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The Sartan Contamination Story

There’s a chemical contamination story in the generic drug industry that just isn’t going away. Late last summer, some lots of valsartan were recalled due to detection of N-nitrosodimethylamine (NDMA), and the problem has just continued since then. We’ll get into the chemistry of this problem in a minute, but first off, looking at this situation in detail tells you a lot about the generic drug business. A key point is that there are often just a few sources of actual API (active pharmaceutical ingredient). Other companies buy this material and formulate it into capsules, tablets, etc., and then still more companies repackage these. The patented drug world, by contrast, is a lot easier to follow, since while a drug is under patent there’s only one company that’s authorized to market it. They may well have several suppliers for different starting materials or for different steps of their synthesis, but it’s at least one defined route managed by one company.

In this case, the valsartan recall was originally traced back to a problem with the material from Zhejiang Huahai Pharmaceuticals. That’s the Chinese manufacturer who made the API itself. There were originally two generic companies whose tablets included the ZHP material, Teva and Prinston. But the Teva material was sold by Major Pharmaceuticals and also by Actavis, while the Prinston was sold by Solco Healthcare – there are those three layers of API production, pill manufacturing, and repackaging. It turned out that there were nine more repackagers of the Teva and Prinston tablets, so valsartan packages under those other names were added to the recall list. But not all of them. To add the confusion, some of the packages from those companies were still OK, because they’d bought the tablets from more than one manufacturer. The recall had to be done by batch number. Meanwhile, Torrent Pharmaceuticals also emerged as a company who had bought the original valsartan API from Zhejiang Huahai, so their products went on the list as well.

But then the FDA found, while testing material from all over, that valsartan manufactured by Hetero Labs of India (and sold as Camber Pharmaceuticals tablets) also had NMDA contamination, so the problem wasn’t just that one manufacturing source in China. This takes us up to late October, and that’s then things really started getting messy. Another drug in the same angiotensin II antagonist class as valsartan (irbesartan) was found to be contaminated, but this time with the N-nitrosodiethylamine (NDEA) instead of the dimethyl compound. This was made by ScieGen, and again was repackaged under still more names. The API manufacturer for the ScieGen material was Aurobindo (of India), and they recalled material. Yet another compound in this class, losartan, turned out to have contaminated material also produced by ZHP, but since ZHP themselves had by that time already been placed on the FDA’s import restriction list, no more of that API was coming in.

Then Mylan pulled several lots of valsartan tablets, using API that they’d made themselves. Teva followed by recalling more lots of their product, since they’d also bought some of the Mylan API for manufacturing. Over the last ten days or so, Torrent and Aurobindo have expanded their own recall of material because of the second NDEA contaminant, and that’s where we are now. So what’s going on?

Well, any synthetic organic chemist will look at the situation and decide that (1) there’s a process chemistry issue, (2) it seems to apply to common chemical features of the “sartan” angiotensin II antagonists, and (3) it could well be related to some change in the synthetic conditions, because this all didn’t seem to be a problem before. And these are indeed the case, but the details don’t make anyone look particularly good. The common feature, in this case, is the synthesis of the tetrazole ring common to all the sartans. And the change apparently was a solvent switch to dimethylformamide (or presumably diethylformamide, in the cases where NDEA is the contaminant?) The dialkylformamides are often contaminated by small amounts of the corresponding dialkylamines, and they are well known to break down to give those (slowly) under heating.

But how do you get N-nitroso compounds from the amines, and why was the solvent switched? Well, the classic industrial syntheses of these molecules involved reacting an aryl nitrile with tri-n-butyltin azide (often formed in situ from the trialkyltin chloride). ZHP themselves appear to have introduced a cheaper, higher-yielding route using just sodium azide and zinc chloride in an aprotic solvent like DMF (here’s what seems to be the patent on that route). The excess azide is consumed at the end of the process using sodium nitrite – but nitrite under acidic conditions will give you some nitrous acid, and nitrous acid will react with secondary amines to give you N-nitrosoamines. That would seem to be the root of the problem.

Well, one of the roots. The second problem is that no one apparently picked up on the N-nitroso contaminants for years. ZHP probably brought this new process online around 2012, and it would appear that other manufacturers came up with their own variations on the route after that. The FDA and EMA have by now both detailed several analytical routes to assaying for the impurities, and the history of the recalls over the last few months is basically the history of more time spent testing more lots of material for what has probably been in there for some time.

That isn’t good, because N-nitrosoamines are definitely genotoxic, at least at high levels. We’re stepping off into a big toxicology argument at this point, because the genotoxicity of these things at lower levels is a matter for (heated) debate. It all depends on how the high-dose animal studies can be extrapolated down, how both high- and low-dose animal studies can be extrapolated to humans in general, and how to interpret human observational data (on, for example, the consumption of cured meats, which contain low levels of nitrosamines) in the presence of multiple other factors. Not least among these is the problem that some of the N-nitroso compounds are in foodstuffs themselves, while others are produced by gut bacteria. Everyone can agree, though, that large amounts of N-nitroso compounds are bad news, for some value of “large”. And everyone can agree that exposing yourself to such compounds for no reason at all is senseless.

The FDA’s standard is to be below an amount that would be expected (by their dose/response modeling) to cause 1 extra cancer case in 100,000 people who were taking the tablets at a standard dose for 70 straight years. That’s pretty stringent, considering the background rates of cancer in people who actually stay alive for 70 years in a row, especially when you factor in that no one goes on valsartan when they’re ten years old. Unfortunately, the ZHP material (according to the FDA) would be expected to cause one extra case of cancer with only 8,000 patients taking the highest dose of the drug for only four years, and that’s definitely unacceptable. It appears that the other manufacturers’ batches had contaminants at lower levels, from what I can see, although the amounts do not appear to have been specified.

So we’re going to have to think about the way that synthetic routes in the generic API business are monitored, it would seem. People seem to have missed that changing the chemistry for the sartans could lead to this problem, so what else are we missing? It’ll be tricky – generic drug synthesis is generally a low-margin business where people compete at least partially on price, so the companies are always looking for new routes that will give them an advantage. And as the present example illustrates, there can be many different manufacturing sources scattered over several different countries. But no one wants to see this sort of thing happening again, either. . .

57 comments on “The Sartan Contamination Story”

  1. A Nonny Mouse says:

    I have used the tin azide route once and would never like to do it again!

    The sodium azide/Zinc chloride (Sharpless) I have used many times and it is a great reaction, though I have always used water/IPA as the solvent. Presumably their intermediate isn’t as soluble under these conditions which is why they switched solvents (though I would always go for NMP as I have generally found that this increases the rate of reaction several fold under the same conditions when compared to DMF and doesn’t have the stability problems. Probably a cost thing here).

    1. Derek Lowe says:

      I would agree, since DMF (relatively speaking) is dirt-cheap.

  2. Emjeff says:

    This is not only a huge public health problem, but a fascinating issue from a scientific view-point. Although it needs to be solved, I foresee a slew of new regulations coming down on the industry, which may make it almost impossible to change a synthetic route. I’d like to believe that the FDA/EMA would propose some sensible focused regulation around this (something clearly needs to be done), but what we may end up with is a whole new regulatory morass. Have fun, chemists!

  3. editthatnmr says:

    One would think that dimethyl signal in the NMR would be fairly distinct from the other methyl functionality in Valsartan. The guys who were making this stuff must have knew something was up.

    1. Derek Lowe says:

      Levels would seem to be too small to be quantified (or perhaps even detected) by NMR, though. . .

      1. Ben T says:

        Is this an excellent argument for making FTIR routine again?

        1. Steve says:

          you wouldnt pick up 0.1% contaimination by FTIR. GC/MS should be the first port of call.

      2. t says:

        This issue with dimethylamine in DMF is well known and typically controlled through sourcing and strict release testing, which of course is costly, but doable at least in the world of branded APIs.

        1. DrOcto says:

          No matter the grade of DMF, often the reaction conditions will liberate dimethylamine in situ (as I have more than once experience to my own dissapointment).
          This leads to the question ‘where did the formaldehyde go?’ to which the answer is often ‘onto your free amine!’

          1. Ric says:

            It is not formaldehyde. It’s carbon monoxide. Some Pd Chemist actually use DMF as a source of CO in Pd-catalyzed Carbonylation reactions.

    2. eub says:

      It’s gonna be interesting to see what comes up in the discovery for the class action suits (and this sounds like a legit time for a class action suit). Did people raise concerns that were suppressed by management? Multiple producers, so it’s not just a single toxic organization. Multiple products. For six years. This really blows my mind.

      (Pretty sure I’ve shipped software that had a bug for six years, so I sort of see how this could be, but usually it was not active, the corner case was never reached for those years. Or it was ongoing but rare and non-repeatable and fell within the failure budget for a known transient failure. What’s the pharmaceutical synthesis equivalent?)

      Amateur question: would GC/MS have picked out the impurity at this level? But surely that had to have been run sometime so I can’t imagine.

      1. Thomas says:

        Software bugs may have a wildly varying impact. Let’s say bills come out too low (company loses money, and will generally notice), too high (customers complain, problem solved). If a route planner cannot go from A to B the user will not remain in A to die, but will work around the problem. Etc.
        For stuff where software is safety-related different standards apply. I understand that automotive safety related software can (apart from the main loop) only contain forward jumps (and I hope they check data dependencies as well).

      2. Analytical QC says:

        The GC they’re running for this is just for the known residual solvents. GTI levels are pretty low but possibly detectable but probably no one working in that shop cared about any peak other than the expected ones they have a standard for. Very easy to miss if you don’t care to look. They should have looked harder into this when they changed the route but I haven’t worked with a CMO yet that does more than the absolute bare minimum for anything analytical. The other question is how many situations like this are there that haven’t been found yet.

  4. loupgarous says:

    It’s a bigger health problem for some of us than others. My wife takes generic valsartan.

  5. cynical1 says:

    So generic manufacturers don’t have to register their synthetic route with their ANDA and any changes they make along the way thereafter?

    1. loupgarous says:

      Aren’t generic bioequivalency studies supposed to show that alternate syntheses of the generic form of a drug create something that works the same way?

      After this, bioequivalence testing for generics should probably include testing for genotoxicity. It doesn’t seem like too big an ask for FDA, EMA, etc to be consulted/asked for permission prior to any change in synthetic route for a generic, just to catch activity in unforeseen contaminants.

    2. A Nonny Mouse says:

      When a route change is made there are supposed to be 3 batches done to validate the process and this is incorporated into the Drug master File for submission.

      I assume that this small molecule has been missed as they were analysing mainly by HPLC. I would have thought that it would have been picked up in the head space analysis which checks for residual solvent levels.

      1. MagickChicken says:

        It probably did show up in HS, but at my CMO at least, we only quantify known residual solvents. I tell you what, though, I see some random unknown peaks that make me buy from other suppliers.

    3. Some idiot says:

      In a previous job, we (an originator company) found significant amounts of a totally new impurity in a generic supplier’s drug product. It had never been clinically qualified, and presumably not tox tested. We told the relevant authorities (in a western country) about what we found. We were told to mind our own business. No mention of further investigations or anything. To the best of my knowledge the material was never withdrawn from the market. So when I am told by a pharmacist that the generic is identical to the originator product, I say “how do you know? Who has done the analysis?”

      That is not to say I do not trust generics generally. There are really good generic producers, and there are, to put it politely, not so good ones. I only buy generic medicines from the good guys (rather, those ones I know to be good).

      1. hn says:

        So who are the good ones?

      2. Anonymous says:

        It is very difficult, but it is sometimes possible to protect yourself but still alert third parties to some problems. The WSJ exposed problems at Theranos (Dx, not Tx). Some legislators can be contacted.

        I know people who worked at US companies producing APIs for various customers. (It isn’t just the generics companies that outsource. Big Pharma sometimes outsources their APIs, too.) In one case, the technician reported a bad batch to the boss. The boss told her to sign off on it anyway. After further discussion, it came down to, “Either you can sign it now or I will sign it after you no longer work here.” The batch went out, as is. I had a friend at another company that shipped sub-spec material over his objections. Both companies no longer exist.

        Derek mentioned three steps (Production of the API; Pill prep; Packaging). At least for some items, one packaging company can make final products for more than one “brand” name. They just put different labels on the bottles or boxes.

        There can be good generics companies with good reputations at the consumer level, but they might not always know if they are getting product made with an impure API, a mis-formulated pill, or a bacteria or glass or metal-shavings contaminated product until after the fact.

  6. Curt F. says:

    Is there any other cheap (ish) way to neutralize azide other than nitrite? Would phosphite work? Is it likely that the whole mess has a technical solution or will folks have to go back to the tin-based process?

    1. milkshake says:

      there is no need to quench azide in situ with nitrite in the reaction mix with the product – they could have done it with mother liquors after acidification and precipitating the product, it is just that the process people are paranoid about the safety and they wanted avoid any chance of hydrazoic acid vapors – literaly a headache-causing problem for the operators who have to filter the stuff on scale

      Also, DMF decomposes to Me2NH and CO and H2O if you heat stuff in it too high. Dimethylacetamide does not have this problem, and it is also much easier to deal with than NMP.

      1. t says:

        Or they could have switched to a mixed solvent system and thrown in a PTC…

        1. milkshake says:

          PTC would not work for ZnBr2-catalyzed azide addition to aromatic nitrile

  7. John Wayne says:

    I’ve never seen any hard number on how much of this contaminant was really in there. Anybody seen this?

  8. Uncle Al says:

    The obvious solutions are for the drug to be co-taken with sufficient crisped bacon, or co-formulated with ascorbic acid (something your body needs anyway).

  9. luysii says:

    ” the genotoxicity of these things at lower levels is a matter for (heated) debate. It all depends on how the high-dose animal studies can be extrapolated down, how both high- and low-dose animal studies can be extrapolated to humans in general, and how to interpret human observational data (on, for example, the consumption of cured meats, which contain low levels of nitrosamines) in the presence of multiple other factors.”

    The other point to consider is that a little toxicity may actually be good for you. No one talks about hormesis presently, but it has been shown in several situations.

    Toxicology basically had two models of how we deal with toxic agents

    l. Threshold model — below a certain dose, no harm results. Arguably true — can one molecule of anything kill you? Used by the EPA for nonCarcinogens

    2. Linear no-threshold model — now matter how lot the dose, damage is seen. This is obviously crazy (see #1 above) but apparently is used by the EPA for carcinogens.

    Enter model #3 — Hormesis

    The best example is the famous J curve for alcohol in which small amounts are beneficial at low doses for the heart and huge amounts are horrible (although a recent meta-analysis has challenged this [ Lancet vol. 392 pp. 1015 – 1035 ’18 ], but I don’t trust them — for why see http://science.sciencemag.org/content/sci/361/6408/1184.full.pdf.

    Hormesis says that other toxic agents (radiation, cadmium, dioxin, saccharin, polychlorinated biphenyls) all have J curves like alcohol. Articles explaining hormesis can be found in — Nature vol. 421 pp. 691 -692 2003, Scientific American 9/2003. The reaction to it — Science vol,. 302 pp. 376 – 379, 2003.

    So the moral might be don’t be an immunological or a toxicological snowflake — that which doesn’t kill you makes you stronger.

    For another example of how a little stress (in the form of infection) could be good for you (with excellent clinical evidence) — see https://luysii.wordpress.com/2018/12/05/is-a-little-infection-good-for-you-if-so-what-about-radiation/

  10. Link to Valsartan structure in handle for those interested.

  11. Utopian says:

    Found an old DE patent from 30s (sorry! don’t have the exact reference at hand right now but it can be found with a Reaxys reaction search) describing a rather straightforward synthesis of NDMA and NDEA from the corresponding tertiary amines with nitrous acid, just conc. HCl and NaNO2 and said amine needed. Not quite sure how one alkyl group is cleaved, but if that’s legit, then any Et3N residues may potentially form NDEA during azide quench with nitrous acid. Also maybe a thing to be on the lookout for if one is planning to use nitrous acid in an API process…

    1. Chemamatic says:

      That sounds probably legit to me. My guess would be oxidation to the iminium ion followed by hydrolysis. Nitrous acid does dealkylate some amines, as will some other oxidants sometimes i.e. strong nitric, strong chlorine sources etc. It is one of those things you won’t find in textbooks because it is pretty substrate dependent and hard to do efficiently.

      1. Utopian says:

        Yes, this would seem right. Also, apparently losartan-containing medicines are now being recalled for containing NMBA (N-nitrosomethylbutylamine). I wonder if someone out there thought that switching the amine base will solve the problem, instead of thoroughly considering the overall azide quench process…

  12. BigSky says:

    In Prof. Electron’s link above there is a further link to this article>
    https://pubs.rsc.org/en/Content/ArticleLanding/2010/EM/c0em00216j#!divAbstract
    looking at wastewater levels of this and other drugs from hospitals…
    “The estimated daily mass loading of all measured cardiovascular APIs ranged from 0.87 g per day at the assisted living facility to 12.5 g per day at the hospital.”
    I hadn’t appreciated this aspect of the drug lifecycle in this way before. Holy crap.

    1. zero says:

      It’s a problem for closed loop water treatment, for sure. So are heavy metals. We have very little hard data on what these discharges are doing to the environment, which should be cause for concern.

    2. Anonymous says:

      Contaminated Drinking Water, too: link Boston Globe article in my handle.

      “Pharmaceuticals found in US drinking water.
      Trace quantities could endanger wildlife, humans.
      By Jeff Donn, Associated Press / March 10, 2008
      NEW YORK – An array of pharmaceuticals – including antibiotics, anticonvulsants, mood stabilizers, and sex hormones – have been found in the drinking water supplies of at least 41 million Americans, an Associated Press investigation found. … The investigation also indicates that watersheds, the natural sources of most of the nation’s water supply, also are contaminated. Tests were conducted in the watersheds of 35 of the 62 major providers surveyed by the Associated Press and pharmaceuticals were detected in 28.”

  13. Mike says:

    Doesn’t the FDA have to approve all changes to manufacturing before the product can be sold?

    In that case, either the FDA approved the synthesis change, but didn’t identify these impurities as potential concerns and the institute cut-off levels or the manufacturers went ahead and just changed the process without getting approval from the FDA?

    1. Anonymous says:

      “Doesn’t the FDA have to approve all changes to manufacturing before the product can be sold?” – I don’t know the current regs, but back in the late 1980s, the FDA approved a change in Showa Denko’s synthesis and purification of L-tryptophan (sold as a nutriceutical) without a lot of investigation or testing. S-D had a long successful history making and selling T, so the FDA took their word for it.

      After several deaths and thousands of cases of EMS (eosinophilia-myalgia syndrome), sales of T were suspended and it took a long to track down the problem to impurities in S-D’s T made by the new procedures.

      Many stories on the web, one linked in my handle.

      NOTE: Richard Wurtman, mentioned in the articles, was also the developer of the “Fen” half of Fen-Phen, the miracle diet drug which became another disaster from unintended consequences.
      content.time.com /time/subscriber /article/0,33009,985187-4,00.html

      1. willie x gluck says:

        “FDA approved a change in Showa Denko’s synthesis and purification of L-tryptophan …”
        Not correct. Dietary supplements get no manufacturing review!

        “Doesn’t the FDA have to approve all changes to manufacturing before the
        product can be sold?”
        Yes, that’s correct, but generally according to the ICH Q3 model, there is a threshold for inclusion in a specification, which is the ID threshold, and another threshold for qualification UNLESS there is deemed to be some special toxicity like genotox.

  14. VANA TURNER says:

    I’ve taken Losartan Potassium for 4 years.
    Was diagnosed with breast cancer in 2017.
    December 31st 2018 New Years eve cancer is back and now on my bones. There were no warnings on the medication about cancer, they just found this cancer causing ingredient in it and recalled it today Jan 4, 2019. Someone has be held accountable!!!

    1. An Old Chemist says:

      From Wikiedia:
      https://en.wikipedia.org/wiki/Valsartan

      Recall of some generic versions:

      On July 6, 2018, the European Medicines Agency recalled certain batches of valsartan and valsartan/HCT film-coated tablets distributed in 22 countries in Europe, plus Canada.[14] Zhejiang Huahai Pharmaceutical Co. (ZHP) in Linhai, China manufactured the bulk ingredient contaminated by N-nitrosodimethylamine (NDMA), a carcinogen. The active pharmaceutical ingredient was subsequently imported by a number of generic drugmakers, including Novartis, and marketed in Europe and Asia under their subsidiary Sandoz labeling, and in the UK by Dexcel Pharma Ltd and Accord Healthcare.[14] In Canada, the recall involves five companies and a class action suit has been initiated by a private law firm.[15][16] Authorities believe the degree of contamination is negligible, and advise those taking the drug to consult a doctor and not to cease taking the medication abruptly. On July 12, 2018, The National Agency of Drug and Food Control (NA-DFC or Badan POM Indonesia) announced voluntary recalls for two products containing valsartan produced by Actavis Indonesia and Dipa Pharmalab Intersains.[17] On July 13, 2018, the FDA announced voluntary recalls of certain supplies of valsartan and valsartan/hydrochlorothiazide (HCTZ) in the U.S. distributed by Solco Healthcare LLC, Major Pharmaceuticals, and Teva Pharmaceutical Industries.[18] Hong Kong’s Department of Health initiated a similar recall.[19] On August 2, 2018, the FDA published two lengthy, updated lists, classifying hundreds of specific U.S. products containing valsartan into those included versus excluded from the recall.[20] A week later, the FDA cited two more drugmakers, Zhejiang Tianyu Pharmaceuticals of China and Hetero Labs Limited of India, as additional sources of the contaminated valsartan ingredient.[21]

      In September the FDA announced that retesting of all valsartan supplies had found a second carcinogenic impurity, N-nitrosodiethylamine (NDEA), in the recalled products made by ZHP in China and marketed in the U.S. under the Torrent Pharmaceuticals (India) brand.[22]

      According to a 2018 Reuters analysis of national medicines agencies’ records, more than 50 companies around the world have recalled valsartan mono-preparations or combination products manufactured from the tainted valsartan ingredient. The contamination has likely been present since 2012 when the manufacturing process was changed and approved by EDQM and FDA authorities. Based on inspections in late 2018, both agencies have suspended the Chinese and Indian manufacturers’ certificates of suitability for the supply of valsartan in the EU and the US.[23]

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  16. eub says:

    Question from the peanut gallery: why isn’t a manufacturer required to sample product and test it for purity level continuously? You want quality, you monitor for quality, whether you make widgets or websites, isn’t that a truism? Even setting aside the deliberate process change, surprises happen.

    Or is that an “of course they do, you ‘why don’t you just’ programmer prat” but not effective here — how many 9s of purity can be assessed by analytical procedures that don’t need to know in advance what they’re looking for?

    A lovely article, Derek, breath of fresh air after the parade of news stories that are muddled whenever they’re not vague. I wish there were a browser plugin that linked a real explanation (curated by angels) whenever you see a science-related news story, especially health-related.

    1. Mike says:

      Manufacturers are required to test for quality throughout the entire process, from starting materials to final API. That’s what GMP regulations are all about.

      However, unless you know what too look for, you won’t find it. The impurities in question were also occurring at very low levels, so the product could still be 99.999% pure. It’s the 0.001% that’s the problem.

      1. Anonymous says:

        If you want a laugh, go look at Chemjobber’s FDA warning letter of the week. There’s rampant falsification of analyses, failure to follow SOP’s, and even refusing entry to inspectors in the API manufacturing industry.

        1. loupgarous says:

          One of our neighbors recommended a local herbal store to me because “they sell natural medication for cancer, and natural medications are better than that synthetic stuff they sell in drugstores”. I shrugged and we changed subjects.

          Well, their Web site attracted FDA’s attention big-time, because some of their “natural products” were “adulterated” with tianeptine, an atypical antidepressant sold in France, Bahrain, Latin America and Singapore, but not here in the US.

          Soooo… “natural” can mean “has an API FDA hasn’t approved yet”. Caveat emptor, folks.

      2. eub says:

        “However, unless you know what too look for, you won’t find it.”

        Okay, yeah, that’ll be tough to work with.

        I know your 99.999% / 0.001% was probably rhetorical, but is that level (five 9s) in the ballpark of what can actually be assured without knowing the identity of an impurity?

        Does anyone know what % nitrosoamine level we’re talking about in these? Or what the FDA’s “per 100K” threshold translates into?

        It would be interesting to get the picture like “LC/MS could have detected 1e-6 mole fraction of an impurity, but the FDA standard requires 1e-8 for this.”

        1. Dr. Nemo says:

          To eub: the 0.001% example is definitely not rhethorical. This is 10 parts per million of a genotoxic impurity in your active pharmaceutical ingredient, or 10 ppm. Depending on the daily dose and expected time of treatment (especially if the drug is expected to be taken for decades in case of a chronic condition) you may need to limit the content of your genotox impurity to single digit ppm or sub-ppm levels (in fact, this is a fairly routine situation). ICH guidelines give information on how to calculate what those specific limits need to be. You can develop analytical methods with single digit ppm and fraction of ppm detection limits for known impurities, but for the unknowns it is not a realistic proposition.

  17. CB says:

    I like the following story about contaminations in drugs:

    the birth control pills, which are being used for over 60 years, contain a progestin/estrogen combination. The positive effect of this combination was serendipitously discovered because of contamination of the first clinical batches of the progestin norethynodrel, which had to be clinically tested as ‘pure’ progestin for birth control.

    Thus, the initial chemical syntheses of the progestin norethynodrel had been contaminated with small mounts (1–2%) of the 3-methyl ether of ethinylestradiol (mestranol). When this impurity was removed later on, higher rates of unwanted breakthrough bleeding occurred. Realizing that the impurity was required for a reliable product the norethynodrel/mestranol combination was developed by G. D. Searle & Co to deliver the first birth control pill: Enovid.

    Hmmm, somebody suggesting now that the NMDA contamination in valsartan may be beneficial because N-nitroso compounds can activate arterial guanylate cyclase and relax isolated arterial smooth muscle………..

    1. loupgarous says:

      Serendipity isn’t likely to strike twice in the same place.

      A paper by Kadowitz’s group at Tulane reported on N-nitrosodimethylamine as an arterial guanylate cyclase activator, comparing it to glyceryl trinitrate and sodium nitroprusside and found it “devoid of vasodilator activity in vivo and exerted only minimal effects on isolated arterial smooth muscle tone or on arterial guanylate cyclase activity.”

      That same group moved on aGC activators such as the pyrazolopyridine compounds BAY 41-8543, BAY 41-2272, and BAY 58-2667 with much better luck.

  18. Scott says:

    So, why were people not using the one test method that would actually discover the problem?

    Wouldn’t Gas Chromatograph or Mass Spectroscopy be the cheapest way to test? And therefore the most desirable? Or is GC/MS slower than the other options?

    What am I missing?

    1. Anonymous says:

      What you are missing is contract API manufacturing companies not only don’t have sophisticated analytical equipment they have financial incentives not to use it.

      1. A Nonny Mouse says:

        Certainly that is rubbish for the 2 Indian companies mentioned. Never seen so many HPLC machines in my life than in Indian API manufacturer QC labs as they are selling so many products. I also expected them to be pretty ancient machines, but they were all the latest spec.

        CIPLA has a whole floor just for FDA submissions with their best people due to the requirements.

  19. FoodScientist says:

    This seems like it’s not an actual problem(doesn’t cause real world issues) and is purely related to how they calculate the extra cancer burden. low level genotoxicity would be concerning for children or people of child bearing age, but it seems unlikely for someone to actually develop cancer from it if they take it for the last 15 years of life. Does the FDA factor in some latency in development of the cancer when the do the calculations?

    Now, aflatoxin is something to be worried about. It seems like it’s been a pretty wet year.

  20. davetox says:

    As a toxicologist, I’ll note that N-nitrosodiethylamine is a carcinogen to be concerned about. Now, agencies like EPA and IARC label virtually anything as carcinogenic, it can be hard to decide what to be concerned about. Most nitrosamines are very dangerous.

    Derek mentioned nitrosamines in cured meats. When the US first started tracking cancer in the 1930s, stomach cancer was the top form of cancer. It still is in much of the world, while in the US, it’s not longer even in the top 10. This is almost entirely due to prevention thru better diets. While all the factors associated with the drop in stomach cancer in the US aren’t known, it is known that stomach cancer is highly tied to diet. While there are negative aspects of modern food, the cancer risk posed by food is far less than it once was. One aspect of this is thought to be less expose to nitrosamines in food.

    To the individual who got breast cancer after 4 years of losartan. Cancer usually occurs about 20 years after exposure (it’s called “latency”). Extremely high doses can cause it to happen more quickly, but the issue with drugs regards very low levels. Cancer within 4 years is not likely.

  21. Do you think this issue of carcinogens may be as old as 2012 since the change of process was initiated at that time? Knowing Hetero Labs also had the same impurities and since most API makers may have followed the economical production and changed the solvent, a thorough review of all sartan API makers is necessary?

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