SQA Regulatory Surveillance Summary | Monthly Update 2022 – May
By Laurel Hacche & Debra Cortner SQA Associates
SQA Regulatory Surveillance Summary 2022 – May
Health Canada published the following non-compliant drug inspections in the first quarter of 2022:
- EGS EuroCam, inspected on 11 January 2022: findings relate to quality control, personnel, premises, equipment, raw material testing, sanitation, manufacturing control, and records (EGS EuroCam Observations)
- West Penetone Inc., inspected on 25 January 2022: findings relate to premises, manufacturing control, quality control, sanitation, stability, raw material testing, equipment, and records (West Penetone Inc. Observations)
- Biomed Pharma, inspected on 10 February 2022: findings relate to quality control, finished product testing, manufacturing control, and records (Biomed Pharma Observations)
- Laboratoire Lalco Inc., inspected on 03 March 2022: findings relate to quality control, records, stability, manufacturing control, packaging material testing, finished product testing, and retain samples (Laboratoire Lalco Inc. Observations)
Recalls published in May 2022 by Health Canada for healthcare, pharmaceutical, and device products included the following:
- Biomed Pharma, last updated 02 May 2022: Recall of one (1) lot of Bio-Calcium. Affected lot may contain Bio-Calcium D tablets (Biomed Pharma Recall)
- Ortho-Clinical Diagnostics Inc., last updated 03 May 2022: Recall of Ortho Vision Analyzer. complaints received about unexpected results (i.e., misidentification of a sample) (Ortho-Clinical Diagnostics Recall)
- Teva Canada Ltd., last updated 07 May 2022: Recall of one (1) lot of Pharmasave Advanced Relief Eye Drops and Compliments Advanced Relief Eye Drops due to a packaging error that may pose health risks (Teva Canada Ltd. Recall)
- Generic Medical Partners, Inc., last updated 13 May 2022: Recall of one (1) lot of Leucovorin Calcium Injection, 1000 mg/100 ml, due to an out-of-specification assay result (Generic Medical Partners Recall)
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances – Quality, Efficacy, Multidisciplinary, and Safety
The ICH E8(R1) Guideline on General Considerations for Clinical Studies reached Step 4 of the ICH Process on 06 October 2021. A Step 4 Introductory Training Presentation has been developed by the E8(R1) Expert Working Group and is now available on the ICH E8(R1) webpage with the Step 4 ICH E8(R1) Guideline.
ICH Q3D(R1) Elemental Impurities is a Quality Guidance for the control of elemental impurities (EIs) in new drug products (medicinal products). This guidance establishes permitted daily exposures (PDEs) for 24 EIs in drug products administered orally, parenterally, and via inhalation. In addition, guidance is provided in ICH Q3D(R1) on how to develop an acceptable level of EIs for drug products administered by other routes of administration. ICH Maintenance Procedures have been applied to the revision of ICH Q3D(R1). This revision includes the incorporation of PDEs for new EIs/routes of administration and revising the PDE for EIs already listed in Q3D(R1), as new toxicological data for each EI becomes available. In April 2022, the ICH Q3D(R2) Guideline reached Step 4 of the ICH EWG process, which included the following revisions:
- Correction of PDEs for gold, silver, and nickel
- Correction of gold and silver monographs
- Addition of limits for EIs by the cutaneous and transcutaneous route
The new ICH draft guidance (Q14) for analytical procedure development describes an enhanced approach for method development, validation, and lifecycle management. ICH Q2 was also updated to reflect the proposal in Q14; both are now available for public consideration and feedback (https://www.ich.org/page/quality-guidelines), and both draft guidelines agree with the proposed United States Pharmacopeia (USP) <1220> chapter on Analytical Procedure Life Cycle management. What’s new is that the enhanced approach described in Q14 employs elements of quality by design (QbD) and risk management tools and applies these to analytical procedures. While the enhanced approach is not mandatory, there are benefits to the methodology.
International Pharmaceutical Excipients Council (IPEC)
The International Pharmaceutical Excipients Council Federation (IPEC Federation) announces the availability of a new position paper, The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products. This paper describes the IPEC Federation’s position on the role of excipients when conducting N-nitrosamine (nitrosamine) risk assessments for drug products. The presence of N-nitrosamines in drug products continues to be a global concern. Excipients are considered as a potential risk factor during drug product risk assessment. The focus of this position paper is to expand on the potential contribution excipients may or may not have on the formation of nitrosamines in final drug products. The presence of nitrites and vulnerable amines in excipients is also considered. The position paper is available for download immediately via the IPEC website.
International Organization for Standardization (ISO)
ISO/TS 5798:2022 In Vitro Diagnostic Test Systems — Requirements and Recommendations for Detection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by Nucleic Acid Amplification Methods, April 2022
ISO/TS 5798:2022 provides requirements and recommendations for the design, development, verification, validation, and implementation of analytical tests for detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using nucleic acid amplification. It addresses pre-examination, examination, and post-examination process steps for human specimens. This document is applicable to medical laboratories. It is also intended to be used by in vitro diagnostic developers and manufacturers, as well as by institutions and organizations supporting SARS-CoV-2 research and diagnostics. This document does not apply to environmental samples.
ISO 14644-9: 2022 Part 9 establishes a procedure for the assessment of particle cleanliness levels on solid surfaces in cleanrooms and associated controlled environment applications. Recommendations on testing and measuring methods, as well as information about surface characteristics, are given in Annexes A to D. This document applies to all solid surfaces in cleanrooms and associated controlled environments, such as walls, ceilings, floors, working environments, tools, equipment, and products. The procedure for the assessment of surface cleanliness by particle concentration (SCP) is limited to particles between 0.05 µm and 500 µm.
ISO 14644-10:2022 establishes appropriate testing processes to determine the cleanliness of surfaces in cleanrooms with regard to the presence of chemical compounds or elements (including molecules, ions, atoms, and particles). This document is applicable to all solid surfaces in cleanrooms and associated controlled environments such as walls, ceilings, floors, worksurfaces, tools, equipment, and devices.
Medicines and Healthcare Products Regulatory Agency (MHRA) – Recalls and Safety Alerts
Pfizer Ltd. is voluntarily recalling all stock of Accupro 5 mg, 10 mg, 20 mg, and 40 mg Film-Coated Tablets as a precautionary measure due to the identification of a nitrosamine above the acceptable limit. Following testing, N-nitroso-quinapril was observed at a level above the acceptable limit. Nitrosamines may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time. The recall is at the pharmacy and wholesaler level. Based on the available data, there is no immediate risk to patients who have been taking this medication. It is advised that patients undergoing treatment not to discontinue Accupro without consulting with their prescriber, as there are potential risks associated with suddenly stopping treatment for blood pressure. Healthcare professionals should advise patients undergoing treatment to discuss any questions or concerns with their prescribing healthcare professional.
National Patient Safety Alert: Philips Health Systems V60, V60 Plus and V680 Ventilators: Potential Unexpected Shutdown Leading to Complete Loss of Ventilation (NatPSA/2022/002/MHRA), Updated 25 May 2022
In March 2022, Philips Health Systems informed the MHRA of an important safety issue due to potential unexpected shutdowns of all their V60 and V60 Plus non-invasive ventilators. All V680 invasive ventilators used in critical care settings are also affected. V60 and V60 Plus devices are designed for in-hospital use. They can be used to provide average volume-assured pressure support (AVAPS), pressure-controlled ventilation (PCV), continuous positive airway pressure (CPAP), and positive pressure ventilation (PPV) treatment to patients in critical care and high-dependency unit (HDU) settings. The safety concern identified relates to a number of electrical faults in the devices, which can result in an unexpected shutdown, leading to loss of ventilation. There are two ways in which this shutdown can occur:
- The first will sound a warning to alert the user that the machine is shutting down. This will let the user know they need to switch to an alternative source of ventilation. There is a risk that the patient will be unventilated while this second source of ventilation is prepared.
- The second failure mode will cause the device to shut down with no warning alarm. If a ventilator fails in use and does not alarm, the patient will be unventilated until the clinician becomes aware and responds.
If unnoticed by healthcare professionals, ventilation failure can have a severe health impact on patients. This can include hypoxia, which can result in long-term cognitive impairment to the patient. There is also a risk of death if a patient is without ventilation for a sustained period. Philips has no permanent solution to correct this issue, so the MHRA is issuing this alert to help hospitals manage the risk. This alert should be acted on immediately.
Note: This is a different alert to the one previously published on 23 September 2020 by the MHRA for a similar range of devices.
National Patient Safety Alert: NovoRapid PumpCart in the Roche Accu-Chek Insight Insulin Pump: Risk of Insulin Leakage Causing Hyperglycemia and Diabetic Ketoacidosis (NatPSA/2022/004/MHRA), 26 May 2022
The MHRA continues to receive serious reports of harm associated with insulin leakage from the NovoRapid PumpCart prefilled insulin cartridge in the Accu-Chek Insight insulin pump. In some patients, there were serious consequences arising from inadequate supply of insulin, including diabetic ketoacidosis (DKA). Although the manufacturer, Roche Diabetes Care (RDC), has implemented a number of risk minimization strategies to reduce the incidence of these events, the impact of these strategies is inconclusive, and MHRA is taking further action to protect patients.
The main reasons for the leakages were as follows:
- Approximately 70% of cases: The adapter needle was inserted in the insulin cartridge at an incorrect angle, which may cause bending of the needle and subsequent insulin leakage from the septum
- Approximately 30% of cases: Cracked cartridges, including non-visible hairline cracks, that may result from mechanical shocks such as dropping the cartridge or pump
Risk minimization strategies have included technical improvements to the pump and adapter and safety communications on how to handle the pump and prefilled cartridge. An enhanced design of the adapter and tubing was implemented in September 2021, but leakage events continue to be reported, albeit at reduced rates. The manufacturer has released a Field Safety Notice (FSN) on this issue, which should be followed in addition to this alert. Patients should be informed of the importance of following the advice in the manufacturer’s latest FSN. This includes using the new versions of the adapter and tubing for certain lot numbers. To protect patient safety, diabetes healthcare professionals should inform patients who use the Accu-Chek Insight of the risk of leakage. Clinical care decisions should be made to ensure patients are moved onto alternative pumps where possible.
Parenteral Drug Association (PDA) – Standards and Technical Reports
ANSI/PDA Standard 02-2021 provides guidance on how to establish suitable procedures for the cryopreservation and recovery of biological cells for use in cell and gene therapy products and regenerative medicine manufacturing, either as an intermediate step or when cryopreservation is the final step. The document presents cryopreservation as a modular process and describes key details that should be considered when developing a cryopreservation and recovery process for a specific use-case. The guide emphasizes the effect that cryopreservation and recovery may have on cell viability and cell function. It is not intended to provide information on the terms and procedures directly associated with regulatory requirements governing cell-based products. However, it can provide general guidance during the assessment of regulatory requirements. The best practices and guidance details outlined in the document provide general procedural support for cryopreservation of cell-based products during both early and late phases of product development. This document is a current best practice standard and guide on how to establish suitable conditions for the cryopreservation and recovery of cells, cell lines, and cell-based products for use in cell and gene therapies and regenerative medicine manufacturing.
PDA Technical Report No. 88 presents a holistic approach for performing a microbiological investigation. It provides a framework to assist with focusing on the investigational areas that may contain or contribute to the root cause of data deviations, such as sampling, test methodology, and suitability of the test, as opposed to providing methods for analysis of batch acceptability. The distinct areas where microbial data is collected and inspected for deviation investigations are the focus of this document, including the following areas:
- Roles and responsibilities of personnel, especially microbiologists, in the laboratory investigations and cross-functional teams responsible for manufacturing investigations
- Conducting laboratory investigations
- Conducting manufacturing investigations
The roles of other contributors to deviation investigations required for effective root cause analysis, such as representatives from manufacturing, process engineering, and quality assurance, are also briefly described. This technical report promotes a lifecycle approach, but greater emphasis is placed on laboratory and manufacturing investigations of marketed drug products.
Nitrosamines have gained unexpected attention again, triggered by their discovery at significant concentrations in some active pharmaceutical ingredients and pharmaceutical products. Regulatory agencies not only expect the marketing authorization holders to include a nitrosamine risk assessment in their drug development process but to also apply it retrospectively to the marketed drug product. As part of this risk assessment, all possible sources of nitrosamines need to be evaluated. This review provides the chemical background of nitrosamines and elastomeric formulations, the current regulatory status in the pharmaceutical and other industries and discusses analytical challenges of nitrosamine measurement. This evaluation of elastomeric components as a potential nitrosamine source proposes how this information can be used in a drug product risk assessment.
This revision of PDA Technical Report No. 13 aligns with current industry trends and regulatory expectations and provides additional guidance and focus on increased expectations concerning data management and data integrity, qualification and maintenance of controlled environments, and rapid microbiological methods (RMM). This technical report will aid in the establishment of an environmental monitoring program that is robust, meaningful, and practical while embracing innovation and the principles of quality risk management. Updates regarding microbiological and total airborne particulate control concepts and principles related to facilities involved in the manufacture of sterile pharmaceutical products and other designated cleanroom environments are also included. While this report may serve as a resource applicable for controlled environments in general, its primary focus is environmental monitoring for sterile product manufacturing.
This Points to Consider document describes steps that can be taken to ensure an effective and efficient remote assessment. It introduces standard nomenclature to describe the types of remote audits and discusses key considerations for their scheduling, duration, planning, conduct, closing, reporting, and follow up. The document focuses on aspects of auditing that are different in the remote setting from those in on-site audits or that have a particular impact in the remote setting. This document is designed to assist both the auditor and auditee as they work through the challenges of remote and hybrid auditing and determine the changes in practices, standard operating procedures, and quality agreements that are necessary to facilitate effective and efficient remote audits.
Personal Care Product Council (PCPC)
PCPC and its member companies are firmly committed to ensuring consumers have access to cosmetics and personal care products with ingredients that have been thoroughly tested for quality, efficacy, and safety, and follow all legal and regulatory requirements. There is nothing more important than safety. If consumers can’t trust the safety of personal care products, then nothing else matters. PCPC is aware of recent studies reporting the presence of trace amounts of benzene in some personal care products. Benzene is a chemical that is ubiquitous in the environment and not an intentionally added ingredient in personal care products. People worldwide are exposed daily to benzene from indoor and outdoor sources, including air, drinking water, and food and beverages. The U.S. Food and Drug Administration (FDA) and product manufacturers are aware that it may be present in food and drug products at trace levels, and those very low levels do not pose a safety concern for consumers.
Cosmetics and personal care products companies are global leaders committed to product safety, quality, and innovation as well as sustainable business practices. The PCPC member companies are some of the most beloved and trusted brands in beauty and personal care today. As the manufacturers, distributors, and suppliers of a diverse range of products millions of consumers rely on to enhance their health and well-being, – from sunscreens, toothpaste and shampoo to moisturizer, makeup, and fragrance – this industry contributes significantly to the world economy.
The PCPC member companies strongly supports a legally binding treaty that will address plastics pollution through improving waste management and recycling systems; by promoting innovation and eco-design; and by reducing the production and use of virgin plastic where possible and beneficial to the environment. The PCPC member companies believe that promoting a circular and sustainable economy is intrinsically related to solving this issue. PCPC companies support the achievement of the UN Sustainable Development Goals (SDGs), and many have made robust pledges while taking progressive action in support of transitioning to a circular economy and ending plastics pollution. In this regard, the beauty and personal care industry is fervently exploring and adopting where currently possible different distribution models including refilling and recharging as well as alternative packaging materials. At the same time, the PCPC member companies recognize the importance of plastics in achieving the UN SDGs and the role they can play toward achieving a circular economy. In many cases, plastics, especially when recovered and reused, may have a lower carbon footprint or be the alternative that best safeguards our environment.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
The PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products has been revised to include:
- A revised Annex 13 on the Manufacture of Investigational Medicinal Products; and
- A new Annex 16 on the Certification by the Authorized Person and Batch Release
PIC/S Annex 13 has been revised based on EC Regulation No. 536/2014 on Clinical Trials, which will replace EU Annex 13. This is in line with the Co-operation Agreement between PIC/S and EMA, which provides that the PIC/S and EU GMP Guides should be harmonized with the aim of keeping GMP standards equivalent, thus facilitating the exchange and use of information concerning the manufacture of medicinal products.
PIC/S Annex 16 is a new annex to the PIC/S GMP Guide. Historically, PIC/S did not adapt EU Annex 16, when it was adopted as part of the EU GMP Guide. Initially, PIC/S considered this annex to be EU-specific and difficult to transpose for PIC/S purposes, since the PIC/S GMP Guide is limited to the manufacture of medicinal products and not to import and distribution. Following a consultation of PIC/S Participating Authorities in 2017, it was agreed to make an attempt to transpose EU Annex 16, considering that a PIC/S adaptation could offer added benefit to better convey expectations associated with product release and further international harmonization efforts in line with PIC/S’ mission to lead the international development, implementation and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products. PIC/S also agreed that elements in Annex 16 related to imported medicinal products would be voluntary, dependent on national law.
Both Annexes were successfully approved by the PIC/S Committee by written procedure on 26 January 2022. The revised GMP Guide (PE 009-16), with the revised Annex 13 and the new Annex 16, will enter into force on 1 February 2022. This coincides with the entry into force of Regulation No. 536/2014 on Clinical Trials replacing EU Annex 13.
Therapeutic Goods Administration (TGA)
The Therapeutic Goods Administration (TGA) is undertaking a post-market review of all devices in the Australian Register of Therapeutic Goods (ARTG) of the following kinds:
- Continuous and non-continuous ventilators
- Acute care ventilators
- Ambulatory ventilators including continuous positive airway pressure (CPAP) devices
- Bi-level positive airway pressure (BiPAP) devices
This post-market review follows the identification of risks posed by a polyester-based polyurethane (PE-PUR) foam used as soundproofing material in ventilator, CPAP and BiPAP devices supplied by Philips Electronics Australia Ltd. The review has two purposes:
- To ensure devices included in the ARTG continue to meet the essential principles set out in the Therapeutic Goods (Medical Devices) Regulations 2002
- To confirm these devices remain safe for use, by checking if they are made using PE-PUR foam or any other potentially harmful soundproofing material.
The TGA has requested sponsors of ventilator, CPAP, and BiPAP devices included in the ARTG provide information to the TGA about their product, including:
- The type of soundproofing material used
- The manufacturer risk assessment and risk mitigation strategies
- Whether the devices pose any unnecessary risk to the health of the user during normal use
The TGA will provide updates and outcomes of the review as they become available. The information about each model will be published on the following pages as reviews are completed. If the model you are interested in is not included in this list , it is still in the process of being reviewed. The table will be updated regularly as the post-market review progresses.
- List of Ventilators, CPAP and BiPAP devices unaffected by foam material
Consumers and health professionals are advised that several sunscreen products, which are regulated as medicines in Australia, are being recalled due to the presence of benzene. Benzene is a chemical that can cause cancer in humans, depending on the level and length of exposure. Benzene is not an ingredient in sunscreens but can be a contaminant in raw materials used in the manufacturing process. It has been detected in one batch of a raw material used in the manufacture of several products, and the TGA is working with affected companies to confirm if benzene is present in their medicines, and if it is, how much is there. Benzene levels in sunscreens sold in Australia must be below 2 parts per million (ppm). Although exposure at the levels detected would not be expected to cause serious adverse health effects and risks to users are considered low, the sunscreens are being recalled to ensure consumer safety. Specific products can be found on the website.
Medtronic Australasia Pty Ltd is updating the software for specified models of Cobalt and Crome Implantable Cardioverter Defibrillators (ICDs) and Cardiac Resynchronization Therapy Defibrillators (CRT-Ds). Medtronic is updating the software for the SmartSync Device Manager tablets, used by clinicians, to version 6.0.3 or higher. This will allow affected devices to then receive the necessary software update. The software update is required to address a software fault that may cause loss of pacing or inadequate CRT support and/or loss of the Recommended Replacement Time (RRT) indicator. These features can be restored with a SmartSync programmer session with your cardiologist. 0.3% of devices worldwide have experienced this problem. To date, no serious adverse events or permanent harms associated with it have been reported.
World Health Organization (WHO)
The WHO Pharmaceuticals Newsletter provides you with the latest information on the safety of medicinal products and legal actions taken by regulatory authorities around the world. It also provides signals based on information derived from the WHO global database, VigiBase, of individual case safety reports. In addition, the No. 1, 2022 edition of the Newsletter includes a short article on the recent Advisory Committee on Safety of Medicinal Products (ACSoMP) meeting.