As China and India continue to manufacture about 80% of all active pharmaceutical ingredients (APIs) for the US market, the US Food and Drug Administration (FDA) is tasked with regulating these manufacturing sites and in 2016 that involved issuing hundreds of Form 483s and responding to more than 700 requests for the inspection reports.
Thanks to the Freedom of Information Act, Focus obtained from FDA two lists detailing not only the 86 requests for the Form 483s issued in 2016 to China-based manufacturers and 620 requests for Form 483s for India-based manufacturers (see below for complete lists), but also the companies, universities, competitors and others who requested access to the inspection reports.
As Focus detailed in 2015 (for India and China), Form 483s are issued following inspections that usually last between three and seven 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.
According to FDA’s lists, media companies looking to break news on the issuance of Form 483s are frequent requestors of the reports, with outlets like Reuters, Bloomberg and others looking to get a jump on potential deficiencies that could have wider ramifications for larger companies or lucrative markets.
Likewise, consulting and investment banks including Morgan Stanley, JP Morgan, Credit Suisse, Goldman Sachs, Merrill Lynch, Citigroup and Jefferies are all listed as having sought Form 483s issued to China and India-based manufacturers in 2016.
Pharmaceutical companies also requested reports, perhaps to gain an edge on competitors. For instance, Novartis requested a Form 483 issued to a Mylan plant in India, while Mylan requested a Form 483 issued to a Hospira site in India.
Many observations detailed in the Form 483s issued in 2016 echoed similar deficiencies documented in 2015.
Sterility concerns highlighted in 2015 Form 483s continued to crop up at sites in 2016. Following a December 2016 inspection at the API manufacturer Granules’ site in Andhra Pradesh, India, FDA inspectors detailed holes in the ceilings, cracks in the walls with "peeling and chipping paint," as well as water damage.
At India-based Ipca Laboratories, FDA inspectors in 2015 found a quality affairs officer had partially shredded training validation forms for multiple manufacturing operators. Similarly, in a December 2016 Form 483 issued to India-based Hetero Labs, FDA says it "observed extensive shredding of what appears to be controlled documents and extensive signing of documents by QA [quality affairs]."
A review of Hetero’s closed circuit TV recordings also found individuals shredding documents in the middle of the night, just hours before FDA officials were set to inspect the site.
Another observation previously noted by FDA inspectors occurred during a June 2015 inspection of China-based API manufacturer Zhejiang Medicine Co., which FDA said was not properly controlling raw data and pretesting samples before performing official/reported analyses.
FDA’s review "identified what appear to be potentially significant differences between the trial and official results, including sample results that appear to include unknown peaks, which may cause the batches to be considered out-of-specification."
As US companies continue to rely on China and India-based API manufacturers to keep the cost of generic drugs low, FDA’s and other regulators’ vigilance will be increasingly important as the number of Americans taking generics continue to rise.
A newly authorized mutual recognition agreement between the US and EU on manufacturing inspections could help to increase harmonization across borders and keep the pressure on companies that violate US and international laws and best practices.
List of 86 Form 483s Requests Issued for China-based manufacturers
List of 620 Form 483s Requests Issued for India-based manufacturers
Editor's note: This article was updated to clarify that the lists provided by FDA are requests for Form 483s.