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US FDA to expand scrutiny into Sun Pharma data

LiveMint logoLiveMint 22-05-2014 C.H. Unnikrishnan

Mumbai: Sun Pharmaceutical Industries Ltd seems headed for more trouble with the US Food Drug Administration (US FDA), which in its latest letter to the company on its Karkhadi factory in Gujarat has pointed to company-wide data integrity issues similar to those that plagued Ranbaxy Laboratories.

In April, Sun acquired Ranbaxy in a deal worth $3.2 billion.

The 7 May letter, posted on the FDA’s website, which says Sun’s response to FDA’s earlier findings is inadequate, was reported in Indian media, including Mint, on Wednesday.

What the reports missed out was that the US regulator was raising concerns about the integrity of “all data” generated by Sun Pharma.

FDA, which has banned imports from Sun Pharma’s factory in Karkhadi, is expanding its scrutiny to the company’s other factories, including the two export-oriented ingredient production sites and two formulation units located in Gujarat, Maharashtra and Dadra and Nagar Haveli, said two people familiar with the development, asking not to be identified.

“We had sent our response to the import alert received earlier and, given that the facility now has a warning letter, it’s clear that the USFDA does not agree with our view,” said a Sun Pharma spokesperson.

A data integrity issue found in a manufacturing compliance inspection process is a serious issue as it could result in charges of fraud and forging of documents. This could attract heavier penalties.

The country’s largest drug maker Ranbaxy, which was allegedly involved in such practices at its FDA-approved manufacturing sites in India in 2008, had to pay a penalty of $500 million three years ago.

Four export-oriented manufacturing units of Ranbaxy, which used to generate almost half of its revenue from the US, are still under an import ban.

The USFDA could inspect all of Sun Pharma’s facilities as early as next week, a third person familiar with the matter said. “FDA inspectors have visited a couple of Sun Pharma units already and there will be detailed inspection in the next few weeks,” said this person, who asked not to be identified.

The issue also highlights problems faced by Indian drug makers operating in an international market for generic or off-patent drugs, which is both extremely competitive and highly regulated.

The data management, documentation and adherence to so-called good manufacturing practices (GMP) have all become critical, as have knowledge of the intellectual property (IP) regime across countries and legal expertise.

Since May 2013, the FDA has clamped down on over 10 big Indian pharmaceutical manufacturers over problems with their data integrity practices. The companies include Sun Pharma, USV Ltd, Wockhardt Ltd and RPG Life Sciences Ltd.

Data integrity or reliability issues of all these pharma companies typically revolve around not reporting “failed” results, conducting unofficial analysis, deleting electronic data, disabling audit trails in electronic data capture systems, fabricating training data, having unofficial batch sheets and analytical reports, re-analyzing failed samples till passing results are obtained, back-dating data, and not reporting stability failures.

Since most plants of these pharma companies are export-oriented, they have to follow current GMP to ensure their products are manufactured to specific requirements including identity, strength, quality and purity.

GMP is regulated by the USFDA, and the Code of Federal Regulations (CFR) is a codification of the general and permanent rules of the federal government. The CFRs that relate to current GMP in pharmaceutical companies comprise 21 CFR (pharmaceutical and biotechnology companies) Part 11, 210 and 211. In general, 21 CFR Part 210 governs current good management practices (cGMP) for manufacturing, processing, packaging or holding of drugs.

Part 210 includes the definitions that are used in the regulations such as batch, lot, etc, while 21 CFR Part 211 is for cGMP for finished pharmaceuticals; 21 CFR Part 11 contains the guidelines on electronic records and electronic signatures. Part 11 defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and are equivalent to paper records. Part 11 also applies to submissions made to the FDA in electronic format.

The integrity of data generated by any company is one of the main criteria to determine its credibility. The problem arises when these standards are not met.

Till about three years back, Indian pharma companies would get time to “clean up their act before USFDA inspections, but now they just get a day’s notice and hence get caught,” said Uday Shetty, a pharmaceutical consultant who runs a website,, and has worked with pharmaceutical companies like Janssen, GSK and Wyeth, where he supervised large teams in quality and product development.

“This is not related to training or understanding a particular technical or quality concept, but mainly related to honesty and ethical issues. Further, what is more disturbing is that senior management and company owners appear to either support such practices covertly or overtly and in many instances encourage them,” said Shetty, who also advises non-governmental organisations (NGOs) about medical malpractices.

India, on its part, does not have stringent laws on data integrity because the Drugs and Cosmetics Act 1940 is an “archaic” law that does not cover this subject, according to Pavan Duggal, a lawyer with the Supreme Court.

There are no specific laws in India to cover data integrity, he said. While the Information Technology (IT) Rules, 2011 of the IT Act 2000 (Amended in 2008) cover electronic medical records, they do not cover medical records pertaining to pharmaceuticals and formulations, though these too are electronic records.

In fact, even the IT Act 2000 did not have any provision for data integrity.

“It only provided for data authentication which contributed to data integrity,” said Duggal, adding that even today the IT Rules 2011 do not cover issues like “passwords, financial services, medical data and biometric data”.

On Tuesday, USFDA posted the warning letter regarding Sun Pharma’s Karkhadi factory after reviewing the company’s responses to the FDA inspection findings in November.

“Several examples suggest a general lack of reliability and accuracy of data generated by your firm’s laboratory, which is a serious cGMP (current good manufacturing practices) deficiency that raises concerns about the integrity of all data generated by your firm,” the FDA said in the warning letter, citing interviews and conversations with employees and material evidence.

“...the inspection revealed numerous examples of the deleted GC electronic raw data files on the computer controlling the GC (gas chromatography) instruments that were replaced with the identical “official” chromatogram file names. The identically named GC data files that were deleted had been created at different times and contained disparate data. Also, it appeared that data was not consistently archived to the central server,” the USFDA added.

The regulator has also asked the company to provide a list of all the batches of drug products shipped to the US market and ingredients intended for use in drugs to be distributed within the US that relied upon missing, inaccurate, or unreliable records.

The letter was a response to Sun Pharma’s first two responses to the regulator. In the letter, the FDA has specified that Sun Pharma’s corrective actions at the site were insufficient.

“This seem to be a case of clear data integrity issue as it was in the case of Ranbaxy,” a USFDA consultant, who was formerly a senior director at its compliance cell, said Thursday.

The consultant declined to be named.

“We will be responding in detail in due course on all the matters highlighted in the (FDA) letter,” Sun Pharma’s spokesperson said.

“In this process, we have learnt and have resolved to work on further strengthening our systems and controls.”

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