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How Not to Do It

Got It All Ready For You, Mr. FDA Inspector

Many folks outside of this industry don’t realize that the FDA sends inspectors to drug manufacturing facilities in other countries. That might sound a bit odd, but agreeing to such inspections is in fact a condition of being able to sell pharmaceutical substances in the US (or to supply other companies that do). It’s a big job, and one feels sure that there are things that slip through the many possible cracks in the system – but still, it is good to see inspection reports like this once in a while that let you know that the system is catching clowns like this bunch (a facility in Gujarat state, India):

On October 24, 2018, our investigator observed torn documents of stability study data, analytical testing sheets, analysis calculations, and release forms that were placed into clear trash bags. Stability study documents for three batches of (b)(4) mg tablets were salvaged from the trash and compared to the official and approved records. Out-of-specification (OOS) results were among the data found, however the official results were recorded as within specification. Additionally, it was observed that blank stability study forms were prepared, pre-signed, and approved by the quality unit before recording the test data.

Um. That is not how you’re supposed to do QC. Heck, that’s not even how you’re supposed to cheat. Clear trash bags full of  torn-up evidence of doctored stability studies? That you didn’t even bother to finish throwing away? Pre-signed, pre-approved forms waiting for someone to fill in the numbers? Never fear, though, there is always a good explanation for such behavior:

In your response, you acknowledged the multiple trash bags containing torn quality control documents and the practice of signing documents before recording the data. You stated the torn documents were from scale-up batches in which you tore the documents so as “not to create confusion in the mind of the investigator.” Your response was inadequate. . .

Just a bit. How people get things like that out with a straight face is always a mystery to me; I’d think anyone with a sense of the ridiculous would find it betraying them at that point. The letter goes on to detail numerous other violations – such as the computers for the HPLC systems used for purity analysis sharing the same user name and password between the QC technicians and company executives, with that set to a high enough level that data could be deleted or modified. And that’s not the only piece of hardware with problems:

. . .our investigator observed (an apparatus) identified as “cleaned.” However, this. . .was found to have visible product build-up. . .Furthermore, the air filter of the equipment was damaged with multiple holes. This equipment was used to manufacture finished drug products shipped to the United States . . . Additionally, a memo provided during the inspection stated these cleaning and equipment maintenance deficiencies were because of a shortage in manpower related to a nine-day dancing festival and government holiday.

“Sorry we couldn’t clean the last drugs off the machinery; too many people were out at the dancing festival” is not an excuse that gets you very far. But hey, I’m sure everything was perfectly clean before the holiday, right? Hardly anything caked on at all. This place was apparently run under a sort of Screwtape Letters version of Good Manufacturing Practices (perhaps AMP, for “appalling”?) The company’s products have been declared adulterated under FDA regulations, you will be glad to hear, and are being refused entry into the US. The letter provides a road map to what they would need to do to get back into compliance, but needless to say it is a list longer than an NBA center’s leg. And even if they try to provide all this documentation, another comprehensive inspection is also very much in order. I know, it shows my suspicious nature to doubt the word of people who tore up all the out-of-spec analysis forms and stuffed them into trash bags before the last visit. It’s a hard business.

Note: Here’s a previous post on such inspections, which contained some pretty spectacular behavior as well, but there’s always more where that came from.. . .

36 comments on “Got It All Ready For You, Mr. FDA Inspector”

  1. electrochemist says:

    No surprise, and unfortunately probably inevitable when you have a general public who have been continually whipped into a frenzy by disingenuous media with their narrative that inexpensive drugs are “fundamental right” and no price is ever too cheap. Caveat emptor.

    1. Anonymous says:

      Let’s keep the blame for corporate misconduct where it belongs – on the corporation and its employees. Even if higher prices were being paid, there’s still every incentive to try and cut costs and increase profits. You don’t get to pretend this can be tied to agitation for lower drug prices in some markets.

    2. Tidal says:

      What an extraordinary logical leap. It is only in your fantasy world that manufacturing costs are the primary driver of drug prices. Plus the whole point is that people take issue with prices as they are now, so your comment makes no sense.

    3. AGJAG says:

      It should also be pointed out that this was a contract manufacturer. Who were they selling their products too? Shouldn’t these American Corporations buying from this company be named also? They are legally obligated to audit their supply chain and confirm that their CMO’s are following cGMP. Is someone like Walgreen’s buying generic drugs from facilities that it never audited, or that it did audit and approved even with horrible compliance?

    4. Lindsay says:

      Wait… that’s what you got out of this?!

  2. MTK says:

    If Bollywood movie finales are in any way indicative, one can see the disruptive power a dancing festival may have.

  3. Anon says:

    Dancing away to their approval! Hahaha…

  4. SirWired says:

    Definitely sounds like a call for more funding for the FDA for foreign inspections. (And an end to the frequent practice of those inspections being arranged in advance; yep, it’s hard for a non-native to get around many foreign countries, reliable interpreters are expensive, etc. but perhaps the answer is for user-fees for foreign manufacturers/suppliers to go up to compensate. (And the money from said fees to stay out of the General Fund.))

    I’m with you; what was that ridiculous response by the factory possibly supposed to accomplish? “We will cease manufacturing and selling drugs and drug components for export to the United States, effective immediately.” would have been sufficient, since the end-result would have been the same.

    1. loupgarous says:

      The appropriate response would be on the part of an overseas FDA inspector on hearing weak excuses (or any excuse) for departure from GMP –

      You will cease manufacturing and selling drugs and drug components for export to the United States, effective immediately.”

    2. MagickChicken says:

      No advance notice for audits? But my managers LOVE spending the day before an audit scouring the lab!

      To be fair, the FDA nailed our CMO with a surprise audit last year, and it turned up some fun things, like fake eyelashes in the screen in the compounder. . .

  5. A Nonny Mouse says:

    The first inspection that I observed was when I was working at a generic manufacturer in Spain. The guy was so observant; he spotted a pipe dead-leg in all of the pipes (this was chopped off and presented to him as a keep-sake!). He was nicknamed “Columbo” as there was always one more thing. By day 3 he was quite relaxed as he knew that everything was being done properly.

    About a year later he was inspecting a tabletting unit in the US which was supposedly using the above drug substance in their product, but he noticed a slight difference in the green of the pass label and called Spain who had only ever sold 25kg to this company (rather than the 20tpa which was 5 tons more than their production capacity). It turns out that this was Chinese material but it was being labelled as from the Spanish company as they had the best product on the market.

    Clearly, some of these guys are pretty good at their job!

    1. NJBiologist says:

      Based on my experiences in a GLP lab, I absolutely concur: some of them are extremely good.

  6. John Wayne says:

    It turns out that offshoring the production of medicines to save some money isn’t good for quality, supply chain stability or national security. Who knew?

  7. Jakob says:

    Talking about FDA. I would like to hear if anybody has a comment about the following:
    I recently heard that European companies can buy fast-track FDA inspection. Goes something like this: The FDA awards smaller upcoming US based companies permission to jump the line and get FDA inspection before everybody else (presumeably this is done to support local innovation?). But these permissions are then sold (big money) to big companies that in this way can get to marked faster. I guess, in principle there is nothing wrong in this. It just seems a bit strange that you can buy your way into getting any kind of special treatment by the FDA. Maybe the EMA does the same?

    1. Derek Lowe says:

      I wonder if you’ve heard a garbled version of the Priority Review Voucher system? That doesn’t have anything to do with FDA inspections, though, but your mention of getting to market faster makes me think that’s what it is.

      https://en.wikipedia.org/wiki/Priority_review#Priority_review_voucher_program

      1. Jakob says:

        Thank you.

  8. AnonEmuss says:

    Umm…what makes you think that conditions at US manufacturing plants are any better? The only thing missing is the 3 stooges attempt at fixing the data and batch records. There are innumerable stories out of sterile product manufacturing sites (the old Hospira – now Pfizer) for example. However, in the interests of being “fair and balanced”, a lot of this enforcement is a sneaky way to throw up trade barriers (the Japanese are the masters at that, claiming US beef does not meet their sanitary and health standards. Everyone is correct to a point here – there are completely unscrupulous actors overseas (just as here); inspections need to be funded better; prices need to be more rational to support the level of quality demanded; etc. etc.

    1. Bob Marlee says:

      At no point did Derek make any claims about the quality of American producers versus foreign, the post simply points out that representatives of the American government operate outside of the country to help ensure best practices are followed for products sold within the U.S. It then outlines the dubious practices and piss-poor excuses of an inspected manufacturer.

      1. AnonEmuss says:

        In no way am I disparaging or diminishing Derek’s posting…just highlighting that this is a widespread problem, distinguished overseas primarily by the amateurish cover-up attempts. And the whole issue is extremely complex, and anyone opining about it is correct, up to a point.

  9. bacillus says:

    I’ve heard rumours, that unlike in the USA when they can just knock at your door without warning, the FDA have to give several weeks of warning before inspecting a foreign manyfacturing plant. I’d be glad if someone could confirm or disavow this “claim”. Also, thank God for the FDA (and USDA) who often catch problems here in Canada before our own regulatory agencies. Just about everyone I know, including many scientists, believe that all generic drugs are made in shiny factories in North America or Europe. They are usually horrified to learn the truth. They’re more than happy to buy just about anything else from China or India without question, but baulk at the fact that most of their drugs are also made there. I’m guessing that this is a widely held belief throughout the west, but now sure how to burst these delusions on a grand scale. I take a generic statin that has had problems in the past, and I’d dearly love to know whether I’ve just been swallowing small pieces of chalk for the past 7 years.

    1. Fluorine Chemist says:

      “I’ve heard rumours, that unlike in the USA when they can just knock at your door without warning, the FDA have to give several weeks of warning before inspecting a foreign manyfacturing plant”

      From personal experience (by the way, I am based in India), that statement is false! Gone are those days when the FDA used to give a three month advance notice of an inspection. The last two audits I experience in our plants, we were given 48 hours notice – the inspector called us on Saturday late morning, informing us that the inspection is scheduled from Monday.

      In a couple of firms, the FDA knocked at the doors and started the inspection straightaway. So, yes, ‘surprise’ audits are becoming more common, at least in India.

      There are a couple of factors that may contribute to the observations mentioned above (no, I am not making any excuses, things have to improve, things will improve!):

      1. People still are coming to grips with Data Integrity and Good Documentation Practices. These concepts are not taught at college level here; people come to know these concepts only after they join industry.

      2. Taking shortcuts is something people do, when the attitude of upper management is to push the product through the door, no matter what (again, no excuses!).

      1. BiologyLabRat says:

        Yes and no. If the FDA has inspectors station in the country in question, they can inspect a facility unannounced at any time. Unfortunately the FDA hasn’t bee able to fully staff foreign offices due to budget cuts and often has to send domestically based inspectors overseas. Depending on the country, this may require getting a visa sponsored by the company to be inspected months ahead of time. Katherine Eban’s book “Bottle of Lies” details some of these issues.

        1. Pharma inspector says:

          If you are going to India (or Russia or China, etc), gone are the days when you need to apply for a visa months ahead of time with an invitation letter from the company. I have been traveling internationally for pharma companies since 2001, and I don’t remember this months-long wait since… 2004, and that was only a rare exception.

          For example, regarding India (where I am now for work) E-visa on arrival is now available. These can be obtained a minimum of 4 days before arrival. Even if you use the standard business visa, U.S. citizens can get a multiple entry visa for up to a maximum of 10 years’ duration, allowing one to enter the country at any time within that window.

          Travel related logistics and technology has been changing at a rapid pace in all countries, enabling fast access to entry for business and tourist visas.

  10. dearieme says:

    “I’d dearly love to know whether I’ve just been swallowing small pieces of chalk for the past 7 years.”

    If your mind is still clear, your memory good, and your muscles not prone to ache, it was quite possibly chalk.

  11. Cellsy says:

    I wonder how their inspections went at all these cell therapy clinics?

  12. Thomas McEntee says:

    While reading Derek’s post and the comments, the term “ethical drug” popped into my head. According to an article posted on the website of the Fiske Drug Discovery Lab at the University of Virginia Medical School (see https://pharm.virginia.edu/fiske/2015/10/26/the-ethics-of-ethical-drugs/) the term came into use in the mid-1930s and peaked around 1977. (I would have guessed it came into use around the turn of the 19th to 20th century) Surprisingly, in this new age of greed, win-at-any-cost , kick ’em when they’re down, and wealth disparity, the author claims it is coming back into use. We used to be able to produce everything here but things started going downhill in the early 1980s as ethical behavior began to be replaced by greed. And in this new age of bad behavior, I can’t imagine that any drug company supports a major increase in FDA Foreign Inspection Program funding.

    1. Anonymous says:

      McEntee: Your link is broken. You need a . after pharma and a . before the edu. (Maybe Derek can edit it?) That source found 1935 as the earliest use of “ethical drug” but I also think usage predates 1935 by several decades. Eli Lilly once included “The Ethical Drug Company” in their official logo. The founder, Eli Lilly, even stated that his company’s mission was to produce “ethical drugs” and that would be around 1876 – 1880s or so. I think they used “Eli Lilly – The Ethical Drug Company” until the 1980s when they promoted their new NSAID Oraflex. It hit the market in April 1982 and it was off the market by August 1982 following numerous deaths and other non-lethal complications. I believe that ~24 Lilly people were criminally charged. “In 1985 Lilly pleaded guilty to criminal charges that it failed to notify federal regulators about deaths and illnesses linked to Oraflex; the company was fined $25,000. The company’s former chief medical officer entered a plea of no contest to similar individual charges. A Justice Department report put the number of deaths the company had covered up at 28.”

      That would seem like a good time to drop “The Ethical Drug Company” part of the logo.

      1. Derek Lowe says:

        Fixed the URL – thanks!

  13. Young Padawan says:

    “How people get things like that out with a straight face is always a mystery to me;” reminded me of the following story:

    I don’t know if the Austrian government crisis made the US news a while back: In short, chancellor and vice had to resign a while ago because of a leaked video implying corruption. Now in this weeks news, a video of the former chancellor’s social media manager emerged shredding hard disks three !!! times. That already seemed suspicious to the company, but amateurishly enough he also “forgot” to pay the bill of around 70 USD and finally was recognized on TV standing next to the chancellor.

    His blatant statement: I was just shredding some unimportant hard disk that was hooked up to a printer.

    Anybody want to to tell stories of their printer hard disks?

    https://www.irishtimes.com/news/world/europe/hard-drive-affair-hangs-over-austrian-conservatives-1.3967472

  14. PhotoDeTox says:

    How about European drug administrations? I’ve heard the Swiss-FDA announces its visits well ahead of time… can somebody confirm this? Thanks good the FDA takes its job seriously. Since most producers want to access the US market the whole world profits from their inspections.

    1. Stephen says:

      Switzerland is not EU. Their regulatory body is named Swissmedic. Probably more tolerant than other EU authorities such as the very rigorous Italian AIFA (which by the way was the agency which discovered last year the issue of genotoxic impurities in sartans produced in India)

  15. m says:

    “Mr. FDA Inspector”

    Women can be FDA inspectors too.

  16. The Iron Chemist says:

    “Are you shocked Mr. Williams?”
    “Only at how sloppy your man works.”

  17. Me says:

    *lol* these always make me chuckle.

    Just wonder why people claim this is all about ‘generics’.

    These GMP facilities often churn out vast quantities of precursors for GMP material that is then coupled up and finished in-house in North America/EU etc. So when acid chloride A is coupled up to amine B in North America, acid A is manufactured in one of these facilities.
    Also, big companies like to reserve their facilities for their biggest, highest-risk products, so they look to get their products out into these facilities as soon as the products are established on the market.

    The whole story reminds me of a safety audit at one of my old med. chem jobs: the head of safety was one of these careerists who put himself forward for every committee because he wanted every opportunity possible to stick his tongue up the management’s hind parts. The company got a dummy audit from a guy who was mimicking a type of government inspection that could (super-rarely) happen on a med chem unit and our head of safety had a complete meltdown and started screaming at the auditor asking him why he felt he had the authority to question our safety practices when he’s not a chemist himself. Lots of new SOPs were developed quickly after that…..

  18. Nile says:

    There are some useful analogies around black holes, and one of them is the ‘Ethics Event Horizon’ that a company or institution or police force crosses when they pass through hiring and retaining amoral people despite their failings, and are promoting such people because of them.

    There can be no ‘reform’ of such an organisation: closure, blacklisting the directors, and starting from scratch is the only way forward.

    I do not doubt that the unnamed company in this post is still trading; and they are probably promoting their products with a public assurance that they have passed the most rigorous of inspections and can export to the USA. The only moral lesson that such men can learn is that they need to lie more boldly; and, on rare occasions, more skilfully.

    Is our country, or yours, becoming an easier place for such people and such companies to prosper?

  19. Joe says:

    Wired magazine just posted “8 Ways Overseas Drug Manufacturers Dupe the FDA”

    1. Serve Inspectors Contaminated Water
    2. Pretest Your Samples in Secret
    3. Change Any Data You Don’t Like
    4. Make Stuff Up
    5. Use a Secret Lab
    6. Allow Your Software to Crash
    7. Don’t Leave a Trail
    8. Take the Investigator Hostage

    Most of the items are clear to anyone following the industry news, but items 1 and 8 are “awesome.” The details behind item 6 are also pretty “cool.”

    One has to love the experience of these inspectors. If FDA has issues with recruiting good inspectors, the should shoot a recruiting video fictionalizing these experiences. These inspectors are living an exciting life.

    Here is the link:
    https://www.wired.com/story/8-ways-overseas-drug-manufacturers-dupe-fda/

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