GxP-Blog

The ongoing coronavirus pandemic has sharply increased demand for disinfectants and has kept the demand high. Some manufacturers of cosmetics, household cleaning agents and disinfectants or classic drugs have recognized the possibility of a new business area in this situation during the past 1 1⁄2 years: manufacturing hand sanitizers.

The number of hand sanitizer products has therefore increased explosively since the outbreak of the coronavirus pandemic.

The sales market for these products is mainly in regions and countries where most people can afford high hygiene standards and manufacturers can expect large profit margins, such as in the European Union and the United States. This goes along with the high legal and regulatory requirements that apply in those countries.

In Europe, hand sanitizers are either considered biocidal products and must be approved before being placed on the market in the EU in accordance with the Regulation on the making available on the market and use of biocidal products (EU) No. 528/2012, "Biocide Regulation" in short, or are subject to approval as drugs. In the United States, the requirements and specifications for approval are defined in the Food, Drug and Cosmetic Act (FD&CAct).

A product labeled as a hand sanitizer, possibly with the specific claim to rendering inactive the SARS-CoV-2 virus (pathogen of Covid-19), has legal consequences and may prove to be an economic success killer in the event of non-compliance with the applicable regulatory and legal requirements.

This issue is explained below with a focus on the U.S. market.

A large number of manufacturers of cosmetics, household cleaning agents and disinfectants as well as classic drugs have the technical capabilities to produce hand sanitizers. This means that the basic requirements for production are on hand. The further the requirements of the respective manufacturer's previous products and production processes differ from the requirements for the hand sanitizers to be incorporated into production, the greater the need for information about and additions to the quality management, quality control and production of these products.

This also includes knowing how to classify the drugs and their active ingredients. In the U.S., hand sanitizers are classified as OTC (over-the-counter) drugs and are further differentiated in terms of their areas of application and type of application.

• Consumer antiseptic rubs are hand sanitizers for private individuals outside the medical area for whom use without water is intended
• Antiseptic washes are hand sanitizers that are used together with water (e.g., disinfectant soaps)
• Healthcareantiseptics are disinfectants intended for use in the healthcare system (doctors, nurses, paramedics, etc.) in hospital facilities and in certain situations outside these facilities.

These classes are subject to different rules and requirements.

They have in common: If the hand sanitizers are not officially recognized as generally safe and effective GRAS/GRAE drugs and active ingredients (GRAS=Generally Recognized As Safe / GRAE= Generally Recognized As Effective) or are subject to certain other exceptions with regard to their use and the data documented in the product description and product labeling, they will be regarded as new drugs. Adequate and well-controlled published clinical studies may support official recognition of the GRAS/GRAE status, but specific characteristics of the product, such as the use of certain active ingredients, may mean that the hand sanitizer must be approved as a new drug.

In accordance with Section 505A of the FD&C Act, United States Code Title 21, 355 (a), Necessity of effective approval of application, it is stipulated that a new drug may not be introduced or delivered for introduction into interstate commerce with the U.S. without official approval. An exception to this would be, for example, the lawful placing on the market in accordance with the conditions of the FD&C Act described in Section 505G, Regulation of certain nonprescription drugs that are marketed without an approved new drug application.

In the past, Section 505G of the FD&C Act allowed certain topical antiseptic OTC products to be placed on the market under certain conditions without approval. For this purpose, these products had to comply with the Tentative Final Monograph (TFM) for topical antiseptic OTC products (TFM: Topical Antimicrobial Drug Products for Over-The-Counter Human Use, Proposed Rule 59 FR 31402 [June 17, 1994], 1994 TFM), as well as the 2016 amendment to the TFM, Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-The-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record, Proposed Rule, 81 FR 42912 (June 30, 2016) (Consumer Antiseptic Rubs Proposed Rule).

The 1994 TFM and its 2016 amendment were concluded with the findings of 21 CFR Part 310, which became effective on April 13, 2020. These relate exclusively to so-called consumer antiseptic rubs.

The stipulations made state that consumer antiseptic rubs require approval as a drug in the event of the use of one of the 28 different active ingredients mentioned in the 2016 amendment. For three additional active ingredients, ethanol, isopropyl alcohol and benzalkonium chloride, the FDA will not make any further determinations (rulemaking) until either the status “monographed” or the status “not monographed” is reached. Until this status is achieved, these active ingredients are classified in category III in accordance with TFM 1994 (available data are insufficient to classify as generally recognized as safe and effective, and further testing is necessary). As a result, these active ingredients do not have GRAS status, and product safety must be demonstrated with suitable studies.

Exceptions to the approval requirement include that the FDA issued a directly applicable policy in March 2020 concerning the manufacture of certain alcohol-based hand sanitizers, a policy that is only valid during the coronavirus-related health emergency: Policy for Temporary Compounding of Certain Alcohol-based Hand Sanitizer Products During the Public Health Emergency – Immediately in Effect Guidance for Industry". March 2020. Updated February 10, 2021. This policy assures certain pharmacies, so-called compounding pharmacies, and companies that are not normally regulated by the FDA that even if good manufacturing practice (GMP) is not complied with, no penalties are to be expected by the FDA if the hand sanitizers are manufactured in accordance with the conditions specified in the policy.

However, the placing on the market of new drugs in interstate commerce in the U.S. without official approval constitutes a violation of Sections 505 (a) and 301 (d) of the FD&C Act, U.S.C. Title 21 355 (a) and 331 (d), and will be punished accordingly as a serious violation of U.S. law (see below).

As with all other drugs, the primary intended effect and the application specifications must be defined for hand sanitizers.

This includes, among other things, specifications regarding the disinfecting substance(s), the chemical-physical composition, the application quantity, the type of application to the hands and the exposure time of the hand sanitizer. Descriptions such as “Applying and spreading a nut-sized portion of disinfectant foam” are generally not sufficient, as it remains unclear whether the intended effect is achieved under these conditions.

As with all other drugs, failures and contaminations must also be ruled out with hand sanitzers. The essential performance and quality requirements of the product, such as rendering germs or viruses inactive, must be scientifically substantiated by microbiological in vitro tests and/or by clinical studies (in vivo). The corresponding evidence for the performance and quality requirements for the hand sanitizer is checked by the FDA as part of the drug approval process.

Before placing the product on the market, the manufacturer must ensure for each batch of the product that all relevant quality properties of the product comply with the defined standards and specifications for identity, effectiveness, quality and purity. For example, it must be ensured that the active ingredient content is set correctly for each batch of hand sanitizer. For the production of alcohol-based hand sanitizers, this means, for example, that content determinations must be carried out for the active ingredient or alcohol batches used and for the manufactured batches of the hand sanitizer.

The FDA is paying particular attention to the banned use of methanol as an active ingredient. When used in hand sanitizers, methanol can be absorbed through the skin and have toxic effects. Despite the ban, some manufacturers have decided to use the cheaper methanol in hand sanitizer compared to ethanol.  Therefore, the FDA is increasingly conducting checks for methanol for hand sanitizers introduced into the U.S. market. In the past, the particularly high number of methanol-contaminated hand sanitizers imported into the U.S. from Mexico had become noticeable.

Furthermore, the FDA requires the denaturation of alcohol-based hand sanitizers, either at the level of the active ingredients to be used (alcohols) or in the context of the manufacture ("compounding") of the hand sanitizer. In doing so, the FDA is responding to the increasing number of severe poisoning either due to incorrect use in the form of an oral intake or an unintentional intake by children.

If a new drug is marketed without approval or without proof of efficacy and without GRAS/GRAE status, such a finding by the FDA will most likely lead to publication in a warning letter.

Examples of warning letters can be found on the FDA homepage at the following link AND by entering the search words “hand sanitizer” or “hand sanitizer AND SARS-CoV-2”.

https://www.fda.gov/drugs/warning-letters-and-notice-violation-letters-pharmaceutical-companies/untitled-letters-2021

The warning letters indicate the violations, e.g,. as a violation due to a new product not approved ("unapproved new drug violation") and/or a violation due to misbranding ("misbranding violation"). The placing of the affected products on the U.S. market is expressly prohibited. A further violation has immediate legal consequences (judicial proceedings, high fines, removal of products from the U.S. market at the producer’s expense).

In addition, this generally results in a ban on the placing on the U.S. market of other products of the manufacturer concerned. This is based on the FDA’s assessment that serious violations of the legal requirements of the FD&C Act have been found for a product from this manufacturer, and thus an increased probability of violations is also assumed for other products. As a result, economic consequences for the company concerned are likely.

It is therefore important to identify and avoid potential violations of regulatory and legal GMP (Good Manufacturing Practice) requirements at an early stage of product development and production, so that ill-considered action or wrong decisions do not ultimately become the killer of your economic success. Our Pharma Compliance Team will be happy to help you with these necessary tasks.