Regulatory Surveillance Summary | February, 2020

By Laurel Hacche and Debra Cortner, SQA Associates

United States Food and Drug Administration (US FDA) Guidances

Current Good Manufacturing Practice – Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, Draft Guidance, January 2020, Revision 2

This guidance revises the draft guidance Current Good Manufacturing Practice – Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act issued in July 2014, as supplement to Revision 1, which was published in December 2018. Revision 1 was developed to include considerations for non-sterile compounded drug products, differentiate between requirements applicable to sterile compounded drug products and non-sterile compounded drug products where appropriate, include changes regarding stability testing (including the assignment of a Beyond Use Date (BUD) as an expiration date), include release testing requirements, address reserve samples, and provide guidance on “in-use times.” Revision 2 refines a description of antimicrobial effectiveness testing and clarifies that section C of appendix B does not apply to non-sterile unpreserved aqueous drug products.

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), January 2020

The purpose of this guidance is to inform sponsors how to provide sufficient CMC information required to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product (21 Code of Federal Regulations (CFR) 312.23(a)(7)(i)). This guidance applies to human gene therapy products and to combination products that contain a human gene therapy in combination with a drug or device. This guidance finalizes the draft guidance of the same title dated July 2018 and supersedes the document entitled “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),” dated April 2008 (April 2008 guidance). The field of gene therapy has progressed rapidly since the April 2008 guidance. Therefore, the FDA is updating that guidance to provide you with current FDA recommendations regarding the CMC content of a gene therapy IND.

US FDA Office of Pharmaceutical Quality 2019 Annual Report February 2020

Since 2015 the Office of Pharmaceutical Quality (OPQ) has provided an annual report on the assessment, inspection, research, surveillance, and policy to support the quality oversight of drugs legally marketed in the US. The report discusses the integrated approach to the assessment of a new drug application in coordination with the facility assessment. They also prioritize the assessment of submissions with the potential to avert drug shortages. The report provides examples of the FDA’s approach to enhancing patient safety and the availability of drug therapy.

United States Food and Drug Administration (US FDA) Recalls

Aurobindo Pharma USA, Inc. Issues Voluntary Nationwide Recall of Lot Number 03119002A3, Mirtazapine Tablets to the Consumer Level, 02 January 2020

Aurobindo Pharma USA, Inc. is voluntarily recalling lot number 03119002A3 of Mirtazapine Tablets to the consumer level. The product is being recalled due to a label error on declared strength. Bottles labeled as Mirtazapine 7.5 mg may contain 15 mg tablets. Taking a higher dose than expected may increase risk of sedation, agitation, increased reflexes, tremor, sweating, dilated pupils, gastrointestinal distress, nausea, constipation, and more. Unexpected levels of sedation in particular can contribute to falls in the elderly or motor vehicle accidents in adults. Mirtazapine tablets are indicated for the treatment of major depressive disorder and are packaged in 500 count bottles. The affected lot number for both Mirtazapine Tablets 7.5 mg and Mirtazapine Tablets 15 mg are 03119002A3, Exp 03/2022. The product can be identified by checking the product name, manufacturer details and batch or lot number on the bottle containing these products. Aurobindo Pharma USA, Inc. is notifying its distributors by letter and is arranging for return of all of the recalled product. Distributors/retailers that have product that is being recalled should return the bottle(s) to place of purchase.

Appco Pharma LLC Issues Voluntary Nationwide Recall of Ranitidine Hydrochloride Capsules 150 mg and 300 mg

Appco Pharma LLC (Appco) is voluntarily recalling all quantities and lots, within expiry, of Ranitidine Hydrochloride Capsules to the Consumer level. Ranitidine Hydrochloride Capsules are being recalled because of the presence or potential presence of N-nitrosodimethylamine (NDMA) levels above the acceptable daily intake levels established by the FDA, based on FDA-validated tests. To date, Appco has not received any reports of adverse events related to use of the product as part of this recall. 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. Ranitidine Hydrochloride in strengths of 150 mg and 300 mg, is a prescription-only oral medication indicated for the treatment of duodenal ulcer, benign gastric ulcer, reflux esophagitis, post-operative peptic ulcer, Zollinger-Ellison Syndrome, and other conditions where reduction of gastric secretion and acid output is desirable.

Stryker Launches Voluntary Field Action for Specific Units of the LIFEPACK^® 15 Monitor/ Defibrillator

Stryker announced today that the company is launching a voluntary field action on specific units of the LIFEPAK 15 monitor/defibrillators. The company is notifying a population of LIFEPAK 15 customers of an issue that may cause their devices to fail to deliver a defibrillation shock after the “Shock” button on the keypad is pressed. This is a result of oxidation that may have formed over time within the “Shock” button. The company is contacting customers with impacted devices to schedule the correction of their device(s), which will include replacement of the affected keypad. Stryker anticipates that all devices subject to this field action will be serviced by June 2021. Most complaints associated with this issue were detected prior to patient use. Routine testing of the device can detect this fault condition. The company is instructing customers to continue to use their LIFEPAK 15 monitor/defibrillator according to the Operating Instructions until the correction can be completed.

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

Yibin Lihao Bio-technical Co., Ltd., Warning Letter, 13 February 2020

The U.S. Food and Drug Administration (FDA) conducted an inspection at Yibin Lihao Biotechnical Co., Ltd, FET 3008846564, at Number 5 Binjiang Road, Luolong Industrial Central Park. Yibin, Sichuan, from July 31, 2019 to August 6, 2019. This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API). Because Yibin Lihao’s methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, its API are adulterated within the meaning of section 501 (a)(2)(B) of the Federal food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351 (a)(2)(B). The FDA reviewed Yibin Lihao’s August 26, 2019, response to the Form FDA 483 in detail. During the FDA’s inspection, the investigator observed specific deviations including, but not limited to, the following: 1) Failure to prepare and use production and control records for each intermediate and API batch, and 2) Failure to establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

Essnd Global, Warning Letter, 14 February 2020

The U.S. Food and Drug Administration (FDA) inspected the drug manufacturing facility, Essnd Global, FEI 3014466792, at C-176 Maharashtra Industrial Development Corp. (MDIC), Sinnare, Nashik, Maharashtra, India, from September 9, 2019 to September 13, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211). Because Essnd Global’s methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, its drug product is adulterated within the meaning of section 501 (a)(2)(B) of the Federal Food. Drug, and Cosmetic Act (FD&C Act). 21 U.S.C. 351 (a)(2)(B). The FDA has not received a response from Essnd Global regarding corrective actions to the observations identified during the inspection. During the FDA inspection, the investigator observed specific violations including, but not limited to, the following:

• The firm failed to perform, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)).
• The firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. The firm also failed to validate and establish the reliability of its component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

Failure to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. (21 CFR 211.22(a) and (d)).

ISO (International Organization for Standardization)

ISO 14971:2019, Medical Devices – Application of Risk Management to Medical Devices, December 2019

The third edition of ISO 14971 — in addition to an updated companion report, ISO/TR 24971 — provides clearer guidance and greater detail in the application of risk management concepts while aligning with essential safety and performance principles. European directives and regulations do not provide enough guidance on additional steps to take in the risk management process, nor on the acceptability of residual risks, so this standard represents the state of the art. The new European EU MDR and IVDR require manufacturers to implement a quality management system that incorporates risk management.

Guidance for Information Security Management Systems Auditors Update, January 2020

ISQ/IEC (International Electrotechnical Committee) 27007, Information Technology – Security techniques – Guidelines for information security management systems auditing, provides extensive guidance on auditing the requirements stated in the standard as well as the competence of information security management system auditors. It is intended to be used in tandem with ISO 19011 Guidelines for auditing management systems.

New International Guidance to Improve Social Responsibility in the Global Food Chain, January 2020

ISO/Ts (technical Standard) 26030, Social Responsibility and sustainable development – Guidance on using ISO 26000:2010 in the food chain provides guidance on how an organization can contribute to sustainable development while considering local laws, regulations, and stakeholder expectations. It will be of assistance to food companies, farms, processors, and retailers of all sizes. The guidance will help meet the increasing consumer demand for sustainable and socially responsible practices.

Improving Biosecurity with First International Standard for Biorisk Management, January 2020

ISO 35001, Biorisk management for laboratories and other related organizations, is the first international standard for a biorisk system. It defines requirements and guidance for laboratories that work with biological agents to control and reduce risks associated with their use. It addresses management of biohazardous materials to reduce risk of accidents, lessen impact on the environment, and more efficiently use time and other resources. It harmonizes regional and national standards.

AAMI (Association for the Advancement of Medical Instrumentation)

HN-1 Manufacturer Disclosure Statement for Medical Device Security, February 2020

The National Electrical Manufacturers Association (NEMA) has published an updated version of its standard, HN-1 Manufacturer Disclosure Statement for Medical Device Security (MDS²). The updated form gives medical device manufacturer’s additional space to collect and report information related to their products’ security capabilities to their customers. The updated MDS² calls for manufacturers to use a new spreadsheet to describe their products’ security features. Users can use the information to perform risk assessments and protect the data created, received, transmitted, and maintained by their medical devices.