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Mid-2017 Recap of FDA Warning Letters, Import Alerts & EU Non-Compliances

Last year, data integrity was a hot topic of discussion in the pharmaceutical industry. According to a recent analysis by GMP (good manufacturing practices) intelligence expert, Barbara Unger, approximately 80 percent of all FDA warning letters in 2015 and 2016 included a data integrity component, and approximately 70 percent of the published European GMP non-compliance reports cited similar shortcomings. With a little over half the year gone, PharmaCompass analyzed the regulatory action for current GMP (cGMP) non-compliance to evaluate how things are looking so far in 2017. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! As per our analysis, of all the non-compliance actions taken by the US and European regulators, India and China continue to see the highest level of activity, followed by the United States. While most of the companies in the list are less known pharmaceutical players, inspections uncovered deficiencies at leading companies like Pfizer, Teva, Mylan and B Braun. Data integrity violations continue to remain high The US Food and Drug Administration (US FDA) and EU inspections continued to uncover data integrity issues across countries such as India, China, Italy and Japan. In a warning letter posted earlier this year, for a January 2016 inspection, FDA investigators uncovered data-integrity violations at ACS Dobfar’s Italian drug manufacturing facility — FACTA Farmaceutici SpA. At FACTA, for multiple lots of sterile drug product, the original data showed failing results. However, the final data reportedly showed passing results. The company was found storing original data in an “unofficial” and uncontrolled electronic spreadsheet on a shared computer network drive. The analyst told investigators that original data was first recorded in the “unofficial” spreadsheet and later transcribed to an “official” form. Investigators also documented that employees at FACTA used paper shredders to destroy critical laboratory and production records. During an inspection performed exactly at the same time, FACTA’s EU GMP certification was renewed by the Italian regulators! Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! Discrepancies in conclusions drawn by regulators This year, while the United States and the European Union (EU) finally announced that they will be able to utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities, the road ahead looks uncertain as, in addition to incidents like FACTA, there have been multiple instances of discrepancies in the conclusions arrived at by regulators. This year saw the WHO grant an all clear for a Mylan facility where the FDA had data-integrity concerns and a similar situation arose at an active pharmaceutical ingredient (API) facility in China. An inspection conducted by the USFDA at Qinhuangdao Zizhu Pharmaceutical from November 28 to December 1, 2016 uncovered significant data integrity concerns and failures in the level of adherence to cGMP for APIs. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! In the warning letter issued to the firm, the laboratory analysts admitted to FDA inspectors that they had been “setting the clock back and repeating analyses for undocumented reasons.” At Qinhuangdao Zizhu, “initial sample results were overwritten or deleted” and the company “reported only the passing results from repeat analyses”. On March 8, 2017, Qinhuangdao Zizhu Pharmaceutical was placed on import alert by the USFDA. Almost a year prior to the USFDA inspection, in October 2015, the company had been inspected by a WHO Prequalification Team (PQT) for levonorgestrel, mifepristone and ethinylestradiol APIs. The inspection concluded with “five major deficiencies, including data integrity issues and several minor deficiencies”. The WHO went ahead and closed their inspection as ‘compliant’, based on corrective and preventive actions (CAPAs) provided by the manufacturer. In view of the US FDA actions, and the fact that Qinhuangdao Zizhu Pharmaceutical was the only WHO-PQT prequalified source of levonorgestrel API, as in the case of Mylan, the WHO approach towards the compliance position was focused extensively on product quality. In Japan, at Sato Yakuhin Kogyo, FDA investigators found analysts performed testing in duplicate without scientific justification, while in China, the French Ministry of Health found manipulation, backdating and falsification of GMP documents such as batch manufacturing records, GC (gas chromatography) and HPLC (high performance liquid chromatographs) chromatograms at Chongqing Succeway Pharmaceutical. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! Heparin makes headlines again in China; Indian firm fakes strike This year, concerns over the testing of Heparin in China re-emerged when FDA issued a warning letter to a contract testing laboratory — Shandong Analysis and Test Center. However, the activities at these companies to deceive inspectors paled in comparison to Vikshara Trading in India where the company faked a strike to prevent an FDA inspection. When the FDA inspection finally occurred, the FDA obtained evidence that the firm actively manufactured numerous products at the time of the supposed strike. Concerns over product quality in the United States In a warning letter issued to ChemRite CoPac in the US, the FDA found that the company was manufacturing oral drug solutions using the same equipment that was being used to manufacture numerous non-pharmaceutical materials including an industrial car care product. The car care product being made was paraffin-based and carried labels such as “harmful or fatal if swallowed” and “keep out of reach of children.” The ingredients of these non-pharmaceutical products were extremely difficult to remove from the manufacturing equipment, and could contaminate the drug products, the FDA said. At Raritan Pharmaceuticals, a company that makes teething tablets, the FDA found the drug contained ingredients, such as belladonna, which could pose potential toxic effects for its consumers — infants and children under two years of age. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! Sterile drug manufacturing continues to be a global challenge Non-compliant operations uncovered at Sato Pharmaceutical (Japan), Euro Far Allergi (Spain), Tubilux (Italy), Biocon (India), Nova DFL Industrie (Brazil), Pfizer’s US operations (ex-Hospira) show that aseptic sterile drug manufacturing continues to be a global challenge as companies struggle to get into compliance. In February 2015, Pfizer acquired a site in McPherson, Kansas, through its US$ 17 billion acquisition of Hospira. Pfizer was aware of Hospira's manufacturing record when it struck the deal, as the company was issued FDA warning letters in four of the seven continents — Europe, North America, Asia and Australia. Approval of two drugs have been held up this year due to compliance concerns at McPherson. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! The USFDA also warned manufacturers of non-sterile, water-based drug products of Burkholderia cepacia complex (BCC or B cepacia) contamination, as there were product recalls due to this and other water-borne opportunistic pathogens found in pharmaceutical water systems. The regulator’s warning stemmed from a multi-state outbreak of infections. In March this year, Phispers had carried a news item on Badrivishal Chemicals & Pharmaceuticals, a manufacturer of docusate sodium. It had been placed on FDA’s import alert list in December last year. Concerns over water systems were also mentioned in the warning letters issued to Humco Holding Group in the United States and Resonance Laboratories in India. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! Omitting names of original suppliers; shipping drugs from banned API makers The USFDA investigators found companies in India (Sal Pharma) and China (Suzhou Pharmaceutical Technology and Lumis Global Pharmaceuticals) omitting the name and address of the original API manufacturers on certificate of analysis and declared themselves to be the manufacturers. In the case of Suzhou, one of its suppliers was placed on FDA’s import alert list. However, the company shipped API manufactured from the banned supplier by providing misleading declarations. Last year, PharmaCompass had reported on Teva’s newly built sterile manufacturing facility in Godollo, Hungary, and the issues highlighted by the FDA in its warning letter and the product recalls from this unit. As part of its global restructuring, while Teva is now winding up its sterile injectables plant in Godollo, it remains to be seen what decision will be taken on its API manufacturing facility in Hangzhou (China), where the FDA had highlighted concerns over process capability and the resulting impact on product quality. Wockhardt’s global compliance problems also continued with its manufacturing facility in the United States — Morton Grove Pharmaceuticals — receiving a warning letter. Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE! Our view Earlier this year, a major Indian API manufacturer — Divi’s Laboratories — was placed on FDA’s import alert list. It was issued a warning letter due to a variety of problems which were uncovered at the site. The concerns raised at Divi’s along with other companies indicate a shifting focus on part of the FDA investigators from audit trails as there is greater depth in the nature of the observations. To assist the industry, the FDA has started posting frequently requested Form 483s on a routine basis which provides insight for the industry to track the new areas of regulatory focus. You can find the Form 483s on PharmaCompass at https://www.pharmacompass.com/radio-compass-news/Quality-Alerts Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!

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10 Aug 2017

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Teva may get foreign CEO; FDA warns drug makers to check water systems

This week, Phispers brings you an update on Teva’s continuing woes that include fines, plant closures and layoffs. With Laurus Labs’ Vizag unit clearing the US FDA inspection, we evaluate what Laurus’ expansion plans could mean for Mylan. And then there is some bad news on Pfizer, Amgen and AbbVie. While arthritis patients in Scotland sued Pfizer for its anti-inflammatory painkiller, Amgen suffered a setback over its osteoporosis drug and AbbVie’s Humira lost a patent battle. Read on. Teva fined in India; may get foreign CEO; to shut down Hungary plant and layoff 500 Teva’s woes are continuing unabated. On Monday, India’s National Green Tribunal (NGT) slapped a fine of US$ 23,139 (INR 1.5 million) on Teva API India Limited for discharging untreated effluents into the Bagad river. The tribunal found the discharge from the sewage treatment plant of Teva API’s Gajraula-based plant in Uttar Pradesh to be below the permissible standards. Last month, the NGT had ordered closure of 13 industrial units in Uttar Pradesh, including the Gajraula plant of Teva API. Globally, the Israel-based generic giant may get a foreigner as its CEO. During a call with analysts recently, Teva’s chairman Sol Barer said: “We are looking around the world for the best candidate.” Teva’s CEO Erez Vigodman had stepped down in February this year. The company’s CFO Eyal Desheh has said he is resigning at the end of June. Teva’s Israeli board members are demanding that an Israeli be appointed CFO if the CEO is a foreigner. And then there is more trouble for Teva in Hungary. Last year, PharmaCompass had reported on Teva’s newly built sterile manufacturing facility in Godollo, Hungary, the issues highlighted by the FDA in its warning letter and the product recalls from this unit. Well, Teva is now winding up its sterile injectables plant in Godollo, and laying off 500 workers in the next few months. The plant had halted production last year after the FDA found manufacturing shortcomings. According to a Reuters report, Teva plans to close down or sell the Godollo plant by 2018-end. The company says its plans do not affect its other two Hungarian plants in Debrecen and Sajobabony. However, Teva isn’t the only one cutting jobs. Novartis announced it will cut 500 traditional production and development roles in Switzerland and another 250 job cuts are planned in the United States. This is part of Novartis’ global restructuring efforts. As G20 meets on antibiotic resistance, DSM wins an amoxicillin patent battle in India Last week, health ministers of the G20 leading economies met for the first time and agreed to work together to combat issues such as a growing resistance to antibiotics. They also agreed on implementing national action plans by the end of 2018. According to the member countries, infectious diseases were spreading more quickly than before due to increased globalization. The 20 nations pledged to strengthen health systems and improve their ability to react to pandemics and other health risks. The results of the meeting will provide key inputs for a G20 leaders’ summit in Hamburg in July. A report last year found that newly resistant strains of bacteria were responsible for more than 25,000 deaths a year in the 28 member nations in the European Union. Meanwhile, the Delhi High Court granted a permanent injunction against Sinopharm Weiqida Pharmaceutical for patent infringement in India. This was announced by DSM Sinochem Pharmaceuticals (DSP), a leading company in the production and commercialization of sustainable, enzymatic antibiotics, next generation statins and anti-fungals, This patent, which is owned by DSP, relates to amoxicillin trihydrate having a low free water content and processes for the manufacture thereof. The permanent injunction prevents the manufacture, use, importation, offering for sale and sale of Weiqida’s amoxicillin trihydrate API in India, as well as any drug product that utilizes the API. Pfizer sued by 70 arthritis patients; study reveals safety risks after drug approvals The world’s biggest pharma company Pfizer is being sued by 70 arthritis patients in Scotland, who say they were hit with terrible side effects from Celebrex, an anti-inflammatory painkiller touted as a wonder drug. The patients — both men and women in the age group of 60 to 90 years — are collectively seeking US$ 4.54 million (£3.5 million) in damages from the New York-headquartered pharma giant. They began taking Celebrex in 2002 to combat the effects of arthritis and muscle and joint stiffness. However, they went on to suffer health problems, including heart attacks and strokes. The Scottish patients hold good chances of winning the case. A recent study — titled Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010 — claims that almost a third of drugs cleared by the American regulator pose safety risks that are identified only after their approval. The study, that appeared in The Jama Network last week, says there is need for ongoing monitoring of new treatments years after they hit the market. Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 (or 32 percent) were affected by a post-market safety event. Post-market safety events were more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval, the study said. After Roche and AstraZeneca, Amgen suffers a setback on its osteoporosis drug Earlier this month, both Roche and AstraZeneca had faced setbacks in the late-stage study of their drugs. Roche had reported its Tecentriq drug failed to significantly improve overall survival in a late-stage bladder cancer study. And an experimental biotech drug for severe asthma from AstraZeneca failed to meet its goal of significantly reducing attacks in a late-stage study. As if to continue the trend, last week Amgen’s top-stage drug prospect aimed at treatment of osteoporosis — romosozumab — faced some serious setbacks. What initially seemed like happy news — that the late-stage trial comparing romosozumab to Fosamax hit its primary and key secondary endpoints — turned into some serious questions about the future of romosozamub. The first big setback was a prominent cardio risk imbalance between romosozumab and Fosamax — 2.5 percent for romosozumab and 1.9 percent for Fosamax. The second big setback came from the FDA, which wants to evaluate the new set of head-to-head data before approving romosozumab. And that means no decision is expected this summer! Humira loses key patent battle as J&J tries to block Samsung’s Remicade biosimilar AbbVie’s Humira — the world’s best selling drug which is a treatment for rheumatoid arthritis — received a setback when the US Patent and Trademark Office’s Patent Trial and Appeal Board (PTAB) handed down a verdict in favor of Coherus BioSciences, a biopharma company in the US. The verdict struck down AbbVie’s ‘135 methods patent on Humira after an inter partes review. The patent had been labelled as a shield and “one of the cornerstones of the Humira IP estate,” by Barclays analysts. However, all IPR decisions are subject to appeal. In a statement, AbbVie said it does plan to appeal against the verdict. Meanwhile, a unit of Johnson & Johnson filed a lawsuit to block the sale of a copy of its rheumatoid arthritis drug Remicade made by South Korea's Samsung Bioepis in the US. Remicade is J&J’s biggest selling drug, with US sales of about US$ 5 billion a year. Through the law suit, the J&J company — Janssen Biotech Inc — has sought a preliminary or permanent injunction to block Samsung Bioepis' biosimilar of Remicade, from sale in the US. Frontida BioPharm gets FDA’s ‘all clear’ for Philadelphia plant bought from Sun In June last year, Frontida BioPharm had bought Sun Pharmaceuticals’ finished pharmaceutical plant in Philadelphia. And barely eight months back, it received an FDA warning letter for this plant, based on an inspection that took place in 2015. The warning letter had mentioned that Sun Pharma’s quality unit at the time had knowingly released 27 lots of various strengths of clonidine HCl tablets, despite evidence that the API used in manufacturing was potentially contaminated. The warning letter had been issued in August 2016, and Frontida knew about the regulatory issues when it acquired the facilities last year from Sun Pharma, India’s largest drugmaker. The good news is that Frontida BioPharm says the US FDA has given the plant an all-clear. Frontida says Sun helped it address these issues. With the regulatory issues behind it, Frontida can now move forward with its expansion plans. “The positive resolution of our regulatory status with the FDA will stimulate Frontida’s expansion and growth, and enable Frontida to better support our partners to bring new products to the market,” Frontida CEO Song Li said in a statement. FDA warns drug makers to check water systems for BCC contamination The US FDA has warned manufacturers of non-sterile, water-based drug products of Burkholderia cepacia complex (BCC or B cepacia) contamination, as there have been recent product recalls due to this and other water-borne opportunistic pathogens found in pharmaceutical water systems. The regulator’s warning stems from multi-state outbreak of infections. In March this year, Phispers had carried a news item on Badrivishal Chemicals & Pharmaceuticals, a manufacturer of docusate sodium. It had been placed on FDA’s import alert list in December last. The FDA warning letter issued to Badrivishal talks about adulteration with BCC. The facility used water as a drug component and for cleaning the facility and equipment. The water source was a river in the vicinity which passes through farmland, where it is subject to agricultural runoff and animal waste, before it reaches the Badrivishal manufacturing site. FDA’s concern was that contaminated water has been the root cause of multi-state outbreak of infections and multiple recalls by other drug manufacturers of non-sterile liquids, including instances of adulteration with BCC. “BCC can survive or multiply in a variety of non-sterile and water-based products because it is resistant to certain preservatives and antimicrobial agents,” the FDA said. Detecting BCC bacteria is a challenge and requires validated testing methods that take into consideration the unique characteristics of different BCC strains. Laurus Labs to enter the US generics market; how will this impact Mylan? Last week, Laurus Labs announced that its API facility at Unit 2 in Vizag (India) cleared the US FDA inspection without any Form 483 observations. The unit manufactures APIs and finished dosage formulations (FDFs). This successful inspection will help the company as it plans to foray into the highly regulated US generics market. Does this suggest trouble for US generic drug giant Mylan? We think so. Laurus was started by Dr Satyanarayana Chava in 2007, and is a key manufacturer and supplier of APIs. With almost US $ 300 million in revenues, it holds its own against better-known competitors like Mylan. In fact, Laurus and Mylan have a lot in common. Both the companies are headed by men who worked together at Matrix Laboratories. Mylan acquired a controlling stake in Matrix around the time Chava founded Laurus Labs. Until then, Chava was the chief operating officer of Matrix, which was being headed by Rajiv Malik, the current president of Mylan. Laurus has also carved a niche for itself by supplying antiretroviral or ARVs (used to fight infections caused by retroviruses like HIV), hepatitis C and oncology drugs. And despite being a relatively new player, its clients include giants like Pfizer, Teva and Merck. APIs generally make up for 20 to 35 percent of the total cost of a drug, but the ones that Laurus develops, like ARVs, constitute 70 to 75 percent of the cost of the drug. Both companies have a stronghold in the treatment of AIDS. Globally, Laurus has achieved a leadership in the manufacture of ARV APIs. And in the case of Mylan, nearly 50 percent of patients receiving treatment for HIV/AIDS in the developing world rely on its product, all of which are made in India. In fact, Mylan is India's third largest pharmaceutical exporter. So seems like Mylan should watch out for Laurus as it forward integrates into making finished formulations. Laurus recently filed 2 Abbreviated New Drug Applications in the United States and submitted a dossier to the WHO (World Health Organization).

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25 May 2017

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Mid-2017 Recap of FDA Warning Letters, Import Alerts & EU Non-Compliances

Teva may get foreign CEO; FDA warns drug makers to check water systems

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