What’s All the Fuss About Number of 483s Issued in India and China?
[Posted on: Thursday, August 23, 2018]

About 80% of all active pharmaceutical ingredients (API) and two-thirds of drug products sold in the US are manufactured in India and China that together boast of about 1000 FDA-registered manufacturing sites. Also, manufacturers based in the two countries hold more generic drug approvals than any other country, including the United States. One can argue that they are, to a large extent, responsible for the low costs of drugs used by American consumers and hence an important component of the US healthcare system. So, rightfully it is important to point the spotlight on regulatory offenders in the two countries whose actions could jeopardize the US drug supply chain. Add on top, both countries are considered developing countries with poor infrastructure, poor populations, cheap labor, and scant local regulatory enforcement. That raises the question of whether these countries are even capable to being compliant with strict FDA requirements. Hence, every warning letter and 483 issued to manufacturers in these two countries gets extra attention from the industry insiders who use the number of regulatory offenders in the two countries to define the entire country’s industry. For the last four years, the Regulatory Affairs Professional Society (RAPS), has taken it upon itself to publish an annual report of sorts based on counting the number of FDA 483s and Warning Letters issued to sites and, by implication, making broad statements about the overall state of regulatory compliance in the two countries. This is a laudable effort and the only one of its kind. However, it would have been great if the information presented be put in context. There is no debate that offenders should be shamed at the least and appropriate punitive action taken against repeat offenders. However, it could lead to wrong perceptions and an overkill if the overall impressions are based solely on the number of FDA 483. Since we are “crunching the numbers”, lets start with the first number, 80%. For locations accounting for 4 out of 5 APIs sold in the US, one would mathematically expect similar ratio of issues found during audits. India and China together account for about half of all Warning Letters, and by extension, presumably about half the 483s issued by FDA. Second is the number 1000; this is how many manufacturing sites are in India and China. With less than 30 FDA inspectors located in India and China combined, inspecting every single site is a Herculean task. The manufacturing sites are mostly located in remote parts of the country with limited transportation connections making it logistically even more challenging for the FDA inspectors. The local regulators offer very limited support due to lack of resources. That could explain why many manufacturing sites in both countries have not be audited as robustly as should have been. The third number to consider is 18; this is the number of manufacturers who have more than two 483s issued to them by FDA. These 18 manufacturers account for about 100 manufacturing sites in India-China or 10% of the total. So, does it mean that the other 90% are compliant and address any issues identified by the FDA inspectors? May be. That brings us back to the first number, 80%. Despite the high volume of India- and China-made drugs in the US market, incidences of safety or other issues linked to these drugs have been rare. Since the primary goal of compliance is safety and if most of the drugs manufactured are safe, should we pay more attention to the overall picture rather than focus too much on the 483s? Is it possible that the so-called “crunching of numbers”, is giving an incomplete and hyped perspective of the situation at hand? One must thank RAPS for trying to do this analysis as no other party, FDA included, has ever published any such analysis but putting numbers in context is as important as generating them in the first place. So, maybe we should stop making so much fuss about the number of 483s alone and try to look at the whole picture, and we may find that we have focused our resources in the wrong place. Yes, FDA should get more aggressive in enforcing its requirements on all manufacturers but in the end, getting safe products to consumers is the primary goal of all.