By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
Understanding the New Rules for Clinical Analysis Laboratories, 12 May 2023
ANVISA has updated the standards that deal with the technical requirements for the operation of laboratories that perform collection, examination, and analysis for the diagnosis of diseases. The rules also cover other services that perform activities related to clinical analysis examinations, such as isolated (private) offices and pharmacies, which are considered health services since the publication of Law 13.021/2014. The measure may allow the expansion of the population’s access to diagnostic procedures in the country. The new standard, RDC 786/2023, was published in the Official Gazette on 10 May 2023 and will enter into force on 01 August 2023, but establishments will have up to 180 days to comply with the updated rules. The rules of RDC 786/2023 correspond to a normative update, which replaces RDC 302/2005. The new resolution applies to health establishments classified as laboratories and services that perform activities related to clinical analysis examinations. The laboratories are those intended for evaluations with clinical purposes, such as the collection and analysis of biological samples for the diagnosis of diseases. The standard is also intended for pathological anatomy laboratories, which perform evaluations and diagnosis of diseases from samples of organs and tissues. It is emphasized that all services that perform clinical analysis examinations and distribution centers must implement a Quality Assurance program. In addition, the establishments that perform these exams must ensure the reliability of the tests, through Quality Control management. The main innovations presented in the new standard are:
The approved resolution introduces a new categorization of health services that carry out activities related to clinical analysis examinations into three types, according to their complexity and infrastructure:
Brazil Moves Toward Leveraging Medical Device Registrations from Other Regulators, 30 May 2023
For the first time, legislation was published in Brazil to permit leveraging authorization from regulators deemed equivalent. In August 2022, ANVISA published Resolution RDC 741/2022, which sets the framework to consider other medical device market regulators’ authorizations. RDC 741/2022 explains that ANVISA would be able to use registrations from foreign regulatory agencies for identical devices (those considered to have the same intended use and same materials). ANVISA and other regulator(s) will exchange information to confirm the devices are identical. ANVISA will continue to require the documents already requested for a registration in Brazil (such as labels and Instructions for Use (IFUs) in Portuguese).
At the most recent Hospitalar Trade Fair in May 2023, ANVISA provided an update on their progress. ANVISA expects to launch the new registration route, referred to as Reliance Registration/Optimized Analysis/Reliance Mechanism. The name for the new route has not yet been defined. The new modality aims to reduce the approval time for device registrations in Brazil. The following conditions apply to this process:
While the regulatory authorities that ANVISA considers equivalent have not been defined, Medical Device Single Audit Program (MDSAP) participating agencies were noted as potential examples. Qualifying Brazil ANVISA applicants will be required to provide registration certificates issued by equivalent regulatory authorities. Companies applying via the new registration route will also need to verify that their devices submitted for ANVISA approval are identical to the devices listed on their registration certificates from equivalent regulators.
National Medical Products Administration (NMPA)
On 24 May 2023, China National Medical Products Administration (NMPA) issued the draft Notice of Enhancing the Supervision of Drug Marketing Authorization Holders (MAHs) That Outsource Manufacture (hereafter referred to as the Notice). The Notice came with an appendix: Guidance for On-site Inspection of Drug MAHs that Outsource Manufacture. The draft was open to public advice until 23 June 2023. The Notice stipulates that provincial medical product administrations should conduct strict inspections of MAHs, with requirements that include the following topics:
With respect to Quality Management for Outsourced Manufacture, the MAH is required to establish a management department with clear responsibilities, equipped with enough personnel suitable for the scale of drug production and supply, and establish a Quality Management System (QMS) covering the entire process of drug production in accordance with regulations. If outsourcing the manufacture of sterile drugs, the MAH’s Responsible Person for Quality and Qualified Person (QP) is required to have at least five years of experience in drug production and quality management, of which at least three years should be for sterile drugs.
MAHs of Traditional Chinese Medicine (TCM) injections and multi-component biochemical drugs are required to have the capability to manufacture the products independently. This requirement is stricter than the Drug Administration Law, which allows all MAHs to choose whether to outsource manufacture or not. Biological product (excluding vaccines and blood products) MAHs are encouraged to have the capability to manufacture the products independently. If the MAH has insufficient production capacity and needs to outsource manufacture to another company’s site, the holder should manage the outsourcing activity according to the regulations on post-marketing changes of drugs.
Supervision Ensures Medical Products Safe, 06 July 2023
With the sale of medical products online skyrocketing in recent years, the NMPA has led a crackdown to ensure that only safe and approved products are available for consumers. By upping its supervision and scrutiny on the production and sales of drugs, cosmetics products, and medical devices, the administration was able to resolve 153,600 cases involving the production of unauthorized medical devices or producing and selling fake drugs and cosmetics last year. Those suspected of violating laws have been transferred to public security organs for further investigation, senior officials at the administration said at a news conference in Beijing on Wednesday. The administration also published and made available online 32 cases as warnings to industry operators and pharmaceutical companies. It is estimated that the online sales of drugs and medical devices last year reached 292 billion yuan ($40.4 billion), and is expected to exceed 350 billion this year, said Huang Guo, Deputy Director of the administration.
European Medicines Agency (EMA)
Guidance for Industry to Prevent and Mitigate Medicine Shortages, 17 May 2023
EMA has published guidance for industry with recommendations on good practices to ensure continuity in the supply of human medicines, prevent shortages, and reduce their impact. The guidance describes the various stakeholders involved in the medicine supply chain and their responsibilities and role in the prevention and management of medicine shortages. It provides ten recommendations for marketing authorization holders, wholesalers, distributors, and manufacturers to minimize the occurrence of medicine shortages and their impact. The recommendations include:
The recommendations are based on the analysis of causes of shortages and regulators’ first-hand experience in coordinating the management of shortages, and industry associations have been consulted.
Health Canada
Non-Compliant Rating for TJP Labs, Inc., 02 May 2023
TJP Labs, Inc., a distributor/importer located in Pickering, Ontario, Canada, received a non-compliant rating from Health Canada for an inspection that started on 02 May 2023. Observations included the following key points:
Additional concerns were noted with respect to:
Bausch Health, Canada Inc. is recalling all lots of Emerade epinephrine auto-injectors (0.3 mg and 0.5 mg) after testing by the company identified the potential risk that the auto-injector may fail to activate, or it may activate prematurely if dropped. The affected lots of Emerade were distributed in Canada between April 2022 and May 2023. Emerade auto-injectors are used to deliver an emergency treatment of epinephrine to patients who are at risk or have a history of serious allergic reactions (anaphylaxis). Failure of the auto-injector to activate may result in patients not receiving the required dose of epinephrine, leading to the worsening of symptoms of anaphylaxis, which could be life-threatening. Health Canada recognizes how important epinephrine auto-injectors are for people with life-threatening allergies. There are alternative epinephrine auto-injectors available in Canada. Ensuring Canadians can get the medicines they need is one of Health Canada’s top priorities. A shortage of alternative products is not expected, but the Department will continue to actively monitor the supply situation.
Health Canada is warning consumers about unauthorized Kobayashi eye washes and Sante FX eye drops seized from the store “Kiokii and…” (actual store name) in Mississauga (719 Central Pkwy W, Suite 211), Ontario, and removed from online sale. The products were seized because they are unauthorized and labelled to contain prescription drug ingredients 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. 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.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
ICH E6(R3) Draft Guideline Reaches Step 2 of the ICH Process, 23 May 2023
The ICH E6(R3) draft Guideline on “Good Clinical Practice (GCP)” has reached Step 2 of the ICH process on 19 May 2023. The E6(R3) draft Guideline is composed of principles and annexes that expand on the principles with specific details for different types of clinical trials. The guideline applies to interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities and may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorization applications in accordance with local requirements. Annex 1, which is included in this Step 2, document is intended to provide information on how the concepts can be appropriately applied to clinical trials. Work on Annex 2, regarding additional considerations for interventional clinical trials, has just been initiated, with an Annex 2 Concept Paper approved in May 2023 by the ICH Management Committee.
International Organization for Standardization (ISO)
ISO/IEC 27032:2023, Cybersecurity – Guidelines for Internet Security, May 2023
ISO/IEC 27032:2023, Cybersecurity – Guidelines for Internet Security provides:
This document is intended for organizations that use the internet.
Laboratory testing is prone to errors that may have a negative impact on test results. This is why Proficiency Testing, a formal type of interlaboratory comparison, plays a crucial role in ensuring the consistency and comparability of results across different laboratories. The newly updated ISO/IEC 17043, Conformity Assessment – General Requirements for the Competence of Proficiency Testing Providers, enables Proficiency Testing providers to competently monitor the quality of a laboratory’s performance. Training material, including slides and a webinar, were made available.
International Society for Pharmaceutical Engineering (ISPE)
2023 ISPE Drug Shortages Prevention Model, May 2023
The ISPE Drug Shortages Prevention Model serves as a guide to help prevent drug shortages by providing quality, regulatory, and technical recommendations for the pharmaceutical manufacturing industry. The ISPE Drug Shortages Task Team developed the model as a follow up to the ISPE Drug Shortages Prevention Plan that was released in 2014. The model provides expanded guidance that reflects new insight and best practices that have emerged in the past several years. Experience with large-scale events such as Hurricane Maria and the COVID-19 pandemic, and more recent geopolitical events, have cast a wider lens on global supply chain and distribution vulnerabilities. In parallel, public and civic demand for change has been accelerating new regulatory requirements in some markets and increased pressure is being placed on manufacturers for supply chain resiliency globally.
Medicines and Healthcare Products Regulatory Agency (MHRA)
Pharmaswiss Česka republika s.r.o. and distributor Bausch & Lomb UK Limited is recalling all unexpired batches of Emerade 500 micrograms and Emerade 300 micrograms adrenaline auto-injectors (also referred to as pens) from patients. This is due to an issue identified during an ISO 11608 Design Assessment study where some auto-injectors failed to deliver the product or activated prematurely. Specifically, the 1-meter free-fall (vertical orientation) pre-conditioning resulted in damage to internal components of the auto-injector, leading either to failure to deliver the product or premature activation. This damage was not visibly apparent following the pre-conditioning but was evident only on subsequent functional testing. It is unclear what impact this has on auto-injectors in clinical use; however, as a precautionary measure and owing to the inability to identify this issue before the auto-injectors are used, the auto-injectors are being recalled.
The MHRA, in conjunction with the Department of Health & Social Care (DHSC), has established that there are sufficient supplies of alternative auto-injectors to allow for a recall at patient level. Pharmaswiss Česka republika s.r.o. and distributor Bausch & Lomb UK Limited has confirmed that future production of Emerade 500 micrograms and Emerade 300 micrograms auto-injectors is on hold. Therefore, no further supplies will be available, and patients will need to be switched to an appropriate alternative.
Parenteral Drug Association (PDA) – Technical Reports
PDA Technical Report No. 43 (Revised 2023): Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing provides an approach to a quality decision-making process and represents best practices for the identification and classification of visual nonconformities for glass containers. TR 43 was originally published in 2007 and revised in 2013 to address industry feedback. This latest revision (2023) is issued to address evolving standards and container types. TR 43 applies solely to empty glass containers.
The standardized quality criteria in TR 43 are intended as guidance for container manufacturers and for incoming container acceptance inspection at pharmaceutical companies. Five detailed lexicons have been updated, and these visually illustrate glass nonconformities—one for molded glass bottles and vials, and four for tubular glass vials, ampoules, cartridges, and syringes. Additionally, defects specific to ready-to-use containers and their categorization are included for use as applicable. Consulting with the appropriate regulatory authorities for agreement on the strategies employed for identification and classification of visual nonconformities of glass containers is always advisable.
Personal Care Products Council (PCPC)
Enacted in December 2022, the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) represents years of efforts by the Personal Care Products Council, the FDA, Congress, and other stakeholders to modernize the U.S. cosmetic regulatory framework. Prepared together with counsel at Covington & Burling, this PCPC MoCRA Toolkit is designed to provide an overview of new requirements and authorities that MoCRA established. Although this Toolkit provides PCPC’s current thinking on MoCRA, companies should be mindful that MoCRA represents meaningful new authorities that FDA has yet to interpret and apply. Compliance with MoCRA requires independent judgement based upon facts of a particular situation, and this Toolkit is not intended to replace regulatory counsel to ensure compliance. This Toolkit covers Adverse Events, Facility Registration, Facility Suspension, Product Listing, Safety Substantiation, Labeling, Recalls, Fragrance Provisions, Cosmetics Records Access, Good Manufacturing Practices Rule, Talc Rule, and Per- and Polyfluoroalkyl Substances (PFAS) report.
“The Personal Care Products Council (PCPC) and our member companies are deeply appreciative of the Senate Appropriations Committee approving the Fiscal Year 2024 appropriations bill, which includes $7 million in funding for the FDA to support the implementation of the Modernization of Cosmetics Regulation Act (MoCRA). This critical action reflects our industry’s advocacy efforts and dedication to consumer safety, product innovation and scientific excellence. PCPC has long supported providing the FDA with the resources it needs to advance modern federal regulatory oversight of cosmetics and personal care products. For more than a decade, PCPC has been at the forefront of advocating on behalf of our member companies for well-crafted, science-based federal reforms to invigorate our industry’s ability to innovate and modernize regulation. The unwavering leadership of Committee Chair Patty Murray and Ranking Member Susan Collins guided the appropriations process. Their commitment not only made MoCRA possible, but their efforts ensure that the FDA has the necessary tools to maintain consistent and effective regulation of cosmetics and personal care products. Consumer and product safety remains at the heart of our industry. PCPC and our member companies look forward to working closely with the FDA and key stakeholders to implement this landmark legislation effectively. Our collective dedication will further reinforce consumer trust in the products they use daily, driving the growth of our science-driven beauty and personal care industry.”
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
Publication of Revised Annex 1 – PIC/S GMP Guide (PE 009-17 – Annexes), June 2023
PIC/S has published the revised PIC/S GMP Guide (PE 009-17 – Annexes), which includes the revised Annex 1. PE 009-17 that will enter into force on 25 August 2023. In the meantime, the current version of the PIC/S GMP Guide (PE 009-16 – Annexes) remains in force. Both versions of these PIC/S GMP Guides are published on https://picscheme.org/en/publications.
Therapeutic Goods Administration (TGA)
TGA Supports MHRA’s New International Recognition Framework for Medicines, 02 June 2023
As a trusted regulatory partner, TGA is committed to support the new international recognition framework that MHRA is introducing for medicines. These international recognition routes have been facilitated by existing international partnerships such as those developed through the Access Consortium and Project Orbis, and are part of a new international recognition framework for medicines that is specific to the UK following their exit from the European Union. The new framework will allow MHRA to utilize the work of, and regulatory decisions made by, the seven nominated international regulatory counterparts to assist in their sovereign decision-making and will be in place by the first quarter of 2024.
Phase Out of ISO 13485 Certificates for IVD Medical Devices, 25 May 2023
The transition period for the TGA to accept ISO 13485 certificates as manufacturer evidence for In Vitro Diagnostic (IVD) medical devices ends on 26 May 2023. This means that TGA can no longer accept ISO 13485 certificates to support IVD inclusion applications. Approved IVD medical devices supported by ISO 13485 certificates remain valid until the certificate expires. Sponsors will then need another form of acceptable manufacturer evidence to support their approved device. TGA will publish guidance on the transition to new manufacturer evidence for IVD medical devices soon.
TGA Publishes Updated Guidelines for Sunscreens, 09 May 2023
The TGA has updated the Australian Regulatory Guidelines for Sunscreens (ARGS) to align with the data requirements for all ingredients proposed to be included in the Therapeutic Goods (Permissible Ingredients) Determination (‘the Permissible Ingredients Determination’). On 01 February 2023, mandatory requirements for applications to vary the Permissible Ingredients Determination under section 26BD of the Therapeutic Goods Act 1989, and accompanying guidelines came into effect. The mandatory requirements describe the data expectations for any new ingredient application for listed therapeutic goods, including new ingredients for use on the skin (such as sunscreen ingredients). The TGA evaluates the quality and safety of all substances to the same standard before they can be included in the Permissible Ingredients Determination. As such, the quality and safety data requirements have been updated in the ARGS version 3.0 to align with the requirements for all new substances for use in topical listed medicines described in the Application Requirements for New Substances in listed medicines (ARNS) last updated on 09 May 2023.
United States Food and Drug Administration (FDA) – Regulations and Guidances
This guidance is intended to alert pharmaceutical manufacturers, compounders, repackers, and suppliers to the potential public health hazard of glycerin and other high-risk drug components contaminated with Diethylene Glycol (DEG) or Ethylene Glycol (EG). FDA has received and continues to receive (most recently in early 2023) reports about fatal poisonings of consumers who ingested drug products in a liquid dosage form (such as cough, allergy, analgesic, and antiemetic drug products) that were manufactured with DEG- or EG-contaminated components.
Public Meeting: Good Manufacturing Practices for Cosmetic Products, 01 June 2023
The FDA held a virtual listening session on 01 June 2023. The purpose of the listening session was to consult cosmetics manufacturers, including smaller businesses, contract manufacturers, consumer organizations, and other experts to inform FDA’s efforts in developing regulations to establish Good Manufacturing Practices (GMPs) for facilities that manufacture, or process cosmetic products distributed in the United States (Modernization of Cosmetics Regulation Act (MoCRA). To facilitate input, the FDA developed a series of topics related to the following:
Event Materials and Resources are available at the FDA website: Public Meeting: Good Manufacturing Practices for Cosmetic Products, 01 June 2023.
United States Food and Drug Administration (FDA) – Recalls
Akorn Operating Company LLC filed Chapter 7 bankruptcy on 23 February 2023. In connection with that filing, the company has ceased, shut down all operations, and terminated all its employees of all domestic United States sites. The Akorn Trustee is initiating a voluntary recall of various within-expiry human and animal products as a result of the closures and discontinuation of the quality activities of these marketed products. The discontinuation of the quality program means the company will not be able to support or guarantee that the products will meet all intended specifications through the labeled shelf life of the product. Further distribution or use of any remaining product on the market should cease immediately.
BearCare, Inc. is initiating a voluntary recall of its rechargeable Walnut Wearable Smart Thermometer (Walnut Thermometer) due to reports of injuries, including skin burns, by users. The Walnut Thermometer is an over-the-counter rechargeable device intended for continuous chest temperature monitoring of children ages 0-6 years which can be identified by its silicone exterior resembling a cartoon penguin. The product under recall was sold and distributed from December 2022 to April 2023 through Amazon.com and Walmart.com.
United States Food and Drug Administration (FDA) – Warning Letters
Steiner Biotechnology, LLC, Warning Letter, 19 May 2023
Steiner Biotechnology, LLC received a Warning Letter from the FDA on 19 May 2023. This Warning Letter was issued as a result of inspections conducted at the companies facility in Henderson, NV on 15 to 19 August 2022 and 03 to 08 November 2022. The FDA investigators determined that the firm manufactures bone grafting materials including, the Socket Graft, Socket Graft Plus, Socket Graft Injectable, OsseoConduct, OsseoConduct Micron, Ridge Graft Kit, Immediate Graft, and Oral Bond. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body. FDA Form 483 observations sited in included the following concerns:
Chengdu KeCheng Fine Chemicals Co., Ltd., Warning Letter, 20 June 2023
Chengdu KeCheng Fine Chemicals Co., Ltd received a Warning Letter from the FDA on 20 June 2023. This company was registered with the FDA as a manufacturer of several Active Pharmaceutical Ingredients (APIs). A review of import records showed multiple shipments of API into the U.S. that declared Chengdu KeCheng Fine Chemicals Co., Ltd. as the drug manufacturer. On 18 July 2022, the FDA sent an electronic request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 374(a)(4), to the contact e-mail address provided in the company registration file. This request went unanswered. A second request was sent via email on 08 August 2022, followed by a telephone call from the FDA on 24 October 2022. During the telephone call, the company refused to provide their full name or an alternate email address for further communication. Chengdu KeCheng Fine Chemicals Co., Ltd stated that they were not shipping products to the United States and that they would deregister their firm as a drug establishment. However, the company has continued to ship API to the United States as recently as January 2023. The FDA sent a follow-up electronic request for such records and other information on 09 March 2023. The company failed to respond to these attempted communications or otherwise provide the requested records or other information. Pursuant to section 704(a)(4), the FDA’s request and follow-up communications included a sufficient and clear description of the records sought. Because the company failed to respond to the section 704(a)(4) records requests and associated communication attempts, there is no indication of the level of Quality Assurance for drugs listed as manufactured at the facility.
The FDA placed all drugs and drug products manufactured by Chengdu KeCheng Fine Chemicals Co., Ltd on Import Alert 66-79 on 08 June 2023. Until the FDA is able to confirm compliance with CGMP and other applicable requirements, the agency may withhold approval of any new applications or supplements listing by the company as a drug manufacturer. In addition, shipments of articles manufactured at Chengdu KeCheng Fine Chemicals Co., Ltd., Floor 9, No. 18 Chuangye Road, Chengdu High-Tech District, Chengdu, Sichuan into the United States that appear to be adulterated or misbranded are subject to being detained or refused admission pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).
World Health Organization (WHO)
WHO: Excipients GMP Guideline Published for Comments, 03 May 2023
In March 2023, the WHO published the first draft of the guideline WHO Good Manufacturing Practices for Excipients Used in Pharmaceutical Products on its website for comments. The public comment period ended on 26 May 2023. The proposals will be reviewed, and the resulting draft is expected to be discussed by a consultation group in July 2023. The current draft is based on The WHO Guideline Good Manufacturing Practices: Supplementary Guidelines for the Manufacture of Pharmaceutical Excipients, which was published in 1999 as Annex 5 in the WHO Technical Report Series No 885. This annex was the starting point for the new guideline.