SQA Regulatory Surveillance Summary | Monthly Update 2023 – February
SQA Regulatory Surveillance Summary for February 2023
By: Laurel Hacche, Rocio Cabeza, and Debra Cortner
Agência Nacional de Vigilância Sanitária (ANVISA)
The ANVISA Strategy Performance and Results Evaluation Report is now available for consultation, for the year 2022. The document details the evaluation of the implementation of actions provided for the Strategic Plan (PE) 2020 to 2023 and the Annual Management Plan (PGA). The first instrument consists of a set of 41 strategic goals and 17 strategic projects, while the second, prepared according to the Objectives and Key Results (OKR) methodology, presents a set of 40 key results, distributed among the 15 strategic objectives of the Agency. The monitoring of these goals, projects, key results, and their associated risks allows ANVISA to observe if everything that was built and predicted by ANVISA in the strategic field is being implemented and internalized, enabling the definition of preventive actions and course corrections over time. The publication also represents another instrument of transparency on the monitoring of goals, key results, and strategic projects. Items that are highlighted for monitoring include:
- Increasing post-market analytical monitoring programs
- Increasing the number of sanitary inspections carried out by the National Health Surveillance System (SNVS) in blood, tissue, and cell establishments
- Increasing the total checks of processes exempt from registration for sanitizing products
Additional focus areas include: increase of technical names of medical devices with monitored price history, reducing strategic corporate risks with specified intolerable levels, improve communication with state Health Surveillances (centralized and decentralized) and with decentralized municipal Health Surveillance.
ANVISA alerts health professionals and the population to the fact that cases of falsification of the drugs Botox® (Lot Number C7654C3F) and Dysport® (Lot Number L25049) have been identified. Details of the counterfeit cases are provided below:
- The company that holds the registration of the drug Botox®, Allergan Produtos Farmacêuticos Ltda., communicated to ANVISA the identification in Brazil of two units of counterfeit product with Lot Number C7654C3F, which is labeled in Portuguese. It is noteworthy that Lot Number C7654C3F is considered valid by the company, as there are original units of the same lot on the market. The main differences between the counterfeit product and the original product are in the labeling, the package insert, and the carton. Additional details (including photographs) are provided that show the differences between the original and the counterfeit product.
- The company that holds the registration of the drug product Dysport®, Beaufour Ipsen Farmacêutica, communicated to ANVISA the identification of counterfeit product with Lot Number 25049. The lot is recognized as the original for the Dysport® product with labeling in Portuguese. Photographs of the counterfeit product are provided.
ANVISA has published new actions for the collection and seizure of hair pomades. The actions are part of the investigative process that the Agency and the National Health Surveillance System (SNVS) are conducting to identify deviations in the market and the cause of several adverse events reported by users of this type of product. All ointments for styling, braiding or fixing hair remain prohibited in Brazil on a precautionary basis so that new events do not occur and until there is a guarantee on the safety of all hair pomades.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
The ICH M13A draft Guideline on Bioequivalence for Immediate-Release Solid Oral Dosage Forms reached Step 2 of the ICH process on 20 December 2022. Part of the foreseen ICH M13 Guideline series (M13A-C), the ICH M13A Guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.
Further information can be found on the M13 page, including the draft guideline available for download.
The ICH Q13 Guideline on Continuous Manufacturing of Drug Substances and Drug Products reached Step 4 of the ICH Process on 16 November 2022. Following the adoption of this Guideline, a Step 4 Introductory Training Presentation has been developed by the Q13 Expert Working Group. Please find the presentation for download on the Quality Guidelines page.
International Organization for Standardization (ISO)
ISO 11140-6:2022, Sterilization of Health Care Products – Chemical Indicators – Part 6: Type 2 Indicators and Process Challenge Devices for Use in Performance Testing of Small Steam Sterilizers, November 2022
ISO 11140-6:2022 specifies the performance requirements and test methods for hollow devices and porous devices as well as the chemical indicators and biological indicators that are utilized within these devices for testing a specific steam penetration performance of type B cycles and some type S cycles of small steam sterilizers according to EN 13060. Note: The hollow and porous devices described in this document are not intended for use as surrogate devices for hollow and porous medical devices used in health care facilities.
- Chemical indicators used with a porous device specified in this document are designed to demonstrate the adequacy of steam penetration into a porous device in small steam sterilizers (see EN 13060). This document specifies the requirements for:
- a reference porous device (RPD) as a reference device by which alternative porous indicator systems (APISs) can be shown to be equivalent in performance according to this document, i.e., a textile test pack in which steam penetration is judged by thermometric means;
- an alternative porous chemical indicator system equivalent in performance to the RPD, i.e., an APIS, usually commercially manufactured, of any design.
- Chemical indicators used with a hollow load device specified in this document are designed to demonstrate the adequacy of steam penetration into a narrow lumen (previously known as hollow load A) in small steam sterilizers (see EN 13060). This document specifies the requirements for:
- a reference hollow device (RHD) used as a reference device in this document, i.e., a lumened device with an attached capsule in which steam penetration is judged by inactivation or survival of a specified biological indicator;
- an alternative hollow device employing the same specific test load as defined for the RHD and a chemical indicator designed specifically for use in the reference hollow test load, i.e., a lumened device with an attached capsule in which steam penetration is judged by visual examination of a chemical indicator;
- an alternative hollow device equivalent in performance to the RHD, i.e., an alternative hollow device, usually commercially manufactured, of any design.
ISO 10943:2023, together with ISO 15004-1 and ISO 15004-2, specifies minimum requirements and test methods for hand-held, spectacle-type, and head-worn indirect ophthalmoscopes for observing indirect images of the eye fundus. This document takes precedence over ISO 15004-1 and ISO 15004-2, if differences exist. This document is not applicable to condensing lenses used for indirect ophthalmoscopy or to accessories. This document is not applicable to table-mounted instruments such as Gullstrand ophthalmoscopes and their derivatives, nor to ophthalmoscopes primarily intended for image capture and/or processing such as those based on scanning laser techniques.
ISO 15854:2023 specifies the classification of and requirements for waxes used for dental casting (including products intended for CAD/CAM milling) using the lost-wax technique and dental baseplate preparation together with the test methods to be employed to determine compliance with these requirements. Solid polymer products (such as acrylics) for CAD/CAM work, and thermoplastic or photo-curing resins used in additive processes, are not covered by this document. This document does not include specific and quantitative requirements for freedom from biological hazards.
International Society for Pharmaceutical Engineering (ISPE)
The ISPE Advancing Pharmaceutical Quality (APQ) Guide: Cultural Excellence provides a quality management framework for assessing and advancing an organization’s culture of quality by evaluating the following aspects:
- Leadership and Vision
- Mindsets and Attitudes
- Gemba and Employee Engagement
- Leading Quality Indicators – Measuring What Matters
- Proactive Oversight, Review, and Reporting
- Cultural Enablers
- Critical Third-Party Partnerships
This APQ Guide builds upon the insight provided in the ISPE Cultural Excellence Report (2017) on quality culture improvements across six dimensions. The Report provided the “what” and “why,” while this APQ Guide provides the “how.” The Report also outlined a series of practical and powerful approaches, practices, and tools for improving the impact of culture on the performance outcomes for an organization. It is a valuable companion to this APQ Guide. The ISPE APQ Guide: Cultural Excellence is the fifth and final guide in the series that seeks to improve the state of pharmaceutical quality and ensure sustainable compliance. The Guide Series is part of ISPE’s initiative, Advancing Pharmaceutical Quality (APQ), a comprehensive program for assessing and improving an organization’s quality management maturity.
The ISPE Good Practice Guide: Containment for Potent Compounds covers all aspects of pharmaceutical containment including background to safe working levels and the mechanisms of exposure and how such exposure can be controlled. There are chapters on typically applied approaches used in containing exposure for commonly applied process systems across all elements of pharmaceutical development and manufacturing. Developed by a multinational team of experts consisting of engineers, toxicologists, hygienists, and analysts from major pharmaceutical companies and suppliers, this Guide aims to consolidate this widely dispersed knowledge base into one document. It describes and discusses the containment methodologies, processes, and technologies commonly used in the pharmaceutical industry when handling potent compounds. The Guide contains numerous photos on the wide range of technologies presented, such as isolators, process interfaces and transfer ports, air locks, filtration systems, containment performance assessments, and cleaning/waste treatment. Additional topics include Good Manufacturing Practice (GMP) aspects, containment systems’ lifecycle, unplanned emission/spillage recovery procedures, and the development of a containment strategy.
Parenteral Drug Association (PDA) – Technical Reports
PDA Technical Report 89 describes different strategies that can be applied to manage the development and lifecycle of vaccine products. The concepts covered are intended to apply to different types of vaccines, for which real world examples are provided. In some cases, the strategy may involve extensive retrospective work that may be required for legacy vaccine products. Building product and process knowledge and including control strategy elements are particularly important for such complex biological products as vaccines. This report addresses that issue by including strategies that can be applied in early development to licensure and those that are focused on lifecycle management of marketed products. Specific aspects of control strategies that are particularly relevant to both prophylactic and therapeutic vaccines are covered in this report, including setting and managing specifications, managing process parameters with respect to classification and lifecycle management, and considering comparability requirements.
Drug manufacturers have employed contamination control measures for decades as a core element of good manufacturing practices. Commonly, these are a collection of generic practices that were developed separately and applied without clear consideration for their interdependence. The ongoing evolution of contamination control principles that this document addresses is a shift to a holistic approach, where the practices are designed to work together to achieve proactive contamination control and are evaluated for their collective effectiveness. The holistic approach also demands that contamination control measures be tailored to the specific risks around each individual process. PDA Technical Report 90 focuses on contamination control practices against microbial and other adventitious agents, endotoxins, and foreign particulate matter in the manufacture of sterile drugs, low bioburden drug substances, and some nonsterile drugs that are vulnerable to contamination.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
A dedicated European Medicines Agency (EMA) Drafting Group, in which PIC/S is represented by Ib Alstrup (Denmark/DKMA), who is also the Chair of the PIC/S Working Group on the revision of PI 011 (PIC/S Recommendation on Computerized Systems), has developed a Concept Paper on the Revision of Annex 11 of the Guidelines on Good Manufacturing Practice for Medicinal Products – Computerized Systems. This concept paper was submitted to a joint PIC/S-EMA public consultation from 16 November 2022 until 16 January 2023 and can be downloaded from the PIC/S Publications page.
PIC/S has published the following two guidance documents for Good Distribution Practice (GDP) inspectors: an ‘Aide-Memoire on the Inspection of GDP for Medicinal Products in the Supply Chain’ (PI 044-1) and a ‘Questions & Answers (Q&A) document regarding the PIC/S GDP Guide’ (PS/INF 22/2017). These documents have been prepared by the PIC/S Expert Circle on GDP and will enter into force on 01 February 2023. They are available for downloading on the PIC/S Publications page.
Therapeutic Goods Administration (TGA)
There are current shortages of some antibiotics in Australia, including amoxicillin, amoxicillin/clavulanic acid, cefalexin, metronidazole, and trimethoprim. TGA is facilitating supply of alternative medicines as a priority. Most of the shortages are caused by manufacturing issues or an unexpected increase in demand. Many of these medicines have alternatives available. Where suitable Australian-registered alternatives are not available, the TGA has taken action to approve overseas-registered alternatives.
The TGA has introduced mandatory requirements for applications to vary the Permissible Ingredients Determination under section 26BD of the Therapeutic Goods Act 1989, and accompanying guidelines. The requirements came into effect on 01 February 2023 and only apply to new applications submitted from this date and specify what information, and how that information must be provided for an application to pass preliminary assessment and progress to the evaluation phase, consistent with other therapeutic goods application processes. This ensures that applications are accepted for evaluation if they have sufficient information that would be required to undertake a meaningful and efficient evaluation of the safety and quality of the substance to be approved. The requirements have been tailored for different types of substances and routes of administration, whilst continuing to allow justifications to be provided for individual circumstances or approaches not covered in the guidance. New mandatory requirements and guidelines documents are as follows:
- Mandatory requirements for an application to vary the Permissible Ingredients Determination
- Application requirements for new substance for use in listed medicines
Guidance on the application process and information required for a substance to be evaluated for use as a new ingredient in listed medicines.
- Overview of compositional guidelines and templates
Guidance about compositional guidelines and templates to help develop them for a new substance application.
- Requirements for microorganism characterization in listed medicines and registered complementary medicines
Data requirements for applications relating to microorganisms used as active ingredients in listed medicines or registered complementary medicines. These are generally referred to as probiotics or postbiotics.
- Comparable overseas bodies (COBs) for complementary medicines
Guidance on using assessments from comparable overseas bodies in evaluations for complementary medicines and listed medicines.
- A new list of approved COBs and updated COB checklists.
Following a safety investigation by the Therapeutic Goods Administration (TGA), 55 products containing pholcodine are being canceled from the Australian Register of Therapeutic Goods and those currently on pharmacy shelves are being recalled from pharmacies. The cancellation and recall actions are being taken because of a link between pholcodine-containing medicines and an increased risk of anaphylactic reactions (a sudden, severe, and life-threatening allergic reaction) to certain medicines used as muscle relaxants during general anesthesia (called neuromuscular blocking agents). Pholcodine has been used in a wide range of over-the-counter pharmacy medicines to treat non-productive (dry) cough, particularly in syrups and lozenges. It is also used in combination with other medicines in products that treat the symptoms of cold and flu. The TGA’s investigation followed a review by the European Medicines Agency (EMA) recommending the withdrawal of marketing authorizations for these products in Europe. The European findings were supported by a Western Australian study which also showed that pholcodine was a risk factor. Up to 09 February 2022, the TGA has also received 50 reports of Australian cases of suspected pholcodine-related anaphylactic reactions to neuromuscular blockers, including one fatality.
United States Food and Drug Administration (FDA) – Regulations and Guidances
The FDA is issuing this guidance to support sponsors in their development of drugs for mpox (monkeypox). This guidance provides nonclinical, virology, and clinical considerations for mpox drug development programs, with a focus on recommendations to support initiation of clinical trials.
CVM GFI #272 Practices to Prevent Unsafe Contamination of Animal Feed from Drug Carryover, 27 January 2023
Drug carryover generally occurs when a drug used in the manufacture of a batch of medicated feed, for which the drug is approved, gets inadvertently included in a subsequent batch of: (1) a non-medicated feed, (2) a different medicated feed for which the drug is not approved (e.g., medicated feed for another species), or (3) a medicated feed that contains the same drug that can result in a higher drug level than is stated on the labeling. Drug carryover can occur for various reasons, including, for example, the use of the same equipment to manufacture both medicated and non-medicated feed; the design, construction, or inadequate maintenance of feed manufacturing equipment; poor dust control in a feed mill; inadequate cleanout practices for manufacturing and distribution equipment between sequential batches of animal feed; or human error. FDA regulation 21 CFR Part 225: Current Good Manufacturing Practice for Medicated Feeds contains requirements for equipment cleanout procedures to avoid unsafe contamination of feeds with drugs (see 21 CFR 225.65 and 225.165). CVM GFI #272 provides information on ways to comply with these requirements to help prevent unsafe contamination of animal feed from drug carryover.
United States Food and Drug Administration (FDA) – Recalls
Hospira, Inc., a Pfizer company, is voluntarily recalling one lot of Vancomycin Hydrochloride Injection, USP, 1.5 g/vial Single Dose Fliptop Vial, Lot Number 33045BA, to the user level due to two visible glass particulates observed in a single vial. If administered intravenously, patients may experience adverse events such as local irritation or swelling, vasculitis/phlebitis, antigenic or allergic reactions, and microvascular obstruction, including pulmonary embolism. If administered orally or via a nasogastric tube, there may be the potential for gastrointestinal trauma. The risk is reduced by the possibility of detection, as the label contains a statement directing the healthcare professional to visually inspect the product for particulate matter and discoloration prior to administration. To date, Pfizer has not received reports of any adverse events related to this recall.
Spectrum Laboratory Products, Inc. is voluntarily recalling three lots of Epinephrine (L-Adrenaline) USP, a bulk active pharmaceutical ingredient (API) used to manufacture or compound prescription products, to the user level. Customer complaints have found the product to be discolored. Epinephrine (L-Adrenaline) USP bulk API Powder, is used in manufacturing and compounding of finished dose epinephrine prescription products which can be used to treat a variety of medical conditions including anaphylaxis and other severe immediate hypersensitivity reactions, asthma, bronchospasm, airway edema, nasal congestion, dilation during intraocular surgery, vasoconstrictor with local anesthetics, hypotension or shock, heart failure, bradycardia or atrioventricular block, and sudden cardiac arrest. The Epinephrine (L-Adrenaline) USP bulk API Powder is packaged in amber glass bottles enclosed in a vacuum sealed pouch. The affected Epinephrine, USP product can be identified by Spectrum catalog number EP130 (affected lot numbers are provided in the recall notice). Product was distributed directly from Spectrum facilities nationwide in the USA and to Canada. Spectrum Laboratory Products, Inc. is notifying its distributors and customers by certified mail, email, and phone, and arranging for return of all recalled products. Consumers, distributors, or retail pharmacies that have Epinephrine, USP catalog number EP130, which is being recalled, should stop use immediately and return to place of purchase. Spectrum Laboratory Products, Inc. has not received any reports of adverse events related to this recall.
Bindle Bottle LLC of Carlsbad, CA, is recalling its Bindle Bottles because they may contain an area of exposed lead located in the bottom storage compartment of the bottle. Unpackaged food stored in the bottom storage compartment of the bottle may have been adulterated by the lead and could pose health problems to people or animals eating that adulterated food. The recalled Bindle Bottles were distributed nationwide via bindlebottle.com, amazon.com, promotional distributors, and in retail stores. The product comes in four sizes: 32 oz., 24 oz., 20 oz., and 13 oz. Bindle Bottle is also recalling the 24 oz. bottle that is part of the Puppy Pack. No illnesses have been reported to date in connection with this problem. Reports by Lead Free Mama and Consumer Reports led the firm to have the bottle tested. The recall was initiated after analytical results revealed that the small, 0.4” diameter soldering dot in the bottom storage compartment contained lead. Subsequent investigation indicates the problem was caused by a lack of a cover or barrier to the exposed soldering dot. Production of Bindle Bottles has been suspended and will be overhauled going forward, eliminating the presence of exposed lead anywhere on future products.
United States Food and Drug Administration (FDA) – Warning Letters
The FDA issued a Warning Letter to Profunda, Inc. on 01 February 2023, based on the outcome of an inspection that was conducted from 03 to 09 August 2022. A summary of the Form FDA 483 observations is as follows:
- The firm failed to provide data to demonstrate that they have validated manufacturing processes for their over-the-counter (OTC) drug products, including but not limited to Rhinase D. The firm lacked qualification protocols, reports, or studies to determine if manufacturing processes were in a state of control and appropriate acceptance criteria were met.
- The firm failed to establish an adequate stability program and determine appropriate expiration dates for the OTC drug products that they manufacture. For example, the firm assigned a five-year expiry period to Rhinase D drug product batch 1J02 (30g), even though sufficient stability data was not available to substantiate the Rhinase D five-year expiry period.
- The purified water system used to manufacture drug products was not designed and maintained appropriately for its intended use. For example, the water system included a dead leg and was not continuously circulating, which could foster the development of biofilms. When the water was not in use, it sat stagnant in the system except when the specified points-of-use (POUs) were opened.
- The firm had inadequate laboratory controls. For example:
- Microbiological methods used for determining the quality of purified water and finished drug products were deficient. Specifically, the firm failed to perform growth promotion testing on every batch of ready-to-use media and to verify microbiological method suitability for each drug product manufactured.
- The firm failed to conduct appropriate laboratory testing for each batch of drug product that is required to be free of objectionable microorganisms. In particular, the firm failed to conduct testing for Burkholderia cepacia complex (BCC) for numerous non-sterile aqueous-based dosage form drug products at release and on stability.
- The firm lacked testing for every shipment of every lot of components used in the manufacture of drug products. Specifically, the firm lacked a specific identity test to detect diethylene glycol (DEG) and ethylene glycol (EG) in all shipments, containers, and lots of glycerin before use in manufacturing drug products. DEG contamination in glycerin has resulted in various lethal poisoning incidents in humans worldwide. In addition, the FDA noted that both glycerin and propylene glycol are ingredients used in drug products. As a drug manufacturer, the firm is responsible for performing specific identity tests for all incoming shipments of component lots prior to release for use in manufacturing.
The FDA issued a Warning Letter to Midlab Incorporated on 15 February 2023, based on the outcome of an inspection that was conducted from 01 to 05 August 2022. A summary of the Form FDA 483 observations is as follows:
- The firm failed to adequately test over-the-counter (OTC) drug products prior to release for distribution. For example, although the batch records for hand sanitizer and antibacterial hand soap drug products include a requirement for microbial testing, the firm failed to test each batch for microbial attributes. Instead, the investigator was informed that the firm only sent [redacted text] to a third-party laboratory for analysis. In addition, the firm did not provide documentation of what was included in the referenced standard plate count testing when requested by investigator or a scientific rationale for the sample testing frequency.
- The firm failed to investigate out-of-specification (OOS) assay results during stability checks for several batches of their antibacterial hand soap drug products. For example, assay testing for chloroxylenol in the antibacterial hand soap drug product revealed results including 0.31% at the [redacted text] timepoint stability check. The firm’s specification for this product attribute was [redacted text]%. The firm failed to conduct any investigation into the OOS result.
- The firm also failed to quarantine or reject expired raw materials and prevent their use in finished drug products. On 28 June 2022, the firm used raw material benzalkonium chloride (BZK), which expired 17 June 2021, to manufacture instant foam hand sanitizer that was released for distribution.
- The Quality Unit (QU) did not provide adequate oversight for the manufacture of the firm’s drug products. For example, the QU failed to ensure the following:
- Adequate procedures describing investigation handling, quarantine products, complaint handling, change control, and stability failures.
- Adequate testing of incoming components for identity, purity, strength, and other appropriate quality attributes.
- Establishment of an adequate, ongoing stability program.
- The firm failed to adequately validate the manufacturing process and water system used in the manufacture of hand sanitizer and antibacterial hand soap drug products. For example, batch records included unvalidated in-process adjustments, such as adding [redacted text] as-needed if the density of antibacterial hand soap was low. The firm did not demonstrate that manufacturing processes were controlled to consistently yield a drug product of uniform character and quality. Furthermore, the firm has not validated the water system, does not maintain procedures, and did not provide specifications upon request by investigators.