SQA Regulatory Surveillance Summary for March and April 2024
SQA Regulatory Surveillance Summary for March and April 2024
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Brazil: Agência Nacional de Vigilância Sanitária (Anvisa)
The validity of the Certificate of Good Manufacturing Practices (CBPF or cGMP) of medical device manufacturers granted through the Medical Device Single Audit Program (MDSAP) was extended from two to four years, through the publication of RDC 850, dated 20 March 2024. The proposal was unanimously approved at the Collegiate Board Meeting (ROP 03/2024) held on 19 March 2024. This change creates a favorable environment for adherence to MDSAP by reducing the regulatory cost for companies, while expanding monitoring and bringing efficiency and agility to the Agency’s work process. Companies participating in the program will receive annual audits to monitor the risk and verify the maintenance of compliance with GMP, contributing to the control of the health risk of the products. The extension of the validity of the certificate to four years is subject to the permanence of the manufacturer in the MDSAP for the entire validity period of the certificate.
ANVISA Publishes Four Public Consultations on Food, 25 March 2024
On 22 March 2024, Anvisa published four public consultations related to food. These measures were approved at the 3rd Ordinary Public Meeting of the Collegiate Board of Directors of 2024 and are summarized below:
- Public Consultation 1,241 aims toauthorize the use of the substances Polyamide-imide 2 (PAI-2) andDiglycidylEtherofTetramethylBisphenolF (TMBPF-DGE) in the elaboration of polymeric coatings intended for contact with food, through the publication of the Resolutionof the Collegiate Board (RDC)amending RDC 56/2012.The authorization of new substances expands the list of technological alternatives available to the productive sector for the elaboration of polymeric coatings intended for contact with food. Thus, it represents a trade-friendly measure in thatit eliminates unnecessary obstacles and facilitates innovation of the sector. In addition, theinitiativecontributes to the maintenance of international convergence within Mercosur (The Southern Common Market), facilitating trade relations between countries.
- Public Consultations 1,242 and 1,243 are proposals for the opening of the regulatory process and public consultationof the RDC and Normative Instruction (IN) for the consolidation and updating of the sanitary regulations of infant formulas, transitional foods, and cereal-based foods for infants and early childhood children; formulas for enteral nutrition; and formulas for innate errors of metabolism.The process aims to simplify the regulatory framework of the products covered in this consolidation,eliminate gaps and inconsistencies identified in the revision of the regulations,and include substances approved by means of a petition and in registration processes in the lists of authorized substances.
- Public Consultation 1,244 aims to authorize the use of the substances silver-magnesium-sodium-boron phosphate (silverglass) anddiethylaminoethanolas additives in the elaboration of plastic materials and polymeric coatings intended to come into contact with food, through the publication of an RDC that aims to amend RDC 326/2019, maintaining the harmonization of the theme in Mercosur.The authorization of new substances expands the list of technological alternatives available to the productive sector, being a favorable measure for trade, so that updating the positive list can contribute to eliminating unnecessary obstacles to trade and innovation in the sector.It also contributesto the maintenance of the international convergence of the positive list ofadditives intended for the elaboration of plastic materials and polymeric coatings in contact with food within Mercosur, facilitatingtrade between countries.
ANVISA will use Analyses from Foreign Authorities for Registration of Medical Devices, 08 April 2024
In the Official Gazette of the Union on 08 April 2024, Anvisa published Normative Instruction (IN) 290//2024, which establishes the optimized procedure for the analysis and decision of petitions for the registration of medical devices. With this measure, the Agency now has more agility in the process of evaluating products already approved by equivalent foreign regulatory authorities, consolidating a major step in the adoption of regulatory confidence mechanisms. The adoption of these mechanisms is recommended and encouraged by the World Health Organization (WHO) so that the population has faster access to health services and technologies. The IN text predicts that from 03 June 2024, medical devices authorized for the markets regulated by four equivalent foreign regulatory authorities (Australia, Canada, USA, and Japan) will be able to have their analyses abbreviated, from the manifestation of the requesting companies. For this, documents are required to be presented that demonstrate that the products intended for the Brazilian market have the same characteristics of production, indications, and intended use approved by the recognized regulatory authority. The publication of IN 290/2024 takes place after extensive debate with the regulated sector, which offered its considerations during the public consultation process.
China: National Medical Products Administration (NMPA)
NMPA Releases Pharmaceutical Guidelines, March 2024
In March 2024, NMPA released the following guidelines:
- Technical Guidelines for Clinical Release and Development of New Traditional Chinese Medicines for Constipation in Pediatric Patients (Trial), 01 March 2024
- Technical Guidelines on Using Growth Hormone Formulations in Clinical Trials for Growth Hormone Deficiency, 22 March 2024
- Guidelines for Compiling Site Master Files (SMF), 27 March 2024
- Principles and Procedures for Exploratory Studies on Drug Sampling Inspection
China Expedites Process for Transferring Overseas Drug Manufacturing, 23 April 2024
On 23 April 2024, the NMPA published the Notice on Optimizing Marketing Authorization Applications for Transferring Manufacturing Sites of Approved Overseas Drugs to China. The notice outlines the following points:
- In the case of drugs that have already received approval in China but are currently manufactured outside of China, if the applicant intends to transfer the manufacturing site to China, they are required to adhere to the requirements for and procedures of submitting drug marketing authorization applications.
- For drugs mentioned in Point 1, for the marketing authorization application in China, the applicant is permitted to submit the original overseas marketing authorization dossier as supporting documentation, along with the research dossiers related to the transfer of the manufacturing site. The dossier requirements will be published by the Center for Drug Evaluation.
- For originator chemical drugs and biological products mentioned in Point 1, their marketing authorization applications will be admitted into the priority review process by the NMPA.
European Commission (EC)
The EC has proposed to amend the variation legislation for medicines, to make the lifecycle management of medicines more efficient and better adapted to the modern context. The Regulation, which is part of the EU’s Pharmaceutical Strategy for Europe, adapts the current system for variations to marketing authorizations, to make it more efficient, reduce administrative burdens, and better respond to scientific and technological advances. Medicines are only granted marketing authorization after their quality, safety, and efficacy have been positively assessed. Marketing authorization holders are responsible for ensuring that the medicine remains compliant throughout its lifecycle and are obliged to report any changes (variations) to the initial authorization, as they arise. These variations can range from administrative details, such as a change in company address, to substantial changes, such as changes to the patient and healthcare information or to the medicine’s active substance or strength. These variations are required to be assessed by the authorities based on their impact on public health and the medicine’s characteristics. Since it was last revised, the Variations Regulation has made a marked contribution in harmonizing and aligning the lifecycle management of medicines post-authorization across the EU. However, the rules need to be updated in line with recent scientific and technological advancements and a rise in the number of variation requests. The proposed revisions will facilitate quicker processing of variations, benefiting both marketing authorization holders and regulatory authorities. They will facilitate more efficient lifecycle management of medicines while awaiting the broader proposed reform of the EU’s legislation.
European Medicines Agency (EMA)
On 21 March 2024, EMA’s Human Medicines Committee (CHMP) confirmed its recommendation to suspend or not grant the marketing authorizations for a number of generic medicines tested by Synapse Labs Pvt. Ltd., a Contract Research Organization (CRO) located in Pune, India. This confirmation concludes the re‑examination requested by the applicants and marketing authorization holders for some of the medicines concerned. The CHMP adopted its initial recommendation in December 2023, after a Good Clinical Practice (GCP) inspection showed irregularities in study data and inadequacies in study documentation and in the computer systems and procedures to manage study data. This raised serious concerns about the data from bioequivalence studies conducted at the CRO. Such studies are carried out to show that a generic medicine releases the same amount of active substance in the body as the reference medicine. For the majority of the medicines tested by Synapse Labs on behalf of EU companies, the CHMP concluded that supporting data were lacking or insufficient to show bioequivalence and therefore recommended suspending the marketing authorizations of these medicines. For a small number of the medicines, sufficient supporting data were available to demonstrate bioequivalence; marketing authorizations for these medicines were maintained, and ongoing marketing authorization applications could continue.
EU Non-Compliance Report Issued after Insufficient CAPA, 27 March 2024
A follow-up GMP inspection was carried out at Cubit Lifesciences in India by the Malta Medicines Authority (MMA), an EU Competent Authority, in early 2024. This inspection was in line with the recommendations from a previous inspection conducted about one year earlier, which had identified two critical, three major, and a 17 other observed issues. The main goal of the recent follow-up inspection was to assess and validate the effective incorporation, spanning the entirety of the facility and the pharmaceutical quality system, of the documented corrective and preventive actions (CAPAs) and commitments presented by Cubit Lifesciences in response to the February 2023 inspection. However, the follow-up inspection revealed that some issues identified in the initial inspection were not fully addressed and implemented, leading to two critical, four major, and 12 other findings. This indicated a lack of proper implementation of the necessary CAPAs. Consequently, the Inspection Review Group at the MMA decided to issue a Statement of Non-Compliance with the principles and guidelines of GMP laid down in Directive 2003/94/EC for the site, reflecting ongoing concerns about compliance and quality management at Cubit Lifesciences. Additionally, for inspection observations, the causes of the problems identified would need to be thoroughly investigated, and CAPAs should be defined to prevent recurrence.
Health Canada
Further to its communication on 25 October 2023, Health Canada is warning consumers about additional unauthorized health products seized from the online retailer UU Zone, based in Markham, ON. These products are labelled to contain prescription, controlled, or over-the-counter drugs and may pose serious health risks. The list of products affected includes the following:
- Rohto Z! Pro, Eye Drops, Labelled to Contain Neostigmine Methylsulfate
- Sante Beauteye Moon Care, Eye Drops, Labelled to Contain Aminocaproic Acid
- Sante PC Contact, Eye Drops, Labelled to Contain Neostigmine Methylsulfate
- Kobayashi Eyewash (Green/Turquoise), Eye Drops, Labelled to Contain Aminocaproic Acid
- Sante 40 Plus, Eye Drops, Labelled to Contain Neostigmine Methylsulfate and Aminocaproic Acid
- Kobayashi AL Eyewash (Green), Eye Drops, Labelled to Contain Aminocaproic Acid
- Kobayashi Eyewash (Blue), Eye Drops, Labelled to Contain Aminocaproic Acid
- Sante PC, Eye Drops, Labelled to Contain Neostigmine Methylsulfate
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, these products may not actually contain the active ingredients that consumers would expect them to contain to help maintain and improve their health.
Non-Compliance Rating for Upmaid Technologies Inc., 06 March 2024
Upmaid Technologies Inc. located in Concord, Ontario, received a non-compliant rating from a Good Pharmacovigilance Practices (GVP) inspection that started on 06 March 2024. Key findings included the following observations:
- No pharmacovigilance records were available for auditing purposes.
- Training records were not available for all staff involved in pharmacovigilance activities.
- The company lacked systems and processes for conducting literature searches.
- The company lacked contractual agreements that defined the responsibilities of all parties involved in pharmacovigilance activities.
- The company lacked systems and processes for receiving, handling, evaluating, and reporting adverse drug reactions.
Additional findings included concerns with respect to lack of adequate resources, internal audits, and annual summary reports not being submitted.
India: Central Drug Standard Control Organization (CDSCO)
The CDSCO has published a Draft Guidance on Good Distribution Practices for Pharmaceutical Products. This document, prepared in line with the WHO Technical Report Series on Good Storage and Distribution for Pharmaceutical Products, presents steps to assist in fulfilling the responsibilities involved in the different stages within the supply chain and to avoid introduction of spurious (falsified), adulterated, misbranded, and not-of-standard-quality products into the market. The Guidance is intended to be applicable to all entities involved in the storage and distribution of pharmaceutical products, from the premises of the medical product manufacturer to their agent, or the person dispensing or providing medical products directly to a patient. The guidance includes requirements for the following Quality System elements:
- Quality Management and Organization
- Quality Risk Management
- Personnel
- Premises, Warehousing and Storage
- Temperature, Environment and Stock Control
- Transportation
- Dispatch and Receipt
- Documentation
- Complaints
- Recalls and Returns
- Spurious, Misbranded, Adulterated and Not of Standard Quality Pharmaceutical Products
- Importation
- Contract Activities
- Self-Inspection
The CDSCO has published a Guidance on Stability Studies of In-Vitro Diagnostic Medical Device (IVDMD). This document is intended to aid manufacturers in the preparation of scientific information to be provided in support of claimed shelf-life, in use stability and shipping studies for IVDMD license applications, and post-approval change applications filed pursuant to the Medical Device Rule, 2017 (MDR-2017). This document was developed by the CDSCO to encourage and support convergence of regulatory systems for medical devices among jurisdictions. CDSCO is looking to adopt the use of this guidance for premarket license applications and post-approval change applications. CDSCO strongly encourages manufacturers to follow this guidance when submitting IVDMD license applications and post-approval change applications.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
ICH Q1/Q5C Expert Working Group, Work Plan, 11 March 2024
Further to the ICH Management Committee’s endorsement of the Q1/Q5C Concept Paper and Business Plan in November 2022, the Q1/Q5C Expert Working Group (EWG) was established to revise the current ICH Stability Guideline Series Q1A-F and Q5C by:
- Streamlining the series, combining the various guidelines into a single guideline focused on core stability principles
- Promoting harmonized interpretation by addressing potential gaps and areas of ambiguity
- Addressing additional technical issues, including relevant stability strategies and innovative tools that strengthen the application of risk management
- Considering inclusion of new topics, such as stability considerations for advanced therapies
The envisioned result is a combined guideline, ICH Q1, with integrated annexes and/or appendices that address specific topics beyond the core stability recommendations and principles, addressing drug product types including substances, intermediates, and devices. Key milestones for this activity are provided in the ICH Q1/Q5C EWG Work Plan that was issued on 11 March 2024.
ICH Q2/Q14 Implementation Work Group, Work Plan, 18 March 2024
Further to the ICH Management Committee’s endorsement of the Q2(R2)/Q14 Implementation Work Group (IWG) Concept Paper in October 2023, the Q2(R2)/Q14 IWG was established to prepare and deliver training materials that will facilitate an aligned interpretation and a harmonized implementation of Q2(R2) Validation of Analytical Procedures and Q14 Analytical Procedure Development Guidelines in ICH and non-ICH regions by:
- Illustrating the general concepts of ICH Q2(R2) and Q14
- Providing more depth to the discussion of the Annexes in ICH Q2(R2) and Q14 to address some specific implementation aspects relevant for different cases
Key milestones for this activity are provided in the ICH Q2/Q14 IWG Work Plan that was issued on 18 March 2024.
International Medical Device Regulators Forum (IMDRF)
Global Medical Device Adverse Event Coding, 07 March 2024
The goal of using IMDRF terminology is to harmonize coding across markets to improve signal detection, enabling a faster response by both industry and regulators. The most recent version of the IMDRF guidance IMDRF/AE WG/N43 Terminologies for Categorized Adverse Event Reporting (AER): terms, terminology and codes was published in 2020, but the document originated in 2006 as a Global Harmonization Task Force guidance document. In addition to the guidance document, seven regularly updated annexes correspond to key variables involved in the reporting and investigation of adverse events. Except for Annex B, each annex includes multiple levels of codes. Generally, the most precise terms and descriptions corresponding to the adverse event should be chosen. The Level 1 terms are typically broad, and many have more specific terms/codes under them at Level 2 and even Level 3. Some markets, such as Malaysia, use the Level 1 terms but not the codes. The IMDRF published the 2024 release of the annexes on 07 March 2024. All annexes except for Annex B changed, with Annex E receiving the most edits (46 new terms and 12 modified terms). The Release Notes for 2024 changes can be found on the IMDRF website, along with the updated files. The links to each of the annexes below are to the IMDRF website and are current as of 07 March 2024.
- Annex A: Medical Device Problem Terms and Codes: Describes the problems (malfunction, deterioration of function, failure) of medical devices that have occurred.
- Annex B: Cause Investigation – Type of Investigation Terms and Code: Describes the type of investigation of the device involved in the event.
- Annex C: Cause Investigation – Investigation Findings Terms and Codes: Describes the findings of the device involved in the reported event.
- Annex D: Cause Investigation – Investigation Conclusion Terms and Codes: Describes the conclusion of the device involved in the reported event.
- Annex E: Health Effects – Clinical Signs, Symptoms and Conditions Terms and Codes: Describes the patient’s clinical signs, symptoms, and conditions observed related to the medical device adverse event.
- Annex F: Health Effects – Health Impact Terms and Codes: Describes the consequences of the medical device adverse event/incident on the person affected.
- Annex G: Component Terms and Code: Describes the parts and components that were involved in, or affected by, the medical device adverse event/incident.
International Organization for Standardization (ISO)
The purpose of ISO/IEC 27001:2022 – Information Security Management Systems – A Practical Guide for Subject Matter Experts is to assist subject matter experts (SMEs) in establishing and maintaining an Information Security Management System in accordance with ISO/IEC 27001, the premier standard for information security. While the standard itself is applicable to organizations of all sizes, this handbook specifically addresses the nuances and challenges faced by SMEs—often seen as enterprises in this context—spanning from small family businesses to community medical centers. SMEs can use this handbook to obtain a brief summary of the requirements of the clauses and subclauses of ISO/IEC 27001. This handbook also includes examples and case studies to help SMEs with limited resources to understand and apply the standards, reducing the need for extensive expertise or significant financial investment.
International Society for Pharmaceutical Engineering (ISPE)
The ISPE Guide: 503A Compounding – Regulatory Basis and Industry Good Practices for Pharmacies provides an overview of United States Food and Drug Administration (US FDA) regulations and guidance necessary for conducting safe compounding to help pharmacies understand the requirements of FD&C Act Section 503A. In addition, the ISPE Guide outlines the authority of State Boards of Pharmacy and their coordination of oversight with the FDA. A significant portion of the Guide addresses United States Pharmacopeia (USP) Chapters <795>, <797>, <800>, and <1163>, which are critical for the operation of 503A pharmacies. The differences in USP <795> for nonsterile compounded preparations and USP <797> for sterile preparations are discussed throughout this ISPE Guide to aid 503A compounders in understanding the requirements and accessing appropriate information. Discussions include general compounding requirements for 503A pharmacies, focusing on the quality system and its application throughout the process, from incoming materials and facilities and equipment to storage, shipping, and transport. Readers will find the information on personnel knowledge and training requirements valuable. To aid pharmacies in maintaining compliance with federal and state regulations, several lists of suggested standard operating procedures based on the type of compounding conducted are included. Although a high-level overview of the state board of pharmacy model is provided, the rules of the State Boards of Pharmacy and other equivalent state regulatory groups are considered out of scope, given the multitude of individual state regulations.
United Kingdom: Medicines and Healthcare Products Regulatory Agency (MHRA)
Disgraced Company Director Convicted of Falsifying Medicine Quality Data, 15 March 2024
A company director and his pharmaceutical manufacturing company were sentenced in court on 15 March 2024 after pleading guilty to two charges of falsifying data that supported the shelf-life of a medicine, adversely affecting its quality in order to obtain a license to sell the medicine in the UK. The sentencing concluded the UK’s first successful prosecution of a manufacturer for knowingly providing falsified data to the MHRA in order to obtain a marketing authorization. Kamlesh Vaghjiani, former director of pharmaceutical company Kappin Ltd., was sentenced to eight and seven months on two counts, to run concurrently, both suspended for 18 months, at Southwark Crown Court, London, following investigations by the MHRA into Kappin’s product, Evotrox Oral Solution. Vaghjiani and Kappin Ltd. were both individually fined £50,000, having previously paid a confiscation order of £1,075,589.88, reflecting Kappin Ltd.’s profit from the crime. Kappin Ltd. was also ordered to pay prosecution costs of £82,262.20. Evotrox Oral Solutions (a liquid solution containing the active ingredient levothyroxine) was licensed in 2006 in three strengths for the treatment of hypothyroidism (underactive thyroid). As part of any license application, manufacturers are required to provide evidence for how long their product remains stable and, thus, fit for its purpose, effective, and safe. This is known as a medicine’s ‘shelf-life.’ The MHRA began to investigate Kappin Ltd. in 2008, following reports that Evotrox was not stable for the whole duration of the shelf-life claimed in the original license application. At this time, Kamlesh Vaghjiani was the Quality Assurance Manager at Kappin Ltd. During these enquiries, the company continued to submit falsified data to the MHRA in support of the medicine’s stability and effectiveness. A comprehensive series of independent testing by the MHRA, together with detailed analysis of data retrieved from laboratory computers, brought the deceptions to light. This culminated in the termination of the marketing authorizations by the MHRA in 2013 and subsequent criminal prosecution, which resulted in this sentence.
Neon Healthcare Ltd. is recalling Batch Number 3F022A of Suprefact 1-mg/ml Solution for Injection (Cheplapharm-Canadian Livery) as a precautionary measure. The recall resulted from the named batch of Suprefact 1-mg/ml solution for injection being distributed in packaging intended for the Canadian market by Cheplapharm, instead of the correct UK packaging by Neon Healthcare Ltd. for Buserelin 1-mg/ml solution for injection. Healthcare professionals are advised to stop supplying the above batch immediately, to quarantine all remaining stock, and to return it to their supplier using the supplier’s approved process. Wholesalers are also requested to check stock of Buserelin 1-mg/ml solution for injection for any packs that match Suprefact 1 mg/ml solution for injection (MAH: Cheplapharm – Canadian Livery) according to the product images provided in the notification. No further action is required by patients, as this is a Pharmacy- and Wholesaler-level recall. 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.
Personal Care Products Council (PCPC)
“Cosmetics and personal care products companies remain committed to advancing innovative approaches while creating products that benefit a variety of consumer needs. The PCPC, working with a variety of stakeholders, supports using alternatives to per- and polyfluoroalkyl substances (PFAS) in product formulations. Our industry has been steadily moving away from PFAS as ingredients and using innovative formulation approaches to deliver high-performance and high-quality products. PCPC member companies take their responsibility for product safety and the trust families put in those products very seriously. Science and safety are at our core. In the United States, cosmetics are regulated by the FDA under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Fair Packaging and Labeling Act. All cosmetics products and their ingredients are subject to the same safety requirement under the FD&C Act: they are required to be shown to be safe for consumers before they are marketed. In a 2021 study published in the Journal of Environmental Science and Technology Letters, some of the fluorine levels detected could be the result of trace amounts from materials naturally occurring in the environment or as a result of the manufacturing process. It is inappropriate to assume that anything with a fluorine atom has the same safety profile. The FDA recognizes the possible presence of trace materials and offers guidance on allowable levels. PCPC supports the FDA’s authority to review these compounds, and they have the expertise to do so. The Modernization of Cosmetics Regulation Act of 2022 (MoCRA), which modernized federal cosmetics regulatory oversight under the FD&C Act, requires the FDA to conduct an assessment and publish a complete report on PFAS in cosmetics by 29 December 2025.”
Australia: Therapeutic Goods Administration (TGA)
Recall Reforms Program Update, 26 March 2024
The second phase of the TGA Recall Reforms program is now being implemented. Updated processes will reduce regulatory burden for sponsors while maintaining a strong emphasis on public safety. The reforms include a simplified and more flexible reporting process, increased stakeholder communication for the ‘Early Advice’ process and improvements to TGA recall documentation and guidance. In 2023, the TGA consulted widely and developed a Discussion Paper on potential changes to how the agency could undertake product recalls in Australia, as part of ongoing reforms. The agency asked a series of questions around five key themes:
- Increasing awareness and understanding
- Improving communication
- Better recall descriptions
- Improving sponsor letters and other recall documents
- Reporting progress with recalls
Reforms to the recall process that received the broadest support from stakeholders are now being implemented. To assist in awareness and understanding of the reforms, a new version of the Uniform Recall Procedure for Therapeutic Goods (URPTG) and updated guidance material have been published on the TGA website.
Nitrosamine Impurities Acceptable Intakes Update, 26 April 2024
The TGA has published updated Acceptable Intake information for nitrosamine impurities in medicines, consistent with recent European Medicines Agency Updated Information. The changes include minor editorial amendments, increases to the Acceptable Intake limit for a nitrosamine impurity, and inclusion of recent internationally determined Acceptable Intake limits for numerous nitrosamine impurities in medicines. Sponsors and manufacturers are expected to be familiar with the current Acceptable Intakes for nitrosamine impurities in medicines that are considered acceptable. This is detailed on the TGA website.
United States Environmental Protection Agency (EPA)
EPA Finalizes Rule to Reduce Ethylene Oxide Emissions from Sterilization Facilities, 14 March 2024
After a year of back and forth with the Medical Technology industry, the US EPA has published a much-anticipated rule that further restricts the use of the medical device sterilization agent Ethylene Oxide (EtO). The agency says the rule would significantly curtail EtO emissions but gives companies ample time and flexibility to comply. The final rule updates the EPA’s policy on Residual Risk and Technology Review for the Commercial Sterilization Facilities source category, which is regulated under the National Emission Standards for Hazardous Air Pollutants (NESHAP) under the Clean Air Act. EPA said the rule is expected to affect nearly 90 commercial sterilizer facilities that 50 companies operate nationwide. The agency’s finalized amendments to NESHAP address issues such as setting new emissions standards for building leaks and chamber exhaust vents, and vents in sterilization chambers and aeration rooms. The amendments also require most commercial sterilizers to ensure continuous emissions monitoring, compile quarterly reports, and set emissions standards for when sterilization facilities are started up, shut down, or malfunctioning.
United States Food and Drug Administration (FDA) Regulations and Guidances
Key Points of the Proposed FDA Modernization Act 3.0, 06 March 2024
On 06 February 2024, new legislation was introduced in the House of Representatives, called the FDA Modernization Act 3.0. This proposed legislation that aims to reduce and replace the use of animals in nonclinical research, improve predictivity of nonclinical testing, and potentially reduce development times for drugs. This legislation has been introduced in Congress and needs to pass the House and Senate and be signed by the president before becoming a law. The key points of the proposed FDA Modernization Act 3.0 include the following:
- Establishment of a Nonclinical Testing Process
- Eligibility for Qualification of Nonclinical Testing Methods
- Qualification Process for Nonclinical Testing Methods
- Adjudication and Timelines for Approval or Denial of Requests for Nonclinical Testing Methods
- FDA Reporting on the Qualification of Process for Nonclinical Testing Methods
- Public Meetings to Review Proposed Legislation on Nonclinical Testing Methods
- FDA Guidance Development for Nonclinical Testing Methods
The Chemistry, Manufacturing, and Controls (CMC) technical section is one portion of an original New Animal Drug Application (NADA), abbreviated New Animal Drug Application (ANADA), and Conditional New Animal Drug Application (CNADA) and is required to contain full information regarding the manufacture of the new animal drug substance and new animal drug product. Animal drug manufacturing processes are required to be robust and able to produce drug product batches of consistent identity, strength, quality, and purity. Primary batches of drug products are manufactured as part of the original application. Data from these batches are used to establish that the manufacturing, sampling, and control processes described in the CMC portion of the application will consistently provide a quality, stable drug product that, within a batch and on a batch-to-batch basis, does not vary beyond the established specification(s). Additionally, they are used in studies to establish that the drug product is safe and effective (or in the case of an ANADA, bioequivalent to the reference listed new animal drug). As such, the primary batches demonstrate that the applicant can consistently manufacture batches of the same quality as those used in safety and effectiveness (or bioequivalence) studies. This guidance provides recommendations for the primary batches of drug products manufactured to support the approval or conditional approval of new animal drug products.
The use of human- and animal-derived materials to manufacture cellular and gene therapy (CGT) products and tissue-engineered medical products (TEMPs) raises several key issues to consider, including transmission of adventitious agents, material lot-to-lot consistency, and material identity, as well as general material qualification considerations. The FDA is providing manufacturers of CGT and TEMP products with recommendations regarding assuring the safety, quality, and identity of materials of human and animal origin used in the manufacture of these products. In addition, recommendations are provided regarding the CMC information submitted in an Investigational New Drug Application (IND) application relating to the use of human- and animal-derived materials. The Draft Guidance for Industry, Considerations for the Use of Human-and Animal-Derived Materials in the Manufacture of Cell and Gene Therapy and Tissue-Engineered Medical Products supplements the following two final guidances: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy INDs, Guidance for Industry, January 2020 and Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs), April 2008.
United States Food and Drug Administration (FDA) – Recalls
Endo International plc announced on 12 March 2024 that one of its operating companies, Par Pharmaceutical, Inc. (Par), is voluntarily recalling one lot of Treprostinil Injection 20mg/20mL (1mg/mL) to the consumer level. The product is being recalled due to the potential for the presence of silicone particulates in the product solution. Administration of an injectable product that contains particulate matter may result in local irritation or swelling in response to the foreign material. If the particulate matter reaches the blood vessels, it can travel to various organs and block blood vessels in the heart, lungs, or brain, which can cause stroke and even lead to death. To date, Par has not received any reports of adverse events related to this recall. Treprostinil Injection is formulated for subcutaneous or intravenous infusion. The product is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension to diminish symptoms associated with exercise and for patients who require transition from epoprostenol to reduce the rate of clinical deterioration. Treprostinil Injection 20mg/20mL (1mg/mL) is distributed in 20-mL multidose vials as sterile solutions in water for injection, individually packaged in cartons under NDC #42023-206-01. Only Lot 57014, expiration date 04/2024, is affected by this recall. The lot was distributed nationwide to wholesalers and hospitals from 16 June 2022 through 17 October 2022.
Dr. Reddy’s Laboratories Ltd., along with its subsidiaries together referred to as “Dr. Reddy’s”, announced that it is voluntarily recalling six lots of Sapropterin Dihydrochloride Powder for Oral Solution 100 mg to the consumer level due to powder discoloration in some packets leading to decreased potency. The issue was discovered during an accelerated stability test, in addition to customer complaints received by the company. Reduced efficacy of the product would result in elevated Phenylalaninemia (Phe) levels in patients. Chronically elevated Phe levels in infants and children are likely to cause permanent neurocognitive deficits, including permanent and irreversible intellectual disability, developmental delay, and seizures. Furthermore, elevated Phe levels during pregnancy, especially in early gestation, are associated with microcephaly and congenital heart disease. Dr. Reddy’s Laboratories Inc. has not received any reports of adverse events related to this recall as of 23 April 2024. The product is indicated to reduce blood Phe levels in adult and pediatric patients one month of age and older with Hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4-) responsive Phenylketonuria (PKU) and is packaged in individual packets, 30 per carton.
United States Food and Drug Administration (FDA) Warning Letters
Deqing Jiarou Daily Chemical Co., Ltd., Warning Letter, 18 March 2024
Deqing Jiarou Daily Chemical Co., Ltd., a manufacturer of over-the-counter drug products, received a Warning Letter on 18 March 2024. This Warning Letter was a result of the FDA review of records that the company submitted in response to a 12 September 2022 request for records and other information. The review of records and other information provided the following concerns:
- The firm failed to conduct at least one test to verify the identity of each component of a drug product. As the firm manufactures Antibacterial Hand Sanitizer, they had not demonstrated that they were testing the active ingredient ethanol for methanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents worldwide.
- 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 identify and strength of each active ingredient prior to release. For example, the certificate of analysis reports that were provided did not include an appropriate assay test for active ingredient content or impurity testing.
- The firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug product. For example, the firm provided a stability test report that only included four weeks of stability data for a batch of hand sanitizer. In addition, the firm failed to provide data demonstrating that appropriate chemical and microbiological testing is performed on drug products during stability studies.
- The firm failed to establish an adequate Quality Control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in process materials, packaging materials, labeling, and drug products.
Antaria Pty. Ltd., Warning Letter, 22 March 2024
Antaria Pty. Ltd., a manufacturer of active pharmaceutical ingredients (APIs), received a Warning Letter on 22 March 2024. This Warning Letter was a result of the FDA review of the company’s response to Form 483 observations that were issued during an onsite inspection at the company’s Queensland, Australia facility from 13 to 17 November 2023. The FDA review of the response provided the following concerns:
- The firm failed to adequately investigate and document out-of-specification (OOS) results and implement appropriate corrective actions. Specifically, the firm lacked adequate investigations and corrective actions for numerous OOS results obtained during laboratory testing of the firm’s API, including assay and loss on ignition (LOI) testing. The root causes were not clearly defined nor adequately documented, and lots with OOS results were released by the firm’s Quality Unit.
- The firm failed to ensure that, for each batch of API, appropriate laboratory tests were conducted to determine conformance to specifications. Based on the review of the firm’s laboratory results, it was determined that the firm failed to appropriately perform analytical testing (assay and LOI) of the firm’s API in accordance to the current version of USP monograph, nor did the firm have data to support that their test method was equivalent or better than the USP method.
- The firm failed to have laboratory control records that included complete data derived from all laboratory tests conducted to ensure their API complies with established specifications and standards. For example, the firm lacked documentation of the preparation of stock solutions, sample solutions, diluents, mobile phases, and reagents used during testing of their API. The firm also failed to document the instruments and equipment used when performing analytical testing.
- The firm failed to design an adequate documented ongoing stability testing program to monitor the stability characteristics of the API and to use the results to confirm appropriate storage conditions and retest or expiry dates. Specifically, the firm failed to place at least one lot of their API manufactured in 2019, 2020, or 2021 on stability annually.
World Health Organization (WHO)
WHO Issues Guidance on Nitrosamine Controls in Drug Manufacturing, 19 April 2024
The WHO released draft guidance for comment this month on GMP for the prevention and control of contamination of nitrosamines, which are a probable human carcinogen. The new GMP guideline applies to all manufacturers of excipients, APIs, and finished pharmaceutical products. Among other things, the document covers definitions of nitrosamines, impurities currently causing concern, and performance of root cause analyses and risk assessments. WHO advised companies to identify biological, chemical, and physical risks or harms that should be controlled in every stage of production.
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