Drug and Device Corner January 2021

EAS Client Updates

Breaking News: FDA Places All Alcohol-Based Hand Sanitizers from Mexico on Import Alert

As part of the U.S. Food and Drug Administration’s continuing efforts to protect consumers from potentially dangerous or subpotent hand sanitizers, the agency has placed all alcohol-based hand sanitizers from Mexico on a countrywide import alert to help stop products that appear to be in violation from entering the U.S. until the agency is able to review the products’ safety. Over the course of the ongoing pandemic, the agency has seen a sharp increase in hand sanitizer products from Mexico that were labeled to contain ethanol (also known as ethyl alcohol) but tested positive for methanol contamination. Methanol, or wood alcohol, is a substance that can be toxic when absorbed through the skin and life-threatening when ingested. Methanol is not an acceptable ingredient in hand sanitizer or other drugs.

“Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19),” is a recently published guidance document, intended to notify drug manufacturers and compounders of new initiatives to protect consumers against methanol poisoning.

As you well know, methanol is not an acceptable ingredient for any drug product and should not be used due to its toxic effects. FDA has received reports of fatal methanol poisoning of consumers who ingested alcohol-based hand sanitizers that were manufactured with methanol or methanol-contaminated ethanol as well as reports of dermal toxicity associated with such products.

Due to demand created by the COVID-19 pandemic for hand sanitizer, pharmaceutical alcohol as the active ingredient, has also increased making ingredients more vulnerable to economic adulteration. It is known that methanol-contaminated ethanol and hand sanitizer products contaminated or substituted with methanol have entered the pharmaceutical supply chain and FDA is further concerned that other drug products containing pharmaceutical alcohol could be similarly vulnerable to methanol contamination, including drugs in oral dosage form presentations.

While the FDA is targeting the emergency use manufacturers it is clear they intend to set this limit for the traditional monograph products as well and will transition this temporary guidance into a more permanent measure within 60 days after the emergency declaration is withdrawn. This is a follow-up to what the FDA put out back in the July-August timeframe when they announced methanol limits of 660 ppm and introduced the requirement for testing. It looks like FDA is still referencing USP as the official monograph and that they have lowered the limit for methanol to not more than 200 ppm.

For those of you keeping track, the FDA has made a 3^rd announcement for the Federal Register notice regarding FY2021 OMUFA user fees. On 29 December 2020, the FDA issued their initial notification of OMUFA facility fees due. The 29 December notice was withdrawn by the FDA on 6 January 2021.

The newest Federal Register notice in Vol. 86, No. 7 published Tuesday 12 January 2021, seeks to clarify that persons entering the OTC drug industry for the first time in order to supply hand sanitizers during the COVID-19 Public Health Emergency, and manufacturing the FDA’s EUA WHO recommended formula, are not considered subject to the FY2021 facility user fee. In addition to the extraordinary circumstances which brought many of these non-drug manufacturing entities to the OTC arena in order to provide enough supply during the pandemic; the CARES Act also specifically notes “a facility identified as an OTC drug monograph facility”. Those manufacturing the EUA hand sanitizer formula do not follow the monograph and therefore their facilities would not be identified as such.

Take note that the agency’s exclusion does not apply to facilities which (1) manufacture, distribute, and sell over-the-counter drugs in addition to hand sanitizer or (2) continue to manufacture (as opposed to hold, distribute, or sell existing inventories) hand sanitizer products as of December 31 of the year immediately following the year during which the COVID-19 Public Health Emergency is terminated. In these cases, the FDA may identify such locations as OTC drug manufacturing facilities.

Avoiding FDA Enforcement Actions: Understanding Quality Systems – EAS authored article published by MedTech Intelligence.

With the plethora of information put out by FDA, trade associations, and industry journals, there should be no excuse for receiving an FDA enforcement letter. But even a cursory glance at FDA’s website, or annual list of enforcement actions for the product areas under their purview, indicates that though there may be no excuse for FDA taking enforcement action, there is clearly a reason.

Whether good manufacturing practices during production, including those of a contract manufacturer, appropriate and correct labeling information on packaging and marketing materials, providing and analyzing sufficient data to support a submission such as a 510(k), De Novo and so on, FDA tries to articulate their expectations across a sea of devices and technologies used for a myriad of indications and purposes. The greatest challenge faced is an understanding of the intent of the written regulations and applying them correctly. Read more…

FDA Virtual Conference Opportunity

The FDA has announced a Drug Master File (DMF) and Drug Substance Workshop designed to provide an update on current agency initiatives. Specifically, the conference will offer guidance on the DMF submission process and expectations for content.

Recently published Guidance Documents

CDER

Protecting Participants in Bioequivalence Studies for Abbreviated New Drug Applications During the COVID-19 Public Health Emergency

FDA is issuing this guidance to provide recommendations to prospective applicants of abbreviated new drug applications on ensuring the protection of participants when resuming or initiating bioequivalence studies conducted to support the approval of an ANDA that have been disrupted during the COVID-19 public health emergency.

This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Secretary of Health and Human Services on January 31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act.

COVID-19: Potency Assay Considerations for Monoclonal Antibodies and Other Therapeutic Proteins Targeting SARS-CoV-2 Infectivity

Due to the current public health emergency, FDA is issuing this guidance to assist sponsors in the development of monoclonal antibodies (mAbs) and other therapeutic proteins for use as COVID-19 therapeutics. A critical quality control measure for these products is the development and implementation of a potency assay(s) adequate to ensure that each lot is consistently produced with the potency necessary to achieve clinical efficacy and that such potency is maintained over the shelf life of the product.

IND Submissions for Individualized Antisense Oligonucleotide Drug Products: Administrative and Procedural Recommendations Guidance for Sponsor-Investigators

This guidance is intended for sponsor-investigators developing individualized investigational antisense oligonucleotide drug products for a severely debilitating or life-threatening genetic disease.

Consumer Antiseptic Rub Final Rule Questions and Answers

This guidance is intended to help small businesses understand and comply with the Consumer Antiseptic Rub Final Rule; Finding of Ineligibility for Inclusion in Final Monograph (Consumer Antiseptic Rub FR) (84 FR 14847, April 12, 2019), which applies to active ingredients used in over-the-counter consumer antiseptic rub products that are sometimes referred to as rubs, leave-on products, or hand sanitizers. The Consumer Antiseptic Rub FR also applies to active ingredients used in OTC consumer antiseptic wipes.

CDRH

Coagulation Systems for Measurement of Viscoelastic Properties: Enforcement Policy During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency

FDA is issuing this guidance to provide a policy to help expand the availability of coagulation systems for measurement of whole blood viscoelastic properties that are used to assess hemostasis, for the duration of the COVID-19 public health emergency.

Mouse Embryo Assay for Assisted Reproduction Technology Devices

FDA is issuing this guidance to outline recommendations on conducting the mouse embryo assay to support premarket submissions and lot release of assisted reproduction technology devices. This guidance provides recommendations for conducting the MEA to support premarket submissions for devices that are intended to contact gametes and/or embryos and to comply with the special controls for those devices classified under 21 CFR 884 that require MEA testing or information.

CDRH & CBER

Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program

The purpose of this guidance is to provide an overview of the mechanisms available to submitters through which they can request feedback from or a meeting with the Food and Drug Administration regarding potential or planned medical device Investigational Device Exemption applications, Premarket Approval applications, Humanitarian Device Exemption applications, Evaluation of Automatic Class III Designations (De Novo requests), Premarket Notification, Clinical Laboratory Improvement Amendments Waiver by Applications, Dual 510(k) and CLIA Waiver by Application Submissions, Accessory Classification Requests, and certain Investigational New Drug Applications and Biologics License Applications submitted to the Center for Biologics Evaluation and Research (specifically, INDs and BLAs for devices that are regulated as biological products under section 351 of the Public Health Service (PHS) Act).

Safer Technologies Program for Medical Devices

The FDA is introducing a new, voluntary program for certain medical devices and device-led combination products that are reasonably expected to significantly improve the safety of currently available treatments or diagnostics that target an underlying disease or condition associated with morbidities and mortalities less serious than those eligible for the Breakthrough Devices Program; for example, this may include devices treating or diagnosing non-life-threatening or reasonably reversible conditions. Devices and device-led combination products are eligible for this program if they are subject to review under a premarket approval application, De Novo classification request, or premarket notification, taking into account the specific eligibility factors described in this document. FDA has modeled STeP on the principles and features of FDA’s Breakthrough Devices Program as mandated in section 515B of the Federal Food, Drug and Cosmetic Act and further described in the FDA guidance document entitled “Breakthrough Devices Program“.

CBER

Investigational COVID-19 Convalescent Plasma

FDA is issuing this guidance to provide recommendations to health care providers and investigators on the use of COVID-19 convalescent plasma or investigational convalescent plasma during the public health emergency. The guidance also provides recommendations to blood establishments on collection. We also describe FDA’s interim compliance and enforcement policy regarding the IND requirements for the use of investigational convalescent plasma. This document supersedes the guidance of the same title issued in November 2020.

Human Gene Therapy for Neurodegenerative Diseases

This guidance provides recommendations to sponsors developing human gene therapy (GT) products for neurodegenerative diseases affecting adult and pediatric patients. This guidance focuses on considerations for product development, preclinical testing, and clinical trial design. The guidance also discusses marketing approval pathways for investigational gene therapy products.

Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency

FDA is issuing this guidance to provide manufacturers of licensed and investigational cellular therapy and gene therapy products with risk-based recommendations to minimize potential transmission of the novel coronavirus, severe acute respiratory syndrome coronavirus 2. This guidance is intended to supplement the recommendations to drug and biological product manufacturers provided in FDA’s “Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing; Guidance for Industry” issued in June 2020 (Ref. 1).