Regulatory Surveillance Summary | April 2020
By Laurel Hacche and Debra Cortner, SQA Associates
United States Food and Drug Administration (US FDA) Guidances
The US FDA has provided blood or plasma establishments with revised recommendations related to biological product deviation (BPD) reporting. The guidance document is intended to assist blood and plasma establishments in determining when a report is required, who submits the report, what information to submit in the report, the timeframe for reporting, and how to submit the report. The revised guidance explains that the US FDA does not consider post-donation information (PDI) events to require BPD reports. PDI includes information that a donor, or other reliable source, provides to a blood establishment after a donation (e.g., at a subsequent donation) that would have resulted in deferral of the donor had the establishment known the information at the time of donation. The revised guidance also contains other technical updates and editorial revisions to improve clarity and provide a more streamlined document. The US FDA also announced the withdrawal of two obsolete memoranda to blood establishments entitled, “Responsibilities of Blood Establishments Related to Errors & Accidents in the Manufacture of Blood & Blood Components,” issued 20 March 1991, and “Guidance Regarding Post Donation Information Reports,” issued 10 December 1993.
This guidance provides recommendations regarding postmarketing adverse event reporting for drugs, biologics, medical devices, combination products, and dietary supplements during a pandemic. The US FDA anticipates that during a pandemic, industry and US FDA workforces may be reduced because of high employee absenteeism, while reporting of adverse events related to widespread use of medical products indicated for the treatment or prevention of the pathogen causing the pandemic may increase. The extent of these possible changes is unknown. This guidance discusses the US FDA’s intended approach to enforcement of adverse event reporting requirements for medical products and dietary supplements during a pandemic. The US FDA believes this approach will make it possible for firms with reporting responsibilities to focus their limited resources on the following types of reports:
- Reports related to medical products indicated for the treatment or prevention of the pathogen causing the pandemic
- Other reports indicated in this guidance
- Reports on products presenting special concerns as specified by the US FDA
This guidance is not intended to discourage adverse event reporting during a pandemic by firms that are able to continue reporting operations. In addition, this guidance does not address monitoring and reporting of adverse events that might be imposed as a condition for medical products authorized for emergency use under section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360bbb-3). This guidance also does not address monitoring and reporting of adverse events as required by regulations establishing the conditions for investigational use of drugs, biologics, and devices (see 21 CFR parts 312 and 812). The US FDA is revising the final guidance entitled “Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During an Influenza Pandemic” (2012 final guidance) to clarify that the guidance is applicable to any pandemic, not just an influenza pandemic. This action is necessary to address the Coronavirus Disease 2019 (COVID-19) pandemic and to ensure that the Agency’s recommendations in the 2012 final guidance apply to any pandemic, including COVID-19. Accordingly, this guidance replaces the 2012 final guidance.
The FDA has issued this guidance to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 public health emergency. The appendix to this guidance further explains those general considerations by providing answers to questions that the Agency has received about conducting clinical trials during the COVID-19 public health emergency. This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Department of Health and Human Services (HHS), including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service (PHS) Act.
Due to the COVID-19 pandemic, the US FDA has been closely monitoring the medical product supply chain with the expectation that it may be impacted by the COVID-19 outbreak, potentially leading to supply disruptions or shortages of drug and biological products in the United States. The US FDA has issued this guidance to assist applicants and manufacturers in providing timely, informative notifications to the FDA about changes in the production of certain drugs and biological products that will, in turn, help the Agency in its efforts to prevent or mitigate shortages of such products.
United States Food and Drug Administration (US FDA) Recalls
Boston Scientific Corporation is recalling IMAGER II 5F Angiographic Catheters because there is a potential for the catheter tip to become detached during a patient procedure or during procedure preparation. Use of the affected product may lead to additional surgical intervention to remove the catheter tip in the patient’s blood vessel and increased time in the hospital. There is also the potential for serious adverse events including obstruction of blood flow (embolism), stroke, or death. There are nine reported injuries.
B. Braun Medical Inc. Issues Voluntary Nationwide Recall of One (1) Lot of Ceftazidime for Injection USP and Dextrose Injection USP (50 mL), Duplex Container Due to Out-of-Specification Results for High Molecular Weight Polymers, 17 April 2020
Braun Medical Inc. (B. Braun) is voluntarily recalling one lot of 2g Ceftazidime for Injection USP (2g) and Dextrose for Injection USP (50 ml) in Duplex® Container from the hospital/user level. During stability testing of Batch H8J812, test results were found to exceed the specification limits for High Molecular Weight Polymers (HMWP) at the 19-month (82-week) stability interval. Elevated levels of HMWP have been shown to cause kidney damage and liver issues in animal studies. While the impact of HMWP on humans is unknown, B. Braun is initiating this voluntary recall out of an abundance of caution to prevent any risk of adverse reactions due to the elevated HMWP levels. To date, there have been no complaints or reports of adverse reactions associated with this product lot.
Fresenius Kabi USA, LLC is voluntarily recalling 13 lots of Ketorolac Tromethamine Injection, USP, 30 mg/mL, 1 mL fill in a 2 mL amber vial and Ketorolac Tromethamine Injection, USP, 60 mg/2 mL (30 mg/mL), 2 mL fill in a 2 mL amber vial from the user level due to the presence of particulate matter composed of the following elements: carbon, silicon, oxygen, and polyamides. Particulate matter was found in eight reserve sample vials. Administration of products containing particulate matter could obstruct blood vessels and result in local irritation of blood vessels, swelling at the site of injection, a mass of tissue that could become inflamed and infected, blood clots traveling to the lung, scarring of the lung tissues, and allergic reactions that could lead to life-threatening consequences.
United States Food and Drug Administration (US FDA) Warning Letters
The US FDA reviewed the BIOTA Biosciences LLC website at biotacbd.com in February 2020 and determined that the website provides a telephone number that customers can call to order various injectable drug products, including but not limited to “Cannabidiol (CBD) Complex,” “Cannabidiol+Curcumin,” and “Curcumin Complex.” Injectable drug products can pose a serious risk of harm to users because they are delivered directly into the bloodstream and bypass many of the body’s natural defenses against toxic ingredients, toxins, or dangerous organisms that can lead to serious and life-threatening conditions such as septicemia or sepsis. The claims on BIOTA’s website establish that their “Cannabidiol (CBD) Complex,” “Cannabidiol+Curcumin,” and “Curcumin Complex” products are unapproved new drugs sold in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). Furthermore, these products are misbranded drugs under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1).
From 10 December 2018 to 28 January 2019, the US FDA inspected Health Solutions Pharmacy Center, Inc. dba Professional Compounding Pharmacy, located at 996 NW Circle Boulevard, Suite 105, Corvallis, OR 97330. During the inspection, the investigators noted that drug products produced failed to meet the conditions of section 503A of the Federal Food, Drug, and Cosmetic (FD&C) Act [21 U.S.C. § 353a] for exemption from certain provisions of the FDCA. In addition, the investigators noted serious deficiencies in practices for producing sterile drug products, which put patients at risk. The investigators issued a Form FDA 483 on 28 January 2019. The US FDA acknowledged receipt of a written response to the 483 on 18 February 2019 and the voluntary recall initiated by Professional Compounding Pharmacy on 21 February 2019. It was also noted that Professional Compounding Pharmacy had ceased all human drug compounding, and the company currently compounds only non-sterile veterinary drug products. Based on the inspection, it appears that Professional Compounding Pharmacy produced drug products that violate the FDCA. Concerns with respect to sterile drug products included the following:
- Professional Compounding Pharmacy did not receive valid prescriptions for individually identified patients for a portion of the drug products produced and distributed from 01 September 2018 to 10 December 2018.
- Drug products intended or expected to be sterile were prepared, packed, or held under unsanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing the drug products to be adulterated.
United States Pharmacopeia (USP)
The chapter provides universal standards for the format, appearance, content, and language of prescription medication instructions to promote patient understanding and reduce medication errors. The Healthcare Quality and Safety Expert Committee plans to revise the chapter to add information to prevent oral liquid dosing errors and better inform patients of the risk of opioids.
USP intends to revise multiple monographs in response to a revision of General Chapter <561>. The chapter was revised earlier to limit Pesticide Residues in monographs for botanical extracts. The requirements for Pesticides Residues for botanical extracts were later introduced in Chapter <565> Botanical Extracts. Proposed cross reference changes from <561> to <565> have been posted in a Compendial Notice.
Due to continuing comment review, the “Expiration Date and Beyond-Use Date” section of General Chapter <7> Labeling will not become effective on 01 May 2020. The Nomenclature and Labeling Expert Committee is evaluating all comments about the proposed changes. The date of implementation has not yet been determined.
India – Central Drugs Standard Control Organization (CDSCO)
Concerns were raised regarding the requirement for testing of new drugs in the Central Government Laboratories before their approval when such drugs are pharmacopeial products or are additional strengths of already approved new drugs. In order to streamline the new drug approval process, timelines for such testing were decided as follows:
- New drugs already approved: 4 weeks
- New drugs that are pharmacopeial: 6 weeks
- Other new drugs: 8 weeks
Concerns were raised regarding the requirement for chemistry, manufacturing, and controls (CMC) documents for additional indication of an already approved drug product. According to Paragraph 3 or Clause 1 of Second Schedule of New Drugs and Clinical Trials Rules, 2019, the CMC data may be omitted depending on whether the drug formulation is already approved and marketed by the applicant in the same dosage form for a certain indication. In that case, no further CMC data is required to be resubmitted, and the applicant shall reference the earlier submission in the application form.
The Indian Ministry of Health & Family Welfare (MHFW) announced that certain drugs approved in major markets such as the EU and U.S. would be automatically approved in India without a further native clinical trial. The MHFW announced the new Drug and Clinical Trials Rules in March 2019. The guidance consists of 13 chapters and eight schedules that apply to all new drugs, as well as investigational new drugs for human use, clinical trials, bioequivalence and bioavailability studies, and ethics committees.