Thanks @DAB
Press release here from MHRA Batch of metformin oral solution recalled by MHRA due to nitrosamine impurity - GOV.UK
Class 2 Medicines Recall: Rosemont Pharmaceuticals Limited, Metformin Hydrochloride 500mg/5ml Oral Solution, PL 00427/0139, EL (21)A/20
Rosemont Pharmaceuticals Limited is recalling a specific batch of Metformin Hydrochloride 500mg/5ml Oral Solution due to the identification of an impurity above the acceptable limit.
During testing prior to batch release, levels of the impurity NDMA in batch number 0LL0018 of metformin oral solution were found to be within acceptable limits. However, routine monitoring of the batch while on the market showed that levels of NDMA were no longer acceptable at 9 months
Interesting find, NDMA issue observed on shelf life.
This perhaps is an indicator of potential risk assessments for Nitrosamines while initiating stability studies, stability screening for Nitrosamines during development
Sure @DAB , we’ve seen about organic peroxides coming from povidone that trigger an oxidation reaction. Now, to add injury to an insult we are facing a stability issue.
Hello @lucas10mauriz
Absolutely in agreement, we will perhaps continue to see Impurities of Genotoxic potential leading to Product recalls as the Regulatory focus on these Impurities & their impact on Product safety & efficacy gains momentum.
Going forward Pharmaceutical operations encompassing development, mfg, pkg, stability will require scrutiny wrt Risk Assessments, testing & control strategies.
Thank you for sharing, @DAB . I’m very interested in the root cause of NDMA in this case, because this Metfromin is not tablet but oral solution. When tablet, root cause of nitrosating agent was considered as nitrocellulose in ink or blister. However in oral solution, situation seems completely different from tablet.
Details are as follows;
Metformin Hydrochloride Oral Solution (Rosemont Pharmaceuticals Limited)
https://www.rosemontpharma.com/products/endocrine-system/metformin-hydrochloride-oral-solution
It looks contained in a brown grass bottle and stored under 25 degree Celsius until 12 months. From the point of formulation, solution is easy to generate nitrosamine compared to tablet. However I have no idea about the source of nitrosating agent which affects to the shelf life of this solution. What guys do you think?
Thanks @Yosukemino for sharing more details. The root cause could be due to some potential interactions between the excipients n active on long term exposure to Temperature n humidity or due to container closure issues at the prescribed stability conditions. Oral solutions employ vehicles, preservatives, antioxidants so depending upon the composition Of the formulation long term excipient interactions perhaps needs attention. It’s either the formula or container closure which could contribute on stability . This is what I could comprehend from the available information. Am sure the MAH would be in a better position to comprehend n investigate. Not sure if the RCs would get published in public domain owing to confidentiality n IPR issues.
Thank you @DAB for sharing your insight. I agree with you. There are lots of factors which should be focused on. And I add the Information of formulation found in the following link.
https://www.medicines.org.uk/emc/product/385/smpc#gref
I think the pH of this solution is one of the most important factor here. It looks buffered with phosphate salt. And I imagine the weak acidic condition of solution, mild storage condition and nitrite contained in certain excipients may cause trace amount of nitrosamine formation. Anyway I hope it will be disclosed for our investigation in future.
Yes @Yosukemino , the flavours and water also require attention. The flavours are many times mixture of complex synthetic compounds and colorants, essential oils, taste maskers n enhancers are also added and these components are not extensively controlled per GMPs . All excipients and their interactions with active and amongst themselves on long term exposure to Temperature and humidity require Investigation . The vehicle in this case is water so there’s a possibility of interactions happening in aqueous medium
Thank you @DAB . Yes, it’s a good point. Flavours are not considered identified risk by EFPIA in their decision tree, but risk assessment is very important.
Water is also the same, though purified water is less risky than tap water. As the manufacturer has identified the risk of nitrosamine contamination, some source of contamination certainly exist in this product. If it is not an identified root cause, it will be added to guidance in future. I want to pay attention to further information.
@lucas10mauriz do you have additional details that we could bring to a new discussion thread, I think this is a great insight
@Naiffer_Host, about the inhibition of nitrosamine formation in drug products, I think the discussion is more than fine. @DAB and @Yosukemino have present relevant points.
Once more, thanks for the exchange group initiative.
Thanks for the perspective @Yosukemino.
While the EFPIA Risk Assessment doesnot consider risks associated with flavours, am not sure how Regulators are going to be assured about the same.Routine QC testing of flavours mainly focusses on Appearance, taste & odour. Liquid formulations do pose a challenge wrt complex matrices as compared to solid orals & drug substance Risk Assessments, hence the hunt for Nitrosamines in these products must consider all aspects to rule out issues post authorisation.
As far as my experience goes, I have not seen MAHs testing the potable water or the raw water supplies for Nitrosamines. Nitrate is often checked as a qualitative parameter per pharmacopoeias so a RA would be essential to rule out presence of Nitrosating agents /Nitrosamines & also an evaluation as to whether the Ion exchangers & EDI process is capable to minimise/eliminate these ions in Purified water below levels where they can’t be of concern wrt Nitrosamine formation. Nitrosamine testing in water is very common in Food & beverage Industry.
For me the learning from this Recall is that Nitrosamines are not just a concern at product release but also need attention during shelf life & stability studies. Perhaps this needs attention as a Key process indicator as applicable depending upon process chemistry/capability, product matrices & Pkg materials. If the Risk Assessment indicates a high Risk then Nitrosamines should be included in the CQAs of the product both at release & shelf life.
One other key piece of information is that this was the only batch impacted according to the press release. Since all batches are formulated the same, that means this one batch was exposed to something different from the other batches. There’s no data about how many other batches were assessed; wording applies it is more than one. It will definitely be interesting to find out the root cause.
Thanks Elizabeth @ejdowse for sharing this update. It will be interesting to follow this Recall & its Investigation.