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FDA, EMA highlight more concerns over APIs from China; FDA slams Apotex’s India operations
This week, Phispers brings you more news on quality problems with active pharmaceutical ingredients from China. The FDA commissioner, through a series of tweets and press statements, announced that the US regulatory agency is sending out a strong message on the need to bolster drug safety and quality, post the valsartan API recall. China sacked senior officials at its food and drug regulator in a crackdown after the vaccine scandal at Changsheng Biotechnology last month. The FDA also posted a warning letter which slammed Apotex’s India operations for non-compliance. And Mylan’s infamous EpiPen will finally have a generic rival as Teva bagged FDA approval for its copycat, life-saving epinephrine auto-injector.
FDA, EMA highlight more concerns over APIs being sourced from
China
Earlier this month, two Chinese companies — Zhejiang Tianyu Pharmaceutical and Zhuhai Rundu Pharmaceutical — had come forth to say they were recalling blood pressure drugs tainted with N-nitrosodimethylamine (NDMA) in the valsartan API which had been used to produce their finished products that had been exported to Taiwan.
Prior to this, Chinese drug company Zhejiang Huahai Pharmaceutical had also halted the supply of valsartan to the US, and globally, regulators recalled blood pressure medicines with the tainted valsartan API manufactured by Huahai. NDMA is a genotoxic substance that could cause cancer.
This week, an EMA press release said Zhejiang Tianyu is no longer authorized to manufacture the valsartan active substance for EU medicines following the suspension of its CEP (a certificate of suitability verifying that the quality of its valsartan meets European requirements).
Though the valsartan API manufactured by Zhejiang Tianyu had lower levels of NDMA compared to Zhejiang Huahai, a CEP suspension indicates that it is likely an inspection of Tianyu’s manufacturing operations was found not to comply with good manufacturing practices.
The FDA commissioner Scott Gottlieb, through a series of his tweets, has said there is a robust effort underway at the agency, guided by its top scientists and senior leaders, to ensure quality and safety of drugs. “I am briefed daily on this effort and we are committed to keeping the public informed,” he tweeted.
“FDA has a major operation underway to get to the bottom of the issues that led to a genotoxic impurity getting into the drug valsartan. We’ll be updating the public this week on the details of that effort, and what we’ve found so far,” Gottlieb tweeted.
Gottlieb also went on to say that the valsartan episode “is limited to a small subset of drugs in that single drug class and the exposure is also limited — we take this matter very seriously and the lessons learned from our investigation will be used to strengthen our oversight going forward.”
However, the news of risks associated with API being sourced from China continues to expand.
Last week, we carried a news report on how Westminster Pharmaceuticals in the United States announced a voluntary recall of levothyroxine and liothyronine (thyroid tablets) due to risk of adulteration.
Post that, on August 17, the FDA confirmed inconsistent potency in the API used in the thyroid tablets. Through a statement, the FDA alerted API repackagers and distributors, finished drug manufacturers, and compounders that Sichuan Friendly Pharmaceutical (China) is recalling certain lots of porcine thyroid API due to inconsistent quality of the API.
“Risks associated with over or under treatment of hypothyroidism could result in permanent or life-threatening adverse health consequences,” the FDA statement said.
The statement said it inspected Sichuan Friendly’s facility in 2017 and discovered serious quality deficiencies. The FDA had placed Sichuan Friendly on import alert in March 2018.
Meanwhile, FDA also announced that Torrent Pharmaceuticals Limited is voluntarily recalling 14 lots of valsartan/amlodipine/HCTZ tablets to the consumer level due to the detection of trace amounts of an unexpected impurity found in an API manufactured by Zhejiang Huahai.
After UK’s MHRA, FDA slams Apotex’s India operations for non-compliance
In April 2018, Apotex Research Private Limited, a division of Canadian generic major Apotex, was placed on FDA’s import alert. The action was the result of FDA’s inspection at the finished pharmaceuticals manufacturing site located in Bengaluru (India) from November 6 to 17, 2017.
The FDA warning letter released last week reveals that Apotex’s investigations into “out-of-specification (OOS) laboratory results and manufacturing deviations were found to be insufficient and did not include scientifically-supported conclusions”.
In one instance, Apotex had a third party perform a retrospective review of nine invalidated OOS investigations and that in “all cases, the investigations were found to be thorough and robust and the findings were sufficiently justified.” However, FDA did not find the response fully consistent with Apotex’s third-party report.
According to the warning letter, in the case of this specific OOS investigation, the third-party report said it “did not believe sufficient scientific evidence was presented in the laboratory OOS investigation process to justify retesting. Only retesting and obtaining passing results are the basis of conclusions.”
FDA also questioned the authority of the quality unit. The FDA warning letter states “your inspectional history indicates that your quality unit does not fully exercise authority, such as ensuring that appropriate investigations are performed with sound conclusions, identifying root causes, and supporting scientific justification.”
FDA also said it has cited similar cGMP violations and deviations at this and other facilities in Apotex’s network. In the last five years, FDA has taken the following actions in response to cGMP violations and deviations at Apotex facilities:
1. FDA placed Apotex Pharmachem India Private Limited on import alert on April 1, 2014, and issued a warning letter on June 16, 2014, which cited failure to investigate and document OOS results.
2. FDA placed Apotex Research Private Limited on import alert on September 22, 2014, and issued a warning letter on January 30, 2015, which cited failure to follow written procedures applicable to the quality control unit.
Previously, at several regulatory meetings, FDA has communicated to the Apotex senior management the need for appropriate and global quality oversight. These repeated failures at multiple sites reveal management oversight and also the fact that control over the manufacture of drugs is inadequate.
The same Apotex site in Bengaluru was also inspected by the UK’s MHRA at the same time as the FDA inspection and was issued a Statement of Non-Compliance with GMP. Interestingly, the observations by the MHRA were different from the FDA as they raised concern over “failures in cross contamination controls applied by the manufacturer resulting in a risk of cross contamination above Permitted Daily Exposure (PDE) from some products”.
Cross-contamination concerns and a failure to adequately validate the process for cleaning and maintenance of equipment also resulted in the FDA issuing a warning letter to Yicheng Goto Pharmaceuticals, a manufacturer of hormonal APIs in China. The inspection found that the firm had failed to perform adequate analytical tests and did not have stability data to support the retest date assigned to its API.
More bad news for Mylan as Teva’s generic EpiPen gets FDA nod; Buffet ups stake in Teva
After news last week that Mylan posted disappointing second-quarter results, and slashed its full-year guidance, this week we have more bad news from the American generic drug major.
After a delay of around one year, last week the US Food and Drug Administration (FDA) finally approved the first generic version of Mylan’s EpiPen and EpiPen Jr (epinephrine) from Teva.
EpiPen is an auto-injector for the emergency treatment of allergic reactions, including those that are life-threatening in adults and children weighing more than 33 pounds.
With the FDA approval, Teva can now market its generic epinephrine auto-injector in 0.3 mg and 0.15 mg strengths. “We’re applying our full resources to this important launch in the coming months and eager to begin supplying the market,” Teva said in a statement.
The US has struggled with the shortage of EpiPens for quite some time, due to regulatory delays in getting a generic on the market.
Mylan had come under intense criticism for raising the price of its EpiPen six-fold since buying it in 2007. Moreover, Mylan’s device had been plagued by periodic shortages, with consumers scrambling to find a reliable supply in recent months.
With this first generic, Mylan’s EpiPen is bound to face more competition, thereby driving down the price of this lifesaving product.
The approval of Teva’s generic, according to FDA commissioner Scott Gottlieb, is part of the agency’s “longstanding commitment to advance access to lower cost, safe and effective generic alternatives once patents and other exclusivities no longer prevent approval.”
Previously, FDA had approved several epinephrine auto-injector products under new drug applications to treat anaphylaxis, including EpiPen, Adrenaclick and Auvi-Q. In addition, ‘authorized generic’ versions of EpiPen and Adrenaclick are marketed without the brand names.
While this may spell bad news for Mylan, this is definitely good news for the beleaguered Israeli generic drugmaker Teva. Billionaire Warren Buffett apparently still likes what he sees at Teva. And his holding company — Berkshire Hathaway — upped its stake in the generics giant in the second quarter to 43.2 million shares, according to a regulatory filing. Those shares were worth more than US$ 1 billion as of June 30.
Novo gets hold of new diabetes technology by acquiring Bristol univ spinout — Ziylo
Last week, Novo Nordisk acquired full rights to Ziylo Ltd’s early-stage glucose binding molecules in a staged acquisition with a potential deal value that could exceed US$ 800 million. The acquisition will give Novo Nordisk full rights to Ziylo’s glucose binding molecule platform to develop glucose responsive insulin molecules.
Ziylo is a University of Bristol spin-out company based out of the Unit DX science incubator in Bristol, UK. Ziylo has been pioneering the use of its platform technology — synthetic glucose binding molecules — for therapeutic and diagnostic applications.
Ziylo’s glucose binding molecules are synthetic molecules that exhibit an unprecedented selectivity to glucose in complex environments such as blood.
The development of glucose responsive insulin molecules is a key strategic area for Novo Nordisk, as it wants to develop this safer and more effective (next generation of insulin) therapy.
A glucose responsive insulin would help eliminate the risk of hypoglycaemia (deficiency of glucose in the blood stream), which is the main risk associated with insulin therapy and one of the main barriers to achieving optimal glucose control. Such an insulin molecule could also lead to better metabolic control.
Just before selling itself to Novo, Ziylo spun out a new company dubbed Carbometrics to develop the diagnostics and glucose monitoring applications of its technology. Carbometrics is now the new home for all Ziylo researchers. Through a research collaboration with Novo Nordisk, Carbometrics will assist with ongoing optimization of glucose binding molecules for use in glucose responsive insulins.
Novo Nordisk has a strong presence in the diabetes care market with a global value market share of 27 percent. In the total insulin market, Novo’s global value market share is 46 percent; and in the modern and new-generation insulin market, it is 45 percent.
Meanwhile, the European discovery outfit at Evotec has tied up with Novo Nordisk to build early-stage pipeline drugs for diabetes, obesity drugs, and also diseases like NASH (non-alcoholic fatty liver disease), cardiovascular diseases and diabetic kidney disease. The scientists at Evotec will build a preclinical pipeline of small molecules primarily concentrating on diabetes and obesity.
While the financial details of the alliance are not known, it is clear that Evotec is adding a major partnership on top of a string of deals with companies like Celgene, Bayer and Sanofi, as well as a number of smaller biotech firms.
China continues crackdown after vaccine scandal; removes six
senior officials
Last weekend, China said it has sacked six senior officials at its food and drug regulator after a safety scandal at vaccine maker Changsheng Biotechnology Co. Ltd revealed failings at the government body, including inadequate supervision.
Changsheng was accused in July of falsifying data for a rabies vaccine and manufacturing an ineffective vaccine for babies, sparking widespread public anger and multiple probes.
The Changsheng case revealed many loopholes such as the lack of supervision by the former State Food and Drug Administration and the State Drug Administration, the lack of supervision and guidance, the lack of strict supervision, and the oversight of the company.
Among officials dismissed were Ding Jianhua, who headed two departments at the China Food and Drug Administration (CFDA). The Chinese government also dismissed Dong Runsheng, deputy director of the Drug and Cosmetics Supervision Department; Sun Jinglin, deputy director of the Department of Drug and Cosmetic Supervision; Ye Guoqing, the director of the Special Drug Supervision Division of the Drug and Cosmetics Supervision Department; Guo Xiuxia, an investigator of the Special Drug Supervision Department of the Drug and Cosmetic Supervision Department; and Wang Youchun, vice president of China Food and Drug Control Research Institute.
While there were no known reports of people being harmed by the vaccines, regulators ordered Changsheng to halt their production and recall the rabies vaccine. Changsheng has apologized and said it is cooperating with the investigations.
Xinhua also reported that more than 40 government officials, including seven at the provincial level, have been held accountable for the scandal and some have been sacked.
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