suggest that it is important to establish the maximum number of personnel for the specific cleanrooms and that the number should not be exceeded at any time. Despite being the major component of microbial contamination, gram-positive cocci rarely pose a hazard to the environment of cleanrooms, personnel, and products, since they are exterminated relatively quickly when treated with conventional disinfectants (for example, based on quaternary ammonium compounds) [13, 14, 17].

            Some of the isolated gram-negative rods can be hazardous to the cleanroom environment. For example, Ralstonia pickettii forms stable biofilms in water treatment systems that pose a risk of microbial contamination in the water during the production process [8]. Aeromonas spp. and Pseudomonas spp. can pose a danger to human health and, therefore, their presence in cleanrooms is also undesirable [8]. The sources of this group of microorganisms could be water, personnel, and raw materials (e.g. sucrose) [11]. Evaluation of the possible microbiological contamination from these sources was not an objective of the present study.

            Most of the identified species of gram-negative rods (6 species) have natural habitat (water and soil), 2 species – Mannheimia haemolytica and Pantoea spp. – are representatives of the human microflora; Serratia ficaria can be found in both the natural environment and human microflora. Representatives of the spore-forming microflora – gram-positive bacilli (Bacillus spp., Brevibacillus spp. and Geobacillus spp.) – as well as mold fungi were isolated practically at all the stages of the study, which indicates the existence of a constant source of these microorganisms on the studied premises.

            Their fraction sharply increased while determining the contamination background. This can be explained by the fact that the premises were carefully cleaned and the influence of the personnel was minimized. Under these conditions, single colonies of the most resistant microorganisms were isolated. They have the ability to form spores and show resistance to adverse factors, including disinfection [8, 13, 14, 16, 17]. The main source of spore-forming microorganisms in the investigated cleanrooms is the footwear of the personnel. Another source of the spore-forming microflora is packaging material (cardboard boxes), which is used in room No. 2 for the raw materials storage.

            The obtained data show that the patterns of change of the microbial contamination level and the composition of the detected microflora are complex. Microbial contamination regularities vary depending on the number of personnel and the type of work performed in the cleanrooms. Our data also indicate the need for the reduction of the microbial contamination in the cleanrooms, namely, for the elimination of spore-forming microflora sources. This requires:

            • - mandatory change of shoes by the personnel;

            • - abandoning cardboard boxes for storing raw materials and parts of production equipment in room No. 2;

            • - weekly cleaning of the cleanrooms using sporicidal agents.

            In order to assess the effectiveness of these measures and to improve the control of the microbial contamination of the investigated cleanrooms, it is necessary to measure the level of microbial contamination of the premises more often and to carry out the identification of the detected microorganisms on a permanent basis.

            In addition, it is necessary to control the raw materials and water for contamination with microorganisms. This will make it possible to identify the potential sources of microbial contamination in cleanrooms, and if such sources are identified, eliminate them in a timely manner.

            CONCLUSIONS

            1. The changes in the level of microbial contamination in cleanrooms have been studied. It was shown that the level of contamination of working surfaces and the proportion of gram-positive cocci in the air and on working surfaces increases when the working personnel are present on the premises. The degree of microbial air contamination varies slightly depending on the type of activities and the number of personnel on the premises.

            2. The class D compliance of the Cleanroom Facility in terms of the level of microbial contamination was confirmed. Nevertheless, it is necessary to measure the microbial contamination of the premises more frequently as well as to tighten the sanitary and hygienic procedures in order to eliminate sources of spore-forming microflora.

            3. In order to minimize the microbial contamination of the premises and the products, the control of microbiological purity should be extended to the raw materials and water used in production facilities. These procedures will help to eliminate the potential sources of microbial contamination.

            Acknowledgements:

            The authors are grateful to N. B. Epstein, Head of the Pharmaceutical Center for Practical Training and Competencies, IATE NRNU MEPhI, and S. G. Kolesnikova, Head of the Department of Microbiology, Virology, Immunology, IATE NRNU MEPhI, for the support provided during the study.

            Footnotes

            Conflict of interest: The authors have no commercial or financial interests.

            REFERENCES

            1. State Pharmacopoeia of the Russian Federation. RF MH. XIV ed. Vol. 1. Moscow, 2018. 1814 p. (In Russian).

            2. USP <1116> Microbiological control and Monitoring of Aseptic Processing Environments, USP 42 NF37, United States Pharmacopeial Convention, 2015. 10 p.

            3. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. Pharmaceutical CGMPs, 2004. 63 p.

            4. Environmental Monitoring of Clean Rooms in Vaccine Manufacturing Facilities. World Health Organization, 2012. 37 p.

            5. Sandle T. Cleaning Cleanrooms. Cleanrooms and technological environments 2011; 2(38), 32-6. (In Russian).

            6. Sandle T. The risk of contamination by microorganisms’ spores in the Cleanrooms. Part 1: Spores of microorganisms and the processes of survival. 2017; 4, 17-21.

            7. Aleksandrov AV. Risk Assessment of the microbial contamination in the operation of cleanrooms. Cleanrooms and technological environments 2010; 2(34), 24-31. (In Russian).

            8. Kusradze I. Undesirable microorganisms in non-sterile production. Cleanrooms and technological environments 2016; 4(60), 59-67. (In Russian).

            9. Pharmaceutical Microbiology Manual. U.S. FDA, 2014. 91 p.

            10. Lysak VV, Zheldakova RA, Fomina OV. Microbiology. Practicum: manual. Minsk, BSU, 2015. 115 p. (In Russian).

            11. Fedotov AE. Cleanrooms. Moscow, Asinkom, 2015. 512 p. (In Russian).

            12. Sandle T. People in cleanrooms: understanding and monitoring of the personnel factor. Cleanrooms and technological environments 2016; 2(58), 51-9. (In Russian).

            13. Sandle T. A Practical Approach to the Selection of Cleanroom Disinfectants. Pharma Focus Asia 2014; 21, 10-5.

            14. Sandle T. Selection and Use of Cleaning and Disinfection Agents in Pharmaceutical Manufacturing. Industrial Pharmaceutical Microbiology: Standards & Controls, Euromed Communications, Passfield, UK, 2014; 9.1-9.32.

            15. Fedotov AE. GMP basics. Moscow, Asinkom, 2012. 576 p. (In Russian).

            16. Sandle T. A new wave of sporicidal disinfectants. Clean air and Containment Review 2012; 10, 10-3.

            17. Steinhauer K. Problems of choosing biocides. Cleanrooms and technological environments 2013; 1(45), 37-9. (In Russian).

            Author and article information

            Journal
            MIR J
            Microbiology Independent Research Journal (MIR Journal)
            Doctrine
            2500-2236
            2021
            25 May 2021
            : 8
            : 1
            : 18-26
            Affiliations
            [-1]National Research Nuclear University MEPhI, 1, Studgorodok, Obninsk, 249040, Russia
            Author notes
            [# ] For correspondence: Anastasia Berestina, National Research Nuclear University MEPhI, 1, Studgorodok, Obninsk, 249040, Russia, e-mail: aberestina@ 123456mail.ru
            Author information
            https://orcid.org/0000-0001-7068-5074
            https://orcid.org/0000-0002-6673-1282
            Article
            10.18527/2500-2236-2021-8-1-18-26
            8ab5a34c-6d0a-480e-81e4-86a16ef6ef7a
            © 2021 Berestina et al.

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License (CC BYNC-SA), which permits unrestricted use, distribution, and reproduction in any medium, as long as the material is not used for commercial purposes, provided that the original author and source are cited.

            History
            : 06 September 2020
            : 03 December 2020
            Categories
            RESEARCH PAPER

            Immunology,Pharmaceutical chemistry,Biotechnology,Pharmacology & Pharmaceutical medicine,Infectious disease & Microbiology,Microbiology & Virology
            cleanrooms,microbiological monitoring,level of microbial contamination

            Comments

            Comment on this article