FDA Form 483s From India: A Deep Dive Into the Problems

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:

In addition, during FDA’s review of batch manufacturing records at Aarti, inspectors found that manual manufacturing activities for two different products were performed at the same time by the same employee, which is physically impossible.

And during FDA’s review of manufacturing operators’ “Training Evaluation Papers,” inspectors found that one quality assurance (QA) officer answered four of seven questions correctly during his evaluation following training on the company’s “Deviation & Change Control” procedures, and the test was scored as “8/10” and considered satisfactory.

Similarly, at Ipca Laboratories, which is also on the import alert list, an inspector found that a quality affairs officer had partially shredded training validation forms for multiple manufacturing operators, though a quality affairs officers said it was a mistake.

Akorn India is another example of a company with a history of issues with FDA. The companyhas its Paonta Sahib site listed on the FDA import alert list, where FDA found during an inspection of the quality assurance validation office, the presence of unauthorized QA document control stamps and partially completed and/or unofficial training records for a significant number of manufacturing operators.

In addition, an environmental monitoring document, known as the “Microbial Air Sampling Report,” was altered during the course of the firm’s photocopying of the record for the agency.

“No explanation was provided regarding the reason for altering this cGMP document requested as a part of this inspection,” FDA said.

For Cadila Healthcare, meanwhile, FDA found the company failed to adequately review 106 consumer complaints in 2013, and 132 in 2014.

FDA also apparently had to deal with a lack of willingness of the company to be forthcoming about incident reports. In one case, the inspector says: “After questioning more than five employees multiple times, the Vice President QA stated that the incident report is located offsite at an employee’s home.”

FDA also said this to Cadila concerning its recent recalls of products:

Data Quality

The issue of recording data properly from manufacturing operations is another one that continues to crop up in the Form 483s and elsewhere. Earlier this year, EMA recommended the suspension of a number of medicines that relied on clinical trials performed by GVK Biosciences that regulators were concerned had been manipulated.

In addition, over at Apotex Research Private Limited, which is dealing with other issues uncovered by Health Canada, FDA inspectors found that a QC microbiologist “was observed overwriting the dates for previously read (awaiting disposal) growth promotion plates using a black marker in order to make it appear that the growth promotion testing had been performed previously.”

And during a review of the firm’s analytical QC laboratories, FDA identified a company practice of retesting drug product samples when failing and/or otherwise undesirable chromatography results were encountered. FDA also had issues with the company's testing of drug samples:

The same issue cropped up at Mylan Laboratories’ Bangalore facility, where FDA inspectors said the good manufacturing practice (GMP) records used to record activities occurring inside the filling rooms are laminated pages. “Original raw data is recorded in marker on the surface of the laminated sheets. The marker can be erased,” FDA said, noting that there were examples where it appeared original data “had been erased and written over.”

In a review of Sun Pharmaceutical’s site in Ahmednagar, India -- which is not the import alert list, though another company site in Karkhadi is -- FDA inspectors found in one of the manufacturing areas, scrap paper for what appeared to be multiple manufacturing batches’ data, and while in the engineering electrical area, an inspector observed seven scrap papers which appeared to contain electrical raw data.

For another Sun site in Dadra, India, inspectors found that six “generic” user accounts had been created in the Laboratory Information Management software system, which are not traceable to the employee using the software, though users could delete particle size values, change sample weights, change related substance value entries and make other changes.

What’s to Come?

Although a number of these companies will (or already have) received warning letters from FDA or been placed on the import alert list based on these initial inspections, it’s difficult to gauge whether FDA has hit the tip of the iceberg with data integrity issues, or is seeing progress in how companies address them.

And because the inspections all deal with sensitive information, the best and only way to track these issues is to continue following the release of inspection reports from regulators worldwide, as well as the slow trickle of companies self-reporting when they receive a 483 or warning letter.