Four major manufacturing scandals hit Chinese pharma this summer, as widespread contamination was discovered in a Chinese-manufactured vaccine and a common blood pressure drug; elsewhere, whistleblowers alleged major GMP violations and deliberate fraud at a Chinese API-maker.
The discoveries have prompted media comparisons to the public’s distrust in Chinese manufacturing that still lingers following the 2008 tainted milk scandal, which saw nearly 300,000 children become ill, and at least six die, from consuming products contaminated with melamine.
As well as the contamination revelations, an explosion at a chemical plant killed 19 people on July 12 at Yibin Hengda Technology facility in Jiang’an, Sichuan. Yibin Hengda Technology is owned by Shanghai SynFarm Pharmaceutical Technology Co., Ltd. (Zhangjiang Drug Valley, China), which performs process development and production of APIs and intermediates, including amino acid derivatives and peptides, according to the company website.
Regulatory firings follow vaccine manufacturing scandal
China sacked six senior officials at its drug regulator, the National Medical Products Administration (NMPA, formerly the China Food and Drug Administration) for dereliction of duty following an investigation into illegal vaccine production by Changchun Changsheng Life Sciences Ltd. (Changchun, China), which is owned by Changchun High & New Tech Industry Inc. (Changchun, China). The company, its chairwoman, and several senior executives are now subjects of a criminal investigation.
The fallout from the scandal has prompted unannounced investigations at vaccine manufacturing facilities across China as the government aims to restore public confidence in product safety.
The NMPA revoked Changsheng’s GMP certificate, ordered production to halt, and issued a recall of its rabies vaccine after a July 5 inspection found the company had fabricated production and inspection records, and arbitrarily changed process parameters and equipment.
The unannounced inspection by NMPA and its counterpart for the northeastern Jilin province came following a tip-off by a former employee, according to China’s state-run press agency, Xinhua. Chinese authorities were swift to condemn the company and many regulatory officials.
By August 16, an investigation established Changsheng’s wrongdoing in its production of the rabies vaccine and in a diphtheria, pertussis, and tetanus (DPT) vaccine, two batches of which, totalling 499,800 units, were also defective. While the affected rabies vaccines had not been distributed, 252,600 doses of the ineffective DPT vaccine had been sold for childhood inoculation.
“In its reckless pursuit of profits, the company committed unlawful acts of grave nature,” reported Xinhua. “The case has exposed supervision failures on the part of local governments and regulatory agencies in implementing their overall responsibility in ensuring food and drug safety, and the fact that state and local supervision authorities lacked severely in lawfully fulfilling their duties of supervision.”
These included the failure to report major risks and potential risky conditions, and improper contingency management. Changsheng had mixed some vaccine batches with expired solution and did not correctly record dates or batch numbers. Falsification of production records for its rabies vaccines began in April 2014, the investigation found.
Chinese President Xi Jinping called Changsheng’s actions “shocking” and called for an immediate investigation into the company and urged severe punishment. The Chinese State Council ordered the prosecution of individuals involved, punishment of the company under “Drug Administration Law,” and the maximum fine and confiscation of illegal profits from Changsheng. Xinhua reported that more than 40 government officials, including seven at the provincial level, have been held accountable for the scandal and several have been sacked.
In a regulatory filing, Changsheng apologised and said it risks delisting from the Shenzhen Stock Exchange due to an investigation by China’s securities regulator into suspected violations of information disclosure.
Changsheng shares have fallen 87% following the revelations, from a market cap of 23.9B CNY ($3.5B) on July 13 to 3.2B CNY ($470M) by August 31.
In a statement, the World Health Organization (WHO) supported the recall and said, “While the current incident is clearly regrettable, the detection of this event by an unannounced inspection shows that the regulatory authority’s system of checks and balances to protect population health is working.”
Whistleblowers claim GMP fraud
The controversy and spot checks prompted by the Changsheng scandal have caught out other Chinese pharmaceutical manufacturers.
In an open letter published on the website of the drug regulator for China’s southwestern Chongqing municipality, anonymous whistleblowers claiming to be employees of Chongqing Pharmaceutical Research Institute (CPRI; Nanan, Chongqing), a generic API and development services subsidiary of Shanghai Fosun Pharmaceutical Group Co. Ltd. (Shanghai, China), denounced the subsidiary as ignoring drug production regulations and lying to regulators.
Management directed staff to fabricate production and inspection records, the letter said. The company also bribed local regulators, it alleged. The letter claimed the antipsychotic aripiprazole and other APIs were manufactured using unapproved processes, and that the company used fraudulent records to apply for GMP certification of a new production facility in Chongqing’s Changshou district.
CPRI manufactures aripiprazole and other products for Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd., owned by Shanghai-listed Shanghai Pharmaceuticals Holding Co Ltd, according to Fosun.
This was not the first trouble for the API-maker: CPRI received an FDA Warning Letter in 2017 concerning a May 2016 inspection of its facility in Nanan District, Chongqing (E/MOR, March 2017). Investigators found evidence that employees had deleted chromatographic sequences and individual injections from records of high-performance liquid chromatography (HPLC)/gas chromatography (GC) analyses. The company also repeated analyses until acceptable results were obtained, without providing scientific justification for doing so, the Warning Letter said.
The FDA conducted another inspection in November 2017, at CPRI’s Changshou site, which also found serious violations and resulted in a Form 483 related to a deviation investigation of aripiprazole, Fosun revealed in a written response to the FDA on August 31.
In its letter, Fosun denied the whistleblowers’ other allegations and said an internal investigation showed CPRI’s products are manufactured in accordance with approved production processes, and changes to the production process have been filed with the relevant drug regulatory authorities.
The company said it has “adopted quality and safety control mechanisms and adverse drug reaction monitoring mechanisms at each stage of the production.” The Chongqing drug regulator made an unannounced inspection at Chongqing Research Institute on 23 August 2018. Findings have not yet been released.
The company whistleblowers said they were motivated by media coverage of the Changsheng scandal.
Teva recalls valsartan after contamination claims
In July, the EMA suspended Zhejiang Tianyu Pharmaceutical Co. Ltd. (Taizhou, China) from manufacturing the API valsartan, used to treat high blood pressure and heart failure, after it found contamination of the drug with N-nitrosodimethylamine (NDMA), a probable carcinogen. The regulator suspended the company’s European Pharmacopoeia and certificates of suitability (CEP) – certificates verifying that the quality of its valsartan meets European requirements.
Zhejiang Tianyu Pharmaceutical Co. did not supply valsartan products to the US market. But in the same month, the FDA discovered NDMA contamination of several valsartan products made by another CMO, Zhejiang Huahai Pharmaceutical Co Ltd. (Linhai, China).
Zhejiang Huahai’s clients Prinston Pharmaceuticals Inc (Cranbury, NJ, US), Major Pharmaceuticals (Livonia, MI, US), Solco Healthcare (Cranbury, NJ, US), Teva Pharmaceuticals Industries Ltd. (Petah Tiqva, Israel), and Torrent Pharmaceuticals Ltd. (Ahmedabad, India), all recalled products containing valsartan API. Currently, more than half of all valsartan products on the US market are being recalled. (See Table below.)
The risk from the trace levels of NDMA found in the contaminated valsartan is low but still unacceptable, the FDA said. The organisation, alongside the EMA, Health Canada, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), has launched major coordinated operations to investigate the valsartan impurities.
The investigations have expanded to all valsartan products marketed in the US and EU, and to encompass other APIs in the same family – angiotensin II receptor blockers (ARBs) – to determine if they also contain NDMA, regulators said. More manufacturers may discover that their products contain NDMA, prompting further recalls, the FDA cautioned.
The revelation that NDMA can occur at these levels in valsartan manufacturing is news to the pharma industry, and manufacturers do not routinely test for it.
In a statement, FDA Commissioner Scott Gottlieb and Director of the Center for Drug Evaluation and Research (CDER) Janet Woodcock said they believe that the impurity resulted from changes that Zhejiang Huahai Pharmaceutical Co Ltd. made to the manufacturing process. However, this is not certain, they said.
Once it is better understood how NDMA impurity can occur as a by-product of the manufacturing process, testing for this impurity will be required for all valsartan manufacturers if there is any risk of NDMA formation, said Gottlieb and Woodcock. Manufacturing processes can also be re-engineered to avoid creating NMDA as a by-product, they added.
NDMA is difficult to find, and CDER scientists have had to develop a new detection method, using gas chromatography-mass spectrometry (GC/MS) headspace testing.
These were not the first problems for Zhejiang Huahai. The FDA released this summer two Form 483s from inspections of Zhejiang Huahai’s finished dose and API facility in Xunqiao, Zhejiang in November 2016, and its API site in Coastal Industry Zone, also in Zhejiang, in May 2017. These showed mistakes in the restricted-access barrier system (RABS), facility cleaning, and in recording data non-contemporaneously at the first site.
At the second site, there were deficiencies in API assay testing and poorly maintained equipment, including paint, rust, and particulate matter on the inside of manufacturing equipment.