SQA Regulatory Surveillance Summary | Monthly Update 2022 – July/August
SQA Regulatory Surveillance Summary for July and August 2022
Health Canada is warning consumers about counterfeit BTNX Rapid Response COVID-19 antigen rapid test kits (25-pack boxes) found in Ontario. The counterfeit devices were sold online by a distributor named Healthful Plus without the required license to import, distribute, or sell medical devices in Canada. The packaging of the counterfeit kits resembles authentic (licensed) BTNX Inc. products in color and typeface and uses the BTNX Inc. device identifier “COV-19C25.” However, unlike authentic BTNX Inc. products, the counterfeit kits:
- Are labelled as manufactured by “Health Advance Inc.” instead of BTNX Inc.
- List Health Advance as an “Official Canadian Distributor”
- Include the text “Health Canada Approved” (Claims of endorsement by government authorities, such as Health Canada, are not permitted.)
Counterfeit health products are imitations of authentic products. The safety and effectiveness of these counterfeit kits have not been assessed by Health Canada. After becoming aware of the potential counterfeit kits, Health Canada confirmed with BTNX Inc. that the devices were counterfeit. Health Canada also received confirmation from the purchaser of the counterfeit products that they had purchased the kits for personal use. The entire shipment, which contained 435 boxes of the 25-pack, was sent to Health Canada for compliance follow-up. Based on information to date, the issue appears to be limited to one manufacturer, Health Advance Inc., and one distributor, Healthful Plus. Health Advance Inc. appears to no longer be manufacturing medical devices. Healthful Plus’s website has been removed, and the company appears to no longer be in operation.
COVID-19 rapid antigen tests are an essential tool in helping to detect infection and slow the spread of the disease. Health Canada recognizes that it is vital that Canadians can trust that the test kits that they rely on are authentic. Heath Canada is informing the provinces and territories about this issue, as well as Medical Device Establishment License holders, advising them to not purchase from the two companies or further distribute.
Health Canada seized numerous unauthorized health products from Productos Latinos El Aguila located at 42 Erie St S, Leamington, Ontario. The seized products include seven that are labeled to contain prescription drugs and may pose serious health risks.
Selling unauthorized health products in Canada is illegal. Unauthorized health products have not been approved by Health Canada, which means that they have not been assessed for safety, efficacy, and quality and may pose a range of serious health risks. For example, they could contain high-risk ingredients, such as prescription drugs, additives, or contaminants that may or may not be listed on the label. These ingredients could interact with other medications and foods. In addition, the product may lack the active ingredients Canadians would expect them to contain to help maintain and improve their health. Prescription drugs should only be used under the advice and supervision of a health care professional because they are used to treat specific conditions and may cause serious side effects. Prescription drugs can only be legally sold with a prescription.
If any new health risks are identified, Health Canada will take action and inform Canadians as needed.\
Taro Pharmaceuticals Inc. is recalling all lots of Taro-Zoledronic acid injection 5mg/100mL (DIN 02415100) because they may contain particulate matter. Zoledronic acid is a prescription drug used to treat and prevent osteoporosis and to treat Paget’s disease (a condition that disrupts the normal cycle of bone renewal).
If particulate matter is injected into a patient, there is potential for injury, such as inflammation or irritation of the veins, infections at the site of injection or in other parts of the body, allergic reactions, and formation of blood clots that can move to other parts of the body. In the most serious cases, blood clots could move to the lungs and cause lung damage (pulmonary embolism), which can be permanent or fatal. Patients who have been treated with a recalled drug should go to the hospital immediately if they develop difficulty breathing, chest pain, or confusion.
Health Canada is monitoring the Taro Pharmaceuticals Inc.’s recall and will inform the public if any new health risks are identified.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
A Step 2 Informational Presentation has been developed by the M12 Expert Working Group, in follow up to the ICH M12 draft Guideline on Drug Interaction Studies reaching Step 2b of the ICH Process on 24 May 2022. The M12 guideline provides general recommendation on how to evaluate the Drug-Drug Interaction (DDI) potential of an investigational drug. It is recognized that the DDI evaluation is generally tailored based on the specific drug, intended patient population, and therapeutic context. Alternative approaches can be used if they satisfy the requirements of the applicable statutes and regulations.
The focus of the guideline is the development of new drugs, but if new scientific information regarding the potential for DDIs is obtained after drug approval, additional DDI evaluation should be considered.
The Addendum to the ICH S1B Guideline has reached Step 4 of the ICH process on 04 August 2022, being integrated with the original guideline, and published as ICH S1B(R1) Testing for Carcinogenicity of Pharmaceuticals. The new Addendum expands the evaluation process for assessing human carcinogenic risk of pharmaceuticals by introducing an additional approach that is not described in the original S1B Guideline.
Application of this integrative approach reduces the use of animals in accordance with the 3R (reduce/refine/replace) principles and shifts resources to focus on generating more scientific mechanism-based carcinogenicity assessments, while continuing to promote safe and ethical development of new pharmaceuticals.
International Organization for Standardization (ISO)
ISO/IEC 23053:2022 establishes an Artificial Intelligence (AI) and Machine Learning (ML) framework for describing a generic AI system using ML technology. The framework describes the system components and their functions in the AI ecosystem. This document is applicable to all types and sizes of organizations, including public and private companies, government entities, and not-for-profit organizations, that are implementing or using AI systems. Sections include Terms and Definitions, ML System, ML Approaches, ML Pipeline, and Annex A: Example Data Flow and Date use Statements for Supervised Learning Process.
Medicines and Healthcare Products Regulatory Agency (MHRA)
Medicines and medical devices valued at over £850,000, totaling more than 285,000 items, have been seized by officers from the Medicines and Healthcare products Regulatory Agency (MHRA) as part of a global operation to tackle the illegal sale of medical products, with United Kingdom (UK) seizures estimated to be worth around 9% of the global total. In the UK, 48 social media accounts unlawfully offering to supply medicines were also shut down. Officers from the MHRA Criminal Enforcement Unit searched five premises in the West Midlands and London, with two suspects arrested.
During the global week of action coordinated by Interpol, which ran from 23 to 30 June 2022, this year’s ‘Operation Pangea’ saw countries across the world joining forces to seize non-compliant medical products. The operation also involved the arrests of several suspected organized criminals. In the UK, anti-depressants, erectile dysfunction tablets, painkillers, anabolic steroids, and slimming pills were among the medicines seized.
Following several high-profile rulings by the Advertising Standards Authority, the MHRA and CAP have issued a joint enforcement notice about the advertising of Kenalog injections on social media. This enforcement notice warns all organizations offering Kenalog as a hay fever treatment to stop advertising it on any of their social media or website advertising.
Kenalog is a Prescription-Only Medicine (POM), which must not be directly or indirectly advertised to the public. Kenalog is not licensed for the treatment of hay fever in the UK, although it is offered by some beauty and aesthetics clinics under the personal responsibility of an individual prescriber, and it is advertised widely on social media. Now, advertisers must ensure that all references to Kenalog in text, images, or emojis on social media are removed, as well as commonly used descriptive phrases for the jab, such as “hay fever injection,” or “hay fever jab,” or any account names, testimonials, or memes by 29 August 2022. After this date, the CAP’s compliance team will remove non-compliant ads using targeted software, and those who continue to promote it may be referred to the MHRA for further enforcement action.
Kenalog is the brand name for triamcinolone acetonide and is a steroid injection that is licensed as a medicine for a number of conditions, though not for the treatment of hay fever.
With the UK’s exit from the European Union (Brexit), a transition period also has started with regard to medical devices. The MHRA has now published plans on how to proceed after this transition period. These plans concern both medical devices and in vitro diagnostics. The UK sees the plans as an opportunity to introduce new regulations after Brexit in order to strengthen the public health sector. The aim is to promote patient safety and innovation. A separate mark, the UK Conformity Assessed (UKCA) mark, will indicate that these new regulations have been implemented.
The following measures are planned:
- Strengthening the MHRA in its enforcement of high-risk products, such as implants, to ensure the performance of these products and patient safety.
- Expanding existing regulations to meet public demands for medical device performance and patient safety.
- Identifying and reducing differences in patient populations across the medical device lifecycle.
- Making the UK the focus of innovation, with the aim of giving the UK population better access to new, highly innovative products.
- Setting world-leading standards, recognizable through the new UKCA mark to replace the CE mark. The UKCA mark will then show that safety, health, and environmental aspects have been met in the manufacture of medical devices. As well as enhancing its reputation, the MHRA expects this to lead to growing partnerships with other regulatory bodies.
A press release issued by the MHRA provides additional information.
Personal Care Product Council (PCPC)
Statement by the PCPC in Response to the National Academy of Sciences (NAS) Report, “Review of Fate, Exposure, and Effects of Sunscreens in Aquatic Environments and Implications for Sunscreen Usage and Human Health,” 09 August 2022
Cosmetics and personal care products companies provide innovative sunscreen products to help protect consumers from the harmful effects of the sun’s ultraviolet (UV) rays. The PCPC and its member companies have welcomed the NAS thorough and comprehensive review of the state of the science (released 09 August 2022) on the use of currently marketed sunscreen ingredients, their environmental impact on aquatic environments, and the potential public health implications associated with changes in sunscreen use.
An ad hoc committee of the NAS calls upon the United States Environmental Protection Agency (US EPA) to conduct an Environmental Risk Assessment (ERA) of sunscreen UV filters to characterize possible risks to aquatic ecosystems and the species that live within them, including coral. The report identified information gaps and research priorities necessary to inform a tiered approach to the ERA. The key conclusions confirm PCPC’s long-held position that there is currently insufficient relevant and reliable scientific data to conduct realistic ERAs, and there is not enough scientific data to support sunscreen ingredient bans. Policymakers, regulators, and legislators should not make any decisions that impact consumers’ access to FDA-approved sunscreen UV filters until the scientific community reaches an informed consensus.
Parenteral Drug Association (PDA) – Technical Reports
Technical Report No. 65 (Revised): Technology Transfer, provides a standardized approach to the technology transfer process. It supplies a matrixed “Reference Guide to Technology Transfer Activities and Deliverables,” which can be used to coordinate cross-functional technology transfer activities that help achieve operational readiness and culminate in regulatory approval. It is intended to provide a level of detail and approaches that can be applied across technology transfer types.
This Technical Report is designed to assist companies in the technology transfer process, and it covers the full range of requirements needed, such as new product introductions and the transfer of products that are being manufactured for phase III clinical trials or commercial release, which are the most comprehensive in nature. While the technical report was not specifically written for products at an earlier stage of development, many of the requirements can still be applied.
Technical Report No. 41 (Revised): Virus Retentive Filtration, provides a summary of best practices for utilization of virus filtration in process development and manufacturing. The document explains what virus filters are and where they can be used in current and emerging bioprocesses. Recommendations for selection of a suitable virus filter are presented, including information on their physical and biological/safety characterization, and guidance on how to incorporate Quality by Design (QbD) principles into virus filtration applications. Strategies for evaluating and validating virus retention by virus filtration, including defining the worst-case test parameters, are also discussed. Considerations that reflect best practices and current thinking for implementing virus filtration into novel manufacturing technologies, such as barrier filters, continuous bioprocessing modes for filtration, or production of Advanced Therapy Medicinal Products (ATMPs), are also included.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
PIC/S Sub-Committees have been elected for a two-year term starting on 01 January 2022 and ending on 31 December 2023. The present Work Plan has been prepared by the newly elected Sub-Committees. As the year has already started, objectives which cannot be completed by the end of 2022 will be rescheduled in 2023.
The following key points are included:
- Due to the pandemic and other events, all assessments and reassessment visits were put on hold in 2020 and 2021. Only a few processes have been able to unfold virtually during the pandemic, such as the pre-accession process of the China National Medical Products Administration (NMPA), the accession of the Bulgaria Drug Agency (BDA) and the Saudi Food and Drug Authority (SFDA), and the reassessment of the New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE). The objective for 2022 is to restart all assessments and reassessments and to reschedule all visits, subject to priorities and availability of resources. All assessment and reassessment activities will be coordinated and monitored by the Sub-Committee on Compliance (SCC). While waiting for these activities to unfold, the SCC will focus on completing the revision of guidelines and procedures related to the Accession and Joint Reassessment Program (JRP).
- Subject to the availability of resources, the SCC will consider proposals for (i) the introduction of annual reporting system, in order to monitor the continued compliance of Participating Authorities (PAs) with PIC/S requirements; and (ii) the establishment of a list of experienced auditors to assist and advise new rapporteurs and auditors.
- The PIC/S GMP Guide will be further revised in close cooperation with the European Medicines Association (EMA).
- The PIC/S GMP Guide will be further revised in close cooperation with the EMA’s Inspectors Working Group (IWG) on GMDP. PIC/S normally participates through experts.
Therapeutic Goods Administration (TGA)
The Therapeutic Goods Administration (TGA) continues to collaborate with the Australian Government’s international regulatory partners to investigate the issue of nitrosamine impurities in medicine products. This includes sharing information, determining the actions that may be required, and coordinating efforts on inspections, risk assessments, and communications. International alignment of the approach to this issue, where possible, is recognized as beneficial. The TGA will share information with the industry should a new risk be identified and will take appropriate regulatory actions, including overseeing the implementation of improved manufacturing and testing processes to ensure the safety and quality of medicines in Australia.
Australian medicine sponsors are responsible for the quality, safety, and efficacy of their medicines, including the active ingredients, excipients, and other raw materials used in the manufacturing of finished products. There are ongoing requirements for sponsors to monitor the quality, safety, and efficacy of their products, as well as to inform the TGA if they become aware of any issues. Sponsors should be aware of the global issue relating to nitrosamine impurities in medicines. Sponsors are required to inform the TGA in writing as soon as they become aware of information that indicates that the quality, safety, or efficacy of their goods is unacceptable. This includes both sponsors and manufacturers of medicines and biologicals informing the TGA if they become aware that their medicine is affected by a nitrosamine impurity exceeding the appropriate Acceptable Intake (AI) limit. Sponsors should consult the TGA recall procedures if a recall may be warranted. Sponsors should report any overseas regulatory actions related to nitrosamine contamination of their medicines to the TGA as a Significant Safety Issue (SSI) to the Signal Investigation Coordinator within the required timeframe.
The TGA expects that sponsors are familiar with the known and plausible causes of nitrosamine impurities in their products. To meet their regulatory obligations, sponsors should take active steps to determine whether their medicines are at risk of containing nitrosamine impurities. Sponsors should ensure that they (and their finished product manufacturers) have access to relevant information from the Active Pharmaceutical Ingredient (API) manufacturer(s) regarding potential formation and presence of nitrosamine impurities, as well as the potential for cross-contamination.
The scope of investigations into the potential presence of nitrosamine impurities is very broad. Sponsors are expected to monitor for signals and respond appropriately. This includes prioritizing APIs that have been reported overseas as being affected. Sponsors should consider the following factors when prioritizing their medicines for consideration:
- Duration of use
- Maximum daily dose
- Size of population using the medicine
- Any other factors relevant to the medicine
Given the nature of the safety concerns for nitrosamines, priority should generally be given to products with a chronic duration of use and a high daily dose. This approach is consistent with that suggested by other international regulators, including the EMA.
The TGA has approved the removal of the geographical deferral of blood and plasma donors from the UK, which was put in place to minimize the risk of variant Creutzfeldt-Jakob disease (vCJD), commonly known as “mad cow disease.”
This decision follows an application made to the TGA from the Australian Red Cross Lifeblood to remove the deferral, which is applicable to blood and plasma donors having spent a cumulative length of time of six months or more in the UK between 1980 and 1996. The TGA conducted a scientific, epidemiological, and clinical assessment of the risk model submitted by Lifeblood. The TGA concluded that the modeled risk is reliable, and by removing the deferral of vCJD, the risk of transfusion transmission of vCJD would remain very low. The change will result in a potential modest increase in the number of blood and plasma donors in Australia.
The article provides a listing of the TGA’s priority areas for compliance activities relating to the import, advertising, and supply requirements of the Therapeutic Goods Act 1989, from 01 July 2022 to 30 June 2023. These should be read in conjunction with the Regulatory Compliance Framework and Principles for Managing Advertising Compliance, which describe TGA’s approach to compliance, including how they encourage compliance and respond to alleged contraventions of the law.
In addition to the priority areas, the TGA manages many individual compliance activities and investigations. Further compliance priority areas may arise during the year and be added to the list. There are several other compliance programs across the TGA that are not covered by the list, such as compliance activities associated with complementary medicine listings, monitoring and vigilance of medical device inclusions, Pharmacovigilance and Good Clinical Practice inspection programs, and the GMP compliance program.
A new version of the Uniform Recall Procedure for Therapeutic Goods (URPTG) (V2.3, June 2022) has been implemented, with an effective date of 30 June 2022. This version includes the following updates:
- Removal of the references to the Crisis Management Guidelines
- Clarification on the submission of customer/distribution lists, including an example list in the appropriate format
- Additional guidance related to the online notification of actions through the TGA Business Services (TBS) website
- Clarification on the submission of final reports, including additional guidance regarding root cause, CAPA information, customer follow-up attempts, and TGA close out letters
- Minor changes to the information on consumer recall notices, including targeted SMS alerts and clarification on website publication timeframes
United States Food and Drug Administration (FDA) – Regulations and Guidances
This guidance describes Chemistry, Manufacturing, and Controls (CMC) post-approval changes related to disposable manufacturing materials that applicants can pursue in drug and biological product manufacturing. This guidance applies to Biologics License Application (BLA) products, human drug products marketed as New Drug Applications (NDAs) or Abbreviated New Drug Applications (ANDAs), and animal drugs marketed as New Animal Drug Applications (NADAs) or Abbreviated New Animal Drug Applications (ANADAs). This guidance applies to all manufacturing establishments, including those that perform functions under contract, as defined in the following guidance for industry: Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016).
This guidance addresses the following questions:
- Q1 – What are some possible changes an applicant can make to disposable manufacturing materials, and what reporting categories are applicable?
- Q2 – Are there steps to lower the reporting category of a supplement?
- Q3 –When and how should an applicant contact the FDA for feedback on a proposed change?
The FDA has updated this guidance to include the FDA’s compliance policy regarding Global Unique Device Identification Database (GUDID) submission requirements for certain Class I devices considered consumer health products. Specifically, the FDA does not intend to enforce the GUDID submission requirements under 21 CFR 830.300 for Class I devices considered to be consumer health products that are required to bear a Unique Device Identifier (UDI) on their labels and device packages. Additionally, the FDA does not intend to enforce the GUDID submission requirements under 21 CFR 830.300 for Class I and unclassified devices, other than Implantable, Life-Supporting, or Life-Sustaining (I/LS/LS) devices, regardless of whether they are consumer health products, before 08 December 2022 (an additional 75 calendar days).
This technical specifications document is to assist interested parties in electronically submitting Individual Case Safety Reports (ICSRs) and ICSR attachments to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to the FDA or Agency. This document describes the FDA’s technical approach for submitting ICSRs, for incorporating its regionally controlled terminology, and for adding FDA Adverse Event Reporting System (FAERS) regional data elements that are not addressed in ICH’s E2B (R3) Implementation Guideline (IG) for the following FDA-regulated products:
- Drug products marketed for human use with approved New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs)
- Prescription drug products marketed for human use without an approved application
- Nonprescription (Over-the-Counter human drug products marketed without an approved application)
- Biological products marketed for human use with approved Biologic License Applications (BLAs)
This guideline presents a discussion of elements for consideration during the validation of analytical procedures included as part of registration applications submitted within the International Conference for Harmonization (ICH) member regulatory authorities. Q2(R2) provides guidance and recommendations on how to derive and evaluate the various validation tests for each analytical procedure. This guideline serves as a collection of terms and their definitions, which are meant to bridge the differences that often exist between various compendia and documents of the ICH member regulatory agencies.
United States Food and Drug Administration (FDA) – Recalls
Mylan Pharmaceuticals Inc., a Viatris Company, Issues Voluntary Nationwide Recall of One Batch of Insulin Glargine (Insulin glargine-yfgn) Injection Pens, 100 units/mL (U-100), Due to the Potential of Missing Labels on Some Pens, 05 July 2022
Mylan Pharmaceuticals Inc., a Viatris company, is voluntarily recalling one batch of Insulin Glargine (Insulin glargine-yfgn) Injection, 100 units/mL (U-100), 3 mL prefilled pens, which are packaged in cartons of five pens at the consumer level. This product is not the branded Semglee® pen but the unbranded Insulin Glargine-yfgn pens. This batch is being recalled due to the potential for the label to be missing on some pens.
For patients receiving treatment with more than one type of insulin (e.g., both short- and long-acting insulin), a missing label on Insulin Glargine pens could lead to a mix-up of products and strengths, which may result in less optimal glycemic control (either high or low blood sugar), which could result in serious complications. To date, no adverse events related to this recall have been received for this product.
This recall pertains only to the unbranded, interchangeable, biosimilar Insulin Glargine-yfgn pens and does not impact the branded, interchangeable, biosimilar Semglee® (insulin glargine-yfgn) injection pens. This product is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. The product is packaged in a 3 mL prefilled pen, which is then packaged in cartons of five pens.
Hopira, Inc., a Pfizer company, is voluntarily recalling one lot of Propofol Injectable Emulsion, USP (containing benzyl alcohol), 100 mL Single Patient Use Glass Fliptop Vial, Lot DX9067, to the user level due to a visible particulate observed in a single vial during annual examination of retain samples. Patients receiving the impacted product are at risk of experiencing life-threatening adverse clinical effects including but not limited to blockage of blood vessels, including decreased blood flow to the brain, heart attack, pulmonary embolus, and tissue necrosis. Hypersensitivity reactions and transmission of infectious disease can also occur.
To date, Hospira, Inc. has not received reports of any adverse events associated with this issue for this lot.
Family Dollar is initiating a voluntary retail-level product recall of specified products regulated by the FDA that were stored and inadvertently shipped to certain stores on or around 01 May 2022 through 10 June 2022, due to product being stored outside of labeled temperature requirements. To date, Family Dollar has not received any consumer complaints or reports of illness related to this recall.
United States Food and Drug Administration (FDA) – Warning Letters
The FDA issued a Warning Letter to Custom Research Labs Inc. on 08 July 2022 based on the result of an inspection of their drug manufacturing facility on 01-04 June 2021. This warning letter summarized significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals.
A summary of the Form FDA 483 observations provided during the inspection is as follows:
- The firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. The firm also failed to validate and establish the reliability of their component supplier’s test analyses at appropriate intervals. Specifically, the firm failed to test incoming APIs (e.g., camphor and menthol) and other components (e.g., deionized water) used to manufacture Over-the-Counter drug products to determine their identity, purity, strength, and other appropriate quality attributes. For APIs, the firm relied solely on Certificates of Analysis (COAs) from suppliers that did not have established reliability. In addition, the firm has not shown that their water system can consistently produce water suitable for drug manufacturing, and, at a minimum, meet the USP monograph for purified water and appropriate microbial limits.
- The firm failed to establish adequate written procedures for production and process control designed to assure that the drug products manufactured have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, the firm failed to validate the manufacturing process for drug product currently in distribution. This was a repeat observation from their 2016 FDA inspection.
- The firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates. This was a repeat observation from their 2016 FDA inspection.
- The firm’s Quality Control (QC) unit failed to exercise its responsibility to ensure drug products are manufactured in compliance with CGMP and meet established specifications for identity, strength, quality, and purity. Specifically, the Quality Unit (QU) failed to review batch records before releasing drug product for distribution. The QU procedure specifies that the Quality Assurance (QA) designee is responsible for reviewing all manufacturing, production, and quality records. However, during the inspection, one of the QU employees stated that the Shipping and Production department had released drug product batches before the batch record had been reviewed by the QU.
The FDA issued a Warning Letter to DSP Skin Care LLC on 19 July 2022 based on the result of an inspection of the company’s Los Angeles, CA drug manufacturing facility, conducted on 07-09 September 2021. The Warning Letter states that the methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, such that DSP Skin Care LLC’s drug products are considered to be adulterated. In addition, the company’s Hongosan Anti-Fungal Set product is an unapproved new drug introduced or delivered for introduction into interstate commerce.
A summary of the Form FDA 483 observations during the inspection is as follows:
- The firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Specifically, the firm released Hongosan Premium Plus Spray and DSP Skin Care Hand Sanitization Gel Over-the-Counter (OTC) drug products without testing to ensure that they met their identity, purity, strength, and other appropriate quality attributes. While the label for Hongosan Premium Plus Spray drug product lists an active ingredient, the firm stated that the contract manufacturer did not test the product since it no longer contained an active ingredient, undecylenic acid. In addition, the firm stated to the FDA investigators that the DSP Skin Care Hand Sanitization Gel drug product was not tested by their contract manufacturer because they had failed to pay them to test the product.
- The firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates. Specifically, the firm lacked an adequate stability program to demonstrate that the chemical and microbiological properties of the Hongosan Anti-Fungal Set and Hongosan Premium Plus Spray drug products remain within specification throughout their labeled expiry period. It was explained to the FDA investigators that the contract manufacturer verbally informed the firm that a two-year expiration date is the appropriate shelf life for these products without conducting stability studies or providing any stability data. The firm had proposed remediation of their stability program during the 2018 inspection.
- The firm’s QC unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity. Specifically, the firm lacked written procedures detailing the roles, responsibilities, and duties of the QU to ensure that QU functions are accurately performed and that drug products meet quality standards. For example, the firm lacks written quality procedures for investigations, corrective and preventive action (CAPA), change control, CGMP training, drug product stability, and finished drug product release. In addition, the firm could not provide batch production records, including lot control numbers, for bulk drug products used in repacking or filling operations for approximately 20 batches of Hongosan Anti-Fungal Cream and Hongosan Premium Plus liquid drug products. During the 2018 inspection, the firm acknowledged the need for a QU to ensure that the manufacturing process of OTC drug products remains in control.
The FDA and Federal Trade Commission (FTC) issued a Warning Letter to FluxxLab LLC on 04 August 2022 based on a review of the firm’s website at the Internet address https://fluxxlab.com/ on 12 July 2022 and 01 August 2022, respectively. The FDA observed that the firm’s website offers the COVID-19 Immune Support Tincture and the CBDA+CBD Oil Tincture products for sale in the U.S., and that these products are intended to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. Based on the FDA review, these products are unapproved new drugs sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act. Furthermore, these products are misbranded drugs. The introduction or delivery for introduction of these products into interstate commerce is prohibited. The FDA is taking urgent measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. The FDA has requested that the firm take immediate action to cease the sale of any unapproved and unauthorized products for the mitigation, prevention, treatment, diagnosis, or cure of COVID-19. Examples of the firm’s products that are misleadingly represented as safe and/or effective for the treatment of COVID-19 include the following:
- CBDA+CBD Oil Tincture
- COVID-19 Immune Support
FDA issued a Warning Letter to Green Wave Analytical, LLC based on the result of an inspection of the company’s San Diego, CA facility from 15 February to 07 March 2022. The inspection determined that the company is a contract testing laboratory for drugs including, but not limited to, finished sterile injectable drugs and components. The Warning Letter summarizes significant violations of CGMP regulations for finished pharmaceuticals, as follows:
- The firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods. Specifically, the firm failed to perform method validation (or verification, as appropriate) of test methods to ensure that they were suitable for their intended use. For example, the firm did not determine the suitability of their assay test for the active ingredient phenobarbital sodium, as the firm had deviated from compendial methods without validation of the method and without performing system suitability to ensure equipment was functioning properly at the time of use. The firm also tested various drug products for sterility, endotoxin, and other microbial attributes using compendial test methods without verifying the suitability of the methods for each drug product under the actual conditions of use.
- The firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards. For example, laboratory records for the chemical and microbiological testing of drugs lacked the identification of the method used; documentation of a method’s execution; identity of standards, reagents, and test kits used; identification of the sample’s lot number for traceability; or equipment used (including, but not limited to, microbiological media, micro-pipette, and High Performance Liquid Chromatography (HPLC) systems).
- The firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records. For example, an HPLC system did not have sufficient controls to prevent deletion and alteration of raw data files. During the inspection, the FDA investigators observed laboratory personnel performing drug testing and analyses, and personnel had administrative privileges to the operating software for the HPLC system. These privileges included, but were not limited to, the ability to delete data sequences and change method parameters.
- The firm failed to establish a system for monitoring environmental conditions in aseptic processing areas. Specifically, the firm performed sterility testing for lots of finished drug products purported as sterile but failed to effectively establish a system for monitoring environmental conditions to ensure ISO 5 air quality within the testing equipment and in adjacent areas. In addition, the firm did not establish a system for monitoring of personnel who performed drug sterility testing.
- The firm failed to establish an adequate QU, and the responsibilities and procedures applicable to the QU are not in writing and fully followed. For example, the firm’s written procedures did not address QU oversight and responsibilities, including the authority to review laboratory records for errors and to ensure the firm maintains adequate laboratory facilities. In addition, many of the written procedures (e.g., Documentation of Work Performed, Recording of Analytical Data, and Evaluation of Out-of-Specification Results) were not implemented or followed by personnel.
World Health Organization (WHO)
The World Health Organization (WHO) has published its first guideline for Ebola virus disease therapeutics, with strong new recommendations for the use of two monoclonal antibodies. The WHO calls on the global community to increase access to these lifesaving medicines.
The WHO Ebola Virus Disease (EVD) Clinical Management: Living Guidance contains the Organization’s most up-to-date recommendations for the clinical management of people with EVD. Providing guidance that is comprehensive and holistic for the optimal care of patients with EVD throughout their illness is important. This first version of the Clinical Management for EVD Living Guidance contains four new recommendations regarding the use of therapeutics for EVD; this includes two strong recommendations for the use of monoclonal antibody therapies. This new living guideline is written to accompany the optimized supportive care for EVD clinical standard operating procedures. The living guideline aims to summarize high-quality evidence for EVD therapeutics and make recommendations for their use.
The goal of the global outbreak response for monkeypox is to stop human-to-human transmission of monkeypox, with a priority focus on communities at high risk of exposure, which may differ according to context, and to effectively use strong public health measures to prevent onward spread of the disease. Judicious use of vaccines can support this response. This interim guidance, developed with the advice and support of the Strategic Advisory Group of Experts (SAGE) Working Group on smallpox and monkeypox vaccines, provides the first WHO recommendations on vaccines and immunization for monkeypox.
Key points are as follows:
- Mass vaccinations are not required nor recommended for monkeypox at this time.
- For contacts of cases, Post-Exposure Preventive Vaccination (PEPV) is recommended with an appropriate second- or third-generation vaccine, ideally within four (4) days of first exposure to prevent onset of disease.
- Primary Preventive Vaccination (PPV) is recommended for persons at high risk of exposure, including but not limited to, gay or bisexual men who have sex with men or other persons with multiple sex partners, health workers at risk, laboratory personnel working with orthopoxviruses, clinical laboratory staff performing diagnostic testing for monkeypox, and others who may be at risk, according to national policy.
- Vaccination programs must be backed by thorough surveillance and contact-tracing and accompanied by a strong information campaign and robust pharmacovigilance, ideally in the context of collaborative vaccine effectiveness studies with standardized protocols and data collection tools.
- Decisions on use of smallpox or monkeypox vaccines should be based on a full assessment of risks and benefits on a case-by-case basis.
Interim recommendations are also provided for off-label use of vaccines. This guidance will be updated as more information becomes available.