SQA Regulatory Surveillance Summary 5 | Monthly Update 2021
By Laurel Hacche, Debra Cortner, & Dondi Pulse-Earle SQA Associates
SQA Regulatory Surveillance Summary #5, 2021
International Organization for Standardization (ISO)
Keeping food safe involves the combined effort of every single player in the food production chain, from farm to fork. That means everyone needs to be speaking the same language and adhering to the same rules. ISO 22000 is an internationally agreed reference in the food industry, and now new guidance has just been published to help users get the most out of it. Published jointly by ISO and the United Nations Industrial Development Organization, the new handbook, ISO 22000:2018 – Food safety management systems – A practical guide, provides in-depth and practical information to help organizations more effectively implement a food safety management system (FSMS) in accordance with ISO 22000:2018. The guide also provides information about the certification process, which will be helpful to any organization seeking to obtain certification or wanting to learn about the ISO 22000 certification process.
ISO/TS 22421, Sterilization of Health Care Products – Common Requirements for Sterilizers for Terminal Sterilization of Medical Devices in Health Care Facilities, provides high-level, overarching requirements and respective test methods, and sets the scene for further, more detailed standards to be developed. This standard takes into account many of the factors that contribute to the safe and effective performance of medical equipment, such as its design and construction; the provision of indicating, monitoring, controlling, and recording devices; emissions from the equipment; and information to be provided by the manufacturer. ISO/TS 22421 was developed by technical committee ISO/TC 198, Sterilization of Health Care Products, whose secretariat is held by the American National Standards Institute (ANSI), ISO’s member for the USA.
A number of ISO standards have been made available to support global efforts to address the COVID-19 crisis. These standards include but are not limited to the following list and are available at no charge in read-only format:
- ISO 374-5:2016, Protective gloves against dangerous chemicals and micro-organisms – Part 5: Terminology and performance requirements for micro-organisms risk
- ISO5356-1:2015, Anesthetic and respiratory equipment – Conical connectors – Part 1: Cones and sockets
- ISO 10651-4:2002, Lung ventilators – Part 4: Particular requirements for operator-powered resuscitators
- ISO 10651-5:2006, Lung ventilators for medical use – Particular requirements for basic safety and essential performance – Part 5: Gas-powered emergency resuscitators
- ISO 10993-1:2018, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process
- ISO 13485:2016, Medical devices — Quality management systems – Requirements for regulatory purposes
- ISO 13688:2013, Protective clothing – General requirements
- ISO 13688:2013/AMD 1:2021, Protective clothing — General requirements — Amendment 1
- ISO/TS 16976-8:2013, Respiratory protective devices – Human factors – Part 8: Ergonomic factors
- ISO 17510:2015, Medical devices – Sleep apnea breathing therapy – Masks and application accessories
- ISO 18082:2014, Anesthetic and respiratory equipment – Dimensions of non-interchangeable screw-threaded (NIST) low pressure connectors for medical gases
- ISO 18562-1:2017, Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 1: Evaluation and testing within a risk management process
- ISO 22301:2019, Security and resilience – Business continuity management systems –Requirements
- ISO 22316:2017, Security and resilience – Organizational resilience – Principles and attributes
- ISO 22320:2018, Security and resilience – Emergency management – Guidelines for incident management
- ISO 31000:2018, Risk management – Guidelines
Parenteral Drug Association (PDA) – Technical Reports
Visual inspection of filled injectable products is an important part of the control strategy of the manufacturing process. It offers a means to improve quality by removing noncompliant units and provides information to drive continuous process improvement. TR 85 addresses test and inspection methods for visible particles in primary packaging components for injectable products, specifically glass vials and syringes, and the elastomeric closures used to seal them. This document is most relevant for ready-to-sterilize (RTS) and ready-to-use (RTU) components because these are not subjected to a further cleaning process immediately before use. These studies and methods were developed as part of a larger initiative to eliminate visible particles in injectable products. The test and inspection methods discussed within this report are the first step in a standard-setting process. Once test and inspection methods are available, accepted, and implemented, they can be used to assess process capability and establish meaningful process control limits. Without reliable measurements, reliable control limits are not possible.
PDA TR 86 is a consensus-based resource surrounding the challenges encountered in using complex package systems and introduces important elements to consider in decision-making. It also offers an examination of the technologies available for package integrity testing not yet established by peer-reviewed research. This technical report focuses on the challenges facing the pharmaceutical industry that use complex packaging systems for sterile drugs and biologics (e.g., syringes, syringe assemblies, and bulk containers). It also presents information on some innovative methods for package integrity testing using existing technologies, including the potential impact of cryogenic conditions. The intent of TR 86 is to update information and incorporate experiential learning, which is not addressed in PDA Technical Report No. 27 (TR 27) Pharmaceutical Package Integrity and United States Pharmacopeia (USP) <1207> Sterile Product Packaging – Integrity Evaluation. TR 86 also serves as a technical resource, focusing particularly on sterile products and encouraging a risk-based approach and leveraging testing to better understand, analyze, and eliminate the risks during developmental phases. Use of the appropriate testing during each manufacturing phase can help in evaluating and mitigating residual risks.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
The PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products has been revised to include a new Annexes 2A and 2B:
- Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP)
- Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use
Annex 2A provides PIC/S GMP requirements for ATMP – it is not a standalone document, but it enables reasonable harmonization with the standalone ATMP Guidelines published by the European Commission. Annex 2B had very minor revisions and continues to harmonize with the EU Annex 2 for human-use biological medicinal substances and products. The revised GMP Guide (PE 009-15), with the new Annex 2A and 2B, entered into force on 01 May 2021. All non-European Economic Area (EEA) Participating Authorities of PIC/S and Applicants have been invited to transpose the revised Chapters of the PIC/S GMP Guide into their own GMP Guides.
The following two PIC/S guidance documents have been revised:
- PE 005-4: PIC/S Good Practice Guidelines for Blood Establishments and Hospital Blood Banks
- PI 008-4: PIC/S Aide Memoire to Inspections of Blood Establishments and Plasma Warehouses
These guidance documents have been revised by the PIC/S Working Group on Blood Guidance, led by Switzerland/Swissmedic, on the basis of the Good Practice Guidelines (GPG) for Blood Establishments drafted by the European Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM) and the European Commission. The revised guidance documents entered into force on 01 June 2021.
United States Department of Health and Human Services (HHS) – Laws, Regulations, and Guidances
The White House, the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) and the United States Food and Drug Administration (FDA) released a series of policy recommendations to address the vulnerabilities in United States pharmaceutical supply chains. Led by the FDA and ASPR, the White House report and its recommendations (report PDF) have been accepted by President Biden. HHS will make an initial commitment of approximately $60 million from the Defense Production Act appropriation in the American Rescue Plan to develop novel platform technologies to increase domestic manufacturing capacity for Active Pharmaceutical Ingredients (APIs). Greater API production domestically will help reduce reliance on global supply chains for medications that are in shortage, particularly during times of increased public health need.
The White House report reveals the pharmaceutical supply chain as complex, global, and highly influenced by market factors that have led to an increasing reliance on foreign countries to manufacture the medicines, APIs, and Key Starting Materials (KSMs) that serve the American public. To secure the supply chain, the report’s recommendations center on four pillars:
- Boosting local production and fostering international cooperation
- Promoting research and development that establish innovative manufacturing processes and production technologies to strengthen supply chain resilience
- Creating robust quality management maturity to ensure consistent and reliable drug manufacturing and quality performance
- Leveraging data to improve supply chain resilience
The report acknowledges that achieving success will require multiple U.S. government agencies and the private sector to collaborate in providing Americans with timely access to pharmaceuticals. Successful implementation of the recommendations will promote economic well-being and emphasizes the role these activities play in shoring up United States health security and national defense.
United States Food and Drug Administration (FDA) – Guidances for Drugs and Biologics
The draft FDA guidance, Sponsor Responsibilities – Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies, provides recommendations to help sponsors comply with the expedited safety reporting requirements for human drug and biological products that are being investigated under an investigational new drug application (IND) (21 CFR 312.32) or as part of a bioavailability (BA) or bioequivalence (BE) study that is exempt from the IND requirements (21 CFR 312.64(b) and 320.31(d)(3)). The draft guidance defines terms used for safety reporting, makes recommendations on when and how to submit a safety report, and provides information on other safety reporting issues raised by sponsors. It should be noted that this draft guidance merges content from the final guidance for industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies, December 2012, and the draft guidance for industry Safety Assessment for IND Safety Reporting, December 2015, on the following topics:
- Planned unblinding of safety data and implications for trial integrity
- Increased flexibility regarding the party reviewing aggregate safety information for IND safety reporting purposes
- Clarification regarding the scope and methodology of aggregate analyses
- Clarification regarding the plan for safety surveillance, including what elements should be included in the plan
The 2015 draft guidance has been withdrawn.
The purpose of the FDA guidance for Evaluating Cancer Drugs in Patients with Central Nervous System (CNS) Metastases is to describe the FDA’s recommendations for clinical trial designs of cancer drugs or biological products regulated by CDER and CBER that are intended to support product labeling describing the antitumor activity in patients with CNS metastases from solid tumors originating outside the CNS. The guidance addresses the following considerations with respect to clinical trial design:
- Patient Population
- Available Therapy
- Prior Therapies
- Assessment of CNS Metastases
- Study Endpoints
- Leptomeningeal Disease (LMD)
United States FDA – Guidances for Devices
FDA guidance Testing and Labeling Medical Devices for Safety in the Magnetic Resonance (MR) Environment provides the FDA’s recommendations on testing to assess the safety and compatibility of medical devices in the Magnetic Resonance (MR) Environment and the recommended format for Magnetic Resonance Imaging (MRI) Safety Information in medical device labeling. This new guidance supersedes the FDA guidance Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment that was published in December 2014.
Medical devices encompass a vast array of products with different technologies, product lifecycles, complexity, intended users, and environments of use. Many devices are reusable and need preventive maintenance and repair during their useful life. For these devices, proper servicing is critical to their continued safe and effective use. However, there is a lack of clarity regarding the distinction between “servicing” and “remanufacturing” of a device. Most notably, remanufacturing has implications for the regulatory responsibilities of entities performing these activities.
The draft FDA guidance Remanufacturing of Medical Devices is intended to help clarify whether activities performed on devices are likely “remanufacturing.” Such clarification is intended to help provide consistency and better understanding of applicable statutory and regulatory requirements. This draft guidance also includes recommendations for information that should be included in labeling to help assure the continued quality, safety, and effectiveness of devices that are intended to be serviced over their useful life. In drafting this guidance, the FDA considered objective evidence and information learned from the Agency’s activities discussed in this draft guidance.
United States FDA – Recalls for Biologics, Drugs, and Devices
Aziyo Biologics, Inc. (Aziyo) is the manufacturer of record for FiberCel Fiber Viable Bone Matrix (FiberCel) and is voluntarily recalling one lot of the FiberCel product, Donor Lot Number: NMDS210011. This voluntary recall is being issued out of an abundance of caution following a customer complaint from one hospital that initially reported post-surgical infection in 7 of the 23 patients that have received FiberCel from this Donor Lot. Four of these patients have tested positive for Tuberculosis. Aziyo issued an Urgent Notification Letter on 02 June 2021. This notification instructs any customer who received FiberCel product from this single Donor Lot to immediately examine its inventory and quarantine any remaining product.
Viona Pharmaceuticals, Inc. is voluntarily recalling two lots of Metformin Hydrochloride Extended-Release Tablets, USP 750 mg to the retail level. The two lots of Metformin Hydrochloride Extended-Release Tablets, USP 750 mg have been found to contain levels of NDMA impurities above acceptable daily limits. This product was manufactured by Cadila Healthcare Limited, Ahmedabad, India in November 2019, for United States distribution by Viona Pharmaceuticals, Inc. To date, neither Viona Pharmaceuticals, Inc. nor Cadila Healthcare Limited have received any reports of adverse events related to this recall.
Risk Statement: NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. Patients who have received impacted lots of Metformin Hydrochloride Extended-Release Tablets, USP 750 mg are advised to continue taking their medication and contact their physician for advice regarding an alternative treatment. According to the FDA, it could be dangerous for patients with this serious condition to stop taking their Metformin without first talking to their healthcare professionals.
Avid Medical is recalling medical convenience kits that include the BD/Carefusion Chloraprep™ 3mL applicator. The applicator was recalled due to the risk of contamination with a specific type of fungus called Aspergillus penicillioides. If skin preparation products are contaminated with Aspergillus penicillioides, the fungus can cause serious systemic infection, sepsis, illness, and death to the patient. If the fungus is introduced in the patient’s bloodstream during placement of an intravascular catheter, the catheter may need to be removed, requiring additional medical procedures. If the fungus infects a surgical site, the patient may require medical and surgical treatments and require long-term treatment with antifungal drugs. There have been no deaths, complaints, or reported injuries related to this issue.
United States FDA – Notifications and Consent Decrees for Food and Devices
The FDA has announced that Real Water, Inc., a Nevada-based bottled water manufacturer, agreed to cease operations until they can comply with the Federal Food, Drug, and Cosmetic Act (FD&C Act) and other requirements listed in a consent decree. United States District Judge Jennifer A. Dorsey entered a consent decree of permanent injunction on 01 June 2021 between the United States and AffinityLifestyles.com, Inc. (majority shareholder of Real Water, Inc.); Real Water, Inc.; Brent A. Jones, President of Real Water, Inc.; and Blain K. Jones, Vice President of Real Water, Inc. According to the complaint filed by the Department of Justice (DOJ) on behalf of the FDA, the defendants violated the FD&C Act by operating facilities that fail to meet preventive control requirements to control food hazards. The complaint also alleges that the defendants violated the FD&C Act by failing to follow current Good Manufacturing Practice (CGMP) requirements for bottled water. The complaint further alleges that the defendants’ products are adulterated within the meaning of the FD&C Act because they have been prepared, packed, or held under unsanitary conditions whereby they may have become contaminated with filth or may have been rendered injurious to health. Additionally, the complaint alleges the defendants’ products are misbranded because their labels fail to declare the common or usual name of each ingredient.
The consumption of “Real Water” brand alkaline water was the only known common link between five cases of acute liver failure in children that occurred in November and December 2020 that was reported to the FDA in March 2021. Since then, 11 additional cases of acute non-viral hepatitis in adults, including one death of a woman with underlying medical conditions, have been identified as possibly linked to the consumption of Real Water brand alkaline water. The FDA issued an outbreak advisory on 16 March 2021 and continues to investigate, along with the United States Centers for Disease Control and Prevention and the Southern Nevada Health District. On 24 March 2021, Real Water, Inc. of Mesa, Arizona, and Henderson, Nevada, issued a recall of all sizes of its Real Water brand drinking water and concentrate.
The FDA is aware of sterility issues with medical devices processed at the Steril Milano S.R.L. Reggiolo and Monza ethylene oxide sterilization facilities in Italy. The FDA became aware that Steril Milano falsified graphs and parameters of sterilization certificates for a variety of FDA-regulated products, dating back to 2016. The FDA is working with medical device manufacturers, international partners, and United States federal partners to investigate the scope of medical devices that may be impacted and intends to contact potentially impacted firms that are known to have contracted medical device sterilization services with these Steril Milano facilities.
The FDA believes that 97 medical device manufacturers may be affected. The types of medical devices that may be affected include biopsy needles, catheters, intravascular administration sets, arthroscopes, syringes, and other medical devices. The Steril Milano S.R.L. Reggiolo and Monza ethylene oxide sterilization facilities were closed in March 2021 and are no longer sterilizing medical devices. Several recalls are associated with the sterility concerns at the Steril Milano S.R.L. Reggiolo and Monza facilities. As of 01 June 2021, 10 firms have voluntarily recalled their affected medical devices. At this time, the FDA is not aware of reports of patient harm associated with impacted products.
The FDA is alerting health care providers that Medtronic has stopped the sale and distribution of the Heartware Ventricular Assist Device (HVAD) System because:
- There is an increased risk of neurological adverse events and mortality associated with the internal pump.
- There is a potential for the internal pump to stop. If the internal pump stops, it may delay restarting or fail to restart.
Both problems may lead to death or serious injuries. Therefore, health care providers should no longer implant the Medtronic HVAD System. Health care providers should continue to manage care of patients with a previously implanted Medtronic HVAD System according to the instructions in the Medtronic Urgent Medical Device Communication Notification letter: Urgent Medical Device Communication Notification Letter. The FDA is issuing this letter to health care providers to ensure that they are informed of this action.
The Medtronic HVAD system is a durable Left Ventricular Assist Device (LVAD) that includes peripheral components (such as controllers, batteries, AC/DC adapters, and carrying case) and was first approved for commercial use in the United States in November 2012. It is approved as a bridge to heart transplantation in patients who are at risk of mortality from end-stage left ventricular heart failure, for heart tissue recovery, and as destination therapy in patients for whom a heart transplant is not planned. Medtronic reports there are currently approximately 2,000 patients implanted with the device in the United States.
There is a growing body of observational clinical comparisons that demonstrates a higher frequency of neurological adverse events and mortality among HVAD System patients as compared to those who receive other commercially available durable LVADs. Medtronic reports there are more than 100 complaints involving a delay or failure to restart of the HVAD internal pump, which led to a total of 14 deaths and 13 pump removals. Medtronic recently recalled a subset of HVAD internal pumps for delayed or failure to restart. For details, see the recall notice, Medtronic Voluntarily Recalled the HVAD Pump Implant Kits Due to Delayed or Failed Restart After the Pump Is Stopped.