Manufacturing and Sterilization for COVID-19

Design, development, prototyping, testing, and validation to help win the fight

Mobile Sterilization

Contents

Need Exploration and Identification

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in December 2019 in Wuhan, the capital of China’s Hubei province, and has since spread globally, resulting in the ongoing 2019–20 coronavirus pandemic. As of 14 June 2020, more than 7.81 million cases have been reported across 210 countries and territories, resulting in over 430,000 deaths (https://coronavirus.jhu.edu/map.html). The pandemic has resulted in travel restrictions and nationwide lockdowns in several countries.  With the sudden surges in patient volume during the COVID-19 outbreak, closing of borders and restrictions on international shipping, and temporary shutdown of manufacturers for medical supplies, personal protective equipment (PPE), ventilators and associated consumables, disinfectants, as well as many other medical supplies have become a scarce resource. 

Disposable filtering facepiece respirators (FFR) is considered an essential piece of PPE for healthcare providers. There is a significant supply shortage of FFRs during the COVID-19 pandemic. Reusing disposable filtering facepiece respirators (FFRs) has been suggested as a potential strategy to conserve available supplies for healthcare facilities. On March 29, 2020, the U.S. Food and Drug Administration (FDA) issued the first Emergency Use Authorization (EUA) for a decontamination process, and additional subsequent EUAs have been issued. While only respirator manufacturers can reliably provide guidance on how to decontaminate their specific models of FFRs, in the absence of manufacturer’s recommendations, third parties may also provide guidance or procedures on how to decontaminate respirators without impacting respirator performance. While decontamination and reuse of FFRs may not be consistent with approved usage, this option may need to be considered when FFR shortages exist.

Existing Solutions

There are many existing solutions that address the issue of disinfection and sterilization of personal protective equipment for medical workers. This section will address approaches involving vaporized hydrogen peroxide (vHP) and aerosolized hydrogen peroxide (aHP).

Vaporized Hydrogen Peroxide

Vaporized hydrogen peroxide (vHP) systems use vaporized 30-35% hydrogen peroxide to provide decontamination of items in an enclosed space. The cycle time is generally 1.5-8 hours and varies based upon the size of the decontamination room and the type of decontamination system used.

Technology Overview

  • STERIS VHP Process Technology
  • VHP denotes a technology that encompasses dehumidification, conditioning, sterilization, and aeration. 
  • VHP gas is generated in a Steris-manufacture unit that vaporizes a 35% liquid hydrogen peroxide product branded as Vaprox. 
  • VHP is maintained at a constant concentration while it is catalytically transformed to oxygen and water in the return air. According to Steris, the process is “dry” because it prevents condensation of the peroxide/water vapors.
  • Panasonic has published an extensive comparison of VHP versus heat for sterilizing CO2 incubators: 
    • The sterilization cycle for HPV lasts just 3 hours, whereas that for heat lasts 8–14 hours. No special materials or construction issues arise for peroxide, whereas incubators designed for heat sterilization components must withstand high-temperature conditions. Incubator components, including the CO2 sensor and HEPA components, can remain inside during sterilization with HPV—not so for heat.

Advantages:

Concerns/Limitations:

  • Due to the higher concentrations of hydrogen peroxide used, mask degradation is a concern (Batelle’s report, Schwartz et al., Degesys et al.). Batelle’s report on the Bioquell system found that the 3M 1860 masks had no filter degradation after 50 VHP cycles nor change in differential pressure drop. They did note that the elastic straps began to degrade after 30 cycles, which resulted in the loss of fit. Additionally, Degesys et al. showed that masks used in the clinical environment as opposed to the experimental setting begin to have fit issues much sooner than experimentally predicted. For dome-shaped masks, fit test failure was associated with a median of 4 shifts (2 for duck-billed), median of 15 donning/doffings (8 for duck-billed), and a median of 14 hours worn (12 for duck-billed).

Current Operational N95 Decontamination Systems or EUAs issued:

Commercially Available Products (not necessarily used for N95 Decon):

  • Stryker Sustainability Solutions VHP Decontamination System
  • Sterilucent, Inc. Sterilization System: vaporized hydrogen peroxide
  • STERIZONE VP4 Sterilizer: vaporized hydrogen peroxide and ozone
  • STERIS Sterilization Systems for Decontamination of N95 Respirators
  • *Bioquell – Has been used in systems which have received EUA but the unit itself has not independently received it as of last page update
  • Other Operational Solutions:

      • Vendors: 

Aerosolized Hydrogen Peroxide

Technology Overview:

Aerosolized hydrogen peroxide (aHP) systems use aerosolized 5-7% hydrogen peroxide combined with other agents (i.e. silver) to provide decontamination of items in an enclosed space. The process time is generally 2-4 hours and varies based upon the size of the decontamination room and the type of decontamination system used. 

Advantages: 

  • aHP has been shown to be effective at decontaminating surfaces infected with various pathogens (Derr et al. [not peer reviewed], Kumar et al, Cadnum et al., Andersen et al., Ghidoni et al.).
  • aHP has also been shown to be safe in terms of residual H2O2 on the respirator surface. In addition, aHP offers the advantage of using a lower level of dH2O2 than comparable methods, such as vHP systems using 30-35% H2O2, or those using 5% H2O2 in combination with silver (Ag) ions, which may leave toxic silver residue on respirator surfaces. (Derr et al. [not peer reviewed])
    • In regards to the Curis system, the complete composition of “Curoxide” is not fully disclosed and whether there are other harmful agents in the composition or not is unknown. 

Concerns/Limitations:

  • In many studies, aHP has been shown to be less effective than vHP (Fu et al., Holmdahl et al.).
  • Some studies have also shown that aHP is not capable of eliminating some pathogens. For example, there have been concerns about aHP being ineffective against tuberculosis (Andersen et al). In addition, aHP (Sterinis) did not completely reduce C. diff contamination while a VHP system (Bioquell) did (Machin et al.). 
  • There have been issues with insufficient distribution of aHP in decontamination rooms (Fu et al.). 
  • There have been some safety concerns associated with aHP. Fu et al. showed that, when the door of the room was not sealed with tape during an aHP cycle, the concentration of hydrogen peroxide outside of the room exceeded the maximum recommended dose of 2 ppm for more than 2 hours. Furthermore, the peak concentration was >20 ppm. When the door was sealed with adhesive tape, the concentration of hydrogen peroxide outside the room was <1 ppm for both aHP and VHP systems.

Current Operational N95 Decontamination Systems or EUAs issued:

  • None identified.

Commercially Available Products (not necessarily used for N95 Decon):

Market Analysis

  • Due to COVID-19, there is a worldwide increase in demand for all types of PPE including N95 respirators resulting in shortages. 
    • Some US stockpiles including N95s have exceeded their manufacturer-designated shelf life. Many of these were retested and continued to meet NIOSH performance standards including: 3M 1860 (8 facilities), 3M 1870 (3 facilities), 3M 8210 (3 facilities), 3M 9010 (3 facilities), 3M 8000 (4 facilities), Gerson 1730 (3 facilities), Medline/Alpha Protech NON27501 (1 facility), Moldex 1512 (1 facility), and Moldex 2201 (1 facility). Others did fail to meet performance standards (CDC Stockpiled N95). 
    • In response to the shortage, FDA authorized the use of imported filtered face respirators that are not NIOSH approved through an EUA (FDA EUA for FFRs).
    • Without the proper supply, the US government has recommended a reuse schedule for disposable FFRs (CDC FFR recommended reuse schedule). 
  • Marketing/supply chain:
    • COVID-19 has caused factory closures, worsening the shortage.
    • Many countries have also banned the exports of face masks in order to utilize them domestically, further reducing supply.
    • Due to these shortages of masks, manufacturers including 3M, governments and related agencies and institutions began to analyze reuse, disinfection, or sterilization of PPE including by: VHP, moist heat, and many more discussed under concept screening (CDC decontamination/reuse of PPE). 
    • On March 29, 2020, the FDA issued the first EUA for a PPE decontamination process 

Alternative Solutions

    • Alternative sterilization techniques must be considered as per the CDC Disinfection and Sterilization Guidelines and based on the tools to be sterilized. 
      • Pages 59-73 of the CDC guideline above summarizes alternative sterilization techniques by providing an overview of the mode of action, microbicidal activity, high level summarizes of protocols, advantages, disadvantages and examples of use cases. 
  • The following resource is the CDC’s most current guidance on the ‘Decontamination and Reuse of Filtering Facepiece Respirators’ tailored to the current pandemic.
      • Tables 1-3 of the above resource prove summaries of crisis standards of care decontamination recommendations, effect on FFR performance and antimicrobial efficacy
      • Additionally, the resource summarizes the current literature to date including overviews of the technology and how it has been implemented in relation to the COVID-19 pandemic
      • The resource also cites a number of methods and resources for consideration that have not yet been tested due to the rapid evolution of the pandemic that may be considered for further evaluation when hospitals possess other decontamination capabilities. 

Concept Screening

Method Manufacturer or third-party guidance or procedures available Recommendation for use after decontamination Additional use considerations
Ultraviolet germicidal irradiation (UVGI) Yes Can be worn for any patient care activities
  • Clean hands with soap and water or an alcohol-based hand sanitizer before and after touching or adjusting the FFR.
  • Avoid touching the inside of the FFR.
  • Use a pair of clean (non-sterile) gloves when donning the FFR and performing a user seal check.
  • Visually inspect the FFR to determine if its integrity has been compromised.
  • Check that FFR components such as the straps, nose bridge, and nose foam material did not degrade, which can affect the quality of the fit, and seal.
  • If the integrity of any part of the FFR is compromised, or if a successful user seal check cannot be performed, discard the FFR and try another FFR.
  • Users should perform a user seal check immediately after they don each FFR and should not use an FFR on which they cannot perform a successful user seal check.
Vaporous hydrogen peroxide (VHP)
Moist heat
Ultraviolet germicidal irradiation (UVGI) No Can be worn for patient care activities except when performing or present for an aerosol generating procedure
Vaporous hydrogen peroxide (VHP)
Moist heat

Table 2 provides a summary of the decontamination methods evaluated in the referenced literature and the reported effect of each method on FFR performance.

Table 2. Summary of the decontamination method and effect on FFR performance

Method Treatment level FFR filtration performance FFR fit performance Other observations References
Vaporous hydrogen peroxide (VHP) Battelle report: Bioquell Clarus C HPV generator: The HPV cycle included a 10 min conditioning phase, 20 min gassing phase at 2 g/min, 150 min dwell phase at 0.5 g/min, and 300 min of aeration.

Bergman et. al.: Room Bio-Decontamination Service (RBDS™, BIOQUELL UK Ltd, Andover, UK), which utilizes four portable modules: the Clarus® R HPV generator (utilizing 30% H2O2), the Clarus R20 aeration unit, an instrumentation module and a control computer. Room concentration = 8 g/m3, 15 min dwell, 125 min total cycle time.

 Passed FFR fit was shown to be unaffected for up to 20 VHP treatments cycles using a head form Degradation of straps after 30 cycles (Battelle report) 3, 4
Ultraviolet germicidal irradiation (UVGI) 0.5–950 J/cm2 Passed 90–100% passing rate after 3 cycles depending on model 2, 3, 7, 8, 9, 10
Microwave generated steam 1100–1250 W microwave models (range: 40 sec to 2 min) All models passed filtration evaluation for 1 or 20 treatment cycles as per test 95–100% passing rate after 3 and 20 cycles for all models tested 9, 10, 14
Microwave steam bags 1100 W, 90 sec (bags filled with 60 mL tap water) Passed Not evaluated 15
Moist heat incubation 15 min–30 min (60°C, 80% RH) 6 of 6 models passed after 3 cycles of contamination Passed 3, 9, 10
Liquid hydrogen peroxide 1 sec to 30 min (range: 3–6%) Passed Not evaluated 3, 7
Ethylene oxide 1 hour at 55°C; conc. range: 725–833/L Passed Not evaluated 2, 3, 7

Table 3 provides a summary of the decontamination methods used, the treatment levels assessed, the microbes tested, and the antimicrobial efficacy as reported in the literature.

Table 3. Summary of decontamination method antimicrobial efficacy

Method Treatment level Microbe tested Antimicrobial efficacy References
Vaporous hydrogen peroxide (VHP) Battelle report: Bioquell Clarus C HPV generator: The HPV cycle included a 10 min conditioning phase, 20 min gassing phase at 2 g/min, 150 min dwell phase at 0.5 g/min, and 300 min of aeration.

Bergman et. al.: Room Bio-Decontamination Service (RBDS™, BIOQUELL UK Ltd, Andover, UK), which utilizes four portable modules: the Clarus® R HPV generator (utilizing 30% H2O2), the Clarus R20 aeration unit, an instrumentation module and a control computer. Room concentration = 8 g/m3, 15 min dwell, 125-min total cycle time.

Kenney personal communication: Bioquell BQ-50 generator: The HPV cycle included a 10 min conditioning phase, 30–40 min gassing phase at 16 g/min, 25 min dwell phase, and a 150 min aeration phase.

 Geobacillus stearothermophilus spores

T1, T7, and phi-6 bacteriophages

 >99.999% 3, 4, 6
Ultraviolet germicidal irradiation (UVGI) 0.5–1.8 J/cm2 Influenza A (H1N1)

Avian influenza A virus (H5N1),

low pathogenic

Influenza A (H7N9),

A/Anhui/1/2013

Influenza A (H7N9),

A/Shanghai/1/2013

MERS-CoV

SARS-CoV

H1N1

Influenza A/PR/8/34

MS2 bacteriophage

 99.9% for all tested viruses 12, 13, 14
Microwave generated steam 1100–1250 W microwave models (range: 40 sec to 2 min) H1N1 influenza A/PR/8/34 99.9% 14
Microwave steam bags 1100 W, 90 sec (bags filled with 60 mL tap water) MS2 bacteriophage 99.9% 15
Moist heat incubation 15–30 min (60°C, 80% RH) H1N1 influenza A/PR/8/34 99.99% 14
Liquid hydrogen peroxide 1 sec to 30 min (range: 3–6%) Not evaluated Not evaluated
Ethylene oxide 1 hour at 55°C; conc. range: 725–833 mg/L Not evaluated Not evaluated
  • Regulatory
  • FDA guidelines published 5/26/2020
      • Tier 1 devices (decontamination of masks for multiple users)
        • ≥ 6-log spore reduction of the most resistant spore for the proposed process OR 
        • ≥ 6-log reduction of a Mycobacterium species (e.g., M. terrae or M. abscessus)
      • Tier 2 devices (decontamination of masks for single users)
        • ≥ 6-log reduction of 3 non-enveloped viruses OR 
        • ≥ 6-log reduction of two gram-positive and two gram-negative vegetative bacteria
      • Tier 3 devices (contaminant reduction for single users to supplement other CDC devices)
        • ≥ 3-log reduction of a non-enveloped virus OR 
        • ≥ 3-log reduction of two gram-positive and two gram-negative vegetative bacteria OR
        • Other evidence demonstrating that the bioburden reduction system will reliably achieve > 3-log reduction in non-enveloped virus or vegetative bacteria, which could include, where appropriate, published scientific literature, and scientific and engineering studies. 
  • FDA approved decontamination devices
        • All FDA approved hydrogen peroxide decontamination devices rely on vaporized H2O2, no aerosolized H2O2 devices are currency approved
        • No pre-COVID FDA approved devices, only EUAs
        • Sterilizer Enforcement Policy: https://www.fda.gov/media/136533/download
        • PPE EUAs: https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ppe
          • Vaporized hydrogen peroxide sterilization
            • Stryker Sustainability Solutions VHP Decontamination System
            • Duke Decontamination System: vaporized hydrogen peroxide
            • Sterilucent, Inc. Sterilization System: vaporized hydrogen peroxide
            • STERIZONE VP4 Sterilizer: vaporized hydrogen peroxide and ozone
            • Advanced Sterilization Products (ASP) STERRAD Sterilization System: vaporized hydrogen peroxide
            • STERIS Sterilization Systems for Decontamination of N95 Respirators: vaporized hydrogen peroxide
            • Battelle CCDS Critical Care Decontamination System: vaporized hydrogen peroxide
          • Moist heat sterilization
            • STERIS STEAM Decon Cycle in AMSCO Medium Steam Sterilizers: 
  • EUA Submissions Steps
  • Federal:
    • State: PA Dept of Health ​Drugs, Devices and Cosmetics Program
      • “Any manufacturer, distributor and/or retailer of medical devices within the Commonwealth physically handling actual FDA approved medical devices or equipment must register unless acting with scope of practice license (i.e. Physician providing medical devices directly to his/her patients, pharmacies dispensing devices to their patients, hospitals providing medical devices directly to their patients, etc)”

Strategic Development

  • Clinical:
    • As per FDA recommendation, the system deployed for single or multiple use decontamination should demonstrate either:
      •  ≥ 6-log spore reduction of the most resistant spore for the proposed process 
      • ≥ 6-log reduction of a Mycobacterium species (e.g., M. terrae or M. abscessus). 
      • FDA believes that data should demonstrate decontamination corresponding to the highest level of resistance in the hierarchy in the figure below when a decontamination system is intended to decontaminate surgical masks and/or respirators for multiple-users because of the increased risk of sharing a person’s bioburden when used across multiple-users:
      • Appropriate instructions for users of the decontamination or bioburden reduction system and facilities regarding: 
        • Identification of surgical masks and/or respirators that are compatible with the decontamination or bioburden reduction system;
        • Limitations of use of the decontamination or bioburden reduction system to FDA cleared or authorized surgical masks and/or respirators only;
        • Collection, sorting, discarding, and decontamination or bioburden reduction of compatible surgical masks and/or respirators;
        • Tracking number of decontamination or bioburden reduction cycles per compatible surgical mask and/or respirator; and
        • User safety with respect to exposure to decontamination or bioburden reduction process residuals.
      • Appropriate conditions of authorization for the monitoring and reporting of adverse events. FDA intends to include conditions of authorization that require adverse event reporting consistent with 21 CFR Part 803, including the following: 
        • Reporting of adverse events associated with healthcare personnel who use decontaminated or bioburden-reduced surgical masks and/or respirators. o Reporting of adverse events for operators of the decontamination or bioburden reduction system and individuals involved in the decontamination or bioburden reduction process.
        • For manufacturers of the decontamination or bioburden reduction system, appropriate conditions of authorization concerning recordkeeping and reporting, including records access by FDA, with respect to emergency use of the device.
      • Sponsors should send pre-EUA and EUA requests for decontamination and bioburden reduction systems for surgical masks and respirators to CDRH-COVID19-SurgicalMasks@fda.hhs.gov
      • Real world extended use may result in earlier fit failure of N95 respirators
        • N95 masks showed a median fit failure after 4 shifts for dome shaped masks and 2 shifts for duckbill masks and a median of 15 donnings and doffings for dome shaped and 8 for duckbill.
  • Implementation: The process disruptive nature of the implementation of this technology would require a thorough assessment of internal capabilities of the institution including but not limited to:
    • Use volume and turn over of tools to be sterilized determination
    • Current sterilizations methods in place including evaluation of personnel and processes currently being utilized
    • Cost benefit analysis and cost implications on health care structure
    • Training requirements 
    • Error of use mitigation strategies
    • Evaluation of efficacy of the implementation 
  • Intellectual Property: Please contact your institution’s legal department for guidance on matters related to IP during the COVID-19 pandemic

 

 

 

 

 

 

 

@CDCgov

@Surgeon_General

@PAHealthDept

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