FDA Overseas Inspection Policy Is Concerning, Says Biosimilars Patent Attorney

The FDA’s decision to discontinue pharmaceutical site inspections abroad appears destined to exacerbate shortages of critical drugs, including biologics, said Imron T. Aly, a patent attorney at Schiff Hardin, which represents numerous India-based manufacturers of small- and large-molecule drugs, in an interview with The Center for Biosimilars^®. “At a time when you’d rather have things expedited, having the FDA pull its inspections in India, in particular, is slowing things down,”

The FDA announced last week that it would stop routine overseas inspections of food, drugs, and medical devices until April, citing the worldwide spread of COVID-19. Instead, the agency said it would rely on border inspections of products and examinations of product data from manufacturers.

Manufacturers in India, which supply 18% of the active pharmaceutical ingredients (APIs) used in the US drug supply, are “extremely concerned” about the move, as it stands to harm manufacturing operations and plans for new manufacturing or drug development activity, Aly noted.

A case in point is Biocon, a Bengaluru, India—based company that hopes to achieve a $1-billion revenue target in biologics by 2022. It is the only Indian pharmaceutical company with 2 biosimilars on the US market: Fulphila (pegfilgrastim) and Ogivri (trastuzumab).

Compounding the problem is that earlier this month, supply chain problems led India to restrict the export of 26 APIs and the medicines and vitamins made from them. These include paracetamol; antibiotics such as tinidazole and erythromycin; the hormone progesterone, which is used in the contraceptive pill; and vitamins B12, B1, and B6.

Further, Indian pharmaceutical companies obtain almost 70% of the APIs for their products from China, particularly Hubei province, the epicenter of the COVID-19 outbreak. The interdependence of markets and fears that India may not be able to provide medicines for its own population of 1.3 billion people contributed to the decision by India’s authorities to tamp down on exports.

“We see the pharmaceutical supply chain exported out of China under significant pressure,” Jim DeYonker of Centrient Pharmaceuticals, which has manufacturing facilities in India, told the Lancet in a February 29 report.

“In addition to a manpower shortage due to more and more provincial governments adopting a mandatory 14-day quarantine policy for returning workers, the transportation and logistics apparatus is also getting clogged up due to various travel restrictions and difficult access to ports,” DeYonker said. The same article noted Indian media reports that traders were hoarding APIs and that prices for medicines were already surging.

The ripple effects from these events are sure to reach the United States, Aly said. “I think we’re guaranteed drug shortages. We just don’t know how soon they’re going to be experienced here. From everything we’re hearing, there are going to be shortages within a matter of 2 months.”

The 26 APIs that India is withholding are a subset of total pharmaceutical products shipped to the United States, and so the FDA policy on inspections raises serious questions about whether the speed and efficiency of imports can be maintained, Aly said.

“Inspections at the border have been rarely used, so Indian manufacturers have big concerns about how that’s going to happen. We’re talking about crates of product that get imported here, and depending on what it is that the FDA is testing or how, there might be disputes about whether that crate of material is allowed to enter or not, when it normally wouldn’t have been an issue because the plant would have been cleared [via a site inspection in India]. So, there’s a lot of uncertainty about how this is going to impact the drugs that can get released from India.”

FDA inspections have been a very important part of the FDA clearance system in India since 2008, when the FDA established the India Office for the purpose of ensuring medical product and food safety.

The importance of foreign inspections was highlighted in a December 2019 report by Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER). Woodcock noted that from 2012 to August 2019, 83% of India’s manufacturing facilities were found to be nondeficient, versus 98% in Europe, 93% in the United States, and 90% in China.

“India had a lower percentage of acceptable outcomes than other countries and regions,” the CDER report said. Standards are identical for foreign and domestic drug manufacturers.

For firms that have received warning notices, having their imports to the United States approved following remediation of the deficiency requires an onsite reinspection, according to the FDA.

In 1991, China-sourced drug ingredients made up only 0.3% of India’s bulk drug imports, according to the Lancet. But as India’s manufacturers switched to making formulations, that percentage climbed much higher.

In India, “about two-thirds of the raw materials for drugs come from China, and that’s just as true for biosimilars as it is for small molecules, so it’s definitely going to be an issue that creates slowdowns, creates delays, and it’s a matter of when that will be,” Aly said.

This year, India’s government and pharma industry have been collaborating on plans to step up API manufacturing in the country to reduce the perceived threat to drug supplies and national health.