The QMN Weekly Bulletin

47 Warning Letters Issued by CDER and Office of Prescription Drug Promotion in 2015

March 4, 2016

The FDA said its Center for Drug Evaluation and Research and the Office of Prescription Drug Promotion issued 47 warning letters last year, compared with 52 in 2014.

The FDA’s data did not include its district office warning letters, which will be issued at a later date.

The most active was CDER’s Office of Manufacturing Quality, which issued 20 warning letters — 13 related to GMP issues, including 10 to manufacturers of active pharmaceutical ingredients. OMQ issued 19 warning letters in 2014.

Data integrity issues were the most striking findings included in OMQ’s warning letters. The API makers that received warning letters for data integrity issues included seven drugmakers in India, two in China and one in Thailand. India has been plagued with warning letters over data integrity issues.

FDA investigators found data manipulation, cover-ups with faked test results, missing computer thumb drives, uneven paper trails, destroyed or misplaced records, backdated production reports, questionable records that were suddenly “found” after inspectors asked for them, and haphazard laboratory controls.

An analysis of the agency’s warning letters sheds light on the FDA’s own procedures as to what questions it posed and the answers it sought.

Each letter singled out unauthorized access or changes to data and failure to prevent data omission. Other oft-cited issues included failure to maintain complete data derived from all testing and destruction of original records.

Many of the issues can be traced to the companies’ quality assurance units. The warning letters note problems such as failure of the quality unit to ensure materials are appropriately tested and the results reported, lack of appropriate controls for batch records and lack of controls for documentation.

Moreover, data integrity issues uncovered during an inspection were almost always red flags for larger quality control issues, warning letters indicate.

Most of the letters urged companies to hire a third-party consultant with expertise in data integrity and GMP issues, and drugmakers were urged to review their entire organizational structure and personnel responsibilities.

The FDA also wants to see detailed management strategies and procedures for getting at root causes of data integrity practices affecting the quality of drug products.

Data integrity lapses have become so widespread globally, that even the World Health Organization stepped in last year, issuing guidance to bridge the gaps between the principles of good data and record management and actual practices.

Companies highlighted in the OMQ annual report were:

Zhejaiang Hisun Pharmaceutical Co, Ltd, China: A December FDA warning letter outlines the company’s “systemic data manipulation” and cGMP deficiencies uncovered during a March 2015 inspection. The warning letter to Hisun — which formed a joint venture with Pfizer in 2012 to make and sell some of the drug giant’s off-patent drugs in China — identifies a series of improper practices such as incomplete drug test results deleted from computer hard drives, a disabled audit trail and discarded chromatograms.

Cadila Healthcare Limited, India: FDA inspectors found numerous deficiencies in two of Cadila’s manufacturing facilities, including a lack of quality controls, improper recordkeeping and inadequate internal investigations. The company was repeatedly warned by the FDA about data integrity and impurity issues.

Dr. Reddy’s Laboratories Ltd, India: Following a November 2015 inspection, the FDA issued a lengthy warning letter over data integrity and GMP issues at three Dr. Reddy’s Laboratories facilities in India. The agency says the problems “represent long-standing failures to adequately resolve significant manufacturing quality problems.”

Unimark Remedies Ltd, India: During a March 2014 inspection, FDA investigators observed that Unimark Remedies had no unique usernames, passwords or user access levels in its computer system to prevent raw data from being deleted or altered. The investigators also noted that analytical testing data were poorly maintained and reviewed.

Pan Drugs Ltd., India: Pan Drugs Limited was hit with an FDA warning letter in September 2015, after an inspection revealed data integrity issues and significant cGMP violations. The FDA noted that the company continued to manufacture APIs for the U.S. market even though the facility was not cGMP compliant.

Sipra Labs Ltd, India: The company received an FDA warning letter for major cGMP violations, including failure to investigate batch discrepancies and failure to establish and document testing methods. During a Feb. 24 to March 1, 2014 inspection of the company’s Hyderabad, India, facility, investigators found that written procedures didn’t address the need to investigate unexpected events and out-of-trend batch results.

Mahendra Chemicals, India: During a May 2014 inspection, FDA investigators observed employees completing batch production record entries days after the operations had ended, releasing lots without proper approval and making notes on loose paper to record original, critical data, and then destroying the notes after transcribing them.

Yunnan Hande Bio-Tech. Co. Ltd., China: The FDA said the drugmaker lacked controls to prevent unauthorized access to and manipulation of raw electronic data, according to the April 6 warning letter. During the April 2014 inspection at the company’s Kunming, Yunnan Province, facility, FDA officials also found that computer software lacked active audit trail functions to record any data alterations.

Novacyl Ltd., Thailand: Novacyl failed to maintain complete raw data from testing and method validation, undermining its ability to evaluate the quality of its APIs, according to the FDA warning letter. During an April 2014, inspection, investigators observed a data analyst selectively invalidating data during API testing. The FDA said the company did not have a secure software system.

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