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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.” BUSTLING
Some of the tens of thousands of people who visited CPhI India.
INSPECTORS WELCOME Executives at CPhI INDIA call FDA scrutiny a part of doing pharmaceutical chemical business AMRUTHANAND NAIR, C&EN CONTRIBUTING EDITOR, MUMBAI
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
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
“If regular crackdowns are not allowed, another health crisis like heparin seems inevitable.”
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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. ◾
NANOTECH IN FOOD Lack of CLEAR REGULATIONS and safety information slows adoption THE YEAR 2000 was supposed to begin
a new era in food technology. Kraft Foods launched an ambitious effort called the NanoteK Consortium, made up of 15 universities and national labs, to fund research into personalized or “smart” foods, such as nanotechnology-enabled products that could respond to a person’s nutritional needs. Now, more than a decade later, Kraft and other food companies say they are not using nanotechnology in their products, at least not yet. The change of heart is not due to any proof that nanotechnology applied to food is harmful. Rather it is because in the years since food and food packaging were first identified as a market for the nanometerscale materials, a lack of understanding of the possible risks and benefits of the technology still exists. Last month, the corporate responsibility advocacy organization As You Sow introduced a framework to help food companies such as Kraft, McDonalds, Whole Foods Market, Yum! Brands, and PepsiCo work with their suppliers to determine whether nanomaterials are present in their products and, if present, to confirm their safety. Food makers, including Kraft, provided perspective and feedback on the framework. As You Sow Senior Strategist Michael Passoff says the food companies he approached were very open to talking about nanotechnology. “They are waiting to see how safety testing comes out, they are taking a precautionary approach,” he explains. “My guess is their stance is due to the controversy and backlash against genetically modified organisms. Also, there are bigger questions with nanotechnology such as, ‘Can the particles lodge in your lungs or get into your brain?’ ” Passoff says. He adds that food companies also feel hampered in the use of nanotechnology because the Food & Drug Administration has not provided industry with regulatory certainty. “There has been little government action. The regulatory agencies are missing in action on this issue,” Passoff says. For now, Kraft does not use nanotechnology in its products, but it has not closed the door on the subject. “As a leading food
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company, we need to understand the potential this technology may hold for us in terms of food safety, product quality, nutrition, and sustainability,” Kraft spokesman Richard Buino says. He identifies packaging as a possible application, “in particular, packaging that requires less material, which helps to reduce waste.” The As You Sow framework suggests that nutritional additives, flavorings and colorings, and antibacterial coatings for packaging are other potential avenues for applying nanotechnology. It warns the food industry to guard against unnecessary risks to consumers, workers, and investors and asks it to be transparent about the use of nanotechnology, including safety concerns, and to make sure suppliers are doing the same. EXPERTS BELIEVE that nanotechnology
is rarely used in foods, but they say it is difficult to find reliable information about the presence of nanoparticles in food. Jaydee Hanson, policy analyst at the watchdog group Center for Food Safety, has found only a few examples. He cites supplements that contain vitamins encapsulated with nanomaterials to improve bioavailability and nanoenhanced barriers to keep food fresher. MillerCoors, for instance, has introduced a plastic bottle that includes a sandwiched layer of nanoclay to keep out ultraviolet light and limit oxygen exchange. Hanson says he expects to soon see what he calls nanopesticides—including antimicrobials—used in packaging that comes into contact with food. Such an application would be regulated by both the Environmental Protection Agency and FDA. Recently, EPA gave conditional approval to the use of HeiQ AGS-20, a nanosilver-based antimicrobial, in textiles for socks, sportswear, undergarments, and other applications (C&EN, Dec. 12, 2011, page 21). “I’m not saying all uses of nanomaterials are bad,” Hanson says. “But certain sizes could be a problem. Particles smaller than 300 nm can cross the placental barrier. Those sizes might be useful for drugs, such as for cancer. But you don’t want a food product to be that small.”—MELODY BOMGARDNER
