SQA Regulatory Surveillance Summary for January and February 2024
SQA Regulatory Surveillance Summary for January and February 2024
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
ANVISA Publishes New Edition of the Biovigilance Manual, 17 January 2024
In Brazil, biovigilance covers a set of monitoring and control actions, ranging from donation to the clinical evolution of a recipient and a living donor. The purpose of biovigilance is to obtain and make available information about risks and adverse events, as well as to prevent their occurrence or recurrence. The National Biovigilance System (SNB) is formed by all entities of the National Health Surveillance System (SNVS) and by establishments and health professionals who develop activities related to the cycle of cells, tissues and human organs. The 4th edition of the ANVISA Biovigilance Manual is now available. The document guides health and health surveillance professionals on the Resolution of the Collegiate Board (RDC) 339/2020, which established the National Biovigilance System. The objective of biovigilance is to oversee the quality and monitoring of processes related to the cycle of cells, tissues, and human organs. The manual presents the concepts and procedures for the surveillance of adverse events related to transplants, grafts, and assisted human reproduction. Biovigilance plays a key role in qualifying the care and safety of recipients and donors of human cells, tissues, and organs. The experience already gained by several countries shows that surveillance systems can reduce the morbidity and mortality of patients.
ANVISA Warns About the Dangers of Misuse of Instant Glues in Beauty Procedures, 08 February 2024
ANVISA issued the GGMON Alert 01/2024, highlighting the dangers related to the misuse of instant glues, which are not regularized as cosmetics, in beauty procedures. Local Health Surveillance reported to the Agency adverse events caused by the use of these glues to fix, for example, nails and false eyelashes. Some of the brands used are: Super Bonder, TekBond, and Three Bond, among others. The use of these products can cause serious damage to health, including blindness, since they are not tested for contact with skin, nails, or eyes. A recent incident involving actress Regina Casé, who suffered a chemical lesion in the cornea, highlights the urgency of attention to the use of glues, especially those not regulated by ANVISA for cosmetic purposes. ANVISA recommends the immediate suspension of the use of these products, encouraging professionals and consumers to use only products regularized by the Agency.
ANVISA Adopts a New Regulatory Approach to the Food Area, 28 February 2024
ANVISA published the new regulatory framework for the regularization of food in the National Health Surveillance System (SNVS). The Resolution of the Collegiate Board (RDC) 843/2024 and the Normative Instruction (IN) 281/2024 improve the pre-market control of food, based on risk criteria. This measure reduces the administration burden both for the regulatory body and for the food sector, in cases of lower risk, and maintains or expands the rigor, in the case of high-risk products or those with a history of complaints. The new standards define three forms of regularization:
1) Registration with ANVISA.
2) Notification to ANVISA.
3) Communication to local health surveillance agencies at the beginning of manufacture or import.
Products with mandatory registration need an approval from ANVISA prior to marketing. In this group, infant formulas and formulas for enteral nutrition were maintained, and the dietary formula for innate metabolic errors was included. For products considered of intermediate risk, such as desalinated seawater, transitional foods and cereals for infant feeding, recycled packaging, and foods with claims, there was the waiver of registration and the creation of a new form of regularization: the “Notification with ANVISA”. With this change, such products will enter the market more quickly, as they do not require prior approval, although companies maintain the obligation to submit information to the Agency. Food supplements and foods for weight control, whose regularization was carried out directly by the local Health Surveillance, will be notified to ANVISA. This change aims to increase product safety and promote fairer competition in the market. The notification will allow the Agency to structure a database on these products, facilitating the organization of post-market control actions, such as monitoring, inspections, and audits.
China: National Medical Products Administration (NMPA)
China’s Regulations on Drug Supply Come into Effect, 01 January 2024
China’s Administrative Measures for Supervising the Quality of Drug Supply and Use (referred to as the Administrative Measures), published by the State Administration for Market Regulation (SAMR), took effect on 01 January 2024. The Administrative Measures are comprised of the following seven chapters, encompassing a total of 79 articles that mainly address the administration of drug supply licenses, obligations of businesses supplying drugs and medical institutions using drugs, as well as regulators’ supervision of stakeholders in drug supply and use.
- General Provisions
- Supply License
- Supply Management
- Quality Management for Drug Use
- Supervision and Inspection
- Liability
- Supplementary Provisions
China Releases Pharmaceutical Guidelines, February 2024
In February 2024, China unveiled 12 guidelines on chemical drugs and biological products. The guidelines include requirements for:
- Chemistry Manufacturing Controls (CMC) Studies for Radiochemical Generic Drugs, Mini-tablets (Chemical Drugs), Antibody Conjugate Drugs (ADC), and Generic Low Molecular Weigh Heparin Drugs (Trial)
- Chinese Translations and Implementation Advice for ICH Q2(R2) Validation of Analytical Procedures and ICH Q4 Analytical Procedure Development
European Commission (EC)
New MDCG Device Specific Vigilance Guidance Documents Published, 06 February 2024
The European Commission’s Medical Device Coordination Group (MDCG) published several updated Device Specific Vigilance Guidance (DSVG) documents on 30 January 2024. The newly released guidance documents cover four of the original five specific devices to which the now-obsolete Medical Device Documents (MEDDEV) DSVGs once applied: cardiac ablation, coronary stents, cardiac implantable electronic devices, and breast implants. The DSVG documents aim to harmonize vigilance reporting for manufacturers of these specific devices. Each guidance includes device-related problem examples for individual serious incidents, periodic summary reports, or incidents that would be reported at the time a trend is identified.
A few changes have been incorporated into all of the new DSVG documents. These now reference the applicable regulations and the Medical Device Coordination Group Document, MDCG 2023-3, instead of the Medical Devices Directive (MDD) or the Active Implantable Medical Devices Directive (AIMD) and the former guidance on vigilance (MEDDEV 2.12/1 rev 8). They also now include the International Medical Device Regulators Forum (IMDRF) codes associated with the incident examples included in each DSVG document. Manufacturers should understand that the incidents provided in the DSVG documents are intended to serve as examples only and are not to be considered an all-inclusive list.
European Medicines Agency (EMA)
EMA Annex 1 Question & Answer Discusses Bioburden Considerations, 06 February 2024
In January 2024, the European Medicines Agency (EMA) published four new Questions & Answers to its catalogue of Annex 1 questions. These included two questions focusing specifically on bioburden level and bioburden sampling:
- What is the maximum bioburden level?
- What are the requirements for the bioburden sampling to support parametric release?
With respect to the maximum bioburden level, the EMA shared that the specification limits should be NMT 10 CFU/100ml, in line with the scientific guideline: Sterilization of the Medicinal Product, Active Substance, Excipient and Primary Container. From a GMP point of view, a bioburden limit of 10 CFUs/100ml before first filtration is not only strongly recommended, but achievable. This limit is applicable when a prefilter is installed, unless otherwise justified. In relation to higher bioburden limits, these should not be justified by the high capacity of two consecutive bacteria retaining filters. Yet, for processes involving fermentation, for instance, or the use of purified water for ophthalmic preparations, EMA stated that, when appropriate justification is submitted, a bioburden limit of higher than 10 CFUs/100ml before prefiltration may be acceptable. EMA noted that, in these cases, the first filter should show it can achieve a bioburden before the last filtration of NMT 10 CFUs/100ml. This is in line with the Notes for Guidance on Manufacture of the Finished Dosage Form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).
With respect to the requirements for the bioburden sampling to support parametric release, the EMA highlighted that, in Annex 1, Section 10.4 for products authorized for parametric release, a supporting pre-sterilization bioburden monitoring program for the filled product prior to initiating the sterilization cycle should be developed and the bioburden assay should be performed for each batch (sub batch). The section also detailed steps for bioburden identification, stating that any organisms found during bioburden testing should be identified and their impact on the effectiveness of the sterilizing process determined. EMA’s answer noted that the endotoxin/pyrogen level should be monitored, as appropriate. In Annex 17, Section 4.9, it states that a pre-sterilization bio-burden monitoring program for the product and components should be developed to support parametric release. Additionally, the sampling locations of filled units before sterilization should be based on a worst-case scenario and be representative of the batch. EMA also emphasized the importance of considering the time between sampling, sterilization, and testing. Moreover, alternatives to this approach should be thoroughly justified. These should consider:
- The materials involved, including packaging materials
- Homogeneity of the bioburden within the different sub-batches
- Presence of organisms
- Time between sampling and sterilization
EMA/CHMP/CVMP: New Q&A Document for the Use of CEPs, 06 March 2024
On 13 February 2024, the document QWP Questions and Answers (Q&A): how to use a Clinical Evaluation Plan (CEP) in the context of a Marketing Authorization Application (MAA) or a Marketing Authorization Variation (MAV), which was prepared by the EMA, the Committee for Medicinal Products for Human Use (CHMP), and the Committee for Medicinal Products for Veterinary Use (CVMP), was published on the EMA website for the first time. The Q&As should be seen as an orientation for marketing authorization holders and applicants when submitting applications and variation notifications. They explain the use of CEPs in this regard. Excipients that are described by a CEP and are used as an API are also mentioned here. The list of questions and answers consists of the following four chapters:
- Introduction
- Summary of Marketing Authorization Holder (MAH)/Applicant responsibilities
- Information to be included in the MAA/dossier
- Changes to the CEP status
Health Canada
Teva Canada Ltd. is recalling one lot of Pediatrix Acetaminophen Oral Solution after routine product testing found a higher than acceptable amount of acetaminophen in the affected lot (approximately 185mg/5mL rather than the approved and labelled 160mg/5mL). This could lead to children receiving too much acetaminophen. Children may be especially at risk of the effects of acetaminophen overdose given their small size and developing bodies. Signs of acetaminophen overdose include nausea, vomiting, lethargy, sweating, loss of appetite, and pain in the upper part of the abdomen or stomach. Abdominal pain may be the first sign of liver damage and may not be apparent for 24 to 48 hours. Liver damage may result in liver failure or, in the most severe cases, death. The product is available without a prescription and is used to relieve mild to moderate pain and fever in children from 2 to 11 years of age. Health Canada is monitoring the company’s recall and its implementation of any necessary corrective and preventative actions. It will inform the public if any new health risks are identified. Given the limited scope of the recall, it will not have any impact on the general availability of children’s acetaminophen products.
Non-Compliant Rating for The Montreal Fertility Centre, 29 January 2024
The Montreal Fertility Centre located in Montreal, Quebec, received a non-compliant rating from a Drug Sperm and Ova inspection that started on 29 January 2024. Key findings included the following observations:
- The primary establishment determined a donor to be suitable even when the donor met criteria that would exclude them from donating.
- The primary establishment did not ensure that establishments conducting processing activities on their behalf were doing so in accordance with the regulations.
- The donor suitability assessment was not always complete or accurate.
- A health professional, in the context of a directed donation, did not create a document stating that, in their medical opinion, the use of sperm or ova would not pose a serious risk to human health and safety.
Additional findings included concerns with respect to document control, records management, and lack of compliance with Standard Operating Procedures (SOPs). In addition, SOPs did not align with specified requirements and did not have a standardized format.
Launch of a Pilot Good Manufacturing Practice Single Inspection Program, 27 February 2024
Health Canada has begun piloting a GMP single inspection program with the Therapeutic Goods Administration (TGA) and the Medicines & Healthcare Products Regulatory Agency (MHRA). These three regulatory authorities are all members of the following organizations:
- Access Consortium
- Pharmaceutical Inspection Co-operation Scheme
- International Coalition of Medicines Regulatory Authorities
This pilot aims to establish a coordinated global approach to GMP inspections of foreign manufacturing sites of common interest. Using their collective inspection resources, each authority has agreed to cover the scope of the other where possible. This reduces the need for multiple inspections of the same site. This builds on the success of the existing collaborative GMP arrangements and will allow for:
- More efficient inspection reliance processes
- Reduced regulatory burden on industry.
- Enhanced collaboration in the regulatory oversight of common global supply chains
Health Canada is currently identifying sites to inspect as a part of this pilot. They may contact the license holder if they select one of the foreign buildings listed on your Drug Establishment License (DEL). There will be no changes to the processesz to:
- Request a GMP inspection of a foreign building.
- Reply for or amend a DEL as stated in GUI-0002: Guidance on Drug Establishment License
India
India’s Health Ministry Revises GMP Rules and Replaces the GMP Term, 07 February 2024
The Indian pharmaceutical industry, which is one of the world’s largest exporters of generic drugs, has been criticized for producing medicines that do not always meet quality standards. Now the Ministry of Health has published revised regulations in accordance with Annex M of the Drugs and Cosmetics Rules. The revision comes in the wake of several incidents of contamination and substandard drugs being exported from India. Last year, the World Health Organization (WHO) issued an alert about cough syrups being contaminated with diethylene glycol and ethylene glycol, which are toxic to humans and can prove fatal. The contamination was allegedly found in samples taken from a batch of cough syrup made by QP Pharmachem Ltd, based in Punjab. The company’s manufacturing license was suspended after cough syrup linked to child deaths in Gambia and Uzbekistan were found to be contaminated. Other cases of alleged contamination have also been reported from cough syrups made in India.
The revision to Schedule M, published on 29 December 2023, aims to bring India’s GMP recommendations at par with global standards, especially those of the WHO, and ensure production of high quality, globally acceptable drugs. The revision was also necessitated by the fast-changing manufacturing and quality domain, and the need to keep pace with the latest technological advancements. The changes introduced in the revised Schedule M include the introduction of a Pharmaceutical Quality System (PQS), Quality Risk Management (QRM), Product Quality Review (PQR), qualification and validation of equipment, and a computerized storage system for all drug products. The revised rules also have five new categories of drugs, such as pharmaceutical products containing hazardous substances, biological products, and radiopharmaceuticals.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
The ICH E2D(R1) draft Guideline on “Post-Approval Safety Data: Definitions and Standards for Management and Reporting of Individual Case Safety Reports (ICSRs)” reached Step 2b of the ICH Process in February 2024 and entered the consultation period. A Step 2 Informational Presentation has also been developed by the Expert Working Group and is now available for download on the E2D(R1) page. The ICH E2D guideline provides guidance on definitions and standard for post-approval individual case safety reporting, as well as good case management practices. This revised guideline, E2DR1, is proposed to clarify the management of post-approval safety information from new or increasingly used data sources including the need to adapt definitions and standards. In addition, the revised guideline provides recommendations that are harmonized to the extent possible given differences in post-market safety reporting requirements among ICH regions.
ICH M10, Bioanalytical Method Validation and Study Sample Analysis Guideline, is intended to provide recommendations for the validation of bioanalytical methods for chemical and biological drug quantification and their application in the analysis of study samples. Adherence to the principles presented in this guideline will ensure the quality and consistency of the bioanalytical fata in support of the development and market approval of both chemical and biological drugs.
The ICH Secretariat is pleased to announce the publication of ICH M10 Bioanalytical Method Validation Study Sample Analysis Training Material. The training presentation is available for download and can be found on the ICH M10 EWG webpage.
International Pharmaceutical Excipients Council (IPEC)
The International Pharmaceutical Excipients Council Federation, (IPEC Federation) announces the availability of its revised position paper, The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products. This paper describes IPEC Federation’s position on the role of excipients when conducting N-nitrosamine (nitrosamine) risk assessments for drug products. The presence of N-nitrosamines in drug products continues to be a global concern. Excipients are considered as a potential risk factor during the drug product risk assessment. The focus of this position paper is to expand on the potential contribution excipients may or may not have on the formation of nitrosamines in final drug products. The presence of nitrites and vulnerable amines in excipients are also considered. This revision highlights the key messages associated with excipients and how they feature in the ongoing debates on the nitrosamines topic and has been updated to reflect current perspectives.
International Organization for Standardization (ISO)
ISO/CD TS 24971-2, Medical Devices, Guidance on the Application of ISO 14971, provides guidance for applying an ISO 14971 risk management process when evaluating medical technology utilizing Machine Learning (ML). It is intended to apply ML-enabled medical devices throughout all phases of the product lifecycle. This document is intended to be used in conjunction with ISO 14971. It does not modify the ISO 14971 risk management process; rather, it provides information and guidance to inform the application of ISO 14971 ML medical technology. ISO/CD TS 24971-2 was listed as under development in the February 2024 International Standards in process listing.
ISO Amendments Provided for every ISO Management System Standard, February 2024
There are new ISO Amendments applicable to every ISO management system standard. These amendments enable implementing organizations to incorporate climate change considerations into their management systems. Amendments are for the following system standards:
- ISO 9001:2015/Amd1:2024 – Amendment 1: Quality management systems – Requirements
- ISO 14001:2015/Amd1:2024 – Amendment 1: Environmental management systems – Requirements with guidance for use
- ISO/IEC 27001:2022/Amd1:2024 – Amendment 1: Information security, cybersecurity, and privacy protection – Information security management systems – Requirements
- ISO 45001:2018/Amd1:2024 – Amendment 1: Occupational health and safety management systems – Requirements with guidance for use
- ISO 50001:2018/Amd1:2024 – Amendment 1: Energy management systems – Requirements with guidance for use
- ISO 22000:2018/Amd1:2024 – Amendment 1: Food safety management systems – Requirements for any organization in the food chain
- ISO 22301:2019/Amd1:2024 – Amendment 1: Security and resilience – Business continuity management systems – Requirements
- ISO/IEC 20000-1:2018/Amd1:2024 – Amendment 1: Information technology – Service management – Part 1: Service management system requirements
- ISO/IEC 19770-1:2017/Amd1:2024 – Amendment 1: Information technology – IT asset management – Part 1: IT asset management systems – Requirements
- ISO 15378:2017/Amd1:2024 – Amendment 1: Primary packaging materials for medicinal products – Particular requirements for the application of ISO 9001:2015, with reference to good manufacturing practice (GMP)
- ISO 37301:2021/Amd1:2024 – Amendment 1: Compliance management systems – Requirements with guidance for use
- ISO 37001:2016/Amd1:2024 – Amendment 1: Anti-bribery management systems – Requirements with guidance for use
International Society for Pharmaceutical Engineering (ISPE)
Guide: Advanced Therapy Medicinal Products (ATMPs) – Allogeneic Cell Therapy, January 2024
Advanced Therapy Medicinal Products (ATMPs) are based on genes, cells, or tissues delivered to patients to provide a therapeutic benefit based on a specific target of interest. For ATMPs, the therapy is cells, engineered tissues, or the manipulation of the patient’s genome. This is in contrast with traditional manufacturing processes for compounds that are synthetically derived (i.e., small molecule) or proteins or peptides expressed by cellular systems (i.e., large molecule biopharmaceuticals). The development, regulatory path, facility design, qualification, and manufacture of ATMPs present significant challenges to manufacturers, engineers, and suppliers. The GMP regulations are evolving as novel processes are presented and manufacturing paradigms are being tested. The ISPE Guide: ATMPs – Allogeneic Cell Therapy addresses facility engineering issues that are most applicable at the time of publication, as based on the experience of the authors. This guide focuses primarily on allogeneic cell therapies, specifically manufacturing facility development and design. Allogeneic cell therapies have unique challenges due to the small manufacturing scale, limitations in scale-up, the need to manufacture multiple lots of products concurrently, and the need for flexibility to accommodate a varied and evolving product portfolio. This guide covers common challenges with allogeneic cell therapy facilities, design concepts specific to allogeneic cell therapy facilities, and GMP layout and architectural design development. Key aspects of the allogeneic cell therapy manufacturing process, including sampling, Quality Control, and process understanding, are presented.
Medicines and Healthcare Products Regulatory Agency (MHRA)
On 09 January 2024, a clear path ahead was set by the MHRA for the development of new and robust regulations for medical devices in the UK. The new regulations will put patient safety first and help to ensure that patients continue to have access without delay to the devices they need, whilst enhancing the UK’s position as a world-leading environment for medical technology innovators. This new roadmap for new regulations from the MHRA will enhance the UK’s ability to benefit from rapidly advancing medical technology, offering significant new opportunities for patients and healthcare. Transformative technologies such as new implantable devices, healthcare AI and software, and diagnostics for early detection and prevention of disease all demand a new regulatory framework. The MHRA’s roadmap sets out a route to deliver enabling regulation via a series of new Statutory Instruments (SIs). Priority measures to protect patient safety will be put in place this year, with core elements of the new framework intended to be in place by 2025. The planned regulations are also designed to deliver greater international harmonization, with more patient-centered, proportionate requirements for medical devices that are responsive to technological advances.
Exeltis UK Limited has informed the MHRA regarding an inconsistency in the Patient Information Leaflet (PIL) packaged in cartons of the specified batches of Gepretix 100mg capsules. The PIL contains the following inconsistency:
- Section 3 states: “The recommended dose is 200 mg daily at bedtime, for twelve days in the last half of each therapeutic cycle (beginning on Day 15 of the cycle and ending on Day 26). Alternatively, 100 mg can be given at bedtime from Day 1 to Day 25 of each therapeutic cycle.”
- However, in the “How much to take” subsection below, the PIL states: “Take one capsule at bedtime on days 15 to 26 of your 28 day cycle.” This section should state “Take two capsules at bedtime on days 15 to 26 of your 28- day cycle”.
Healthcare professionals are recommended to reiterate the prescribed dosage to their patients and to ensure that patients follow the dispensing advice. The product quality of Gepretix 100mg capsules is not impacted by this issue; therefore, the affected batches are not being recalled. The manufacturer has confirmed that the batch distributed on 30 January 2024 will be accompanied by a note explaining the issue to supplement dispensing at pharmacies. These batches will not be repackaged to avoid any supply concerns. Exeltis UK Limited has confirmed that all future batches of the product will contain the corrected PIL. No action is needed from patients. The issue is related to inconsistencies contained within the PIL of the specified batches of Gepretix 100mg capsules. The quality of the medication itself is not affected. Patients should continue to take medicines from these batches as prescribed by their healthcare professional and as per the advice on the dispensing label. Patients who experience adverse reactions or have any questions about the medication, should seek medical attention. Any suspected adverse reactions should also be reported via the MHRA Yellow Card scheme.
Novartis Pharmaceuticals UK Limited is recalling Adakveo 10 mg/ml concentrate for solution for infusion, batch number SJFN5, due to the benefit-risk balance of Adakveo no longer being considered favorable by the MHRA. This is because the Phase III study (STAND) of Adakveo in sickle cell disease patients with vaso-occlusive crises did not confirm its clinical benefit. Consequently, the conditional marketing authorization in the UK is being revoked. Healthcare professionals are advised to stop supplying the above batch immediately. All remaining stock should be quarantined. Await contact from the Novartis Pharmaceuticals UK Limited Customer Care Team, who will contact healthcare professionals directly to arrange return. Novartis Pharmaceuticals UK Limited has a direct-to-pharmacy supply chain agreement based on the specialist use of the product and know the exact hospitals who have been supplied with the impacted batch.
- Clinicians and prescribers who initiated patients on Adakveo 10 mg/ml concentrate for solution for infusion should inform patients of the license revocation and discuss alternative treatment options with them. No new patients should be started on Adakveo in the UK.
- Healthcare professionals who receive any questions from patients related to the recall notice should advise patients undergoing treatment to discuss any questions or concerns with their prescribing healthcare professional. No new patients should be started on Adakveo in the UK.
Parenteral Drug Association (PDA) – Technical Reports
Points to Consider No. 9 Lessons Learned from the COVID-19 Pandemic, January 2024
As a result of the COVID-19 pandemic, many industries (the pharmaceutical included) went through a substantial disruption. Some of these disruptions included facility shutdowns, unprecedented supply chain challenges, worker availability, and quality system limitations (e.g., physical signatures, investigations, document originals, risk assessments, or audits). For many pharmaceutical companies, challenges increased as they raced to provide a vaccine or a therapeutic treatment for COVID-19. Manufacturing operations were changed over to accommodate the creation of the vaccine and, to get the vaccine to patients quickly, many logistical challenges arose. Points to Consider No. 9 Lessons Learned from the COVID-19 Pandemic provides lessons learned from pharmaceutical manufacturing. Areas covered include manufacturing, people, quality, regulatory, and the supply chain.
The European Union regulation (EU) 2017/745 on medical devices, referred to as MDR, introduced new requirements for manufacturers of medical devices. These new requirements, according to MDR Articles 1(8) and 1(9), subparagraphs 2, also apply to pharmaceutical companies developing manufacturing combinations of medicinal products and medical devices, included Prefilled Syringes (PFS), both integral and single integral products. The device part of these PFS must comply with the rules outlined in MDR Annex I: General Safety and Performance Requirements (GSPRs). Evidence of compliance as described in Article 117, must be provided by requesting an opinion from a Notified Body (NB) appropriately accredited for the issuance of such an opinion.
PDA Technical Report No. 73-2: Application of Medical Device Regulation Annex I Requirements for Staked Needle Syringes represents the current state of knowledge as to its application. As this is a new process based on a new regulatory requirement, expectations of the NBs and competent authorities may diverge as the process evolves. Ultimately, the responsibility of the entire contents of the submission file that is reviewed by the NB lies with the applicant. Accordingly, the intended users of TR-73-2 are applicants, i.e., pharmaceutical companies, their suppliers, and other interested parties.
United States Food and Drug Administration (FDA) – Regulations and Guidances
FDA Reports on Good Guidance Practices, 03 January 2024
In 2011, FDA issued a report entitled “Food and Drug Administration Report on Good Guidance Practices: Improving Efficiency and Transparency.” Developed by a cross-agency working group, the report identified best practices and recommendations to streamline the development of guidance documents, reduce the time between issuing draft and final guidance documents, and make it easier to find guidance documents on FDA’s website (2011 Report on Good Guidance Practices: Improving Efficiency and Transparency (PDF- 138 KB)). Since 2011, FDA has made significant strides to modernize and enhance best practices for the efficient initiation, prioritization, development, review, clearance, and issuance of guidance documents. FDA has prepared a draft document entitled “Food and Drug Administration’s Draft Report and Plan on Best Practices for Guidance”. This draft report responds to section 2505(a) of the Consolidated Appropriations Act (Public Law 117-328) of 2023, which directs FDA to issue a report identifying best practices for the efficient prioritization, development, issuance, and use of guidance documents and a plan for implementation of such best practices (2023 Food and Drug Administration’s Draft Report and Plan on Best Practices for Guidance [PDF – 1.17 MB]).
The FDA Draft Guidance – Good Manufacturing Practice for Active Pharmaceutical Ingredients is aligned with the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) document GL60. This guidance has been developed by the appropriate VICH Expert Working Group and will be subject to consultation by the parties, in accordance with the VICH Process. At Step 7 of the process, the final draft will be recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. This document provides guidance regarding good manufacturing practice for the manufacturing of Active Pharmaceutical Ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess.
The Draft Guidance for Industry: Hazard Analysis and Risk Based Preventive Controls for Human Food is directed to companies who are subject to the hazard analysis and risk-based Preventive Controls for Human Food (PCHF) requirements of 21 CFR Part 117. Establishing risk-based preventive controls enables these companies to apply a proactive and systematic approach to their food safety program through the establishment of preventive controls designed to protect food, and the consumer, from biological, chemical (including radiological), and physical hazards. Risk-based preventive controls will not provide a “zero-risk” system for manufacturing, processing, packing, and holding food; rather, risk-based preventive controls are designed to minimize the risk of known or reasonably foreseeable food safety hazards that may cause illness or injury if they are present in the products manufacturers produce. This draft guidance is intended to help manufacturers comply with the following specific PCHF requirements established in subparts C and G of part 117:
- A written Food Safety Plan (FSP)
- Hazard Analysis
- Preventive Controls
- Monitoring
- Corrective Actions
- Verification
- Associated Records
This guidance is not directed to persons who are exempt under 21 CFR Part 117.5 (exemptions). However, such persons may find some of the principles and recommendations in this guidance helpful in manufacturing, processing, packing, and holding human food.
United States Food and Drug Administration (FDA) – Recalls
Leiters Health is voluntarily recalling a total of 33 lots of vancomycin IV bags, phenylephrine IV bags, and fentanyl IV bags. These lots are being recalled due to the potential for superpotency because they may contain twice the labeled amount of drug. It has been determined that the semi-automated IV bag filling equipment used to fill the recalled batches may not eject the IV bags properly when compressed air tanks become low or a leak was detected, causing the recalled IV bags to be dosed twice. There is a reasonable probability that the use of the defective vancomycin and fentanyl IV bags will be associated with life-threatening adverse events. Administration of vancomycin at twice the infusion rate has been associated with low blood pressure, including shock and cardiac arrest, as well as wheezing, shortness of breath, hives, itchy skin and skin redness. Also, overdosing of vancomycin may be associated with acute kidney injury and ototoxicity. Administration of higher doses of fentanyl than intended can result in profound respiratory depression, which may not automatically be mitigated and treated, resulting in potential for delay in care and serious adverse outcomes from hypoxia, including permanent neurologic sequelae and death. In addition to respiratory depression, fentanyl can cause serious cardiac adverse events, such as hypotension, bradycardia, and vasodilation resulting in a decrease in cardiac output and cardiac arrest. In addition, administration of a higher dose of phenylephrine than intended may cause higher-than-intended blood pressures in some patients. To date, Leiters Health has not received any reports of adverse events related to this recall.
In direct response to the Nurse Assist, LLC voluntary recall of pre-filled syringes and other sterile water products, Avanos Medical, Inc. voluntarily recalled specific lots of MIC* Gastric – Jejunal Feeding Tube Kits on 16 January 2024. These kits include Nurse Assist supplied syringes, pre-filled with sterile water, essential for inflating the retention balloon of the feeding tube. The Nurse Assist voluntary recall was initiated due to concerns about the potential lack of sterility assurance in these water-based products. This deficiency may lead to non-sterile products, posing a risk of the water coming into contact with a patient’s surgical site. Any open wound exposed to non-sterile products could potentially put the patient at risk of infection. The pre-filled syringe is the only item in the Avanos feeding tube kit affected by the Nurse Assist recall. As of 06 February 2024, the FDA reported receiving adverse events associated with use of Nurse Assist products and is further evaluating this information. Avanos has not been directly contacted with any reported adverse events.
United States Food and Drug Administration (FDA) – Warning Letters
EzriCare LLC Warning Letter, 13 February 2024
EzriCare LLC received a Warning Letter on 13 February 2024. This Warning Letter was issued as a result of an inspection conducted at the company’s facility in Lakewood, New Jersey from 08 March 2023 to 21 March 2023. The FDA inspection revealed violative conditions at Global Pharma Healthcare Private Limited, a Contract Manufacturing Organization (CMO) used to manufacture ophthalmic drugs for EzriCare LLC. The FDA inspection of this foreign facility revealed significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, causing these drug products to be adulterated. Because these products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, these drug products are also adulterated. The inspection of the EzriCare LLC Lakewood, New Jersey facility revealed that it operates as a distributor of EzriCare’s Artificial Tears. The receipt in interstate commerce of adulterated drugs, and the delivery or proffered delivery thereof, is a violation of the FD&C Act, and the distribution of adulterated drugs violates section 301(a) of the FD&C Act. In addition, EzriCare Artificial Tears is misbranded under section 502(j) of the FD&C Act, Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited. Sited violations were related to the following concerns:
- Pseudomonas aeruginosa outbreak and FDA testing of samples – Nonsterile batches of EzriCare Artificial Tears.
- FDA inspection of Pharma Healthcare Private Limited – CGMP violations, including but not limited to the use of filling equipment that was inadequate for its intended use.
- Receipt and distribution of adulterated drugs – nonsterile drug product.
- Inspection of EzriCare LLC – inadequate supplier qualification, including lack of a Quality Agreement.
- Misbranded drug violations – nonsterile drug product.
Exactech, Inc. Warning Letter, 19 January 2024
Exactech, Inc. received a Warning Letter on 19 January 2024. The Warning Letter was the result of a FDA inspection that was conducted at the company’s facility in Gainesville, Florida from 18 September 2023 to 26 September 2023. Exactech, Inc. is a manufacturer of Equinoxe aTSA and Equinoxe rTSA devices and other orthopedic implants and accessories. The inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. Sited violations were related to the following concerns:
- Failure to adequately establish procedures for Corrective and Preventive Actions.
- Failure to establish and maintain design validation procedure to ensure that proper risk analysis is completed.
- Failure to adequately develop, maintain, and implement written Medical Device Reporting (MDR) procedures.
- Failure to submit a report to FDA no later than 30 calendar days after the day that the firm receives or otherwise becomes aware of information, from any source, that reasonable suggests that a device that your firm markets has malfunctioned and this device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur.
World Health Organization (WHO)
WHO Publishes the WHO Medically Important Antimicrobials List for Human Medicine, 08 February 2024
The responsible and prudent use of antimicrobials needs to be improved in all sectors: human, animal, plant/crop, and environment, to preserve their public health benefits. In particular, antimicrobials that are medically important for human medicine need to be preserved by reducing their use in the non-human sectors. The WHO list of Medically Important Antimicrobials for human medicine (WHO MIA List) is a risk management tool that can be used to support decision-making to minimize the impact of antimicrobial use in non-human sectors on antimicrobial resistance (AMR) in humans. The WHO MIA List is created to guide international, national, and subnational (local, state, provincial) antimicrobial stewardship efforts. It complements the WHO Access, Watch, Reserve (AWaRe) framework and antibiotic book, which provide guidance on appropriate use of essential antibiotics within the human health sector. The list categorizes antimicrobial classes based on their importance for human medicine and according to the AMR risk and potential human health implications of their use in non-human sectors: critically important, highly important, and important to human medicine. The publication is intended to serve as a reference tool to support decision-making by national regulators and policymakers in ministries of health and agriculture, authorities responsible for regulating, monitoring, and assuring the responsible and prudent use of antimicrobials, and professional prescribers in different sectors.
WHO Launches Pharmaceutical Quality Assurance Guidelines, 10th Edition, 29 February 2024
The 10th Edition of the Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials is an essential resource for the global healthcare community, designed to strengthen pharmaceutical standards worldwide. The compendium, developed for national regulatory authorities, pharmaceutical manufacturers, healthcare professionals, and procurement agencies, is instrumental in upholding the globally acceptable standards of Good Manufacturing Practices (GMP) and inspections. With forty-six guidelines, including eight new and ten revised ones, it provides a comprehensive framework for enhancing regulatory systems and international standards for pharmaceutical quality assurance. The recent alerts on contaminated pediatric syrup medicines underline the urgency for strengthened measures in pharmaceutical manufacturing and for Member States to enforce these international standards to safeguard public health. Applying internationally acceptable standards supports local and regional production of medicines and the quality and safety of medicines circulating in international commerce. In the context of global healthcare, the 10th edition of the WHO Quality Assurance of Pharmaceuticals compendium, volume 2, is a commitment towards ensuring the quality, safety, and efficacy of pharmaceuticals worldwide. The compendium is one of several WHO initiatives aimed to strengthen quality assurance and access to medicines.
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