APR January/February 2022 - 81

VENDOR VIEWPOINT
to remove their temporary registration from the FDA's electronic drug
registration database. FDA instructions for deregistration can be found in
Reference 4.
Procedures to Continue
Manufacturing ABHRs
As with any new human use product entering the market, the FDA
requires Good Manufacturing Practices, safety data, and in vitro and
in vivo efficacy data before the product is marketed to the public. For
companies who manufactured ABHRs under a temporary policy and
would like to continue manufacturing ABHRs after December 31, 2021,
the FDA has communicated compliance requirements in accordance
with the following regulations: 1) the FDA's monograph for overthe-counter
(OTC) drugs (Code of Federal Regulations Title 21 Parts
330) and 2) either the 2019 Consumer Antiseptic Rub Final Rule (7)
or the 2017 Healthcare Antiseptics Final Rule (6) in combination
with the 1994 Tentative Final Monograph for Healthcare Antiseptic
Drug Products (5). These regulations define which active ingredients
are generally safe and effective (GRAS/GRAE) and can be marketed
without pre-approval and which active ingredients must be preapproved
through a New Drug Application review process, in
addition to information such as the usage, dosage, labelling and
testing requirements to market ABHRs and other antiseptics for
either consumer use or healthcare use. The safety and efficacy testing
requirements are summarized below.
Safety Testing
The FDA's safety testing listed in the 2017 and 2019 Final Rules for
hand sanitizers consists of four types of tests: 1) nonclinical studies
to evaluate developmental toxicity, reproductive toxicity, and
carcinogenicity, 2) characterization of potential hormonal effects,
3) clinical maximal usage trials (MUsT), and 4) characterization of
potential for development of antimicrobial resistance.
In vitro Efficacy Testing
The FDA's in vitro efficacy testing listed in the 2017 and 2019
Final Rules consists of two types of tests: minimum inhibitory
concentration (MIC)/minimum bactericidal concentration (MBC)
evaluations and time-kill evaluations. MIC evaluations determine the
lowest concentration of an antimicrobial that inhibit bacterial growth,
while MBC evaluations determine the lowest concentration that kills
bacteria. Manufacturers may conduct either a MIC or MBC evaluation
and are not required to conduct both types. MIC/MBC evaluations are
required to be conducted with 25 clinical isolates and 25 reference
strains of 18 species (900 total strains). Time-kill evaluations determine
the efficacy of an antimicrobial in killing bacteria following specific
exposure times. Time-kill evaluations are required to be conducted
with a total of 31 total reference strains.
In vivo Efficacy Testing
The FDA's in vivo efficacy testing listed in the 2017 and 2019 Final
Rules consists of two clinical evaluations conducted at two separate
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American Pharmaceutical Review | January/February 2022
laboratories with two independent principal investigators. Each
clinical evaluation consists of evaluating simulated usage of three
test materials (vehicle/negative control, test product, and active
control) with ≥ 100 human subjects per test material. Following
usage, statistical comparisons are conducted to determine the
average treatment effect (ATE), the estimated difference of the effect
of two different test materials. The test product must be superior to
the vehicle/negative control by a ≥ 1.5 log10 margin at the lower
95% confidence bound. The test product must also be non-inferior
to the active control by a ≤ 0.5 log10 margin at the upper 95%
confidence bound.
FDA Deferral of Rulemaking for Select
Active Ingredients
It is important to understand that while the FDA has provided a
tentative final monograph and final rules for consumer and healthcare
antiseptics, the Agency is currently re-evaluating data gaps for some
active ingredients; ethanol and isopropanol were part of this group.
In preparation for issuing the 2017 Healthcare Antiseptics Final Rule
and the 2019 Consumer Antiseptic Rub Final Rule, the Agency first
published these rulemakings as " Proposed Rules " in 2015 and 2016,
respectively, and entertained questions and comments from the
public and industry members for about six months following their
release. As a response to feedback provided during this period,
the FDA granted more time for additional data to be submitted for
specific active ingredients, including ethanol and isopropanol, and
in the meantime deferred further rulemaking on these actives until
additional studies could be conducted and their analyses completed.
Due to this temporary deferment and state of uncertainty, it is highly
recommended that each manufacturer of a hand sanitizer should
consult with the FDA, or work with an experienced laboratory or
regulatory consultant, to determine what safety and efficacy testing
is required for their hand sanitizer formulation.
References
1.
2.
3.
4.
5.
6.
7.
FDA Guidance for Industry, Temporary Policy for Manufacture of Alcohol for Incorporation
into Alcohol-Based Hand Sanitizer Products During the Public Health Emergency
(COVID-19). Issued March 2020; Updated February 10, 2021.
FDA Guidance for Industry, Temporary Policy for Preparation of Certain Alcohol-Based
Hand Sanitizer Products During the Public Health Emergency (COVID-19). Issued March
2020; Updated February 10, 2021.
FDA Guidance for Industry, Policy for Temporary Compounding of Certain Alcohol-Based
Hand Sanitizer Products During the Public Health Emergency. Issued March 2020;
Updated February 10, 2021.
FDA Electronic Drug Registration and Listing Instructions. https://www.fda.gov/drugs/
electronic-drug-registration-and-listing-system-edrls/electronic-drug-registration-andlisting-instructions
1994
Tentative Final Monograph for Healthcare Antiseptic Drug Products (Federal
Register, Volume 59 Number 116, pages 31402-31452)
2017 Healthcare Antiseptics Final Rule (Federal Register, Volume 82 Number 243, pages
60474-60503)
2019 Consumer Antiseptic Rub Final Rule (Federal Register, Volume 84 Number 71, pages
14847-14864)

https://www.fda.gov/drugs/electronic-drug-registration-and-listing-system-edrls/electronic-drug-registration-and-listing-instructions

APR January/February 2022

Table of Contents for the Digital Edition of APR January/February 2022