SQA Regulatory Surveillance Summary | August 2020
By Laurel Hacche and Debra Cortner, SQA Associates
European Pharmacopoeia (Ph. Eur.)
Published in Ph. Eur. Supplement 10.3, the new general chapter 2.6.32., “Test for bacterial endotoxins using recombinant factor C,” describes a test for bacterial endotoxins (BET) that can be used as an alternative to the classic limulus amoebocyte lysate (LAL)-based methods for the quantification of endotoxins from gram-negative bacteria. The method described involves the use of a recombinant factor C (rFC) based on the gene sequence of the horseshoe crab and fluorometric detection, in keeping with the kits currently available on the European market. Also published in Supplement 10.3 is the revised chapter 5.1.10., “Guidelines for using the test for bacterial endotoxins,” which has been updated to reflect the new status of rFC-based methods and gives prerequisites for their deployment by users of the pharmacopoeia.
With the introduction of general chapter 2.6.32, Ph. Eur. users will have the opportunity to use a standardized method, which will become official in the 39 signatory countries to the Ph. Eur. convention. A test for bacterial endotoxins using rFC can be used in the same way as LAL-based methods, after demonstration of its fitness for use for the specific substance or product. The use of rFC for BET testing does not need to be validated, thus facilitating the implementation of rFC-based methods by users. The replacement of an LAL-based method prescribed in a monograph with an rFC-based method is considered as the use of an “alternative method,” as described in the Ph. Eur. General Notices. For BET testing, the world currently relies on a single source of lysate, the horseshoe crab family, and more specifically, two species of the crab, Limulus Polyphemus and Tachypleus Tridentatus (both of which are known to be endangered). The publication of the new general chapter 2.6.32 therefore marks a significant step toward alleviating the need for these animal resources. The new general chapter 2.6.32 and the revised general chapter 5.1.10 will become effective on 01 January 2021.
India – Central Drugs Standard Control Organization (CDSCO)
A previous order from the Drugs Controller General (India) had extended the validity of a Certificate of Pharmaceutical Product (CoPP) issued for the purpose of international commerce from two years to three years. In light of the current COVID-19 pandemic, the Drugs Controller General (India) has decided to extend the validity of CoPPs expiring from March to August 2020 by six months from the date of expiry.
Procedure to be Followed for Subsequent Application in Respect of Fixed Dose Combinations (FDCs) Relating to Vitamins, Minerals, and Micronutrients Declared as Rational by Prof. Kokate Committee and Approved by Drugs Controller General (India), 03 August 2020
In addition to the list of previously issued FDCs, a list of 471 additional FDCs has been forwarded to the State Licensing Authorities (SLAs). These additional FDCs have been accepted by the Ministry of Health and Family Welfare, and the following pathway for the granting of product licenses by SLAs is to be followed:
- Applicants submit the requisite fees, preferably through Bharatkosh, for each FDC to CDSCO as specified under the Drugs and Cosmetic Act, 1940 and existing rules.
- The application is submitted to the SLA according to the Drugs and Cosmetics Rules, 1945 for the granting of manufacturing licenses. Information for stability studies (six months accelerated), test specifications of the FDC, the method of analysis, labels, and other documents specified in the Drugs and Cosmetics Rules are required.
- The SLA grants the product licensure without seeking a No Objection Certificate (NOC) from the Drug Controller General (DCG) if conditions are found to be fulfilled.
- Every manufacturer permitted to manufacture these FDCs submits periodic safety update reports according to the New Drugs and Clinical Trials Rules – 2019 to the central Licensing Authority.
United States Food and Drug Administration (US FDA) – Guidances and Checklists
This guidance outlines US FDA’s current thinking on several topics relevant to clinical research related to the development of drugs containing cannabis or cannabis-derived compounds. Cannabis and cannabis-derived compounds that may be used in drug manufacturing include botanical raw materials, extracts, and highly purified substances of botanical origin. This guidance does not address development of fully synthetic versions of substances that occur in cannabis, sometimes known as cannabis-related compounds, which are regulated like other fully synthetic drugs. This guidance is limited to the development of human drugs and does not cover other FDA-regulated products. The guidance includes recommendations with respect to the following topics:
- Sources of Cannabis
- Resources for Information of Quality Considerations
- Percent Delta-9 Tetrahydrocannabinol (THC) Calculation
The US FDA and the Occupational Safety and Health Administration (OSHA) are providing a checklist for US FDA-regulated human and animal food operations to use when assessing operations during the COVID-19 pandemic, especially when re-starting operations after a shutdown or when reassessing operations because of changes due to the COVID-19 public health emergency caused by the virus SARS-CoV-2. Some or all of this checklist may be useful to persons growing, harvesting, packing, manufacturing, processing, or holding human and animal food regulated by FDA. This includes produce, seafood, milk, eggs, grains, game meat, and other raw materials or ingredients, as well as their resulting human or animal food products. This checklist is not exhaustive of all things human and animal food operations may do for employee health and food safety during the COVID-19 pandemic and can be used in conjunction with additional information from the Centers for Disease Control and Prevention (CDC), OSHA, and other federal, state, local, tribal, and territorial authorities. Not all of the items are relevant to all types of food operations; there is additional sector-specific information available, such as guidance from the CDC and the US Department of Labor for Agriculture Workers and Employers, Seafood Processing Workers (developed in consultation with US FDA), and Meat and Poultry Processing Workers and Employers. Some human and animal food operations producing food subject to US FDA regulations are located in foreign countries, though these operations are not subject to OSHA requirements discussed in this document. This checklist provides information useful for foreign facilities that manufacture, process, pack, or hold food for consumption in the United States.
The US FDA has issued a temporary guidance for industry entitled, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers.” The FDA recognizes that the COVID-19 public health emergency is having an impact not only on public health, but also drug development programs, ongoing manufacturing operations, and the FDA’s ability to conduct inspections. The agency also recognizes that sponsors and applicants have many questions related to FDA inspections. The FDA developed this guidance to provide answers to a number of frequently asked questions.
United States Food and Drug Administration (US FDA) – Recalls
Ferring Pharmaceuticals US is voluntarily recalling all lots on the market of DDAVP® Nasal Spray 10 mcg/0.1mL, Desmopressin Acetate Nasal Spray 10 mcg/0.1mL, and STIMATE® Nasal Spray 1.5 mg/mL from the consumer level. These products are being recalled due to superpotency or amounts of desmopressin higher than specified. These out-of-specification results were obtained during routine testing. The risks associated with higher than specified amounts of desmopressin relate to abnormally low levels of sodium in the blood (i.e., hyponatremia), which could eventually lead to seizure, coma, and death. To date, Ferring has not received an increase in adverse event reports due to increased concentrations of desmopressin from users of the nasal spray. A single non-fatal adverse event potentially associated with this issue was reported in the US during the timeframe that the affected product was distributed.
BD (Becton, Dickinson and Company), a leading global medical technology company, announced a voluntary recall on 23 June 2020 for specified catalog numbers of the ChloraPrep™ 3 mL applicator due to possible fungal contamination, which only affects climate zone IV regions in specific US territories and countries. BD has identified that storage of the ChloraPrep™ 3 mL applicator in regions of the world with high heat and humidity, where product may be consistently exposed to temperatures of 30°C (86°F) and 75% relative humidity for more than six months, may result in the growth of Aspergillus Penicillioides. The recall does not apply to any states in the United States; it only applies to the US territories of Puerto Rico, Guam, US Virgin Islands, Northern Mariana Islands, and American Samoa. This recall does not include 3 mL applicators found in kits. It also does not include any other ChloraPrep™ product presentations. All other ChloraPrep™ products are manufactured with different packaging materials that are not affected by this issue.
As part of the voluntary recall from the user level, the company notified customers and distributors affected by the recall and provided guidance on potential impact when the affected products were used. Through internal product quality testing, BD has identified that storage of the ChloraPrep™ 3 mL applicators where product may be consistently exposed to temperatures of 30°C (86°F) and 75% relative humidity for more than six months can result in the growth of Aspergillus Penicillioides, a type of fungus, resulting in a breach in the outer package integrity. The Aspergillus penicillioides within the packaging can contaminate the surface of the applicator and/or gloved hands of the healthcare professional and then consequently the sterile field. Contamination of skin preparation products with Aspergillus Penicillioides may lead to serious systemic infection, sepsis, illness, and death. If the fungus is introduced into the patient’s bloodstream during placement of an intravascular catheter, the catheter would most likely have to be removed, necessitating another procedure. Aspergillus Penicillioides infection of a surgical site may result in the need for medical and surgical interventions and long-term treatment with antifungal drugs. To date, no complaints, adverse events, injuries, or deaths have been reported related to this voluntary recall.
SCA Pharmaceuticals (SCA) is voluntarily recalling 10 lots of Heparin Sodium from the hospital/user level. The compounded Heparin Sodium bag contains the undeclared preservative benzyl alcohol. The labeling lists methylparaben and propylparaben as preservatives; however, these specified preservatives are not present in the product. SCA identified this labeling issue during the investigation of a low potency test result for Heparin Sodium (NDC 70004-0650-46).
Serious adverse reactions, including fatal reactions and “gasping syndrome,” are likely to occur in premature neonates and low-birth weight infants in the neonatal intensive care unit who receive benzyl alcohol as a preservative in infusion solutions, in any amount. Additional adverse reactions include gradual nervous system deterioration, seizures, bleeding in the skull, blood abnormalities, skin breakdown, liver and kidney failure, low blood pressure, slower than expected heart rate, and loss of sufficient brain blood flow to maintain consciousness. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. Furthermore, benzyl alcohol present in mother’s serum is likely to cross into human milk and may be orally absorbed by a nursing infant. For this reason, preservative-free heparin sodium injection is recommended when heparin therapy is needed during pregnancy. Benzyl alcohol is contraindicated in pediatric patients as well as pregnant or nursing women. SCA has not received any complaints or reports of adverse events to date related to this recall. However, out of an abundance of caution, SCA is voluntarily recalling specified lots.
United States Food and Drug Administration (US FDA) – Warning Letters
US FDA Sends Warning Letters to Seven Companies Illegally Selling Hangover Products, 29 July 2020
On 29 July 2020, the US FDA issued warning letters to seven companies whose products claim to cure, treat, mitigate, or prevent hangovers. A hangover can occur after alcohol intoxication. Alcohol intoxication, like all poisonings, causes dose-related dysfunction and damage, ranging from mild impairments to death. Alcohol intoxication causes temporary damage to brain function, causing impairments of judgment, attention, reflexes, and coordination. The products outlined in these letters, which are labeled as dietary supplements, are unapproved new drugs and have not been evaluated by the FDA to be safe and effective for their intended use. Dietary supplements that claim to cure, treat, mitigate, or prevent hangovers could potentially harm consumers, particularly young adults, who may be led to believe that using these products, rather than drinking in moderation or not at all, can prevent or mitigate health problems caused by consuming too much alcohol. Consumers should not rely on these products as an alternative to responsibly limiting their consumption of alcoholic beverages. Warning letters were sent to the following companies: Double Wood LLC, Ebnsol, Inc., Vita Heaven, LLC dba Hangover Heaven, Happy Hour Vitamins, LES Labs, Mind, Body & Coal LLC, and Purple Biosciences LLC.
United States Pharmacopeia (USP)
USP and its Expert Committees, as applicable, provided a notice of the intent to revise multiple monographs in response to the revision of General Chapter <1079> “Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products.” General Chapter <1079> was proposed for comment in Pharmacopeial Forum 45(5) and will appear in USP43-NF38 Second Supplement. USP has identified other documentary standards that reference General Chapter <1079> and thus require revision to modify these references. These references will be updated when the General Chapter appears in USP43-NF38 Second Supplement. A list of the monographs that will be modified can be found on the USP website. All modifications will become official on 01 December 2020, to coincide with the official date of revised General Chapter <1079>.
USP is providing guidance on the use of alternative methods/reagents for endotoxins testing as permitted under General Notices (GN) 6.30, “Alternative and Harmonized Methods and Procedures.” USP recognizes the need for guidance to drive the adoption of recombinant reagents as alternatives to naturally sourced reagents from horseshoe crabs (LAL or TAL). This approach advances USP’s commitment to transitioning methods from using animal-derived materials to synthetic and recombinant materials. In a recent publication in the Pharmacopeial Forum [45(5)], the USP Microbiology Expert Committee proposed the inclusion of recombinant factors for endotoxin testing in chapter <85> “Bacterial Endotoxins” (currently, the official procedure is based on the naturally derived reagent, LAL). Based on public comments received, the Microbiology Expert Committee decided to cancel this proposal and start the development of a separate chapter that expands on the use, validation, and comparability of endotoxin tests based on recombinantly derived reagents. Nevertheless, companies retain the option to use an alternative to the compendial method if they prove that their method is validated and provides comparable results to the compendial procedure.
USP intends to develop a new informational general chapter to align with current scientific and regulatory approaches to provide information useful for ensuring the appropriate control of nitrosamine impurities in drug substances and drug products. The goal is to provide a risk-based approach for the control of nitrosamine impurities in order to reduce or eliminate their presence in drug products. The chapter provides suitable performance criteria for analytical procedures used in the identification and quantification of nitrosamine impurities.
This is an update for the Reporting Threshold in USP–NF Monographs: Proposed Policy Change Compendial Notice, posted on the USP website for public comments from 13 August 2019 to 31 December 2019. In order to facilitate further discussion, USP published comments received from 22 stakeholders who provided permission. Based on the comments received, USP has determined that removal of reporting thresholds from monographs needs further evaluation. USP intends to host a virtual roundtable in the fall of 2020 to continue the discussion on reporting thresholds and other impurities topics. The US FDA has signaled that they will be providing additional information and context related to reporting thresholds. In the interim, USP is taking the following actions:
- USP intends to move previously deferred monographs with reporting thresholds to ballot so that the responsible Expert Committees can approve them for publication, thus ensuring quality updated standards for these substances and drug products.
- A new subsection is being proposed for addition to the General Notices and Requirements, 5.60.40. ,“Impurities that are Unusually Toxic and/or Mutagenic.” The proposal was presented as a Proposed Interim Revision Announcement in Pharmacopeial Forum (PF) 46(3) [May-Jun 2020]. The new subsection is intended to address potential safety concerns resulting from very toxic impurities not being controlled at appropriate levels in cases where a reporting threshold or disregard limit is included in official USP–NF monographs.
- USP intends to move related general chapters <476>, “Control of Organic Impurities in Drug Substances and Drug Products,” and <1086>, “Impurities in Drug Substances and Drug Products,” to ballot so that the responsible Expert Committee can approve them for publication.