Market Place
Mylan’s valsartan facility gets FDA warning letter; US sues Gilead over HIV drug patents
This week, Phispers has news on Mylan’s valsartan facility in India receiving an FDA warning letter for nitrosamine contamination.
The US government sued Gilead for infringing patents related to the HIV drug Truvada.
While Strides Pharma relaunched ranitidine tablets in the US as the nitrosamine impurity in its product was found to be within acceptable limits, Aurobindo Pharma USA is conducting a voluntary recall of the drug.
In compliance news, Denmark revoked Scanpharm’s manufacturing authorization, and FDA issued a warning letter to Chinese drugmaker Bingbing Pharmaceutical for data integrity issues.
In the US, confirmation hearing on appointment of Stephen Hahn as the FDA chief will take place next week. Indian drugmaker Lupin exited Japan, while Sandoz expanded in Japan in the midst of delay in generics sell-off to Aurobindo.
And Mylan and Pfizer announced the name of the new company to be formed by the merger of Mylan and Upjohn.
Mylan’s valsartan facility gets slammed by FDA in warning letter
As the fallout of cancer-causing nitrosamine impurities continues, this week the US Food and Drug Administration (FDA) posted a warning letter to Mylan Laboratories’ active pharmaceutical ingredient (API) manufacturing facility located in India.
The FDA inspection of Mylan’s Unit 8 facility (in Kandivalasa, Andhra Pradesh), which was conducted from May 27 to June 5, 2019, found that Mylan had not anticipated the presence of nitrosamine impurities in its assessment of the valsartan API manufacturing process.
Mylan had recalled all valsartan API batches by the end of 2018 after tests determined that majority of batches contained the cancer-causing impurity— N-Nitrosodiethylamine (NDEA) above the acceptable limit.
Mylan’s investigation determined that the nitrosamine contamination was from recovered solvents which contained more than 40 times the limit set by Mylan. However, Mylan concluded that such high levels of NDEA would not result in significant levels of NDEA in the final API.
The warning letter also highlights that Mylan was supplied solvents that were contaminated with nitrosamines from multiple contract manufacturers.
Even after Mylan suspended the use of recovered solvents from contract manufacturers and began relying on in-house solvent recovery, the solvents were found to contain nitrosamine impurities.
In August, Lantech Pharmaceuticals Limited, a firm which undertakes contract solvent recovery facility for valsartan API manufacturing operations, was issued a warning letter by the FDA after being placed on an import alert in June.
The warning letter had stated that in December 2018, a Lantech customer notified the company that solvents recovered by Lantech contained NDEA.
In the investigation performed by the company, which was reviewed by the FDA, samples collected from Lantech’s equipment were found to contain mutagenic impurities.
The warning letter also mentions a lack of assurance over Mylan’s cleaning methods to prevent contamination or carry-over drugs manufactured on non-dedicated equipment. Equipment labeled as clean when wiped with lint-free cloths was found to contain residual valsartan API.
As a result of these observations, the FDA strongly recommended that Mylan engage a consultant qualified to evaluate its operations to assist the firm in meeting cGMP requirements.
US government
sues Gilead over patent rights to HIV drug Truvada for PrEP
Last week, the US government took the rare step of suing Gilead over patent rights to the HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (or PrEP).
PrEP is a way to prevent HIV infection in people who are at very high risk of catching it by taking a pill (Truvada) every day. It is said to be 99 percent effective in preventing HIV transmission, according to the Centers for Disease Control and Prevention (CDC).
The lawsuit was filed on November 6 in US District Court for the District of Delware. It alleges that CDC researchers began studying the preventive use of HIV treatment drugs — like tenofovir and emtricitabine (the two compounds in Truvada) — as early as 1998, before Gilead sought a patent.
Importantly, the lawsuit alleges that the government owns the PrEP patent for both Truvada and Descovy, Gilead’s next generation PrEP approved last month, setting up the possibility that both HIV prevention drugs could see drastic price reductions.
“Gilead’s conduct was malicious, wanton, deliberate, consciously wrongful, flagrant, and in bad faith,” the complaint says.
According to the complaint, Gilead increased its funding of PrEP clinical trials only after the commercial success of Truvada for PrEP. Following CDC’s decision to recommend daily PrEP in 2014, “sales for Truvada for PrEP skyrocketed, both in the United States and worldwide. In 2016, there were 77,120 PrEP users in the United States, as compared to 8,768 PrEP users in 2012.”
The price for Truvada also rose from about US$ 1,250 per month to about US$ 1,800 per month in the US as demand began to increase, the complaint says.
Company formed through merger of Mylan with Pfizer’s Upjohn named Viatris
Mylan NV and Pfizer Inc announced that the name of the new company to be formed by the planned combination of Mylan and Upjohn, a division of Pfizer, will be Viatris. However, the name is awaiting shareholder and regulatory approval.
Viatris is Latin for “via-three” — which also embodies the new company’s three core goals: expanding access to medicines, leading by innovating to meet patient needs, and being a trusted partner for the healthcare community worldwide.
“We wanted a name that would differentiate our new company and clearly explain how we will be a champion for global health,” said Robert J. Coury, who will serve as Executive Chairman of the new company, as previously announced. “We are creating a company unlike any other – a company focused on building a more hopeful and sustainable healthcare journey, empowering patients to live healthier at every stage of life,” he added.
The new company plans to have a meaningfully expanded geographic reach for its broad product portfolio and future pipeline. Viatris will unite Upjohn’s strong leadership position in China and emerging markets with Mylan’s significant presence in the US and Europe.
Mylan didn't have to look far for this name. In July 2016, Mylan had acquired German drugmaker Meda in a US$ 7.2 billion deal aimed at bolstering the drugmaker’s OTC franchise. As part of that deal, Mylan also picked up Viatris GmbH, a German specialty drugmaker.
Denmark
revokes Scanpharm’s
approval; FDA warns Chinese drugmaker
Last week, the Danish Medicines Agency revoked Danish drug firm Scanpharm’s authorization to manufacture medicinal products and intermediate products.
An inspection undertaken by the agency had uncovered GMP deficiencies. A three-day inspection in September showed the company lacked the necessary knowledge regarding its responsibilities related to qualified persons, as well as other issues with reporting of out-of-specification (OOS) results, OOS and missing data for stability studies and inconsistencies between registration files and specifications.
The Danish Medicines Agency also found the company used non-validated analytical methods and did not perform its self-inspection sufficiently.
The company has been removed from the agency’s list of companies holding a valid manufacturing authorization, and the authorization is also highlighted as suspended in the European database on compliance with GMP, known as Eudra GMP. But the Danish Medicines Agency said it expects the suspension to be temporary.
FDA raises concerns with API drugmakers: Last week, Donald Ashley, director of FDA’s Office of Compliance, raised several major concerns with the API industry. The concerns involved three trends — obfuscation of supply chain information, an increasing number of data integrity question marks and impurity concerns that have led to recalls.
Ashley said API companies sometimes fail to obtain and retain documents with the identity of the original manufacturer and certificate of analysis.
In addition, APIs, including opioids, are often distributed with inadequate certificates of analysis, which he said, “compromises supply chain accountability and traceability and may put consumers at risk.”
On data integrity, which often includes incomplete, inconsistent or inaccurate data, Ashley said 73 percent of all warning letters issued to API manufacturers over the past four years included data integrity charges.
FDA warns Chinese firm over data integrity concerns: Last month, the FDA warned Chinese drugmaker Bingbing Pharmaceutical for good manufacturing practice (GMP) and data integrity issues, some of which stem from the company losing records after moving to a new facility.
The warning letter details four violations related to record keeping, ingredient testing, quality control and complaint handling. It follows a four-day inspection of the company’s Hubei facility in May 2019.
According to the agency, Bingbing failed to retain records, reports and samples for its over-the-counter (OTC) drugs made at its former facility in Wuhan after transferring production of the products to the Hubei facility in May 2018. The FDA said Bingbing needs to conduct an independent assessment of its documentation systems and develop a corrective and preventative action (CAPA) plan to address various documentation issues.
The company also released OTC drugs “without testing the identity and strength of each active ingredient,” the FDA said.
In response, Bingbing committed to discontinuing distribution of those products until it establishes validated analytical methods for testing the ingredients.
Confirmation
hearing on appointment of Stephen Hahn as FDA chief next week
Last week, Senate health committee chairman Lamar Alexander released a statement after meeting Stephen Hahn, US President Donald Trump’s nominee to lead the US Food and Drug Administration (FDA). In the statement, Alexander said he had an excellent meeting with Hahn and believes he is “well-qualified to lead the FDA”.
On November 20, the Senate health committee will hold a confirmation hearing on the nomination of Hahn to serve as Commissioner of the FDA. Hahn currently serves as the chief medical executive at the University of Texas MD Anderson Cancer Center in Houston.
If it goes through, Hahn’s appointment will come at a crucial time when the FDA is implementing the 21st Century Cures Act, regulating tobacco and vaping products, addressing the opioid crisis, and protecting our nation’s food supply.
“As a successful chief executive, he will bring a guiding hand to an agency tasked with protecting the public’s health,” Alexander said.
As
Lupin exits Japan, Sandoz expands there in midst of delay in generics sell-off
to Aurobindo
This week, we have two different kinds of news from Japan. The first news involves Indian drugmaker Lupin Ltd, which said it is selling its entire 99.82 percent stake in its Japanese subsidiary Kyowa Pharmaceutical Industry Company Limited for an enterprise value of US$ 527 million (57.4 billion yen) to Plutus Ltd.
The divested business recorded revenues of US$ 130.7 million (14.24 billion yen) in the first half of the year. The sale is subject to approvals from Japan Fair Trade Commission, shareholders of Lupin and such other approvals, consents, permissions and sanctions as may be necessary.
Lupin said the deal will bring down its net debt to US$ 156.6 million (Rs 11.29 billion) compared to US$ 605 million (Rs 43.618 billion) as on September 30.
Plutus is owned by Unison, a three-way joint venture of Unison Capital Partners IV, LPS and Unison Capital Partners IV (F).
The second news pertains to Novartis, which is beefing up its hospital portfolio in Japan through a deal to buy Aspen Pharmacare’s local operations for US$ 442 million (€400 million).
“The acquisition of Aspen’s Japanese operations would significantly strengthen our position in this country, a stable but growing generics market,” Sandoz CEO Richard Saynor said in a statement.
Aspen CEO Stephen Saad, on the other hand, said the Japanese operations “do not provide appropriate scale and leverage” for the company.
But for Sandoz, adding the portfolio will strengthen its existing hospital generic and biosimilar pipeline, and, together with a dedicated sales, marketing and medical organization, the deal could help its reach in Japan’s hospital channel, it said.
However, Novartis’ Sandoz is yet to nail down its generics selloff to Aurobindo Pharma. The Indian drugmaker will become the second largest generics company in the US if it completes a US$ 1 billion deal to buy Sandoz oral solids and dermatology business in the US.
Aurobindo is yet to meet Federal Trade Commission (FTC) terms to complete a US$ 1 billion deal to buy a significant chunk of Sandoz’s US generics business. It also continues to struggle to meet FDA terms for its manufacturing plants.
The FDA issued a four-observation Form 483 following inspections of its API plants at Pashamylaram, Hyderabad, and Gaddapotharam, Hyderabad. The FDA is currently taking a look at its formulation manufacturing facility at Pashamylaram, Hyderabad.
Earlier this year, the agency had issued a warning letter to Aurobindo’s facility in the Srikakulam district for issues the FDA said contributed to its valsartan products being tainted with a suspected carcinogen.
Strides
relaunches ranitidine; Aurobindo recalls it in US as more details emerge
Strides Pharma Science on Friday said it has relaunched ranitidine tablets used in ulcer treatment in the US as the level of NDMA (N-nitrosodimethylamine) in its product was found to be within acceptable limits.
The company had suspended sales of its generic ranitidine tablets after the FDA found it to be contaminated with NDMA, which is a potentially cancer-causing impurity.
FDA had tested numerous ranitidine tablets on the market over the past few months and released a summary of the results on November 1, 2019. The agency had indicated that if the NDMA levels were found to be above acceptable limits (96 nanograms per day or 0.32 ppm), they would ask companies to recall Ranitidine products voluntarily, Strides said.
“Strides’ Ranitidine tablets 300 mg were within the acceptable limits for NDMA of 96 nanograms per day or 0.32 ppm,” it added.
Meanwhile, Aurobindo Pharma USA, Inc is conducting a voluntary recall of one lot of Ranitidine Tablets 150 mg to the retail level and 37 lots of Ranitidine Capsules 150 mg, Ranitidine Capsules 300 mg and Ranitidine Syrup 15 mg/mL to the consumer level due to the detection of NDMA impurity in the finished product.
The escalating global recall of Zantac (ranitidine) has its roots in a tiny online pharmacy — Valisure — whose founders feared that the US drugs might not be as safe as people think.
Valisure is a start-up with only 14 full-time employees. Ever since Valisure’s scientists alerted FDA that ranitidine contained NDMA, more than 40 countries from Australia to Vietnam have either stopped sales, launched probes or otherwise stepped in to protect the consumers.
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