SQA Regulatory Surveillance Summary for March and April 2023

By: Laurel Hacche, Rocio Cabeza, and Debra Cortner

Agência Nacional de Vigilância Sanitária (ANVISA)

ANVSA Recommends Intensification of Actions Against Arboviruses, 22 March 2023

ANVISA has published Technical Note 12/2023 which recommends the intensification of measures or the reduction of mosquito breeding sites and control of adult vectors, airports, and border areas, which are points of entry and exit of the country. The objective is to reinforce actions for the prevention and control of diseases such as dengue and chikungunya, arboviruses transmitted by the Aedes aegypti mosquito.  As recommended by the International Health Regulations (IHR), there must be a vector-free zone at seaports, airports, and land crossing and within a perimeter of 400 meters around these entry points. For this, it is necessary to maintain regular active surveillance and vector control so that the risk of disease transmission is reduced.

ANVISA Resumes Inspections in the Area of Technovigilance, 29 March 2023

In partnership with local Health Surveillance, ANVISA technical teams carried out in March 2023 two (2) medical device manufacturer inspections with an aim to strengthen the monitoring of these products in Brazil, ensuring their safety, performance, and quality. The technovigilance inspection consists of:

• Evaluation of compliance with technovigilance standards by companies
• Monitor the behavior of products in the post-marketing phase
• Evaluate the effectiveness of filed actions that affect medical devices
• Collect data and information of adverse events and technical complaints, as well as evaluate the investigative process triggered by the registration holder in the face of such situations

The selection of companies for inspection includes the following criteria: silent companies (absence of notifications of adverse events, technical complaints, or field actions), quantity of products regulated by ANVISA and the risk class of these products.

ANVISA Warns of New Cases of Botulinum Toxin Counterfeiting, 05 April 2023

ANVISA alerts health professionals and the population to the fact that new cases of adulteration/falsification of the drug Botox® 100U (botulinum toxin A), Batch Number C6835C3 have been identified. ANVISA has intercepted international shipments of Batch Number C6835C3 which presented a false description of content and contained bottles in packaging in the Turkish language with expirations dates 10/2024 (bottle) and 12/2024 (secondary packaging). The company that holds the registration of the drug Botox, Allergan Produtos Farmacêuticos Ltda., confirmed to ANVISA that the original Batch Number C6835C3 has a shelf life of 12/2023 and was marketed only in Turkey, and has not been imported into Brazil by official means. Thus the seizer and prohibition of marketing, distribution, and use of Batch Number C6835C3 was determined by means of Resolution-RE 796 of March 9, 2023.

China: National Medical Products Administration (NMPA)

China Update: Announcement No. 124 of 2022; Draft Guidelines for the Registration of Implantable Medical Devices, 06 January 2023

The NMPA and Center for Medical Device Evaluation (CMDE) published new rules for the supervision and management of enterprises implementing medical device safety, as well as draft guidelines for the registration and review of implantable medical device batteries. Following the draft consultation in November 2022, the NMPA announced the issuance of the Regulations on the Supervision and Management of Enterprises Implementing the Main Responsibility for the Quality and Safety of Medical Devices, which will come into force on 01 March 2023. This requires medical device registrants and record filers to fulfill the main responsibility for medical device quality and safety. It also includes provisions that emphasize the implementation of responsibilities for medical device registrants, filers, and entrusted manufacturers and personnel in key positions of quality and safety in medical device production and operating enterprises.  The Interpretation of Regulations on the Supervision and Management of Enterprises Implementing the Main Responsibility for the Quality and Safety of Medical Devices further discusses the provisions of the Regulations.

2022 Recap & 2023 Outlook: China Pharmaceutical Regulatory Updates, 28 February 2023

In 2022, China issued and implemented a series of drug regulations, including new rules for marketing authorization holders to manage drug quality and guidelines for pharmacovigilance inspections. Last year also saw China’s first regulation permitting online sales of prescription drugs nationwide. The regulations impact how pharmaceutical companies apply for marketing authorization, sell drug products, ensure drug safety, and fulfill other obligations. ChemLinked BaiPharm Team held this webinar to review the significant regulatory updates, which can help stakeholders keep compliant with current regulations and prepare for the upcoming ones. Key points for the webinar include:

• China’s Drug Regulatory System
• 2022 Regulatory Updates
• 2023 Outlook

European Commission (EC)

New European MDCG Guidance on Medical Device Vigilance Requirements, 17 February 2023

The long-awaited Medical Device Coordination Group (MDCG) Guidance on Vigilance has been published to the European Commission website. MDCG 2023-3, Questions and Answers on Vigilance Terms and Concepts as Outlined in the Regulation (EU) 2017/745 on Medical Devices, provides additional information on key vigilance terms. Interestingly, the guidance only covers devices under the scope of the Medical Devices Regulation (MDR) and not those under the scope of the In Vitro Diagnostic Medical Devices Regulation (IVDR). The guidance clarifies key differences in vigilance reporting between MEDDEV 2.12/1 rev.8 and the Regulations:

• The guidance features a flowchart that illustrates the process of analyzing complaints to determine reportability under the MDR.
• The difference between the term “incident” and the new term “serious incident” introduced in the Regulation are also discussed in detail.
• The deadline for reporting serious incidents not constituting serious public health threats, deaths, or unanticipated serious deteriorations in state of health was reduced to 15 calendar days. The reporting period begins on the day after the awareness date of a serious incident.
• The awareness date may change if, during the investigation of an incident, the manufacturer receives additional information which subsequently changes the determination of the report to a serious incident. Although the original awareness date in Section 1.2c of the Manufacturer Incident Report (MIR) should still be identified, an explanatory comment may be placed within Section 5 of the MIR.
• It can be challenging to understand when the MIR report type, Final (non-reportable), may be used. The guidance describes the two main situations appropriate for its use:
  • After submitting an MIR, further investigation of the incident and device involved reveals that the criteria for a serious incident were not fulfilled.
  • The manufacturer receives a user report of a potentially serious incident from a competent authority but establishes that the criteria for a serious incident are not met.

• The terms “ergonomic features” and “use-errors due to ergonomic features” are defined and clarified.

 

European Parliament Votes in Favor of Amendment Extending MDR, IVDR Timelines, 17 February 2023

The European Parliament has voted overwhelmingly in favor of an amendment to extend transition timelines for the Medical Devices Regulation (MDR) and In Vitro Diagnostic Medical Devices Regulation (IVDR).  The vote occurred on 16 February 2023 following a plenary meeting of the European Parliament, and represents a significant step towards a formal extension of MDR and IVDR compliance deadlines for some device manufacturers.   The amendment will enter into force on the date of its publication in the Official Journal of the European Union (OJEU), but first the amendment must be adopted by the European Council (expected by the end of February). Following adoption by the European Council, the formal process of publication in the OJEU may begin, and typically takes up to 30 days. The amendment will set the following transition timelines for affected devices:

• Legacy Class III and Class IIb implantable devices: December 2027
• Legacy Class IIa and Class I devices: December 2028
• Class III implantable custom devices: May 2026

Manufacturers whose CE Mark certificates are set to expire before final publication of the amendment in the OJEU may qualify for temporary market access under Article 97 MDR until new compliance deadlines become official.

European Medicines Agency (EMA)

Final GCP Guideline on Computerized Systems and Data Integrity, 11 April 2023

Following the draft guideline published in June 2021 the final EMA Guideline on computerized systems and data integrity in clinical trials has now been published. The document will become effective 6 months after publication (10 September 2023). The guideline aims in understanding of regulatory expectations to validation, operation, and safe use of Information Technology (IT) systems in clinical trials. It replaces the Reflection Paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials. In addition, a new expression is defined: ALCOA+. In addition to the ALCOA+ principles it includes Traceability. This means that data should be traceable throughout the data life cycle. Any changes to the data should be documented as part of the metadata (e.g., audit trail).

Health Canada

Non-Compliant Rating for Vereburn Medical, 11 January 2023

Vereburn Medical received a con-compliant rating from Health Canada for an inspection that started on 11 January 2023. Observations were summarized as follows:

• Devices available for sale were improperly labelled.
• Devices not authorized for sale by Health Canada were sold by the company.
• The company’s website and/or catalog advertised device(s) not authorized for sale by Health Canada.
• The written procedure for incident reporting was inadequate.
• The company did not have a written procedure in place for the provision of information related to serious risk of injury to health, contrary to what was committed to on it establishment license application.
• The company’s written procedures and implantation of processes for storage, distribution, delivery, handling, installing, and/or servicing of medical devices were inadequate.
• The company could not provide a complete record of complaints.
• The written procedure for complaint handling was not implemented by the company. In addition, the procedure for complaint handling was inadequate.
• The written procedure for recall was inadequate and this procedure had not been implemented. It addition, the company did not report one or more recalls.
• The name and address of manufacturers provided by the company on its establishment license application were not accurate.

Non-Compliant Rating for McGill University Health Center, 23 January 2023

McGill University Health Center received a con-compliant rating from Health Canada for an inspection that started on 23 January 2023. There was a total of 19 observations. The first 10 were summarized as follows. The summary for all observations is provided on the Health Canada website.

• The establishment did not have sufficient personnel with the appropriate education training or experience to conduct its activities.
• The establishment did not ensure that blood was always stored under appropriate environmental conditions.
• The records of staff qualification, training or evaluation of their competency were not always sufficient.
• The qualification and calibration of the equipment used to store blood was not sufficient.
• The establishment did not ensure that critical equipment was validated, calibrated, cleaned or maintained properly.
• The operating procedures did not meet all requirements.
• The internal audit system was not sufficient.
• Some operating procedures were not always followed.
• The establishment did not thoroughly investigate errors and accidents and determine Corrective and Prevent Actions (CAPA).
• The establishment did not have documented evidence to show that some or all of the operating procedures for processing and transforming blood would consistently lead to expected results.

Public Advisory: Robikids and Solmux are Unauthorized Syrups for Thinning Mucus and May Pose Serious Health Risks, 03 March 2023

Health Canada is warning parents and caregivers about two unauthorized children’s syrups for thinning mucus, Robikids and Solmux, seized from Kamshoppe, which advertised the products on Facebook. Both products are labelled to contain carbocisteine, a prescription drug that may pose serious health risks such as nausea, diarrhea, allergic reactions (e.g., anaphylaxis) and gastrointestinal bleeding. Should Health Canada identify other distributors or retailers of these unauthorized health products, it will take action and inform the public as appropriate.

India

Center Directs Manufacturers to Not Use Excipient Propylene Glycol Supplied by Maya Chemtech, 16 March 2023

The Central India Government has asked drug licensing authorities of the states and Union territories to direct pharmaceutical manufacturers not to use the excipient propylene glycol supplied by Delhi based Maya Chemtech India Pvt Ltd, in connection with the cough syrups which allegedly resulted in adverse events and death of children overseas. The government has also informed that tests conducted on the samples from Noida based Marion Biotech, which has allegedly resulted in adverse events in Uzbekistan, has revealed that out of the 30 drug samples form the company tested, 24 samples were declared as Not of Standard Quality (NSQ) and out of that, 22 samples fell under the category of adulterated or spurious. The Ministry of Uzbekistan alleged that the cough syrup manufactured by Marion Biotech has resulted in the death of 18 children.

Uzbekistan Cough Syrup Deaths – Marion Biotech’s License Cancelled, 23 March 2023

The Uttar Pradesh Ministry of Food and Drug Safety has cancelled the drug license of Noida-based Marion Biotech Pvt Ltd after 18 children died in Uzbekistan, last year, allegedly after consuming cough syrup manufactured in India. According to a letter written by Drugs Controller General of India (DCGI) Rajeev Raghuvanshi to alert State licensing authorities, 22 out of 33 samples of Marion Biotech’s cough syrup have been found to be adulterated with ethylene glycol, a substance linked to the Uzbek deaths.

 

International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety

The ICH S12 Guideline Reaches Step 4 of the ICH Process, 17 March 2023

The ICH S12 Guideline on Nonclinical Biodistribution Considerations for Gene Therapy Products has reached Step 4 of the ICH Process on 14 March 2023. This guideline is intended to provide guidance on the conduct of Nonclinical Biodistribution (BD) studies in the development of Gene Therapy (GT) products that mediate their effect by the expression (transcription or translation) of transferred genetic materials, and harmonized recommendations to facilitate the development of GT products while avoiding unnecessary use of animals, in accordance with the Reduce/Refine/Replace (3Rs) principles. In addition, a Step 4 Introductory Training Presentation has been developed by the S12 Expert Working Group (EWG) to summarize the content of the guideline.

 

The ICH M7(R2) Guideline Reaches Step 4 of the ICH Process, 04 April 2023

The ICH M7(R2) Guideline on the Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk and the accompanying M7(R2) Addendum Application of the Principles of the ICH M7 Guideline to Calculation of Compound-Specific Acceptable Intakes have reached Step 4 of the ICH Process on 3 April 2023. The M7(R2) Guideline is intended to provide guidance for new drug substances and products during their clinical development and subsequent applications for marketing. It also applies to post-approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product, in both cases only where:

• Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities.
• Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products.
• Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

The ICH M7(R2) Addendum describes Acceptable Intakes (AIs) or Permissible Daily Exposures (PDEs) which have been derived for a set of chemicals that are considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7(R2).

International Pharmaceutical Excipients Council (IPEC)

IPEC Federation Questionnaire for Excipient Nitrosamines Risk Evaluation, 21 February 2023

IPEC Federation announces the availability of the Questionnaire for Excipient Nitrosamines Risk Evaluation (version 1, 2023). This document is equivalent to the form developed and previously published by IPEC Europe, of which the latest version was made available in January 2023 (version 4.3). Its aim is to assist excipient manufacturers with collecting data in a standardized format that drug product manufacturers need to perform their nitrosamine risk assessments. This rebranding was deemed appropriate as the IPEC Europe Questionnaire has been adopted and used globally and a decision was taken to make the same format available through all IPEC associations. It is recommended that the IPEC Federation Questionnaire be used for new evaluations only as the content of the form remains largely unchanged. Clarifications were made in both IPEC Federation and Europe documents on Question 4 in relation to process water quality.

Now Available: Excipient Information Package User Guide and Template, Part IV: Sustainability, 08 March 2023

The International Pharmaceutical Excipients Council Federation, (IPEC Federation) announces the availability of the new Excipient Information Package User Guide and Template, Part IV: Sustainability. This guide is applicable globally. The original IPEC Excipient Information Package (EIP) was developed as a means of efficiently communicating a significant amount of information about the Excipient (Part I), the Excipient Manufacturer (Part II) and the Distribution and Supply Chain (Part III). The information facilitates and aids the excipient user in their qualification of the excipient supplier and the excipient. This Part IV of the EIP focuses on sustainability matters relating the excipient supplier and the excipient(s). The information provided by the excipient supplier using this part of the EIP is generally expected to provide suitable and sufficient information related to sustainability policies and commitments made by the excipient supplier, thus aiding the excipient users’ own commitments to sustainability. The guide will be available initially to IPEC members for a three-month period, on the IPEC Federation and national/regional members’ websites. Thereafter, the guide will be made available to the general public.

Medicines and Healthcare Products Regulatory Agency (MHRA)

Class 2 Medicines Recall: Various Marketing Authorization Holders, Pholcodine-Containing Products, 14 March 2023

Following the conclusion of a review of post-marketing safety data by the MHRA, all pholcodine-containing medicines are being recalled and withdrawn from the UK as a precaution. The Commission on Human Medicines (CHM), the independent advisory body that provides expert advice on the safety, quality, and efficacy of medicines, has considered the evidence of an increased risk of the very rare event of anaphylaxis when exposed to Neuromuscular Blocking Agents (NMBA) and advised that pholcodine-containing medicines should be withdrawn. The available data has demonstrated that pholcodine use, particularly in the 12 months before general anesthesia with NMBAs, is a risk factor for developing an anaphylactic reaction to NMBAs. Given the advice of the CHM, and the lack of identifiable effective measures to minimize the increased risk of anaphylactic reactions to NMBAs, pholcodine-containing medicines are being withdrawn from the UK market and will therefore no longer be available in pharmacies. All pholcodine-containing medicines are Pharmacy (P) only medicines and therefore have only been sold or dispensed under the supervision of a suitably trained healthcare professional.

 

Government Response to Consultation on Legislative Proposals for Clinical Trails, 21 March 2023

The MHRA and the Department of Health in Northern Ireland, working closely with the Health Research Authority (HRA), consulted on a set of proposals to update, improve, and strengthen the United Kingdom (UK) legislation that underpins the regulation of clinical trials. Having analyzed over 2000 responses received, the government will now take forward legislation to reform of the UK clinical trials regulatory framework that will:

• Ensure patients and their safety are at the focus of all clinical trials and bring the benefits of clinical trials to everyone.
• Create a proportionate and flexible regulatory environment.
• Cement the UK as a destination for international trials.
• Provide a framework that is streamlined, agile and responsive to innovation.

This package of changes will deliver the MHRA’s vision for a more proportionate, streamlined, flexible and effective clinical research environment, putting patients at the heart and the UK at the forefront of innovative regulation for clinical trials.

Medical Devices – Extended Acceptance of CE Marked Medical Devices on the Great Britain Market, 28 April 2023

A statutory instrument has been laid in Parliament, which will enable an extended timeframe for acceptance of CE marked medical devices on the Great Britain market. Subject to Parliamentary approval this will mean that CE marked medical devices will be accepted on the Great Britain market beyond the current deadline of 30 June 2023. This will support the ongoing, safe supply of medical devices to Great Britain and is designed to ease the transition to a future strengthened regulatory framework for medical devices. The government will ensure that there is a proportionate, phased approach to the implementation of the future regulatory framework, which supports system readiness and minimizes the risk of supply disruption for UK patients. The government is aiming for the revised framework to now apply from July 2025. This timeline is based on board feedback from external stakeholders, such as concerns about limited capacity of conformity assessment bodies. As communicated in March 2023 that the EU has taken steps to give manufacturers more time to get certain medical devices certified under the EU Medical Devices Regulation (EU MDR), including extending validity of certain CE certificates. To provide greater clarity for industry, the government has published guidance about acceptance of such certificates on the Great Britain market. MHRA guidance has been updated to reflect these planned changes to the acceptance of CE marked medical devices in Great Britain.

Personal Care Products Council (PCPC)  

Statement by Lezlee Westine, President & CEO, Personal Care Products (PCPC), on Proposed FDA Reorganization, 28 February 2023

The PCPC is committed to working with the United States Food and Drug Administration (FDA) to support its mission to protect consumer health and to understand better how the FDA’s proposed reorganization could impact cosmetics and personal care products regulation. As in the past, the PCPC stands ready to collaborate with the FDA and other stakeholders to ensure any reorganization enables the beauty and personal care industry to continue to provide innovative, safe, and effective products while maintaining consumer trust. PCPC’s current priority is to work with the FDA to effectively implement the Modernization of Cosmetics Regulation Act of 2022. This historic legislation gives the FDA additional tools to ensure cosmetics’ safety and to protect public health, reinforcing consumer confidence in the products they trust and use every day. The Modernization of Cosmetics Regulation Act (MoCRA) also brings the FDA’s oversight of the beauty and personal care sector more in line with other categories the FDA regulates and helps contribute to global regulatory alignment. The PCPC looks forward to working with FDA Chief Scientist Namandjé Bumpus, Ph.D., who will be leading the effort on MoCRA implementation as cosmetics and personal care products will now reside in the Office of the Chief Scientist within the Office of the Commissioner. The PCPC believes the Commissioner’s decision is the right one.

 

Pharmaceutical Inspection Co-Operation Scheme (PIC/S)

Two New PIC/S Good Distribution Practice (GDP) Guidance Documents Published, 28 March 2023

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has published two guidance documents for GDP inspectors, an Aide-Memoire on GDP inspections and a Questions & Answers (Q&A) document. these documents have been prepared by the PIC/S Expert Circle on GDP and entered into force on 01 February 2023. Both publications are available for download as a PDF file free of charge on the PIC/S website. The Aide-Memoire on GDP inspections provides guidance for GDP inspectors to assist in training and preparing for inspections.  To be precise, it is about GDP inspection of manufacturers and wholesale distributors. The Q&A document provides input with respect the PIC/S GDP Guide (PE 011-1) that was published in June 2014.

 

Therapeutic Goods Administration (TGA)

TGA’s New Powers Will Help Reduce the Impact of Medicine Shortages on Patients, 24 March 2023

From 22 March 2023, TGA can approve the temporary import or supply of an overseas-approved medicine as a substitute for one that is in short supply if it has been previously registered in Australia. These changes have been introduced to help alleviate the effects of medicine shortages on patients.  This includes medicines that have been discontinued, suspended, or cancelled from the Australian Register of Therapeutic Goods (ARTG) but can still assist patients who don’t have other treatment options. Previously, TGA could only grant temporary approval for import and supply of a substituted overseas medicine if the Australian medicine was currently included in the ARTG.  In addition, updates have been made to improve the accuracy of the information published on the TGA Medicine Shortage Reports Database. The changes clarify requirements around updating and resolving shortages. These changes to the Therapeutic Goods Act 1989 will help reduce the impacts that medicine shortages have on Australian patients.

Changes To Medical Device Essential Principles for Nanomaterials, 29 March 2023

Essential Principle 7.7 Minimization of Risks Associated with Nanomaterials now explicitly requires that particular attention must be given to the chemical and physical properties and biocompatibility of materials used in medical devices in relation to nanomaterials.  This obligation already existed. Additional detail has been included to help clarify it without introducing new or additional obligations. The Therapeutic Goods (Medical Devices) Regulations 2002 now includes for Essential Principle 7.7:

1. A medical device must be designed and produced in a way that ensures that any risks associated with the size and the properties of particles which are, or can be, released into a patient’s or user’s body are minimized.
2. In minimizing risks, particular attention must be given to the use of nanomaterials.
3. Subclause (1) does not apply to particles that come into contact with intact skin only.

Changes To Dual Labelling Period for Some Dual Labelled Ingredient Names, 05 April 2023

Currently some medicine ingredient names must be dual labelled on labels and Product Information (PI) and Consumer Medicines Information (CMI) documents. This means labels display both the old and new ingredient name. This was to allow people to become familiar with the new names which were chosen because they are recognized internationally. The dual labelling period for most dual labelled names will end on 30 April 2023.  Medicine sponsors have 3 years to update labels to show only the new name for these ingredients.  For some ingredient names dual labelling will continue for longer. These names were identified during consultation- external site with health professionals and others who wanted more time. For more information about the transition to sole names see Dual labelled medicine ingredient names start the transition to sole names on 30 April 2023.

United States Food and Drug Administration (FDA) – Regulations and Guidances

Guidance for Industry, Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act, March 2023

This guidance is intended to help industry identify suspect and illegitimate product in the United States pharmaceutical supply chain by interpreting certain terms used in the definitions of suspect product and illegitimate product.  Trading partners are required to take specific actions if they identify such products. Although this guidance does not create an exhaustive list of the circumstances that may result in a counterfeit drug, a diverted drug, a stolen drug, a fraudulent transaction, or a drug that is unfit for distribution, it describes the most common scenarios that FDA believes trading partners will encounter.

Draft Guidance for Industry, Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions, April 2023

FDA is issuing this draft guidance to further develop a regulatory approach tailored to Artificial Intelligence/Machine Learning (AI/ML)-enabled devices to increase patients’ access to safe and effective AI/ML-enabled devices, in order to protect and promote public health. This draft guidance describes a least burdensome approach to support the iterative improvement of Machine Learning-enabled Device Software Functions (ML-DSF) while continuing to assure their safety and effectiveness, as described in FDA’s 2019 AI/ML Discussion Paper and 2021 AI/ML Action Plan. The draft guidance provides recommendations on the information to be included in a Predetermined Change Control Plan (PCCP) that may be provided in a marketing submission for ML-DSF. The PCCP mechanism includes the planned ML-DSF modifications, the associated methodology to implement and validate those modifications, and an assessment of the impact of those modifications. Since the introduction of the PCCP concept, there has been significant interest in using this mechanism for AI/ML-enabled medical devices. FDA continues to receive an increasing number of marketing submissions and pre-submissions for AI/ML-enabled medical devices, which can have a significant positive impact on healthcare, and the Agency expects this to increase over time. The guidance builds on FDA’s longstanding commitment to develop and apply innovative approaches to the regulation of medical device software and other digital health technologies to assure their safety and effectiveness. The recommendations in this guidance apply to the device constituent part of a combination product, such as drug-device and biologic-device combination products, when the device constituent part includes an ML-DSF.

Modernization of Cosmetics Regulation Act of 2022, 14 April 2023

The Modernization of Cosmetics Regulation Act of 2022 (MoCRA) is the most significant expansion of the FDA’s authority to regulate cosmetics since the Federal Food, Drug, and Cosmetic (FD&C) Act was passed in 1938. This new law will help ensure the safety of cosmetic products many consumers use daily. MoCRA provides new authorities to the FDA including:

• Records Access
• Mandatory Recall Authority

MoCRA establishes the following new requirements for industry:

• Adverse Event Reporting
• Facility Registration
• Product Listing
• Safety Substantiation

MoCRA also requires that industry comply with regulations that will be established by the FDA for:

• Good Manufacturing Practice (GMP) requirements for facilities that manufacture cosmetic products.
• Fragrance allergen labeling requirements.
• Standardized testing methods for detecting and identifying asbestos in talc-containing cosmetic products.

MoCRA exempts certain small businesses from GMP, registration, and product listing requirements. However, such exemptions do not apply to manufacturers or facilities that manufacture or process the following cosmetic products:

• Products that regularly come into contact with mucus membrane of the eye under customary or usual conditions of use.
• Products that are injected.
• Products that are intended for internal use.
• Products that are intended to alter appearance for more than 24 hours under customary or usual conditions of use and removal by the consumer is not part of such conditions of use.

Exemptions also exist for certain products and facilities that are subject to requirements for drugs and devices.

 

United States Food and Drug Administration (FDA) – Safety Notifications and Recalls

Pharmedica USA LLC Issues Voluntary Worldwide Recall of Purely Soothing 15% MSMDrops Due to Non-Sterility, 03 March 2023

Pharmedica USA LLC is voluntarily recalling two lots of Purely Soothing, 15% MSM Drops to the consumer level. This product is being recalled due to non-sterility. To date, Pharmedica USA LLC has not received any reports of adverse events or illness related to this recalled product. The product was distributed worldwide by Purely Soothing LLC via online e-commerce and Trade shows, e.g., Amazon Marketplace, etc. The eye drop is used as an anti-inflammatory aimed to assist with symptoms of ocular irritation and/or swelling and is packaged in white, cylindrical high density polyethylene bottles. The eye drops (Lot Number 2203PS01, 1 oz, UPC 7 31034 91379 9 and Lot Number 1808051, ½ oz, UPC 7 31034 91382 9) have eye dropper caps and white lids. Pharmedica USA LLC is advising customers to immediately stop using the product and return it to the place of purchase. Wholesalers and retailers should stop distributing and return to Pharmedica USA LLC immediately or confirm that the product has been disposed of with proper verification.

 

Abbot Issues Safety Notification for Free Style Libre Family of Readers in the United States, 03 April 2023

Abbott initiated a voluntary medical device correction in February 2023 to emphasize instructions for its FreeStyle Libre®, FreeStyle Libre® 14 day and FreeStyle Libre® 2 Readers in the United States due to a limited number of reports worldwide (0.0017%) from users over several years that their reader’s lithium-ion battery swelled, infrequently overheated or, in very rare cases, sparked or caught fire. No Readers are being physically recalled and customers can continue to use their Readers with the Abbott-provided USB cable and power adapter. The steps outlined below provide guidance on how to properly store, charge and use a Reader and its accompanying USB cable and power adapter. This communication applies to the Readers used as part of the FreeStyle Libre, FreeStyle Libre 14 day, and FreeStyle Libre 2 Flash Glucose Monitoring Systems (all Reader serial numbers). This does not affect any of the FreeStyle Libre family of sensors.

• If not properly stored, charged, or used with the Abbott-provided yellow USB cable and power adapter, a potential exists for battery swelling and, in rare cases, extreme overheating, which may pose a fire hazard.
• Users should ensure they always use the Abbott-provided yellow USB cable and power adapter.
• The FreeStyle Libre family of Readers use lithium-ion batteries, like the kinds used in mobile phones and many other handheld electronic devices, which have the potential for battery swelling, leakage, or extreme overheating.
• The Readers are safe when properly stored, charged, and used only with their accompanying USB cable and power adapter, as outlined.

 

Teva Pharmaceuticals USA Initiates Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII due to a Labeling Error, 28 April 2023

Teva Pharmaceuticals USA has initiated a voluntary nationwide recall of specific lots of various strengths of FENTANYL Buccal Tablets CII to the consumer Level. Teva USA manufactured and labeled these product lots exclusively for Mayne Pharma Inc. under Mayne’s label. This recall has been initiated because safety updates were omitted in the Product Insert/Medication Guide (MG) that are provided with these recalled lots.The main safety concern is a potential for incomplete information needed by health care providers and patients regarding safe use of the product. Not following, or not being aware of, the omitted safety updates in the MG could lead to life-threatening adverse events; although, based on a Health Hazard Assessment conducted by Teva, the likelihood of the harm occurrence is considered remote. To date, Teva has not received any complaints related to the product labeling.

 

United States Food and Drug Administration (FDA) – Warning Letters

Olympus Medical Systems Corp., Warning Letter, 15 March 2023

The FDA inspected the Olympus Medical Systems Corp. facility located in Tokyo, Japan from 07 to 10 November 2022. The inspection revealed that the devices manufactured by the company are adulterated in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. Observations relating to Part 820 are as follows:

• Failure to adequately establish and maintain procedures for implementing corrective and preventive action, including analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems, as required by 21 CFR 820.100.
• Failure to ensure that when changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate, as required by 21 CFR 820.75.
• Failure to adequately establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198.

The inspection also revealed that the Company Single-Use Distal Cover (MAJ-2315) devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that the company failed or refused to furnish material or information respecting the device that is required by or under Medical Device Reporting. Significant violations include, but are not limited to, the following:

1. Failure to adequately develop, maintain, and implement written Medical Device Reporting procedures as required by 21 CFR 803.17
2.  Failure to submit a report to FDA no later than 30 calendar days after the day that your firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that your firm markets has malfunctioned and this device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur, as required by 21 CFR 803.50.

Pharmedica USA LLC, Warning Letter, 28 April 2023

An FDA inspection of the Pharmedica USA, LLC drug manufacturing facility in Phoenix, Arizona was conducted from 01 to 07 November 2022. The FDA determined that drug products manufactured at this facility are adulterated under section 50 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351 in that they have been prepared, packed, or held under insanitary conditions. The warning letter provided as a outcome of the inspection summarized significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. Methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, such that the company’s drug products are adulterated within the meaning of section 501 of the FD&C Act, 21 U.S.C. 351. Observed Specific violations include but are not limited to the following:

• The firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. The firm also failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.113 & 211.42).
• The firm failed to establish adequate written procedures for production and process control designed to assure that the drug products they manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100).
• The firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release, and conduct for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms. (21 CFR 211.165 and 21 CFR 211.165).
• The firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. The firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84 and 211.84).
• The quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

On 02 February 2023, FDA held a teleconference with the firm. FDA recommended that the firm consider removing any batches of Purely Soothing 15% MSM Drops and Purely Soothing MSM Nasal Spray drug products currently in distribution from the United States market. On 14 February 2023, the firm communicated their commitment to cease the manufacturing and distribution of all drug products with no intention of producing drug products in the future and agreed to voluntary recall all drug products manufactured with active ingredient MSM. On 03 March 2023, the rim issued a voluntary worldwide recall of Purely Soothing, 15% MSM Drops (i.e., ophthalmic) due to non-sterility. The company announcement was posted to the FDA website.  The FDA acknowledged the firm’s commitment to cease production of all drugs at this facility.

United States Pharmacopeia (USP) 

USP: New General Chapter Supplier Qualification <1083>, 15 March 2023

The new USP Chapter <1083> Supplier Qualification will officially come into force on 01 August 2023. The final version of the new chapter now focuses on the three types of suppliers for:

• Materials (e.g., active pharmaceutical ingredients, excipients, and other components and materials)
• Packaging materials, e.g., primary, secondary, and tertiary packaging
• Service providers, e.g., contract manufacturers, packers, repackagers, transportation and storage services, calibration and qualification services, analytical services, and software services

The chapter, now final is divided into the following paragraphs and subsections:

• Introduction
• Scope
• Supplier Qualification Life Cycle: Steps for a Supplier Qualification
• Preparation
• Identification and Selection of Supplier for Materials and Services
• Evaluation and Acceptance
• Performance Monitoring
• Supplier Disqualification
• Conditional Approval of an Existing Supplier
• Glossary