環境感染誌

Vol. 38 no. 3, 2023

〈原 著〉

Effect of the Clean Bench Configuration Environment on Cleanliness during
Intravenous Hyperalimentation Infusion Preparation
Seiichiro KURODA1）, Anna KIYOMI2）, Shinobu IMAI3） and Munetoshi SUGIURA2）
Department of Pharmacy, IMSUT Hospital-The Institute of Medical Science, The University of Tokyo, 2）Department

1）of Drug Safety and Risk Management, Faculty of Pharmaceutical Sciences, Tokyo University of Pharmacy and Life
Sciences, 3）Department of Pharmacoepidemiology, Faculty of Pharmaceutical Sciences, Showa University(Received: November 25, 2022; Accepted: February 18, 2023)
Abstract
When mixing and compounding injectable agents, performing aseptic manipulations on a clean
bench maintained according to the requirements of the US Federal Standard Class 100 (≤100
pcs/ft3) is crucial for the prevention of contamination by airborne particulates or microbes. Owing to air turbulence generated by the compounding manipulations and other factors, the level ofcleanliness in the clean bench may be affected by the configuration environment. We configured
clean benches in different environments with mean airborne particulate counts of (A) 1,000, (B)30,000, and (C) 300,000/ft3 and with the sash opened to 20 and 40 cm and measured the amountof particulate matter and microbes when preparing intravenous hyperalimentation infusions. For
the particulate count, Class 100 was maintained in all configuration environments when the sash
was opened to 20 cm, but Class 100 was not maintained in any of the environments when the
sash was opened to 40 cm. When the sash was opened to 20 cm, no microbes were detected;
however, at 40 cm, microbes were detected in all environments, with the level exceeding theNASA reference range (≤0.1 pcs/ft3) in environment C. Therefore, the configuration environmentof the clean bench and size of the sash opening impact the level of cleanliness regarding theamount of particulate matter and microbes in a clean bench. This study prescribes conditions
necessary for maintaining cleanliness in clean benches from an air cleanliness perspective whenpharmacists are mixing and compounding injectable agents in hospital wards or pharmacies.
Key words: clean bench, airborne particulates, airborne microorganisms, compounding environment, aseptic formulation

operation Scheme (PIC/S) Guide to Good Manufactur-

Introduction
When injecting a patient with a drug, the sealed am-

ing Practice for Medical Products annexes１０）, and thepoule or vial is opened and the drug is extracted andJapan Society of Hospital Pharmacists Guidelines forcompounded using a syringe or another device, with a

Injection Mixing 2004１１） describe the environments re-risk of contamination from particulates such as glass

quired for sterile compounding, including cleanrooms

pieces or microbes. Because the administration of con-and clean benches. In the classifications (1-8) based on

taminated pharmaceutical liquids can lead to thrombus

airborne particulates, as defined by the Internationalor sepsis, comprehensive aseptic procedures andOrganization for Standardization (ISO) 14644-1 (Clean-

proper compounding environments are required whenrooms and associated controlled environments ― Part

compounding injectables１〜８）.

1: Classification of airborne cleanliness by particle con-

The United States pharmacopeia chapter 797: Phar-centration), environments for sterile compounding(USP-

must conform to ISO Class 5 (Class 5). Classifications

797) , the European Pharmaceutical Inspection Co-

have traditionally used the United States Federal Stan-

maceutical
９）

compounding-sterile

preparations― 114 ―

環境感染誌
Table 1Vol. 38 no. 3, 2023

Prescriptions for the compounding of intravenous infusions in the current study

Product Name

Product Name (English)

AmountForm

HICALIQ-2
HICALIQ-3
PROTEAMIN 12X injection
Elemenmic Injection
Heparin Sodium Injection 10,000 units/10 mL

HICALIQ-2
HICALIQ-3
PROTEAMIN 12X Injection
Elemenmic Injection
Heparin Sodium Injection

700 mL × 1 Bag
700 mL × 1 Bag
200 mL × 3B
2 mL × 1A
2 mL

Soft bag
Soft bagGlass bottle
AmpouleVialdard, and although ≥ 0.5 μm/ft3 of airborne particulate

Materials and Methods

had been used as an indicator, ISO standards are cur-

1．Measurement of airborne particulates

rently used. In addition to this classification, USP-797

1.1

and PIC/S require that airborne particulates and air-

(1) Clean bench configuration environment

Measurement conditions

borne microbes be used as monitoring indicators not

A one-person, vertical, laminar flow-type clean bench

only during off-times but also during work hours, and(CCV type, Hitachi Industrial Equipment Systems Co.,

that environments obtain qualifications for sterile com-

Ltd., Tokyo, Japan) was installed in a cleanroom with apounding.

mean of 1,000 particulates/ft3 (environment A). By tem-

However, the actual compounding of injectables isporarily shutting down the air conditioning in the

not limited to cleanrooms, and in numerous situations,cleanroom, an environment with a mean of 30,000 par-compounding occurs using equipment such as clean

ticulates per ft3 was established to simulate a generalbenches installed in quasi-clean areas such as hospitalclean area, such as a hospital ward (environment B).

wards. However, compared to a cleanroom where the

The same clean bench was installed in a regular in-entire room is a clean area, with a clean bench, cleanli-door environment with a mean of 300,000 particulates/

ness is only maintained within the space inside theft3 (environment C). The particulate counts in the con-glass door (sash) in the quasi-clean areas. Therefore,

figuration environments were measured before com-the level of cleanliness in a clean bench may vary de-pounding the infusions to confirm that they were uni-

pending on the configuration environment and theform.

movements of the preparer during compounding. How-(2) IVH infusion compounding methods

ever, the available guidelines do not indicate how theThe IVH infusions were prepared by a single person

configuration environment may impact the level ofwearing a specialized separated, polyester, dust-freecleanliness of a clean bench. In addition, there is no

garment, cap, mask, and sterile latex gloves. The com-

unified index for specific clean bench configuration en-

pounding contents were two soft bag formulations,vironments, and the instruction manual for each clean

three glass bottles, one ampoule formulation, and one

bench states that “the opening width of the front open-

vial formulation (Table 1). The IVH infusion bag anding and closing glass door (Sash) should be maintained

disposable syringe were washed with sterile distilled

at approximately 20 cm” or is not described, so thatwater and sprayed with an ethanol disinfectant before

they are configured according to each institutionʼsbeing placed in the clean bench.

standards.

The soft-bag and glass bottle formulations were

Therefore, in the present study, we investigated thehung on the upper part of the clean bench, and the

optimal environment for compounding injectables, us-

opened rubber stopper was disinfected using an etha-

ing airborne particulate and microbe counts as indica-nol cotton swab. The ampoule and vial formulations

tors to clarify how the configuration environment influ-

were individually apportioned using a disposable syr-ences the level of cleanliness of clean benches and theinge, mixed in the glass bottles, and placed in the IVH

bacterial contamination of the compounded intrave-infusion bags by administration from above. A 21 G

nous hyperalimentation (IVH) infusions.

Veress needle (TERUMO Co., Ltd., Tokyo, Japan) wasused for the glass bottle formulations for air injection
cannula. Compounding tasks such as disinfection andweighing of the ampoule and vial formulations were
performed at least 15 cm inside the clean bench from― 115 ―

環境感染誌

Vol. 38 no. 3, 2023

Fig. 1
Description of the compounding environment for the preparation of intravenous infusions
HEPA, high efficiency particulate air

Table 2

Existing standards for airborne particulates and airborne microorganisms
Airborne particulate countAirborne microorganism
count

Name
(Class)ISO 14644-1(Class 5)

Federal Standard 209D
(Class 100)

NASA NHB5340.2

Units ofmeasure

/m3

/ft3

/ft3

Reference
Values＜＿ 3,520 pcs＜＿ 100 pcs＜
＿ 0.1 CFU

the sash１２）. IVH infusions were prepared four times installed at a point 15 cm inside the clean bench fromeach environment (A, B, C) with the clean bench sash

the sash and 10 cm above the working surface (Fig. 1;

opened to 20 cm (sash20) and to 40 cm (sash40), the★ surface).
The air in the clean bench was continuously aspi-

recommended opening width for this clean bench (Fig.

rated at 500 mL/min and particulates of ≥ 0.5 μm

1).
1.2

were measured every 0.01 ft3 (40 s) and converted to 1

Measurement standards

The ISO 14644-1 (Class 5) is currently used for air-ft3. Measurements were carried out continuously fromborne particulate count. However, in the Federal Stan-the beginning to the end of the IVH infusion com-

dard (209D; Class 100) １３） used in the present study

pounding process. Measurements started after the(which has different unit volumes but is essentially thepharmaceutical products and the equipment necessary

same standard), the number of particulates ≥ 0.5 μm

for compounding were loaded into the clean bench and3left in place for 80 s, and once the airborne particulate

Measurement methods

count was confirmed to be 0, compounding took 480-

per 1 ft is set to ≤ 100 (Table 2).
1.3

The measurements were performed using an optical
diffusion-type particle counter (Particle Counter KC-01,

520 s. Four measurements were performed in each environment (A, B, C).

Sibata Scientific Technology Ltd., Tokyo, Japan) in― 116 ―環境感染誌
5．Statistical Analysis

2．Measurement of airborne microbial count
2.1

The Mann-Whitney U-test was used to compare par-Measurement conditions

Measurements were performed under the same con-ticulate and microbe counts for sash20 and sash40 inenvironments A, B, and C (significance level < 0.5%).

ditions as for airborne particulate count.
2.2

Vol. 38 no. 3, 2023

Spearmanʼs product-moment correlation coefficients

Measurement standards

The airborne microbe standard was ≤ 0.1 colony
3

were calculated for the particle and microbe counts.

forming units (CFU) per 1 ft based on the National

All statistical analyses were conducted using EZR ver-Aeronautics and Space Administration (NASA) stan-sion 1.36 (Saitama Medical Center, Jichi Medical Uni-

１４）

dard NHB5340
2.3

versity, Saitama, Japan).

(Table 2).

Measurement methods

The measurements were performed using an air

Results
1．Airborne particulate countsampler (RCS air sampler, Biotest Ltd., Dreieich, Germany) equipped with a special medium (Agar strip for

Figure 2 shows the particulate counts during infu-

general bacteria, Biotest) installed at a point 15 cm in-sion compounding. In sash20, the measurements wereside the clean bench from the sash and 10 cm above

Class 100 or below in environments A, B, and C,

the working surface (Fig. 1; ★ surface). The 320 L ofwhereas in sash40, the median particulate counts were

air inside the clean bench during compounding wasover Class 100 for environment A (162.4/ft3), environ-suctioned to collide with the medium, and the number

ment B (106.5/ft3), and environment C (100/ft3). In addi-

of colonies (CFU) after culturing (32-37ºC for 3 days)

tion, while there was a difference in the particulate

were counted and converted to the number of mi-

count between sash20 and sash40 in environment A (Pcrobes per 1 ft3 using the following formula. Four

< 0.05); the count between environments B and C wasmeasurements were performed in each environment

similar.
2．Airborne microbe count(A, B, C).
3

Figure 3 shows the microbe counts during infusion

Microbe count (CFU/ft ) = Number of colonies oncompounding. No microbes were detected in environ-

medium (CFU) × 0.708/sampling time (min)3．Measurement of the frequency of microbial con-ments A, B, or C with sash20. However, with sash40,

tamination in the compounded IVH infusions

the microbe count exceeded the NASA standard in en-

Microbial contamination in the IVH infusions com-vironment C (the median was 0.17/ft3) and the microbe

pounded in environments A, B, and C were compared

count was higher than that with sash20 (P < 0.05).

in terms of the frequency of colony development.

3．Frequency of microbial contamination in com-

The chemical solution was suction-filtered (pore size:

pounded IVH infusions

0.45 μm) using an aspirator equipped with a 55-Plus

Table 3 shows the frequency of microbial contamina-

Monitor (Millipore), and 2 mL of general bacterial cul-tion in the IVH infusions. With sash20, no microbes

ture medium was added to the base where the filter

were detected in the infusions mixed in environments

was installed and used as the Petri dish for culturing.

A, B, or C. However, with sash40, 25% (1/4 bags) ex-

Culturing was performed at 32-37°C for 3 days１５）.

hibited microbial contamination in environment B andAs a control, the same technique was used to pre-25% (1/4 bags) in environment C. However, the fre-pare infusions at an infusion stand without a clean

quency of contamination did not increase due to dete-bench in environment C. Microbial contamination ofrioration of the configuration environment. In addition,

the infusions was measured in the same manner.

when compounding was performed in environment C

Measurements were performed four times in each en-

without a clean bench, the frequency of microbial con-vironment, A, B, C, and the control.

tamination was 75% (3/4 bags).
4．Relationship between airborne particulate and

4．Relationship between particulate and microor-

microbe counts

ganism counts
Correlation coefficients were calculated to examine

Figure 4 shows the relationship between the particu-

the relationship between the particulate and microbelate and microbe counts. A weak, positive correlation

counts in environments A, B, and C. Correlation coeffi-

was observed between the particulate and the microbe

cients were also calculated for sash20 and sash40.

count (R2 = 0.60). The correlation coefficients were cal― 117 ―環境感染誌

Vol. 38 no. 3, 2023
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Fig. 2
Airborne particulate count in the preparation of compounded intravenous infusions on clean bencheswith mean airborne particulate counts of (A) 1,000, (B) 30,000, and (C) 300,000/ft3, with the sash opened
to 20 cm or 40 cm.
The box plots show indicate an 〜 95% confidence interval of the median calculated as median±1.58×
IQR/√ (n), with iqr being the difference between the third and first quartiles.

culated for the particulate and microbe counts for eachsash was opened to 40 cm, Class 100 was not met,

sash size. No correlation coefficient was calculated foreven in environment A. In addition, the particulate

sash20 because no microbes were detected at any ofmatter count tended to increase as the configuration

the measurement points (Fig. 4, 〇, △, □). For sash40,

environment deteriorated (Fig. 2). In a study using awhile no correlation was observed in environment A

safety cabinet with an air barrier, Chiba et al .１６，１７）

2(R = ­0.26, Fig. 4●), strong positive correlations were2

found that movements of the preparerʼs arms caused

observed in environment B (R = 0.77, Fig. 4▲) and en-

airborne particulates in the external environment tovironment C (R2 = 0.89, Fig. 4■).

cross the air barrier and enter the cabinet. A clean
bench is thought to maintain cleanliness by supplying
a constant air volume (Q) to the workspace area (A),Discussion
When mixing and compounding injectables, it isand the cleanliness of a clean bench is given by Q (m3/critical to do so using aseptic manipulations in an envi-h) = passing air velocity V (m/s) × A (m2). Conversely,ronment maintained at Class 100 to prevent contami-

in the one-sided, vertical, laminar flow-type cleannation by airborne particulates and microbes. The re-bench, the air supplied to the workspace is discharged

sults of the present study indicated that when IVH in-

only from the Sash opening surface, so that theoreti-

fusions were compounded at a point 15 cm inward

cally, the passing wind velocity in Sash40 is consideredfrom the sash, with the sash opened to 20 cm, the par-to be lower than that in Sash20. In addition, the pre-ticulate count inside the clean bench was not affected

sent study used a clean bench without an air barrier.

by the configuration environment of the clean benchThis is the first study to provide objective data dem-and Class 100 was maintained. However, when the

onstrating that increasing the size of the sash opening― 118 ―

環境感染誌

Vol. 38 no. 3, 2023

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Fig. 3
Airborne microorganism count on clean benches with mean airborne particulate counts of (A) 1,000, (B)30,000, and (C) 300,000/ft3, with the sash opened to 20 cm or 40 cm.
The box plots show indicate an 〜 95%confidence interval of the median calculated as median±1.58×
IQR/√ (n), with iqr being the difference between the third and first quartiles.

Table 3Frequency of microbial contamination in compounded intravenous infusions on clean benches with mean airborne
particulate counts of (A) 1,000, (B) 30,000, and (C) 300,000/ft3, with the sash opened to 20 cm or 40 cm

Compounded environment
mean airborne particulate counts (/ft3)
sash opened (cm)Counts of IVH infusions in whichmicroorganisms were detected

A

B

C

1,000

30,000300,000

20

40

20

40

20

40

clean bench
unusednotdetectednotdetectednotdetected

1/4

notdetected

1/4

3/4

affects the entry of airborne particulates from the ex-

even when compounding is performed using a clean

ternal environment.

bench.

In addition, the microbe count was 0 CFU/ft3 in all

The particulate and microbe counts inside the clean

environmental configurations with sash20, whereas mi-bench exhibited a weak positive correlation (R2 = 0.60;

croorganisms were observed in all environments with

Fig. 4) although environment A did not exhibit the

sash40, exceeding the NASA standard in environment

higher correlation reported by Simones et al .１８，１９） With

C (Fig. 3). In environment C, where the NASA stan-

sash40, a strong correlation was observed between thedard was not maintained, microbes were detectedparticulate and microbe counts as the configuration en-

from infusions compounded without a clean bench andvironment deteriorated. In the present study, exclud-

those compounded with a clean bench with sash40 (Ta-ing in environment A, the indoor air conditioning wasble 3). This suggests that bacterial contamination of in-turned off and disturbances in airflow from the move-fusion solutions can occur in configuration environ-ment of people and objects were eliminated. In addi-

ments with higher particulate and microbe counts,

tion, when preparing for formulation, items and phar-― 119 ―

環境感染誌

Vol. 38 no. 3, 2023&)8IW&ODVV

Airborne microorganism count

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Fig. 4
Correlation between particulate and microorganism counts in the preparation of compounded
intravenous infusions on clean benches with mean airborne particulate counts of (A) 1,000, (B)30,000, and (C) 300,000/ft3, with the sash opened to 20 cm or 40 cm,
NASA, National Aeronautics and Space Administration

maceuticals such as syringes brought into the cleantings, the airflow in the clean bench configuration envi-

bench were disinfected with an ethanol disinfectant;ronment may be disturbed by people or objects, which

the preparer wore a separated, polyester, dust-free

is something that needs to be considered. In addition,

garment that did not expose the skin; and aseptic com-the mixing and compounding of injectables may bepounding was performed. Consequently, we do notcomplicated by the combination of different prescrip-

think that any bacteria adhered to the inside of thetions, depending on an individualʼs pathology. The pre-clean bench or that any particulate matter or microbes

sent study used a one-sided, vertical, laminar flow-type

originated from the compounderʼs skin. Therefore, weclean bench. In future, differences between models

presume that the microbes in the clean bench wereshould be examined. However, the one-sided, vertical,

particulate matter and microbes from the configura-laminar flow-type clean bench used in the presenttion environment that entered through the sash during

study is structurally supplied with air from the top of

the compounding work. Because the particulate andthe clean bench to the work surface, and exhausted

microbe counts exhibited a stronger correlation as the

only through the sash opening. In addition, widelyconfiguration environment deteriorated, in addition toused clean benches comply with Japanese Industrial

using appropriate sterile compounding techniques２０，２１）,

Standards (JIS) B9922２２） and meet the air velocity andit may be possible to prevent microbial contamination

air volume standards. Therefore, considering theby compounding injectables in a suitable environment.

movement of the airflow and the performance of the

A limitation of this study is that in actual clinical set-clean bench, we believe that the results of the present― 120 ―

環境感染誌

sion, and medication vial practices in health care. Am J Infect Control 2010; 38(3): 167-72.
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11）Japan Pharmaceutical Association: Notification No. 151, 24
August, 2012.
12）Hotoda S, Aoyama T, Sato A, Yamamura Y, Nakajima K,
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benches during preparation of intravenous hyperalimentation (IVH) admixtures. Yakugaku Zasshi 1999; 119(12): 9218.
13）Whyte W: A multi-centre investigation of clean air requirements for terminally sterilized pharmaceuticals. J
Parenter Sci Technol 1983; 37: 138-44.
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1-44.
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on a filter utilizing airborne silver nanoparticles. Journal of
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16）Chiba Y, Takahashi M, Amano K, Tani H: Abstracts of paper. The Annual Meeting of the Society of Heating, AirConditioning, and Sanitary Engineers of Japan. Nagoya,2017. p. 109-12.
17）Tani H, Takahashi M, Amano K, Chiba T: The Annual
Meeting of the Society of Heating, Air-Conditioning, andSanitary Engineers of Japan (Abstract). Nagoya, 2018. p.
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20）Isanhart CM, McCall KL, Kretschmer D, Grimes BA: Parenteral laboratory course to reduce microbial contamination rates in media fill tests performed by pharmacy students. Am J Pharm Educ 2008; 72(2): 27.
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22）Japan Standards Association, JIS B9922, (2001).
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study are also applicable to other one-sided, vertical,
laminar flow-type clean benches.
According to the results of the present study, when
performing sterile compounding in a clean bench atleast 15 cm from the sash, the opening of the sash
should be no more than 20 cm to prevent the configuration environment from having an impact while maintaining Class 100. As reported by Kata et al .２３） thecompounding environment and standards for the mixing and compounding injectables differ from facility tofacility. Therefore, it is necessary to protocol compounding environments and procedures for mixing andcompounding injectables. The present study prescribes
conditions necessary for maintaining cleanliness inclean benches from an air cleanliness perspective
when pharmacists are mixing and compounding injectables in hospital wards or pharmacies.
Acknowledgments: We express our sincere gratitude to former Professor Takao Aoyama of the Faculty of Pharmaceutical
Sciences, Tokyo University of Science, for advice on experimental methods.

Conflicts of interest declaration: There are no conflicts of interest to disclose with regards to this study.

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Yoshimura A, Hirai Y: Bacillus cereus bacteremia outbreak due to contaminated hospital linens. Eur J Clin Microbiol Infect Dis 2011; 30(2): 219-26.
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Vol. 38 no. 3, 2023

〔Reprint request:― 121 ―

環境感染誌

Vol. 38 no. 3, 2023

Seiichiro Kuroda, Department of Pharmacy, IMSUT HospitalThe Institute of Medical Science, The University of Tokyo, 4-61 Shirokanedai, Minato Ward, Tokyo 108-8639
E-mail: hotoda-tky@umin.ac.jp〕

IVH 用輸液調製時のクリーンベンチ設置環境がクリーンベンチ内清浄度に及ぼす影響
黒田誠一郎 1）・清海杏奈 2）・今井志乃ぶ 3）・杉浦

宗敏 2）

1）
東京大学医科学研究所附属病院薬剤部，2）東京薬科大学薬学部医薬品安全管理学教室，3）昭和大学薬学部薬剤疫学部門

要

旨
注射薬を混合調製する場合は空気中の浮遊微粒子や微生物による汚染を防ぐために米国連邦規格
Class 100（100 個/ft3 以下）に維持されたクリーンベンチで，無菌操作を行うことが重要である．
しかし，調製作業時の気流の乱れなどにより，クリーンベンチ内の清浄度が設置環境の影響を受ける可能性がある．我々は，クリーンベンチを平均浮遊微粒子数（A）1,000，（B）30,000，（C）300,000
個/ft3 の異なる環境下に設置し，かつ Sash を 20 cm および 40 cm に開口した条件で IVH 用輸液の混合調製を行った時のクリーンベンチ内の微粒子数および微生物数を測定した．微粒子数は Sash
を 20 cm に開口した場合，いずれの設置環境でも Class 100 を維持していたのに対し，40 cm 開口した場合はいずれの設置環境においても Class 100 を維持できなかった．また，微生物数は Sash
を 20 cm に開口した場合は，すべての測定点で微生物の検出はなかったが，40 cm に開口した場
合は，すべての環境で微生物が検出され，（C）において NASA の基準範囲である 0.1 個/ft3 以下を超えていた．以上から，クリーンベンチ設置環境と Sash の開口幅がクリーンベンチ内の微粒子数および微生物数清浄度に影響を及ぼすことが示唆された．
Key words：クリーンベンチ，空気中浮遊微粒子，空気中浮遊微生物，調製環境，無菌調製〔連絡先：〒108-8639 東京都港区白金台 4-6-1
東京大学医科学研究所附属病院薬剤部
E-mail: hotoda-tky@umin.ac.jp〕― 122 ―

黒田誠一郎