Form 483s in India and China: Crunching the Numbers

Regulatory NewsRegulatory News | 14 August 2018 |  By 

As China and India manufacture about 80% of all active pharmaceutical ingredients (APIs) for the US market, the US Food and Drug Administration (FDA) has the enormous task of chasing down and regulating more than 1,000 manufacturing sites.

Thanks to the Freedom of Information ActFocus obtained from FDA a list of all 483 Form 483s issued to China- and India- based manufacturers in 2017 – revealing many repeat offenders, many warning letters and many companies that received multiple 483s in 2017.

But the burden of inspecting these numerous manufacturing sites rests on the shoulders of only about three dozen FDA and local employees based in both China and India, in addition to those who are flown in for specific inspections.

Currently, as of 14 August, FDA told Focus that FDA’s India office has 14 US direct hires on staff (of which six are currently deployed to India while others await deployment) and five locally employed staff. But not all India office employees are investigators, and India office staff who perform inspections share the inspectional burden with FDA investigators based in the US who travel to India on temporary assignments.

And as of 14 August, FDA’s China office had 20 US direct hires on staff, with six waiting deployment and six locally employed staff. That compares with a previous tally from December 2015 when FDA told Focus the agency had 17 employees assigned to its Beijing office.

But as with India, not all China Office employees are investigators and China staff that perform inspections share the inspectional burden with US-based investigators deployed on temporary assignments, FDA said.

As Focus detailed in 2015 (for India and China) and 2016, Form 483s are issued following inspections that usually last between three and 10 days and contain observations of any conditions that in the inspector’s judgement may constitute violations of the US Food Drug and Cosmetic Act and related acts.

Usually issued as a prelude to a warning letter or import alert banning a manufacturing site from shipping products to the US, FDA investigators are trained to ensure that each observation noted on the Form 483 is clear, specific and significant, though no two 483s are alike, and even the forms provided to the companies vary.

Companies typically have 15 days to respond to FDA before further action is taken. As part of its transparency efforts, FDA posts Form 483s that are frequently requested online.

2017 Numbers

A closer look at 2017 shows again just how much work the agency puts into these two countries and how no two situations are alike. For instance, many of the manufacturing sites are inspected multiple times per year, and some companies receive multiple Form 483s for the same site.

Lupin Limited, for instance, was the only company in 2017 to receive six Form 483s in 2017 – from April to August – and the company also received one warning letter in November 2017. Similarly, Mylan Laboratories received five Form 483s from February to May of 2017, and one warning letter in April 2017.

The time between when a company receives a Form 483 and when it receives a warning letter also varies widely. For instance, China-based Wuhan Chinese Moxibustion Technology Dev. Co., Ltd. received a Form 483 on 26 May 2017, and seven months later, in December, received a warning letter. Whereas China-based Shanwei Honghui Daily Appliance Co., Ltd. received a Form 483 on 3 August 2017, but received a warning letter just four months later on 5 December 2017.

In addition, the FDA list revealed 18 companies that received two or more Form 483s in 2017, some of which were issued for the same site and some of which were repeats from previous years. Those companies, predominantly from India, included:
  • Alkem Laboratories (same site – Form 483s received in March and September)
  • Aurobindo Pharma
  • Biocon Limited
  • Cadila Healthcare
  • Cipla
  • Dr Reddy's Laboratories
  • Fresenius Kabi Oncology
  • Gland Pharma
  • Glenmark Pharmaceuticals
  • Henan Lihua Pharmaceutical Co.
  • Intas Pharmaceuticals
  • Malladi Drugs & Pharmaceuticals
  • Planet (Suzhou) Medical Products Co., Ltd. (same site – Form 483s received in August and September)
  • Shilpa Medicare Limited (same site – Form 483s received in July and November)
  • Sun Pharmaceutical Industries
  • Unichem Laboratories


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