Last week’s round -up;
05-09 July 2021
Ph. Eur. to put an end to rabbit pyrogen test
The Ph. Eur. Commission has decided to completely replace the rabbit pyrogen test (RPT) in the Ph. Eur. with a suitable in-vitro alternative, within approximately 5 years. The test was first published in the Ph. Eur. in 1986 and consists of measuring the rise in body temperature evoked in rabbits by the intravenous injection of a sterile solution of the substance to be examined. Most pyrogens are bacterial endotoxins and can be detected using the bacterial endotoxins test (BET) (Ph. Eur. general chapters 2.6.14 Bacterial endotoxins and 2.6.32 Test for bacterial endotoxins using recombinant factor C). However, non-endotoxin pyrogens may also be present in certain cases and these are not detected by the BET. General chapter 2.6.30 Monocyte-activation test (MAT), provides an in-vitro alternative to the RPT that is capable of detecting both endotoxin and non-endotoxin pyrogens. However, the RPT is still extensively used to detect pyrogens in favour of the MAT. There are also currently 59 Ph. Eur. texts that make reference to the RPT and the Ph. Eur. aims to replace the test for pyrogens for all these texts and eventually completely eliminate the RPT.
https://bit.ly/RealCMC-3qSw1fD
New FDA Studies Show No Post-ingestion NDMA From Ranitidine
In April 2020, FDA pulled all ranitidine products from the market due to the risk of contamination with the potential carcinogen N-nitrosodimethylamine (NDMA). Recently the FDA has led two studies which showed that NDMA is not produced in the human body after ingestion of ranitidine. One study involved a randomized crossover clinical trial of 18 participants who ingested either 300 mg of ranitidine or placebo and then ingested either a noncured-meats diet or a cured-meats diet. The study found no statistically significant difference in urinary NDMA levels between participants ingesting ranitidine or the placebo, thus, the presence or absence of cured meats did not affect urinary NDMA levels. The second study involved the addition of 150 mg ranitidine to simulated gastric fluid followed by the variation of gastric nitrite concentrations from the upper range of physiologic levels to supraphysiologic levels. The acidity of the simulated gastric fluid was also varied and it was found that “NDMA did not form when gastric nitrite concentrations were at the upper range of physiologic or at nitrite concentrations as much as 50-fold greater than the upper range”.
https://bit.ly/RealCMC-3jROfvZ
Updated EMA Nitrosamines Q&A
The EMA has updated its Questions and Answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. The following Q&As have been updated: • Q&A 3. For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? • Q&A 10. Which limits apply for nitrosamines in medicinal products?
https://bit.ly/RealCMC-3Ax4jsZ
Revised EMA Investigational Medicinal Products Dossier Guidance
The EMA has released the following revised guidelines with tracked changes for public consultation: · Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials. · Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. The changes bring the guidances into compliance with the Clinical Trials Regulation (CTR) and relate to the classification of a change to IMP/auxiliary medicinal product quality data to either a substantial modification (Art. 2.2.13), a change relevant to the supervision of the trial (Art. 81.9) or a non-substantial modification (changes outside the scope of substantial modifications and changes irrelevant to the supervision of the trial). The draft guidance documents are open for comments until the 31st August 2021.
https://bit.ly/RealCMC-3AmFS1o
https://bit.ly/RealCMC-3htKiLa
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Last week’s round-up;
19 – 23 October 2020
Reflection paper on pharmaceutical development for the geriatric population
The CHMP has adopted a reflection paper on the pharmaceutical development of medicines for use in the older population, which comes into effect as of 1st May 2021. The paper focuses on the design of medicines used in the elderly population, such as selecting appropriate routes of administration and dosage forms, dosing frequency, excipients, container closure systems, devices and technologies, and user instructions in the product information. Pharmaceutical developers are also encouraged to take a more patient-centred approach when developing medicines for the geriatric population. The EMA is seeking feedback from pharmaceutical developers who have applied the principles outlined in the reflection paper.
More details are available in the following link: https://bit.ly/RealCMC-3knv6Qb
Food contact materials safety and quality
The Committee of Ministers of the Council of Europe has adopted a new resolution on the safety and quality of materials and articles for contact with food, which supplements the relevant EU and national regulations. The aim of this resolution is to improve the protection of consumers from contaminants which may be released by materials in contact with food, including containers, work surfaces or packaging. Potential contaminants may include metals, antioxidants, stabilisers, colorants and plasticisers. The resolution also includes an annex with guiding principles for the implementation of suitable policies in member states and technical guidance for specific materials, such as paper and board, metals and alloys, coatings or silicones.
https://bit.ly/RealCMC-3m8D3ZW
EMA: Qualification of novel methodologies for medicines development
The EMA has announced the latest process for which the IRIS platform should be used for applications. This is the process through which companies should apply for scientific advice to support the qualification of innovative development methods for a specific intended use in the context of research and development into pharmaceuticals.
Details, including links on how to access the IRIS platform can be found under this link: https://lnkd.in/eVNixXw
Nitrosamine testing of Metformin-containing medicines
The EMA and national competent authorities (NCAs) are now asking marketing authorisation holders for metformin-containing medicines to test their products for carcinogenic nitrosamine impurities prior to their release on the market. This precautionary step is in line with the measures introduced by EMA’s Article 5(3) review to limit the presence of nitrosamines in human medicines, and is aimed at ensuring patient safety while the Authorities’ investigation on the impact of tests which detect NDMA in metformin medicines is ongoing. The EMA and NCAs have advised that MAH responses to this request will be monitored and that action will be taken if required.
http://bit.ly/RealCMC-3m8vYbF
Useful paediatric formulations for possible COVID-19 treatment
The European Paediatric Formulary (PaedF) Working Party is currently compiling existing knowledge on paediatric formulations for active substances under investigation as well as known authorised medicinal products that may be used for the treatment of COVID-19. The information that is being gathered by the Working Party includes paediatric formulations of active substances used in clinical trials and also experimentally in clinical practice throughout the world. The information will be published in tables on the EDQM website and will be continuously updated. However, the PaedF Working Party has stressed that it is not in a position to verify the quality of the listed formulations due to the exceptional circumstances brought on by the COVID-19 pandemic and also due to the limited knowledge available. The PaedF Working Party and the EDQM have also highlighted that it is the prescriber that is responsible for making individual risk assessments for each patient before using these potential COVID-19 treatments.
Tables for Dexamethasone and Lopinavir/Ritonavir are currently available and may be viewed at the following link: http://bit.ly/RealCMC-349uHLj
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Last week’s round-up;
15 – 19 June 2020
Ph.Eur. Supplement 10.3
The EDQM has published the contents of the Ph.Eur. Supplement 10.3. The list includes several new texts, such as the new monograph for testing bacterial endotoxins using recombinant factor C (2.6.32), as well as many revised general chapters and monographs. These new and revised texts will be implemented by 1st January 2021. Several corrected texts are also included in the list and these should be implemented by 31st August 2020. The list also includes texts that will be deleted from the Ph.Eur.
The entire list of contents of Supplement 10.3 may be viewed here: https://bit.ly/Realcmc-2BiFQxI
New EMA Bioequivalence Guidance for Levothyroxine Tablets and Abiraterone Tablets
The EMA has released the following draft product-specific guidelines: • A new bioequivalence guideline for Levothyroxine tablets 12.5 mcg, 25 mcg, 50 mcg, 75 mcg, 100 mcg (and additional strengths) and 200 mcg. • An updated bioequivalence guideline for Abiraterone tablets, which includes the addition of the 500 mg strength.
These draft guidelines are open for public consultation until 30th September 2020. https://bit.ly/RealCMC-2UVpfae
EMA, EC and Health Canada Confidentiality Arrangement
EMA, the European Commission and Health Canada signed a confidentiality arrangement in 2007. This was renewed in 2013 and 2020. The most recent changes introduced in 2020 include references to personal data legislation and to ensure the permanent validity of the arrangement.
The full document is available here: https://lnkd.in/gHugfvC
FDA testing methods to detect nitrosamine impurities in Metformin
The FDA has published two analytical methods that regulators and pharmaceutical companies may use to detect nitrosamine impurities in metformin APIs and drug products: • LC-HRMS method: an LC-MS method for the detection of NDMA in metformin drug substance and drug products. • LC-ESI-HRMS method: an LC-HRMS method for the measurement of amounts of eight nitrosamine impurities in metformin drug substance and drug products. Users are required to validate these methods if the resulting data is used to support a quality assessment of the API or drug product or regulatory submissions: https://bit.ly/RealCMC-3ftP7lh
Global regulators work towards alignment
The International Coalition of Medicines Regulatory Authorities (ICMRA) convened its regular meeting on 12 June 2020 to discuss high-level policy and regulatory approaches in response to COVID-19. They agreed that a clear distinction between exploratory clinical trials and confirmatory studies with investigational or repurposed medicines for treatment of COVID-19 is critical for prioritisation. Regulators also shared concerns about the discontinuation of clinical trials globally and the growing number of underpowered studies that might not generate the robust data required for decision-making. Full details of the output from the meeting can be found here https://lnkd.in/dgmFZgQ
EDQM companion list of training materials for vaccines
In order to support vaccine developers during the COVID-19 pandemic, the EDQM has made the Ph.Eur. quality standards for vaccines freely accessible through an online database on the EDQM website. Further to this, the EDQM has now also compiled a companion list of training materials related to vaccines. The document is intended for COVID-19 vaccine developers, including universities and small and medium-sized enterprises, with the intention to fast track their understanding of the Ph. Eur. and to help them to apply the relevant texts. The EDQM’s companion list includes hyperlinks to various presentations that were originally given at an EDQM Training Session on Biologicals held in February 2020 and any content of specific interest for vaccine developers is highlighted.
The list is not exhaustive and will be reviewed and updated as required. https://bit.ly/RealCMC-2BgwAd6
EMA and HMA news: Mandate of the European Innovation Network
EMA and HMA have issued an update to the document describing the mandate of the European Innovation Network (EU-IN), which seeks to coordinate and integrate views of national agency innovation offices and EMA’s Innovation Task Force for the early identification of promising developments, integration in the EU adaptive pathways, facilitate national designation of small and medium enterprises (SMEs) and to investigate the establishment of harmonised criteria for borderline products.
The full mandate can be found here: https://lnkd.in/dBXHQby
Last weeks round-up; 9 – 13 December 2019
EMA NEWS: PRAC SIGNAL ASSESSMENTS
In the six years since implementation of the pharmacovigilance legislation over 26,000 potential signals were reviewed, resulting in 453 signals assessed by EMA’s safety committee (PRAC). More than half of the PRAC recommendations resulted in changes to medicine product information supporting the safe and effective use of medicines. The system also proved responsive with recommendations for risk minimisation measures made in as little as five days of a signal being confirmed (median of five months). A recent article describes the process for signal management in place in the EU, and outlines the specific actions to rapidly communicate reliable information on the safety of medicines. The article can be found under this link – https://lnkd.in/d8evMMd
EMA UPDATE ON METFORMIN DIABETES MEDICINES
EMA update on metformin diabetes medicines On the 6th December the EMA issued a press release indicating that the levels of NDMA in the affected non-EU metformin medicines are very low and appear to be within or even below the range that people can be exposed to from other sources, including certain foods and water. Patients in the EU should continue taking their metformin medicines as normal. EMA will provide further updates as more information becomes available. https://lnkd.in/dKzYKru
