A Focus review (thanks to the Freedom of Information Act) of 50 Form 483s issued by the US Food and Drug Administration (FDA) to Indian pharmaceutical and active pharmaceutical ingredient (API) manufacturers over the past two years reveals a slew of detailed quality concerns from the agency.

And although the products described in the 483s have been redacted, and a majority of the FDA observations are for relatively commonplace documentation or procedural issues that will be (or already have been) corrected, there are a number of surprises, particularly as so many of the observations are for egregious errors like altering official documents in front of an inspector, or not maintaining bathrooms for employees, or documenting important manufacturing or electrical data on scrap paper in pencil.

What Is a 483?

Following an FDA inspection for a manufacturing plant – which usually lasts between three and seven days -- the agency provides a review of what it found, and based on that review, can issue a Form 483 to a company’s management with observations of any conditions that in the inspector’s judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related acts.

FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant, though as this review of 483s reveals, no two 483s are alike, and even the forms provided to the companies vary.

FDA Presence in India

As the Indian generic drug and API industries continue to be one of the main suppliers to the US, FDA’s presence in the country is important for ensuring the products are safe and effective. In February, FDA announced plans to double the number of its inspectors in India – from about nine to 19.

But even if FDA quadrupled its inspectorate in India, the agency would still have problems trying to physically inspect the more than 550 manufacturing sites the Indian government says are registered with FDA.

As far as the public release of Form 483s, FDA issues some of what it sends to foreign companies, though the vast majority of the reports have to be obtained via the Freedom of Information Act.

In addition to FDA, India’s regulator, known as the Central Drugs Standard Control Organization (CDSCO), also inspects local and multinational companies’ manufacturing facilities, although those inspection reports are not released publicly on its website and only one of the 50 Form 483s reviewed by Focus noted that CDSCO representatives were present for an inspection.

Recently, CDSCO announced it would set up a training program to address gaps in inspections. And CDSCO also has been uploading to its website a monthly list of drugs, devices and cosmetics that are either not of standard quality, spurious, adulterated or misbranded.

Companies Involved

All of the Indian companies receiving FDA Form 483s reviewed by Focus have products that are or were on the US market, though the sizes of the companies vary from small, like Divis Laboratories, to multi-national companies, like Hospira, Dr. Reddy’s and Wockhardt, which has other manufacturing sites in the UK, Ireland, US and France.

Other companies receiving the 483s reviewed include: Aarti, Akorn India, Ajanta Pharma, Agila Specialties, Apotex, Aurobindo, Cadila, Claris Injectables, Cipla, Emcure Pharmaceuticals, Glenmark Generics, Hetero, Indoco Remedies, Ipca Laboratories, Lupin, MegaFine Pharma, Nosch Labs, Pan Drugs, Shlipa Medicare and Sri Krishna Pharmaceuticals.

How Bad Does it Get?

Currently, 46 Indian manufacturing sites are listed on FDA’s import alert list, which bars the sites from shipping products to the US. Some of the Form 483s reviewed by Focus deal with these restricted sites.

For instance, analysts working at Aarti Drugs, which has two facilities on the FDA import alert list, had directed company software to overwrite previously collected chromatography data, causing the originally collected result to be automatically deleted. FDA noted:

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