US FDA Inspections in China: An Analysis of Form 483s from 2015

Regulatory NewsRegulatory News | 10 February 2016 |  By 

As the US becomes increasingly dependent on Chinese and Indian active pharmaceutical ingredient (API) and drug manufacturing, a deeper look into the inspection reports from the US Food and Drug Administration (FDA) in China reveals a number of question marks that parallel the same sort of issues found in Form 483s issued after inspections in India.

A Focus review (thanks to use of the Freedom of Information Act (FOIA)) of eight FDA Form 483s for Chinese manufacturers in 2015 paralleled some of the same data integrity deficiencies listed in the 50 Form 483s Focus reviewed back in November.

Currently, 41 pharmaceutical manufacturing sites in China and five in Hong Kong are included on FDA’s import alert list, which is a list of all the sites banned from shipping products to the US. China’s Zhejiang Hisoar Pharmaceutical is the most recent addition (from 20 January) for good manufacturing practice deficiencies.

By comparison, there are 42 sites under import alert from India, though FDA notes that some of those facilities listed are only banned for certain products and not the entire site.

China v. India

But there are major differences between how FDA operates in the two countries, which collectively account for about 80% of the world’s APIs.

Unlike in India, it’s become increasingly difficult for FDA to obtain visas for its inspectors in China and in 2014, FDA closed two of its offices in Shanghai and Guangzhou, China, and consolidated operations at its Beijing location.

As of 18 December, FDA told Focus the agency has 17 employees assigned to the Beijing office, including five new hires who have yet to deploy to China (only three of those five will work on drug-related issues). Six employees from the FDA’s China office were scheduled to begin conducting inspections from January to March, FDA said, which would be a slight boost from a few months prior when FDA only had two inspectors overseeing the roughly 700 manufacturing facilities there.

Similarly in India, FDA has plans to double the number of its inspectors there – from about nine to 19, though even if that number is actualized the agency would still be tasked with inspecting more than 500 manufacturing sites exporting products to the US.

Concerns over how FDA can adequately track the drug and API supply chain is starting to worry Congress. In December, the House Committee on Energy & Commerce sent a letter to the US Government Accountability Office calling on the oversight office to investigate whether FDA can adequately monitor the manufacturers in India and China, which in the past have had a history of counterfeiting, adulteration, substandard manufacturing and data falsification.

And though both China and India have domestic pharmaceutical inspectors and regulators (China FDA and Central Drugs Standards Control Organization, respectively), the standards used for these inspections are not yet on par with FDA’s.

Chinese Form 483s

Through the use of FOIA (Form 483s are not generally released publicly by FDA), Focus found that more than 80 Form 483s were issued to Chinese manufacturers in 2015 after 132 inspections by FDA staff. The 132 inspections is only 15 more than the number conducted in 2014, but up significantly from the paltry 19 inspections conducted in 2007, according to FDA.

By comparison, FDA conducted 203 inspections at Indian manufacturing sites in 2015, up significantly from the 114 inspections conducted in 2014, and the 66 inspections from 2007.

Unfortunately, because of delays in the FOIA system and the cost of obtaining the documents, Focus was only able to obtain eight of the 80 documents for review.


Zhejiang Hisoar Pharmaceutical Co., the most recent addition to FDA’s import alert list, was cited in a 483 by the agency after a three day inspection in August with seven observations. Hisoar claims to manufacture four products for the US, four for the EU and three for Japan, and lists Pfizer, BASF, Sanofi and Novartis among its partners.

Among the most egregious observations are numerous data manipulation findings, in addition to the company’s failure to locate a logbook documenting the manufacture of APIs, and individual equipment logs not including entries for uses of each piece of manufacturing equipment.

In addition, “sample raw data file names are altered in an attempt to hide deleted data files,” FDA inspectors said, noting the history of raw data modifications could not be tracked.

At Chongqing Kangle Pharmaceutical Co.’s manufacturing site in Chongqing, which the company claims is used mostly for producing anti-malarial APIs and is not included on FDA’s import alert list, inspectors found that a fan blows outside air onto raw ingredients used for API manufacturing, which poses contamination issues. FDA also found “significant rust and flaking paint” in a wet chemistry quality control laboratory.

Another facility that’s allowed to ship products to the US and claims to have customers in about 50 countries -- Qilu TianhePharmaceutical’s manufacturing site in Jinan, China -- was inspected by FDA twice back in May and June, with 15 observations cited.

During an inspection of the company’s quality control lab, FDA found partially incomplete or “otherwise undesirable” gas chromatography results were moved into an auxiliary folder entitled “test.” The large number of sample sets within this test folder “containing TNTC [too numerous to count] unreported sample injection results for finished APIs prevented our comprehensive review of the results,” FDA said. These types of sample "tests" were also uncovered at Indian manufacturing sites last year.

FDA also found that the Qilu site failed to follow batch manufacturing instructions and lab control procedures, in addition to questions about the facility’s design:


FDA inspections at sites for Hangzhou Huadong Medicine Group Kangrun Pharmaceutical Co., Ferring Pharmaceutical, and Shanghai Desano Chemical Pharmaceutical Co. also revealed data integrity questions, particularly around the control of computer and software systems, incomplete lab records of instrumentation calibration and sampling plans not based on scientific principles.

At Shanghai Desano -- which is part of a group of five member companies making about 20 APIs and 15 finished products, mostly anti-virals, antibiotics and anti-malarials -- FDA inspected one site last May and “noted the presence of what appear to be too numerous to count instances of unreported incidents required to be reported as manufacturing deviations.”

The eight 483s also include one for Pfizer’s Dalian, China-based manufacturing site (though the 483 for another Pfizer manufacturing site in Fuyang City was not released by FDA to Focus). At the Dalian site, FDA officials found “the presence of uncontrolled records for a number of manufacturing records” which were supposed to be part of the company’s document control program. Pfizer told Bloomberg in October that it addressed the issues.

The list of nearly 80 Chinese and Hong Kong firms also receiving Form 483s in 2015 includes:

Company Name

Hubei Wurui Bio-engineering Co., Ltd.

Luohe Huisheng Bio-tech Co.,Ltd

Hangzhou Huadong Med. Group Kangrun Pharmaceutical Co Ltd

Chongqing Daxin Pharmaceutical Co.

Shandong Lukang Pharmaceutical Co. Ltd.

Chongqing Kangle Pharmaceutical Co., Ltd

Zhejiang Hisun Pharmaceutical Co., Ltd.

Zhejiang Xianju Junye Pharmaceutical Co Ltd

Guilin Pharmaceutical Co., Ltd.

Chongqing Taihao Pharmaceutical Co Ltd

Cspc Zhongnuo Pharm (shijiazhuang) Co. Ltd

Jilin Shulan Synthetic Pharmaceutical Co. Ltd.

Shanghai Hengrui Pharmaceutical

Yung Shin Pharmaceutical Industrial (Kunshan) Co., Ltd.

Second Pharma Co., Ltd.

The Central Pharmaceutical Co., Ltd.

Yantai Dongcheng Biochemicals Co., Ltd.

Lights Medical Manufacture Co Ltd

Kingkey Group Kingkey Daily Chemical Co., Ltd.

Yancheng Suhai Pharmaceutical Co., Ltd.

Dalian Goodwood Medical Care Ltd

Shanghai Desano Chemical Pharmaceutical Co., Ltd.

Shanghai Wonder Pharmaceutical Co., Ltd.

Mentholatum (China) Pharmaceuticals Co., Ltd.

Ferring Pharmaceuticals (China) Co. Ltd

Zhejiang Huayi Pharmaceutical Co., LTD.

Hisun Pfizer Pharmaceuticals Co.

Shandong Keyuan Pharmaceutical Co. Ltd

Tai Heng Industry Co., Ltd.

CSPC Ouyi Pharmaceutical Co. Ltd.

Qilu Tianhe Pharmaceutical Co Ltd

Zhuhai United Laboratories Co. Ltd.

Jiangsu Gold Worldworks Household Chemicals Co., Ltd.

Qilu Pharmaceutical Co., Ltd.

Nantong Acetic Acid Chemical Co., Ltd.

Chan Yat Hing Medicine Factory

Wong To Yick Wood Lock Ointment LTD.

Suzhou Amerigen Pharmaceutical

Zhejiang Tianyu Pharmaceutical Co Ltd

Hebei Jiheng (Group) Pharmaceutical Co- Shenzhou Plant

Hybio Pharmaceutical Co. Ltd

Zhejiang Medicine Co. Ltd. Xinchang Pharmaceutical Factory

Shanghai Sine Pharmaceutical Laboratories Co., Ltd.

Changzhou Ruiming Pharmaceuticals Co. Ltd.

Guangzhou Haishi Biological Technology Co., Ltd.

Jiangxi Guoyao Pharmaceutical, LLC, Co.

Jiangsu Tianhe Pharmaceutical Co.

Fujian Kerui Pharmaceutical Co., Ltd.

Nanjing King-Friend Biochemical Pharmaceutical Co., Ltd.

Zhejiang Dayang Biotech Group Co. Ltd.

Zhejiang Hisoar Pharmaceutical Co. Ltd.

Sagent (China) Pharmaceuticals Co., Ltd.

Hysan Pharmaceutical Co., Ltd.

Brightgene Pharmaceutical Co., Ltd.

Hubei Yidu Huayang Chemical Co.,Ltd

Sunshine Lake Pharma Co., Ltd

Shandong Rellet Cosmetic Co. Ltd.

Qilu Antibiotics Pharmaceutical Co. , Ltd.

Fujian South Pharmaceutical Co. Ltd

Hebei Yuxing Bio-Engineering Co Ltd

BrightGene Fine Chemical Co., Ltd

CSPC Ouyi Pharmaceutical Co Ltd

CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd.

Hainan Hailing Chemipharma Corporation Limited

Xinxiang Tuoxin Biochemical Co. Ltd

KYJ Medical Products Co., Ltd.

Xinxiang Pharmaceutical Co. Ltd.

Concept Products Limited

Ningbo Liyuan Daily Chemical Products Co.

Henan Dongtai Pharm Co., Ltd.

Porton Fine Chemicals Ltd

Huzhou Aupower Sanitary Commodity

Hunan Erkang Pharmaceutical Co., Ltd.

Beijing Yiling Bio-engineering & Technology Ltd.

PRS (Jiangsu) Biotechnology Co., Ltd

Zhejiang Top Medicine Co., Ltd.

Zhejiang Jinhua Conba Bio-Pharm. Co., Ltd.

Beyond Technology Corporation Nanchang





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