Microbiological, scientific and regulatory perspectives of hand sanitizers

Generics and Biosimilars Initiative Journal (GaBI Journal). 2021;10(3):130-40
DOI: 10.5639/gabij.2021.1003.017

Published in: Volume 10 / Year 2021 / Issue 3
Category: Review Article
Page: 130-40
Visits: 1778 total, 2 today
Keywords: Effectiveness, hand sanitizers, myths, regulatory framework, safety, standards

Author byline as per print journal:
Adjunct Associate Professor Sia Chong Hock, BScPharm, MSc; Tan Ying Ting, BSc Pharm (Hons); Associate Professor Chan Lai Wah, BSc Pharm (Hons), PhD

Abstract:
Hand sanitizers are rub-on formulations for the purpose of inactivating microorganisms on the hands. With the recent COVID-19 pandemic, a surge in the manufacturing, sale and use of hand sanitizers is observed. However, the effectiveness and safety of hand sanitizers are not well understood by the public; thus, hand sanitizer usage may not confer adequate protection and may pose safety threats. Globally, the emergence of safety threats and inappropriate manufacturer claims also suggest that regulatory frameworks are insufficient in ensuring optimal effectiveness and safety standards for hand sanitizers. This paper presents an overview of the activity of antimicrobials as active ingredients in hand sanitizers and the principles of test methods to evaluate the effectiveness of hand sanitizers. Different antimicrobials confer different activities, rendering some more useful than others. There are also no specific compendial test for efficacy of hand sanitizers and the choice of test method is left to the discretion of manufacturers. It has also been reported that a significant number of hand sanitizers were improperly labelled or had inappropriate claims. Implementing a tighter regulatory framework, developing pharmacists’ knowledge and capabilities, raising consumer awareness and debunking common myths are some possible solutions to address the problems encountered.

Submitted: 17 March 2021;Revised: 13 May 2021; Accepted: 15 May 2021; Published online first: 28 May 2021

Introduction

Globally, millions of people suffer from healthcare-associated infections (HCAIs) each year [1]. HCAIs occur in patients while receiving care for another medical condition [2] and one identified cause is poor hand hygiene [3]. Recently, the emergence of Coronavirus Disease 2019 (COVID-19) poses an unprecedented challenge to healthcare globally. In light of persistent HCAIs and this public emergency, strategies to mitigate infectious spread are crucial.

According to the World Health Organization (WHO), the most crucial measure towards mitigating the spread of harmful microbes is practicing proper hand hygiene [4]. Following COVID-19, the Center for Disease Control (CDC) recommends the use of alcohol-based hand sanitizers as a substitute to handwashing with soap and water [5, 6]. Consequently, the sale, supply and use of hand sanitizers have skyrocketed. Hand sanitizers are rub-on formulations [7] categorized as alcohol-based (ABHS) or non-alcohol-based (NABHS). ABHS contain alcohol and components, such as water and humectants [8]. The alcohols commonly used include ethanol (ethyl alcohol) and isopropyl alcohol [9]. NABHS, also known as “alcohol-free hand rub”, commonly contain benzalkonium chloride, chlorhexidine gluconate, hydrogen peroxide or iodine [9]. Hand sanitizers may be liquids, gels or foams used to inactivate or suppress the growth of microorganisms found on hands [8].

Many manufacturers claim that their products kill 99.9% of microbes effectively. Such claims have become common practice [10] and have misrepresented the effectiveness of hand sanitizers because the percentage of kill claimed is specific to the microorganisms used in the test method. Currently, the US Food and Drug Administration (FDA) allows manufacturers to produce hand sanitizers without formal approval [11]. This may encourage the rise of ineffective hand sanitizers by unethical manufacturers. In fact, the lack of tighter regulatory controls has compromised safety, as evident in recent cases of methanol poisoning due to the use of methanol-contaminated hand sanitizers [12]. More regulatory oversight is warranted to ensure safety checks and balances are in place to avoid safety threats.

With the perceived ‘shortage of supply’ of hand sanitizers amid the COVID-19 pandemic, consumers have become less discerning. They may also hold misconceptions regarding hand sanitizers which hinder them from receiving the desired protection. The misconceptions have resulted in safety issues for consumers. In this regard, there is a need to debunk these myths, raise consumer awareness and promote consumer education.

Studies have investigated the efficacy of using hand sanitizers vis-a-vis handwashing with soap and water [13, 14]. Some studies have also compared the efficacies of different hand sanitizer brands [15-18]. As there is no specific compendial test for efficacy of hand sanitizers, various methods have been used and the results obtained may not be comparable or may not provide useful information. There is also a lack of studies to investigate the multitude of factors that can affect the efficacy of hand sanitizers and to debunk the misconceptions regarding their activity and safety. To date, there is no reported survey on the quality, safety and efficacy of commercial hand sanitizers available to consumers.

This paper aims to highlight useful antimicrobial compounds and provide a better understanding of the different test methods. It also aims to debunk myths and identify factors that affect the activity and safety of hand sanitizers, and consequently, propose solutions to educate consumers. Last, but not least, a regulatory framework for control of hand sanitizers, is proposed.

The microbiology of bacteria, fungi and viruses

To evaluate the effectiveness of hand sanitizers, it is necessary to understand the nature of microorganisms, which are targets of hand sanitizers. Microorganisms are tiny living things not visible to the naked eye unless they proliferate to form a mass. Scientifically, bacteria and fungi are considered microorganisms, but viruses are not because viruses exist in sub-micron size and are non-living outside of a host [19]. However, manufacturers of hand sanitizers have often claimed that their products kill 99.9% of microorganisms [10, 20] which is perceived to include viruses. Moreover, common efficacy tests employed consist of methods developed for bacteria and fungi, suggesting that viruses are not covered.

Bacteria are prokaryotes with each cell consisting of a double-stranded DNA (dsDNA), plasmids and ribosomes in the cytoplasm surrounded by a plasma membrane, see Figure 1a, [21, 24]. Most bacteria have a cell wall made up of a continuous peptidoglycan. Gram-positive bacteria have a thicker peptidoglycan than Gram-negative bacteria. Some bacteria also possess flagella which enable bacterial motility, and fimbriae and capsule which enable attachment to surfaces. The capsule also provides additional protection to the cell. Some bacteria may produce spores which are highly resistant to chemicals.

Figure 1 pending to upload

Fungi consist of yeast and mould. Unlike bacteria, fungi are eukaryotic. Their cells consist of nucleus, mitochondrion, Golgi apparatus and vacuole, which are membrane-bound, in a cytoplasm surrounded by a plasma membrane and cell wall, see Figure 1b [22]. The cell wall of fungi is typically composed of mannoproteins, chitins and glucans [25]. Fungi produce spores that are less resistant than bacterial spores.

Viruses are obligate parasites consisting of genetic material, either DNA or RNA, enclosed within a capsid composed of protein, see Figure 1c [23, 26]. Structurally, viruses are described as enveloped when their capsid is enclosed by an outer lipoprotein envelope, or non-enveloped. The envelope consists of peplomers for attachment to the host organism. Some pathogenic viruses include, for example, those belonging to the families Adenoviridae, Coronaviridae and Herpesviridae [26]. The coronavirus is part of the Coronaviridae family.

It can be clearly seen that bacteria, fungi and viruses possess characteristic structures that may differ in chemical composition. Therefore, depending on their mechanisms of action, some compounds are effective only against certain microorganisms.

Antimicrobial compounds and their applications in hand sanitizers
The antimicrobial compounds are classified based on their chemical composition, see Table 1. They may show one or more mechanisms of action against one or more types of microorganisms.

Table 1 pending to upload

Ethanol and isopropyl alcohols are ABHS recommended by WHO. Some studies have shown that alcohols are sporicidal [9,28] or sporostatic [29]. Other studies have shown that alcohols lack activity against fungi [30, 31] including two common fungal species found in indoor air, namely Aspergillus fumigatus and Penicillium chrysogenum [30]. With conflicting findings, the effectiveness of alcohols on fungi cannot be ascertained, but their activities on bacteria and viruses are conclusive.

Quaternary ammonium compounds (QAC) are usually dissolved in an aqueous medium to produce NABHS, which are non-volatile. A commonly used QAC, benzalkonium chloride, is regarded as one of the safest and most efficacious synthetic biocides [28]. It is thought to interfere with the plasma membrane of microorganisms, thereby inducing leakage of its cellular contents [28]. Another example of a QAC that was widely employed is benzethonium chloride. It was, however, banned from use in hand sanitizers by FDA in 2019 due to insufficient efficacy data. Although it has not been found to cause harm, its use in hand sanitizers may mislead consumers on its effectiveness and result in false protection [39].

Biguanides are also employed in NABHS. The most notable example is chlorhexidine gluconate (CG) which is commonly used in hospitals. CG is highly bactericidal against Gram-positive bacteria, microbiocidal against enveloped viruses and has some weak activity against Gram-negative bacteria and fungi [9, 34]. Several studies demonstrated its rapid kill of two commonly found bacteria, namely Escherichia coli (E.coli) and Staphylococcus aureus (S.aureus) [36, 40-42]. However, CG lacks sporicidal activity and is ineffective against spore-forming bacteria. CG was reported to cause damage to the plasma membrane of yeast cells, leading to the leakage of intracellular components and cell death [36, 43-46].

Chlorine and iodine are examples of halogens used for antisepsis. Chlorine is more commonly used to disinfect water. Iodine, commonly available as povidone-iodine, is more often used for skin disinfection before and after surgery. Both halogens have broad activity against bacteria and viruses. Some studies on chlorine have postulated activity against spores [36, 47-49]. Povidone-iodine, which is used at 5%–10% in formulations for skin application, inactivates but does not kill spore-forming bacteria [9]. At 2%, povidone-iodine is effective against E. coli but a higher concentration of 7.5%–10% is needed against non-enveloped viruses [50].

Chloroxylenol is used in antimicrobial hand soaps and surgical hand scrubs. Chloroxylenol exerts strong activity against bacteria and enveloped viruses, with the exception of Pseudomonas aeruginosa (P. aeruginosa) [9, 51-53]. However, chloroxylenol is not used in hand sanitizers despite its strong efficacy and safety for cosmetic use because studies have concluded that chloroxylenol has less immediate efficacy and less residual activity compared to CG and povidone-iodine [8, 51, 53-56].

Triclosan is an example of a bisphenol with strong bactericidal activity against Gram-positive bacteria and mycobacteria. In the past, triclosan was used in hand sanitizer formulations. However, in 2019, it was banned under the FDA Consumer Antiseptic Rub Proposed Rule [57], after studies highlighted toxicities of triclosan, such as decreased thyroid hormone levels [58] and breast cancer with long-term use [59, 60]. In fact, a study also found that the effectiveness of triclosan products was similar to plain soap [61]. Therefore, the risks from triclosan use outweigh its benefits, limiting its application in hand sanitizer formulations.

Hydrogen peroxide is a peroxygen which damages cell lipids, proteins and DNA of microorganisms [9, 36]. Although it damages these structures, it exhibits little antimicrobial effectiveness when used alone; hence, it is often combined with other active ingredients such as alcohol [8]. Today, possible damage to fibroblasts and risk of bleeding limits its use [62]. FDA recommends the use of ABHS or BKC-containing NABHS in the COVID-19 pandemic, while Centers of Disease Control and Prevention (CDC) recommends the use of ABHS [63]. However, studies have shown that CG and povidone-iodine are also useful against the coronavirus [9]. At a concentration of 0.12%, CG is postulated to demonstrate antiviral activity against the coronavirus [9, 64]. Nasal povidone-iodine has also been shown to prevent perioperative spread of COVID-19, though the efficacy of povidone-iodine in hand sanitizers has yet to be proven [9, 65].

Test methods used to evaluate efficacy/effectiveness of hand Sanitizers
There are no compendial methods (pharmacopeial standards) for evaluating the efficacy of hand sanitizers and the choice of method is left to the discretion of manufacturers. Standards such as the European Standards (EN) and the American Society for Testing and Materials (ASTM) standards are more commonly employed. Within these standards, there are different methods for hand sanitizers including EN1500, EN1040, ASTM-E1174 and ASTM-E2755, see Table 2.

Table 2 pending to upload

EN1500, ASTM-E1174 and ASTM-E2755 are in vivo tests while EN1040 is an in vitro test. In vivo tests are preferred as they are more realistic. The microbial load, which will have an impact on the outcome, is not always clearly stated. The exposure time to the test hand sanitizer is currently not standardized. It is 30 seconds for the in vivo tests but 5 minutes for the in vitro test. EN1500 has a control to exclude confounding factors but ASTM-E1174 and ASTM- E2755 do not include any control. The acceptance criteria are different, with EN1040 being the most stringent. The test organisms used are also not similar, with some organisms known to be more susceptible than others. ASTM-E1174 is recommended in the FDA Tentative Final Monograph 2016 revised version [8] and is more widely used in the US and Canada [67]. Nevertheless, the choice of test method lies with the discretion of the manufacturer of the hand sanitizer.

It can be clearly seen that the test methods apply only to bacteria. Additional tests should be performed to encompass a wider range of ‘microorganisms’ to support the claim of being effective against 99.9% of microorganisms. The ASTM-E1838 is a finger pad method for viruses [73]. In contrast, the ASTM-E2613 is a finger pad method for fungi [74] while the ASTM-E2011 is a whole hand method for viruses [75]. In principle, manufacturers should consider these additional tests to substantiate the efficacy of their hand sanitizers beyond solely bacteria.

Factors affecting the effectiveness and safety of hand sanitizers

To derive solutions to tackle the effectiveness and safety of hand sanitizers, factor affecting these issues need to be investigated.

The contact time of a hand sanitizer is a particularly important determinant of its effectiveness. Contact time refers to the duration of exposure of microorganisms to the antimicrobial compound. For a particular concentration of antimicrobial compound, the percentage of surviving microorganisms is dependent on the contact time. However, contact time required varies across microorganisms. A study showed that a 15 second contact time for 85% w/w ethanol effectively killed Gram-positive and Gram-negative bacteria as indicated by a 5-log- reduction in bacterial count [76, 77]. Another study demonstrated that 70% ethanol, isopropanol and other ABHS inactivated the coronavirus in 30 seconds [78]. Conversely, 0.2% BKC required at least 10 minutes of contact time to inactivate the coronavirus [78]. Due to its excessively long contact time, BKC is not useful as a hand sanitizer formulation.

Hand sanitizers can be formulated in different forms, such as liquids, gels and foams. Studies have shown that the mode of delivery affects the drying time of hand sanitizers but not their effectiveness [79, 80]. While gels take longer to dry than liquids, they are equally effective against test organisms [79, 81]. The active ingredient and its concentrations play a larger role in determining effectiveness. The spectra of activity of antimicrobial compounds used in hand sanitizers have been discussed in Section 3. FDA recommends a concentration of 60%–95% w/w ethanol or 70%–85% w/w isopropanol in ABHS [50, 82-84]. QACs, such as BKC are effective against enveloped viruses at concentrations of 0.05%–0.1% [50]. However, this finding is specific to certain enveloped viruses that do not include the coronavirus.

Different hand sanitizer formulations containing the same antimicrobial compound have been reported to exhibit different effectiveness [8, 9, 27]. In the formulation of hand sanitizers, ingredients used should be compatible and do not interfere with the action of the antimicrobial compound. Coupled with appropriate contact times and proper usage, hand sanitizers can deliver protection for consumers.

Importantly, safety issues may occur when manufacturers do not provide appropriate information to alert consumers. This is more commonly seen in ABHS than NABHS. Globally, cautionary labels relating to flammability and inadvertent ingestion of alcohol are not mandatory. In the absence of such labels, consumers are unknowingly exposed to safety threats. For example, leaving ABHS near open flames may ignite a fi re in the hand sanitizer. ABHS should be rubbed to complete dryness to prevent alcohol on hands from triggering a fi re. Labels should warn consumers of the dangers and precautions to be taken.

Lastly, with the rise in use of hand sanitizers, manufacturers who advocate for environmental protection have initiated campaigns to recycle containers [85]. However, the use of recycled containers can pose contamination and quality issues if it is inadequately controlled. A report by Health Canada warned consumers against using food and beverage containers for hand sanitizers [86]. Coupled with inadequate cautionary labels, consumers especially young children may inadvertently ingest the hand sanitizer, resulting in acute toxicity. The ingestion of BKC could lead to vomiting, respiratory distress [87], kidney damage [88] and fatality [87, 88]. As for alcohol, ingestion could result in central nervous system depression and respiratory distress and fatality [89]. In fact, during this COVID-19 pandemic, US poison control centers have received a 79% increase in calls relating to accidental hand sanitizer ingestion compared to March 2019 [63]. In Spain, the number of hand sanitizer intoxications during COVID-19 is 10-times of that reported in 2019, and children accounted for two-thirds of these cases [89]. These figures highlight the need for tighter safety controls.

FDA policy for testing of alcohol and USP limits for methanol
In response to emerging cases of methanol poisoning, FDA has issued a guidance document on Policy for Testing of Alcohol and Isopropyl Alcohol for Methanol [90]. Due to the toxicity of methanol, FDA has formally requested for a test on methanol limits in the United States Pharmacopeia (USP) monograph for alcohol (ethanol) and isopropyl alcohol [90]. An impurity

level of methanol below 630 ppm is mandated by FDA [90]. For both ethanol and isopropyl alcohol, FDA recommends the test method described in the USP monograph for alcohol. Given the risks to consumers (including death) associated with methanol substitution, FDA strongly recommends the test for methanol be conducted in a laboratory that has been previously inspected by FDA and found in compliance with current good manufacturing practice (cGMP). Any ethanol or isopropyl alcohol that contains more than 630 ppm methanol is not consistent with this latest Policy for Testing of Alcohol and Isopropyl Alcohol for Methanol and may be considered as evidence of substitution and/or contamination. Hand sanitizers containing methanol-contaminated ethanol or isopropyl alcohol are subject to adulteration charges under the Food, Drug and Cosmetic Act. Such contaminated alcoholic materials should be destroyed, and the manufacturer should contact FDA regarding the contaminated materials and their sources [90].

To prevent accidental ingestion of methanol containing alcohols by children, FDA recommends the inclusion of denaturants into hand sanitizers or the use of denatured alcohol, which confer an unpleasant taste to deter inadvertent ingestion [63, 90]. The alcohol is denatured either by the alcohol producer or at the point of production of the finished hand sanitizer product by the manufacturer. In addition to methanol poisoning due to accidental oral ingestion of hand sanitizers by children, harmful effects of methanol may also come from other routes of administration. When hand sanitizers adulterated with methanol are applied on the skin, absorption through the skin is rapid and this can cause toxicity in the same way as methanol ingestion via the oral route. Therefore, both denaturing of alcohol and laboratory test to limit the amount of methanol are necessary to mitigate the toxic effects of methanol via both the oral and transdermal routes [90].

Common myths about hand sanitizers
According to WHO and CDC, there are a number of myths perceived by consumers in relation to hand sanitizers. Debunking these myths is important to promote effective and safe use of hand sanitizers.

Myth 1: All hand sanitizers effective against bacteria can also inactivate viruses
As discussed in Section 3, there is a wide variety of hand sanitizers in the market containing different active ingredients, which confer different spectra of activity. For example, QAC has high activity against bacteria but limited against viruses. In this COVID-19 pandemic, FDA, CDC, WHO and Australia Therapeutic Goods Administration (TGA) have published consumer advisories on hand sanitizers and advocated the use of ABHS as they are known to be effective against viruses [63, 91, 92].While some postulate the potential of BKC to provide effective protection against the coronavirus, TGA and FDA have stated that QAC-based hand sanitizers including BKC, which are NABHS, lack activity against the coronavirus [63]. Hence, in the COVID-19 pandemic, ABHS is the mainstay.

Myth 2: Higher alcohol content in hand sanitizers equates with greater effectiveness against microorganisms
Many consumers assume that a higher alcohol content in hand sanitizers offers greater protection against microorganisms. Notably, FDA recommends the use of an ABHS with a concentration of 60%–95% w/w ethanol or 70%–85% w/w isopropanol as they have the greatest antimicrobial activity [93]. Beyond the upper limit of alcohol concentration, the rate of kill decreases tremendously [93]. This may be attributed to the higher alcohol content which evaporates more rapidly, hence remaining on hands for a shorter time period. The contact time between the hand sanitizer and microorganisms on the hand is decreased, reducing the hand sanitizer activity. To obtain the same extent of kill, contact time needs to be increased through continuous reapplication of the hand sanitizer. This is inconvenient and is not practised in reality. Additionally, a 100% alcohol concentration or ‘absolute-alcohol’ is completely ineffective in inactivating or killing microorganisms, as water is crucial for alcohol activity [93]. Water is a catalyst in denaturing proteins which make up important components of the microbial cell and virus. It also assists alcohol to penetrate the cell wall, cause protein coagulation and kill the bacterial cell [93].

Myth 3: Hand sanitizers are more effective than handwashing with soap and water
The CDC recommends the public to use hand sanitizers only when soap and water are not accessible [5, 6]. Proper handwashing with soap and water is more effective. However, the portability of hand sanitizers is advantageous with regard to availability and convenience of use. Although hand sanitizers do not kill all microorganisms, they still confer some protection. In fact, studies have shown that hand sanitizer usage reduced transmission of diseases at home and in school [94-96]. Therefore, the use of hand sanitizers is undoubtedly better than leaving hands contaminated with microorganisms. There are recommendations and training courses on good hand hygiene practices, and how viral outbreaks may be managed through handwashing [97-100].

Although handwashing with soap and water is more effective, the CDC and WHO recommend ABHS as the preferred choice for healthcare personnel, when hands are not visibly soiled [8]. Performing hand hygiene using ABHS confers several advantages over soap and water in a healthcare setting. Firstly, ABHS contains alcohol which can kill common vegetative bacteria found on human skin [27]. ABHS has a more persistent activity; hence it slows down the proliferation of microorganisms on hands. Hand sanitizers containing alcohols are also more efficient for healthcare providers working in a bustling environment and having to perform hand hygiene routines repeatedly throughout the day. ABHS provide greater convenience and can be placed directly in wards, dispensing counters and consultation clinics [101-104]; thus, immediate hand hygiene can be performed without causing work disruption.

Myth 4: Hand sanitizers can ‘sterilize’ hands
Hand sanitizers do not kill all microorganisms. Microorganisms such as Clostridium difficile and Cryptosporidium produce spores that are not destroyed by hand sanitizers [6]. Neither handwashing with soap and water nor hand sanitizers can ‘sterilize’ hands. When exposed to body fluids and dirty facilities during an infectious outbreak, one should perform handwashing with soap and water to prevent the transmission of diseases [101-103]. When consumers perform activities such as eating food with bare hands, the CDC recommends handwashing with soap and water as hand sanitizers may cause health hazards when ingested. It has been reported that the norovirus, a group of viruses that are a common cause of food poisoning and gastroenteritis, which is transmitted via close conversations and sharing food, is not killed by the use of hand sanitizers. Upon ingestion, the norovirus can proliferate, leading to the norovirus infection [100]. Moreover, mucus from coughing and sneezing forms a protective barrier, blocking the action of hand sanitizers against viruses. These viruses may be ingested together with food and cause infections. For food store workers, the use of ABHS to disinfect hands is not advised as their hands are often contaminated with fatty or protein-rich food [101-103] which reduce effectiveness of the alcohol against pathogens. Therefore, before the preparation of meals, the use of soap and water for handwashing is recommended.

Myth 5: All hand sanitizers are approved by regulatory authorities (RAs) and are therefore safe and effective
According to the FDA, hand sanitizers are not subject to premarket approval. Therefore, labels of hand sanitizers which claim FDA approval are fake and misleading. This is also the case for other RAs such as the UK Medicines and Healthcare products Regulatory Agency (MHRA), the European Medicines Agency (EMA) and the Singapore Health Sciences Authority (HSA). Hand sanitizers currently have relatively free entry into the consumer market as many RAs do not mandate pre-market registration. Nevertheless, RAs such as TGA allows hand sanitizers which make claims against specific microorganisms to be labelled ‘AUST R’ if they have been evaluated and approved by TGA [91]. Although there are policies and guidelines published by RAs relating to compounding of ABHS and limits of methanol, this should not be interpreted that the ABHS offered for sale, have been approved by the RAs [105-108].

Myth 6: Prolonged use of hand sanitizers can cause bacterial resistance
Several researchers have postulated that prolonged exposure of hand sanitizers to microbes can drive mutations and bacterial resistance [109-113]. However, FDA is of the view that the risk of development of bacterial resistance from the use of hand sanitizers is low due to the rapid speed of action and mechanism of action of ABHS [114]. For example, ABHS can exert bactericidal effect within 15 seconds [76, 77] by coagulating or precipitating the proteins in bacteria [27]. The rapidness and the way hand sanitizers act on bacteria do not potentiate resistance. In addition, the volatility of alcohol denies bacteria of an environment for prolonged exposure and the opportunity to adapt themselves to the ABHS. Thus, prolonged use of ABHS is unlikely to cause bacterial resistance.

A lack of regulatory framework
The forensic classification of hand sanitizers varies across national jurisdictions. For example, countries such as the US, Australia and Singapore, have classified hand sanitizers as over-the-counter (OTC) drugs, therapeutic goods and medicinal products, respectively. In general, hand sanitizers are perceived to be of lower risks in comparison to other prescribed health products. Therefore, hand sanitizers have not been subjected to the same extent of pre-market regulatory approval and licensing requirements as for prescription medicines and other classes of therapeutic products. Generally, there is still a lack of regulatory framework for hand sanitizers internationally. Labelling of expiry dates should be mandatory as it indicates the duration when active ingredients remain stable and effective. Manufacturers can determine this time period using the test methods described (Section 4). Since alcohols confer antimicrobial activity, the loss of alcohol content indicates a reduction in antimicrobial activity and protection. Due to the COVID-19 pandemic, consumers have stockpiled on hand sanitizers. The absence of expiry dates may create misconceptions that hand sanitizers are effective for an indefinite period of time and can be used beyond their shelf-life.

Safety issues have surfaced due to insufficient controls. With the exception of Health Canada, a product license or registration is not required by other RAs. Ingredients that make up hand sanitizers need not be manufactured in accordance with GMP, yet the hand sanitizers can still be placed on the market. As a result, consumers may be exposed to contaminated, adulterated and harmful products. This is evident in cases of methanol poisoning where numerous ABHS were reported to have caused blurred vision and seizures to consumers during post-market surveillance [109]. In retrospect, if more regulatory controls had been placed on manufacturers, such problems may be avoided. The COVID-19 pandemic has caught many off-guard, causing the demand for hand sanitizers to surge. Regulators may postpone the need for tighter regulations in lieu of concerns over shortage and access. However, post-COVID-19, regulators should look into tightening controls to ensure quality safety and efficacy of hand sanitizers, beyond just assuring supply and access. Regulations could come in the form of regular inspection of manufacturers to assure GMP compliance and ascertain validity and sufficiency of test method documents. These costs will be borne by the manufacturers and passed on to consumers. Hence, the rise in regulatory and compliance costs may create socio-political problems and have to be properly managed.

Proposed solutions

Tightening the regulatory framework
Table 3 introduces a stricter regulatory framework. A listing or certification is recommended for the product to be manufactured and placed in the market. Product licensing or registration is not always feasible as it can severely increase regulatory costs. Therefore, the proposed idea balances the current lack of regulatory oversight versus over-regulation and increasing compliance costs. Moreover, to safeguard consumers, sale in bulk volumes/packs should be prohibited, hand sanitizers should not be enclosed in bottles resembling food packaging and cautionary labels should be mandatory. Regulations should also include the need to perform the efficacy tests (Section 4) and to seek approval by RAs to ensure effectiveness of hand sanitizers. Additionally, it is important to prevent consumer misinformation by restricting advertisements to company websites, prohibiting unfounded claims and labelling of a blanket claim on killing 99.9% of microorganisms.

Table 3 pending to upload

The proposed framework may encounter difficulty for international harmonization. Similar to other health products, such as therapeutics, quasi-medicinal products and medical devices, differences in regulations exist across RAs. Furthermore, a tighter framework adds regulatory burden and redirects resources away from more important domains, such as other higher-risk medicinal products.

Training pharmacists on hand sanitizer vigilance
Hand sanitizers may be sold in pharmacies or other retail outlets. In comparison to supermarkets and other general retail outlets, pharmacies are managed under the personal supervision of licensed pharmacists. Hence, pharmacies have been perceived to be ethical retail outlets which offer for sale and supply health products, including hand sanitizers, that are reliable. Pharmacies should restrict themselves only to the sale of reliable and accurately labelled hand sanitizers to safeguard consumer health. Pharmacists can be trained to possess adequate knowledge on the regulations of antiseptics. This could be performed through the provision of regulatory and international guidelines. The knowledge could be used to identify inappropriately sold hand sanitizers and pharmacists should be given the autonomy to request for removal of the product from the store. In fact, pharmacists should better educate and address consumers’ queries on hand sanitizer effectiveness.

Public Education
Apart from regulation, conscious efforts should be placed on educating the public. Consumers hold misconceptions about hand sanitizers and safety issues have occurred due to the lack of knowledge in this fi eld. Therefore, public education is necessary in collaboration with relevant stakeholders [99, 100]. Public education can focus on general hand hygiene, including the myths and benefits of hand sanitizers and the harms of using disinfectant- grade antimicrobial agents interchangeably with antiseptic-grade skin formulations. Additionally, collaborations with pharmacies can be explored. For example, the placement of posters next to sales counters of hand sanitizers can provide a second line of defence to combat consumers’ misinformation. Some content could include sharing on the WHO 6 Steps of ‘How to hand- rub’ technique to promote effective use and storage advice to reiterate safety precautions. Collaboration with stakeholders facilitates the education of a wider target group due to the extensivity of outreach. Collaborative education also reduces the burden on regulators.

Conclusion

The multifaceted challenges of safety, effectiveness will grow and hence, regulatory control will continue to evolve with the progression of COVID-19 pandemic. This paper has shown that hand sanitizers are assets to hand hygiene, especially during the COVID-19 pandemic, provided they are used properly. Therefore, educating the public on hand sanitizers, including misleading claims and proper use, is crucial. ABHS remain the mainstay as recommended by WHO and other international organizations and should be more tightly regulated due to safety concerns. Future developments can consider the feasibility of international harmonization of regulations and explore other standards for testing efficacy that may be more representative of all microorganisms. A tripartite relationship among consumers, regulators and manufacturers should be established for the ultimate benefit of everyone.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Adjunct Associate Professor Sia Chong Hock, BSc Pharm, MSc
Tan Ying Ting, BSc Pharm (Hons)
Associate Professor Chan Lai Wah, BSc Pharm (Hons), PhD

Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543

References pending to upload

Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543

Disclosure of Conflict of Interest Statement is available upon request.

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