SQA Regulatory Surveillance Summary | Monthly Update 2022 – Spring

By Laurel Hacche & Debra Cortner SQA Associates

SQA Regulatory Surveillance Summary 2022 – Spring

Agência Nacional de Vigilância Sanitária (ANVISA)

Brazil’s ANVISA Issues Registration Rules for Software, 01 April 2022

ANVISA has published new regulations focused on software as a medical device (SaMD), set to take effect on 01 July 2022. ANVISA’s RDC 657/2022 (link in Portuguese) covers registration requirements for SaMD, for which Brazilian regulators had not previously issued specific rules. The new RDC 657/2022 makes clear which software types do not fall under the new regulation, including the following:

  • Software for well-being of users
  • Software already listed by ANVISA as a non-regulated product
  • Software used only for administrative and financial purposes within healthcare organizations
  • Software to process demographic and epidemiological medical data without providing any diagnostic or therapeutic function
  • Software shipped within medical devices that are already under ANVISA surveillance

In cases where medical software is considered an accessory to a device or software contains embedded medical applications, that software is required to undergo ANVISA registration along with its associated devices. Requirements for classification and related issues established under RDC 185/2001, as well as other relevant medical device regulations, will apply for SaMD, as well. SaMD products registered with ANVISA will be subject to audis, market monitoring, surveillance, and inspections by the regulator.


Brazilian Regulators Update Good Manufacturing Practices for Medical Devices and IVDs, 12 April 2022

ANVISA has issued a new resolution that updates Brazilian Good Manufacturing Practices (BGMP) for medical devices and in vitro diagnostic (IVD) products. ANVISA’s RDC 665/2022 (link in Portuguese) replaces previous regulations, including RDC 16/2013 and IN 08/2013, and went into effect on 02 May 2022. The new BGMP requirements will apply to medical device and IVD manufacturers, as well as distributors, retailers, and importers doing business in Brazil. RDC 665/2022 covers BGMP quality management system requirements for methods, controls and other processes related to the design, purchase, and manufacture of devices and IVDs; the updated BGMP requirements also address device packaging, labeling, storage, distribution, installation, and technical assistance related to device manufacturing.


China: National Medical Products Administration (NMPA)

NMPA Announcement on Two Guidelines for Registration Review of Drug-Device Combination Products with Device Taking Primary Mode of Action, 17 January 2022

To enhance the regulation and guidance for the registration of drug-device combination products, further encourage the marketing of drug-device combination products with clinical value, and build a management mode for drug-device combination products suitable for China’s national conditions, NMPA has set the technical evaluation of drug-device combination products as a research project in regulatory science. The following guidelines were issued on 11 January 2022:

  • Guideline for Registration Review Drug-Device Combination Products with Device Taking Primary Mode of Action
  • Guideline for Registration Review of Qualitative, Quantitative and In Vitro Release Studies of Drugs in Drug-Device Combination Products with Device Taking Primary Mode of Action


China Regulatory Roundup: Latest Guidelines for Medical Device and IVD Compliance, 17 March 2022

Medical device market regulators in China have issued several guidelines and updates this year that cover issues such as registration of additive manufacturing and 3D-printed devices, recordkeeping requirements for low-risk medical devices and in vitro diagnostic (IVD) products, and compilation of product technical requirements. Guidelines are summarized below (all links to regulatory documents below are in Chinese):

  • China’s Center for Medical Device Evaluation (CMDE) has issued new guidelines covering registration of additive manufactured devices, including polyetheretherketone implants; research on the physical and chemical properties of additive-manufactured metal implants; and registration of laser-selective melting metal materials for additive-manufactured prosthodontic devices.
  • NMPA has opened a consultation period for revised guidance on Class I medical device record filing requirements. The revisions align more closely to current NMPA regulations for medical devices and IVDs.

The NMPA has also published its National Medical Device Sampling Product Inspection Plan for 2022, which lists device types that the regulator plans to inspect, as well as associated rationales for inspections, such as compliance to mandatory standards or technical requirements. The plan also identifies relevant sampling and re-inspection institutions, along with specific requirements for re-inspections.


China’s New Cosmetics Regulation (CSAR) Subsidiary Regulations: China NMPA Consults on the Inspection Points and Judgement Principles of Cosmetic Good Manufacturing Practices, 01 April 2022

On 07 January 2022, China NMPA issued the finalized Good Manufacturing Practices for Cosmetics, which will be implemented on 01 July 2022. Cosmetics registrants, notifiers, and entrusted production enterprises will be required to organize cosmetic production in accordance with the Practices. On 30 March 2022, NMPA released the draft of Inspection Points and Judgment Principles of Cosmetic Good Manufacturing Practices (hereafter referred to as “Points”) for public consultation.  Regulatory authorities across China will use the Points as a basis to determine whether enterprises comply with GMP. The Points is an upgraded version of Practice for Cosmetics Production Licensing, implemented in 2016, with more stringent inspection requirements. The expected effective date of the Points is 01 July 2022,  the same as that of Good Manufacturing Practices for Cosmetics.


European Medicines Agency (EMA)

EMA Updates to Good Clinical Practice (GCP) Inspection Procedures, 29 April 2022

The European Medicines Agency (EMA) has published the following updates to their procedures for conducting GCP inspections requested by the Committee for Medicinal Products for Human Use (CHMP):

  • Annex I to Procedure for Conducting GCP Inspections Requested by the CHMP: Investigator Site, EMA/INS/GCP/143492/2022, 02 May 2022
  • Annex II to Procedure for Conducting GCP Inspections Requested by the CHMP: Clinical Laboratories, EMA/INS/GCP/154768/2022, 02 May 2022
  • Annex IV to Procedure for Conducting GCP Inspections Requested by the CHMP: Sponsor and Clinical Research Organization (CRO), EMA/INS/GCP/155794/2022, 02 May 2022
  • Annex VI to Procedure for Conducting GCP Inspections Requested by the CHMP: Record Keeping and Archiving of Documents, EMA/INS/183077/2022, 02 May 2022
  • Annex VII to Procedure for Conducting GCP Inspections Requested by the CHMP: Bioanalytical Part, Pharmacokinetic and Statistical Analysis of Bioequivalence Trails, EMA/INS/188326/2022, 02 May 2022

Each of the above annexes provides detailed lists of elements to be examined for specific subject areas. For Investigator Sites, the subject areas are Organizational Aspects, Informed Consent of Trial Participants, Review of Trial Participant Data, and Management of Investigational Medicinal Product(s). Additional details for each annex are provided within the content section of the document.


United States Food and Drug Administration (FDA) – Regulations and Guidances

Proposed Rule: Quality System Regulation Amendments – Frequently Asked Questions, 23 February 2022

On 23 February 2022, the United States Food and Drug Administration (FDA) issued a proposed rule to amend the current good manufacturing practice (cGMP) requirements of the Quality System (QS) Regulation for devices to align more closely with the international consensus regulatory standard for quality management systems for medical devices. The FDA proposes to do so primarily by incorporating by reference the 2016 edition of the international standard specific for medical device quality management systems set by the International Organization for Standardization (ISO), ISO 13485. Through this rulemaking, the FDA is also proposing additional requirements that help connect and align ISO 13485 with existing requirements in the Federal Food, Drug, and Cosmetic Act and its implementing regulations, as well as making conforming edits to 21 CFR Part 4 to clarify the device cGMP requirements for combination products. This action, if finalized, will continue the FDA’s efforts to align its regulatory framework with that used by other regulatory authorities to promote consistency in the regulation of devices and provide more efficient introduction of safe, effective, high-quality devices for patients.


Guidance for Industry: Certain Ophthalmic Products: Policy Regarding Compliance with 21 CFR Part 4, March 2022

In March 2022, the United States Food and Drug Administration published the following guidance for industry: Certain Ophthalmic Products: Policy Regarding Compliance with 21 CFR Part 4. This guidance is intended to provide information to applicants and manufacturers on compliance with the requirements in 21 CFR Part 4’s current Good Manufacturing Practices (cGMP) requirements for combination products for ophthalmic drugs packaged with eye cups, eye droppers, or other dispensers. The new publication applies to products with pending applications, approved products, and products marketed pursuant to section 505G of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355h) without an approved application under section 505 of the FD&C Act (21 U.S.C. 355) (commonly referred to as Over-the-Counter (OTC) monograph drugs). This guidance requires that when a device is packaged  with the drug with which it is intended to be used, the FDA regulates that the drug and the device together is a combination product. It also states that because the drug constituent part provides the primary mode of action, generally, the Center for Drug Evaluation and Research (CDER) will have primary jurisdiction over these products.


Draft Guidance for Industry: Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions, April 2022

Effective cybersecurity that ensures medical device functionality and safety has become more important with the increasing use of wireless, internet, and network-connected devices, portable media (e.g., USB or CD), and the frequent electronic exchange of medical device-related health information. In addition, cybersecurity threats to the healthcare sector have become more frequent, more severe, and more clinically impactful. Cybersecurity incidents have rendered medical devices and hospital networks inoperable, disrupting the delivery of patient care across healthcare facilities in the US and globally. Such cyberattacks and exploits can delay diagnoses and/or treatment and may lead to patient harm. In April 2022, the United States Food and Drug Administration (US FDA) published a draft guidance for industry and FDA staff, Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions. This guidance is intended to provide recommendations to industry on cybersecurity device design, labeling, and the documentation that the FDA recommends be included in premarket submissions for devices with cybersecurity risk. These recommendations can help facilitate an efficient premarket review process and ensure that marketed medical devices are sufficiently resilient to cybersecurity threats.


United States Food and Drug Administration (FDA) – Recalls

Plastikon Healthcare Issues Voluntary Nationwide Recall of Milk of Magnesia Oral Suspension 2400 mg/30 mL, Magnesium Hydroxide 1200 mg/Alluminum Hydroxide 1200 mg/Simethicone 120 mg per 30 mL, and Acetaminiophen 650 mg/20.3 mL, Unit Dose Cups, Due to Microbial Contamination, 24 March 2022

Lawrence, KS, Plastikon Healthcare, LLC is voluntarily recalling three (3) lots of Milk of Magnesia 2400 mg/30 mL Oral Suspension, one (1) lot of Acetaminophen 650mg/ 20.3mL, and six (6) lots of Magnesium Hydroxide 1200mg/Aluminum Hydroxide 1200mg/Simethicone 120mg per 30 mL to the hospital, clinic, and patient level.  The products are being recalled due to microbial contamination and failure to properly investigate failed microbial testing.

  • Risk Statement: This product potentially could result in illness due to intestinal distress, such as diarrhea or abdominal pain.  Individuals with a compromised immune system have a higher probability of developing a wide-spread, potentially life-threatening infection when ingesting or otherwise orally exposed to products contaminated by micro-organisms. To date, Plastikon has not received any customer complaints related to microbial concerns or reports of adverse events related to this recall.

The product is packaged for institutional use and is sold to clinics and hospitals nationwide in single use cups with a foil lid.  The affected lots were distributed to Major Pharmaceuticals Distribution Center (wholesaler) between 01 May 2020 and 28 June 2021, who shipped to hospitals, nursing homes, and clinics nationwide.  The products are private labeled for Major Pharmaceuticals.


Teva Issues Voluntary Nationwide Recall of One Lot of IDArubicin Hydrochloride Injection USP 5 mg/5 ml Due to the Presence of Particulate Matter, 29 March 2022

Teva Pharmaceuticals has initiated a voluntary nationwide recall of lot 31329657B of IDArubicin Hydrochloride Injection USP 5 mg/5 mL vial, to the user level in the United States. This voluntary recall was initiated based on an internal inspection that found particulate matter in one vial of the product, identified as silica and iron oxide. No other vials have been observed to contain this defect. To date, Teva has received no product quality complaints or adverse event reports of this nature for the subject recall lot. The 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. While the health hazard risk could be severe if particulate matter is infused, Teva’s internal health assessment determined that the likelihood of patient harm is remote or unlikely. IDArubicin Hydrochloride Injection USP, in combination with other approved anti-leukemic drugs, is indicated for the treatment of acute myeloid leukemia (AML) in adults. Teva distributed 1,565 vials nationwide from 04 December 2020 through 18 August 2021 to four of its wholesale customers under the label for Teva Pharmaceuticals USA, Inc.


Pfizer Voluntary Nationwide Recall of Lots of Accupril (Quinapril HCl) Due to N-Nitroso-Quinapril Content, 22 April 2022

Pfizer is voluntarily recalling five (5) lots of Accupril (Quinapril HCl) tablets distributed by Pfizer to the patient (consumer/user) level due to the presence of a nitrosamine, Nnitroso-quinapril, observed in recent testing above the Acceptable Daily Intake (ADI) level. Nitrosamines are common in water and foods, including cured and grilled meats, dairy products, and vegetables. Exposure to nitrosamines above acceptable levels over long periods of time may increase a person’s risk of cancer. Accupril is indicated for the treatment of hypertension, to lower blood pressure. Accupril is also indicated for the management of heart failure as an adjunctive therapy when added to conventional therapy, including diuretics and/or digitalis. Accupril has a safety profile that has been established over 30 years. To date, Pfizer is not aware of reports of adverse events that have been assessed to be related to this recall. Pfizer believes the benefit/risk profile of the products remains positive based on currently available data. Although long-term ingestion of N-nitroso-quinapril may be associated with a potential increased cancer risk in humans, there is no immediate risk to patients taking this medication. Patients currently taking the products should consult with their doctor or healthcare provider about alternative treatment options. The product lots were distributed nationwide to wholesalers and distributors in the United States and Puerto Rico from December 2019 to April 2022.


United States Food and Drug Administration (FDA) – Warning Letters

Warning Letter, Case 622087, Vi-Jon, LLC, 31 March 2022

Vi-Jon, LLC was issued a Warning Letter on 31 March 2022 by the United States Food and Drug Administration (FDA) Division of Pharmaceutical Quality Operations III for significant violations of cGMP regulations for finished pharmaceuticals, in accordance with the requirements of 21 CFR Parts 210 and 211. The Warning Letter was issued after the FDA review of a response to a Form FDA 483 (reviewed by FDA on 03 November 2021). The response was determined to be inadequate, as it did not provide sufficient detail of evidence of corrective actions to bring the Vi-Jon, LLC operations into compliance with cGMP.

During the FDA inspection of Vi-Jon, LLC, the investigator observed specific violations, including but not limited to the following:

  • Vi-Jon, LLC manufactures over-the-counter (OTC) drug products, including benzalkonium chloride-based hand sanitizer, in which water is a component. The sampling plan for the company’s water system is not representative of the overall system and is not appropriate to provide meaningful results for detecting system variability. Specifically, the company samples from only one Point of Use (POU) port for chemical and microbial attributes. However, the investigator noted additional POU ports where water is obtained for drug product manufacturing. Additionally, the company has detected Burkholderia cepacia (B. cepacia)in finished drug products on numerous occasions. Since  cepacia is a waterborne organism, this recurring product contamination further indicates the impact of insufficient monitoring and control of the water system. The company did not have appropriate limits to identify an adverse pattern of B. cepacia in the water system and was not routinely testing the water system for the presence of B. cepacia with validated methods.
  • The FDA investigators documented several deficiencies in the equipment maintenance and cleaning program. For example, a leak was observed from a pump within the water purification system. A work order dated 07 May 2021 documented the leak, but as of the date of the inspection, the Quality Unit had not been notified of the leak, as required by the company’s procedure. Accordingly, an investigation or deviation had not been initiated. A second undocumented leak was observed, with water-absorbent pads in place to contain the leak. The water system operating procedure states that leak checks are to be performed. The company lacked documentation to support the occurrence of these water leak checks. Water leaks are potential areas of entry for microbial growth, which may contaminate component water and subsequently have an adverse impact on the quality of drug products manufactured. Investigators also observed raw material leaking from a valve in the material transfer manifold located above tank Number 422. A bucket underneath the leak was nearly half full of what appeared to be a green-blue gelatinous material, and the outside of the bucket appeared to be encrusted with white and brown filth. This material was identified as a surfactant. The company’s procedure for the storage of raw materials did not adequately assure the proper cleaning and maintenance of equipment. The FDA also observed rust in the laboratory’s laminar air flow hood.


Warning Letter, WL 622823, Cetylite Industries, Inc., 14 April 2022

Cetylite Industries, Inc. was issued a Warning Letter on 14 April 2022 by the United States Food and Drug Administration (US FDA) Division of Pharmaceutical Quality Operations I for significant violations of cGMP regulations for finished pharmaceuticals, in accordance with the requirements specified in 21 CFR Parts 210 and 211. The Warning Letter was issued after the FDA’s review of a response to a Form 483 on 14 October 2021. The response was determined to be inadequate, as it did not provide sufficient detail of evidence of corrective actions to bring Cetylite Industries, Inc. operations into compliance with cGMP. During the FDA inspection of Cetylite Industries, Inc., the investigator observed specific violations, including but not limited to the following:

  • Cetylite Industries, Inc. manufactures Cetacaine Mint Gel Topical Anesthetic, a United States Pharmacopeia (USP) article. The company has utilized a compendial method for the aerosol form instead of the compendial method for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel to analyze the drug product. The company had not appropriately validated that the aerosol method was suitable for testing the gel form of this product. The company deviated from the USP for testing the potency of the finished aerosol, liquid, and gel topical anesthetic drug products from March 2019 onwards. Additionally, the company failed to complete method validation studies for the method used for the release testing of finished drug products. Therefore, the company did not adequately demonstrate that the method is equivalent to or better than the current USP compendial method.
  • Cetylite Industries, Inc. failed to adequately investigate an out-of-specification (OOS) test result when a gel product was analyzed with an unvalidated method. The analysis revealed an OOS for tetracaine HCl for potency of 114.7% and 115.2%. During the OOS investigation, the company retested using the USP compendial method for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel, which resulted in an OOS of 118.9% and 118.3%. Without adequate scientific justification, the company again retested the sample using two additional methods and obtained passing results. The company then released the product without adequate justification to invalidate the OOS test results, including an OOS test result using a compendial test method.