SQA Regulatory Surveillance Summary | Monthly Update 2023 – January
SQA Regulatory Surveillance Summary for January 2023
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
China: National Medical Products Administration (NMPA)
NMPA Announcement on putting into use the electronic certificates of Documentation for Export of Active Pharmaceutical Ingredients (APIs) to the European Union (EU) and Certificate of a Pharmaceutical Product (No. 95, 2022), 08 November 2022
As part of the effort to implement the major decisions and plans of the Communist Party of China Central Committee and the State Council on deepening the reforms to separate operating permits from business licenses, in order to further improve the business environment, stimulate the vitality of market entities, optimize the service capacity for “internet + drug supervision” of the NMPA, and provide drug export enterprises with more efficient and convenient administrative services, it is decided that the electronic certificates of the Documentation for Export of Active Pharmaceutical Ingredients (APIs) to the European Union (EU) and Certificate of a Pharmaceutical Product will be officially put into use from 01 December 2022. Relevant matters are hereby announced as follows:
- As of 01 December 2022, the Electronic Certificates of Documentation for Export of APIs to the EU and Certificate of a Pharmaceutical Product will be put into use. The electronic certificate and the paper version are equally authentic.
- A new template for the Certificate of a Pharmaceutical Product will be put into use in line with China’s pharmaceutical export practices and the latest World Health Organization (WHO) guidelines. From 01 December 2022, all provincial-level drug regulatory authorities shall issue the Certificate of a Pharmaceutical Product in accordance with the new template.
- Efforts should be made to promote and guide the use of electronic certificates. To use the electronic certificate produced and issued by the application system of the NMPA, the applicant shall first register and be authenticated with a real name in the Online Office Hall of the NMPA.
- Where electronic certificates produced and issued by the provincial application system are used, the provincial drug regulatory department shall clarify the relevant guidelines to enterprises within its administrative region and provide guidance and services.
On 29 November 2022 the NMPA released the draft of Administrative Rules on Supervising Marketing Authorization Holder (MAH) as the Main Entity to Fulfill Responsibilities for Drug Quality (hereafter referred to as theAdministrative Rules). China’s drug MAH system has been implemented nationwide since the revised Drug Administration Law came into force in 2019. The obligations for MAHs are mentioned in Drug Administration Law,and are now detailed in the Administrative Rules. The Administrative Rules applies to MAHs in China, requiring them to establish a drug quality management system and be responsible for the safety, effectiveness, and quality controllability during drug development, manufacture, supply, and use according to the Drug Administration Law, Good Manufacturing Practices (GMP), Good Supply Practices (GSP), Good Pharmacovigilance Practices (GVP), and relevant regulations. Key focus areas for the Administration Rules include:
- Key Personnel
- Quality Management System
- Management of Active Pharmaceutical Ingredients (APIs), Excipients, and Packaging Materials
- Management of Post-Approval Changes
- Management of Entrusted Manufacture
The NMPA and the Center for Medical Device Evaluation (CMDE) published new rules for the supervision and management of enterprises implementing medical device safety, as well as draft guidelines for the registration and review of implantable medical device batteries. Following the draft consultation in November 2022, the NMPA announced the issuance of the Regulations on the Supervision and Management of Enterprises Implementing the Main Responsibility of the Quality and Safety of Medical Devices, which will come into force on 01 March 2023. This requires medical device registrants and record filers to fulfill the main responsibility for medical device quality and safety. It also includes provisions that emphasize the implementation of responsibilities for medical device registrants, filers, and entrusted manufacturers and personnel in key positions of quality and safety in medical device production and operating enterprises. The Interpretation of Regulations on the Supervision and Management of Enterprises Implementing the Main Responsibility of the Quality and Safety of Medical Devices further discusses the provisions of the Regulations.
Eudralex, Volume 4: GMP Guidelines and Annexes
On 16 November 2022, the European Medicines Agency EMA published a concept paper on the planned revision of Annex 11 “Computerized Systems.” The reason: The existing document of the EU GMP Guideline dates back to 2011 and no longer corresponds to the state of the art in various areas or does not consider increasingly important new technologies for the GMP field, according to the EMA. A new focus is to be on data integrity, in particular the requirements for “data in motion,” and data in archives or in backup, the so called “data at rest.” The requirements for providers (e.g., cloud services) are also to go into more detail and the meaning of “validation and qualification of the systems” is to be clarified in greater depth. This also applies to the term “commercial off-the-shelf products.” References to ICH Q9 and thus to quality risk management will also be added. In addition to these classic topics, developments in the field of artificial intelligence (AI) will be included in the future. There are currently no regulatory guidelines or expectations for AI or machine learning (ML). The main focus here should be on the relevance, appropriateness, and integrity of the data with which these models are tested and, on the results (metrics) of such tests. Of interest is a reference to the FDA’s draft document “Computer Software Assurance for Production and Quality System Software,” which was recently published on 13 September 2022. This important US document is to be reviewed for possible regulatory relevance to Annex 11. The consultation period for the revised new Annex 11 ends on 16 January 2023, with a draft document to be released for consultation in December 2024. Finalization of the document is planned for 2026.
European Commission (EC)
This guideline gives supplementary advice on the information sponsors must provide when applying for designation of a medicinal product as an orphan medicinal product. It covers both the format and content of the application and should be followed unless good reasons are given for deviating from it. Required sections of the application include:
- Description of the condition
- Prevalence of the condition
- Potential for return on investment
- Other methods for diagnosing, preventing, or treating the condition
- Description of the stage of development
- Transfer of the orphan designation to another sponsor and change in the name or address of the sponsor
- Amendment of an existing designation
The requirements for timing of applications are also provided.
The European Commission’s Medical Device Coordination Group (MDCG) has published a guidance document MDCG 2022-20: Substantial modification of performance study under the In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746, December 2022. The document clarifies guidance for obtaining permission to conduct a substantial modification of a performance study in European Union Member States according to the IVDR. The document includes a form, which is to be used by the sponsor of a performance study. The sponsor of a performance study is required to submit an application/notification to the Member State(s) in which a performance study is to be conducted, accompanied by the documentation referred to in Chapter I of Annex XIV IVDR. The application/notification must be submitted via the EUDAMED database (Article 69 IVDR). Additionally, the sponsor is also required to notify the aforementioned Member State(s) via EUDAMED of modifications to a performance study that are likely to have a substantial impact on the safety, health, or rights of the subjects or on the robustness or reliability of the data generated by the performance study. Until EUDAMED is brought fully online, a series of performance study application/notification documents have been created to support performance study procedures with respect to the IVDR (see MDCG 2022-19). To add to these documents, a template for “Substantial modification of performance study under Regulation (EU) 2017/746” is also provided. The modification of the performance study form includes the same data fields as the future EUDAMED module for performance study notifications.
Following up on its announcement in the EU Employment, Social Policy, Health, and Consumer Affairs Council (EPSCO) Meeting, the European Commission (EC) released on 06 January 2023, a proposal (Proposal) to amend the transitional regime under the Medical Device Regulations (MDR) and certain related rules under the In Vitro Diagnostic Medical Device Regulations (IVDR). It is based on suggestions made by the EC at the end of last year:
- An extension of the validity of certificates (MDR)
- An extension of the transition period (MDR)
- The removal of the “sell-off” periods (MDR and IVDR)
As becomes apparent from the above, the changes to the transition periods are limited to the MDR. The transitional regime of the IVDR was already extended at the beginning of 2022, so that the Commission deems the capacity challenges to no longer be so severe for in vitro diagnostics. The Commission suggests extending the transition period for higher-risk devices (Class III and Class IIb implantable devices, except certain devices for which the MDR provides exemptions) from 26 May 2024, until 31 December 2027, and for medium- and lower-risk devices (other Class IIb devices and Class IIa, Im, Is, and Ir devices) until 31 December 2028 only if specified conditions are met. Additional details are provided with respect to the validity of certificates and “sell-off” periods. The Proposal needs to be adopted by the European Parliament and the Council, and it might still undergo some changes in this process. While it is unclear when and if the proposed amendments will become effective, the previous corrigenda of the MDR have demonstrated that adoption can be swift, which in this case is necessary to ensure that patients and healthcare systems have continuous access to all categories of medical devices. At present, stakeholders should further pursue their transition strategy but should closely monitor these critical developments in the coming months.
European Medicines Agency (EMA)
The International Coalition of Medicines Regulatory Authorities (ICMRA) highlights successful regulatory and non-regulatory interventions used in different countries to address the growing public health problem of antimicrobial resistance (AMR) in a new report published in November 2022. AMR threatens the ability to effectively treat infections because of an ever-increasing range of bacteria and other microorganisms that have adapted to become resistant to available treatments. Tackling AMR is one of ICMRA’s strategic priorities. ICMRA recognizes that AMR is a complex, multifaceted problem and calls for better coordination across all sectors, including public health, animal health, and the environment, through a ‘One Health’ approach. A concerted and collaborative effort is essential to address this threat to global health, economies, and security effectively. The report presents case studies on best practices from different countries that were developed in line with the ‘One Health’ approach and address AMR and antimicrobial use in humans, animals, and the environment. The best practices include focus on the following topics:
- Regulatory flexibilities that help bring novel therapies to market
- Sales reporting of medically important antimicrobials for veterinary use that informs antimicrobial resistance/antimicrobial use surveillance and stewardship initiatives
- Lessons learned from the regulatory agilities implemented in response to the COVID-19 pandemic
- Restriction of the sale and supply of non-prescription availability of antibiotics
- Development and progress of a pilot study on reimbursement models for novel antimicrobials
- Reporting of selective antibiograms to inform antimicrobial choice
- Feedback on prescriber data for antibiotics
- Treatment recommendations for common infections in outpatient care
- Development of methods for monitoring AMR in the environment
Case studies also serve as tools to promote further discussions and collaboration and strengthen the resolve to take steps to address AMR.
The EC, the Heads of Medicines Agencies (HMA), and the EMA have published recommendations that aim to facilitate the conduct of decentralized clinical trials (DCT) while safeguarding the rights and well-being of participants as well as the robustness and reliability of the data collected. This is an outcome of their joint initiative to Accelerate Clinical Trials in the European Union (ACT EU). Traditionally, clinical trials have been conducted at specific clinical trial sites, to which patients had to travel to. The aim of DCTs is to make it easier for patients to participate in clinical trials by reducing the need to travel to central trial sites. This approach has the potential to make clinical trials available to a wider demographic of participants and reduce drop-out rates. Decentralization is enabled by the advancement of digital tools, telemedicine, and more mobile and local healthcare. It includes aspects such as home health visits, remote monitoring and diagnostics, direct-to-patient shipment of study drugs, and electronic informed consent. The recommendations include an overview of national provisions for specific decentralized clinical trial elements to be used in clinical trials. They were put together by the European medicines regulatory network with experts from regulatory bodies responsible for the authorization of clinical trials, members of ethic committees, good clinical practice inspectors, methodology experts, and representatives of patient organizations. The initiative was launched in January 2022 and aims to further develop the EU as a focal point for clinical research, to promote the development of high-quality, safe, and effective medicines, and to better integrate clinical research in the European health system. ACT EU will strengthen the European environment for clinical trials, while maintaining the high level of protection of trial participants, data robustness, and transparency that EU/European Economic Area (EEA) citizens expect. ACT EU features ten priority action areas that are the basis for the ACT EU 2022-2026 workplan.
A Health Canada inspection of Applied Chemistry Labs Ltd. was conducted on 07 November 2022. The inspection resulted in a non-compliant rating. There were seven (7) observations with respect to the following:
- Quality Control Department:
- The establishment and/or the maintenance of a data governance plan was inadequate.
- The electronic system was not validated for its intended use.
- The recorded information or details were inadequate
- The change control system was inadequate for ensuring changes are properly documented, evaluated, and/or approved.
- The system for reviewing, revising, and approving standard operating procedures was inadequate.
- The traceability, legibility, documentation, formatting, and/or the accuracy of records was inadequate.
- The maintenance of records was inadequate.
- The usage logs for the equipment used for significant processing and/or testing operations were inadequate.
- The training of personnel in good manufacturing practices and/or the maintenance of records was inadequate.
- The ongoing training of personnel was inadequate.
Health Canada removed various unauthorized health products from sale from More to Shoppe, an online Facebook store, and from its warehouse in Edson, Alberta. The seized products are as follows:
- Abimox – Antibiotic
- Megalin – Pain Relief
- Solmux and Solmux Advance – Mucolytic (Mucus Thinner)
- Brilliant Skin Essential Rejuv Set, Topical Solution, and Topical Cream – Skin Lightening
The products 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, these products may not actually contain the active ingredients that consumers would expect them to contain to help maintain and improve their health.
International Pharmaceutical Excipients Council (IPEC)
IPEC Federation and the Pharmaceutical Quality Group (PQG) have announced the general availability of the revisedIPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients (version 5, 2022). The IPEC-PQG GMP Guide is an invaluable tool in helping to achieve a high level of excipient quality and maintain the integrity of the supply chain for the benefit of patients. This important revision presents the latest thinking on good manufacturing practices for excipients, and while the fundamental principles of GMP remain the same, the guide has been revised to align with ISO 9001:2015 requirements. This will be of great benefit to the parties responsible for understanding and complying with GMP for pharmaceutical excipients worldwide. Another significant enhancement is the provision of examples for GMP interpretation and implementation, without adding further requirements. For this reason, this guide is published in two parts:
- Part 1 includes Good Manufacturing Practices for excipients
- Part 2 includes Good Manufacturing Practices for excipients with notes providing common examples
This updated version becomes the sole reference for IPEC-PQG GMP, and previous versions are obsolete. IPEC-PQG recommends that users of the guide study its contents carefully. This will enable any existing descriptions of how an excipient manufacturer’s quality system aligns with the IPEC-PQG GMP requirements to be represented according to the guide’s new structure. In addition, updates to the following guidances were published in November 2022:
- IPEC Excipient Stability Guide for Pharmaceutical Excipients
- IPEC Certificate of Analysis for Pharmaceutical Excipients
Medicines and Healthcare Products Regulatory Agency (MHRA)
Specific batches of Fluphenazin-neuraxpharm D 25 & 100 mg/ml Solution for Injection have been recalled by Mawdsley-Brooks & Company Limited as a precautionary measure due to validation tests demonstrating the leaching of filter additives that are above the acceptable limit. This recall is being issued as a company-led medicines recall as the products are only supplied to a limited number of customers, and the manufacturer has full traceability of the product’s distribution.
Device Safety Information: Belzer UW Cold Storage Solution and Belzer MPS UW Machine Perfusion Solution manufactured by Carnamedica (UKRP:Bridge to Life): Contamination of Fluid; DSI/2023/002, 31 January 2023
Carnamedica has identified a number of issues with their third-party suppliers of Belzer UW Cold Storage Solution and Belzer MPS UW Machine Perfusion Solution. Concerns have been raised about the aseptic filling process, leak testing of the bags, and the conditions under which filled bags are stored and transported. To date, two strains of microbial organisms, Brachybacterium conglomeratum and Kocuria rhizophila, have been cultured from contaminated Cold Storage Solution (CSS). The potential clinical consequences of using a product with microbial contamination include peritonitis, infection, sepsis, and failure of graft. In the UK, reports of discolored solution, later identified as microbial contamination, have been received involving two lot numbers of 1L of CSS, 010722 and 061022, to date. In addition, bags have been identified containing visible particulate matter. Carnamedica has identified that this is hydroxyethyl starch precipitated from the solution. This could potentially occlude small capillaries in transplant organs and result in regional ischemia, regional necrosis, delayed graft function, and loss of the graft. In the UK, reports of particulate matter have been received involving one lot number of 2L CSS, 030122, to date. Reports have also been received concerning leaking bags of 1L CSS, affecting lots 022422, 030222, 030322, and 090122. Unlisted lot numbers are not guaranteed to be unaffected by these issues. Lot numbers involved in confirmed cases have been provided to support clinicians in targeting of increased vigilance measures to patients who have received organs where affected lots were used. The MHRA has not received reports of adverse events involving Belzer UW MPS Machine Perfusion Solution. However, they are not guaranteed to be unaffected.
Personal Care Product Council (PCPC)
Washington, D.C. – PCPC and its member companies applauded Congress for including legislation that modernizes federal regulatory oversight of cosmetics and personal care products and creates a comprehensive and uniform national framework for cosmetics regulation. The long-awaited legislation advances product safety and innovation for the science-driven beauty and personal care industry and reinforces consumer confidence. Consumer and product safety are top priorities for the beauty and personal care industry. PCPC looks forward to working with the FDA and key stakeholders to implement this important legislation.
United States Food and Drug Administration (FDA) – Warning Letters
A US Food and Drug Administration (FDA) official has stated that most warning letters issued for drug Good Manufacturing Practice (GMP) issues in fiscal year 2022 were the result of onsite inspections, reversing a pandemic-era trend of enforcement actions triggered by the use of alternative tools. Yet the agency faces “incredible challenges” going forward, as it tackles a backlog of inspections that were put on hold during the pandemic, asserted Jeffrey Meng, program division director, Division of Pharmaceutical Quality Operations III, Office of Regulatory Affairs, who provided an update on compliance activities at the PharmaLink conference hosted by the Regulatory Affairs Professionals Society (RAPS) and the Association of Food and Drug Officials (AFDO). In FY 2022, the FDA issued 62 warning letters and 23 import alerts related to drugs, excluding compound related actions. The number of warning letters prompted by onsite inspections increased dramatically in FY 2022; 42 (67.7%) of the warning letters followed onsite inspections, while 16 (25.8%) resulted from inspecting samples and four (6.5%) were the result of a records request. In FY 2021, fewer warning letters followed onsite inspections, as the pandemic halted many inspections, except for those deemed mission critical. In FY 2021, 21 (25.3%) of such warning letters followed onsite inspections. The remainder stemmed from alternative tools: 59% were from testing samples, and 13.3% emanated from a records request, while 2.4% were from a refusal of a section 704 records request. Meng told attendees that onsite inspections are the “gold standard, because it allows a more holistic snapshot of a firm’s operations,” while alternative methods only allow the FDA to see “a fraction of the firm’s operations.”
The systematic analysis of the GMP deficiencies recorded during an inspection reflects on the one hand, what FDA inspectors focus on and, on the other hand, provides clues for preparing for an upcoming inspection by the FDA. The sometimes quite detailed descriptions of the GMP violations are facilitated by topic-related statistics, which are carried out annually by Concept Heidelberg in the context of the respective completed fiscal year. In the fiscal year 2022 (October 2021-September 2022), a total of 42 Warning Letters were sent to medicinal product manufacturers, each explicitly describing the GMP deficiencies in connection with the paragraphs of 21 CFR 211. After analyzing these “Drugs” Warning Letters, the “hit parade” of the 10 most frequently cited GMP sins are as follows:
- 211.22 Responsibilities of quality control unit – cited in 23 Warning Letters
- 211.192 Product record review – cited in 19 Warning Letters
- 211.165 Testing and release for distribution– cited in 17 Warning Letters
- 211.100 Written procedures; deviations – cited in 16 Warning Letters
- 211.84 Testing and approval or rejection of components, drug product containers, and closures – cited in14 Warning Letters
- 211.67 Equipment cleaning and maintenance – cited in 13 Warning Letters
- 211.166 Stability Testing – cited in 11 Warning Letters
- 211.160 General requirements – cited in 10 Warning Letters
- 211.68 Automatic, mechanical, and electronic equipment – cited in 8 Warning Letters
- 211.42 Design and construction features – cited in 4 Warning Letters
- 211.113 Control of microbiological contamination – cited in 4 Warning Letters
- 211.188 Batch production and control records – cited in 4 Warning Letters
The GMP Violations described in the 23 Warning Letters can be grouped as follows:
- Quality Assurance review of batch documentation and batch release
- Responsibilities of the Quality Unit toward contract manufacturers and contract laboratories
- Quality Assurance responsibility for procedural instructions, SOPs, GMP documents
- Quality Assurance responsibility for root cause analysis in case of deviations
- Quality Assurance responsibility for trained personnel
This compilation shows that most violations of basic GMP rules are closely related to the Quality Unit’s failure to take responsibility. Ultimately, the GMP deficiencies associated with the other paragraphs of 21 CRF 211 also result from this failure of Quality Assurance.
World Health Organization (WHO)
The following WHO Public Inspection Reports (WHOPIRs) were published on 27 January 2023: