Nitrosamine Episode Could Lead To Paradigm Shift In Quality
Just How Well Do Companies Know Their Products?
Executive Summary
The detection of cancer-causing impurities in drugs with well-established safety profiles may force regulators across the globe to revise their approach for evaluating quality.
The discovery of carcinogenic nitrosamine impurities in certain well-established antacid and blood pressure medicines implies that drug companies do not fully understand their products. Incidents such as these should serve as a wake-up call for regulators to review their age-old models for quality evaluation and result in a paradigm shift in how drug impurities are qualified.
These were the conclusions of a discussion at a recent industry conference in a session on establishing Europe as a centre for regulatory excellence.
Against a backdrop of industry calling on regulators to embrace innovative concepts like artificial intelligence in drug development and evaluation, senior European Commission official Florian Schmidt said it was important not to lose sight of ongoing problems, such as improving affordability and problems with drug manufacturing oversight.
“We currently have a big problem with nitrosamines” being detected in medicines, said Schmidt, who is deputy head of the medicines policy, authorization and monitoring unit at DG Santé, the commission's Health and Food Safety Directorate General. According to Schmidt, such incidents raise the question of “whether our quality system is adequate and strong enough to discover these kinds of problems early enough.”
The commission official was speaking at the 2019 Annual Symposium of The Organisation for Professionals in Regulatory Affairs (TOPRA), which was held in Dublin, Ireland, from 30 September to 2 October.
Future Developments
Schmidt explained that he had raised the nitrosamine issue in the middle of a discussion on using artificial intelligence and algorithms to “reflect on the capabilities of manufacturers, who should have the full responsibility” for their products, including quality related aspects. The nitrosamine incident, he said, means it has to be asked whether “companies fully understand the products that they are producing” or whether they are simply “relying on third party suppliers” and have lost control over their product.
Placing greater reliance on artificial intelligence may have the same effect in the future, Schmidt said. For example, it might be valid to ask whether the marketing authorization holder understands the algorithms built into a product’s clinical development. This, Schmidt explained, is “quite a standard question” for quality-related aspects, but it may have to be “translated for future developments.”
“Do companies fully understand the products that they are producing or are they simply relying on third party suppliers?” – Florian Schmidt, European Commission
The nitrosamine incident is a global issue underpinned by cross-country supply chains. According to Schmidt, it highlights the fact that by allowing more diversification and more players into the drug manufacturing system, “we also create new risks and challenges for which we will have to find answers.”
Schmidt praised the way in which the EU has responded to the nitrosamine episode. This has included the European Medicines Agency asking sponsors of all medicines containing chemically-synthesized active substances to review their products for the possible presence of nitrosamines and to test all products at risk.
The EMA is also developing guidance to prevent nitrosamines in medicines and is investigating whether patients taking antacid ranitidine medicines are at any risk. While there have been some company-led recalls of ranitidine, most EU countries are waiting to hear from the EMA on its EU-wide investigation. (Also see "Ranitidine Recalls Begin As European Regulators Take Action" - Generics Bulletin, 18 Sep, 2019.) The “way we reacted,” showed the “strength of the [medicines] network,” Schmidt said.
Global Paradigm Shift In Quality
The EMA’s Anthony Humphreys explained that there was already consensus among regulators to investigate the issue more globally.
“That’s something that we will have to deliver collectively with the manufacturers and industry… because at stake is patients’ trust in the regulatory system” with regard to pharmaceutical products with established safety profiles that have been used in large volumes for 40 to 50 years, said Humphreys, who heads the EMA’s scientific committees regulatory science strategy division.
Humphreys believes the nitrosamine episode will involve a “very heavy investigation” and that the investigation has the “potential to go in many different ways.” He said the incident was a “sort of wake-up call for us perhaps to go back over some of the models that we have developed through the ‘70s, ‘80s and ‘90s on how we qualify impurities for which we have very nice guidelines” from the International Council for Harmonisation.
The nitrosamine impurities in ranitidine medicines came to light after a US-based online pharmacy, Valisure, conducted its own tests as a matter of routine. Valisure explained that it validates every batch of medicine it dispenses with “laser-based technology” that its “Harvard- and Yale-trained scientists” have developed. (Also see "FDA And EMA Evaluate Claims As Nitrosamine Worries Turn To Zantac" - Pink Sheet, 15 Sep, 2019.)
This is a… wake-up call for us to go back over some of our models on how we qualify impurities.” – Anthony Humphreys, EMA
Humphreys said this was not the first time that someone had applied a very sensitive analytical methodology to a pharmaceutical product “and found something that we weren’t particularly happy to know that it was there.” He explained that there were some very “high-tech detector-type systems that pick-up things that just aren’t in the mainstream, like finished product control or pharmacopoeial control… and it sort of challenges us every time.”
The challenge is not unique to the EU system. “We are in an era of global supply chains and we all know where active substances largely get manufactured… so we need these global responses” but, Humphreys added, that may be easier said than done.
Proper Risk Assessment
Pär Tellner of the European industry trade body, EFPIA, said it was reassuring that regulators were considering global collaboration on this issue. It’s a “difficult topic” and the “industry is very concerned by it”, he said. Before any regulatory action is taken, a proper risk assessment should be carried out to give priority to substances that are at the highest risk, Tellner advised.
Both Humphreys and Lorraine Nolan of the Health Products Regulatory Authority in Ireland believe that the nitrosamine episode will lead to changes in the quality paradigm.
“We are seeing more and more incidents of quality defects and manufacturing, and increasingly we are seeing more problems with APIs [active pharmaceutical ingredients]. While these are a consequence of many issues, but I think a change in paradigm in this area is what we are looking at,” said Nolan, HPRA chief executive.
Humphreys said he found the whole conversation “interesting” given that regulators were constantly being challenged to adopt innovative approaches to deal with quality issues concerning advanced therapies, continuous manufacturing and digitized controls. This all involves moving away from the more classical approach.
“While on the one hand, we are being asked to consider the very new, but then on the other hand, there still are issues with the well-established gold standard sort of risk management approaches that are throwing up issues [where we have to ask] ‘Hey guys, how do you account for this?’.”