「By 1995, Ranbaxy was the first company in」
「In an email to Robertson, the whistleblower Sunny described how Ranbaxy used hidden areas of the plant to store and cover up testing machines that were not connected to the company’s main computer network. He was referring to the crucial high-performance liquid chromatography (HPLC) machines, the workhorses of any good testing laboratory. The bulky machines looked like a stack of computer printers. Once a drug sample is mixed with a solvent, injected into the machine, and pressed through a column filled with granular material, the machine separates out and measures the drug’s components, including impurities. It displays them as a series of peaks on a graph called a chromatogram. In a compliant laboratory, HPLC machines would be networked with the main computer system, making all their data visible and preserved. During a recent inspection, Sunny wrote, the unauthorized HPLC machines were kept in two ancillary labs: 「Ranbaxy creates small such hidden areas where these manipulations can be done.」 Sunny estimated that some thirty products on the U.S. market did not pass specifications and advised Robertson that the agency needed to raid Paonta Sahib and Dewas, just as it had done in New Jersey, to find the evidence. He warned, 「The move has already started in Ranbaxy to share such details of problematic products personally and not on emails or letters.」 But because the U.S. Attorney had no jurisdiction in India, the FDA couldn’t execute a search warrant there. Robertson felt thwarted: 「People said, 『You need to go to India.』」 But her response was, 「What am I going to do [over there], knock on people’s doors and hope they talk to me? I don’t have authority over in India. It’s all a voluntary, good-faith system.」 The case had crashed like a wrecking ball into the overtaxed agency, exposing the fact that the FDA had no effective way to police a foreign drug company.」
「That very month, at the St. Louis Children’s Hospital, two young patients experienced strange and alarming symptoms. As they underwent dialysis, a lifesaving procedure to filter blood for those whose kidneys don’t work properly, the patients』 eyes started swelling, their heart rates escalated, and their blood pressure dropped. These were signs of a life-threatening allergic reaction. Dr. Anne Beck, the director of the nephrology unit, directed her staff to wash out the tubing with extra fluid before hooking the children back up to the dialysis machines. For the next two months, everything seemed fine. But in January 2008, the symptoms struck again. Beck contacted an epidemiologist specializing in children’s infectious diseases who immediately assembled a command center where a team worked around the clock to uncover the cause of the strange reactions. But as more children succumbed and the staff grew frightened, the epidemiologist notified the Centers for Disease Control and Prevention. The CDC immediately contacted dialysis centers in other states and learned of similar reactions elsewhere. As the CDC and the FDA began a joint investigation, their efforts pointed to a common denominator: all the sickened patients had been given heparin made by the brand-name company Baxter, the nation’s biggest heparin supplier. It was a drug that patients took intravenously during dialysis to ensure that they didn’t suffer blood clots. Within weeks, Baxter—at the FDA’s urging—began a sweeping series of recalls, until finally the allergic reactions stopped. Yet」
「the mystery was far from solved. Nobody understood why heparin—which is made from the mucosal lining of pig intestines, most of which come from China—was suddenly making patients sick. In February 2008, the FDA discovered the likely source of the contamination: a Chinese plant supplying crude heparin to Baxter. In a clerical blunder, the FDA had completely overlooked and failed to inspect the facility, Changzhou SPL, located about 150 miles west of Shanghai. Instead, it inspected and approved a plant with a similar-sounding name. Predictably, once FDA officials finally traveled to Changzhou in February 2008 to make an on-the-ground inspection, they found serious problems. The facility had dirty manufacturing tanks and no reliable method of removing impurities from heparin, and it acquired the crude heparin from workshops that had not been inspected. Chinese regulators were no help at all. A loophole in Chinese regulations allowed certain pharmaceutical plants to register as chemical plants, which made them subject to far less oversight. For U.S. congressional investigator David Nelson, whose committee was now immersed in the heparin crisis as well, the situation laid bare the 「classically good reason to be suspect of production coming from any country that doesn’t have competent regulatory authority.」 The FDA issued an import alert in March 2008, meaning that Changzhou SPL’s shipments would be stopped at the U.S. border. Though」
「investigators had identified Baxter’s heparin as the source of the contamination, and the Changzhou plant as deficient, neither the FDA nor Baxter could find any contaminant in the heparin. Urgently needing help to figure out what was wrong with its own product, Baxter reached out to Dr. Robert Linhardt, a chemist at Rensselaer Polytechnic Institute in Troy, New York, who had been studying heparin for years. He promptly sidelined his other work to dig into the mystery, and his laboratory joined several others working on the crisis. Stumped, the research teams finally turned to sophisticated nuclear magnetic resonance spectroscopy machines, which revealed evidence of a contaminant: a synthetic substance called oversulfated chondroitin sulfate (OSCS). The ingredient mimicked heparin, was almost impossible to detect, and produced life-threatening reactions. The FDA formally named OSCS as a likely contaminant in March 2008 and concluded that it had been added, somewhere along the supply chain, to increase the yield, and profitability, of the drug. The contamination exposed perilous gaps in the FDA’s oversight and intensified the long-simmering conflict between Congress and the agency.」
「In July 2018, a safety crisis rocked the global drug supply—and seemed to prove Baker’s point. Regulators in Europe announced a harrowing discovery: the widely used active ingredient for valsartan, a generic version of the blood pressure drug Diovan, contained a cancer-causing toxin known as NDMA (once used in liquid rocket fuel). The drug had been made by the Chinese company Zhejiang Huahai Pharmaceuticals, the world’s largest manufacturer of valsartan active ingredients. In the United States, over a dozen drug manufacturers, all of which used the Chinese ingredient, recalled their products, as did dozens more manufacturers around the world. The Chinese company tried to defend itself by explaining that it had altered its production process in 2012 to increase yields of the drug, a change that had been approved by regulators. In short, the change had been made to maximize profit. Some patients had been consuming the toxin for six years. As the FDA tried to reassure consumers that the risk of developing cancer, even from daily exposure to the toxin, was extremely low, a second cancer-causing impurity was detected in the ingredients. Though the valsartan catastrophe seemed to take the FDA by surprise, it shouldn’t have. In May 2017, an FDA investigator had found evidence at the plant in Linhai, China, that the company was failing to investigate potential impurities in its own drugs, which showed up as aberrant peaks in its test results. The investigator designated the plant as Official Action Indicated, but the agency downgraded that to VAI. In short, the company was let off the hook—only to wind up in the middle of a worldwide quality scandal less than a year later. By」
「With her suspicions aroused, Spreen began asking her Indian counterparts to send underlying data that supported their test results. They repeatedly promised that the information was on the way. When it didn’t arrive, she got excuses: it was a 「mess,」 they』d be 「embarrassed.」 She begged her colleagues in India, 「I don’t care if it’s written on the back of toilet paper. Just send me something.」 But no data came. Spreen kept thinking that if only she could explain American regulations more clearly, Ranbaxy’s executives would understand. But no amount of explaining seemed to change how the company did business. Indian executives approached the regulatory system as an obstacle to be gamed. They bragged about who had most artfully deceived regulators. When sales of a diabetes drug were sluggish, one executive asked Spreen if she could use her medical license to prescribe the drug to everyone in the company so they could record hundreds of sales. Spreen refused.」
「That sentiment seemed absent, and shockingly so. In a conference call with a dozen company executives, Spreen expressed her fears about the quality of the AIDS medicine that Ranbaxy was supplying for Africa. One of the company’s top medical executives responded, 「Who cares? It’s just blacks dying.」
「No market or type of drug was exempt, including antiretrovirals purchased by the United States and the World Health Organization to fight HIV in Africa. In Europe, the company used ingredients from unapproved sources, invented shelf-life data, tested different formulations of the drug than the ones it sold, and made undocumented changes to the manufacturing process. The PowerPoint also noted that the fallout from the Vimta audit, which had initially taken Kumar to South Africa, was already drawing the attention of regulators and could do further damage to the company’s reputation.」
「As Graedon scrutinized the FDA’s standards for bioequivalence and the data that companies had to submit, he found that generics were much less equivalent than commonly assumed. The FDA’s statistical formula that defined bioequivalence as a range—a generic drug’s concentration in the blood could not fall below 80 percent or rise above 125 percent of the brand name’s concentration, using a 90 percent confidence interval—still allowed for a potential outside range of 45 percent among generics labeled as being the same. Patients getting switched from one generic to another might be on the low end one day, the high end the next. The FDA allowed drug companies to use different additional ingredients, known as excipients, that could be of lower quality. Those differences could affect a drug’s bioavailability, the amount of drug potentially absorbed into the bloodstream. But there was another problem that really drew Graedon’s attention. Generic drug companies submitted the results of patients』 blood tests in the form of bioequivalence curves. The graphs consisted of a vertical axis called Cmax, which mapped the maximum concentration of drug in the blood, and a horizontal axis called Tmax, the time to maximum concentration. The resulting curve looked like an upside-down U. The FDA was using the highest point on that curve, peak drug concentration, to assess the rate of absorption into the blood. But peak drug concentration, the point at which the blood had absorbed the largest amount of drug, was a single number at one point in time. The FDA was using that point as a stand-in for 「rate of absorption.」 So long as the generic hit a similar peak of drug concentration in the blood as the brand name, it could be deemed bioequivalent, even if the two curves reflecting the time to that peak looked totally different. Two different curves indicated two entirely different experiences in the body, Graedon realized. The measurement of time to maximum concentration, the horizontal axis, was crucial for time-release drugs, which had not been widely available when the FDA first created its bioequivalence standard in 1992. That standard had not been meaningfully updated since then. 「The time to Tmax can vary all over the place and they don’t give a damn,」 Graedon emailed a reporter. That 「seems pretty bizarre to us.」 Though the FDA asserted that it wouldn’t approve generics with 「clinically significant」 differences in release rates, the agency didn’t disclose data filed by the companies, so it was impossible to know how dramatic the differences were.」
「The company’s problems with the FDA were far bigger than just the drugs intended for Africa. Ranbaxy had not properly tested the stability of almost any drugs on the U.S. market. The most basic good manufacturing practices require continuous monitoring of drug quality. Drug stability must be tested at intervals called 「stations」: three months, six months, nine months, and so on. So long as a drug is on the market, that data has to be filed in an annual report with the FDA. One is never out of data, because obtaining it is simply part of the process.」
「Graedon was sick of waiting for the FDA’s test results. He spoke with experts about what could produce the symptoms that patients were reporting. He even reached out for help to independent laboratories. Tod Cooperman, the president of ConsumerLab in White Plains, New York, was quick to join his cause. ConsumerLab tested the 300-milligram dose of Teva’s Budeprion XL against that of GSK’s Wellbutrin XL. The results revealed the likely source of patient distress: the generic dumped four times as much active ingredient during the first two hours as the brand name did. Graedon compared the effect to guzzling alcohol. 「If you sip a glass of wine over the course of two or three hours, you’re not going to feel drunk,」 he explained. 「But if you drink the whole thing in fifteen minutes, you’re getting too much too fast.」 The Graedons believed that this 「dose dumping」 explained why many patients were experiencing signs of overdose, such as headaches and anxiety, followed by symptoms of withdrawal, including renewed depression and suicidal thoughts. Teva flatly rejected the ConsumerLab report and claimed that the independent laboratory’s testing method was 「inappropriate.」 The FDA was silent.」
「Thakur still felt that he was groping in the dark. He needed numbers. Arun called in his executive assistant to help. Thakur asked the young man what percentage of the dossiers submitted to regulators contained data that did not match what the company had on file. The assistant was evasive: 「It . . . varies from region to region.」 「Give me an estimate in each region,」 said Thakur. 「How about in the U.S.?」 The assistant thought for a moment, then estimated, 「Perhaps between 50 and 60 percent?」 Thakur could barely breathe. Ranbaxy had faked over half its dossiers to the FDA? And that was one of the better regions? 「How about Europe?」 「About the same,」 came the assistant’s reply. 「And India?」 After some hemming and hawing, the assistant answered, 「100 percent.」 Testing the drugs for India was just a waste of time, he explained, because no regulators ever looked at the data. So the regional representatives just invented the dossiers on their own and sent them to the Drug Controller General of India (DCGI). What was needed for the DCGI was not real data but good connections, which they had, the assistant explained. The scale of the deception stunned Thakur. He felt physically sick thinking about the patients. Thakur told the men he wanted a breakdown: each product by year, and the problem with each dossier.」
「Little by little, as the team members stitched together small pieces of information, they stumbled into Ranbaxy’s secret: the company manipulated almost every aspect of its manufacturing process to quickly produce impressive-looking data that would bolster its bottom line. Each member of Thakur’s team came back with similar examples. At the behest of managers, the company’s scientists substituted lower-purity ingredients for higher ones to reduce costs. They altered test parameters so that formulations with higher impurities could be approved. They faked dissolution studies. To generate optimal results, they crushed up brand-name drugs into capsules so that they could be tested in lieu of the company’s own drugs. They superimposed brand-name test results onto their own in applications. For some markets, the company fraudulently mixed and matched data streams, taking its best data from manufacturing in one market and presenting it to regulators elsewhere as data unique to the drugs in their markets. For other markets, the company simply invented data. Document forgery was pervasive. The company even forged its own standard operating procedures, which FDA investigators rely on to assess whether a company is following its own policies. In one instance, employees backdated documents and then artificially aged them in a steamy room overnight in an attempt to fool regulators during inspections.」
「There was little effort to conceal this method of doing business. It was common knowledge, from senior managers and heads of research and development to the people responsible for formulation and the clinical people. Essentially, Ranbaxy’s manufacturing standards boiled down to whatever the company could get away with. As Thakur knew from his years of training, a well-made drug is not one that passes its final test. Its quality must be assessed at each step of production and lies in all the data that accompanies it. Each of those test results, recorded along the way, helps to create an essential roadmap of quality. But because Ranbaxy was fixated on results, regulations and requirements were viewed with indifference. Good manufacturing practices were stop signs and inconvenient detours. So Ranbaxy was driving any way it chose to arrive at favorable results, then moving around road signs, rearranging traffic lights, and adjusting mileage after the fact. As the company’s head of analytical research would later tell an auditor: 「It is not in Indian culture to record the data while we conduct our experiments.」
「It laid bare systemic fraud in Ranbaxy’s worldwide regulatory filings. 「The majority of products filed in Brazil, Mexico, Middle East, Russia, Romania, Myanmar, Thailand, Vietnam, Malaysia, African Nations, have data submitted which did not exist or data from different products and from different countries.」 Kumar’s document explained that while the company had slashed production costs and used the cheapest ingredients in those markets, it submitted data from the drugs that had been made for more regulated markets, a dangerous bait-and-switch that concealed the low quality.」
「The report also noted that active pharmaceutical ingredient (API) that failed purity tests had been reblended with good API until it met requirements.」
「The report noted the 「non-availability」 in India and Latin America of validation methods, stability data, and bioequivalence reports. In short, Ranbaxy had almost no method for confirming the content of drugs in those markets. For example, the data collected by Thakur’s team showed that of the 163 drug products approved in Brazil since 2000, almost all had been filed with phony batch records and stability data that did not exist. The report noted that in a majority of regulatory filings, Ranbaxy had 「intentionally misrepresented」 small research and development batches (some two thousand doses) as exhibit batches one hundred times the size, and then deceptively performed crucial tests for bioequivalence and stability on the smaller, easier-to-control batches. The result was that its commercial-sized batches had not actually been tested before being sold, putting millions of patients at risk.」
「In an email to Tempest marked 「confidential」 accompanying the report, Kumar noted that lack of adherence to regulation was only part of the problem. 「It appears that some of these issues were apparent over a year ago and I cannot find any documents which sought to address these concerns or resolve the issues.」 In closing, he made clear that his ultimate loyalties lay not with the company but with the truth. 「I can not allow any information to be used for any dossier unless fully supported by data,」 he wrote, adding: 「With your permission, I would like to take advice from legal counsel in London as to my current responsibility and indemnity with respect to the above issues.」 In response, Tempest assured Kumar that the company would do the right thing. Though the picture was grim, Kumar confided to Thakur that he believed he could fix the problems, if given the authority.」
「Thakur’s findings were not news to Ranbaxy’s top executives. Just ten months earlier, in October 2003, outside auditors started investigating Ranbaxy facilities worldwide. In this case, the audits had been ordered up by Ranbaxy itself. This was a common industry practice: drug companies often hired consultants to audit their facilities as a dry run to see how visible their problems were. If the consultants could find it, they reasoned, then most likely regulators could too. The fact-finding mission by Lachman Consultant Services left Ranbaxy officials under no illusion as to the extent of the company’s failings. At Ranbaxy’s Princeton, New Jersey, facility, auditors found that the company’s Patient Safety Department barely functioned and training was essentially 「non-existent.」 The staff had no written protocols for investigating patient complaints, which piled up in boxes, uncategorized and unreported. They had no clerical help for basic tasks like mailing out the patients』 samples for testing. 「I don’t think there’s the same medicine in this medicine,」 was a common refrain from patients. Even when there were investigations, they were so perfunctory and half-hearted that expiration dates were listed as 「unknown,」 even when they could easily have been found from a product’s lot number. An audit of Ranbaxy’s main U.S. manufacturing plant, Ohm Laboratories in New Jersey, found that the company, though required to report adverse events to the FDA, rarely did so. There was no system to capture patient complaints after hours, and no global medical officer to ensure that any potential negative consequences for patients were being monitored. The consultants from Lachman urged Ranbaxy to address these problems globally. Ranbaxy’s initial reaction to the findings was to question the number of hours, and the resulting invoice, that Lachman had sent for its work.」
「In 1883, a square-jawed, meticulous doctor from the Indiana frontier, Harvey Wiley, took over the division. At thirty-seven, Wiley was known as the 「Crusading Chemist」 for his single-minded pursuit of food safety. He rallied Congress, without success, to introduce a series of anti-adulteration bills in the 1880s and 』90s. By 1902, his patience worn out, Wiley recruited twelve healthy young men and fed them common food preservatives such as borax, formaldehyde, and salicylic, sulfurous, and benzoic acids. The diners clutched their stomachs and retched in their chairs. The extraordinary experiment became a national sensation. Wiley called it the 「hygienic table trials,」 while the press named it the 「Poison Squad.」 Outrage fueled the movement for improved food quality.」
「Patients tend to assume that their generic drugs are identical to brand-name drugs, in part because they imagine a simple and amicable process: as a patent expires, the brand-name company turns over its recipe, and a generic company makes the same drug, but at a fraction of the cost, since it no longer has to invest in research or marketing. But in fact, generic drug companies fight a legal, scientific, and regulatory battle, often in the dark, from the moment they set out to develop a generic. Mostly, their drugs come to market not with help from brand-name drug companies, but in spite of their efforts to stop them. Brand companies often resort to 「shenanigans」 and 「gaming tactics」 to delay generic competition, as the exasperated FDA commissioner Scott Gottlieb put it. They will erect a fortress of patents around their drugs, sometimes patenting each manufacturing step—even the time-release mechanism, if there is one. They may make small alterations to their drugs and declare them new, to add years to their patents, a move known as 「evergreening.」 Rather than sell samples of their drugs, which generic makers need in order to study and reverse-engineer them, brand-name companies will withhold samples, which in 2018 led the FDA to begin publicly shaming the companies accused of such practices by posting their names on its website.」
「To successfully launch a product, generic drug companies must tread in reverse through this obstacle course. Once a generic company zeroes in on a molecule, and its scientists figure out how it operates in the body, its lawyers get to work to establish how well protected it is legally. The next step takes place in the laboratory: developing the active pharmaceutical ingredient by synthesizing it into ingredient form. That alone can take several years of trial and error. Once successful, the finished generic has to take the same form as the brand, whether that be pill, capsule, tablet, or injection. Formulating it requires additional ingredients known as excipients, which can be different, but might also be litigated. Then comes testing. In the lab, the in-vitro tests replicate conditions in the body. During dissolution tests, for example, the drug will be put in beakers whose contents mimic stomach conditions, to see how the drugs break down. But some of the most important tests are in-vivo—when the drug is tested on people. Brand-name companies must test new drugs on thousands of patients to prove that they are safe and effective. Generic companies have to prove only that their drug performs similarly in the body to the brand-name drug. To do this, they must test it on a few dozen healthy volunteers and map the concentration of the drug in their blood. The results yield a graph that contains the all-important bioequivalence curve. The horizontal line reflects the time to maximum concentration (Tmax) of drug in the blood. The vertical line reflects the peak concentration (Cmax) of drug in the blood. Between these two axes lies the area under the curve (AUC). The test results must fall in that area to be deemed bioequivalent. Every batch of drugs has variation. Even brand-name drugs made in the same laboratory under the exact same conditions will have some batch-to-batch differences. So, in 1992, the FDA created a complex statistical formula that defined bioequivalence as a range—a generic drug’s concentration in the blood could not fall below 80 percent or rise above 125 percent of the brand name’s concentration. But the formula also required companies to impose a 90 percent confidence interval on their testing, to ensure that less than 20 percent of samples would fall outside the designated range and far more would land within a closer range to the innovator product.」
「After the active ingredients are manufactured, the additional ingredients chosen, and the principal laboratory and clinical tests conducted, the formula then moves to the manufacturing floor to see if it can be made on a commercial scale. As the manufacturing runs become larger, the processes become harder to control. If something can go wrong, it will. You can build a fortress of current good manufacturing practices around the drug-making process and still 「shit happens,」 as Malik liked to say. Conscientious manufacturers try to protect against past disasters and prevent new ones. But because manufacturing plants are operated by humans, the systems will break down, no matter how perfectly designed they are. For example, Johnson & Johnson’s epilepsy drug was fine until the company stacked it on wooden pallets that likely leached solvents into the medicine. At Mylan’s Morgantown plant, one lab technician left a note for another stating that he had to 「rig」 a hose on the equipment to get it to work properly—a word choice that easily could have shut down the plant had an FDA investigator stumbled across it and suspected fraud instead of primitive problem-solving. The only remedy for this variability is for plants to adhere scrupulously to good manufacturing practices and create real-time records of each drug-making step. The resulting data serve as a blueprint for finding and fixing the inevitable errors, a process that FDA investigators scrutinize. How well and how closely did the company investigate itself? The goal is to address a problem 「in a way that it never happens again,」 as Malik explained.」
「Thakur later returned home to find his three-year-old son, Ishan, playing on the front lawn. He suddenly recalled an incident from the previous year when the boy had developed a serious ear infection. The pediatrician prescribed Ranbaxy’s version of Amoxyclav, a powerful antibiotic. Despite his son’s taking it for three days, the boy’s 102-degree fever persisted. So the pediatrician changed the prescription to the brand-name antibiotic made by GlaxoSmithKline. Within a day, Ishan’s fever was gone. Thakur took the boy in his arms, resolving not to give his family any more Ranbaxy medicine until he knew the truth.」