OMQ’s End-of-Year Review Finds Many Issues With Overseas cGMP Practices

The FDA repeatedly blasted overseas drugmakers last year for disregarding compliance orders and not living up to their own promises to carry out proper cGMP practices for active pharmaceutical ingredients.

Along the way, the FDA inspectors allegedly found data manipulation, cover-ups or faked test results, missing computer thumb drives, mysterious lost-or-found documents, rough-notes and haphazard laboratory controls. Those findings were among the many reasons the FDA said it needed to raise questions about the drugmakers’ data reliability and authenticity.

They were the most striking findings included in the FDA Office of Manufacturing Quality’s 2015 annual report list of warning letters to companies for cGMP violations. The targeted companies included seven in India, two in China and one in Thailand.

The agency’s warning letters, which mostly came in the wake of Form 483 reviews, shed light on the FDA’s own procedures — what questions it posed and answers it sought — from drugmakers in the spotlight.

Time after time, FDA inspectors said drugmakers weren’t specific or “clear” enough in their answers to questions they posed. Often, they advised drugmakers to hire independent third-party auditors or contractors to assist the companies in evaluating product quality and obtain the details necessary about operations. The FDA also advised companies that sell drugs worldwide to conduct a review of their global operations to ensure cGMP compliance.

In that way, the FDA said, drugmakers could take steps to ensure the quality of APIs and the integrity of data used, as well as put together a comprehensive plan. It is “essential” and “critical” that each drugmaker implement controls to prevent data omissions or alterations, as well as have a proper risk assessment of the potential impact of drug product quality and management strategy.

Those 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 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 following inspections in 2014. It has been repeatedly warned by the FDA about data integrity and impurity issues. At its Ahmedabad facility, the FDA told Cadila its manufacturing process “is not in a state of control,” yet drugs were still being released to market. The company also used “rough or unofficial” notebooks to document GMP activities.
  • Dr. Reddy’s Laboratories Ltd, India: Following a Nov. 5, 2015 inspection, the FDA issued a lengthy warning letter to Dr. Reddy’s Laboratories for three India facilities for data integrity and cGMP issues that the agency says “represent long-standing failures to adequately resolve significant manufacturing quality problems.” In the warning letter, the FDA sternly told the drugmaker: “It is apparent that you have not implemented a robust quality system at your sites.”
  • Unimark Remedies Ltd, India: During a March 18 to 21, 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: Sipra 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 19, 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, 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 a warning letter. During the April 14 to 17, 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 21 through April 25, 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.
  • Cadila Pharmaceuticals Ltd, India: The FDA warned Cadila Pharmaceuticals in a Feb. 25, 2015 warning letter about cGMP violations that include quality controls, complaint handling and data integrity at its Gujarat, India, active pharmaceutical ingredients manufacturing plant. Cadila’s APIs failed to meet specifications for quality and purity, and the company released an API batch with an unknown peak in the residual solvents chromatogram that neither the analyst nor supervisor noticed or evaluated during reviews, the agency says. This is not the first time Cadila has been warned on data integrity and impurity issues, the FDA said.
    — Joe Cantlupe


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