Hydrocortisone
Mid 2018 – Recap of Warning Letters, Import Alerts and Non-Compliances
In our mid-2018 compliance review, we look at inspection challenges faced by companies across the world. In the first half of this year, manufacturing compliance challenges dominated headlines. But we also saw shortcomings at major pharmaceutical companies like Pfizer, Bayer and Akorn generate news. While China, India and the US continued to be the top three countries where regulators uncovered compliance issues, this year has also seen the FDA take action against many South Korean companies. The European authorities found concerns in India, Taiwan, Italy and Spain. However, there were no non-compliance reports issued to firms in China until the end of June 2018. While data-integrity violations and a failure to thoroughly investigate deviations continued to remain a major concern for inspectors, this year the real concern emanated from the supply of product to market (which had the potential to impact product quality or patient safety). Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! China: API with a cancerous impurity, vaccine scandal and data-integrity woes   The most recent regulatory non-compliance issue pertains to the European Medicines Agency (EMA) raising concern over the active pharmaceutical ingredient (API) valsartan supplied by China’s Zhejiang Huahai Pharmaceuticals. The concern was the impurity — nitrosodimethylamine (or NDMA) — detected by the company in their valsartan API. NDMA is classified as a probable human carcinogen and its presence was unexpected as it was not detected by routine tests carried out by Zhejiang Huahai. Zhejiang Huahai sold over US$ 50 million of the API in 2017 and supplies to most major manufacturers producing valsartan medicines available in the EU and United States. While a review is underway, national authorities across the EU, US and Asia are recalling medicines containing valsartan supplied by Zhejiang Huahai. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! Vaccine scandal: A major vaccination scandal has sparked off a huge outcry in China as vaccine maker Changsheng Biotechnology was found to have falsified production data for its rabies vaccine. Changchun Changsheng Bio-tech Co, in Changchun, reported serious irregularities, including fabricating production records in the manufacture of rabies vaccines for human use, during an inspection by the State Drug Administration, China FDA said in a statement. Although there has been no evidence of harm from the vaccine, the firm has been ordered to halt production and recall rabies vaccines. And Chinese Premier Li Keqiang has urged severe punishment for the people involved, saying the incident had “crossed a moral line”. Data-integrity violations: This year, the FDA also posted the warning letter issued to Henan Lihua Pharmaceutical in China, a company that produces steroid APIs like hydrocortisone and prednisone. The warning letter highlighted data integrity concerns that landed Henan on FDA’s import alert list in March 2018. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! During the inspection, the FDA investigator observed numerous blank batch manufacturing records in an open cabinet in the firm’s manufacturing workshop office. Among these was multiple blank, product release forms marked with a red quality assurance release stamp stating ‘Permitted to Leave [the] Factory’. The FDA also posted a warning letter issued to Jilin Shulan Synthetic Pharmaceutical, a manufacturer of caffeine API in China. The letter revealed flagrant data-integrity violations. Another warning letter was issued by the FDA to API manufacturer Lijiang Yinghua Biochemical and Pharmaceutical, following an October 2017 inspection. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!   United States: Drug shortages due to Pfizer’s manufacturing problems    Drug major Pfizer’s production problems continued to make headlines this year. An article in Fortune put the blame on Pfizer’s much-touted US$ 17 billion acquisition of Hospira in 2015 for turning the United States’ chronic drug shortage into a full-blown crisis.  According to the article, as of May 11 this year, Pfizer — which is the world’s largest maker of sterile injectable drugs — had 370 products that are depleted or in limited supply, 102 of which the company has indicated will not be available until 2019. “The simple answer to why America currently has so many shortages of generic sterile injectable drugs: America’s leading manufacturer of generic sterile injectable drugs hasn’t been making them,” the article said. Mylan’s flagship product EpiPen is also likely to face shortages due to problems at Pfizer. Although Mylan owns the rights to the EpiPen, it subcontracts manufacturing of the auto-injector to Meridian Medical Technologies, a division of Pfizer. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! While Mylan is putting pressure on Pfizer to do more to tackle shortages of this life-saving medicine, Pfizer has struggled to meet demand for the EpiPen and the FDA had put the medicine on its official shortages list. In September last year, the FDA had issued a warning letter to Meridian Medical Technologies over serious component and product failures that had been associated with patient deaths.  Pfizer’s troubles are far from over as an FDA inspection of an ex-Hospira sterile manufacturing facility in India resulted in the issuance of a 32 page Form 483.  The same facility was issued a warning letter  by the FDA in 2013. Germany: FDA highlights contamination, data-integrity concerns at Bayer facility   In a shocking warning letter issued by the FDA to Bayer Pharma’s finished pharmaceuticals manufacturing facility located in Leverkusen, Germany, investigators found compliance shortcomings ranging from concerns over data-integrity to serious product contamination problems.   While reviewing a drug product manufacturing operation, FDA investigators found residue on equipment which seemed most likely from a drug product that had been previously processed in the same room. When Bayer tested the samples of the tablets being produced to “assess the potential of cross-contamination”, the testing confirmed contamination of the previously processed product inside the tablets which resulted in a recall of several lots of drug products. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! Before the FDA inspection, Bayer had started its own data-remediation program to discontinue the practice of using “test” injections during testing. However, when the FDA investigators performed their own inspection, they found unreported data from in-process tablet weight checks. Bayer’s staff had programmed their in-process weight checker not to report values that varied more than a specified amount from the tablet target weight. The inspection was held between January 12 and 20, 2017, and responses submitted to the FDA in May and August 2017 failed to address the concerns of the agency. Fresenius aborted US$ 4.3 billion takeover of Akorn: ‘Blatant fraud’ or buyer’s remorse?   This year also saw German healthcare group Fresenius abandon its US$ 4.3 billion takeover of US generic drugmaker Akorn over data-integrity concerns. Illinois-based Akorn filed a lawsuit in the Delaware Chancery Court asking that Fresenius be required to “fulfill its obligations” under the buyout agreement. In a court filing made public, Fresenius alleged that its investigation uncovered “blatant fraud at the very top level of Akorn’s executive team, stunning evidence of blatant and pervasive data integrity violations.” Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! Akorn’s lawsuit acknowledged it investigated the possible submission of falsified data and fired an executive who was involved. Fresenius claims the executive involved in the fraud wasn’t fired. Instead, he was suspended and given a consulting position with a US$ 250,000 salary. The executive, whose name is redacted from the court filings, stands to receive a payout if the merger is consummated.  The most significant instance of a data integrity issue involves an ANDA for the drug product azithromycin that was pending with the FDA, which Akorn had submitted on December 21, 2012. The court will decide if the data-integrity concerns are truly legitimate or being blown out of proportion by Fresenius, who may be suffering from buyer’s remorse and wants to exit the deal.  The court agreed to put Akorn’s case on fast track and the trial is currently underway. South Korea: Teva’s potential blockbuster gets delayed due to problems at Celltrion   As Korea emerges as a force to reckon with in the emerging world of biosimilars, the USFDA's issuance of a warning letter to Celltrion (a major manufacturer of biosimilars that has also partnered with Pfizer for commercialization in the United States) came as a major setback.   In an inspection conducted by the FDA from May 22 to June 2, 2017, the investigators raised concerns over multiple poor aseptic practices during the set-up and filling operations. The warning letter highlights an example where during the aseptic filling of vials, an operator used restricted access barrier system (RABS) to remove a jammed stopper by reaching over exposed sterile stoppers in the stopper bowl. The RABS disrupted the unidirectional airflow over the stopper bowl, creating a risk for microbial contamination. After the operator removed the jammed stopper, the filling line was restarted, but the affected stoppers were not cleared. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! At Celltrion, the FDA raised concern over 140 complaints received between October 2015 to May 2017, which were identified to have occurred because of vial stoppers.  The deficiencies at Celltrion impacted Teva as the Korean company is the main API supplier for Teva’s migraine drug fremanezumab. Teva confirmed that the USFDA had extended the goal date of the Biologics License Application (BLA) for fremanezumab. The Prescription Drug User Fee Act (PDUFA) action date for fremanezumab is currently set for September 16, 2018. The Celltrion warning letter was followed by an announcement by the US-based Evolus that a USFDA pre-approval inspection of  Daewoong Pharmaceutical’s plant in South Korea, where a botox biosimilar is being produced, resulted in 10 observations. Back in 2013, Daewoong had inked a contract with Evolus to export DWP-450 (a botulinum neurotoxin candidate), which was expected to be released in the US market around 2017-18. While Daewoong said it expects “no significant further actions”, Evolus’ SEC filing highlights that “any failure to adequately resolve the FDA’s observations at the Daewoong facility would likely cause FDA approval of DWP-450 to be delayed or denied”.  In May, the FDA declined to approve Evolus’ Botox rival citing deficiencies related to the chemistry and manufacturing of its potential treatment for frown lines. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!   India: Data-integrity violations, invalidation of OOS results continue   Alkem has ‘no quality control unit’: After eight days of inspecting Alkem Laboratories’ finished formulation facility in India in March 2018, the FDA investigators concluded — “there is no quality control unit”. Alkem’s head of quality control (QC) and quality assurance (QA) confirmed out-of-specification (OOS) results for the assay for a batch of tablets. However, the company did not recall the product, which was distributed in the US market. Less than three weeks before the inspection, the “firm’s QC department deleted two-thousand one hundred one (2,101) files” on its computer network.  Alembic invalidated OOS results: In the seven days that the FDA investigator — Jessica L Pressley — spent at Alembic Pharmaceuticals’ oral solid dosage manufacturing facility in Tajpura, Gujarat, she uncovered that the firm invalidated 131 of the 140 OOS results (an invalidation rate of 94 percent) for products marketed in the US.  The firm attributed the invalidation to analyst errors. In 2017, the invalidation rate was 91 percent. The Form 483 shares a concern that the “OOS results that were invalidated by the firm’s QC unit were without rationale and supporting documentation.” Alchymars falsified lab data: A September 2017 inspection by the USFDA at Alchymars ICM SM Private Limited in India uncovered that the firm “was falsifying laboratory data”. During the inspection, the FDA investigator found that an analyst reported far fewer colony-forming units (CFU) in a water sample than those observed on the plate by the investigator.  The FDA raised serious concerns as Alchymars uses the water to manufacture APIs intended for use in sterile injectable dosage form drug products.  Alchymars is part of a group of companies and the factory is controlled by Trifarma in Italy, a company which was cited by the FDA for data-integrity violations in 2014. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!   Our view   This year, concerns over pharmaceutical manufacturing spread beyond China, India and the United States as data integrity issues also emerged in Japan and Australia. In Taiwan, the failure to establish an adequate system for monitoring environmental conditions in aseptic processing areas was a problem uncovered by both the FDA and EU inspectors. A firm in France released an over-the-counter (OTC) drug product without testing if the active ingredients conformed to specifications. PharmaCompass’ review of the observations indicates that as inspectors start adopting a more standardized approach towards inspections, the problems they uncover across countries are along similar lines.  At PharmaCompass, we believe that a review of our Mid-Year Non-Compliances in 2018 will provide you with the insights necessary to prepare and insulate your business from the concerns raised during regulatory inspections.  Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!  

Impressions: 9159

https://www.pharmacompass.com/radio-compass-blog/mid-2018-recap-of-warning-letters-import-alerts-and-non-compliances

#PharmaFlow by PHARMACOMPASS
26 Jul 2018
Emcure’s US CEO ‘looted millions’, fixed prices with Mylan, Teva and others
As 2016 draws to a close, we look at some recent cases of (alleged) drug price-fixing and examines its implications on a fast-changing global pharmaceutical industry. Last week, federal prosecutors in the US unsealed criminal information against Jeffrey Glazer, the former CEO and founder of Heritage Pharmaceuticals — a generic drug maker which was sold to India’s Emcure Pharmaceuticals in 2011. This way, Heritage Pharmaceuticals became the base of Emcure’s US operations. It generates several hundred million dollars of annual revenue, according to IMS Health data.  Federal prosecutors have also filed criminal information against Heritage’s former president, Jason Malek, who is Glazer’s brother-in-law. Interesting, Emcure was placed on the US Food and Drug Administration’s (FDA) import alert list last year. The warning letter posted earlier this year unveiled data integrity violations, thereby making it a part of the list of Indian companies facing compliance troubles. The Heritage Pharmaceutical case only compounds the troubles for Emcure. The ring leader of price manipulation Following the federal criminal investigation, 20 states in the US filed a lawsuit against Mylan, Teva and four other generic drug makers, saying they conspired on the pricing of two common generic drugs. The lawsuit, filed in the district court of Connecticut, names Heritage Pharmaceuticals as a “ring leader” of the price manipulation, and also lists Mayne, Aurobindo and Citron as participants. According to federal prosecutors, Glazer participated in a price-fixing conspiracy related to two generic drugs, doxycycline hyclate (used primarily to treat severe acne) and glyburide (an oral diabetes medicine). The government says between April 2013 and December 2015, Glazer and his co-conspirators worked together to fix and maintain prices of doxycycline hyclate. The price of doxycycline increased 8,000 percent — from US $ 20 for 500 tablets to US $ 1,849 between October 2013 and May 2014 — according to Senator Amy Klobuchar. According to the complaint, Glazer and Malek communicated with Mylan executives over phone calls and emails and agreed to allocate market share. They also agreed not to indulge in a price war for doxycycline. Mylan agreed to walk away from at least one large national wholesaler and one large pharmacy chain to let Heritage increase its market share, the complaint says. Malek also had a direct relationship with an unnamed Teva employee and the two agreed to raise prices on glyburide, the complaint adds. The embezzling brothers-in-law Heritage fired Glazer and Malek in August. In November, the company filed a massive racketeering lawsuit against the brothers-in-law, accusing Glazer and Malek of running “a criminal enterprise” that included five dummy corporations — Tal Pharma LLC, Dorado Pharma LLC, Element Pharma LLC, VetGen Pharma LLC, and Astor Pharma LLC — and numerous schemes “to steal the company’s profits and property.”  In a detailed 130-page complaint filed in federal court in New Jersey, Heritage claimed that Glazer and Malek had the company sell deeply discounted drugs to their dummy corporations that sold the drugs to Heritage’s own customers that paid the market price.  The complaint alleges that Glazer and Malek redirected US $ 9 million worth of Heritage’s sales to one of these dummy corporations — Dorado Pharma — between 2012 and 2015.  Heritage also claimed that Glazer and Malek embezzled the company’s intellectual property through the transfers of abbreviated new drug applications (ANDA). The accusations against Glazer and Malek Here is a list of some accusations made by Heritage against Glazer and Malek: •  “Over the course of at least seven years, Glazer and Malek looted tens of millions of dollars from Heritage by misappropriating its business opportunities, fraudulently obtaining compensation for themselves, and embezzling its intellectual property.” •  “The magnitude of defendants’ theft is captured in an August 2015 text message exchange, in which Glazer told Malek that their scheme had netted US $ 466,000 in profit that day.” •  “Similarly, during a text message exchange with Malek in September 2015, Glazer spoke boastfully about the “healthy orders” coming into Dorado Pharma, one of their dummy corporations, and his conclusion that they would generate US $ 2.85 million. Malek later confirmed that his calculations showed profits totalling more than US $ 2.5 million.” •  “Malek even went so far as to falsely pretend on multiple occasions to be a female customer service representative named “Judy Jones” while communicating with Heritage employees through an email account associated with Dorado Pharma, one of the defendants’ dummy corporations. •  “In May 2012, Glazer instructed a Heritage employee to complete an FDA submission transferring the company’s ANDA for the generic drug Ketoprofen to defendants’ company Dorado Pharma — with no compensation of any type to Heritage. Shortly thereafter, Glazer and Malek entered into contracts for the manufacture and marketing of Ketoprofen through Dorado Pharma.” • “In February 2016, Glazer sold an ANDA held by Heritage at a below-market price to a close business associate. In exchange for this favorable sales price, the purchaser agreed to pay kickbacks to Glazer and Malek through Tal Pharma.” • “Shortly after his termination from Heritage, Glazer also embezzled more than six million membership rewards points from the company’s American Express account. As the primary cardholder for Heritage’s account, Glazer had sole access to these points and the ability to transfer or redeem them at his sole discretion. Based on information and belief, Glazer has converted these membership rewards points accrued by the company, with an estimated value of US $ 60,000, for his own personal benefit” Price fixing case against Impax While US regulators filed charges of price-fixing, another US-based generic company — Impax Laboratories — received a subpoena in the same case. According to the Financial Times, Impax’s pricing came under scrutiny yet again this week.  The company started selling mebendazole this year at an average wholesale price of US $ 442 per pill. Due to this steep price, the two-pill treatment for pinworm (a parasitic infection) costs US $ 884 in the US, where it is a prescription-only drug. In the UK, however, it is available over the counter for £6.99 (or US $ 8.65) for a pack of four pills, or £1.75 (US $ 2.17) each. In the developing world it can be bought for less than 1 cent per pill.  Mebendazole is on the World Health Organisation’s list of essential medicines. Pinworms are common in children and affect 200 million people a year worldwide. It is recommended that a family takes treatment for this infection at the same time. Therefore, a family of four would have to shell out a whopping US $ 3500 or more for the treatment.  Drug prices under scrutiny in UK too Earlier this month, Pfizer was fined £84.2 million (US $ 104.24 million) in the UK by the Competition and Markets Authority (CMA) for ramping up the cost of an epilepsy drug to the NHS by as much as 2,600 percent. Issuing its biggest fine, the CMA had said the “extraordinary price rises have cost the NHS and the taxpayer tens of millions of pounds”. Pfizer, however, had rejected CMA’s findings. This week, Allergan was provisionally found to break competition law by raising the price of 10 mg hydrocortisone tablets by more than 12,000 percent. Hydrocortisone tablets are used as the primary replacement therapy for people whose adrenal glands do not produce sufficient amounts of natural steroid hormones, as in the case of Addison’s disease. The condition can be life threatening.  Our view Across the world, pricing of both branded and generic drugs is coming under scrutiny. As political winds push for faster drug approvals and the possibility of cross-border trade of drugs, the pharmaceutical industry should brace for a 2017 where routine business practices will most likely stop becoming routine.       

Impressions: 6230

https://www.pharmacompass.com/radio-compass-blog/emcure-s-us-ceo-looted-millions-fixed-prices-with-mylan-teva-and-others

#PharmaFlow by PHARMACOMPASS
22 Dec 2016