SQA Regulatory Surveillance Summary | September 2020
By Laurel Hacche and Debra Cortner, SQA Associates
Eudralex – Volume 4 – Good Manufacturing Practice (GMP) Guidelines and Annexes
There were no updates noted for Eudralex – Volume 4 – GMP Guidelines and Annexes for September 2020.
European Federation for Cosmetic Ingredients (EFfCI)
There were no updates noted for EFfCI for September 2020.
European Medicines Agency (EMA)
Treatments and Vaccines for COVID-19, 02 September 2020
EMA has finalized 17 scientific advice procedures for potential medicines to treat COVID-19, with a further 22 ongoing (https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/covid-19-whats-new ). The agency has also been in contact with the developers of potential COVID-19 treatments and vaccines. The European Medicines Agency’s (EMA) is interacting with the developers to enable promising medicines to reach patients as soon as possible. It is also making use of real-world data to monitor the safety and effectiveness of medicines used in patients with COVID-19.
Remdesivir is a “viral RNA polymerase inhibitor” (a medicine that interferes with the production of viral genetic material, preventing the virus from multiplying) given by infusion (drip) into a vein. Remdesivir has been authorized in the European Union under the invented name Veklury, since 03 July 2020. Remdesivir has a conditional marketing authorization for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen.
Dexamethasone is a corticosteroid with anti-inflammatory and immunosuppressant effects. It is authorized at national level in the European Union (EU) and is used in a wide range of conditions, including rheumatic problems, skin diseases, severe allergies, asthma and chronic obstructive lung disease. EMA’s human medicines committee (CHMP) has concluded that dexamethasone can be used to treat hospitalized adults and adolescents with COVID-19 who are receiving respiratory support. It has endorsed the use of the medicine in patients from 12 years of age weighing at least 40 kg, when taken by mouth or when given as an injection or infusion. Companies that market a dexamethasone-containing medicine can request that this indication be added to their product’s marketing authorization. To do this, they should submit an application to a national medicines agency or to EMA.
Guideline on Registry-based Studies – Launch of Public Consultation, 24 September 2020
The EMA published a draft guideline for a three month public consultation. The new draft guidance aims to optimize the use of registry-based studies as a source of real world evidence. Patient registries are databases containing quantitative and qualitative data about patients who are affected by a particular condition. Studies based on patient registries generate real world evidence that can complement the knowledge gained through preclinical studies and clinical trials during the development of a medicine. Studies derived from patient registries can also provide information that is critical to understanding the benefits and risks of medicines in everyday use. The guideline addresses methodological, legal and operational aspects in the use of registry-based studies to support regulatory decision making. Stakeholders are invited to send their comments via a Microsoft Office document online form by 31 December 2020. Following the public consultation, comments from stakeholders will be analyzed and considered in the final document that will be published in 2021.
Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP), 14 to 17 September 2020
The EMA’s CHMP recommended seven medicines for approval at its September 2020 meeting:
- Exparel(bupivacaine), for the treatment of post-operative pain.
- MenQuadfi(meningococcal group A, C, W and Y conjugate vaccine), for prophylaxis against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W and Y.
- Supemtek(Quadrivalent Influenza Vaccine (recombinant, prepared in cell culture)), for prophylaxis against influenza.
- Obiltoxaximab SFL(obiltoxaximab), for the treatment or post-exposure prophylaxis of inhalational anthrax.
- Biosimilar medicine Nyvepria(pegfilgrastim) for reducing the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy.
- Generic medicine Rivaroxaban Accord(rivaroxaban), an anticoagulant intended for the treatment and prevention of venous thromboembolism, pulmonary embolism and the prevention of atherothrombotic events in adults with various risk factors for such events.
- Phelinun(melphalan), a hybrid medicine for the treatment of certain hematological and other cancers and as reduced intensity conditioning treatment prior to allogeneic hematopoietic stem cell transplantation in hematological diseases in adults and children.
The CHMP confirmed its recommendation to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA). This follows a re-examination of CHMP’s April 2020 opinion, which was requested by one of the companies marketing ranitidine medicines. NDMA is classified as a probable human carcinogen based on animal studies.
Joint Technical Notice by the European Commission, EMA and the Heads of Medicines Agencies (HMA), Technical Notice to Sponsors Regarding Continuous Compliance with the European Unition (EU) Legislation for Clinical Trials Following the Withdrawal of The United Kingdom from the EU, July 2020
Since 01 February 2020, the United Kingdom (UK) has withdrawn from the European Union and has become a “third country”. The Withdrawal Agreement provides for a transition period ending on 31 December 2020. Since no extension was requested as of 01 July 2020, there is no possibility for further extension beyond that date. Therefore, sponsors of clinical trials conducted in the EU Member States are reminded of the legal situation applicable after the end of the transition period as described in the Commission Brexit readiness notice regarding Clinical Trials. Most importantly, according to Article 13(2) of Directive 2001/20/EC, the qualified person has to be established in the EU/European Economic Area (EEA). Investigational medicinal products used in clinical trials can be imported only after their batch release has been certified by a qualified person (QP) in the EU.
Sponsors of all ongoing trials need to establish a QP in the EU. Failure to do so could, in the worst case, result in discontinuation of trial treatment, and thus jeopardize trial participants’ safety. In addition, according to Article 19 of Directive 2001/20/EC, the sponsor of a clinical trial or a legal representative must be established in the EU. For trials authorized in at least one Member State where the sponsor is established in a third country and with a legal representative in the UK, the sponsor needs to establish its legal representative in the EU by the end of the transition period. At the end of the transition period, the sponsor or its legal representative has to be established in the EU for all ongoing trials. Failure to meet this requirement will be a breach of Directive 2001/20/EC and could trigger a request for corrective actions by Member State competent authorities.
Health Product InfoWatch, Monthly Recap of Health Product Safety Information September 2020
The following is a list of health product advisories, type I recalls and summaries of completed safety reviews published in August 2020 by Health Canada.
Certain Hand Sanitizers that May Pose Health Risks
Health Canada advised Canadians that certain hand sanitizers were recalled because they either contain ingredients that are not permitted by Health Canada or are not properly labeled and are missing important information.
Prescription Cough and Cold Products Containing Opioids
Prescription cough and cold products containing codeine, hydrocodone or normethadone are NOT indicated for use in children and adolescents (younger than 18 years of age). There is a risk of opioid toxicity due to the variable and unpredictable metabolism of codeine or hydrocodone. The benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of opioids in these patients. Health Canada continues to work with the manufacturers of affected prescription opioid-containing products to include this new safety information in their respective Canadian product monographs.
Pharmascience Inc. recalled one lot of prescription PMS-Ranitidine (150 mg strength tablet) as a precaution after tests found N-nitrosodimethylamine (NDMA), a nitrosamine impurity, at close to the acceptable level. Health Canada also provided an update on the status of ranitidine drugs in Canada, including enhanced safety measures the Department is putting in place to detect NDMA. A table with detailed information on the recalled lot (lot 619003) is provided in the information update.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances
Q3D(R2) Maintenance Expert Working Group (EWG) Revision of Q3D(R1) for Cutaneous and Transdermal Products, 25 September 2020
ICH Q3D(R1) Elemental Impurities is a quality guideline for the control of elemental impurities in new drug products (medicinal products), and it establishes Permitted Daily Exposures (PDEs) for 24 Elemental Impurities (EIs) for drug products administered by the oral, parenteral and inhalation routes of administration. In addition, guidance is provided in Q3D(R1) on how to develop an acceptable level for EIs for drug products administered by other routes of administration. The Q3D(R2) Maintenance EWG is currently undertaking a maintenance of the Guideline to develop PDE levels for cutaneous and transdermal products (https://database.ich.org/sites/default/files/Q3D-R2_Step2_Extracts_Appendix-2-3-5_2020_0925.pdf).
The ICH E14/S7B Draft Questions & Answers (Q&As) Available now on the ICH Website, 27 August 2020
The ICH E14/S7B draft Q&A document on “Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential” reached Step 2b of the ICH Process on 27 August 2020 and now enters the consultation period. ICH S7B and ICH E14 describe nonclinical and clinical risk assessment strategies to inform the potential risk of proarrhythmia of a test substance and contribute to the design of clinical investigations. Emergent data over the past several years demonstrate that difference experimental results can arise for the same compound as a function of the study conditions used in nonclinical assays. From 15 to 16 October 2020, a public webinar will be held to provide an overview of the high level principles and rationale behind the new interconnected Q&As to ICH E14 and S7B and to answer questions received during the webinar. Further information can be found on the E14/S7B IWG page, including the Step 2 ICH E14/S7B draft Q&A document and the agenda for the public webinar.
Medicines & Healthcare Products Regulatory Agency (MHRA)
Letters and Drug Alerts Sent to Healthcare Professionals in August 2020, 23 September 2020
In August 2020, the following letters were sent or provided to relevant healthcare professionals:
- RoActemra (tocilizumab) 162 mg Solution for Injection in Pre-filled Syringe: Interim supply of Irish livery stock to mitigate supply disruption
- Fresenius Propoven 2% Emulsion for Injection or Infusion (propofol): Interim Supply of European Stock to Mitigate Supply Disruption
- Wockhardt UK’s Amoxicillin Sodium 250mg, 500mg and 1g powder for solution for injection: caution and monitoring requirements
As of 23 September 2020, the following has been provided to healthcare professionals to support the supply of medicines:
- Ativan 4mg/ml Solution for Injection (Lorazepam): Temporary supply of a different presentation and changes to the instructions (updated)
04 August 2020. A specific batch of Clexane 4,000IU (40mg)/0.4ml syringes has an error on the labeling affixed to the plastic blister packaging encasing the syringe (the label incorrectly states ‘Clexane 6,000IU (60mg)/0.6ml Syringes’). Stop supplying the products immediately and return to supplier. Inform patients who have been supplied this batch that the error is only with the labeling on the plastic blister packaging encasing the syringe.
10 August 2020. The listed batches of phosphates solution for infusion have been recalled due to observation of precipitation in one batch. Stop supplying the products immediately and return to supplier.
24 August 2020. Batch number A9306 has been recalled as a precautionary measure due to an out of specification result. Stop supplying the products immediately and return to supplier.
Class 3 Medicines Recall: Accord-UK Ltd, Digoxin Tablets BP 250 micrograms, EL (20)A/35, 03 August 2020. There is an issue related to decommissioning of a specific batch. Although there is no risk to product quality, any remaining stock should be quarantined and returned.
Class 4 Medicines Defect Information: Crescent Pharma Ltd, SyreniRing 0.120 mg/0.015 mg per 24 hours, vaginal delivery system, EL (20)A/36, 03 August 2020. The Patient Information Leaflet (PIL) within the packs for the listed batches are missing important safety relevant text changes. If dispensing any of the listed batches, ensure patients are aware of any missing information.
Class 4 Medicines Defect Information: SmofKabiven extra Nitrogen Electrolyte Free, EL (20)A/39, PL 08828/0269, 13 August 2020. There is an error on the bag labels for SmofKabiven extra nitrogen electrolyte free emulsion for infusion. Healthcare professionals should be aware that there is a product available with electrolytes and caution should be exercised when dispensing and administering this product.
MHRA Post-Transition Period Information, Guidance for Industry and Organizations to follow from 1 January 2021, 01 September 2020
As of 01 January 2021, the MHRA will be the UK’s standalone medicines and medical devices regulator. The transition from the EU allows the UK to offer fully independent regulatory decisions for both devices and pharmaceuticals, both nationally and in joint work with other international regulators. Stakeholders need to get ready for new rules by 01 January 2021. This webpage includes requirements for management of the transition for the following subject areas:
- Clinical trials
- Importing and Exporting
- Information Technology (IT) Systems
United States Food and Drug Administration (US FDA) – Guidances
Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry, September 2020
This guidance recommends steps manufacturers of Active Pharmaceutical Ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities. The recent unexpected finding of nitrosamine impurities, which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs), ranitidine, nizatidine, and metformin, has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence.