EU Regulatory Roundup: EMA Expands Nitrosamines Investigation to All Chemically Synthesized APIs

RoundupsRoundups | 03 October 2019 |  By 

Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Expands Nitrosamines Investigation to All Chemically Synthesized APIs
The European Medicines Agency (EMA) has asked manufacturers of medicines made with chemically synthesized active pharmaceutical ingredients (APIs) to test their products for nitrosamines. EMA’s request follows the discovery of the carcinogenic contaminants outside the sartan class of drugs.
Nitrosamines, such as N-nitrosodimethylamine, were initially found in sartans but were subsequently detected in ranitidine medicines. The contaminants have also been found in low levels in a batches of pioglitazone produced by Hetero Labs, indicating the potential for the carcinogens to affect products other than sartans and ranitidine medicines.
EMA thinks the risk of other classes of medicine being contaminated is low, as they lack the tetrazole ring structure that is linked to the generation of nitrosamines. However, EMA wants manufacturers of other types of medicines to look for the contaminants as they can enter products via other routes.
“It is now known that these impurities can form during production under certain conditions and when certain solvents, reagents and other raw materials are used. In addition, impurities can be carried over during the manufacturing process when using already-contaminated equipment or reagents,” EMA wrote in its letter to manufacturers.
EMA wants finished product manufacturers to source information from their API suppliers about the potential for nitrosamine contamination, either because the carcinogen is formed during production or transferred from equipment or reagents used to make other ingredients. Companies have six months to evaluate the risk of nitrosamine contamination.
If a company discovers nitrosamine contamination, EMA wants it to inform authorities “promptly” so actions can be taken. Companies affected by contaminants will need to make changes to address the risk. EMA wants the whole process to be completed within three years. By prioritizing high-risk APIs, EMA hopes to mitigate the threat posed by the most dangerous products before then.
EMA Notice, Letter
Ireland to End Falsified Medicine Implementation Phase in February 2020
Ireland’s Health Products Regulatory Authority (HPRA) is set to end the “use and learn” phase of the Falsified Medicines Directive (FMD) implementation on 31 January. The use and learn period will end “on a phased basis” starting on that date.
HPRA expended the original September deadline for the end of the use and learn period last month but shared scant details about the next steps. Now, HPRA has provided additional information, telling the industry that the current approach, which is more about monitoring than enforcement, will stay in place until next year. FMD will properly come into force once the use and learn period ends.
“After the use and learn period ends, every single alert will have to be investigated and the risk of the pack being falsified must be ruled out before it can be supplied. It is therefore critical to ensure that all avoidable alerts are eliminated early before the use and learn period ends to minimise disruption for everyone, especially patients,” HPRA wrote in its latest notice.
The alert rate has fallen from 20% to 1.6% during the use and learn period, in part because using the system has generated insights into how to eliminate avoidable errors. HPRA wants to bring the alert rate down further still by the end of the use and learn phase and has called on organizations affected by FMD to “intensify” efforts to address the underlying causes of false alarms.
HPRA lists incorrectly uploaded pack data, software issues at pharmacies, wholesalers and hospitals, incorrectly configured scanners and user errors as among the causes of alerts. The Irish Medicines Verification Organisation plans to raise awareness of these underlying problems and how to fix them over the coming weeks. Irish authorities will also create a national procedure detailing how to review and close out alerts.
HPRA Notice
MHRA Writes to Industry About Converting to UK Marketing Authorizations
The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) has written to the pharma industry about converting marketing authorizations. MHRA sent the letters to follow up on a statement about preparing for a no-deal Brexit that it issued at the start of the year.
In the original letter, MHRA outlined the grandfathering process by which it will convert centrally authorized products (CAP) to UK marketing authorizations. The letter featured a list of steps MHRA wanted marketing authorization holders (MAHs) to take to increase the likelihood of the process going smoothly.
Now, MHRA has sent three different letters to the heads of regulatory affairs departments at MAHs that sell medicines in the UK. MHRA has sent one of the letters to companies that failed to reply to its original communication.
The agency has asked these companies to run through a list of steps that cover ground similar to its original letter. MHRA wants the companies to check that its list of CAPs that need converting is right and provide it with a single point of contact for all the products on the list. MAHs can opt out of the grandfathering process by writing to MHRA by 21 November.
One of the other letters went to MAHs that replied to MHRA’s original communication. MHRA wants these MAHs to let it know if they have received a new European Union product license since 29 March, the date on which Brexit was originally due to happen.
The third letter issued by MHRA is targeted at companies that have pending centralized applications. MHRA has provided guidance for companies in this situation but also plans to offer more active support. The agency plans to arrange telephone calls with the affected companies to help it prioritize applications “that are at the later stages of assessment.”
MHRA Correspondence
France Moves to Slash Regulatory Review Times for Production Plants, Medicines
The French National Agency for Medicines and Health Products Safety (ANSM) has detailed plans to cut the review time for some regulatory processes by one-third. ANSM aims to process filings related to new manufacturing facilities and innovative medicines in 60 days, down from 90 days today.
The plan grew out of measures published last year intended to simplify the formalities involved in setting up as a drug company in France. In order to meet the truncated timeline, ANSM wants companies to contact it three months before they submit their application.
ANSM shared details of the new procedure alongside news that it has created an online portal. The portal will support the electronic processing of certain administrative procedures. ANSM is accepting filings either via the portal or on paper until the end of the year. After that, ANSM will make use of the portal mandatory.
ANSM Notice (French)  
Other News:
EMA has clarified that companies should only add the qualifier “liposomal” or “pegylated liposomal” to the invented names of products if there is a clear risk of medication errors. The clarification comes shortly after EMA asked manufacturers of medicines containing liposomal drug delivery systems to request name changes. EMA Notice
MHRA has advised that an extra processing step will apply to companies that request a Certificate of Pharmaceutical Product (CPP) for currently centrally authorized products. The process for seeking a CPP will otherwise be unchanged in the event the UK leaves the EU without a deal. MHRA Notice
ANSM has taken action against an organization accused of conducting an illegal clinical trial. ANSM Notice (French)


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