SQA Regulatory Surveillance Summary | Monthly Update 2023 – July and August 2023
SQA Regulatory Surveillance Summary for July and August 2023
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
During the week of 12-16 June 2023, ANVISA and state and municipal health surveillance agencies carried out an investigative inspection of two manufacturers of food supplements located in the municipality of Campos dos Goytacazes/RJ: Dr. Candal Ltda. and Rodrigues & Florindo Saúde e Vida Ltda. The inspection was motivated by complaints received by health surveillance agencies located in different Brazilian states, which reported on irregularities related to the composition of the companies’ products and divergences related to the labeling information of manufacturers and those responsible for the products. During a visit to the establishments, evidence of the manufacture of herbal medicines without registration and with a fraudulent label was observed, as the materials were produced in an environment with inadequate hygiene and sanitary conditions. In addition, raw materials and finished products were found without identification, and with no means to verify the identity and origin of the products, which included a diverse array of vegetable drugs and many irregular products and labels stored in the inspected establishments. In view of these facts, the Federal Police were involved in the case, which resulted in the seizure of irregular finished products (specifically, medical drug without registration, with false labeling information) and raw materials (specifically, vegetable drugs) that were used in the manufacture of irregular products. For a list of the products seized, click here.
ANVISA determined the precautionary interdiction of all batches of Cosmobeauty Dermo Biostimulator and Filler and Cosmobeauty Tonifying Ultraconcentrated Fluid, manufactured by the company Bio Essencialli Indústria e Comércio de Cosméticos. The measure, adopted through Resolution – RE 2910/2023, was made after the Agency was informed by the Sanitary Surveillance of Goiás about the occurrence of serious adverse events associated with the incorrect use of the products. Although the products were identified to ANVISA as cosmetics, there are no injectable cosmetics. To be injectable, the product must be registered with the Agency as a medicine or health product. ANVISA also verified that the company promoted the products in the form of injectable use. The occurrences are being investigated by the Civil Police and by the Sanitary Surveillance for the performance of all the necessary measures.
ANVISA issued the communication GGMON Alert 03/2023, which contains warnings about the incorrect use of cosmetics in injectable procedures. The action was adopted after the occurrence of serious adverse events associated with the use of these products. Aimed at both consumers and professionals of aesthetic clinics, the alert clarifies the precautionary ban on certain products. In addition, it contains essential recommendations to avoid complications and protect public health. As part of the measures adopted, the Agency ordered the precautionary ban on all batches of Dermo Biostimulator and Cosmobeauty Filler products, as well as the Cosmobeauty Ultra Concentrated Toning Fluid, both of the company Bio Essencialli Indústria e Comércio de Cosméticos.
National Medical Products Administration (NMPA)
After consulting on the draft in 2022, the NMPA issued the Administrative Measures for Drug Good Laboratory Practice (GLP) Certification earlier this year. The regulation, effective on 01 July 2023, stipulates that GLP certification is mandatory for institutes that conduct non-clinical safety evaluation studies for drug registration applications in China. The regulation includes requirements for the following:
- Competent Authorities
- GLP Certification Applicants
- GLP Application Dossier
- GLP Certification Procedures
The GLP certificate is valid for five years. GLP certified institutes are required to apply for certificate renewal six months before the expiration. Every December, GLP certified institutes are required to submit a GLP Annual Report to the provincial medical products administration of the province where the institutes are located. The report will include the institute’s information, the Quality Management System operation, research state, issues in the process of implementing GLP, and the measures for the issues.
On 10 July 2023, China’s Center for Drug Evaluation released a draft guidance for a two-week comment period titled Safety Information Assessment and Risk Management Work Procedures. It outlines the agency’s expectations for the monitoring, identification, evaluation, control, and communication of safety risks during clinical trials conducted in China. According to the public notice, the Center for Drug Evaluation implemented internal changes in January 2021 that have been evaluated and are now being published in draft form for public comment. The draft release includes a document listing the revisions and the draft for comment. The Revision Explanation document includes background information and seven amendments that list the changes being proposed in the draft. The changes are a mixture of internal agency requirements and industry requirements, summarized here:
- Clarification of the responsibilities of the Center for Drug Evaluation Clinical Trial Management Office
- Clarification of risk management notification
- The addition of emergency prevention and control drugs
- Content of expert consultation meeting
- Content of risk communications
- Adjustment of the working time limit in Annex 2
- Amendments to other terminology, such as changing applicant to sponsor
On 21 July 2023, the NMPA released the revised Administrative Measures for Drug Inspections (Trial) (hereafter referred to as the Inspection Measures) with immediate effect. The revisions mainly took place in Chapter 3, Inspection Procedures, and Chapter 9, Handling of Inspection Conclusion. The Inspection Measures document, first issued in May 2021, has replaced two abolished regulations: Administrative Measures on Good Manufacturing Practices (GMP) and Administration Measures on Good Supply Practices (GSP) Certification, as China has cancelled the GMP and GSP certifications since the revised Drug Administration Law took effect in 2019.
European Commission (EC)
At a meeting of the European Union-United States (EU-US) Trade and Technology Council, the US and the EU agreed to mutually recognize the results of GMP inspections for veterinary medicinal product manufacturers. This means that veterinary medicines manufactured in the EU can now be exported to the US and marketed there without the EU manufacturers having to be inspected by a US authority beforehand, and vice versa. Nevertheless, the authorities can reserve the right to carry out GMP inspections in certain cases despite the agreement. This extends the sectoral annex for pharmaceutical GMP inspections under the Mutual Recognition Agreement (MRA) to veterinary medicinal products. The US FDA has already recognized the ability of 16 EU Member States to conduct GMP inspections of manufacturers of veterinary medicinal products. At the same time, the EU has recognized the US FDA as an equivalent authority to carry out these inspections. The US assessment of the remaining Member State Competent Authorities will continue according to a timetable agreed with the US. The target date for completion of the assessment of all EU authorities has been set at July 2024.
European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA)
EMA has published a draft reflection paper outlining the current thinking on the use of artificial intelligence (AI) to support the safe and effective development, regulation, and use of human and veterinary medicines. This paper, which is now open for public consultation, reflects on principles relevant to the application of AI and Machine Learning (ML) at any step of a medicine’s lifecycle, from drug discovery to the post-authorization setting. The reflection paper is part of the joint Heads of Medicines Agencies-European Medicines Agency (HMA-EMA) Big Data Steering Group (BDSG) initiatives to develop the European medicines regulatory network’s capability in data driven regulation. It has been developed in liaison between the BDSG, EMA’s Committee for Medicinal Products for Human Use (CHMP), and its Committee for Veterinary Medicinal Products (CVMP). All interested stakeholders are invited to comment on the draft reflection paper and to identify potential opportunities and risks of AI in the field of medicines. The public consultation is open until 31 December 2023 and the topic will be further discussed during a joint HMA/EMA workshop scheduled for 20-21 November 2023. The feedback from stakeholders will be analyzed and considered for the finalization of the reflection paper and future development of guidance as relevant.
Following the European Pharmacopoeia (Ph. Eur.)’s revision of two major general monographs: Substances for Pharmaceutical Use (2034) and Pharmaceutical Preparations (2619), revised in January 2023, the European Pharmacopoeia Commission (EPC) reviewed its current approaches, considering both current texts on N-nitrosamines, including general monographs 2034 and 2619.These texts are included in a corresponding statement in Supplement 11.3, which was recently published. In the EPC’s 176th session from 20-21 June 2023, members decided to review the original strategy for N-nitrosamine control in individual monographs on active substances as well as medicinal products. The following is summary of the recommendations were provided by the EPC:
- Deleting the Production section coveringN-nitrosamine impurities from individual monographs on active substances. The EPC also suggested not including these statements in future new monographs. The reasoning was that the general requirement for N-nitrosamines in the revised general monograph 2034 applies to all ingredients applicable to the text.
- To improve clarity, the EPC also suggested that clear rules are needed to define when to add a specification forN-nitrosamine impurities in the tests section of an active substance monograph.
- Additionally, it was suggested that the “test and limit would be included in an individual monograph if the impurity has been detected in several sources of the substance and once a limit approved by competent authorities or recommended by the Non-clinical Working Party (NcWP) becomes available”.
On 07 July 2023, the European Medicines Agency (EMA) updated its guidance on nitrosamine impurities. The EMA has amended Question & Answer 10 to include the Carcinogenic Potency Categorization Approach (CPCA) and the Enhanced Ames Test (EAT) for establishing Acceptable Intakes (AIs) for N-nitrosamines. In addition to the amendment to Question & Answer 10, a summary of additional updates to the guidance is provided below:
- The addition of Appendix 1. It lists the nitrosamines for which AIs have been established by the Non-clinical Working Party (NcWP), including new AIs forN-nitrosamines determined using the CPCA.
- The addition of Annex 2, which describes the CPCA forN-nitrosamines.
- The addition to Annex 3 which describes the EAT Conditions forN-
The assessment report of the Committee for Medicinal Products for Human Use (CHMP)’s Article 5(3) of Regulation (EC) No 726/2004 opinion on nitrosamine impurities in human medicinal products offers guidance and recommendations on mitigation and prevention of nitrosamine-contaminated human medicinal products.
Rhinaris Nasal Mist is an over-the-counter drug used to moisturize and lubricate dry nasal passages in adults and children at least two years of age. The Pendopharm Division of Pharmascience Inc. is recalling Lot Number 230391A of Rhinaris Nasal Mist due to the risk of microbial growth. Using a product contaminated with microbes may lead to rhinosinusitis (a sinus infection).
Children, pregnant people, seniors and people with weaker immune systems may be more susceptible to infection or complications from microbial contamination. Although rare, rhinosinusitis can lead to more serious complications, such as nasal abscesses (a collection of pus), cellulitis (skin infection), or meningitis (infection and inflammation of the fluid and membranes surrounding the brain and spinal cord).
Pendopharm’s testing of Lot Number 230391A of Rhinaris Nasal Mist showed that the preservative in the product may not be as effective as expected, which could lead to an increased risk of growth of microbes such as molds or bacteria over time if they are introduced into the product. While the growth of other microbes may be possible, the testing showed that the preservative may not prevent the growth of a specific type of bacteria called Pseudomonas aeruginosa if it is introduced into the product. For someone whose immune system has been weakened by other serious conditions, especially cystic fibrosis, HIV/AIDS, severe lung disease, cancer, diabetes, or burns, Pseudomonas aeruginosa can cause serious infections including pneumonia, bone infections, urinary tract infections, gastrointestinal infections, meningitis, and blood infections.
Minerals are essential substances that our bodies need to develop and function normally. Minerals are commonly used as dietary supplements, and may be prescribed or recommended by healthcare professionals for a variety of reasons. In Canada, mineral supplements are regulated as natural health products (NHPs) under the Natural Health Products Regulations. These products are widely used by Canadians. In a 2015 survey, the overall prevalence of mineral supplement or vitamin use among Canadian men and women was 38% and 53%, respectively.
Health Canada has reviewed Canadian reports of medication errors, submitted by healthcare professionals, involving mineral supplements, specifically single-ingredient products containing calcium, iron, magnesium, and zinc. These errors have led to overdoses and, in some cases, serious harm. Confusion with the strength of the elemental and salt content, as displayed on the mineral supplement’s product label, was identified as a contributing factor for these medication errors. Misinterpretation due to confusion with the labelled strength of mineral supplements can lead to over- or under-dosing. Concerns regarding the labeling of mineral supplements have been raised by healthcare professionals and poison centers across Canada. The following is a summary of a Canadian case report that was evaluated by Health Canada, describing an error associated with confusion about the labelled strength of a mineral supplement:
- In this case, the prescription was dispensed by the pharmacy using a product labelled as “Calcium Carbonate 500 mg”. While preparing the patient’s compliance pack, the pharmacy misinterpreted the product to contain 500 mg of Calcium Carbonate when each tablet actually contained 500 mg of elemental Calcium. As a result, the patient received 2.5 times the intended dose and required intervention in a hospital.
- After becoming aware of this medication error, Health Canada worked with the manufacturer to modify the product label (change from Calcium Carbonate 500 mg to Calcium 500 mg) to assist in reducing confusion and prevent similar incidents happening in the future.
The NewLife Fertility Centre, a donor sperm and ova collection facility located in Mississauga, Ontario, Canada received a non-compliant rating from Health Canada for an inspection that started on 17 July 2017. Observations included the following key points:
- The establishment’s structured donor screening questionnaire(s) did not include some criteria outlined in the Directive. In addition, the establishment did not always perform donor screen in accordance with the requirements set out in the Directive.
- The establishment did not always perform donor testing in accordance with the requirements set out in the Directive.
- The Medical Director did not always create and sign a summary document to confirm donor suitability. In addition, the summary document confirming donor suitability did not always include some required information.
- The establishment did not always perform infectious disease testing in accordance with the requirements in the Directive. In addition, the establishment did not always perform some donor testing within the timeframe(s) set out in the Directive.
- The establishment did not always perform the physical examination in accordance with the requirements set out in the Directive.
Additional concerns were noted with respect to the following:
- Quality Management System
- Personnel, Facilities, Equipment, and Supplies
- Labelling and Storing
- Errors and Accidents
Central Drugs Standard Control Organization (CDSCO)
With the rule on printing barcode or Quick Response (QR) code on the label of top 300 brand drugs to be implemented from 01 August 2023, the drug regulator affirmed that any batch of brands of drug formulations as specified in its notification and manufactured on or after the stipulated date, irrespective of the manufacturing site, shall have the barcode or QR code on its label. In accordance with the notification, the manufacturers of drug formulation products as specified in the Schedule H2 are required to print or affix a barcode or QR code that lists particulars including a unique product identification code, the proper and generic name of the drug or the brand name, the name and address of the manufacturer, batch number, date of manufacturing, date of expiry, and manufacturing license number. The unique product identification code will be determined by the manufacturer according to their own Standard Operating Procedure to ensure the identification of the product. While it is mandatory to print the code on these 300 brands, if any manufacturer voluntarily wants to affix or print the code for any other brand, they are free to do so, said the regulator in a response to Frequently Asked Questions (FAQs) prior to the implementation of the amended rule.
International Pharmaceutical Excipients Council (IPEC)
IPEC Federation announces the availability of an updated position paper on latest fatal incidents with contaminated medicinal syrup during 2022 and 2023. This paper describes IPEC Federation’s position on the importance of ensuring security of the excipient supply chain in light of occurrences of contaminated medicinal syrups in different areas of the world in recent years. The presence of numerous cases that have caused several hundred deaths due to the use of excipients of inappropriate quality in pharmaceutical formulations continues to be a global concern. The focus of the position paper is to remind all actors involved to refer and apply the existing tools to ensure security of the supply chain. Other areas requiring greater awareness are also considered.
International Organization for Standardization (ISO)
ISO has published its new standard Sterilization of Health Care Products — Microbiological Methods — Part 3 Bacterial Endotoxin Testing (ISO 11737-3:2023). The document contains requirements and guidance for testing for bacterial endotoxins. This includes products that must be non-pyrogenic based on either intended use, non-pyrogenic label claim, or both. ISO 11737-3:2023 includes general criteria for determining bacterial endotoxins on or in health care products, components, or raw materials using Bacterial Endotoxins Test (BET) methods, which use amebocyte lysate reagents. Only Gram-negative BET using amebocyte lysate reagents from Limulus polyphemus or Tachypleus tridentatus are covered.
Medicines and Healthcare Products Regulatory Agency (MHRA)
The MHRA’s Criminal Enforcement Unit (CEU) seized a quantity of suspected unlicensed medical products following coordinated raids at three residential and six business premises in Bolton, Greater Manchester, UK. The operation saw raids across nine addresses in Bolton, Westhoughton, and Leigh in the early hours of Thursday 13 July 2023, where two women and one man were arrested. Officers from the MHRA and Greater Manchester Police seized unlicensed medical products including unlicensed versions of Botox, numbing agents, and dermal fillers.
The United Kingdom (UK) government has made regulations (The Medical Devices (Amendment) (Great Britain) Regulations 2023) that enable CE marked medical devices to be accepted in Great Britain for defined periods beyond 30 June 2023. This measure aims to support the ongoing and safe supply of medical devices within Great Britain and facilitate a smooth transition towards a future strengthened regulatory framework for medical devices. It is the first statutory instrument in a series that are planned to implement the strengthened framework. Next in the series, the MHRA intends to lay a statutory instrument later this year that will put in place enhanced post-market surveillance requirements. Core aspects of the future framework for medical devices are intended to apply from 01 July 2025. This timeline is subject to ongoing review as the MHRA continues to monitor feedback from external stakeholders, for instance on the capacity of conformity assessment bodies.
The MHRA has released guidance to support implementation of new requirements for medicine packaging in 2025 under the Windsor Framework. The Windsor Framework, announced on 09 June 2023 by the MHRA, provides a long-term solution for the supply of medicines into Northern Ireland. The agreement stipulates that certain conditions must be met in the labeling and packaging of these medicinal products. In preparation for the implementation of these requirements under the Windsor Framework, new guidance for the industry was published by the MHRA on 28 July 2023. The following new measures are set to be introduced on 01 January 2025. After this date:
- Under the framework, medicines can have the same packaging and labeling across the UK. All medicines on the UK market must be labelled as for sale only within the UK, including in Northern Ireland.
- New medicines for the UK market will be authorized by UK authorities. UK packaging must carry a clearly legible “UK only” label to be allowed onto the UK market.
- These products will only be able to be sold in the UK, and will not be available on the market in Ireland or elsewhere in the EU
- Medicines entering Northern Ireland will not display features required under the EU Falsified Medicines Directive (FMD), including 2D barcodes and serialization numbers that are compliant with the EU FMD Directive.
- The MHRA expects anti-tamper devices to remain on all medicine packaging.
The MHRA will provide a single deadline for new packaging requirements. This will continue to allow medicine manufacturers to use legacy EU packaging until 31 December 2024. This extends the earlier 31 December 2023 deadline, which requires medicines for Great Britain (GB) to be presented in GB compliant packaging.
Personal Care Products Council (PCPC)
A recent nationwide study, Application Habits of SPF Users in the United States: Results of a Nationwide Survey, surveyed more than 2,200 regular sunscreen users in the U.S. about how they use sunscreen products. Unlike previous studies, which have primarily focused on recreational use of sunscreen, this study also evaluated how individuals are using the wide variety of available sunscreen products, including facial skin care, cosmetics, and lip care. The study found that spray sunscreen is applied more often on larger areas of the body and hard-to-reach areas than lotion sunscreen, whereas the latter is applied more often on sensitive areas like the face and neck. Survey data also highlighted parents’ awareness of the importance of reapplying sunscreens, paying significantly more attention to water exposure, number of hours passed since application, or redness for their children than for themselves.
Unique drivers such as weather conditions, time spent outside, and planned activities impact the types of sunscreen products used. Survey respondents were more likely to use sunscreens on sunny days, when spending more than three hours outside and participating in beach activities. The study also demonstrates a variety of safe-sun behaviors by regular sunscreen users such as other forms of sun protection, but less than 15% of survey respondents know that FDA regulates sunscreens as over-the-counter (OTC) drugs requiring rigorous testing. FDA ensures that broad-spectrum sunscreens protect against both Ultraviolet A (UVA) and Ultraviolet B (UVB) radiation and are safe and effective.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
The revised PE 009-17, Annex 1, Manufacture of Sterile Medicinal Products entered into force on 25 August 2023 and has been published on the PIC/S publications website. It entered into operation the same day as the revised Annex 1 of the EU GMP Guide, which is identical to the PIC/S Annex 1 (with some minor differences). The revised PE 009-17, Annex 1 is now applicable except for paragraph 8.123, which includes specific controls for lyophilizers. This paragraph has a later date of entry into force: 25 August 2024. The revised Annex 1 is an integral part of the PIC/S GMP Guide (PE 009-17), which has also been revised. The GMP Guide has 4 parts: Introduction, Part I, Part II, and Annexes. Annex 1 can be found under PIC/S GMP Guide (PE 009-17) Annexes.
Therapeutic Goods Administration (TGA)
TGA has published its Import, Advertising, and Supply Compliance Priorities for 2023-24 with nicotine vaping products, medicinal cannabis advertising, and the wellness and beauty industries among the focus areas. A key priority for the TGA this year will be to detect, deter, and disrupt the unlawful import, advertising, and supply of nicotine vaping products. Young Australians, in particular, are vulnerable to the risks associated with using nicotine vaping products. The TGA will dedicate resources to help stamp out unsafe access to these products. The public promotion of medicinal cannabis, psilocybin, and 3,4-methylenedioxy-methamphetamine (MDMA) to Australian consumers is illegal. The TGA will prioritize the disruption of the unlawful advertising of these products, through a combination of education, intelligence, and compliance action where necessary. Any public promotion of these medicines may inappropriately influence demand, disrupt the relationship between patients and medical professionals, and bring disrepute to the industry.
Another priority is to detect and disrupt unlawful advertising of unapproved and high-risk medicines and medical devices used in the wellness and beauty industries, including those intended to alter the body’s performance and appearance. Examples of these products include sports supplements, weight loss medications, intravenous (IV) drips, and cosmetic injectables. Australians seeking therapeutic results may be vulnerable to the sale of substandard and falsified therapeutic goods online or at physical locations by specialist retailers. The TGA has included the detection and disruption of these unlawful imports as another priority area for 2023-24.
Companies supplying medicines in Australia will be required to provide additional information to the TGA if their products go into shortage. Upcoming changes to reporting requirements will assist health professionals and patients in managing shortages by keeping the TGA’s Medicine Shortage Reports Database as up-to-date as possible. From 22 September 2023, companies supplying medicines (known as “sponsors”) will be required to specify the period of each medicine shortage in Australia. This follows changes to the Therapeutic Goods Act that came into force in March 2023. A six-month grace period was provided to allow sponsors time to refine their internal shortage reporting processes to manage the change. Sponsors will be required to report:
- Changes to the shortage duration or end date and resolution of the shortage.
- The period of the shortage of the medicine in Australia.
- Any changes to the period and resolution date of a medicine shortage where the medicine shortage period ends on or after 22 September 2023, regardless of when the shortage was first notified.
Reporting timeframes are in line with the assessed impact rating on patients. Notification should occur as soon as possible in the interest of affected patients:
- For critical shortages, changes must be reported within two working days of discovering the change to the shortage period or resolution date.
- For all other shortages, changes must be reported within 10 working days of discovering the change to the period or resolution date.
United States Food and Drug Administration (FDA) – Regulations, Guidances, Policies and Procedures
In a continuing effort to improve the quality system effectiveness of human drug manufacturing sites, FDA revised the Manual of Policies and Procedures (MAPPs) Section MAPP 5014.1: Understanding CDER’s Risk-Based Site Selection Model. The Center for Drug Evaluation and Research’s (CDER’s) MAPPs are federal directives and documentation of internal policies and procedures. MAPPs are required by law and made available to the public to make CDER a more transparent organization. The Site Selection MAPP outlines the risk-based approach the Office of Pharmaceutical Quality (OPQ) and Office of Quality Surveillance (OQS), a subpart of OPQ, employ to manage the Site Selection Model (SSM) they use to prioritize manufacturing sites for routine quality-related (i.e., current good manufacturing practice [cGMP]) surveillance inspections. Manufacturing sites are assigned a risk score and priority based on a variety of risk factors set forth in the policy. An overarching policy goal of the amended Site Selection MAPP is to determine the effectiveness of a drug manufacturer’s quality system. FDA noted in the amended policy that, during inspections, it will be attempting to determine if a quality system results in a robust state of control and promotes a quality culture that allows for exceeding the cGMP standard. CGMP compliance is the floor and FDA is looking for companies to exceed those standards.
FDA Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products provides recommendations and instructions to assist persons submitting cosmetic product facility registrations and product listings to FDA. This guidance document explains, among other things:
- The statutory requirement to submit cosmetic product facility registrations and product listings.
- Who is responsible for making the submissions.
- What information to include in the submissions.
- How to make the submissions.
- When to make the submissions.
FDA intends to make the new electronic submission portal available for submitting registration and product listing information under Section 607 of the Federal Food Drug and Cosmetic Act (FD&C) Act in October 2023. FDA is developing a paper form as an alternate submission tool. FDA strongly encourages electronic submissions to facilitate efficiency and timeliness of data submission and management for the agency. Registration timelines are as follows:
- Every person that, on 29 December 2022, owns or operates a facility that engages in the manufacturing or processing of a cosmetic product for distribution in the United States must register each facility no later than 29 December 2023.
- Every person that owns or operates a facility that first engages in the manufacturing or processing of a cosmetic product for distribution in the United States after 29 December 2022 must register each facility within 60 days of first engaging in such activity or by 27 February 2024, whichever is the later.
- Every person who is required to register must update their registration within 60 days of any changes to the information required for registration (amended registration). This includes any changes that result in cancellation of the registration.
- Every person who is required to register a facility must renew such registration biennially (every two years).
United States Food and Drug Administration (FDA) – Recalls
Drägerwerk AG & Co. KGaA initiated a voluntary recall notification for Dräger Carina Sub-Acute Care Ventilators to address possible contamination of the breathing gas with 1,3- Dichloropropan-2-ol, a constituent of the Polyester-Based Polyurethane (PE-PUR) foam used for sound insulation. To date, Dräger’s market surveillance activities show that no complaints relating to this problem have been reported. To determine the long-term stability of the PE-PUR foam used for sound insulation in Carina ventilators, Dräger subjected devices of different ages to biocompatibility tests. For Carina ventilators operated for periods of up to 15 years, no age-related degradation or decay products associated with degradation were found in those standard tests. However, certain standard tests conducted by Dräger measured concentrations of 1,3-Dichloropropan-2-ol above the acceptable uptake level during continuous use (>30 days) in pediatric patients. Dräger’s investigations determined that a setting of higher minute volumes leads to lower concentrations in the breathing air. At a minute volume greater than 3.6 l/min, the measured concentrations were in the acceptable range for continuous use in adult patients.
1,3-Dichloropropan-2-ol is a constituent of polyurethane foam, which was not discovered in the breathing gas during previous biocompatibility tests conducted within the framework of product approvals and modifications. In literature, 1,3-Dichloropropan-2-ol is considered to be acutely toxic and a potential carcinogen. Potential risks of chemical exposure due to off-gassing include headache or dizziness, irritation (of eyes, nose, respiratory tract, or skin), hypersensitivity, nausea or vomiting, or toxic and carcinogenic effects. There have been no reports of death as a result of such exposure. These issues may result in serious injury, which can be life-threatening, cause permanent impairment, or require medical intervention to preclude permanent impairment. To date, Dräger has not received any reported symptoms of an acute toxic reaction, nor any other complaints relating to this issue via their market surveillance.
Although Dräger discontinued production of the Carina ventilator in 2019, the company is planning to remove the foam from Carina ventilators still in use and replace it with a newly designed blower cover, without additional foam, for noise reduction purposes.
Inmar Supply Chain Solutions, LLC (“Inmar”), is voluntarily recalling FDA regulated products contained in pallets stored in Inmar’s Arlington, Texas facility between 01 May 2022 and 30 June 2023. The FDA recalled products were stored in this facility during a time when there may have been a pest control problem at the facility. In addition, because of recent unusually hot weather, the FDA recalled products may have been subjected to temperatures in excess of the storage condition instructions on the product labeling. The FDA recalled products were sold to salvage buyers. Inmar has notified those salvage buyers by email and notified them to destroy any FDA recalled product. Inmar has not received any customer complaints or reports of adverse events related to this recall.
Risk Statement: There are numerous hazards associated with rodents including the potential presence of Salmonella. Use or consumption of affected products may present risk of illness due to the potential presence of Salmonella, an organism that can cause serious and sometimes fatal infections in infants, young children, frail or elderly people, pregnant persons, persons with pre- existent pathology (e.g., patients with cancer undergoing chemotherapy treatments or organ transplant recipients) and others with weakened immune systems. Healthy persons infected with Salmonella often experience fever, diarrhea (which may be bloody), nausea, vomiting, and abdominal pain. In rare circumstances, infection with Salmonella can result in the organism getting into the bloodstream and producing more severe illnesses such as arterial infections (i.e., infected aneurysms), endocarditis, and arthritis. Additionally, products stored under temperatures in excess of storage conditions instructions in the product labeling could potentially lead to decreased product effectiveness.
United States Food and Drug Administration (FDA) – Warning Letters
Gadal Laboratories Inc. received a Warning Letter from FDA on 15 August 2023. This Warning Letter was issued as a result of an inspection conducted at the company’s facility in Miami, Florida from 13-17 February 2023. The investigators determined that the methods, facilities, or 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 failed to validate and establish the reliability of their component supplier’s test analyses at appropriate intervals. For example:
- One of the active ingredients was sourced from an unqualified supplier and was approved for use without establishing the reliability of the supplier’s Certificate of Analysis (COA).
- The microbiological testing of an excipient in the supplier qualification document only included a general statement that it should be free from pathogens but lacked any further specificity on the microorganisms that the firm considers to be objectionable.
- The firm lacked a specific identity test to detect potential contaminantsin all shipments, containers, and lots of materials before use in the manufacturing of drug products. It was noted that some of the drug products containing these ingredients are intended for oral use in pediatric populations. Reference: FDA Guidance – Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol, May 2023.
- The firm’s Quality Control Unit did not review and approve written procedures for production and process control, including any changes to them, designed to ensure that the drug products manufactured have the identity, strength, quality, or purity they purport or are represented to possess. For example:
- The firm failed to adequately validate production and process controls and did not have assurance that it was capable of consistently manufacturing OTC drug products with defined quality attributes. During the inspection, the firm acknowledged that none of the initial process validation studies (i.e., Process Performance Qualification [PPQ]) were complete.
- The firm failed to adequately qualify and test a specifiedsystem to assure the material produced from the system consistently meets chemical and microbiological standards and is suitable for use as a raw material in drug manufacturing or for cleaning.
- The firm had not thoroughly validated the cleaning processes and the cleaning verification program did not adequately detect potential cross-contamination between products or microbiological contamination.
- The firm failed to establish adequate written responsibilities and procedures applicable to the Quality Control Unit and to follow such written procedures. For example:
- The firm replaced an inactive ingredient with another inactive ingredient, without documented scientific rationale and justification, in multiple batches of OTC drug products.
- Analysts documented original laboratory data on uncontrolled sheets of paper. Analysts also recorded raw data in pencil and changed written data using correction fluid to obscure the original result.
World Health Organization (WHO)
Medical Product Alert No5/2023 refers to a batch of substandard (contaminated) Naturcold Syrup identified in Cameroon and first reported to WHO on 13 March 2023. All reasonable precautions have been taken by WHO to verify the information contained in this alert and this may be updated as more information becomes available. The stated active ingredients of Naturcold Syrup are listed as paracetamol, phenylephrine hydrochloride, and chlorpheniramine maleate. The combination of these three ingredients are used to relieve symptoms associated with the common cold, flu, and allergic rhinitis. Samples of the Naturcold Syrup from Cameroon were made available to WHO on 27 June 2023 and analyzed in a WHO contracted and prequalified laboratory. The analysis found that the product contained unacceptable amounts of diethylene glycol as contaminants. Diethylene glycol was detected in samples of Naturcold Syrup as much as 28.6%. The acceptable limit for Diethylene Glycol is no more than 0.10%. The stated marketer of the affected product is listed on the product packaging as Fraken International (England). The United Kingdom (UK) national regulatory authority, the MHRA, has confirmed that no such manufacturer exists in the UK.
Enquiries are still underway to determine the origin of the Naturcold Syrup. Therefore, the stated manufacturer has not provided guarantees to WHO on the safety and quality of these products. The substandard products referenced in this alert are unsafe and their use, especially in children, may result in serious injury or death. Toxic effects can include abdominal pain, vomiting, diarrhea, inability to pass urine, headache, altered mental state, and acute kidney injury, which may lead to death. WHO has previously published four alerts on other contaminated liquid dosage medicines: Medical Product Alert N°6/2022, Medical Product Alert N°7/2022, Medical Product Alert N°1/2023, and Medical Product Alert N°4/2023.