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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
additional tests to substantiate the ecacy of their hand sanitizers
beyond solely bacteria.
Factors aecting the eectiveness and safety of
hand sanitizers
To derive solutions to tackle the eectiveness and safety of hand
sanitizers, factor aecting these issues need to be investigated.
The contact time of a hand sanitizer is a particularly important
determinant of its eectiveness. 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 eectively 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 dierent forms, such as liquids, gels and foams. Studies have shown that the mode of delivery
aects the drying time of hand sanitizers but not their eectiveness
[79, 80]. While gels take longer to dry than liquids, they are equally
eective against test organisms [79, 81]. The active ingredient and
Hand Sanitizers
its concentrations play a larger role in determining eectiveness.
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 eective 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.
Dierent hand sanitizer formulations containing the same antimicrobial compound have been reported to exhibit dierent eectiveness [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.
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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 fire in the hand sanitizer. ABHS should
be rubbed to complete dryness to prevent alcohol on hands from
triggering a fire. 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
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
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 high- light 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
Hand Sanitizers
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].
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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 eects 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 eects of methanol via both the oral and transdermal routes [90].
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
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 eective and safe use of hand
sanitizers.
Myth 1: All hand sanitizers eective against bacteria can also inactivate
viruses
As discussed in Section 3, there is a wide variety of hand sanitizers
in the market containing dierent active ingredients, which confer dierent 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
eective against viruses [63, 91, 92]. While some postulate the potential of BKC to provide eective 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
eectiveness against microorganisms
Many consumers assume that a higher alcohol content in hand
sanitizers oers 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].
Hand Sanitizers
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 practiced 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 eective 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 eective. 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].
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Although handwashing with soap and water is more eective,
the CDC and WHO recommend ABHS as the preferred choice
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
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 ecient 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 dicile 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
Hand Sanitizers
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
eectiveness 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 eective
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 oered for sale, have been approved
by the RAs [105–108].
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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].
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
For example, ABHS can exert bactericidal eect 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
eective. 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
eective for an indefinite period of time and can be used beyond
their shelf-life.
Hand Sanitizers
Safety issues have surfaced due to insucient 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 o-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 ecacy 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 suciency 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.
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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