Environmental Monitoring in the Clean RoomMicrobiological Clues to Improving Your Practice

State of Control

Air and Surface

Sampling

By Abby Roth, CMQ/OE

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

35

Author Bio:

Abby Roth, CMQ/OE, is the Director of Microbiology at Clinical IQ LLC, a health care consulting firm. She has more than 13 years of experience in supporting the testing and consulting needs of the pharmaceutical, medical device, and compounding industries. Her background in pharmaceutical microbiology includes extensive knowledge of environmental monitoring, including program development, sampling technique, sample analysis, and data trending, as well as product testing. Roth also has experience in consulting on microbial contamination sources and remediation. She is currently serving as a member of the 2015 to 2020 USP Expert Panel on Sterile Compounding and is an active member of Controlled Environment Testing Association (CETA) and speaks at their annual meeting and other events.

Roth holds a bachelor of science degree in Biology with a minor in Chemistry from York College of Pennsylvania. In 2014, she became a Certified Manager of Quality/Organizational Excellence (CQM/OE) through the American Society for Quality (ASQ).

AUTHOR DISCLOSURE STATEMENT:

Abby Roth declares no conflicts of interest or financial interest in any product or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.

Questions or comments regarding this article should be directed to: Abby.Roth@Clinicaliq.com.

PHARMACISTS AND PHARMACY TECHNICIANS This INFUSION article is cosponsored by Educational Review Systems (ERS), which is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. ERS has assigned 1.0 contact hours (0.1 CEU) of continuing education credit to this article. Eligibility to receive continuing education credit for this article begins September 15, 2017 and expires September 15, 2020. The universal activity numbers for this program are: 0761-9999-17-267-H07-P and 0761-9999-17-267-H07-T. Activity Type: Knowledge-Based.

NURSESEducational Review Systems is an approved provider of continuing nursing education by the Alabama State Nurses Association (ASNA), an accredited approver of continuing nursing education by the American Nurses Credentialing Center (ANCC), Commission on Accreditation. Program #05-115-17-007. Educational Review Systems is also approved for nursing continuing education by the state of California, the state of Florida, and the District of Columbia. This program is approved for 1.0 hours of continuing nursing education. Eligibility to receive continuing education credit for this article begins September 15, 2017 and expires September 15, 2020.

DIETITIANS Educational Review Systems (Provider number ED002) is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered dietitians (RDs) and dietetic technicians, registered (DTRs) will receive 1.0 hour or 0.1 continuing professional education unit (CPEU) for completion of this program/material. Eligibility to receive continuing education credit for this article begins September 15, 2020 and expires September 15, 2020.

Dietitian Knowledge Level: 2Dietitian Learning Codes:2080 Microbiology, food toxicology5030 Home care5440 Enteral and parenteral nutrition support7100 Institution/regulatory policies and procedures, HCFA,

OBRA, Joint Commission, NCQA, OSHA, USDA

7160 Quality management

CPEAccreditedProvider

Approval as a provider refers to recognition of educational activities only and does not imply Accreditation Council for Pharmacy Education, ERS, or ANCC Commission on Accreditation, approval or endorsement of any product.

This continuing education activity is intended for pharmacists, pharmacy technicians, nurses, and other alternate-site infusion professionals.

In order to receive credit for this program activity, participants must complete the online post-test and subsequent evaluation questions available at www.nhia.org/CE_Infusion. Participants are allowed two attempts to receive a minimum passing score of 70%.

EDUCATIONAL LEARNING OBJECTIVES:1. List three common sources of microorganisms in the clean room.

2. Differentiate between environmental sampling that can be performed in-house and sampling that should be outsourced to professionals.

3. Identify five high-impact places within the sterile compounding environment that should be included in an environmental monitoring program.

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

36

In the interest of patient safety, home and specialty infusion providers are required to conduct environmental monitoring of their pharmacy facilities. Most comply with the hope that nothing out-of-the-ordinary will be found. While no one wants to see microbial load in their facility, it happens. Clean rooms are work areas where particle-generating people, products, and equipment coalesce.

Providers should come to the environmental monitoring process with the mindset of a detective. Even when the lab findings are within acceptable ranges, the data in these reports can provide clues that can identify areas where controls can be improved. Designing and conducting a meaningful environmental monitoring program—and looking closely at the findings—is a significant contribution to patient safety.

For something—an object, surface, liquid, etc.—to be considered sterile, it must be free from all forms of viable microorganisms. The process known as “sterile compounding” is not technically sterile, but aseptic (see box, p. 37). When clean room personnel perform aseptic processing, they are working in a controlled environment, using specific procedures to exclude microorganisms from the process and preventing microorganisms from entering open containers during manipulation. Essentially, aseptic procedures are designed to produce a sterile product.

This is an important distinction because when people use these terms interchangeably—a common mistake—expectations surrounding the presence of microbes can become distorted. In reality, microbial

contamination, at some level, in any environment where people are present, is inevitable. In the case of the sterile compounding clean room, it is to be expected.

However, many sterile compounding pharmacies have the unrealistic expectation that there should be no microbial contamination in any location, at any time. They conduct environmental sampling with the idea that the results should be consistently negative. Technically, this is not possible. And, it’s even more unrealistic given that sampling should be performed under dynamic operating conditions, meaning while people are present in the clean room simulating regular activities.

Action Levels

Essential Clean Room Definitions

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

37

in the recovery of microorganisms, which in turn can identify possible changes in the state of control of the clean room.

The clean room environment changes constantly. People and materials are moving in and out of the controlled space, triggering changes in room pressures. Environmental sampling just shows you what is happening at the sampling location at one point in time. A sample in the same location 10 minutes later could yield completely different results.

Maintaining a state of control goes beyond meeting the criteria for acceptable limits of microbial growth. It’s tempting for providers to look at their lab results, see that they passed, and move on. Even with a passing report, it’s important to review the data and look for trends. Do the numbers indicate that a certain location may be drifting out of control? As an example, if an air sample location in an ISO Class 8 anteroom, which has acceptance criteria of less than or equal to 100 CFU/m3, consistently recovers 10 colony forming units (CFU)/m3 and then recovers 90 CFU/m3, this should be evaluated and investigated. It indicates the location may be drifting out of the normal state of control.

Sterile VS. Aseptic

An article is deemed sterile when there is complete absence of viable microorganisms.

A set of specific practices and procedures performed under carefully controlled conditions with the goal of minimizing contamination by pathogens.

Sources: United States Pharmacopeial Convention, Inc. Chapter <1116>--Microbial Evaluation of Clean Rooms and Other Controlled Environments. United States Pharmacopeia 40 –National Formulary 35. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2016: 1336-1349. Encyclopedia of Surgery. 2017; Advameg, Inc.

Sterility

Aseptic processing

A properly designed clean room will help control the microbial contamination shed from humans, but cannot eliminate it. Factors such as people, products, equipment, and actions within the clean room combine to affect the bioburden potential in the environment. This is where good practices come into play. Proper hand hygiene, garbing, and other practices, are necessary to help reduce the microbial contamination from people. Thus, proper sampling—under dynamic conditions and in high-impact areas—offers a realistic picture of microbial presence in the environment. This data provides the necessary clues for action. Environmental monitoring should not occur in a vacuum—it’s a powerful tool in maintaining the controlled conditions required for aseptic processing.

Purpose of Environmental MonitoringIt’s essential to understand that microbial environmental monitoring “cannot and need not identify and quantify all microbial contaminants”1 in the clean room. Quantitative sampling is impossible—there would be no way to sample all the air and all the surfaces in a clean room. So, microbiological monitoring is semi-quantitative. It is equally important to understand that environmental monitoring cannot be directly correlated to sterility assurance. Finding microbial growth in the buffer room or anteroom does not necessarily mean that the sterility of compounded sterile preparations (CSPs) has been compromised.

Another crucial point is that environmental monitoring cannot prove the absence of microbial contamination—even when no microorganisms are recovered. Sampling results that indicate zero colony forming units (CFUs) only indicate that growth was not discovered, not that the clean room is completely free of microorganisms. There is no way to demonstrate that the air and surfaces within the clean room are sterile.

What sterile compounding pharmacies want is to show a state of control. Routine monitoring under dynamic operating conditions provides the data needed to demonstrate that state of control. The purpose of the environmental monitoring program is to confirm that the conditions in the clean room are consistent and appropriate. By performing routine sampling, a monitoring program can identify changes

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

38

Microbiology laboratories that specialize in the analysis of USP Chapter <797> environmental samples tend to see the same kind of organisms over and over, regardless of the clean room facility from which they were taken. The microbiologist can tell the source, generally, of the organisms by their type. This, in turn, can help the pharmacy evaluate its daily practices to identify the true nexus of the recovered growth. Following are a few examples.

Staphylococcus, Micrococcus, Corynebacterium, and Yeast Staphylococcus, micrococcus, corynebacterium, and yeast are commonly found on the skin and hair of people. People are the most significant particle generators in the clean room environment. The average person sheds approximately nine pounds of dead skin cells each year.2 These skin cells act as transport vehicles for bacteria, viruses, and other harmful microbes and can potentially introduce them into the compounding process. Staphylococcus, micrococcus, corynebacterium, and yeast will be present in environmental samples even if clean room personnel are garbing properly.

However, when lab results show microbial counts that exceed acceptable limits, the first culprits are usually practices designed to minimize particle shedding in the clean room. When microbiologists counsel pharmacies on their results, we suggest that they examine their garbing and hand hygiene

Common Findingsfrom the Lab Bench

processes. Although many pharmacies have a clearly defined and documented hand hygiene and garbing processes, there may be significant variation in how these activities are actually performed. Common issues include inconsistencies between individual staff members and improper donning of certain pieces.

Hair covers, for example, are typically the piece of garb donned incorrectly. When auditing employee practices, providers often find hair falling from under the cover, or covers that are not sufficiently pulled down over the ears. In other cases, gowns are not closed properly or may be ripped or torn during the compounding process and not replaced. Face masks are also an issue, as many clean room personnel are not aware that the mask must be donned with the folds on the outside of the mask, facing down. This ensures that the inside of the mask will catch more exhalation contaminates. The mask must fit snugly and stay in place without needing adjustments. It is important that the pharmacy culture empower personnel to approach coworkers in the event they notice garb is not worn properly or is compromised in any way.

Proper clean room behavior is also critical to reduce particle shedding and ensure that people are not contributing to excessive contamination in the room. It’s not uncommon for pharmacy

bacillus

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

39

Exhibit 1 Particles Shed by Activity

Activity Particles Generated

Sitting quietly 100,000

Walking slowly (1.9 miles/hour)

5,000,000

Walking medium (3 miles/hour)

7,500,000

Walking fast (5 miles/hour)

10,000,000

personnel to “pop” into a buffer room to grab an item or check something without performing the full hand hygiene and garbing procedures. While it may appear innocuous, this is not an acceptable practice because it can introduce large quantities of microbes into the environment at one time.

The pharmacy clean room is a busy place, but slow and controlled movements are necessary to reduce the number of particles that are shed. See Exhibit 1 for a comparison of particles shed with different activity. Personnel should also be aware of other behaviors that could contribute to contamination, such as leaning on walls, unnecessarily touching garb, handling cell phones, and excessive talking.

Mold and BacillusMold and bacillus are common contaminates brought into clean rooms on packaging materials as well as human hair, shoes, and clothing. These organisms can typically be found in soil and on cardboard packaging materials. If mold and bacillus are present, microbiologists suggest auditing personnel practices to see if shoe covers are being worn properly. Repeated issues with these types of organisms may warrant the use of dedicated shoes or double shoe covers.

The material transfer process is another procedural area to investigate. If mold is identified, consider

bacillus

Source: Particle Measuring Systems. Basic Guide to Particle Counters and Counting. 2011.

wiping materials with a sporicidal agent prior to brining them into the anteroom, as both mold and bacillus produce spores. Then as the material is transferred to the next ISO-classified space, it should be wiped again with 70% isopropyl alcohol (IPA).

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

40

Cleaning and Contamination ControlThere are three elements of contamination control that are essential in keeping microorganisms out of the controlled environment: material handling, hand hygiene and garbing, and proper conduct in controlled environments. These three checks work under the assumption that if a microbe doesn’t get into the controlled environment, it can’t pose a risk to the CSPs being prepared there. Cleaning, however, is necessary to address the breaches in contamination control that we have already established are unavoidable.

Similar to the words “sterile” and “aseptic,” there is an important semantic distinction between cleaning and disinfecting as relates to the controlled environment of clean rooms (see box, right). Cleaning is a mechanical process that is enhanced by germicidal detergents. Germicidal detergents remove dirt, debris, biofilm, and microbes. The use of a germicidal detergent is a cleaning step, which prepares the surface to be disinfected.

Most general cleaning agents have a surfactant that removes dirt. The daily use of a germicidal detergent to clean the primary engineering control (PEC), followed by 70% isopropyl alcohol (IPA), will eliminate most of the microorganisms found in a clean room. Note: 70% IPA is a disinfectant, not a cleaning agent. See Exhibit 2 for a list of properties of an ideal disinfectant.

A common misconception is that sterile water and sterile 70% IPA are the only agents required to clean a PEC. Cleaning of the PEC with a germicidal detergent is considered best practice. Another commonly misused agent is bleach. Bleach is not a cleaning agent and does not have a surfactant. It can, however, be used as a sporicide. A sporicidal agent should be incorporated into the cleaning process if environmental monitoring results indicate the presence of spore-forming organisms, such as mold and bacillus.

It’s the pharmacy’s responsibility to ensure that the personnel performing the cleaning are properly trained in cleaning procedures. From my experience, it is better for pharmacy personnel to perform the cleaning than to rely on environmental services (either internal to an institution or contracted). Proper technique, along with the required dwell time of the cleaning and disinfecting agents used will have a significant impact on the effectiveness of the cleaning. From the laboratory’s perspective, it is difficult to tell from sampling alone whether the cleaning process is sufficient. In many cases where a standardized cleaning process is used, the cleaning agents may not always be appropriate for the organisms recovered in sampling. This underscores the importance of closely reviewing the environmental monitoring reports and adjusting practices—even when bioburden is at acceptable levels.

Cleaning VS. Disinfecting

Removing visible soil (e.g., organic and inorganic material) from objects and surfaces. Normally accomplished manually or mechanically using water with detergents or enzymatic products.

Eliminating many or all pathogenic microorganisms, except bacterial spores, on inanimate objects. In health care settings, objects usually are disinfected by liquid chemicals or wet pasteurization.

Source: U.S. Centers for Disease Control and Prevention (CDC). Guideline for disinfection and sterilization in healthcare facilities, 2008.

Cleaning

Disinfecting

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

41

Sampling ProcessThe best thing a home or specialty infusion provider can do is to conduct its own environmental sampling. Many organizations are already performing their own surface and gloved fingertip sampling, so adding viable air sampling is not a stretch. The benefit to performing all the sampling internally is that it’s much quicker to resample and obtain additional data when necessary.

Viable air samplers involve an upfront investment, but if the sampler can be shared throughout a health system or across multiple locations, purchasing one can offer cost savings compared with paying a vendor. There are many different types of samplers available. Volumetric, impaction air samplers are appropriate for home and specialty infusion pharmacies. Be aware that some types of viable air samplers require special proprietary media sold by the equipment manufacturer. Choosing a sampler that uses standard plates allows more flexibility when purchasing media—in some cases the same media

plates can be used to sample both air and surfaces. The pharmacy personnel doing the sampling must be trained and have documentation to show they are competent. There is no need for a pharmacy to perform non-viable particle counts. These are required for clean room certification, and must be performed by a qualified certifier.

Many providers worry that the counts in their lab results are erroneously high. From a laboratory’s perspective, false positives are uncommon and difficult to identify, unless they can be traced to issues with sample handling or contamination. In this case, there may be obvious contamination around the edges of the plate. A laboratory should notify the pharmacy if it suspects the samples were contaminated. The lab should also contact the pharmacy if it knows of sample handling issues or any other lab deviations that would affect the results. Any questionable results must remain as part of the pharmacy’s documentation and resampling should be performed.

When sampling, it is important to properly handle the media plates to avoid inadvertent contamination. Gloves must be worn during sampling and they must be sanitized frequently with 70% IPA. Special care should be taken when loading and unloading the air sampler. The lid of the plate should be returned promptly and gloves must be sanitized before handling the plates. The media plates should not be handled around the edges, as this is the most common way plates are contaminated.

Partnering with Outside VendorsFrom having worked in a contract microbiology laboratory that processed USP <797> samples for 13 years, I recommend using a laboratory that has experience processing pharmaceutical environmental monitoring samples. A qualified lab should have ISO 17025 accreditation and be registered with the U.S. Food and Drug Administration (FDA).

Many hospital labs are Clinical Laboratory Improvement Amendments (CLIA) accredited. The requirements for this accreditation are stringent, but they may not always be appropriate for processing samples from a pharmacy environment.

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

42

CLIA defines a laboratory as a facility for the biological, microbiological, serological, chemical, immunohematological, hematological, biophysical, cytological, pathological, or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings. Based on that definition, CLIA accreditation would not cover environmental monitoring samples. In addition, many clinical microbiology laboratories set their incubators at temperatures higher than suggested USP <797> incubation temperatures.

Some labs are CLIA exempt, as per the Centers for Medicare & Medicaid Services (CMS), because their state licensing requirements are equal to or more stringent than CLIA requirements. However, I would still recommend using a pharmaceutical microbiology laboratory because this type of lab will have experience in handling environmental monitoring samples, employ appropriately trained personnel, and possess the proper incubation capabilities.

Exhibit 4 Areas Suggested for Clean Room Sampling

Area Air Surface

Class 5 Primary Engineering Control (PEC)

Immediately outside of PEC where the technician is; cart or table the technician uses to stage materials

Cart used to transfer materials

Near anteroom door inside and outside of negative pressure room where hazardous drugs are used/stored

High-touch surfaces such as printers and phones to ensure that workers spray their hands before returning to work

Doors, especially if people use their body to open the door

Anteroom - around sink, on counters, and/or nearby shelves

Pass through, especially on the side of higher classification

Automatic compounding devices for total parenteral nutrition

Avoid floors and walls unless performing an investigation

Not on the dirty side of the line of demarcation because that area should be dirty

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

43

Any medium used for microbiological testing must be prepared by a known manufacturer that has quality systems in place to assure the medium is appropriate for use. A reputable company is one that has an ISO Certificate of Registration as an ISO 9001 or ISO 13485 facility. In addition, manufacturing facilities must be registered with the FDA.

It is the pharmacy’s responsibility to ensure it has received a quality product. Each lot of media must have a certificate of analysis that documents the results of the quality control testing performed by the manufacturer to ensure the lot is suitable for release. These certificates should be examined upon receipt for accuracy and completeness and retained on paper or electronically.

Media purchased for environmental monitoring (viable air, viable surface, and gloved fingertip) must be irradiated and double or triple bagged. This allows a layer of packaging to be shed as the media moves into the clean room from one ISO Class into the next. Liquid media (tryptic soy broth, TSB) used in media fill competency tests for low- and medium-risk must be sterile. Dehydrated TSB used for high-risk media fill competency must be non-sterile.

Creating an Environmental Monitoring PlanAn environmental monitoring plan is a blueprint for assessing the state of control within the sterile compounding environment at regular intervals. Collecting and analyzing sample data offers clues to what is happening microbiologically inside the facility, and in turn, can suggest which practices can be targeted for improvement. The environmental monitoring plan must be documented and include specific elements (see Exhibit 3).

The sampling locations should be determined based upon an assessment of risk to the CSP. Many times, pharmacies allow the technicians who certify their clean rooms and equipment to make the decisions about where to sample. Each pharmacy knows best where to sample since it understands the workflow, CSPs produced, and equipment use that could potentially contribute to a higher probability of adversely affecting the CSPs. According to USP Chapter <797>, “selected sampling sites shall include locations within each

ISO Class 5 environment and in the ISO Class 7 and 8 areas and in the segregated compounding areas at greatest risk of contamination (e.g., work areas near the ISO Class 5 environment, counters near doors, pass-through boxes).” See Exhibit 4 for examples of high-contact areas that are suggested for sampling.

Regarding frequency, USP <797> lays out specifics for when and why sampling should occur (see Exhibit 5). As mentioned previously, the only way to ensure the controlled environment is in a state of control is to sample more frequently. For example, monthly sampling can provide enough data to trend for abnormalities. While monthly sampling is not required, one advantage to sampling more frequently is to identify seasonal changes and help the pharmacy understand how they affect the controlled space. As an example, a pharmacy in proximity to farmland may see an increase in mold and bacillus in the spring and fall when the fields are being plowed and harvested.

When action levels are exceeded, FDA and state board of pharmacy inspectors will expect evidence of an investigation and remediation. There must also be documentation regarding the remediation efforts

Source: United States Pharmacopeial Convention, Inc. Chapter <797>. United States Pharmacopeia 39 –National Formulary 34. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2016: 626-670.

www.nhia.org/CE_Infusion

Sept

embe

r/O

ctob

er 2

017

44

and whether or not they were successful. However, as mentioned previously, some results, even if they do not exceed acceptable levels, may require further investigation and corrective action. By being proactive and implementing corrective actions when results indicate a negative trend, a pharmacy can avoid potential excursions and major investigations.

ConclusionIt’s often said that you can’t manage what you don’t measure. This adage applies to effective clean room facility management as well. For a pharmacy to ensure that it is producing the safest possible CSPs, it must maintain a state of control in the clean room. That does not mean a complete absence of microorganisms, which is impossible. It means a bioburden that is consistently within acceptable levels, and a well-constructed plan for monitoring and implementing corrective action to ensure that it remains under control. Pharmacies are encouraged to play an active role in sampling and analyzing data so that they may learn more about the factors that affect their clean room environment.

References1. United States Pharmacopeial Convention, Inc.

Chapter <1116>—Microbial Evaluation of Clean Rooms and Other Controlled Environments. United States Pharmacopeia 40 –National Formulary 35. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2016: 1336-1349.

2. Donovan S. Stay Clear!: What You Should Know about Skin Care. Health Zone. Lerner Books. September 2008.

3. United States Pharmacopeial Convention, Inc. Chapter <797>. United States Pharmacopeia 39 –National Formulary 34. Rockville, MD: United States Pharmacopeial Convention, Inc.; 2016: 6 6-670.

Learn more about nutritional therapiesNHIA Module 4: Nutrition Therapies: Parenteral Nutrition, Enteral Nutrition, and Hydration

• Available in PDF and print

• Self-study program

• 5 contact hours of continuing education credit awarded after successful completion of online post-test.

Developments in Home Parenteral Nutrition: Preventing and Managing Complications in Pediatric Patients (1 CE credit)

Order today. www.NHIA.org/store

NHIA Talk Infusion Webinar

Thursday, October 26, 2017 | Noon – 1:00 PM, ET

Includes Q & A with speaker Kathleen Gura, PharmD, BCNSP, FASHP, FPPAG, FASPEN

NHIA Members: FREE See details online at www.nhia.org

This webinar is supported by

Talk Infusion Webinars are sponsored by the NHIA Future of Infusion Advisory Council (FIAC)