SQA Regulatory Surveillance Summary 2 | Monthly Update 2021
By Laurel Hacche, Debra Cortner, & Dondi Pulse-Earle SQA Associates
SQA Regulatory Surveillance Summary #2, 2021
International Organization for Standardization (ISO)
ISO 14155:2020 addresses good clinical practice for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness and safety of medical devices. For post-market clinical investigations, the principles set forth in this document are intended to be followed as far as relevant, considering the nature of the clinical investigation. This document specifies general requirements intended to:
- Protect the rights, safety, and well-being of human subjects
- Ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results
- Define the responsibilities of the sponsor and principal investigator
- Assist sponsors, investigators, ethics committees, regulatory authorities, and other bodies involved in the conformity assessment of medical devices
One of the most common types of tests for identifying and understanding microbial pathogens in healthcare is the nucleic acid amplification test (NAAT). Accuracy and reliability of such tests is, in some cases, a matter of life and death for both patients and laboratory professionals. It is a highly regulated area and, while the types of tests abound, laboratories often need to develop their own methods to meet their own specific needs. ISO 17822:2020, In vitro diagnostic test systems – Nucleic acid amplification-based examination procedures for detection and identification of microbial pathogens – Laboratory quality practice guide, details quality practices for the design, validation, and verification of methods needed for testing microbial pathogens in human samples. This standard provides guidance and recommends best practices to laboratories that not only help them demonstrate conformity to the many regulatory requirements, but also ensure better results for improved patient outcomes.
When the COVID-19 pandemic took hold, so too did the demand for ventilators. With patient safety at its heart, ISO’s committee for respiratory devices began to work on a new standard to support the manufacture of new, high-quality medical equipment that could help. ISO/FDIS 80601-2-90, Medical electrical equipment — Part 2-90: Particular requirements for basic safety and essential performance of respiratory high-flow therapy equipment, is in draft format.
Parenteral Drug Association (PDA) – Standardized Methods and Technical Reports
This draft test method establishes a standardized method for filter manufacturer rating of nominal 0.1-micron rated filter membrane for retention of mycoplasma using 47 mm discs and using A. laidlawii as the test organism. It is also necessary for the filter manufacturer to validate filter devices that may require testing a wide variety of device sizes and configurations. Validation of the actual filter device is not addressed in this standard test method. Any appropriate end-user validation and/or qualification of 0.1-micron rated filter devices incorporating such membrane is also outside of the scope of this standard. This test is intended to be used by the filter manufacturer to validate a mycoplasma-retentive filter within a manufacturing process and to quality a filter for a mycoplasma retentive claim. Validation of a drug manufacturing process employing such a filter must be performed under applicable process-specific conditions.
The concepts presented in PDA Technical Report No. 60-3 (TR 60-3): Process Validation: A Lifecycle Approach, Annex 2: Biopharmaceutical Drug Substances Manufacturing are intended to assist in the design and implementation of globally compliant validation programs to ensure process reproducibility and robustness as they relate to biotechnology-derived, purified protein drug substances. These models are based on the material and practices established in PDA TR 60 and global regulatory guidances. Points to consider are provided to facilitate the collection of data in support of a regulatory filing for the approval of a biopharmaceutical drug substance intended to be used in a pharmaceutical product. The approaches are intended to add value, support good business practices, and meet current compliance and regulatory expectations.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
The following PIC/S guidance documents have been revised: PI 009-4, Aide Memoire on Utilities; PI 024-3, Aide Memoires on Biotech; PI 028-2, Aide Memoire on Packaging; and PI 038-2, Aide Memoire on Assessment of Quality Risk Management (QRM) Implementation. The revision process consisted of updating the cross-references to the PIC/S GMP Guide. No other changes were made. The revised Aide Memoires enter into force on 01 January 2021.
United States Food and Drug Administration (FDA) – Regulations and Guidances for Biologics and the Bioresearch Monitoring Program (BIMO)
In January 2021, the FDA issued a new guidance, Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency, to provide manufacturers of licensed and investigational cellular therapy and gene therapy (CGT) products new risk-based recommendations to minimize potential transmission of the novel coronavirus (SARS-CoV-2). The guidance is intended to supplement the June 2020 GMP Guidance, Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing; Guidance for Industry. The recommendations in this guidance specifically consider the source material (cells and/or tissues) recovered from donors and how the CGT product will be manufactured (e.g., cell expansion in culture, viral reduction steps, and formulation). This new guidance applies to CGT products regulated by the FDA, Center for Biologics Evaluation and Research (CBER) as biological products under section Public Health Service (PHS) Act section 351(i). This guidance does not apply to those human cells, tissues, and cellular- or tissue-based products (HCT/Ps) regulated solely under section PHS Act section 361, as described in 21 CFR Part 1271. In addition, many of the recommendations in this guidance may apply to combination products that consist of a biological product combined with a drug and/or a device.
To address the impact of emerging variants of SARS-CoV-2 on the development of monoclonal antibody products targeting the virus, the FDA has issued a new guidance, Development of Monoclonal Antibody Products Targeting SARS-CoV-2, Including Addressing the Impact of Emerging Variants, During the COVID-19 Public Health Emergency. The new guidance provides recommendations for developers of SARS-CoV-2-targeting monoclonal antibodies during the COVID-19 public health emergency. Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses, like SARS-CoV-2. The FDA is aware that some of the monoclonal antibodies that have been authorized are less active against some of the SARS-CoV-2 variants that have emerged. This guidance provides recommendations on efficient approaches to the generation of non-clinical, clinical, and chemistry manufacturing and control data that could potentially support an Emergency Use Authorization (EUA) for monoclonal antibody products that may be effective against emerging variants.
The FDA has also revised a second guidance covering drugs and biological products more broadly for COVID-19, COVID-19: Developing Drugs and Biological Products for Treatment or Prevention. The revised guidance covering drugs and biological products more broadly, originally published in May 2020, describes the FDA’s current recommendations regarding phase 2 and phase 3 clinical trials for drugs and biological products under development to treat or prevent COVID-19, including the patient population, trial design, efficacy endpoints, safety considerations, and statistical considerations for such trials and more. This guidance was updated to address the evolving landscape of COVID-19 drug development, including the emergence of SARS-CoV-2 variants and the availability of authorized COVID-19 vaccines.
With these guidances, the FDA is encouraging developers of drugs or biological products targeting SARS-CoV-2 to continuously monitor genomic databases for emerging SARS-CoV-2 variants and evaluate phenotypically any specific variants in the product target that are becoming prevalent or could potentially impact its activity.
The FDA has issued a new guidance to collate recommendations for the reporting and implementation of some common changes to container closure system (CCS) components, specifically glass vials and stoppers for approved sterile drug products, including biological products, administered parenterally. Due to the COVID-19 pandemic, some injectable products, either approved or pending approval, may need some changes to the primary packaging components (e.g., glass vials and stoppers) due to supply chain issues affecting their availability. Supplies of these components may become constrained and manufacturers may have to make changes to the components, requiring changes to their Drug Master File (DMF). This guidance also discusses pathways available to application holders to obtain Agency feedback. Additionally, this guidance discusses risk-based tools available to facilitate the implementation of changes to CCSs consisting of glass vials and stoppers. This guidance does not apply to CCS types other than glass vials and stoppers.
United States FDA – Regulations and Guidances for Drugs, Devices, Food, and Cosmetics
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 (PMA), De Novo classification request (“De Novo request”), or premarket notification (510(k)), taking into account the specific eligibility factors described in this document. Consistent with the Agency’s statutory mission to protect and promote public health, the FDA believes that this “Safer Technologies Program” or “STeP” will help patients have more timely access to these medical devices and device-led combination products by expediting their development, assessment, and review, while preserving the statutory standards for premarket approval, De Novo marketing authorization, and 510(k) clearance. The FDA has modeled STeP on the principles and features of their Breakthrough Devices Program as mandated in section 515B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360e-3) and further described in the FDA guidance document, Breakthrough Devices Program. As resources permit, the FDA intends for STeP to incorporate similar features offered under the Breakthrough Devices Program, such as interactive and timely communications, early engagement on Data Development Plans (DDPs), sprint discussions, and senior management engagement.
The FDA has published a revision to its September 2020 guidance for industry, Control of Nitrosamine Impurities in Human Drugs. The revision extends the recommended timeframe for manufacturers to assess the risk of nitrosamines in Active Pharmaceutical Ingredients (APIs) and drug products from six months to seven months from the publication of the original guidance. The guidance recommends steps manufacturers of APIs and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance describes the three-step process manufacturers should follow to mitigate nitrosamine impurities in their products. The first of these steps is assessing the risk of nitrosamine impurities in APIs, marketed products, and products under approved and pending applications. If an API or drug product is determined to be at risk, manufacturers should perform the second step: conducting confirmatory testing for the presence of nitrosamine impurities. To ensure the safety of the U.S. drug supply, the guidance recommends that manufacturers should conclude the first step, the risk assessment of approved or marketed products, within six months of the original guidance publication. Based on the current guidance revision, the FDA has extended the recommended timeframe for completion of risk assessments to 31 March 2021. Manufacturers do not need to submit risk assessment documents to the agency, but they should retain these documents, so they are available if requested.
United States FDA – Recalls for Drugs, Devices, Food, and Cosmetics
Nostrum Laboratories, Inc. Expands Voluntary Nationwide Recall of Metformin HCl Extended Release Tablets, USP 750 mg, Due to N-Nitrosodimethylamine (NDMA) Content Above the Acceptable Daily Intake (ADI) Limit, 04 January 2021
Nostrum Laboratories, Inc. is voluntarily recalling one lot of Metformin HCl Extended Release Tablets, USP 750 mg (generic equivalent to Glucophage Tablets) to the consumer level. The Metformin HCl Extended Release Tablets, USP 750 mg (generic equivalent to Glucophage Tablets) have been found to contain levels of nitrosamine impurities above the ADI limit of 96 ng/day as published in the FDA Guidance Document issued in September 2020. This is an expansion of the recall initially announced on 02 November 2020. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and is found in water and foods, including meats, dairy products, and vegetables. To date, Nostrum Laboratories, Inc. has not received any reports of adverse events related to this recall.
Boston Scientific is recalling the EMBLEM S-ICD (Subcutaneous Implantable Cardioverter Defibrillator) system because a manufacturing process may allow moisture to get inside the defibrillator and cause a short-circuit when it tries to deliver high voltage shocks. If this happens during use, this may lead to serious adverse events, including injury or death. The FDA has identified this as a Class I recall, the most serious type of recall.
United States FDA – Warning Letters for Biologics
The FDA and the Federal Trade Commission (FTC) issued warning letters to seven companies for selling fraudulent COVID-19 products. These products are unapproved drugs that pose significant risks to patient health and violate federal law. The FDA and FTC are taking this action as part of their response in protecting Americans during the global COVID-19 outbreak. The warning letters are the first to be issued by the FDA for unapproved products intended to prevent or treat “Novel Coronavirus Disease 2019” (COVID-19). The FDA and FTC jointly issued warning letters to Vital Silver, Quinessence Aromatherapy Ltd., Xephyr, LLC doing business as N-Ergetics, GuruNanda, LLC, Vivify Holistic Clinic, Herbal Amy LLC, and The Jim Bakker Show. The products cited in these warning letters are teas, essential oils, tinctures, and colloidal silver. The FDA has previously warned that colloidal silver is not safe or effective for treating any disease or condition. The FDA and FTC requested that the companies respond in 48 hours describing the specific steps they have taken to correct the violations. Companies that sell products that fraudulently claim to prevent, treat, or cure COVID-19 may be subject to legal action, including but not limited to seizure or injunction.
United States FDA – Warning Letters for Drugs, Devices, Food, and Cosmetics
The U.S. FDA posted warning letters to 10 companies for illegally selling dietary supplements that claim to cure, treat, mitigate, or prevent depression and other mental health disorders. The dietary supplements discussed in these letters are unapproved new drugs and have not been evaluated by the FDA to be safe and effective for their intended use.
Consumers who rely on dietary supplements in lieu of discussing their symptoms with a health care professional could potentially suffer harm and may not receive appropriate therapies that have been determined to be safe and effective to treat depression and other mental health disorders. Warning letters were sent to the following companies:
- ProHealth Inc.
- Garber’s Natural Solutions
- FDC Nutrition Inc.
- Blossom Nature LLC
- Silver Star Brands, Inc.
- Wholesome Wellness
- SANA Group LLC
- Mountain Peak Nutritionals
- Lifted Naturals
- Enlifta LLC
Under the Federal Food, Drug, and Cosmetic Act, products intended to cure, treat, mitigate, or prevent disease are drugs and are subject to the requirements that apply to drugs, even if they are labeled as dietary supplements. Unlike drugs approved by the FDA, the agency has not evaluated whether the unapproved products subject to the warning letters are effective for their intended use, what the proper dosage might be, how they could interact with FDA-approved drugs or other substances, or whether they have dangerous side effects or other safety concerns. The FDA has requested responses from the companies within 15 working days stating how they will address these issues or providing their reasoning and supporting information as to why they think the products are not in violation of the law. Failure to correct violations promptly may result in legal action, including product seizure and/or injunction.
A dietary supplement manufacturer and two of its executives have been ordered by a federal court to stop manufacturing, holding, or distributing any articles of food, including dietary supplements, until they come into compliance with federal dietary supplement current Good Manufacturing Practice regulations and other Federal Food, Drug, and Cosmetic Act (FD&C Act) requirements. Judge Edward R. Korman of the U.S. District Court for the Eastern District of New York entered an order of permanent injunction against Confidence USA Inc., of Long Island, New York, and the company’s president, Helen Chian, and general manager and founder, Jim Chao. The permanent injunction requires the defendants to cease manufacturing, holding, or distributing dietary supplements until the FDA notifies the defendants that they may resume operations. The court found that the defendants violated the FD&C Act because their products were prepared, packed, or held in violation of the current Good Manufacturing Practice (cGMP) regulations for dietary supplements. Multiple FDA inspections showed that the defendants repeatedly failed to verify the identity of each dietary ingredient used in the manufacture of their supplements. The defendants also failed to verify that their products met specifications for purity, strength, composition, and contamination limits.