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GUEST EDITORIAL - By Guest Malcolm Holmes, PHSS Pharmaceutical Regulatory SME


It’s what we do


In the Pharmaceutical industry we discover new molecules with a potential to be used as medicines. Then we commence the long journey to turn that discovery into safe and effective medicines. All the time we should strive to gather knowledge which helps us understand and improve our products and processes, to ensure that the resultant medicines remain safe, effective and available to healthcare professional and patients.


But there are hurdles to overcome


Manufacturing issues leading to shortages


When a medicine becomes not available it is consequently of no use to the patient. From time to time firms experience manufacturing issues which can cause them to restrict or cease supply of a medicine until such issues are resolved. Regulators have in recent years placed a significant focus on need for reporting such shortages caused by such manufacturing issues and then steps being taken to alleviate the shortage as well as to prevent it happening in the future.


Product recalls arising from previously unknown product and process issues


Where a medicine is found to be sub-standard a common outcome following risk-based discussions between regulators and manufacturers is a product recall. Usually such events involve an individual batch or specific batches of a product which may be implicated. From time to time however the impact is much wider. For example, in 2007 it was noted that tablets of an antiviral drug VIRACEPT® (nelfinavir mesylate) exhibited a bad odour. This odour arose from ethyl mesylate – a genotoxic chemical. Product was recalled world-wide and the product authorisation in the EU was withdrawn by EMA and not reinstated until October that year. The investigation into the cause of the contamination of the product concluded that it had been caused by a reaction between ethanol, used in a cleaning process which was left in a manufacturing vessel subsequently used to hold methanesulphonic acid. An event such as this was very rare indeed.


More recently, in the summer of 2018 a U.S. drug manufacturer told the US FDA that it had discovered the impurity N-nitrosodimethylamine (NDMA) in a valsartan active pharmaceutical ingredient made its Chinese API supplier. Subsequently the FDA found NDMA and a similar chemical, NDEA, had contaminated certain valsartan APIs for years. The agency said the two contaminants, (both probable carcinogens) can form through specific and commonly used manufacturing processes.


Regulators worldwide were alerted and conducted their own investigations as well as jointly with the USFDA. Similar problems were identified with other Sartans and then in recent weeks with Ranitidine products. Multiple batch recalls have been undertaken as precautionary measures. These products are commonly used medicines and are often taken over long time periods by patients thereby potentially increasing the risk of harm.


On 11 November 2019 EMA issued a Q&A document on “Information on nitrosamines for marketing authorisation holders”. This 12-point Q&A indicates that all marketing authorisation holders (MAHs) of all human medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) should work with the manufacturers of their APIs and finished products in order to evaluate the risk of nitrosamines being present in their products, and take appropriate risk mitigating measures.


A risk-based prioritisation of products to be reviewed should be used and the outcome of the risk evaluation of all products should be concluded at the latest within 6 months of the publication of the Q&A i.e. by 11 April 2020.


Section 12 of the Q&A covers currently identified root causes for presence of nitrosamines. In this section the EMA has highlighted the involvement of agents such as sodium nitrite, and recovered solvents, but also reported that the use of certain packaging materials may contribute to contamination. Section 12, Point 8 notes that “Nitrosamine contamination has been observed by one MAH in a finished product stored in blister” and “the MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in the printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions”.


Since that time Metformin tablets (used as a regular medicine for diabetes) have also been potentially implicated.


Next steps


Readers attention is drawn to the EMA Q&A document which is available on the EMA website and which should be urgently and carefully reviewed for scope, methodology and timelines. The timeline for compliance is short and the clock has been ticking since 11 Nov 2019.


Further information can be found in the Regulatory Updates in this and previous editions of EJPPS as well as on the PHSS and Regulators websites. PHSS has also issued two Impact Statements on this topic the first in May 2019 and most recently in Nov 2019.

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