Road to USP <800> Compliance
Section 15: Deactivating, Decontaminating, Cleaning, and Disinfecting
Sections 1 through 14 of USP Chapter 800: Hazardous Drugs—Handling in Healthcare Settingsprovides the blueprint for safely getting a hazardous drug into our facilities and compounding. On our road to compliance, Section 15 provides us with a very comprehensive overview of the concept of ‘cleaning’ and its importance in the process of safely handling hazardous drugs.
IMPORTANT: Isopropyl Alcohol is NOT a cleaning agent.
Sterile compounding requires a robust contamination control program that must consider personnel and material flow; personnel gowning, training and behavior; aseptic manipulation, interventions management, and environmental monitoring. Integrated within this complex system lies cleaning and disinfection. The concept of a formal cleaning program was brought to light with the introduction of USP <797> in 2004. Prior to the introduction of this minimal practice standards document, compounding locations classified cleaning as a non-formal process in the management of medications. Hospital pharmacy departments, due to the nature of state regulations, accreditation interpretations and fear of pilfering, often limit environmental services (EVS) from conducting formal cleaning programs for which they have been trained. This limitation of EVS to pharmacy departments has relegated the cleaning processes to pharmacy staff with varying, inconsistent and inadequate results due to lack of training and validation.
The Food and Drug Administration (FDA) has highlighted the concern over the cleanliness of compounding conditions for medications for patients in their recently revised guidance document ‘Insanitary Conditions at Compounding Facilities Guidance for Industry.’ In the introduction the FDA reminds us that, “Under section 501(1)(2)(A) of the Federal Food, Drug, and Cosmetic Act 351(a)(2)(A)), a drug deemed to be adulterated ‘if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health’.” Although not an enforceable document, it serves as a guidance for the protection of the public. The guidance document clearly states, ‘Drugs (including biological products) prepared, packed, or held under insanitary conditions are deemed to be adulterated, regardless of whether the drugs qualify for exemptions set forth in sections 503A or 503B of the 28 FD&C Act,’which encompasses hospital and alternate care locations. The unfortunate impetus for FDA publishing this guidance is based on ‘insanitary conditions that FDA has observed’on inspections of compounding locations which include hospitals, 503A pharmacies, 503B compounding manufacturers and the pharmaceutical industry. FDA states the scope of the guidance ‘are applicable to both sterile and non-sterile drug production.’
Proposed revisions to USP <795> Pharmaceutical Compounding – Non-Sterile Preparations, USP <797> Pharmaceutical Compounding – Sterile Preparations, and, proposed USP <800> Handling Hazardous Drugs in Healthcare Settings each have sections devoted to cleaning and surface sampling. Proposed/revised USP <795> defines Cleaning as “The process of removing soil (e.g., organic and inorganic material) from objects and surfaces, normally accomplished by manually or mechanically using water with detergents or enzymatic products.”,, Proposed/revised USP <797> defines a Cleaning Agent as; “An agent for the removal of residues (e.g., dirt, debris, microbes, and residual drugs or chemicals) from surfaces,” and, proposed USP <800> adds complexity to the process by building on the ‘cleaning’ definition under section 14.4 Cleaning C-PEC and Other Devices Used for Compounding HDs by adding the additional steps of Deactivation, Decontamination, Cleaning, and Disinfecting.
Historically, sites compounding medications for patients have customarily used 70% isopropyl alcohol as a ‘cleaning’ agent. However, isopropyl alcohol is not a cleaning agent; it is a disinfectant and does not meet the definitions listed within the noted USP standards as a cleaning agent. The use of isopropyl alcohol as a misunderstood surrogate cleaning agent in non-cGMP compounding locations has been employed without a validation process to support the effectiveness of the agent. As noted, for an agent to be defined as a cleaning agent it must remove dirt, debris, microbes and drug residues. The lack of cleaning-ability of isopropyl alcohol is most evident with hazardous drug compounding.
For more than 30 years, studies have found residues of hazardous drugs present in measurable concentrations throughout the environments where they are handled. We also know that these residues can carry-over throughout the line of handling—from the receipt of the drug at the loading dock to compounding, to administration, and to its final disposal.
The goals for the USP <800> cleaning program must be viewed as protective for the patient, protective for all healthcare individuals all the continuum of handling and the environment. For sites to be compliant with USP <800> for cleaning, they must be compliant with the requirements set under USP <795> for non-sterile and USP <797> for sterile pharmaceutical preparations. Establishing a cleaning program for hazardous drugs must have both under-chapters as the base to build from and sites should not establish a program in a vacuum. USP <800> has devoted an entire section to cleaning, highlighting the importance. Section 15 outlines the 4-step process of DEACTIVATING, DECONTAMINATING, CLEANING, AND DISINFECTING noting that not one single method or cleaning process exists as a universal standard for all hazardous drugs. Due to the importance of the 4-step process, USP <800> defines each step and provides the ‘why’ for each step with the goal of removing hazardous drug residue, returning the cleaned location to baseline (no-residue or contamination), not damaging the cleaned, and providing a suitable work environment to protect personnel and patients. Simplistically defining each step will help staff understand the importance of each step:
Deactivation is intended to render any hazardous drug surface contamination inert or inactive. It is important to recognize that in terms of deactivation, there is no one proven method for inactivating all compounds. EPA-registered oxidizing agents represent the most widely used option and should be used when possible (e.g., peroxide formulations, sodium hypochlorite, etc.). However, it is important to recognize that agents are caustic, and products such as sodium hypochlorite will pit or stain stainless steel surfaces if left in contact too long.
Decontamination focuses on inactivating, neutralizing and physically removing surface contamination by the deactivation agent and hazardous drug residue and transferring it to sterile, lint-free, absorbent, disposable materials. Chemicals such as sodium thiosulfate can help neutralize chemicals used in the deactivation step to minimize corrosion and pitting of stainless steel. As a bonus to enhancing the cleaning process, this step should be strongly considered for each drug vial that may come contaminated from the manufacturer. Applying this step to vials can reduce contamination introduced into the sterile compounding engineering controls (hoods). It is important to ensure that the solvent used for wiping vials does not alter the product label.
Cleaning is intended to remove contaminants from surfaces using water, detergents, surfactants, solvents or other chemicals, and the Cleaning section in Chapter <797> is appropriate for both hazardous and nonhazardous drugs. It is very important to make sure that any products used for cleaning do not introduce microbial contamination. Facilities should look to the product material specifications to ensure they are EPA-registered to meet the five “-cidal” criteria: bactericidal, fungicidal, virucidal, tuberculocidal and sporicidal. If an agent states that it “kills spores” or that it kills a specific type of spore, that is not the equivalent of being labeled as a sporicidal agent. If a product that is being used is not clearly labeled as sporicidal, a sporicidal-labeled agent should be added to a scheduled cleaning regimen. Another important note about cleaning agents is the contact time of an agent with a surface to induce the specific -cidal response. Some agents require up to five minutes of direct contact time to be effective, meaning applying the agent in the defined quantity and allowing it to stay on the surface for the noted time. Wiping away the agent(s) too soon removes the benefits of the cleaning agents and may allow microbes to proliferate.
Disinfection is intended to inhibit or destroy any microorganisms and must be done for areas needed to be sterile. EPA-registered disinfectants and/or sterile 70% isopropyl alcohol are appropriate agents for this step. The use of ultraviolet light as a means for disinfection should only be considered as an adjuvant to physically applying and removing liquid disinfecting solutions. The biofilm that might be left on surfaces can be removed with the physical wiping motion.
Following the cleaning process, it is important to examine the areas for visible residue that may be left behind by some products, often denoted by hazy/white-ghost smears or drops. Visible residue is unacceptable, and it must be understood that dried chemicals no longer possess their desired activity. Dried residue is considered a contaminant and represents potential air pockets between the surface and the residue that can harbor spores and can easily be transferred to the sterile field or products. In addition, dried residue left on surfaces can lead to corrosion of the surfaces if not removed for long periods. Regulatory inspectors often see residue as an indication of inadequate cleaning and the FDA issued a guidance document on the concern of residues.
As sites define each location where hazardous drugs are handled, they must employ certain steps of the 4-step cleaning program. For example,non-sterile areas where HDs are handled (receiving containment ventilated enclosures (CVE)) and reusable equipment and devices (counting trays; spatulas; unit dose devices) must be deactivated, decontaminated, and cleaned. For sterile preparation areas, as directed by USP <797> must include the final step of disinfecting. It is important that cleaning solutions that are selected are not reactive to surfaces to be cleaned and will not harm equipment or impact the protective nature of devices employed to provide safety (e.g. melting surfaces, pitting stainless steel, melting casing of electrical wires, penetrating gloves, impacting the HEPA filter seals in primary engineering controls).
Clearly written standard operating procedures must be in place and should include the specific name of defined chemicals used for the 4-step cleaning process, any dilutions of solutions, assigned expiration dates to on-site prepared solutions, frequency, and documentation steps.
The process of employing the cleaning methods listed should be classified as a hazardous process, thus, requiring formal education and documentation of training of personnel performing these activities. Sites must clearly define what personal protective equipment must be donned when handling cleaning solutions. Noted cleaning solutions can be caustic to skin and may illicit respiratory reactions. All personal protective equipment (PPE) must be vetted to demonstrate they are resistant to the cleaning solutions use. It should not be assumed that hazardous drug rated PPE is suitable for all cleaning solutions. As a starting point sites should review the literature of their PPE and consider the use of two pairs of hazardous drug gloves rated to ASTM 6978D and impermeable disposable gowns rated to ATM 739. Since the process of cleaning has the potential to splash sites should strongly consider the use of tight-fitting eye protection or face shields. As noted, some solutions may require the addition of respiratory protection beyond a ‘paper-mask’ and sites should consider a fitted N95 mask and to assist solutions with nauseous odors, a carbon based R95 mask.
The World Health Organization (WHO), released a report identifying hospital cleaning solutions as a potential cause of respiratory and reproductive disorders, eye and skin irritation, central nervous system impairment, cancers and other human health effects. Under the U.S. Occupational Safety and Health Administration’s (OSHA) Hazard Communication Standard (HCS) (29 CFR 1910.1200(g)), chemical manufacturers, distributors or importers must provide SDS (formerly known as material safety data sheets or MSDS) to communicate the hazards of hazardous chemical products. The SDS includes the properties of each chemical; the physical, health, and environmental health hazards; protective measures; and safety precautions for handling, storing and transporting the chemical. Sites should share with all staff, especially those with active airway diseases (asthma, COPD), the Safety Data Sheets for cleaning solutions and an employee assessment of risk to exposure must be conducted.
The application of cleaning solutions should be with equipment designed for cleaning cleanrooms and not ‘over-the-counter’ equipment that may react or melt due to repeated exposure. Cleaning equipment should themselves be placed on a routine cleaning schedule and sites should define when equipment must be replaced due to wear/ tear and contamination-risk. Cleaning solutions should be poured onto disposable, low-linting wipes and not ‘sprayed’ due to the aerosolization of the solution(s) and the potential to aerosolized moistened hazardous drug residue. All cleaning materials and PPE must be considered contaminated and disposed according to state and facility policies for hazardous materials.
USP <800> Requires More Frequent Cleaning Than Traditionally Practiced
Twelve published papers have strikingly demonstrated measurable residues of drugs on the outside of vials, accompanying package inserts and outer shipping boxes of vials. USP <800> highlights sites can reduce the amount of contamination by wiping down all vials prior to placing them on any surfaces (preparation tables, staging bins, primary engineering controls). It important that the cleaning solutions used for this process not impact the readability of the label.
In addition to wiping down each hazardous vial, sites must clean their containment primary engineering controls at least daily and the compounding surface of the containment primary engineering controls must be decontaminated between each unique drug to prevent any potential cross contamination of products. This process is clearly supported by the previously mentioned 2018 FDA Guidance Document on Insanitary conditions. As an example, case reports have demonstrated cross contamination of BCG to sterile compounded products subsequently prepared, leading to patient harm and deaths. The deactivation, decontamination, cleaning should immediately take place in the presence of spill, with the addition of disinfecting the surface for compounding surfaces. To minimize the exposure of hazards to maintenance and certifying personnel, surfaces should be cleaned prior any servicing by personnel outside of the department.
Containment primary engineering controls are designed to circulate ISO 5 classified air in a ‘unidirectional’ pattern. To accomplish this process, their design may include areas under the compounding work surface trays, (Figure from Baker). These under-spaces assist with moving air through vents located near to the compounding surface to move contaminates away from the compounding surface. Due to this design, these under-spaces can accumulate hazardous drug residues/spills and other items used during the compounding process (vial caps, syringe packaging, pens, alcohol swabs). USP <800> clearly states that the under spaces must be cleaned (4-step process) on a monthly basis to reduce contamination build-up. It should be noted that access to the under space may be difficult and may require assistance with lifting and holding the upper work surface in place during cleaning. The process of cleaning this surface will disrupt the protect airflow of the containment-primary engineering control and should be classified as a hazardous process requiring additional PPE and specialized training. Sites are encouraged to check with the manufacturer’s maintenance information on the proper process for accessing the under spaces of containment-primary engineering controls.
Commercially Available Cleaning Systems
Currently, the U.S. market has a variety of integrated cleaning systems. These systems have made a point to ease the complicated cleaning process for hazardous drugs. Some systems employ the use of pre-saturated wipes of cleaning solutions used for each step of the cleaning process. It is important to note that some systems may not address each of the 4-steps, thus requiring sites to supplement the step with an additional product. Examples of cleaning systems: Surface Safe®; HDClean®; VIA Wipe 1-2-3®; Peridox RTU®; Pharma-Surface-Guard®.
Some vendors have enhanced their testing to validate that their products can be used for multiple steps of the 4-step cleaning process.
For any product(s) that sites may choose to use, you must get validation from the company that demonstrates the desired result of the product(s). In addition, sites should work with their infection control, employee health. Safety and EVS departments to assist with the selection, training and monitoring the use of products.
Assessing Cleaning Programs
Due to the increased number of hazardous drug wipe sampling test kits, sites can use results as a process to validation cleaning practices and cleaning solutions. There are the traditional wipe analysis kits which quantify defined hazardous drugs and the newly introduced quick test systems that detect the presence of defined residues without quantifying. Proposed USP <800> recommends conducting surface sampling for hazardous drug (HD) residue ‘routinely.’ The chapter recommends an initial wipe analysis to establish a baseline and every 6 months thereafter or as determined by the needs of the site. When a facility begins the process of redesigning and reconfiguring workspaces to meet USP <800> standards, the ideal time to conduct a wipe analysis is prior to any drugs being brought into the space, as this provides a true baseline. To assist sites with conducting consistent wipe analysis, commercially available wipe kits are available. It is important to note, these commercial kits only test for a handful of specific hazardous drugs and the results do not represent all drugs. As such, non-detectable results from a specific analysis do not guarantee that no HD residue is present. Result assessment is further complicated by the fact that there are currently no standards for acceptable limits for residues; however, the goal should be a zero tolerance of measurable residue(s).
Sites have not fully embraced the process of conducting hazardous drug wipe analysis. This was illustrated in the 2017 CriticalPoint survey of annual compliance with 454 hospitals reporting and only 13% (N= 59/454) of sites reported ever conducting an environmental wipe sampling for hazardous residue.
Best practice for a hazardous drug safety program would be to wipe analysis to go beyond defining a historical issue and concurrently validate processes within the hazardous drug continuum. For example, each compounding location (sterile and non-sterile) could conduct an immediate wipe test to confirm surfaces are clean and ready for use. This approach would provide information necessary to help minimize the transfer of residue from surface to surface, or from surface to products destined for patient administration. A recent Danish study demonstrated the use of frequent wipe sampling to assess contaminated locations and improve the cleaning processes to greatly reduce positive samples.
Becton Dickenson (BD) released in 2018 the HD Check Analyzer as a system to provide results in as little as 10 minutes for the hazardous drug residues.
Visante consultants are using HD Check Analyzer in the field. The system requires minimal training for results. The HD Check Analyzer is designed to be an intuitive and easy process, with just 8 steps:
- Assemble supplies and don personal protective equipment;
- Identify test surface using the HD Check template;
- Swab test surface;
- Transfer swab to the sampling tube and invert 5 times;
- Squeeze 4 drops from sampling tube onto the methotrexate or doxorubicin drug assay cartridge;
- Allow 5 minutes for drug assay cartridge to develop;
- Turn on the analyzer and place the developed cartridge in system when prompted;
- Read the positive or negative result
At the time of writing, the system was limited to methotrexate and doxorubicin, which is used at most facilities in the U.S. Unlike the commercially available wipe analysis kits, the HD Check Analyzer checks for the presence of the drug without quantifying the results. The mere presence of residue results in the same response to a quantified sample; recleaning and reassessment to baseline. BD is currently developing a catalog of the most frequently handled hazardous drugs in the U.S.
Sites should consider the continuum of the hazardous drug handling process and assign routing sampling intervals for assessing for residue.
Due to the immediacy of the results, the HD Check Analyzer can be used: daily to validate cleaning processes, whenever cabinets and surfaces where hazardous drugs are used are cleaned, and whenever a spill occurs to validate the spill has been fully cleaned. Conducting real-time wipe analysis to identify any hazardous drug residue serves as a tool that can assist sites with validating their entire hazardous drug handling practices.
Using FDA Guidance Can Enhance Cleaning Validation Check-Points
Sites should use this document as a routine inspection template based on the examples. Selective examples cited for consideration for sites:
“Vermin (e.g., insects, rodents) or other animals (e.g., dogs) in the production area or adjacent areas:” Look at light lens with bugs in areas where drugs are located
– “non-microbial contamination in the production area (e.g., rust, glass shavings, hairs, paint chips).” Look for rust, hair, chipped paint on equipment/walls and exposed drywall
-“Exposing sterile drugs and materials to lower than ISO 5 quality air for any length of time. This would include, … open packages of sterile wipes.” Look at how staff use sterile wipes and where they are located.
– “Producing drugs while construction is underway in an adjacent area without adequate controls to prevent contamination of the production area and product.”
-“Standing water or evidence of water leakage in the production area or adjacent areas” Look for water stained ceiling tiles, dried stains on flooring
-“Handling hazardous, sensitizing, or highly potent drugs (e.g., hormones) with inadequate controls to prevent cross-contamination, including: … inadequate cleaning of rooms, work surfaces, and equipment (e.g., utensils)….” Look at hazardous drug wipe residue test results for positive samples and assess risk of cross-contamination.
-“Using non-sterile disinfecting agents and cleaning pads/wipes in ISO-classified areas” NOTE not required under USP <797>, however, this is a best practice in light of the potential for pathogens to grow in non-sterile solutions (fungal spores, etc.)
– “Lack of, improper, or infrequent use of a sporicidal agent in the facility’s ISO 5 areas and other classified areas.” Look at sporicidal agent in use and ensure labeled as ‘Sporicidal’ and not ‘Kills Spores’ or ‘Kills C. difficile Spores’.
-“Failing to appropriately and regularly clean and disinfect (or sterilize) equipment 306 located in the ISO 5 area.” Look at the process how equipment is cleaned within the PEC (hoods) like IV Workflow hardware; Repeater pumps; collaborative robots
Without conducting a hazardous drug residue wipe analysis, facilities are blindly assuming they their cleaning programs are adequate and they are immune to this widely established pattern of environmental contamination. Conducting regular wipe studies identifies the site’s active risk, allowing the facility to either improve practices or praise staff for following well-defined SOPs. Thereafter, a well-defined, systematic program for routine sampling will assist in monitoring the staff’s diligence at following standard operating procedures.
United States Department of Health and Human Services; Food and Drug Administration Center for Drug Evaluation and Research ; Office of Compliance; Compounding and Related Documents Revision 1: Insanitary Conditions at Compounding Facilities Guidance for Industry; September 2018 https://www.fda.gov/downloads/Drugs Accessed November 19, 2018.
Proposed revision, USP General Chapter: USP <795> Pharmaceutical Compounding – Non-sterile Preparations. http://www.usp.org/compounding/general-chapter-795 Accessed November 19, 2018.
Proposed revision, USP General Chapter: USP <797> Pharmaceutical Compounding – Sterile Preparations. https://www.usp.org/compounding/general-chapter-797 Accessed November 19, 2018.
Proposed, USP General Chapter: USP <800> Hazardous Drugs—Handling in Healthcare Settings http://www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare Accessed November 19, 2018.
United States Health and Human Services: Centers for Disease Control. Guideline for Disinfection and Sterilization in Healthcare Facilities (2008) https://www.cdc.gov/infectioncontrol/guidelines/disinfection/disinfection-methods/chemical.html Accessed November 19, 2018.
Sessink PJM, Anzion RB, Van den Broek PHH and Bos RP. Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharm Weekbl (Sci). 1992; 14:16-22.
United States Department of Health and Human Services; Food and Drug Administration Center for Drug Evaluation and Research ; Office of Compliance; Compounding and Related Documents. GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES https://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074922.htm Accessed November 19, 2018.
Merck BCG Package Insert: https://www.merck.com/product/usa/pi_circulars/t/tice_bcg/ticebcg_pi.pdf Accessed November 19, 2018.
Douglass K, Kastango E. USP <800> Let’s Get Started. Pharmacy Purchasing and Products; December 2017 supplement
Crul M, Simons-Sanders K. Carry-over of antineoplastic drug contamination in Dutch hospital pharmacies. J Oncl Pharm Pract. 2018;24(7):483-489.