SQA Regulatory Surveillance Summary | Monthly Update 2024
SQA Regulatory Surveillance Summary for Quarter 4, 2023
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
ANVISA and the Federal Revenue Service carried out a joint operation in Foz do Iguaçu (Paraná) to combat the illegal import of products subject to health surveillance (medicines, cigarettes, cosmetics, and medical equipment, among others). The action was held from 26 to 28 September 2023, at the city’s international entry points. Agents inspected the luggage of travelers who crossed the land borders between Brazil and Paraguay (International Friendship Bridge) and Brazil and Argentina (Tancredo Neves Bridge). During the operation, food supplements, cannabidiol in various presentations, testosterone, perfumes, and sibutramine tablets were identified, including about 6,000 units of electronic cigarettes and 35,500 packs of cigarettes. The products found, subject to retention and seizure, were retained by the Federal Revenue Service. Importers of these products are given a period of 45 days to make the regularization. After this period, the product is characterized as an “abandoned commodity.”
If the product is prohibited in Brazil, a notice of infraction is drawn up for smuggling of goods (Article 334 A, item II, of the Criminal Code), which is then sent to the Public Prosecutor’s Office for criminal investigation.
ANVISA Publishes New Measures to Prohibit Cosmetic Products Used in Injectable Form, 10 October 2023
ANVISA published two resolutions that suspended the trade, distribution, manufacture, advertising, and use of products from PHD Cosméticos Ltda. and Biometik Indústria e Comércio de Cosméticos. The 2023 resolutions, RE nº 3,770 and nº 3,771, cover several of these companies’ products. The products had been improperly regularized in ANVISA as cosmetics since they are indicated for injectable use, a form that is not authorized for this category of product. After receiving complaints, ANVSA performed joint inspections with local health surveillance agencies. The reported irregularities and the manufacturing conditions of the products, that is, compliance with Good Manufacturing Practices, were verified on the spot. The Agency has worked to combat the irregular practice of using cosmetics as injectables since last year, when the first serious adverse events involving this type of product occurred. Since then, ANVISA has also been alerting professionals and the general population about the dangers of this practice. Several related actions have been taken, such as the publication of the following alerts:
- ANVISA prohibits cosmetics used irregularly as injectables
- ANVISA warns consumers and professionals about aesthetic products used in injectable form
- ANVISA intensifies inspection in manipulation pharmacies
ANVISA has received information about serious adverse events related to injectable products for aesthetic purposes, improperly regularized as “cosmetic products.” The Agency became aware of these adverse events through local health surveillance agencies, which identified health risks associated with the use of these products in invasive aesthetic procedures. Following the complaints, ANVISA found that some notified products listed several characteristics on the packaging and labeling that, combined, could mislead the professional or final consumer as to the correct destination of the product. As an example, some products are labeled “sterile product,” with packaging that allows for the immediate fixation of needles. As a response to information about serious adverse events related to injectable products for aesthetic purposes, improperly regularized as “cosmetic products.” ANVISA published Technical Note 33/2023, which provides companies with guidance on the regularization of cosmetics. The purpose of the note is to clarify that products for invasive aesthetic treatments cannot be regularized in the category of cosmetics.
China: National Medical Products Administration (NMPA)
China Requires ANDAs Without Reference Drugs to Demonstrate Clinical Value, 17 October 2023
On 13 October 2023, the NMPA announced regulations on generic drug registration / Abbreviated New Drug Application (ANDA) with no Reference Listed Drugs (RLDs). On the same day, the Center for Drug Evaluation (CDE) implemented supportive regulations on technical dossiers and communication applications regarding such ANDAs. According to the announcement, an ANDA without an RLD means that the applicant plans to copy a drug that is not in the RLD Catalog. For such a generic candidate, NMPA requires the applicant to fulfill the following requirements:
- Conducting chemistry, manufacturing, and controls (CMC) studies to prove the proposed generic drug’s equivalence to marketed drugs with the same active pharmaceutical ingredient (API).
- Assessing and demonstrating the proposed drug’s clinical value.
- Submitting a communication application for having a Type-III meeting with CDE.
Generic drug applicants should submit a Type-III meeting application to communicate with CDE, in accordance with the Provisions for Communication About Drug Research and Development and Technical Review. The applicants should also meet with CDE to undergo product-by-product analyses for the generics exempted from clinical trials.
On 23 October 2023, the NMPA issued the Notice on Enhancing the Supervision and Management of Outsourced Manufacturing for Drug Marketing Authorization Holders (MAHs) (referred to as the Notice), which took immediate effect. While the official Notice highly resembles the draft Notice on Enhancing the Supervision of Drug Marketing Authorization Holders, which Outsources Manufacture issued earlier this in May 2023, its focus is primarily on regulating outsourced manufacturing activities rather than the MAHs themselves. The Notice came out in response to the growing trend for Research and Development institutions and Contract Sales Organizations (CSOs) utilizing the MAH system to obtain drug marketing authorizations and, subsequently, outsource manufacturing activities to Contract Manufacturing Organizations (CMOs). However, some of these MAHs lack qualified personnel for quality assurance, raising doubts about their ability to effectively oversee the manufacturing activities of CMOs. To address the potential compliance issues associated with outsourced manufacturing, the NMPA enforces the Notice to strengthen the authorization process for outsourcing manufacturing and outline MAH’s quality management obligations with regard to outsourced manufacturing activities.
NMPA becomes the applicant for PIC/S 09, November 2023
In late September 2023, the NMPA submitted the formal application to the Pharmaceutical Inspection Co-operation Scheme (PIC/S). On 08 November 2023, PIC/S sent a letter to NMPA confirming the applicant status. Following this confirmation, NMPA will strengthen communication and cooperation with the PIC/S, promote itself to become a full member of PIC/S, and take the opportunity to continuously improve the country’s drug inspection system and standards, constantly enhance its drug inspection quality management system, and steadily promote the development of its inspectors’ team so as to modernize national drug regulation in China.
European Commission (EC)
New Measures to Fight Organized Crime and Drug Trafficking, 18 October 2023
In 2021 alone, 303 tons of cocaine were seized in the EU. To step up the fight against criminal networks, the Commission has implemented new measures to fight organized crime and the drug trade.
The new measures include 17 actions, such as:
- Strengthening ports against criminal infiltration via a new European Ports Alliance
- Dismantling high-risk criminal networks through financial and digital investigations and reinforced cooperation
- Preventing organized crime by exchanging best practices among various countries
- Working with international partners to address this global threat
Fighting organized crime and drug trafficking is a priority for the European Union, its Member States, and its international partners. The Commission will take more steps this and next year, including legislative measures, financial support, and creating an EU Drugs Agency by summer 2024.
The MDCG 2023-4 guidance intends to examine and clarify which specific regulatory considerations are applicable when the hardware or hardware component incorporating the data collection element (camera, electrical/optical sensors, etc.) is a medical device or an accessory to a medical device. This guidance also outlines scenarios where the hardware or hardware component incorporating a data collection element is not a medical devices or accessory to a medical device. This guidance does not intend to elaborate on aspects related to the clinical evaluation or cybersecurity for these products, as those are described in other guidelines (MDCG 2020-1 on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software; MDCG 2019-16 on Cybersecurity for medical devices).
On 24 October 2023, the EC adopted a set of actions to better prevent and mitigate critical medicine shortages in the European Union (EU) this winter, next winter, and beyond. Recent critical shortages, including shortages of certain antibiotics last winter, show that continued coordinated action is needed to address supply challenges and to make Europe’s medicine supply chains more resilient in the long run. The key goals are to prevent and mitigate critical shortages at the EU level. It puts a particular focus on the most critical medicines, for which security of supply in the EU must be ensured at all times. This EC builds on work by the European Health Union, notably the reinforced mandate of the European Medicines Agency (EMA) and the recently published pharmaceutical reform. This follows a strong call by Member States at the 2023 June European Council, confirmed in Granada in October 2023, and from the European Parliament.
European Medicines Agency (EMA)
Synapse Labs Pvt. Ltd, a Contract Research Organization (CRO) in Kharadi, India, was subject to a Good Clinical Practice (GCP) inspection in November 2020 and November 2022 by the Spanish Agency for Medicines and Medical Devices (AEMPS). At that inspection, critical findings were identified that cast serious doubts on the reliability of the analytical and clinical data generated by this CRO. The severity and extent of the findings raised serious concerns regarding the suitability of the Quality Management System (QMS) at Synapse Labs Pvt. Ltd. and the overall reliability and quality of data (both clinical and analytical) submitted to support marketing authorizations for medicinal products in the European Union (EU). Amongst others, the findings included significant deficiencies in the following areas:
- Computerized Systems and Data Management
- Pharmacokinetics anomalies (considered coherent with profile duplication)
- Unclear source documentation for clinical and bioanalytical research
- The CRO’s failure to rule out potentially intentional misrepresentation of data
The European Medicines Agency has been notified by relevant national competent authorities that pre-filled pens falsely labelled as the diabetes medicine Ozempic (semaglutide, 1 mg solution for injection) have been identified at wholesalers in the European Union (EU) and the United Kingdom (UK). The pens, with German-language labels, originated from wholesalers in Austria and Germany. The pens have batch numbers, 2D barcodes, and unique serial numbers from genuine Ozempic packs. In the EU, each medicine pack has a unique 2D barcode and serial number so that it can be tracked in an EU-wide electronic system. When the packs of the falsified Ozempic were scanned, the serial numbers were shown to be inactive, thereby alerting operators to a potential falsification. The appearance of the falsified pen differs from the appearance of the original pen. A picture of the falsified pen has been published by the German medicines agency (please note that the picture of the falsified pen is just one example and falsified pens with other features are also likely).
Health Canada
Non-Compliant Rating for Biomed Pharma, 18 September 2023
Biomed Pharma, located in Montreal, Quebec, received a non-compliant rating from a Good Pharmacovigilance Practice (GVP) inspection that started on 18 September 2023. Key findings are as follows:
- The company lacked systems and processes for handling and evaluating adverse drug reactions.
- The company’s processes for inspecting its own pharmacovigilance system were inadequate.
- Some of the contractual agreements that defined the responsibilities of all parties involved in pharmacovigilance activities did not reflect the company’s current practices.
- Annual summary reports were incomplete.
- Systems and processes were inadequate to update product safety information once a new safety issue was identified and to send the changes to Health Canada in a timely fashion.
- The company lacked procedures to perform signal detection.
- The company lacked systems and processes for handling and evaluating cases of unusual failure in efficacy of new drugs in Canada.
Additional findings focused on notification requirements for Health Canada, literature searches, staff education, training, experience, and inadequate staffing (lack of qualified substitutes in the event of an absence).
Non-Compliant Rating for OttawaHeart Institute Research Corporation, 25 September 2023
Ottawa Heart Institute Research Corporation, located in Ottawa, Ontario, received a non-compliant rating from a Good Clinical Practice (GCP) inspection that began on 25 September 2023. Key findings are as follows:
- The clinical trial was not conducted according to the protocol.
- The sponsor did not implement systems and procedures to ensure:
- The drug was properly handled.
- Adequate monitoring of the clinical trial.
- Deviations from the protocol were documented and reported.
- Quality of the clinical trial.
- The required information was submitted to the Research Ethics Board.
- The required information was communicated to and/or reviewed by appropriate study personnel in a timely manner.
- The study records were maintained and archived.
- The label of the drug did not contain the required information.
- Clinical trial records had errors and/or missing information that did not allow for complete and accurate reporting, interpretation, and verification.
- The sponsor did not record, handle, and store all information for the delegation of tasks in the clinical trial to allow for complete and accurate reporting, interpretation, and verification.
- The sponsor did not record, handle, and store all information for a clinical trial to ensure the data transcribed from the original documents to case reports was accurate and complete.
Health Product Recall – ENDOEYE HDII Rigid Videoscope, 08 November 2023
Olympus has identified a total of 1,003 complaints, including 372 adverse events (since September 2020 to August 2023) related to pink or green coloration of the image, including cases with reported delays of treatments and/or prolonged surgery with the ENDOEYE HDII Videoscope. Olympus investigated the complaints and determined the CCD chip that produces the image had been damaged. The CCD chip is sensitive to heat and mechanical shocks. Olympus’s risk management is taking this into account, and the instructions for use mention necessary steps to prepare the video telescope prior to usage. This medical device recall has been launched to remind customers to follow the steps in the instructions for use, to always have a spare laparoscope available, and, in particular, to inspect the image prior to a clinical procedure.
Health Canada is warning consumers not to buy unauthorized injectable drug products from Canlab Research because they may pose serious health risks. The products are promoted as peptides and are sold via Canlab Research websites, including www.canlabresearch.com and www.canlab.net. Peptides perform a range of important functions in the body. Some peptides can be produced for use in medications. Examples of injectable prescription drugs available for sale on Canlab Research websites include oxytocin and triptorelin. Health Canada has ordered Canlab Research to stop advertising and selling all unauthorized health products and will take further compliance and enforcement action to protect consumer health and safety if necessary. Health Canada is also working with the Canada Border Services Agency to help prevent importation of these unauthorized health products.
India – Central Drugs Standard Control Organization (CDSCO)
Drug Alert for the Month of November 2023, 20 December 2023
The CDSCO has published the list of drugs, medical devices, vaccines, and cosmetics declared Not of Standard Quality, Spurious, Adulterated, or Misbranded for the month of November 2023. The total number of samples tested was 1,197. There were 1,133 samples determined to have standard quality, and62 samples determined not to be of standard quality. One (1) sample was determined to be spurious, and one (1) sample was determined to be misbranded. Test failures included Disintegration, Dissolution, Particulate Matter, Identification, pH, Water Content, Related Substances, Endotoxin, Sterility, and Assay for Preservative or Active Ingredient.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance – Quality, Efficacy, Multidisciplinary, and Safety
The ICH Secretariat is pleased to announce the publication of ICH Q9(R1) Quality Risk Management Training Materials. The ICH Q9(R1) training presentations are available for download and can be found on the ICH Q9(R1) Expert Working Group (EWG) webpage in the ICH Training Library. Training presentations are provided for the following topics:
- Formality in Quality Risk Management
- Hazard Identification – Part I
- Hazard Identification – Part II
- Product Availability Risks
- Risk Based Decision Making (RBDM)
- Risk Review
- Case Study: The Impact of Subjectivity on a Remediation Approach to Data Integrity Issues
- Subjectivity in Quality Risk Management, Part I: How to Identify and Control Subjectivity
- Subjectivity in Quality Risk Management, Part II: What Subjectivity in Quality Risk Management Is – Background and Theory
The Q2(R2)/Q14 Expert Working Group (EWG) developed a new ICH Quality Guideline, ICH Q14 on Analytical Procedural Development, and revised the ICH Q2(R1) Guideline on Validation of Analytical Procedures. ICH Q14 harmonizes the scientific approaches of Analytical Procedure Development and provides principles related to the description of the Analytical Procedure Development process. ICH Q14 intends to improve regulatory communication between industry and regulators and facilitate more efficient, scientifically sound, and risk-based approval, as well as post-approval change management of analytical procedures. The scope of the revision of ICH Q2(R1) includes validation principles that cover analytical use of spectroscopic or spectrometry data (e.g., Near-Infrared (NIR), Raman, or Mass Spectrometry (MS)), which often require multivariate statistical analyses. The guideline continues to provide a general framework for principles of analytical procedure validation applicable to products mostly in the scope of ICH Q6A and Q6B. ICH Q14 and Q2(R2) are intended to complement ICH Q8 to Q12 Guidelines as well as ICH Q13 for Continuous Manufacturing.
International Pharmaceutical Excipients Council (IPEC)
Updated: IPEC Glossary of Terms and Acronyms, 14 December 2023
The IPEC Federation announces the availability of the revised and updated IPEC General Glossary of Terms and Acronyms for Pharmaceutical Excipients (version 2, 2021). The glossary was originally published in 2014 and has been used to define excipient terms and acronyms commonly found in IPEC guides. While updating the glossary, the team developed a strategy with the following rationale for determining when a term/definition should be included in the glossary:
- Terms/definitions included in the IPEC Glossary should be one of the following:
- Specific to excipients
- Used/referenced in multiple IPEC guides
- Provide a better understanding of manufacture or application of an excipient
- Describe and/or differentiate regulatory requirements for an excipient
- Terms/definitions not included in the IPEC Glossary:
- Commonly used dictionary terms
- Terms generally used by other industries, e.g., Standard Operating Procedure (SOP), Statistical Process Control (SPC), and Active Pharmaceutical Ingredient (API)
- Terms specific to one IPEC guide (better to describe and/or include reference in guide versus adding to the glossary)
- Terms defined in other official, publicly available guides/resources
International Organization for Standardization (ISO)
ISO/TR 14644-21:2023 Cleanrooms and Associated Controlled Environments, August 2023
ISO/TR 14644-21:2023 Cleanrooms and Associated Controlled Environments discusses the physical limitations of probe and particle counter placement and any tubing that connects the two, particularly in providing representative samples where particles 5 micrometres and greater are of interest. This document further identifies the key factors of sampling performance when classifying and monitoring and good practices for determining and maintaining an acceptable compromise between attainable accuracy in counting and feasibility of counting in real-life situations. The document includes a decision tree, which is used to identify key considerations when sampling airborne particles, and whether the system requires further assessment. Examples are also provided to illustrate typical application challenges and to show how the decision tree can be used. It is assumed that this document is read in conjunction with ISO 14644-1 and ISO 14644-2. This document is not a manual, but an explanatory document. It does not describe measurement methods, which are handled in ISO 14644-1 and ISO 14644-2, but provides information to help make effective choices on sampling configurations when evaluating a new or existing system.
ISO/IEC 42001:2023, Information Technology, Artificial Intelligence Management System, December 2023
As the capabilities of Artificial Intelligence (AI) grow exponentially, so do serious concerns about privacy, bias, inequality, safety, and security. Examining how AI risk impacts users is crucial to ensuring the responsible and sustainable deployment of these technologies. More than ever, businesses today need a framework to guide them on their AI journey. ISO/IEC 42001, the world’s first AI management system standard, meets that need. This standard is a globally recognized standard that provides guidelines for the governance and management of AI technologies. It offers a systematic approach to addressing the challenges associated with AI implementation in a recognized management system framework covering areas such as ethics, accountability, transparency, and data privacy. Designed to oversee the various aspects of artificial intelligence, it provides an integrated approach to managing AI projects, from risk assessment to effective treatment of these risks.
International Society for Pharmaceutical Engineering (ISPE)
ISPE Good Practice Guide: Process Gases 2nd Edition, October 2023
The ISPE Good Practice Guide: Process Gases, 2nd Edition presents recent advances in construction materials and updates on current good practices. This edition is aligned with the latest regulatory guidelines, including EU Annex 1 (revised 2022), EU Annex 15, the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practices, and the FDA Draft Guidance for Industry: Current Good Manufacturing Practice for Medical Gases. Additionally, content was revised based on the latest ISO, ASTM, and American Society of Mechanical Engineers (ASME) standards, as well as the ISPE Good Practice Guide: Critical Utilities GMP Compliance and the ISPE Good Practice Guide: Good Engineering Practice. This Guide covers all aspects of pharmaceutical gas systems, including sustainability requirements as well as generation technologies and design options for control/monitoring and system operation. General properties and characteristics of the atmospheric gases (nitrogen, oxygen, and argon), carbon dioxide, and compressed air are presented, along with pharmacopeia requirements.
ISPE Baseline Guide Volume 6: Biopharmaceutical Manufacturing Facilities 3rd Edition, November 2023
The biopharmaceutical industry has adapted to reflect available technologies such as single-use technologies and modular construction methodologies, products with more focused patient populations, evolving regulatory conditions, unrelenting pressures on costs, and increased focus on robust product supply while maintaining high-quality standards. The ISPE Baseline Guide Volume 6: Biopharmaceutical Manufacturing Facilities 3rd Edition presents concepts that reflect how these changes affect biopharmaceutical manufacturing facilities without sacrificing product quality, by reducing risk, and by enhancing the manufacturing control strategy. This third edition of the guide intends to further reinforce the concepts described in the second edition of the guide, provide examples of how these concepts can be put into practice, and detail the value and benefits of the approaches described. In addition, this revision includes new topics and details regarding Quality Risk Management (QRM), Contamination Control Strategies (CCS), and the impact of closed processes on facility design.
Medicines and Healthcare Products Regulatory Agency (MHRA)
MHRA Warns of Unsafe Fake Weight Loss Pens, 26 October 2023
The Medicines and Healthcare products Regulatory Agency (MHRA) is warning the public not to buy pre-filled pens claiming to contain Ozempic (semaglutide) or Saxenda (liraglutide) but to consult a healthcare professional qualified to prescribe medicines and obtain a prescription. Semaglutide and liraglutide are prescription-only medicines. Saxenda (liraglutide) is authorized in the UK for weight loss alongside diet and exercise. Ozempic (semaglutide) has been authorized for the treatment of adults with type 2 diabetes alongside with diet and exercise. It is not authorized for weight loss, but it is used off-label for that purpose. The MHRA has seized 369 potentially fake Ozempic pens since January 2023, and has also received reports of fake Saxenda pens that have been obtained by members of the public in the United Kingdom through non-legitimate routes (any route that does not require a prescription from a qualified prescribing healthcare professional). None were seized prior to January 2023. Buying prescription-only medicines online without a prescription poses a direct danger to health. The MHRA has received reports of a very small number of people who have been hospitalized after using potentially fake pens.
The MHRA has today issued precautionary safety advice regarding possible contamination of certain eye gels and has told patients and users of the affected products to stop using them immediately and return their product to the place of purchase. Anyone feeling unwell, for example with symptoms of eye infection, such as reduced vision or red and painful eyes, should contact a healthcare professional and tell them that they have been using a recalled eye gel. These types of products are known as carbomer-containing eye gels and are generally used to relieve the symptoms of dry eye. Those branded Aacarb, Aacomer, and Puroptics carry a potential risk of microbial contamination, which can lead to infection if the gel is used. Investigations are ongoing to determine if there is a link between the infections that have been identified and these products. The action is being taken as a precaution, and the risk to the general public is considered to be low.
Parenteral Drug Association (PDA) – Technical Reports
Technical Report 91 Post-Approval Change Management, September 2023
PDA Technical Report 91 (TR-91) expands on the latest concepts and tools for improving Post-Approval Change (PAC) management, as published in ICH Q12. It provides a practical guide for the pharmaceutical industry on how to implement PACs within the framework of an effective Pharmaceutical Quality System (PQS) and in alignment with ICH quality guidelines. It recognizes the challenges that the limited amount of global harmonization among regulators presents with respect to PACs and attempts to provide some insight on how the industry can work with regulators to improve in this area. Though TR-91 aligns with ICH Q12, it also provides guidance for non-ICH regions. It suggests how to implement the tools described in ICH Q12 and provides examples of the concepts that can facilitate aligned industry understanding for PACs.
Points to Consider No. 1 Aseptic Processing (Revised 2023), October 2023
PDA Points to Consider No. 1 Aseptic Processing (Revised 2023) provides topics for evaluation that are related to the physical environment in which aseptic processing is conducted, monitoring of that environment, cleanroom personnel, material transfer, aseptic process simulation and validation, modern blow-fill-seal technology, cleaning, disinfection and sterilization, and critical utilities. This Points to Consider document also includes points to consider on aspects of filter-integrity testing and Water-for-Injection (WFI) preparation. For additional information on specific topics, other PDA points to consider are referenced as well as technical reports and similar documents.
Personal Care Products Council (PCPC)
The Personal Care Products Council (PCPC) supports the U.S. Food and Drug Administration’s (FDA) announcement to exercise enforcement discretion on the Modernization of Cosmetics Regulation Act’s (MoCRA) facility registration and product listing compliance deadline for six months, which moves the compliance date from 29 December 2023 to 01 July 2024. PCPC provided feedback to the FDA on the development of an efficient electronic submission program (Cosmetics Direct) and recognizes that the FDA’s development of Cosmetics Direct is ongoing. PCPC will continue to offer feedback to the FDA on the agency’s implementation of MoCRA and is encouraging member companies to prepare for registration and listing. PCPC has shared the FDA’s instructions with member companies on obtaining an FDA-assigned Establishment Identifier (FEI) number for each facility that manufactures or processes cosmetic products, as needed. PCPC has also shared information with member companies to help facilitate communications between companies that intend to coordinate their registration and listing activities. PCPC looks forward to the FDA’s public launch of Cosmetics Direct once the platform is complete.
Therapeutic Goods Administration (TGA)
Changes to the Regulation of Sports Supplements in Medicinal Dosage Forms, 01 September 2023
As of 30 November 2023, sports supplements that make claims relating to performance in sport, exercise, or recreational activity and are in a medicinal dosage form (i.e., tablet, capsule, or pill) will be regulated as therapeutic goods. This means they must be included in the Australian Register of Therapeutic Goods (ARTG) and will need to meet the applicable legislative requirements for manufacturing, formulation, labelling, and evidence. Anyone advertising these products must also comply with the relevant advertising requirements. This completes the three (3) year transition period of a declaration made under subsection 7(1) of the Therapeutic Goods Act 1989 (the Act) on 23 September 2020, which stated that certain sports supplements are to be regulated as therapeutic goods (medicines).
Medical Devices Vigilance Program Pilot, 11 September 2023
The TGA is commencing a new Medical Devices Vigilance Program (MDVP), which will begin as a 12-month pilot. The pilot is designed to support medical device sponsors comply with regulations and to ensure the public that sponsors are meeting their responsibilities. Sponsors who have medical devices included in the Australian Register of Therapeutic Goods (ARTG) can volunteer for the pilot. Sponsors need to have systems in place to monitor the performance of the devices they supply, receive, update, and maintain information about their devices and report details of adverse events and performance issues to us. These are requirements of the Therapeutic Goods (Medical Devices) Regulations 2002. The MDVP pilot aims to identify areas that may require improvement in order to ensure appropriate monitoring and communications are in place to support the ongoing safety of medical devices available to the Australian public.
The Therapeutic Goods Administration (TGA) has accepted a court enforceable undertaking from Yossef Wahib, operator of the online store Aussie Mega Supplements, in relation to alleged illegal manufacture, supply, and advertising of unregistered therapeutic goods. It is alleged that Mr. Wahib manufactured, supplied, and advertised “EVA B17” products, which were found to contain amygdalin, a substance listed under Schedule 10 of the Poisons Standard. In Australia, medicines and chemicals are classified into schedules according to the level of regulatory control required to protect public health and safety. Schedule 10 lists substances of such danger to public health as to warrant their prohibition from supply and use. The undertaking is enforceable for a period of three years, and requires Mr. Wahib to:
- Educate current and former suppliers of the TGA’s action.
- Recall unregistered therapeutic goods.
- Inform the TGA within seven (7) days of recommencing operations of his business or commencing a new business dealing with therapeutic goods.
- Engage an externally qualified compliance professional to advise regarding regulatory procedures.
In addition to the enforceable undertaking, Mr. Wahib was also issued an infringement notice for $3,756.00. The TGA reminds individuals and businesses that serious penalties can apply for breaches of the Therapeutic Goods Act 1989, including fines and civil or criminal court action.
United States Food and Drug Administration (FDA) – Regulations and Guidance
The FDA Final Guidance, Cybersecurity in Medical Devices: Quality Systems and Content of Premarket Submissions, provides FDA recommendations to industry regarding cybersecurity device design, labeling, and the documentation that the FDA recommends including in premarket submissions for devices with cybersecurity risks. These recommendations are intended to promote consistency, facilitate efficient premarket review, and help ensure that marketed medical devices are sufficiently resilient to cybersecurity threats. This document supersedes the final guidance Content of Premarket Submissions for Management of Cybersecurity in Medical Devices, issued 02 October 2014.
Policy of Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, October 2023
The FDA Final Guidance, Policy of Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol is intended to alert pharmaceutical manufacturers and pharmacists in state-licensed pharmacies or federal facilities who engage in drug compounding to the potential public health hazard of alcohol (ethyl alcohol or ethanol) or isopropyl alcohol contaminated with or substituted with methanol. During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency (PHE), the FDA became aware of reports of fatal methanol poisoning of consumers who ingested alcohol-based hand sanitizer products that were manufactured with methanol or methanol-contaminated ethanol. The FDA is concerned that other drug products containing ethanol or isopropyl alcohol (pharmaceutical alcohol), which are widely used active ingredients in a variety of drug products, could be similarly vulnerable to methanol contamination. This guidance replaces the industry guidelines entitled Policy for Testing Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19), which was published in January 2021.
The FDA Final Guidance for Industry: Compliance Policy for Cosmetic Product Facility Registration and Cosmetic Product Listing, November 2023, is intended to assist owners or operators of cosmetic product facilities subject to the requirements related to facility registration and responsible persons themselves subject to the requirements related to cosmetic product listing under the Federal Food, Drug, and Cosmetic Act (FD&C Act). This guidance document discusses the FDA’s compliance policy for these requirements. The FDA intends to delay enforcement of these requirements for six months to help ensure that the industry has sufficient time to submit facility registration and product listing information. This guidance is being implemented without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate. This guidance is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices.
Quality Considerations for Topical Ophthalmic Drug Products, December 2023
The FDA Draft Guidance, Quality Considerations for Topical Ophthalmic Drug Products, discusses certain quality considerations for ophthalmic drug products (i.e., solutions, suspensions, emulsions, gels, ointments, and creams) intended for topical delivery in and around the eye. Specifically, the guidance discusses:
- Approaches to evaluating visible particulate matter, extractables and leachables, and impurities and degradation products.
- Use of in vitro drug release/dissolution testing as an optional quality control strategy for certain ophthalmic dosage forms.
- Recommendations for design, delivery, and dispensing features of Container Closure Systems (CCSs).
- Recommendations for stability studies.
United States Food and Drug Administration (FDA) – Recalls
Medtronic has issued a notification to inform the public of stolen defective McGRATH™ MAC video laryngoscopes that have been illegally offered for sale by unauthorized third parties through various social media platforms. These affected products did not pass Medtronic’s rigorous quality tests established for the product, were not released for sale, distribution, or importation, and were designated for destruction. These affected products are defective and should not be used. Medtronic is working closely with regulatory authorities and law enforcement organizations to help ensure that unauthorized advertisements are being removed as identified, and that actions to recover the stolen defective products are underway.
The McGRATH™ MAC video laryngoscope is a device used to facilitate intubation of the trachea. The use of a defective McGRATH™ MAC video laryngoscope may result in patient harm, including failed laryngoscopy and/or intubation, potentially resulting in respiratory failure (including hypercarbia), hypoxia (leading to bradycardia, dysrhythmias), hypercapnia, tissue damage/tissue trauma, and/or a delay to treatment (prolonged procedure/extended hospitalization). A population of products affected by this notice (Item Code 301-000-000) are marked with the serial numbers listed in the notice. Additionally, any McGRATH™ MAC video laryngoscopes without a serial number marked on the device are affected by this notice.
Exela Pharma Sciences, LLC Issues Voluntary Nationwide Recall of 8.4% Sodium Bicarbonate Injection, USP, 50 mEq/50 mL, Midazolam in 0.8% Sodium Chloride Injection 100 mg/100 mL, and ELCYS (cysteine hydrochloride Injection), USP 500 mg/10 mL Due to the Presence of Particulate Matter, 25 October 2023
Pharma Sciences, LLC, (Exela) is voluntarily recalling the following injectable products at the consumer level. Particulate matter identified as silicone was observed during routine inspection of retain samples.
- 4% Sodium Bicarbonate Injection, USP, 50 mEq/50 mL, 50 mL Single Dose Vial
- Midazolam in 0.8% Sodium Chloride Injection, 100 mg/100 mL, 100 mL Single Dose Vial
- ELCYS (cysteine hydrochloride Injection), USP, 500 mg/10 mL, 10 mL Single Dose Vial
From a risk perspective, administration of an injectable product that contains particulate matter may result in local irritation or swelling in response to the foreign material. If the particulate matter reaches the blood vessels, it can travel to various organs and block blood vessels in the heart, lungs, or brain, which can cause stroke and even lead to death. Exela has not received any reports of adverse events related to this recall.
SugarMDs, LLC is voluntarily recalling Lot: 22165-003 Advance Glucose Support Supplement in 60, 120, and 180 count bottles at the consumer level. FDA analysis has found the product to be tainted with glyburide and metformin. Glyburide and metformin are active ingredients found in several FDA-approved prescription drugs used to treat type 2 diabetes. Products containing glyburide and metformin cannot be marketed as dietary supplements. Advanced Glucose Support Supplement is an unapproved new drug for which safety and efficacy have not been established and, therefore, is subject to recall. Glyburide may pose serious and potentially life-threatening risks to consumers because this ingredient may result in unsafe drops in blood sugar levels (hypoglycemia). Common symptoms of hypoglycemia include fast heartbeat, shaking, sweating, nervousness or anxiety, irritability or confusion, dizziness, drowsiness, headache, and hunger. Hypoglycemia may quickly become severe, resulting in seizures, coma, or death. Metformin may pose a serious risk to consumers because this ingredient can cause a rare but serious side effect called lactic acidosis (a build-up of lactic acid in the blood) that can lead to death if left untreated. Symptoms of lactic acidosis include nausea, vomiting, fatigue, body aches, respiratory distress, abdominal pain, and fast, deep breathing. Metformin may also cause hypoglycemia when taken together with other medications to lower blood sugar. To date, SugarMDs LLC has not received any reports of adverse events related to this recall.
Insight Pharmaceuticals, a Prestige Consumer Healthcare Inc. company (“Insight”), is voluntarily recalling one lot of Americaine® 20% Benzocaine Topical Anesthetic Spray (Batch Code 1A16420) at the consumer level. While benzene is not an ingredient in any Americaine® 20% Benzocaine Topical Anesthetic Spray products, a recent review by the manufacturer and their third-party laboratory found that a sample from one lot of the product showed a low level of benzene, which came from the propellant that sprays the product out of the can. Importantly, no other lots of Americaine® 20% Benzocaine Topical Anesthetic Spray (either before or after this batch code) are in the scope of this recall and may continue to be used by consumers safely and as intended.
Benzene is classified as a human carcinogen. Exposure to benzene can occur by inhalation, orally, and through the skin, and it can potentially result in cancers, including leukemia and blood cancer of the bone marrow, and blood disorders, which can be life threatening. Insight is recalling this lot out of an abundance of caution. To date, the company has not received any serious adverse events related to this recall. Benzene is ubiquitous in the environment. Humans around the world have daily exposures to it, both indoors and outdoors, from multiple sources.
United States Food and Drug Administration (FDA) – Warning Letters
Safecor Health, LLC, Warning Letter, 12 September 2023
Safecor Health, LLC received a Warning Letter on 12 September 2023. This Warning Letter was issued as the result of an inspection conducted at the company’s facility in Miami, Florida from 13 February 2023 to 17 February 2023. The investigators determined that the methods, facilities, and controls for manufacturing, processing, packing, or holding finished drug products, including pediatric Over-the-Counter (OTC) drugs, did not conform to CGMP. FDA Form 483 observations included the following concerns:
- The firm does not adequately inspect the packaging and labeling facilities immediately before use to ensure that all drug products have been removed from the previous operations.
- The firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment.
- The firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality.
- The firm’s quality control unit failed to exercise its responsibility to ensure that manufactured drug products are in compliance with Current Good Manufacturing Practices, and meet established specifications for identity, strength, quality, and purity.
Suther Feeds, Inc., Warning Letter, 24 October 2023
Suther Feeds, Inc. received a Warning Letter on 24 October 2023 as the result of an inspection conducted at the company’s Clay Center, Kansas animal food manufacturing facility from 24 January to 30 January 2023. The inspection was conducted as a follow-up to a Reportable Food Registry (RFR) report regarding suspected monensin poisoning from medicated feed that resulted in numerous cattle deaths. A sample of the medicated cattle feed labeled for beef cattle was collected by the FDA on 27 January 2023. Analysis of the feed found it contained a super potent concentration of monensin in grams/ton, which is above the labeled monensin concentration of 20 grams/ton. On January 10, 2023, the firm initiated a voluntary Class I recall of this animal food due to excessive monensin. This Type C medicated cattle feed containing the Type A medicated article of monensin is unsafe because the new animal drug was not used in conformance with the drug approval. As a result, the animal feed containing the new animal drug is adulterated.
During the inspection, the FDA investigator found evidence of a significant violation of the Current Good Manufacturing Practice for Medicated Feeds. For example:
- The firm failed to properly identify, handle, and control drugs in the mixing areas to maintain their integrity and identity. This was evidenced via a review of records associated with the production/rework of Type C grain mix mineral for beef cattle.
- The firm did not perform a daily comparison of the actual amount of drug used with theoretical drug usage, as required. Specifically, a review of ten days of the drug inventory records between 19 July 2022 and 02 January 2023 revealed that although the firm is recording the daily usage for the animal drugs currently on-site, the firm is not completing daily comparison of the theoretical daily usage with the actual inventory on hand.
- The firm neither prepared nor implemented a written food safety plan, as required.
- The firm failed to evaluate and use raw materials and other ingredients susceptible to contamination with mycotoxins or other natural toxins in a manner that does not produce animal food that can cause injury or illness to animals or humans. Specifically, the firm receives, stores, and uses grain and grain co-products susceptible to mycotoxin contamination, including corn, dried distillers’ grain, and wheat midds in animal food at the facility. However, the firm does not have procedures or conduct testing to determine whether mycotoxins, such as aflatoxin, fumonisin, or deoxynivalenol (DON), are present in these ingredients or in the finished product. During the inspection, the staff confirmed that the firm does not have procedures for mycotoxins; likewise, there are no tests for them.
Hua Da Trading, Inc., Warning Letter, 20 December 2023
Hua Da Training, Inc. received a Warning Letter on 20 December 2023. This letter was to advise the company that the FDA had reviewed their website at the Internet address, https://www.eshoponlineusa.com, from July to December 2023, where the company takes orders for “WeFun.” The FDA obtained a sample and labeling of the “WeFun” product and confirmed through laboratory analysis that the sample of the “WeFun” product contained the undeclared pharmaceutical ingredient sildenafil. Sildenafil is a phosphodiesterase type-5 (PDE-5) inhibitor and the active ingredient in the FDA-approved prescription drug Viagra, used to treat erectile dysfunction (ED). This undeclared ingredient may interact with nitrates found in some prescription drugs, such as nitroglycerin, and may lower blood pressure to dangerous levels. Men with diabetes, high blood pressure, high cholesterol, or heart disease, often take nitrates. Information on the label of the “WeFun” product demonstrates that this product is marketed as a dietary supplement. However, a dietary supplement may not include an article that is approved as a new drug unless that article was marketed as a dietary supplement or food before its approval as a drug. The FDA approved Viagra (containing sildenafil as the active ingredient) as a new drug on 27 March 1998. Given that sildenafil was not marketed as a dietary supplement or as food before Viagra was approved, the “WeFun” product is excluded from the definition of a dietary supplement (i.e., the “WeFun” product is an unapproved new drug). Additional information is provided in the Warning Letter with respect to misbranding of the drug product.
World Health Organization (WHO)
Medical Product Alert N°7/2023: Falsified DEFITELIO (defibrotide), 04 September 2023
This WHO Medical Product Alert refers to one falsified batch of DEFITELIO (defibrotide sodium). This falsified product has been detected in India (April 2023) and Turkey (July 2023) and was supplied outside of regulated and authorized channels. DEFITELIO (defibrotide) is indicated for the treatment of severe hepatic Veno-Occlusive Disease (VOD), also known as Sinusoidal Obstructive Syndrome (SOS) in Haematopoietic Stem-cell Transplantation (HSCT) therapy. It is indicated for adults, adolescents, children, and infants over one (1) month of age. VOD is a condition in which the veins in the liver become blocked and stop the liver working correctly. The genuine manufacturer of DEFITELIO has confirmed that the product referenced in this Alert is falsified. The genuine manufacturer has advised that:
- Genuine DEFITELIO with Lot 20G20A was packaged in German/Austrian packaging.
- The falsified products are instead in UK/Ireland packaging.
- The stated expiry date is falsified and does not comply with the registered shelf life.
- The stated serial number is not associated with batch 20G20A.
- DEFITELIO does not have marketing authorization in India and Turkey.
WHO has previously issued Alerts for falsified DEFITELIO detected in other countries and regions. Please refer to Medical Product Alert N°5/2020 and Medical Product Alert N°3/2023.
This WHO Medical Product Alert refers to five different syrup and suspension medicines initially detected in the Maldives and Pakistan. WHO was notified of these products on 08 November 2023. Some of the affected products have also been detected in Belize, Fiji, and Lao People’s Democratic Republic.
The five products are ALERGO Syrup, EMIDONE Suspension, MUCORID Syrup, ULCOFIN Suspension, and ZINCELL Syrup. A total of 23 batches of these products are affected. The stated manufacturer of all the affected products is PHARMIX LABORATORIES (PVT.) LTD (Pakistan). In November 2023, samples of five different batches of ALERGO syrup were screened for non-compliance by the quality control laboratory of the Maldives Food and Drug Authority (MFDA) in accordance with the thin layer chromatography (TLC) test for Diethylene Glycol and Ethylene Glycol for inclusion in The International Pharmacopoeia. The routine screening detected potentially unacceptable amounts of diethylene glycol and ethylene glycol as contaminants. Laboratory testing conducted by the Therapeutic Goods Administration of Australia confirmed that all five batches were contaminated with ethylene glycol at levels ranging from 0.62 to 0.82% w/w relative to the accepted limit of not more than 0.10% w/w.
WHO has previously published six Alerts on other contaminated liquid dosage medicines. Please see Medical Product Alert No.6/2022, Medical Product Alert No.7/2022, Medical Product Alert No.1/2023, Medical Product Alert No.4/2023, Medical Product Alert No.5/2023, and Medical Product Alert No.6/2023.
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