SQA Regulatory Surveillance Summary for May and June 2024
SQA Regulatory Surveillance Summary for May and June 2024
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
In the Official Gazette of the Union, ANVISA has published the Normative Instruction (IN) 292/2024, which establishes the optimized procedure for the purpose of analyzing the certification of Good Manufacturing Practices (GMP) and the criteria for defining the Equivalent Foreign Regulatory Authorities (EFRA) for the inspection process of medicines, biological products, cannabis products for medicinal purposes, and Active Pharmaceutical Ingredients (APIs). According to this regulation, authorities that are members of the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the International Council for the Harmonization of Technical Requirements for Medicines for Human Use (ICH) will be considered EFRA. Currently, 42 authorities meet the EFRA requirement for inspection purposes and are listed in Annex I of this regulation.
This optimized analysis procedure aims to speed up the analysis of the petitions for certification requests filed with the Agency without renouncing the technical rigor necessary to conclude by meeting GMP requirements. Three levels of regulatory confidence are defined in the regulation that are based on documents from the PIC/S reliance working group:
- Level 1: When a complete analysis of the inspection report or equivalent document of EFRA is performed to evaluate the service to GMP requirements and can be adopted unilaterally by ANVISA.
- Level 2: When a simplified analysis of the EFRA inspection report is performed to evaluate compliance with the GMP requirements and may be adopted unilaterally by ANVISA.
- Level 3: Mutual recognition, when, from a regulatory trust program and signing of a mutual bilateral agreement, ANVISA and EFRA will accept the inspection report or GMP certificate of the counterparty.
The regulation comes into force on 01 June 2024. Companies interested in adopting the optimized analysis procedure may, through a specific subject code, use this analysis route.
Death of Skin Peeling Patient Raises Concerns About Aesthetic Procedures in Brazil, 18 June 2024
Phenol peeling is a procedure recommended for treating severe facial aging. When performed correctly and according to guidelines, it yields results in collagen production and a significant reduction in wrinkles and spots, as it completely rejuvenates the skin. However, since it is an invasive procedure involving a toxic substance, complications may occur, such as intense pain, changes in skin color, and even unpredictable cardiac issues, regardless of the phenol concentration, application method, and depth reached in the skin. On 03 June 2024, a patient died after undergoing a phenol peeling at an aesthetic clinic in São Paulo. The patient fell ill a few minutes after the peeling procedure and was reported to have shortness of breath and tremors. The clinic called an ambulance, but when the medical team arrived, they confirmed he was dead.
In the Official Gazette of the Union, ANVISA has published a resolution that prohibits the import, manufacture, manipulation, marketing, advertising, and use of phenol-based products in general health or aesthetic procedures. Products duly regulated by ANVISA under the exact conditions of registration and products for use in analytical or clinical analysis laboratories remain authorized. There is no phenol-based product regulated by ANVISA with the indication for peeling procedures. This precautionary measure adopted by the agency aims to ensure the health and physical integrity of the Brazilian population since, to date, no studies have been presented to ANVISA that prove the effectiveness and safety of the phenol product for use in such procedures. The resolution will be in force while investigations are conducted on the potential damage associated with the use of phenol, which has been used in several invasive procedures. ANVISA reinforces that the precautionary measure was motivated by concerns about the negative impacts to health and reflects the agency’s commitment to protecting the health of the Brazilian population.
China: National Medical Products Administration (NMPA)
China Consults on Guidelines for Switching Prescription Drugs to OTC Status, 23 May 2024
On 20 May 2024, the NMPA released the draft guidelines on the Scope of Applications for switching prescription drugs to Over the Counter (OTC) drugs for public consultation. The draft guidelines outline the key criteria and exclusions for such drug switching. According to the draft, Marketing Authorization Holders (MAHs) or the agents designated by MAHs of imported drugs can apply for switching prescription drugs to OTC if the drugs meet specified criteria. Excluded drugs include drugs used for emergency treatment, injections and implants, drugs requiring special storage conditions, Active Pharmaceutical Ingredients (APIs), pharmaceutical excipients, and decoction pieces.
NPMA Issues Draft Guidelines for Inspection of Medical Device Clinical Trial Sites, 14 June 2024
China NMPA has released a new guideline that aims to enhance the management of clinical trial institutions for medical devices, ensuring compliance with regulatory standards and safeguarding public health. The guideline is designed for use by regulatory drug authorities when organizing supervision and inspections of medical device clinical trial institutions. It provides a structured approach to assess the qualifications, management, and operational practices of these institutions, ensuring adherence to relevant laws and regulations, such as the regulations on the registration and filing of medical devices and the Good Clinical Practices (GCP) for medical devices. The document outlines 16 inspection areas, covering 96 specific items. These areas are divided into two main sections: institutional qualifications and clinical trial professional standards. Each item is categorized as critical (total of 8), major (total of 43), or general (total of 45), depending on the impact to the trial’s quality and safety. Deficiencies identified during inspections are classified into three levels: serious, major, and general. The classification criteria include:
- Serious deficiencies: Typically linked to non-compliance with critical items.
- Major deficiencies: Associated with major items.
- General deficiencies: Related to general items.
Institutions must meet all requirements to pass inspections, with the final assessment based on the severity and impact of any deficiencies found.
European Commission
Updated European Commission Data Dashboard, 07 June 2024
Earlier this year, the European Commission (EC) rolled out a new data dashboard in an effort to provide more transparency in terms of medical device availability across European Union (EU) member states. The EC engaged Gesundheit Österreich GmbH (Austrian National Public Health Institute), Civic Consulting, and Areté to collect data on the availability of medical devices in the EU and the progression of transitions to the Regulation (EU) 2017/745 on Medical Devices (MDR) and Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR). The study began in December 2022 and is expected to run for three years until the end of 2025. The dashboard was updated on 07 June 2024 with data collected during the January and March 2024 surveys. Key points with respect to the updated dashboard include the following:
- An upward trend is visible when looking at the percentage of issued MDR Quality Management System (QMS) certificates and product certificates compared to the previously published percentages.
- The number of IVDR applications, IVDR QMS, and product certificates is also increasing, although not as quickly.
Other interesting data that can be found on the updated dashboard include the reasons for refusal of MDR and IVDR applications by Notified Bodies (NBs). Still, most refusals of MDR applications are caused by manufacturers applying at an NB that does not have the devices in question in its scope. IVDR application refusals are mainly caused by reasons such as non-resolved non-conformities, withdrawal of the application by the client, or negative outcomes of the preliminary assessment.
European Medicines Agency (EMA)
Medical Devices: Guidance for Industry and Notified Bodies, 03 May 2024
A new revision of the following guidance has been published: Questions and Answers for Applicants, Marketing Authorization Holders of Medicinal Products and Notified Bodies with Respect to the Implementation of the Regulations on Medical Devices and In Vitro Diagnostic Medical Devices (Regulations (EU) 2017/745 and (EU) 2017/746). This question-and-answer document provides practical considerations on the implementation of the medical devices and in vitro diagnostic regulations for combinations of medicinal products and medical devices. Products that combine a medicinal product (or substance) and a medical device are regulated either under the pharmaceutical framework or the medical device framework, depending on their main mode of action. This new revision is based on the experience gained since the implementation of the new regulations and actual cases encountered. The document covers regulatory and procedural guidance for:
- Integral drug-device combinations (medical devices that form an integral product with a medicine, such as pre-filled syringes) and their lifecycle management.
- Medicinal products that include a medical device in their packaging (referred to as co-packaged) and how these should be labelled.
- The consultation procedure for medical devices with an ancillary medicinal substance (a substance that supports the proper functioning of the device).
- The consultation procedure for companion diagnostics (diagnostic tests that are essential for the correct use of a specific medicine).
Faster Access to Clinical Trial Information in Europe, 18 June 2024
The launch of a new version of the Clinical Trials Information System (CTIS) will allow earlier and more efficient access to information about clinical trials in the EU for patients, healthcare professionals, and other stakeholders. This is due to the revised transparency rules. One of the key changes is earlier availability of information on authorized clinical trials. Importantly, the new rules eliminate the previously available deferral mechanism, which allowed clinical trial sponsors to delay publishing certain data and documents for up to seven years after a trial’s completion to protect commercially confidential information. Under the new rules, approximately 4,000 clinical trials with issued decisions are now publicly accessible through the CTIS search. The CTIS portal will add approximately 500 newly authorized clinical trials per month. This includes ongoing trials that have been transitioned to CTIS from the Clinical Trials Directive. Over the next few months, additional features will be added to the CTIS public portal to further enhance overall usability.
The updated rules strike a balance between transparency of information and protection of commercially confidential information. The updated rules also provide the following benefits:
- They benefit patients because key clinical trial information, which patients flagged as being most relevant for them, is published early.
- They benefit clinical trial sponsors because they introduce process simplifications.
- Finally, they benefit healthcare professionals because the resulting system is more user-friendly, facilitating access to information on clinical trials and enrollment in clinical trials, as well as increasing awareness of possible treatment options.
European Directorate for the Quality of Medicines and HealthCare (EDQM)
Draft Guideline for the Content of the Dossier for Sterile Substances, May 2024
The fourth draft of the guidelines for the Content of the Dossier for Sterile Substances was published for comments by the EDQM in May 2024. Remarks and comments could be submitted until 15 August 2024. The guideline provides guidance for the content on the following sections of the Dossier for Sterile Substances:
- Justification for method of sterilizing manufacturing areas
- Manufacturing areas
- Summary of manufacturing process related to sterile filtration/aseptic processing
- Information on filters used
- Validation of filters used
- Sterilization of filters and processing equipment
- Pre-filtration bioburden
- Re-use of filters
- Aseptic processing
- Process simulation/validation
- Sterilization of packaging
- Re-test period
Health Canada
Health Canada is proposing an amendment to the Food and Drug Regulations and the Medical Devices Regulations to:
- Help prevent shortages of drugs and medical devices for human use
- Reduce the impact of shortages that can’t be prevented
The regulatory amendments Health Canada is proposing, in addition to other actions the agency plans to take over the next four years, will help improve collective capacity in three areas:
- Planning
- Designing systems and Standard Operating Procedures (SOPs) that promote readiness and rapid response to shortages
- Prevention
- Detecting risks of shortages
- Intervening to avoid shortages before they happen
- Response
- Detecting shortage signals early
- Minimizing the impacts of shortages when they occur
- Quickly restoring access to needed products
Additional details are provided in Building Resilience: Health Canda’s Plan to Address Health Product Shortages, 2024 to 2028. The deadline to submit feedback for this plan is 25 July 2024.
Teva Canada Ltd. is recalling one lot of ratio-ECTOSONE (TEVA-ECTOSONE) 0.05% mild lotion in 60 mL bottles. This action follows testing that detected an impurity (betamethasone enol aldehyde) above the accepted limit in the affected lot. This impurity can form due to a chemical change in the drug during storage that may pose health risks, including the possibility of adverse reactions on the skin or elsewhere in the body after being absorbed into the bloodstream. The risk may be greater in children, who may absorb proportionally larger amounts of the impurity and may be more susceptible to adverse reactions. The product is a prescription corticosteroid lotion used to relieve skin inflammation and itch caused by skin conditions such as eczema, psoriasis, and dermatitis. The affected lot was distributed to pharmacies in Canada between 24 November 2022 and 22 March 2023. Health Canada is monitoring the company’s recall and its implementation of any necessary Corrective and Preventative Actions to prevent this issue from reoccurring.
Health Canada is warning consumers not to buy unauthorized injectable drugs from Quadragen and Advanced Research websites because they may pose serious health risks. Unauthorized injectable drugs carry significant health risks due to the potential for infection, allergic reactions, and other poor outcomes. The two websites are associated with Quad Inc., a company located in Beloeil, Quebec. Health Canada seized injectable peptides, along with unauthorized bodybuilding drugs, from Quad Inc. At Health Canada’s request, the company has stopped advertising and selling unauthorized health products, and has taken down its Quadragen and Advanced Research websites.
Peptides perform a range of important functions in the body. Injectable peptide drugs are often marketed for bodybuilding, anti-aging, and enhancing athletic performance. Some peptides can be produced for use in medications. Most synthetic injectable peptides are regulated as prescription drugs in Canada and require a prescription from a licensed healthcare professional. Prescription drugs should only be used under the advice and supervision of a healthcare professional because they are used to treat specific conditions and may cause serious side effects.
OriginElle Fertility Clinic and Women’s Health Centre, which are located in Quebec, Quebec, received a non-compliant rating from a donor sperm and ova inspection that started on 21 May 2024. Key findings included the following observations:
- The primary establishment did not ensure that sperm or ova were processed in accordance with the regulations prior to distributing or making use of them.
- The establishment did not notify Health Canada before distributing or importing sperm or ova.
- The establishment did not always perform a physical exam on the directed donors in accordance with the directive.
- The establishment did not use appropriate and effective tests for infectious disease testing set out in the directive.
- The establishment’s document control/record management system was not sufficient.
Additional findings included concerns with respect to gaps in the establishment application for registration, required notifications to Health Canada, failure to perform required testing on directed donors, risk assessment, and insufficient Standard Operating Procedures (SOPs).
India
The Guidance for Industry on Submission of Clinical Trial Application for Evaluating Safety and Efficacy (Biologicals) provides the requirements for a clinical trial sponsor for submitting an application (Form CT-04) for the purpose of conducting a clinical trial in India and submitting documents in accordance with the New Drugs and Clinical Trials Rules for 2019. The sponsor is also responsible for implementing a Quality Assurance system to ensure that the clinical trial is conducted and data generated, documented, and reported in compliance with the protocol and Good Clinical Practice (GCP) guidelines issued by the CDSCO Directorate General of Health Services Government of India. Additional details are also provided with respect to requirements for sponsors.
The Guidance of Industry on Post Approval Changes in Biological Products: Quality Safety and Efficacy Documents is intended to provide guidance to manufacturers on regulating changes to already licensed biological products in order to ensure their continued quality, safety, efficacy, and continuity in supply and access. Requirements are provided for:
- Reporting categories for quality changes
- Documentation – quality changes
- Reporting categories for safety, efficacy changes
- Special considerations
- Post approval changes
- Post approval change management protocol
- Efficacy post approval changes
- Administration changes
- Product labelling information changes
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance – Quality, Efficacy, Multidisciplinary, and Safety
The ICH M12 Guidelines Reach Step 4 of the ICH Process, 24 May 2024
The ICH M12 guidelines on Drug Interaction Studies and the related questions-and-answers document reached Step 4 of the ICH process on 21 May 2024. The guidelines provide recommendations to promote a consistent approach to designing, conducting, and interpreting enzyme- or transporter-mediated in vitro and clinical Drug-Drug Interaction (DDI) studies during the development of a therapeutic product. The supporting questions-and-answers document is intended to provide additional clarification and improve harmonization of drug interaction assessments. A Step 4 Introductory Training presentation has been developed by the M12 Expert Working Group (EWG) to summarize the content of the guidelines.
Draft ICH M14 Guidelines on Real-World Data for Safety Assessment, 20 June 2024
The ICH M14 Harmonized Guidelines, General Principles on Plan, Design and Analysis of Pharmacoepidemiological Studies that Utilize Real-World Data (RWD) for Safety Assessment of Medicines was published on 21 May 2024 for public consultation. The guidelines focus on non-interventional pharmacoepidemiological studies using RWD and include basic principles that may apply to these studies when RWD elements are included. In addition, the document provides internationally harmonized guidance and outlines recommendations and high-level best practices for the conduct and analysis of non-interventional pharmacoepidemiological studies using fit-for-purpose data for the assessment of the safety of medicines (i.e., drugs, vaccines, and other biological products).
International Pharmaceutical Excipients Council (IPEC)
Eighty participants from 27 countries across Africa, Asia, South-East Asia, Europe, and America joined the hybrid workshop known as the Dashboard Development and Diethylene Glycol/Ethylene Glycol (DEG/EG) Screening Technologies at Jesus College in Oxford from 09 to 12 April 2024. Participants were from regulatory medicine agencies in low-, middle-, and high-income countries; experts on and developers of screening technologies and other key stakeholders, including the World Health Organization (WHO), Interpol, UNICEF, and the United States Pharmacopeia (USP). The group looked at the current evidence around screening technologies; defined the knowledge gaps and how information could be better shared with regulatory medicine authorities and other organizations to inform decisions on buying detection equipment. During the workshop, interactive sessions, demonstrations, and displays took place. These included:
- Developing a freely available digital guide on screening technologies to help with decision making
- Medicines Quality Research Groups (MQRGs) work with chemists and physicists to detect DEG/EG in pharmaceuticals
- Using screening technologies
- Developing a target product profile to enable development of specific devices to detect DEG/EG
- A roadmap for collaborative research
International Organization for Standardization (ISO)
ISO Circular Economy Standards, May 2024
The ISO 59000 family of standards is specifically designed to foster a shift towards a circular economy. The following standards were published in May 2024 in support of a circular economy: ISO 59004:2024, ISO 59010:2024, and ISO 59020:2024. The linear model of the global economy, which is characterized by extraction, production, use, and disposal, has led to significant environmental challenges, including resource depletion, climate change, and biodiversity loss. ISO 59004:2024 addresses these issues by advocating for a circular economy model, which emphasizes the sustainable management and renewal of natural resources. By adopting this standard, organizations can:
- Deliver more sustainable and ambitious solutions.
- Improve relationships with stakeholders.
- Engage in more effective and efficient fulfillment of voluntary and legal obligations.
- Contribute to climate change mitigation and adaptation.
- Increase resilience against resource scarcity and other environmental, social, and economic risks.
ISO 59010:2024 provides guidance for organizations wishing to transition their value creation models and networks from a linear to a circular framework. This standard focuses on business-oriented strategies to implement circular economy practices at both organizational and interorganizational levels. It complements ISO 59004 by offering more detailed guidance on assessing current value creation models, mapping value chains and value networks, and developing strategies for circularity. ISO 59010 is designed to help organizations make this transition effectively, contributing to sustainable business practices and a resilient economy.
ISO 59020:2024 sets the requirements and guidance for organizations to measure and assess their circularity performance within defined economic systems. This document aims to standardize the process by which organizations collect and calculate data using mandatory and optional circularity indicators, ensuring consistent and verifiable results. It provides a structural framework for setting system boundaries, selecting appropriate indicators, and interpreting data to evaluate the circularity performance at multiple levels from regional and interorganizational to organizational and product-specific levels.
International Society for Pharmaceutical Engineering (ISPE)
The ISPE Good Practice Guide: Unique Identification of Glass Primary Containers in Pharmaceutical Fill and Finish Operations describes processes for applying a Unique Identifier (UID) on each primary parenteral container. The guide outlines best practices for developing, implementing, and managing a traceability project across one or more processes. The unique identification of single glass containers described in this guide represents a technological advancement that can support the robustness of pharmaceutical manufacturing processes. It encompasses all types of primary glass containers made from tubular glass or molded glass for the containment of pharmaceutical liquids or lyophilized products. Covered topics include:
- UID methods/technologies for different container types
- The UID structure
- Performance requirements for glass containers
- Barcode readability and verification
- Radio-Frequency Identification (RFID) technologies
- Reading different formats
- Automated inspection processes
- Traceability in processes
This guide also discusses how to manage the container UID without affecting package serialization required by the European Union (EU) and the United States Food and Drug Administration (FDA).
Medicines and Healthcare Products Regulatory Agency (MHRA)
In April 2024, the MHRA set out its strategic approach to AI in response to a white paper that was published in 2023. This pilot project is a key part of that approach. It will help the Agency to identify and address the challenges for regulating standalone AI medical devices (AIaMD), initially seeking out and supporting four to six virtual or real-world projects through simulation. This will allow the MHRA to test a range of regulatory issues for these devices when they are used for direct clinical purposes within the National Health Service (NHS). The regulatory sandbox model is a recognized mechanism to help address novel regulatory challenges across sectors. The AI Airlock is a world-leading version in healthcare, designed to assist in the safe development and deployment of AIaMDs, and this project will follow that robust process so manufacturers can deliver what is required to ensure the real-world viability of these devices.
The MHRA’s regulatory AI Airlock takes into account evidence-based work produced by other bodies with a similar focus. The MHRA will work collaboratively with the NHS AI Lab and the Department of Health and Social Care (DHSC). AIaMD products are deployed via NHS infrastructure, making the Devolved Nations crucial to regulatory discussions around deployment and post-market surveillance. The findings from this partnership between government, regulators, and industry will inform future AI Airlock projects and influence future UK and international AIaMD guidance, including how we work with UK approved bodies on UK Conformity Assessed (UKCA) marking and with trusted regulatory partners on international recognition of medical devices.
MHRA Announces a Proposed Framework for International Recognition of Medical Devices, 21 May 2024
The Medicines and Healthcare products Regulatory Agency (MHRA) has published a statement of policy intent for international recognition of medical devices. The MHRA’s statement of policy intent describes how the UK government intends to recognize regulatory approvals from Australia, Canada, the European Union, and the United States of America depending on device type, class, and prior approval. The MHRA continues to review the list of comparable regulator countries and is in active discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) to explore the recognition of medical device approvals from Japan. The MHRA’s statement of policy intent focuses on ensuring safe access to quality-assured medical devices and reducing the duplication of assessments by comparable regulators to enable resources to be focused on more innovative products for the benefit of patient health. This statement will also allow manufacturers to start considering whether their devices will be eligible for the proposed alternative routes to market. The proposed framework is still in draft, and the final version would be integral with the future core regulations.
Desitin Pharma UK Ltd is recalling all batches of Lamotrigine Desitin 10mg/ml Oral Suspension as a precautionary measure due to an out of specification observation in the appearance of samples during routine stability testing. Desitin Pharma UK Ltd believe that this is a homogeneity issue with the batches manufactured. This issue means that there is the potential for some doses to have too little active ingredient (lamotrigine) in them while some doses contain too much active ingredient. This could result in potential underdosing or overdosing. No such confirmed reports have been received to date. The root cause of this issue is under investigation, but based on the potential for a homogeneity issue, the product is being recalled as a precautionary measure.
Parenteral Drug Association (PDA) – Technical Reports
PDA Technical Report No. 68: Risk-Based Approach for Prevention and Management of Drug Shortages was originally developed in 2014. The approach to risk-based prevention of drug shortages presented in this revision remains unchanged. This revision focuses on updating references and progress related to the current regulatory environment, regional regulations and guidelines, and terminologies used for drug shortages that have since been published. Elements in the templates and forms included in this revision have been updated to reflect current regulatory expectations and terminology. Drug shortages have become more frequent, more severe, and longer-lasting globally since the early 2000s for a variety of reasons. Sustainable access to safe, efficacious, and high-quality products every time a patient needs them is just as important as the therapeutic advances that have transformed the lives and survival of patients worldwide.
Therapeutic Goods Administration (TGA)
The PIC/S Guide to GMP PE009-16 is for Australian sponsors and manufacturers of medicines, Active Pharmaceutical Ingredients (APIs), and sunscreens made or supplied in Australia. It provides a summary of the changes in GMP requirements resulting from the recent replacement of the PIC/S Guide to GMP for Medicinal Products (PE 009-15, 01 May 2021) with PE 009-16, 01 February 2022. The most significant change resulting from the adoption of the more recent version of the PIC/S Guide is the inclusion of the new Annex 16.
As of 03 June 2024, the PIC/S Guide to GMP version 16 applies to the manufacture of medicines, APIs, and sunscreens, unless exempt under provisions in the Therapeutic Goods Act 1989 (the Act). There is a three-month transition period for adoption of the new Annex 16 to allow manufacturers to review and make necessary operational changes. All other changes are minor (i.e., clarifications in Annex 13) and are in force from 03 June 2024.
Medical Device Regulation Change for Software-Based Medical Devices, 26 June 2024
In February 2021, the TGA provided transitional arrangements for software-based medical devices transitioning to a higher risk classification. The transitional arrangements will end on 01 November 2024. On 15 June 2024, the TGA amended the requirements to also allow sponsors who had notified TGA they were transitioning their device to a higher classification and had applied for a TGA conformity assessment certificate before 01 November 2024, six months following issue of the conformity assessment certificate to submit their application to include their device in the Australian Register of Therapeutic Goods (ARTG). This means that sponsors of devices transitioning to higher classifications can continue to supply their software-based medical devices if they have submitted by 01 November 2024:
- An application for ARTG inclusion or
- An application for TGA conformity assessment.
Sponsors can then continue to supply their software-based medical devices past 01 November 2024 until their application is decided. This only applies to sponsors who notified TGA before 25 May 2022.
United States Food and Drug Administration (FDA) – Regulations and Guidelines
The FDA plays a critical role in protecting the United States from threats such as emerging infectious diseases, exposure to harmful chemicals, and public health emergencies. The FDA is issuing this draft guidance to describe the Agency’s enforcement policy for certain laboratory manufacturers offering certain unauthorized in vitro diagnostic devices for immediate response to chemical, biological, radiological, or nuclear agents in the absence of a declaration applicable to IVDs under section 564 of the Federal Food, Drug, and Cosmetic Act. This policy set forth in the draft guidance is intended to help ensure the government’s coordinated and effective public health response during an emergent situation.
Medical devices encompass a vast array of products with different technologies, product lifecycles, complexity, intended users, and environments of use. Many devices are reusable and need preventive maintenance and repair during their useful life. For these devices, proper servicing is critical to their continued safe and effective use. However, there is a lack of clarity regarding the distinction between “servicing” and “remanufacturing” of a device. Most notably, “remanufacturing” has implications for the regulatory responsibilities of entities performing these activities. The final guidance is intended to help clarify whether activities performed on devices are likely “remanufacturing.” This final guidance also clarifies existing regulatory requirements for remanufacturers and includes recommendations for information that should be included in labeling to help ensure the continued quality, safety, and effectiveness of devices that are intended to be serviced over their useful life.
The FDA is announcing the availability of draft guidelines for industry entitled Processes and Practices Applicable to Bioresearch Monitoring Inspections. The draft guidance is being issued to comply with the Food and Drug Omnibus Reform Act of 2022, which directs the Agency to issue guidance describing the processes and practices applicable to inspections of sites and facilities inspected under the FDA’s Bioresearch Monitoring inspection program to the extent not specified in existing publicly available FDA guides and manuals. The draft guidelines are intended to cover the following: the types of records and information required to be provided, best practices for communication between the FDA and industry in advance of or during an inspection or request for records or other information, and other inspections-related conduct.
Facility Readiness: Goal Date Decisions Under Generic Drug User Fee Amendments (GDUFA), 18 June 2024
The guidance provides information to applicants on how the FDA intends to assign a goal date based on a facility’s readiness for inspection as certified on Form FDA 356h, submitted as part of an original abbreviated New Drug Application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act. This guidance explains how the FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to reauthorization of the Generic Drug User Fee Amendments (GDUFA), as described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027” (GDUFA III commitment letter).
CVM GFI #278 Human User Safety in New and Abbreviated New Animal Drug Applications, 18 June 2024
Human User Safety (HUS) is an integral component of the overall safety evaluation of proposed new animal drugs. The FD&C Act does not provide specific guidance on data requirements or assessment methods to identify the risks or the risk mitigation measures for human users of new animal drugs. The guidance clarifies the current approaches and recommendations for HUS assessment and submission of HUS information to support the overall safety of proposed new animal drugs prior to approval.
United States Food and Drug Administration (FDA) – Recalls
MEGADYNE™ is initiating a voluntary recall of all MEGADYNE™ MEGA SOFT™ Pediatric Patient Return Electrodes. The product is being removed because MEGADYNE™ has received reports of patient burn injuries in procedures where the Mega Soft Patient Return Electrodes were used. A root cause investigation in the reports included testing that showed that when a combination of factors were present together, the potential for thermal injuries was a potential result. The combination of these conditions may be more likely when the pad is used with infants and small children. Because the pediatric pad is designed for patients between 0.8 to 50 pounds, which would predominantly be patients under the age of 12, the decision was made to discontinue and recall the 0840 pediatric pad product. Between 2018 and 10 May 2024, there have been four reported injuries and no reports of death associated with this product. The company has decided to discontinue and voluntarily recall the MEGADYNE™ MEGA SOFT™ Pediatric Patient Return Electrode. The FDA has been notified of this action. MEGADYNE™ is notifying global customers and distributors by mail and is arranging for return of impacted product. Product was distributed in the United States and international markets.
Hospira, Inc., a Pfizer company (Pfizer), is voluntarily recalling two lots of Buprenorphine Hydrochloride Injection CarpujectTM units and three lots of Labetalol Hydrochloride Injection, USP CarpujectTM units to the user level. The recall was initiated due to the potential for incomplete crimp seals; one customer complaint has been received for one leaking unit. In the event that the impacted lots are administered to a patient, there is a potential for an increased risk of lack of therapeutic effect and systemic infection that may result in the need for additional medical treatment. To date, Pfizer has not received reports of any relevant adverse events associated with this issue for these lots. Wholesalers and hospitals with an existing inventory of any of the lots being recalled should discontinue use, stop distribution, and quarantine the product immediately. If you have further distributed the recalled product, please notify your accounts and/or any additional locations which may have received the recalled product.
Glenmark Pharmaceuticals Inc., USA, Mahwah, NJ is voluntarily recalling 114 batches of Potassium Chloride Extended-Release Capsules, USP (750 mg) 10 mEq K, to the consumer level. The product is being recalled because of failed dissolution. The failed dissolution of potassium chloride extended-release capsules may cause high potassium levels, also known as hyperkalemia, which can result in irregular heartbeat that can lead to cardiac arrest. For patients who require chronic use of potassium chloride extended-release oral capsules, especially patients with underlying comorbidities or conditions that cause altered excretory mechanisms for potassium such as hypertension, heart failure, or renal dysfunction, there is a reasonable probability of developing hyperkalemia that may lead to a range of severity of adverse events from being asymptomatic to more severe potential life threatening adverse events of hyperkalemia such as cardiac arrythmias, severe muscle weakness, and death. To date, the firm has not received any reports of hyperkalemia or serious adverse events from spontaneous sources related to this recall.
Glenmark is notifying its wholesale and distributor customers by written letters and is arranging for the return of all recalled batches. Wholesalers, distributors, and retailers that have the recalled products should immediately discontinue distribution of the recalled product lots and follow the instructions provided in the written recall letter. Wholesalers and distributors should conduct a sub-recall to retail or pharmacy customers. Consumers that have Potassium Chloride Extended-Release Capsules subject to the recall should consult with their physician or healthcare provider before they stop using the product. Consumers should also contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using this drug product.
United States Food and Drug Administration (FDA) – Warning Letters
Cosmetic Solutions, LLC – Warning Letter, 31 May 2024
Cosmetic Solutions, LLC received a warning letter on 31 May 2024. This warning letter was a result of the FDA’s review of the company’s response to 483 observations issued during an on-site inspection that was conducted at the Cosmetic Solutions, LLC drug manufacturing facility in Boca Raton, Florida from 12 to 21 September 2023. The FDA review of the response to the 483 observations provided concerns with respect to cGMP violations:
- Quality Unit (QU) oversight:
-
- The QU failed to follow stability testing procedures
- The QU failed to establish the reliability of the company’s component supplier’s test analysis at appropriate intervals. In addition, the QU failed to follow the written procedure for incoming sampling, inspection, and release of raw materials.
- The QU failed to follow the company’s change control procedure.
- Inadequate response regarding the stability program, supplier qualification, and change control system.
- Production and process control:
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- Lack of water system qualification and validation.
- Lack of cleaning validation.
Additional concerns were also noted with respect to unapproved new drug violations. These concerns were related to product labels and labeling, including the product websites.
Neobiosis, LLC, Warning Letter, 05 June 2024
Neobiosis, LLC received a warning letter on 05 June 2024. This warning letter was the result of the FDA’s review of the company’s response to 483 observations issued during an on-site inspection conducted at the Neobiosis, LLC drug manufacturing facility in Gainesville, Florida from 23 January to 21 February 2023. The company manufactures products derived from human amniotic fluid and umbilical cord. The firm has sold and distributed these products directly to customers, including, but not limited to, third-party distributors, medical centers, pain clinics, wellness centers, and physicians. The firm admitted to FDA investigators that the products are sold to physicians for research purposes. However, they have not distributed the products in accordance with the requirements for clinical investigations under 21 CFR part 312. The warning letter provided details with respect to unapproved drug and biological product violations and current Good Manufacturing Practice violations. It also included FDA concerns with respect to the Corrective Actions taken for the responses to the 483 observations.
Aqualex Co., Ltd., FDA Warning Letter, 12 June 2024
Aqualex Co., Ltd. received a warning letter on 12 June 2024. This warning letter was the result of the FDA’s review of the company’s response to 483 observations issued during an on-site inspection conducted at the Aqualex Co., Ltd. drug manufacturing facility in Gyeonggi-do, Korea, from 16 to 20 October 2023. Aqualex Co., Ltd. manufactures Over the Counter (OTC) sun protection factor (SPF) ultraviolet (UV) sunscreen protection drug product. The FDA review of the response to the 483 observations provided concerns with respect to the following cGMP violations:
- They failed to provide data to demonstrate that they had adequately validated the manufacturing processes used to manufacture OTC drug product and to demonstrate that the processes are reproducible and controlled to consistently yield drugs of uniform character and quality.
- The firm failed to adequately design their water system to ensure that it was suitable for producing water used in the formulation of their drug product. For example, a water system utilized for production of drug product had points of stagnant water, including one located at a point-of-use in the production area. Stagnant water can foster the development of biofilms.
- The Quality Unit (QU) failed to ensure adequate control over cGMP records. For example, the QU failed to ensure adequate controls were in place to ensure that changes to cGMP records can be made only by authorized personnel, as employees were able to freely print out and discard documents without adequate QU reconciliation. The FDA investigator also observed multiple original records (e.g., checklists associated with temperature and differential pressure monitoring) in a container marked for shredding.
- The QU does not adequately ensure the accuracy and integrity of data to support the quality of the drugs manufactured. Notably, the laboratory employees indicated that laboratory data is routinely recorded on temporary records, and discarded, after later transcribing the data onto a final laboratory record.
- The firm failed to perform adequate release testing for each batch of drug product prior to distribution. For example, the firm released multiple batches of OTC SPF sunscreen drug product to the United States market without performing growth promotion testing on the media used for finished product. Furthermore, the firm failed to perform growth promotion testing on the media used for water testing and failed to validate the test method for the determination of total microbial count in water samples.
Additional findings were related to stability testing and the use of ingredients contaminated with Diethylene Glycol (DEG) or Ethylene Glycol (EG).
World Health Organization (WHO)
WHO Issues Warning on Falsified Medicines used for Diabetes Treatment and Weight Loss, 20 June 2024
The World Health Organization (WHO) issued a medical product alert on falsified semaglutides, the type of medicines that are used for treatment of Type 2 diabetes and obesity in some countries.
The alert addresses three falsified batches of product of semaglutide class of medicines (of specific brand Ozempic), which were detected in Brazil in October 2023, the United Kingdom of Great Britain and Northern Ireland in October 2023, and the United States of America in December 2023. WHO Global Surveillance and Monitoring System (GSMS) has been observing increased reports of falsified semaglutide products in all geographical regions since 2022. This is the first official notice issued by WHO after confirmation of some of the reports.
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