Russell Griggs, M.S., CCRC and Margaret Butler, Ph.D., BioScience Laboratories, a Nelson Labs company
Background
All hand sanitizers, whether used by consumers or healthcare professionals, are considered over-the-counter (OTC) drugs that are regulated by the FDA. The most common type of hand sanitizer has historically been alcohol-based, often called alcohol-based hand rubs (ABHRs). Prior to the COVID-19 pandemic, hand sanitizers were exclusively produced by companies that met FDA requirements for drug manufacturers [e.g., those who already complied with Good Manufacturing Practices (GMP)] and that had submitted safety and efficacy data required to market these products. However, at the onset of the COVID-19 public health emergency these traditional suppliers could not increase their supply rapidly enough to meet the high demand for hand sanitizers that was driven by a CDC recommendation that ABHRs be used to reduce the spread of COVID-19 when soap and water were not available.
In order to meet the increased demand for ABHRs, the FDA produced three temporary policies to add regulatory flexibility to allow entities that were not recognized as meeting FDA requirements for drug manufacturing(e.g., distilleries) to begin to manufacture ethanol and/or prepare final ABHR formulations. These policies, initially issued in March 2020, included (1) guidance on how to manufacture acceptable alcohol (ethanol only) to be used in ABHRs (1), (2) guidance on how to prepare a pre-approved mixture of ingredients (alcohol, glycerin, hydrogen peroxide, water, and denaturant) to produce a standardized ABHR formulation (2), and (3) guidance for the temporary compounding of the above standardized ABHR formulation by pharmacists in state-licensed pharmacies or federal facilities and registered outsourcing facilities (3). These policies applied solely to ABHRs and did not include other hand- or skin-hygiene products.
FDA’s Withdrawal of Temporary Policies and Deadlines
On October 12, 2021 the FDA’s Center for Drug Evaluation and Research (CDER) released a notification stating that on December 31st, 2021, it intends to withdraw the three guidance documents regarding temporary policies for production / preparation of ABHRs due to the observation that supply of hand sanitizers by traditional drug manufacturers now meets demand. In order to provide time for manufacturers to respond to the removal of these temporary policies, companies must halt manufacturing by no later than December 31, 2021, but will have until March 31, 2022 to completely halt distribution and sale of affected ABHRs. If a companydoes not intend to manufacture ABHRs past the December 31st deadline,they are expected 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 over-the-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 pre-approved 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 laboratories with two independent principal investigators. Each clinical evaluation consists of evaluating simulated usage of 3 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 6 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
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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.
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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.
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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.
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FDA Electronic Drug Registration and Listing Instructions. https://www.fda.gov/drugs/electronic-drug-registration-and-listing-system-edrls/electronic-drug-registration-and-listing-instructions
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1994 Tentative Final Monograph for Healthcare Antiseptic Drug Products (Federal Register, Volume 59 Number 116, pages 31402-31452)
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2017 Healthcare Antiseptics Final Rule (Federal Register, Volume 82 Number 243, pages 60474-60503)
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2019 Consumer Antiseptic Rub Final Rule (Federal Register, Volume 84 Number 71, pages 14847-14864)
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