Inspectors Welcome

The fifth CPhI India, held in Mumbai in November, saw some 28,000 visitors on just the first day of the fine chemicals trade show. The numbers swelled over the next two days, and the meeting buzz was mostly about how Indian manufacturers appear to be taking the lead in the global battle for market share in active pharmaceutical ingredients (APIs). With around 120 approved facilities, India enjoys the largest number of U.S. Food & Drug Administration-inspected API plants outside the U.S.

But with FDA inspections can come FDA warning letters, and Indian drug and fine chemicals companies have of late been hit with a few such missives. Last May, for example, Aurobindo Pharma’s stock took a nosedive after the firm received a multipart letter detailing problems at a cephalosporin facility in Hyderabad.

Yag-Mag Labs was served with a letter in September complaining about deviations from current Good Manufacturing Practices (cGMP) at its API facility in Andhra Pradesh. And Ranbaxy Laboratories just set aside $500 million to resolve claims connected to an FDA investigation of its manufacturing practices after a critical 2008 inspection of generic drugs produced by Ranbaxy’s Dewas and Paonta Sahib plants in India.

Most attendees interviewed at CPhI India said they see FDA scrutiny as a part of doing business in the U.S. and not necessarily a sign of unsafe or egregious practices. “Warning letters are alerts on GMP deviations. They should be taken as such and not blown out of proportion,” said Pradeep Y. Anaokar, senior marketing manager at S. A. Pharmachem, which produces or distributes APIs such as ceftazidime, cefazolin, lactitol, and cyclosporine.

Senthil Ramesh, a marketing representative with S. D. Fine Chem, which regularly supplies Ranbaxy and other large firms, said the warnings don’t perturb him. The company operates a facility in Tarapur that produces analytical reagents, complex organic compounds, and rare and research chemicals. “This facility is one of the most modern plants and is FDA-approved and GMP-certified,” Ramesh said. “We should be glad that FDA is inspecting regularly. It means better quality products.”

Sanjeev Dua, a manager at IOL Chemicals & Pharmaceuticals, agreed that increased FDA oversight would only ensure quality products. IOL supplies APIs and other fine chemicals to firms such as Ranbaxy, Hetero Drugs, Aurobindo Pharma, and Aventis Pharma from its plant in Uttar Pradesh.

Dua contended that Aurobindo rapidly moved to clean up its act after the FDA crackdown. When reporting financial results in August, Aurobindo stated that it has been taking “all the steps necessary to address and resolve the regulatory challenges” with FDA around its cephalosporin manufacturing facility.

For Dipali Bapat, deputy manager of regulatory affairs at Teva Pharmaceutical Industries’ API division, known as TAPI, FDA audits are de rigueur. “We have an FDA audit going on as we speak,’’ she told C&EN at the Mumbai event.

TAPI reports more than $1 billion in annual sales based on API production at 18 sites in the U.S., Italy, China, India, and Israel. The company’s Indian plants are in Gajraula, Uttar Pradesh; and in Malanpur and Gwalior, Madhya Pradesh. It operates an R&D center in Noida, an industrial township.

“Teva offers over 250 different APIs using a variety of production technologies and is among the world’s principal suppliers of many of these chemicals,” Bapat said. “In order for APIs to be approved for use, the facilities and production procedures must meet the requisite standards. Our plants are regularly inspected by FDA. It is necessary that FDA be allowed to do its job.”

In the U.S., Bapat noted, Congress blasted FDA last October for failing to find those responsible for the contamination of heparin, an anticoagulant, imported from China. The heparin scandal was linked to 81 deaths in 2007 and 2008. “Although this brought on harsh criticism of FDA and its findings with regards to foreign facilities, especially in China, if regular crackdowns are not allowed, another health crisis like heparin seems inevitable,” she warned.

TAPI’s plants are regularly inspected. In 2008 alone, FDA conducted five inspections: Teva API in the U.S., Ivax Pharmaceuticals in the Czech Republic, Teva Pharmaceutical Works in Hungary, Teva Tech in Israel, and Sicor de Mexico in Mexico.

The magnitude of FDA’s inspection challenge was clear from talks given at CPhI India conference sessions. The agency reported last year that it increased the number of foreign drug manufacturing inspections by 27% between 2007 and 2009 and has opened several international offices in locations such as China and India. Overall FDA had roughly 3,500 foreign drug plants to keep track of in 2008, a 185% increase from 2001, according to Surinder Raina, head of international marketing at Inventia Healthcare, an Indian drug company. In 2008, the U.S. Government Accountability Office reported that in the prior year FDA examined just 8% of foreign establishments subject to inspection.

For P. Reddy, business development manager at Hyderabad-based Hetero Drugs, manufacturing and marketing of APIs necessarily includes FDA inspections. HIV drugs are a prime focus for the company, which posts annual sales of more than $1 billion. Reddy said Hetero’s July agreement with Gilead Sciences for the manufacture and marketing of three of the U.S. firm’s developmental HIV drugs would not have been possible without a clean bill of health from FDA.

Some CPhI India attendees called for more FDA inspections, particularly for facilities operated by rival API manufacturers in China. Som Sekara of Central Drug House, an Indian fine chemicals importer and distributor that exhibited at CPhI India, said: “FDA is unable to keep up with globalization of the drug industry. As a result, inspections at several plants in China are almost nonexistent compared with facilities in the U.S. and Europe.”

Others noted that industry has a responsibility for self-policing. P. Chandrashekar, country manager for India at Carbosynth, a British firm that offers more than 2,000 carbohydrates and nucleosides, said proactively meeting high standards without regulatory prodding should be part of doing business. “Multinational pharmaceutical companies are eyeing the Indian specialty chemical market in a big way given the wide range of product availability and APIs,” he said. “It is imperative that Indian companies follow GMP standards.”

Carbosynth’s range includes monosaccharides, enzyme substrates, oligosaccharides, detergents, and nucleosides. Speaking about the foreign offices of FDA, including in China, Chandrashekar said, “FDA’s infrastructure is inadequate to inspect factories.” It’s better that companies take the initiative to ensure safe manufacturing, he added.