Exploring options for reprocessing of N95 Filtering Facepiece Respirators (N95-FFRs) amidst COVID-19 pandemic: A systematic review.

BACKGROUND: There is global shortage of Personal Protective Equipment due to COVID-19 pandemic. N95 Filtering Facepiece Respirators (N95-FFRs) provide respiratory protection against respiratory pathogens including SARS-CoV-2. There is scant literature on reprocessing methods which can enable reuse of N95-FFRs. AIM: We conducted this study to evaluate research done, prior to COVID-19 pandemic, on various decontamination methods for reprocessing of N95-FFRs.
METHODS: We searched 5 electronic databases (Pubmed, Google Scholar, Crossref, Ovid, ScienceDirect) and 1 Grey literature database (OpenGrey). We included original studies, published prior to year 2020, which had evaluated any decontamination method on FFRs. Studies had evaluated a reprocessing method against parameters namely physical changes, user acceptability, respirator fit, filter efficiency, microbicidal efficacy and presence of chemical residues post-reprocessing. FINDINGS AND
CONCLUSIONS: Overall, we found 7887 records amongst which 17 original research articles were finally included for qualitative analysis. Overall, 21 different types of decontamination or reprocessing methods for N95-FFRs were evaluated. Most commonly evaluated method for reprocessing of FFRs was Ultraviolet (Type-C) irradiation (UVGI) which was evaluated in 13/17 (76%) studies. We found published literature was scant on this topic despite warning signs of pandemic of a respiratory illness over the years. Promising technologies requiring expeditious evaluation are UVGI, Microwave generated steam (MGS) and based on Hydrogen peroxide vapor. Global presence of technologies, which have been given Emergency use authorisation for N95-FFR reprocessing, is extremely limited. Reprocessing of N95-FFRs by MGS should be considered for emergency implementation in resource limited settings to tackle shortage of N95-FFRs. SYSTEMATIC REVIEW IDENTIFIER: PROSPERO, PROSPERO ID: CRD42020189684, (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020189684).

Introduction

Global pandemic of Corona Virus Disease of 2019 (COVID-19) has led to over 37 million cases and 1 million deaths worldwide and still counting [1]. It is caused by a novel Corona virus (nCoV), a member of family Coronaviridae, now renamed as SARS-CoV-2 [2]. Transmission of this virus occurs through direct, contact and airborne routes, latter particularly when aerosol generating procedures (AGPs) are done during patient care [3]. Consequently, healthcare workers (HCWs) require a full set of personal protective equipment (PPE) including gowns, gloves, facemasks, face-shields or goggles and respirators for their protection during patient care, particularly in intensive care unit settings where AGPs are done regularly [4]. This has created an unprecedented demand for PPEs leading to their global shortage forcing administrative authorities to relook the recommendations of PPE usage in a whole new light [5]. Previously, focus of PPE use strategy was not to share them between patients [6] however, due to this unprecedented crisis, it has radically shifted to optimizing the use of PPEs, their extended use and limited reuse [4, 5]. Respiratory protection is one of the fundamental rights of any employee in workplace. In healthcare settings, HCWs need to be protected against bioaerosols at all costs, which at minimum, is offered by use of N95 Filtering Facepiece Respirator (N95-FFR). These FFRs have a class of filters which is not resistant to degradation by oil and is able to remove 95% particles of 0.3 μm in size, at minimum [7]. They are single use devices ought to be discarded after use to avoid self-inoculation & cross-contamination [8].

Shortage of FFRs is not new, pangs of which were first felt during Severe Acute Respiratory Syndrome (SARS) outbreak in 2003 [9]. The possibility was also predicted for an impending Influenza pandemic consequent to which U.S. Strategic National Stockpile had plans for providing 100 million N95-FFRs nationally, but it was deemed insufficient in event of a longer pandemic [9-11]. Hence, in 2006, Institute of Medicine (IOM) constituted a committee to address reusability of facemasks. Reuse of an FFR was defined as repeatedly donning and doffing of respirator by the same wearer, with or without undergoing reprocessing in between, till it is discarded. The committee recommended reuse of respirators in the event of acute shortage provided they are not obviously damaged or soiled [11]. However, committee specified that no method exists currently for reprocessing of N95-FFRs and identified it as a research priority [11]. Consequently, various research groups began their quest to search a reprocessing method which is efficacious against respiratory pathogens, is safe for human use and maintains the integrity of various components of the respirator. Even after a decade of research, prior to COVID-19 pandemic, no method has been recommended for reprocessing of N95-FFRs. Hence, we conducted this systematic review to determine the status of research done, prior to COVID-19 pandemic, to identify technologies which can be utilized for reprocessing of N95-FFRs in present situation and can be explored in near future to tackle the global crisis of respirator shortage.

Methods

We report this systematic review (PROSPERO ID: CRD42020189684) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12] and checklist is provided in S1 Table.

Search strategy

We searched five databases–Pubmed, Google Scholar, Crossref, Ovid and ScienceDirect in May 2020. Grey literature was searched using OpenGrey repository. Search strategies employing combinations of various keywords is provided in S2 Table. Searches in Google Scholar and Crossref were done using Publish or Perish 7 software (Harzing, A.W. 2007) to limit article hits and sort relevant ones. Additionally, we manually searched the back references of included studies and relevant review articles on the topic to identify further eligible studies. Articles in languages other than English were considered only when their abstracts were available in English.

Eligibility criteria

Original research articles in any language, which evaluated a single or multiple decontamination or reprocessing methods on N95-FFRs were eligible for analysis in this study. Exclusion criteria were (i) Abstracts, posters, review articles, book chapters, letters, guidelines, point of views (ii) articles published in year 2020 and (iii) involving reprocessing or decontamination of other types of masks or respirators such as Gauze, Cloth, Spun-lace, Elastomeric and Powered-air-purifying, only.

Data extraction

After searching all databases, we exported data in Microsoft® Excel and removed duplicates. Two reviewers (DP & AG) screened titles to remove clearly irrelevant studies. All three reviewers (AG, DP, AKM) independently screened the abstracts and full text of remaining articles to determine final eligibility and resolved any discrepancies through discussion and consensus. After included studies were finalized, data on various variables such as reprocessing method exposure variables, number, type and replicates of FFR models, parameters which were evaluated and final results was entered in Microsoft® Excel independently by all three reviewers. Extracted data was checked and analysed by one reviewer (AG) and disagreements were resolved prior to final analysis.

Quality assessment

To assess methodological quality and risk bias of studies, a self-developed tool was designed on the basis of STROBE statement [13] due to unavailability of a validated quality assessment tool for such studies. Two authors (AKM and DP) independently assessed the methodological quality and risk bias as per tool. The scheme of scoring and grading of studies is given in S3 Table along with the final quality assessment results. Inter-author concordance on grading of studies was evaluated by third author (AG). Final quality assessment results for included studies, as shown in S3 Table, were prepared by resolving inter-author disagreements by discussion and building consensus.

Results

Search results

Our search strategy identified 7887 records of which 17 original research articles fit inclusion criteria for qualitative analysis [8, 14–29], methodology of the same has been described in Fig 1. No records were found in OpenGrey database using search strategy.

Fig 1

Summary of search, selection and inclusion process.

Excluded studies [30–36] Abbreviations: FFR: Filtering Facepiece Respirator, n: Number.

Of 17 studies, 14 were graded as high quality and 3 as moderate quality (S3 Table). Inter-author agreement in grading of studies was 88% (15/17). Overall agreement in quality assessment scores was 64% (11/17).

Study characteristics

Amongst 17 included studies, 15 were conducted in U.S. [8, 14–27] and 2 in Taiwan [28, 29]. Ten out of 15 studies were conducted by research groups from NIOSH as the principal investigator [8, 14, 16, 17, 21–26], 4 by researchers at Applied Research Associates (ARA) in collaboration with Air Force Research Laboratory at Tyndall Air Force Base, Panama City [18–20, 27] and in 1 study, principal investigators were from University of Nebraska (UoN) [15]. Three studies were an outcome of collaboration between NIOSH, ARA & UoN in various combinations [14, 15, 18]. Two studies from Taiwan were conducted by same researchers at Department of Occupational Safety and Health, Chung Shan Medical University [28, 29]. First study evaluating reprocessing methods for FFRs was published in 2007 [22] and last study in 2018 [29].

Decontamination/reprocessing methods

Overall, 21 different types of decontamination or reprocessing methods for N95-FFRs were evaluated in included studies against various parameters namely physical changes, user acceptability, respirator fit, filter efficiency, microbicidal efficacy and presence of chemical residues post-reprocessing. Number of studies conducted for each reprocessing method, on these parameters are given in Fig 2. Overall, these studies evaluated 9 Physical (Energetic) reprocessing methods namely Ultraviolet (UV-C) Irradiation (UVGI) [8, 14–16, 19, 20, 23–25, 27, 29], UV-A [29], UV-B [27], Moist heat delivered using Microwave generated Steam (MGS) [14, 15, 20, 22, 23, 26], Lab Incubator (MHI) [14, 15, 20, 22, 23] and Autoclave (MHA) [22, 28, 29], Dry heat delivered by Microwave (MGI) [16, 22], Hot Air Oven (DHO) [22] and Traditional Electric Rice Cooker (TERC) [28, 29]; 3 Gaseous chemical decontamination methods namely Hydrogen Peroxide Gas Plasma (HPGP) [14, 16, 22, 27], Hydrogen Peroxide Vapor (HPV) [14] and Ethylene Oxide (EO) [14, 16, 22, 27]; 6 Liquid chemical decontamination methods namely Bleach [14, 16, 22, 25–29], Hydrogen Peroxide (LHP) [14, 22], Alcohols [22, 28, 29], Mixed Oxidants [27], Dimethyl dioxirane [27] and Soap & water [22]; and in one study [18], wipes of Bleach (0.9%), Benzalkonium chloride and Inert substance for surface decontamination of N95-FFRs. Fourteen (14) studies [14–18, 20–29] did comparative evaluation of multiple methods for reprocessing of FFRs whereas in 3 studies only 1 method was evaluated, which was UVGI in all [8, 19, 24]. In 12 studies [14–16, 16–23, 25, 27], intact respirators were exposed to the decontamination method whereas in 5, cut pieces of facepiece portion were exposed [8, 24, 26, 28, 29]. Furthermore, in one study [8], pieces of straps were also exposed separately to UVGI. In 4 studies, FFRs underwent multiple cycles (3 in all studies) of decontamination for reprocessing [14, 17, 18, 23].

Fig 2

Summary of studies [Total Number, n[Reference] conducted, prior to 2020, on various parameters related to reprocessing of N95 Filtering Facepiece Respirators (FFRs).

Coloured cells represent cumulative results of these studies (See Legend Below). Numbers in each coloured cells represent total number of studies conducted on a reprocessing method: parameter combination. Numbers in Parentheses denote the reference number of studies. Green Cells: Evidence shows no negative effect of the reprocessing method on the evaluated parameter. Red Cells: Evidence shows a negative effect of the reprocessing method on the evaluated parameter. Orange Cells: Evidence shows an effect which is either in conflict in different studies or requires careful consideration. Grey Cells: No study done on the reprocessing method: parameter combination. * User Acceptability is a composite parameter including odor, wear comfort & donning ease. References 14,16,27 only evaluated odor. α- Fisher et al 2011 [17] used Commercial steam bags for generation of steam, other studies used a water reservoir. β- Ethanol (70%) [28, 29] and Isopropyl alcohol (70% [28] and 100% [22]) were used. Abbreviations: UVGI: Ultraviolet Irradiation (Type-C, 254 nm), MGS: Microwave Generated Steam, MHI: Moist heat Incubation in Lab Incubator, MHA: Moist Heat in Autoclave, DHO: Dry Heat in Oven (Till 80°C), TERC: Traditional Electric Rice Cooker, EO: Ethylene Oxide, HPGP: Hydrogen Peroxide Gas Plasma, HPV: Hydrogen Peroxide Vapor, LHP: Liquid Hydrogen Peroxide, BAC: Benzalkonium Chloride. Note: The summary is only indicative of the collective results of various studies done (prior to 2020) to evaluate effect of reprocessing method on a particular parameter. It doesn’t attempt to endorse or refute any method as the authors strongly believe that there is insufficient data to reach any conclusion.

Respirator models

In 10 of 17 studies, the identities of N95-FFR models used was disclosed [8, 15, 17, 19, 21, 23–25, 28, 29], details of which against the reprocessing method and parameters evaluated are given in S4 Table. Overall, 23 different models of N95-FFRs were disclosed in 10 studies, 19 of which are approved as surgical respirators by FDA, whereas 4 are Particulate respirators. All respirators used in these studies, irrespective of whether identities were disclosed or not, were NIOSH approved. 3M1860 [8, 15, 19, 21, 23], 3M1870 [15, 17, 19, 21, 23] & 3M8210 [21, 23, 24, 28, 29] were the most commonly used N95-FFRs, each being used in 5 studies. 3M1860 & 3M1870, both surgical respirators were tested against three reprocessing methods i.e. UVGI, MGS and MHI, where identity was disclosed whereas 3M8210, a particulate respirator was exposed to 7 different reprocessing methods. Furthermore, in 2 studies, P100 respirators were also evaluated but in both identities were not disclosed [16, 22].

Decontamination methods

A. Physical (Energetic) methods

i. Ultra-Violet Irradiation (UVGI). Thirteen studies [8, 14–16, 19–25, 27, 29] evaluated exposure to UV-C (254 nm) as a reprocessing method for FFRs, as shown in Fig 2. All 23 known models of N95-FFRs were reprocessed using UV-C in at least one study (S4 Table). Furthermore, one study each also examined the microbiological efficacy of UV-A [29] and presence of chemical residues after using UV-B [27]. Exposure variables of UVGI (UV-C) on N95-FFRs and summary of results are provided in Table 1. Different parameters evaluated against UVGI are detailed in Fig 2. Overall, UVGI has shown to be microbiologically efficacious [15, 19, 20, 24, 25, 29], preserve physical appearance of FFRs [8, 14, 16, 20–23] & their filter efficiency [8, 14–16, 22], acceptable to users in terms of odor, donning ease and wear comfort [21], maintain respirator fit [21, 23] and devoid of any toxic residues post-exposure [27]. UVGI has shown to preserve filter efficiency & achieve adequate microbicidal efficacy post-exposure in 9 [8, 15, 24] & 18 different N95-FFR models [15, 19, 24, 25, 29], respectively, where identity of models was disclosed.

Table 1

Summary of characteristics of studies using Ultraviolet Irradiation (UVGI) as a reprocessing method for N95-FFRs.

Authors (Year)		Variables of UVGI Irradiation					Variables of FFRs			Results
	Type	Irradiance (mW/cm2)	Duration	Dose (J/cm2)	Sides Exposed to UVGI	No. of Cycle	Total no. of Models used	Part of FFR exposed to UVGI	Repli-cates	Parameters Assessed	Summary of Results
Bergman et al [14] (2010)	C	1.8	45 m	-	Outer (Convex)	3	6	Intact	3	Physical Changes	No observable physical changes on FFRs
										Odor	No comment on odor
										Filter Efficiency	Expected levels of Filter Aerosol penetration (<5%) & filter airflow resistance
Lore et al [15] (2012)	C	1.6–2.2	15 m	1.8	Outer (Convex)	1	2	Intact	9	Filter Efficiency	No significant degradation of filter performance
										Microbicidal Efficacy	>4 log10 TCID50/ml reduction of H5N1 Avian Influenza virus
Viscusi et al [16] (2009)	C	0.18–0.2	30 m	0.17–0.18	Each side	1	9	Intact	3	Physical Changes	No observable physical changes on FFRs
										Filter Efficiency	Didn’t affect Filter efficiency
Lindsley et al [8] (2015)	C			120, 240, 470, 950 (For mask layers);	NA	1	4	Facepiece Coupons and Straps	4	Structural Integrity	Strengths of respirator materials was substantially reduced (in some cases>90%)
										Filter Efficiency	Slight increase in particle penetration but no effect on airflow resistance
				590, 1180, 2360 (For straps, each side)
Mills et al [19] (2018)	C	17	60–70 s	1	Outer (Convex)	1	15	Intact	3	Microbicidal Efficacy	≥3 log10 TCID50/ml reduction in Influenza virus (H1N1) viability on 12/15 FFR models and straps from 7/15 FFR models
Heimbuch et al [20] (2011)	C	1.6–2.2	15 m	1.8	Outer (Convex)	1	6	Intact	3	Physical Changes	No observable physical changes on FFRs
										Microbicidal Efficacy	>4 log10 TCID50/ml reduction of Influenza virus (H1N1)
Viscusi et al [21] (2011)	C	1.8	30 m	-	Each side	3	6	Intact	2	Physical Changes	No observable physical changes on FFR
											No clinically meaningful reduction in respirator fit, increase in odor, increase in discomfort or increased difficulty in donning
										User Acceptability
										Respirator Fit
Viscusi et al [22] (2007)	C	0.24	15/ 240 m	-	Each side	1	2	Intact	4	Physical Changes	No observable physical changes on FFRs
										Filter Efficiency	Not significantly affected by both time durations on both types of FFRs (N95 and P100)
Bergman et al [23] (2011)	C	1.8	15 m	-	Outer (Convex)	3	3	Intact	2	Physical Changes	No observable physical changes on FFRs
										Respirator Fit	No significant changes in Respirator fit
Fisher et al [24] (2010)	C	2.5	1, 2, 4, 10 m on 3M 8210,1870	0.03, 0.1 & 0.3 on Wilson, 3M 1860 and KC	Each side	1	6	Facepiece Coupons	3	IFM specific dose for	Log Reduction of MS2 Coliphage is a function of FFR model specific IFM UV-C dose
			10m on Cardinal N95-ML							Microbicidal Efficacy
Lin et al [29] (2018)	C	18.9	1, 2, 5, 10, 20 m	-	NA	1	1	Cut pieces	3	Microbicidal Efficacy	99–100% biocidal efficacy against Bacillus subtilis spores
Vo et al [25] (2009)	C	0.4	1, 2, 3, 4, 5 hr	1.44, 2.88, 4.32, 5.76, 7.2	One side	1	1	Intact	3	Microbicidal Efficacy	3 log reduction of MS2 Coliphage at dose of 4.32 J/cm2 and complete removal at dose of ≥7.2 J/cm2
Salter et al [27] (2010)	C	3.4	1 hr	27	NA	1	6	Coupons, straps,	3	Presence of Toxic Chemical residues Post-exposure	No toxic residues post-exposure
								Nose cushion,
								Nose pieces
Lin et al [29] (2018)	A	31.2	1, 2,5, 10, 20 m	-	Each side	1	1	Cut pieces	3	Microbicidal Efficacy	Poor Microbicidal efficacy against Bacillus subtilis spores
Salter et al [27] (2010)	B	4	1 hr	-	NA	1	6	Coupons, straps, nose cushion,	3	Presence of Toxic Chemical residues Post-exposure	No toxic residues post-exposure
								Nose pieces

ABBREVIATIONS: mW/cm: milli Watt per square centimetre, J/cm: Joules per square centimetre m: Minute, NA: Not Applicable, FFR: Filtering Facepiece Respirator, TCID: Tissue Culture Infectious Dose, s: Seconds IFM: Internal Filtering Media, hr: Hour

ii. Moist heat. Delivering moist heat to FFRs has been evaluated in 10 studies [14, 15, 17, 18, 21–23, 26, 28, 29]. Modalities of exposure involved exposing FFRs to steam created in a microwave (MGS), either by using water reservoir [14, 15, 20, 21, 23, 26] or commercial steam bags [17]; in a lab incubator with a water reservoir heated at 60-70°C (MHI) [14, 15, 18, 21, 23] and by autoclaving at 121°C (MHA) [22, 28, 29]. Parameters evaluated for these treatments are given in Fig 2 and the exposure variables and results of individual studies are described in Table 2. Known FFR models which underwent reprocessing by both MGS and MHI were 3M1860, 3M1870, 3M8000 and 3M8210, whereas, for MHA only known FFR model was 3M8210. MHA physically destroyed FFRs thus deemed unsuitable for further evaluation [22]. Both MGS & MHI methods showed acceptable microbiological efficacy [15, 17, 20, 26] and no significant effect on user acceptability [21], respirator fit [21, 23] and filter efficiency [14, 15, 17], till 3 cycles of decontamination.

Table 2

Summary of characteristics of studies using physical decontamination methods, other than UVGI, for reprocessing of FFRs.

	Variables of Decontamination Methods				Variables of FFRs			Results
Authors (Year)	Mode of Delivery	Temperature	Duration	No. of Deconta-mination Cycle	Total no. of Models used	Part of FFR exposed	Replicates	Parameters Assessed	Summary of Results
DRY HEAT
Viscusi et al [16] (2009)	Microwave	-	2 m	1	9	Intact	3	Physical Changes	Observable physical changes on many models of FFRs
			(1 m each side)		(6 N95
								Filter Efficiency	Expected levels of Filter Aerosol penetration (<5%) & filter airflow resistance
					3 P100)
Viscusi et al [22] (2007)	Microwave	-	2 and 4 m	1	2	Intact	4	Physical Changes	No visible changes after 2 min for both models
					(1 N95
			(1 & 2 m each side)
					1 P100)
									Visible damage after 4 min for both models
								Filter Efficiency	Filter efficiency not significantly changed after 2 min for both models
									Filter efficiency of N95-FFR was significantly increased after 4 min
Viscusi et al [16] (2009)	Hot air Oven	80-120° C	1 hr	1	9	Intact	3	Physical Changes	No Comment
					(6 N95 3 P100)
								Filter Efficiency	Temperature affected filter aerosol penetration and component melting which was model specific
Viscusi et al [22] (2007)	Hot air oven	80° C & 160° C	1 hr	1	2	Intact	4	Physical Changes	No visible changes for either type of respirator at 80° C
					(1 N95
					1 P100)
									Complete destruction of both types of respirators at 160° C
								Filter Efficiency
									Small increase in average penetration for both types of respirators
Lin et al [28] (2017)	Rice Cooker	149-164° C	3 m	1	1	Cut pieces	3	Filter Efficiency	Decontamination reduced the filter quality but less than liquid chemical methods
Lin et al [29] (2018)	Rice Cooker	149-164° C	3 m	1	1	Cut pieces of FFR layers	3	Microbicidal Efficacy	99–100% Biocidal efficacy against Bacillus subtilis spores
MOIST HEAT
Bergman et al [14] (2010)	Microwave (MGS)		2 m	3	6	Intact	3	Physical Changes	Partial separation of inner foam cushion of 1 FFR model
								Odor	No comment on odor
								Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
Lore et al [15] (2012)	Microwave (MGS)		2 m	1	2	Intact	9	Filter Efficiency	No significant degradation of filter performance
								Microbicidal Efficacy	>4 log10 TCID50/ml reduction of H5N1 Avian Influenza virus
Fisher et al [17] (2011)	Microwave (MGS)		90 s	3	3	Intact	3	Microbicidal Efficacy	>3 log10 reduction in pfu/FFR of MS2 Coliphage
Heimbuch et al [20] (2011)	Microwave (MGS)		2 m	1	6	Intact	3	Physical Changes	Slight separation of foam nose cushion in 1 FFR model
								Microbicidal Efficacy	>4 log10 TCID50/ml reduction of Influenza virus (H1N1)
Viscusi et al [21] (2011)	Microwave (MGS)		2 m	1	6	Intact	2	Physical Changes	Slight separation of inner foam nose cushion in 1 FFR model
								User Acceptability	No significant changes in odor, increase in discomfort or increased difficulty in donning
									Strap breakage during multiple donning not more frequent than in controls
								Respirator Fit	No clinically meaningful reduction in respirator fit
Bergman et al [23] (2011)	Microwave (MGS)		2 m	3	3	Intact	2	Physical Changes	Slight separation of inner foam nose cushion in 1 FFR model
								Respirator Fit	No significant changes in Respirator fit
Fisher et al [26] (2009)	Microwave (MGS)		15, 30, 45, 60, 75, 90 s	1	1	Cut pieces	4	Microbicidal Efficacy	>4 log10 reduction in MS2 Coliphage pfu/ml after ≥ 45 seconds
Bergman et al [14] (2010)	Lab Incubator (MHI)	60°C	30 m	3	6	Intact	3	Physical Changes	Partial separation of inner foam cushion of 1 FFR model
								Odor	No comment on odor
								Filter Efficiency	Expected levels of Filter Aerosol penetration (<5%) & filter airflow resistance
Lore et al [15] (2012)	Lab Incubator (MHI)	65 ± 5°C	3 hr	1	2	Intact	9	Filter Efficiency	No profound reduction in filter efficiency
								Microbicidal Efficacy	>4 log10 TCID50/ml reduction of H5N1 Avian Influenza virus achieved
Heimbuch et al [20] (2011)	Lab Incubator (MHI)	65 ± 5°C	30 m	1	6	Intact	3	Physical Changes	No obvious signs of deformation or deterioration of FFRs
								Microbicidal Efficacy	>4 log10 TCID50/ml reduction of Influenza virus (H1N1)
Viscusi et al [21] (2011)	Lab Incubator (MHI)	60°C	30 m	1	6	Intact	2	Physical Changes	Slight separation of inner foam nose cushion in 1 FFR model
								User Acceptability	Mean Odor scores were increased only for 1 FFR model
									No significant increase in discomfort or increased difficulty in donning
									Strap breakage during multiple donning not more frequent than in controls
								Respirator Fit	No clinically meaningful reduction in respirator fit
Bergman et al [23] (2011)	Lab Incubator (MHI)	60°C	15 m	3	3	Intact	2	Physical Changes	Slight separation of inner foam nose cushion in 1 FFR model
								Respirator Fit	No significant changes in Respirator fit
Viscusi et al [22] (2007)	Autoclave (MHA)	121°C	15/ 30 m	1	2	Intact	4	Physical Changes	N95-FFRs were deformed in both conditions and P100 FFRs were unchanged but respirator media felt softer
								Filter Efficiency	Degradation in filter efficiency of both Respirator types
Lin et al [28] (2017)	Autoclave (MHA)	121°C	15 m	1	1	Cut pieces of FFR facepiece	3	Filter Efficiency	Decontamination reduced the filter quality but less than liquid chemical methods
Lin et al [29] (2018)	Autoclave (MHA)	149-164° C	3 m	1	1	Cut pieces of FFR facepiece	3	Microbicidal Efficacy	99–100% Biocidal efficacy against Bacillus subtilis spores

ABBREVIATIONS: UVGI: Ultraviolet Irradiation, FFR: Filtering Facepiece Respirator, m: minute, hr: hour, TCID: Tissue Culture Infectious Dose, s: second, pfu: Plaque Forming Unit

iii. Dry heat. Dry heat for reprocessing of FFRs has been evaluated in 4 studies [16, 22, 28, 29] wherein microwave (MGI) [16, 22], Hot Air Oven (DHO) [16, 22] and Electric Rice Cooker (TERC) [28, 29] have been used. 3M8210 was the only known N95-FFR model which underwent reprocessing by any dry heat delivering method [28, 29]. Various parameters which have been evaluated against them are shown in Fig 2 and their exposure variables and results are summarized in Table 2. In MGI method, respirator models were destroyed in both studies [16, 22]. FFRs reprocessed by DHO were able to physically withstand temperatures at 80°C without affecting durability and filter efficiency [16, 22]. Electric rice cooker (TERC) was able to provide 99–100% biocidal efficacy against Bacillus subtilis spores [29].

B. Gaseous chemical methods

Only 4 studies [14, 16, 22, 27], prior to 2020, had evaluated a gaseous disinfection method for reprocessing of N95-FFRs. The methods used were Ethylene Oxide (EO) [14, 16, 22, 27], Hydrogen peroxide in a Plasma Sterilizer (HPGP) [14, 16, 22, 27] and Hydrogen Peroxide in vaporized form by using a commercial automated vapor generator [22]. FFR models were not disclosed in any of the studies. Parameters against which they were evaluated; and their exposure variables and findings of the studies are provided in Fig 2 and Table 3, respectively. After EO sterilization, FFRs didn’t showed any physical changes [14, 16, 22], or had offensive odor [14, 16], and filter efficiency was also not degraded significantly [14, 16, 22] even after undergoing 3 cycles [14]. In 3 studies, where HPGP was evaluated, no significant physical changes on the FFRs were noted [14, 16, 22] but filter efficiency of 25% (9/36) respirators was noted to be degraded in one [14] of three [14, 16, 22] studies. However, similar effect was not noted when FFRs were treated with vaporized form [14, 22].

Table 3

Summary of characteristics of studies using gaseous chemical methods for reprocessing of FFRs.

Authors	Variables of Decontamination Methods				Variables of FFRs			Results
	Disinfectant Sterilizer	Packaging Conditions	Duration	No. of Decontamination Cycles	Total no. of Models used	Part of FFR exposed	Replicates	Parameters Assessed	Summary of Results
Bergman et al [14] (2010)	Ethylene Oxide	Kept in Tyvek® pouches	1 hr exposure	3	6	Intact	3	Physical Changes	Partial separation of inner foam cushion of 1 FFR model
	Amsco® Eagle® 3017
			12 hr aeration
								Odor	No comment on odor
		6 FFR per pouch
								Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
Viscusi et al [16] (2009)	Ethylene Oxide	Individual poly/paper pouch	1 hr exposure	1	9	Intact	3	Physical Changes	No observable physical changes on FFRs
	3 M Steri-Vac 5XL				(6 N95
			4 hr aeration
					3 P100)
								Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
Viscusi et al [22] (2007)	Ethylene Oxide	Individual poly/paper pouch	1 hr exposure	1	2	Intact	4	Physical Changes	Straps of P100 FFRs were slightly darkened
	3 M Steri-Vac 4XL & 5 XL
								Filter Efficiency	Average penetration increased for both respirator types but were within NIOSH certification criteria
			4 hr aeration
Salter et al [27] (2010)	Ethylene Oxide	Individual sterilization pouch	3 hr exposure	1	6	Intact	3	Presence of Toxic Chemical Residues	EO was not detected on any of the model
	Amsco® Eagle® 3017		12 hr aeration
									Treated EO contained Diacetone alcohol and a possible mutagen and carcinogen, 2-hydroxyethyl acetate (HEA)
Bergman et al [14] (2010)	H2O2 Gas Plasma (HPGP)	Mylar/Tyvek® pouch	55 m cycle time	3	6	Intact	3	Physical Changes	No physical changes on FFRs
								Odor	No comment on odor
	STERRAD® 100S	6 samples per pouch						Filter Efficiency	25% (9/36) samples had aerosol penetration >5% suggestive of degradation in filter efficiency
Viscusi et al [16] (2009)	H2O2 Gas Plasma (HPGP)	Mylar/Tyvek® pouch	55 m cycle time	1	9	Intact	3	Physical Changes	Metallic nose bands not as shiny as unexposed controls
					(6 N95			Filter Efficiency	Expected levels of Filter Aerosol penetration (<5%) & filter airflow resistance
	STERRAD® 100S	6 samples per pouch			3 P100)
Viscusi et al [22] (2007)	H2O2 Gas Plasma (HPGP)	Mylar/Tyvek® pouch		1	2	Intact	4	Physical Changes	Aluminium nosebands slightly tarnished with both cycles
								Filter Efficiency	Average penetration not significantly increased & remained within limit of NIOSH certification criteria for both respirator types and cycling conditions
	STERRAD® 100S		55 m
	STERRAD® NX		100 m
Salter et al [27] (2010)	H2O2 Gas Plasma (HPGP)	Sterilization pouches	55 m	1	6	Intact	3	Presence of Toxic Chemical Residues	No residues on FFRs
									Sterilization cycle aborted when >6 FFRs were loaded in the sterilization chamber
	STERRAD® 100S
Bergman et al [14] (2010)	H2O2 Vapor (HPV)		15 m dwell	3	6	Intact	3	Physical Changes	No physical changes on FFRs
								Odor	No comment on odor
			125 m total cycle time					Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
	Clarus® R HPV Generator

ABBREVIATIONS: FFR: Filtering Facepiece Respirator, hr: Hour, m: Minute, HO: Hydrogen Peroxide

C. Liquid chemical methods

Six different liquid decontamination methods have been evaluated on N95-FFRs in 8 studies [14, 16, 22, 25–29]. These are Bleach [14, 16, 22, 25–29], Liquid Hydrogen Peroxide (LHP) [14, 22, 27], Alcohols [22, 28, 29] including Ethanol and Isopropyl Alcohol, Mixed oxidants [27], Dimethyl Dioxirane [27] and Soap solution [22]. Parameters against which they were evaluated, their exposure variables and results of the studies are provided in Fig 2 and Table 4, respectively. Against Bleach, only known N95-FFR models evaluated were 3M8210 and Wilson SAF-T-FIT Plus (S4 Table). 3M8210 was the only known N95-FFR which was evaluated for Alcohols [28, 29].

Table 4

Summary of characteristics of studies using liquid & miscellaneous chemical methods for reprocessing of FFRs.

Authors	Variables of Decontamination Methods				Variables of FFRs			Results
	Disinfectant	Concentration	Duration	No. of Decontamination Cycles	Total no. of Models used	Part of FFR exposed	Replicates	Parameters Assessed	Summary of Results
Bergman et al [14] (2010)	Liquid H2O2 (LHP)	6%	30 m Submersion	3	6	Intact	3	Physical Changes	Staples were oxidized to varying degree
								Odor	No comment on odor
								Filter Efficiency	Expected levels of Filter Aerosol penetration (<5%) & filter airflow resistance
Viscusi et al [22] (2007)	Liquid H2O2 (LHP)	3%	30 m submersion	1	2	Intact	4	Physical Changes	No observable changes on both respirator types with 3% H2O2 & slight fading of label ink with 6% H2O2
					(1 N95
					1 P100)
								Filter Efficiency	Average penetration within NIOSH certification limit for both respirator types & both concentrations
		6%
Salter et al [27] (2007)	Liquid H2O2 (LHP)	3%	30 m submersion	1	6	Intact	3	Presence of Toxic Chemical Residues	No deposition of significant quantities of toxic residues on FFRs
Bergman et al [14] (2010)	NaOCl (Bleach)	0.6%	30 m Submersion	3	6	Intact	3	Physical Changes	Metallic nosebands were tarnished, Staples were oxidized to varying degree, discoloured inner nose pads, dry to touch
								Odor	All FFRs had a characteristic bleach odor after overnight air drying
								Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
Viscusi et al [16] (2009)	NaOCl (Bleach)	0.6%	30 m Submersion	1	9	Intact	3	Physical Changes	Metallic nose bands were tarnished
								Odor	All FFRs had a scent of bleach and after rehydration with water, increase in chlorine off-gassing was measured
								Filter Efficiency	Expected levels of filter aerosol penetration (<5%) & filter airflow resistance
Lin et al [28] (2017)	NaOCl (Bleach)	0.5%	10 m Submersion	1	1	Cut pieces of facepiece	3	Filter Efficiency	Decontamination reduced the filter quality
Viscusi et al [22] (2007)	NaOCl (Bleach)	0.52%	30 m Submersion (both)	1	2	Intact	4	Physical Changes	Aluminium nose bands were tarnished at both concentrations
					(1 N95
		5.2%			1 P100)
								Filter Efficiency	At 0.52% & 5.2% conc., average penetration for both respirator types were within NIOSH certification criteria
Lin et al [29] (2018)	NaOCl (Bleach)	0.54%	NA Inoculated	1	1	Cut pieces of Face-piece	3	Microbicidal Efficacy	100% Biocidal efficacy against Bacillus subtilis spores at the lowest concentration
		2.7%
		5.4%
Vo et al [25] (2009)	NaOCl (Bleach)	0.005/0.01/0.05/0.1/	10 m Submersion	1	1	Intact	3	Microbicidal Efficacy	≥0.5% bleach causes 4 log10 reduction in pfu/ml of MS2 Coliphage
		0.25/0.5/
		0.75%
Fisher et al [26] (2009)	NaOCl (Bleach)	0.0006%, 0.006%, 0.06%, 0.6%	2 m Submersion	1	1	Cut Coupons of Face-piece	3	Microbicidal Efficacy	0.6% bleach causes 4 log10 reduction in pfu/ml of MS2 Coliphage
Salter et al [27] (2010)	NaOCl (Bleach)	0.6%	30 m Submersion	1	6	Intact	3	Physical changes	Corrosion of metal parts was noted
								Odor	FFRs retained a bleach odor following an off-gas period of 18 hour
								Presence of Toxic Chemical Residues	Measured amount of residual chlorine was below permissible exposure limit
Viscusi et al [22] (2007)	Soap & Water	1g/L	2 m	1	2	Intact	4	Physical Changes	No physical changes observed for both durations
			20 m Submersion (both)		(1 N95
					1 P100)
								Filter Efficiency	Average penetration increased for both durations and both respirators
Salter et al [27] (2007)	Mixed Oxidants	(10% Oxone, 6% Sodium Chloride, 5% Sodium Bicarbonate)	30 m submersion	1	6	Intact	3	Physical Changes	Oxidised metal parts
								Odor	Left distinct odor on FFRs
								Presence of Toxic Chemical Residues	No comment
Salter et al [27] (2007)	Dimethyl Dioxirane	(10% Oxone, 10% Acetone, 5% Sodium Bicarbonate)	30 m submersion	1	6	Intact	3	Physical Changes	Oxidised metal parts
								Odor	White residue accumulated on FFRs
								Presence of Toxic Chemical Residues	Left distinct odor on FFRs
									Retained in quantity by all 6 FFRs
MISCELLANEOUS METHODS
Heimbuch et al [18]	NaOCl (Bleach) wipes	0.9%	Surface Cleaning of outer and inner layers	3	3	Intact	3	Microbicidal Efficacy	3–5 log reduction of S. aureus in the presence of mucin
								Filter Efficiency	Mean particle penetration was <5%
								Mucin removal	No mucin detected, likely due to interference in measurement assay by NaOCl
Heimbuch et al [18]	BAC wipes		Surface Cleaning of outer and inner layers	3	3	Intact	3	Microbicidal Efficacy	>4 log reduction of S. aureus in the presence of mucin in most FFR samples
								Filter Efficiency	Mean particle penetration was <5% but more than Bleach
								Mucin removal	Removal efficiency ranged from 21.47–76.41% but was poorer than inert wipes
Heimbuch et al [18]	Inert wipes		Surface Cleaning of outer and inner layers	3	3	Intact	3	Microbicidal Efficacy	No antibacterial activity
								Filter Efficiency	Mean particle penetration was <5%
								Mucin Removal	Removal efficiency ranged from 21.47%-76.41% and better than BAC wipes

ABBREVIATIONS: FFR: Filtering Facepiece Respirator, HO: Hydrogen Peroxide, m: Minute, NaOCl: Sodium Hypochlorite, NIOSH: National Institute of Occupation Safety & Hygiene, g/L: Gram/Liter, Staphylococcus aureus, BAC: Benzalkonium Chloride

D. Miscellaneous methods

In one study [18], commercial wipes of 0.9% Sodium Hypochlorite, Benzalkonium Chloride and an Inert material were evaluated for changes in filter efficiency and microbicidal efficacy by applying them on surface of N95-FFRs, as shown in Fig 2 & Table 4.

Discussion

An Influenza pandemic was always on the horizon and in 2009, it became reality. Researchers at NIOSH have been looking actively for finding a suitable method for reprocessing of FFRs since 2006 after the report of IOM Committee to tackle global shortage of FFRs [11, 22]. Consequently, search for a suitable reprocessing method began under NIOSH. During 2007–2012, 12 studies were published which evaluated reprocessing methods for FFRs, most of them were conducted by or in collaboration with NIOSH [14–17, 20–27]. In contrast, between 2013–2019, only 5 published studies had evaluated a reprocessing technique for N95-FFRs [19, 20, 28, 29], with last study published by NIOSH in 2015 [8]. Ongoing COVID-19 pandemic has brutally exposed the stalled progress in research to address this issue.

It has been shown that the surface stability of SARS-CoV-2 on various surfaces lasts up to 3 days but this study didn’t include porous surfaces like that of respirators [37]. However, a study recently, showed it to be present on outer layer of surgical masks on day 7 [38]. This recent data makes it imperative to decontaminate FFRs in between use as the risk of contact transmission without decontamination is considerable. Previously, CDC also discouraged reusing N95-FFRs whenever risk of contact transmission of a pathogen was high [6]. Furthermore, it is in larger global interest to find a suitable reprocessing method for N95-FFRs as they are not used frequently by HCWs in low to middle income countries (LMICs) while tackling airborne pathogens, such as Mycobacterium tuberculosis, against which their use is mandatory [39, 40]. Finding a reprocessing method for FFRs will lead to provision of adequate respiratory protection for HCWs in such resource limited settings.

We found that UVGI was the most frequently evaluated reprocessing method for N95-FFRs, as shown in Fig 2 and Table 3. Reprocessing by UVGI method maintained the overall physical structure and filter efficiency of the FFRs and was able to demonstrate sufficient microbicidal efficacy. Furthermore, it had insignificant influence on the respirator fit and reprocessed FFRs were devoid of any toxic residues but studies which evaluated these parameters were few. Furthermore, these findings should be assessed in view of varying exposure variables of UV dose used in these studies and the methodological variations in estimating the measures of microbicidal efficacy, as shown in Table 1.

Dose of irradiation is the most important variable for determining microbiological efficacy of UVGI method which, in turn, is determined by irradiance at the surface of FFR and duration of exposure [19]. All studies [15, 19, 20, 24, 25], except one [29], which evaluated the microbicidal efficacy of UVGI used enveloped viruses as the challenge micro-organism. Total doses around 1–2 J/cm2 have shown to provide ≥4 log10 reduction of viruses inoculated on FFRs [15, 20, 25]. Lin et al [29] used Bacillus subtilis spores as challenge micro-organisms and found that from a 18.9mW/cm2 UV-C source, exposure for 5 min (corresponding to a dose of 5–6 J/cm2) was able to kill all spores. However, this study measured relative survival of spores (in percentage) on exposed respirator coupons as compared to control coupons (unexposed) instead of log reduction of spores. Whether such doses will be effective against other airborne pathogens, such as M. tuberculosis should be assessed in future research. Furthermore, a study by Fisher et al [24] concluded that the UV-C dose required for microbicidal efficacy is a function of the dose available to the electret medium rather than total dose, which in turn, is dependent on the penetrance (transmittance) of the layer above it. Hence, effective doses of UV-C for microbicidal efficacy will be model specific and needs to be established accordingly. We conclude that UVGI has great potential to be utilized as an effective decontamination method for N95-FFRs during this time of crisis however, more studies are needed to validate the various variables associated with the delivery of the UVGI method and respirator model specific doses will need to be established.

MGS & MHI methods delivered moist heat to FFRs in a microwave and a bench top laboratory incubator, respectively and have shown no significant effect on user acceptability, respirator fit and filter efficiency till 3 cycles of decontamination [14, 15, 21, 23]. However, multiple studies evaluating physical changes noticed partial separation of inner foam nose cushion in both methods for a particular FFR model (3M1870), where model identity was disclosed, but effect was not pronounced after undergoing multiple cycles of decontamination [14, 23]. Whether it is a model specific issue or not should be evaluated in future studies. In terms of microbicidal efficacy, ≥4 log10 reduction of enveloped viruses was demonstrated for both methods [15, 17, 20, 26]. We are of opinion that these methods are low cost, easily doable in any setting, but require more validation in terms of other respirator models and cycles of decontamination, in future studies. MGS method is particularly suitable for implementation by individuals at home and smaller healthcare settings. Sparking due to placing metallic components in microwave has been a concern but it has not been noticed in MGS method [14].

Few studies were done on Dry heat as a modality to reprocess FFRs [16, 22, 28, 29]. Physical degradation of the respirators was noted, in varying degree, with these methods using Microwave (MGI), Hot air oven (DHO) and traditional electric rice cooker (TERC). Of these, TERC has shown to be microbiologically efficacious against B. subtilis spores and preserve physical architecture and filter efficiency of the respirators in limited studies conducted using it [28, 29] We opine that the literature is insufficient to either recommend or refute dry heat as a method of reprocessing for FFRs.

Ethylene oxide (EO) and Hydrogen peroxide (H2O2) are ideally suited for reprocessing of temperature sensitive articles hence, their use for reprocessing N95-FFRs is particularly promising. They have been evaluated as a reprocessing method for N95-FFRs simultaneously in 4 studies [14, 16, 22, 27] in which, FFRs were exposed to EO and H2O2 (HPGP) in their respective sterilizers for standard cycling conditions, as described in Table 3. In addition, Viscusi et al [22] evaluated vaporized H2O2 (HPV) generated in a commercial, automated vapor generator (BIOQUELL®). FFR models were not disclosed in any of these studies. The studies found that EO performed suitably in maintaining the physical architecture and filtration efficiency of the respirators however microbicidal efficacy, user acceptability and effect of respirator fit on N-95 FFRs were not evaluated in any study. Furthermore, a study by Salter et al [27] found possible carcinogen and mutagen, 2-hydroxyethyl acetate (HEA) on FFRs which had undergone EO sterilization. Hence, this method cannot be recommended for reprocessing of N95-FFRs due to safety concerns and improving the safety profile of EO by increasing aeration duration post-sterilization can be explored in future studies.

Hydrogen peroxide provides microbicidal activity by way of generating free radicals and its degradation products are safe. In 3 studies, where HPGP was evaluated, no significant physical changes on the FFRs were noted [14, 16, 22] but one study [14] noted degradation in filter efficiency of 25% (9/36) respirators. However, this effect was not noted when FFRs were treated with vaporized form [22, 41]. In a commercial evaluation done for FDA by Batelle Institute on Clarus C HPV generator (BIOQUELL®) in 2016, no filter degradation was noted on 3M1870 FFR even after undergoing 50 cycles of decontamination [41]. This system has been granted emergency use authorization (EUA) by FDA, after COVID-19 pandemic, for reprocessing N95-FFRs [42]. Concerns have been raised regarding throughput of HPGP as in a study authors noticed cycles were aborted in STERRAD® Sterilizer whenever >6 FFRs were placed [27]. This could be due to presence of cellulose in the straps of the respirators leading to absorption of H2O2 [27]. Prior to 2020, no study, in published literature, had evaluated microbicidal efficacy of H2O2 on FFRs, but recently, Fisher et al [43] found it effective in removing SARS-CoV-2 from N95-FFRs. Furthermore, Batelle report, also showed 6 log reduction of Geobacillus stearothermophilus spores on FFRs which underwent reprocessing by HPV [41]. Overall, Hydrogen peroxide in gaseous form is a suitable option for reprocessing N95-FFRs but it needs to be evaluated rigorously for other parameters such as respirator fit and also against other N95-FFR models. However, at present its availability is restricted to limited resource rich settings.

Submersion of FFRs in liquid disinfectants is a simple method of decontaminating them. Bleach was the most frequently evaluated liquid disinfectant for reprocessing of FFRs, being evaluated in 9 studies [14, 16, 18, 22, 25–29] of which, 1 used disinfectant wipes [18]. Exposure to bleach caused physical changes in the FFRs in terms of being stiff, mottled and tarnishing of metallic nosepiece [14, 16, 18, 22]. Offensive odor from FFRs was noticed in most studies [14, 16, 27]. Furthermore, chlorine release has been noted when respirators were exposed to moisture, raising concerns regarding the safety of this method if a person breathes through it [16, 27]. Though it has been found to have no significant degradation in the filter quality of the FFRs [14, 16, 18, 22] and have excellent microbicidal efficacy [18, 25, 26, 29], FFRs decontaminated by bleach are not safe.

Liquid Hydrogen peroxide (LHP) in 3% concentration was able to preserve filter efficiency & physical architecture [14, 22] of the N95-FFRs and was devoid of any toxic residues post-exposure [27]. Alcohols (Ethanol and Isopropyl alcohol) have also been evaluated in 3 studies, but they are known to significantly degrade the filter efficiency due to removal of electrostatic charges from the electret media [22, 28, 29]. Similarly, soap & water degraded the filter efficiency, as noted in a study [22].

We found that UVGI was the most widely evaluated reprocessing method, being evaluated for 23 different known FFR models. Nine known FFR models preserved their filter efficiency and 18 known FFR models achieved adequate microbicidal efficacy after undergoing reprocessing by UVGI method. However, the same FFR model: Parameter combination for UVGI was not evaluated in more than two studies. Six known FFR models were reprocessed by MGS [17, 21, 23] & MHI [21, 23] methods. Except for 3M1870, as discussed previously, none of the FFRs showed physical changes after undergoing reprocessing. In none of the studies which evaluated Gaseous chemical methods, identity of FFR models was disclosed. Thus, we suggest that future studies should include multiple known FFR models while evaluating a reprocessing method as compatibility of the FFR with the reprocessing method is of paramount importance.

A summary assessment of the body of literature, published prior to 2020, on reprocessing of N95-FFRs has been provided in Fig 2. However, the findings of this systematic review and opinion of the authors should be assessed in light of limited literature available on this topic, prior to 2020. Furthermore, readers should also consider the variability in exposure variables of the reprocessing methods and methodological variabilities in the evaluated parameters within and between reprocessing methods. For example, to evaluate microbicidal efficacy, studies have used different categories of micro-organisms and growth parameters accordingly while few included additional soiling challenges to mimic micro-organisms in human secretions. Some parameters were evaluated only in few studies such as odor, wear comfort, and donning ease were evaluated objectively only in 1 study [21], respirator fit in 2 studies [21, 23] and chemical safety in 1 study [27]. Hence, changes in these parameters which are not studied much, nevertheless are important, should be the focus of future studies. We didn’t do a meta-analysis as the number of studies done to evaluate a particular parameter for a reprocessing method were few and heterogeneous in terms of both exposure & methodological variables.

As we write this review, a large body of literature on reprocessing of N95-FFRs has been already published [43-57], but when we did literature search, only few studies were published [44, 45, 49, 57] and majority were in preprint, non-peer reviewed versions. Hence, in this systematic review, we only included studies which were published prior to COVID pandemic. This review may help administrators, infectious disease specialists and infection control personnel to formulate policies for effective utilization of single use, N95-FFRs to prevent respiratory transmission of SARS-CoV-2 as well as other airborne pathogens. It will help researchers to find existing knowledge gaps in respirator reprocessing techniques and help them to design future studies. Furthermore, manufacturers may find it useful by knowing existing limitations and work their way around by developing new respirator material or design, more amenable to commonly available reprocessing techniques.

Conclusions

We found that published literature on evaluation of reprocessing methods of FFRs was scant, prior to COVID pandemic. Physical methods of decontamination, such as using heat or radiation, were the most commonly evaluated methods for reprocessing of FFRs. Majority of studies evaluated either physical changes or effect on filter efficiency of respirators after undergoing decontamination and the microbicidal efficacy of the decontamination method. Only few studies evaluated the effect of decontamination methods on respirator fit or their chemical safety profile. We found that there was a lot of heterogeneity amongst the studies regarding the exposure variables of UVGI method, used respirator models and methodology to evaluate microbicidal efficacy in terms of challenge micro-organisms, method of exposure of challenge micro-organism to FFRs, use of a soiling challenge and evaluated parameters.

We found that UVGI was the most commonly evaluated method in the published literature, prior to 2020 and it ticks all the boxes required for an ideal reprocessing method for N-95 FFRs. However, doses of UV-C irradiation which can achieve satisfactory microbicidal efficacy needs to be determined specifically for each FFR model. Majority of heat-based methods caused physical changes in the respirators, in varying degree, but adequately removed viral micro-organisms from the surface of FFRs without compromising filter efficiency, even after undergoing multiple cycles of decontamination. In particular, MGS method had extremely short cycle time & seems easy to implement in any setting. Few studies evaluated gaseous chemical methods such as EO and Hydrogen peroxide & found that filter efficiency of FFRs was maintained. However, safety concerns were raised on reusing FFRs which underwent reprocessing by EO, in the only study evaluating it.

To summarize, reusing N95-FFRs is need of the hour due to COVID-19 pandemic. Choosing a reprocessing method for FFR decontamination requires careful considerations of various factors such as physical changes, respirator fit, filter efficiency and chemical safety profile, besides being microbiologically efficacious. Furthermore, compatibility of reprocessing method with the FFR models used in a setting, duration of reprocessing cycle and costs involved make it an extremely complex decision for the infection control personnel and administrators. Presently, promising technologies which need to be evaluated rigorously include UVGI, HP, MGS & MHI. Though, emergency use approvals have been given to Hydrogen Peroxide STERRAD® Gas Plasma Sterilizer and BIOQUELL® Clarus C HPV generator, their presence is extremely limited worldwide, particularly in LMICs. Finding a suitable reprocessing method for N95-FFRs is also important from the perspective of infection control against airborne pathogens in LMICs, such as Mycobacterium tuberculosis. MGS and MHI have shown to be efficacious against enveloped viruses and not compromise the filter efficiency up to 3 cycles of decontamination, in multiple studies. Of them, MGS has an extremely short cycle and should be considered for emergency implementation in resource limited settings.

PRISMA checklist.

(DOCX)

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Search strategy.

(DOCX)

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Results of quality assessment & risk bias of included studies (after inter-author agreement).

(DOCX)

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Summary of various reprocessing parameters evaluated for specific FFR models (where disclosed in included studies) by various reprocessing methods.

(DOCX)

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14 Sep 2020

PONE-D-20-23922

Exploring options for reprocessing of N95 Filtering Facepiece Respirators (N95-FFRs) amidst COVID-19 pandemic: a systematic review

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Reviewer #1: Thank you for the opportunity to review this manuscript. The authors have performed an extensive literature search and review on N95 make re-processing. The topic is pertinent in the current setting, although rapidly changing. The authors have mostly stuck to peer-reviewed content, which is not always the case for studies at this time, but is beneficial to their work. The manuscript is very comprehensive, perhaps a little too much for a topic that they comment on as inadequate and sparse.

My concerns are:

• The comments “full set of personal protective equipment (PPE) including gowns, gloves, facemasks, face-shields or goggles and respirators for their protection during patient care” and “HCWs need to be protected against bioaerosols at all costs, which at minimum, is offered by use of N95 Filtering Facepiece Respirator (N95-FFR)” are misleading. In fact, citation (4) by the authors states that N95s are only needed during aerosol generating procedures. The authors should clarify this in the introduction.

• “removes > 95% particles of around 300 nm” – there is an official definition of what an N95 filters, the authors should use that

• The statement “No independent study prior to 2020 has evaluated microbicidal efficacy of H2O2 on FFRs” is not correct, see Fischer et. al 2020, among others

• The discussion is far too long, essentially putting the tables into text. As such:

• Paragraph 1 of the discussion is off topic and tangential opinion, it should be removed

• The paragraph that starts “A typical N95-FFR consists of facepiece…” was not material analysed by the literature search and should be removed

• The statement “N95-FFRs are difficult to decontaminate owing to the porous nature of the main body and electrostatically charged nature of electret media” needs a reference, this is debatable

• The discussion needs to be reduced to key points and synthesis, with a cohesive analysis of the literature. At least two pages could be removed.

• The conclusion doesn’t provide any conclusion regarding the review, but comments on the need for the review and then, again, summarizes the general concepts. There is no analysis here. There is also a dichotomy here, with one sentence stating a need for solution for low income countries (which I agree with), to the very next sentence stating an urgent need to study UV and HPV (not low income country solutions, by the authors own admission).

• My biggest concern here is that this really isn’t a systematic review. It attempts to be, and provides the needed supplementary info (i.e. PRISMA diagram) but doesn’t provide any significant analysis. This is really a narrative review with an extensive literature search.

Minor

• The virus name is actually “SARS-CoV-2” not “SARS-COV-2”

• Figure 2 legend “plotted against the reprocessing method” – not sure what the authors mean, it is a table, nothing is “plotted”

**********

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Reviewer #1: No

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13 Oct 2020

Comment 1: Section: Introduction

The comments “full set of personal protective equipment (PPE) including gowns, gloves, facemasks, face-shields or goggles and respirators for their protection during patient care” and “HCWs need to be protected against bioaerosols at all costs, which at minimum, is offered by use of N95 Filtering Facepiece Respirator (N95-FFR)” are misleading. In fact, citation (4) by the authors states that N95s are only needed during aerosol generating procedures. The authors should clarify this in the introduction.

Author’s Reply: The authors have suitably modified the sentence as suggested by the reviewers in the Introduction section (Page 4, Paragraph 1).

Comment 2: Section: Introduction

removes > 95% particles of around 300 nm” – there is an official definition of what an N95 filters, the authors should use that

Author’s Reply: The authors have modified the sentence and provided the reference of the official definition (Reference 7). In previously submitted manuscript, reference 5 & 7 were duplicated, now the new reference is given in place of Reference 7 (Page 4, Paragraph 1).

Comment 3: Section: Discussion

The statement “No independent study prior to 2020 has evaluated microbicidal efficacy of H2O2 on FFRs” is not correct, see Fischer et. al 2020, among others.

Author’s Reply: Fischer et al (2020) have referenced Batelle report which evaluated microbicidal efficacy of Hydrogen peroxide for decontamination of N95-FFRs. It was a third party “commercial” evaluation of Clarus C Hydrogen Peroxide vapor generator done by Batelle Institute on behalf of FDA. This wasn’t an independent study published in scientific domain. Hence, we are of the opinion that the statement is correct. Furthermore, we have referenced findings of Batelle report in the Discussion section of the manuscript, where deemed suitable (Page 42, Paragraph 1).

Comment 4: Section: Discussion

The discussion is far too long, essentially putting the tables into text. As such:

i. Paragraph 1 of the discussion is off topic and tangential opinion, it should be removed

Author’s Reply: In our opinion, this paragraph is important as it highlights the chronology of the scientific progress made in finding a suitable reprocessing method for enabling reuse of FFRs. We humbly opine that had such a method been found in the previous decade, the crises of FFRs wouldn’t have been of this humongous proportions during COVID-19 pandemic. In late to 2000s to late 2010s, there was scientific thrust in finding such a reprocessing method which got derailed in the mid to late 2010s contributing partly to the current crises of shortage of FFRs.

ii. The paragraph that starts “A typical N95-FFR consists of facepiece…” was not material analysed by the literature search and should be removed.

Author’s Reply: The paragraph has been removed as suggested by the reviewers (Omitted).

iii. The statement “N95-FFRs are difficult to decontaminate owing to the porous nature of the main body and electrostatically charged nature of electret media” needs a reference, this is debatable

Author’s Reply: The statement & paragraph containing it has been removed in the revised Discussion (Omitted).

iv. The discussion needs to be reduced to key points and synthesis, with a cohesive analysis of the literature. At least two pages could be removed.

Author’s Reply: Discussion has been extensively modified as suggested by the reviewers.

Comment 5: Section: Conclusion

The conclusion doesn’t provide any conclusion regarding the review, but comments on the need for the review and then, again, summarizes the general concepts. There is no analysis here. There is also a dichotomy here, with one sentence stating a need for solution for low income countries (which I agree with), to the very next sentence stating an urgent need to study UV and HPV (not low income country solutions, by the authors own admission).

Author’s Reply: The conclusions are now modified, hopefully to the reviewer’s satisfaction. The first 2 paragraphs summarize the findings of the study whereas the last paragraph gives general concepts and way for the future (Pages 45-46).

Comment 6: Section:

My biggest concern here is that this really isn’t a systematic review. It attempts to be, and provides the needed supplementary info (i.e. PRISMA diagram) but doesn’t provide any significant analysis. This is really a narrative review with an extensive literature search.

Author’s Reply: We wholeheartedly accept the criticism of the reviewer. However, we will like to counter on the following points:

1. Systematic reviews address a specific research question using explicit methodology of collecting, selecting and appraising studies and synthesizing the results qualitatively or quantitatively, as appropriate.

2. Our review appears as a narrative review because it addresses a broad research question and the outcome of the included studies is discussed more in “Qualitative terms” rather than quantitatively.

3. We are of the opinion that the included studies varied extensively in terms of heterogeneity hence discussion in quantitative terms will not do justice to the essence of the article. Hence, qualitative results of included studies were taken into account in discussion and Quantitative details are provided in the Tables.

4. Overall the studies have not shown conflicting results between themselves for a particular reprocessing method despite being extremely heterogeneous. Hence the findings appear as General concepts, when in fact they are qualitative synthesis of the published literature on the topic. Wherever, conflicting results for a particular reprocessing method have been observed amongst studies, we have made an attempt to discuss.

5. Hence, as suggested by the reviewer, we have revised the Discussion & Conclusion sections extensively focusing now more on the qualitative findings pertaining to the review, hopefully to the reviewer’s satisfaction.

Minor

Comment 7:

The virus name is actually “SARS-CoV-2” not “SARS-COV-2”

Author’s Reply: This has been corrected in all the relevant places

Comment 8:

Figure 2 legend “plotted against the reprocessing method” – not sure what the authors mean, it is a table, nothing is “plotted”

Author’s Reply: The legend has been suitably modified

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

27 Oct 2020

PONE-D-20-23922R1

Exploring options for reprocessing of N95 Filtering Facepiece Respirators (N95-FFRs) amidst COVID-19 pandemic: A systematic review

PLOS ONE

Dear Dr. Gupta,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Your manuscript can be accepted subject to minor revisions as detailed by the reviewer. Please check the term "systematic" in the title, and consider whether it may be changed to "Narrative" review.

==============================

Please submit your revised manuscript by Dec 11 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Amitava Mukherjee, ME, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: >> The statement “No independent study prior to 2020 has evaluated microbicidal efficacy

of H2O2 on FFRs” is not correct, see Fischer et. al 2020, among others.

Author’s Reply: Fischer et al (2020) have referenced Batelle report which evaluated

The authors must have the wrong Fischer et al. (2020) – I am referring to 1. Fischer, R. J., (2020) Effectiveness of N95 Respirator Decontamination and Reuse against SARS-CoV-2 Virus. Emerging Infect. Dis. 10.3201/eid2609.201524. This article does not reference any other article, but does the experiments themselves. This is but one example. It is actually very important to the manuscript, as this is now the most common method for commercial decontamination.

The discussion is still too long and re-states the results. I encourage the authors to think of how to discuss the results, not re-state them.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

1 Nov 2020

To

The Editor

PLOSONE

Sir

At the outset we would like to thank the Reviewer(s) for critically reviewing our manuscript. Here is our point by point rebuttal to the suggestions/ concerns raised by the Reviewer:

COMMENT 1: SECTION: TITLE

Please check the term “systematic” in the title, and consider whether it may be changed to “Narrative review.

Author’s Reply: In our humble opinion, a “Systematic review” differs from a “Narrative review” in the following points:

a. The research question is well defined.

b. There is clearly defined criteria for selection for articles published in literature

c. Methods of extraction of and synthesis of data are explicit

d. The critical appraisal of the quality of included studies is explicitly done

In summary, systematic reviews differ from narrative reviews in their “Methodology” rather than the “Results”. We are of the opinion that our review ticks all the boxes in this regard. Furthermore the protocol of the article is also registered with the International prospective register of systematic reviews (PROSPERO) beforehand.

We have already explained that the results of our article are synthesized and discussed more in the qualitative terms rather than quantitative terms due to the heterogeneity in the methodologies of various articles who have researched this topic. Hence, we humbly request that we should persist with the word “Systematic” in the title.

COMMENT 2: SECTION: DISCUSSION

The authors must have the wrong Fischer et al. (2020)- I am referring to 1. Fischer R.J., (2020) Effectiveness of N95 Respirator Decontamination and Reuse against SARS-CoV-2 Virus. Emerging Infect Dis 10.3201/eid2609.201524. This article doesn’t reference any other article , but does the experiments themselves. This is but one example. It is actually very important to the manuscript, as this is now the most common method for commercial decontamination.

Author’s Reply: We had cited the same study which the reviewer is referring to but it was a preprint version which we cited (Reference 43). Our statement in previous rebuttal “Fischer et al (2020) have referenced Batelle report which evaluated microbicidal efficacy of Hydrogen peroxide for decontamination of N95-FFRs”was based on this pre-print version but their comment about Batelle report are now removed from the final print when this article is published as “Letter” in Emerging Infectious Disease, which the reviewer is referring to, hence the confusion. Thus, we have now modified the reference of this article (No. 43) in our manuscript to final print version from the originally given pre-print version.

In the first cycle of peer review, the reviewer had commented “The statement- No independent study prior to 2020 has evaluated microbicidal efficacy of H2O2 on FFRs - is not correct, see Fischer et al 2020, among others.” We modified it in our article as “Prior to 2020, no study, in published literature, had evaluated microbicidal efficacy of H2O2 on FFRs, but recently, Fisher et al[43] found it effective in removing SARS-CoV-2 from N95-FFRs”. Our statement in the manuscript is correct probably the phrase “Prior to 2020” is ignored. This study by Fischer et al is published online in June 2020 (preprint version) & final version in September 2020. They evaluated the efficacy of VHP (Vaporized Hydrogen Peroxide) on N95 respirators contaminated with SARS-CoV-2 virus, a virus which was non-existent prior to 2020, so how can our statement be deemed as incorrect as we are specifically talking about research done Prior to 2020.

Furthermore, it is said that such inaccuracies are an example. We humbly request the reviewer to provide specific statements which are inaccurate and require correction.

Comment 3: Section: Discussion

The discussion is still too long and re-states the results. I encourage the authors to think of how to discuss the results, not re-state them.

Author’s Reply: We humbly request the reviewer’s criticism in terms of 2 things: length of discussion and re-stating the results in discussion, but kindly consider this:

a. The discussion appears lengthy because there are multiple methods which have been evaluated in the published literature for reprocessing of FFRs. We believe that all these methods needs to be discussed individually in terms of their variables, pros, and cons so that their suitability in reprocessing of FFRs in a particular setting can be assessed.

b. Regarding, the re-stating of results in discussion section, we believe that some form of re-stating of the result is required to initiate discussion of a particular issue.

Hence, taking the criticism in our stride, we have once again attempted to reduce the length of the discussion, hopefully to the reviewer’s satisfaction. Overall word count of our manuscript text (without abstract, tables/ figures and their legends, references) is 4633, which in our opinion is usual for such articles.

Dr. Ayush Gupta

Assistant Professor

Department of Microbiology

AIIMS Bhopal

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

4 Nov 2020

Exploring options for reprocessing of N95 Filtering Facepiece Respirators (N95-FFRs) amidst COVID-19 pandemic: A systematic review

PONE-D-20-23922R2

Dear Dr. Gupta,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Amitava Mukherjee, ME, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

9 Nov 2020

PONE-D-20-23922R2

Exploring options for reprocessing of N95 filtering facepiece respirators (N95-FFRs) amidst COVID-19 pandemic: A systematic review

Dear Dr. Gupta:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Dr. Amitava Mukherjee

Academic Editor

PLOS ONE