The QMN Weekly Bulletin
Pharmaceuticals / Quality / Regulatory Affairs

Warning Letters Reveal Quality Systems Issues for Finished Drugmakers

April 1, 2016

Batches of hastily assembled drug products distributed too soon and failure to document quality systems activities were among a host of GMP issues drugmakers violated, sometimes more than a year after the FDA first expressed concerns about companies’ repeated lapses during inspections.

Companies consistently failed to provide adequate information on their quality system methodology, detailed testing procedures and validation reports, and they ignored significant consumer complaints, according to an analysis of 2015 warning letters issued by FDA’s Office of Manufacturing Quality.

What flummoxed FDA investigators most was that some drug companies showed the same violations, despite the agency expressing concerns previously. For instance, some did not test APIs from suppliers to make sure they met standards, and often had no procedures in place to cull products that didn’t meet specifications. Problems also were linked to improper monitoring systems, inadequate recording of test results and inadequate cleaning room practices.

In some cases, companies failed to properly package products in a sterile environment, and the FDA noted that cleaning was not a substitute for segregation. Of the nine companies cited for finished products, four were in India, and the others were in Canada, Hong Kong, the Czech Republic, New Zealand and Italy.

Data integrity issues once again topped the agency’s list of concerns for finished drug makers. An analysis of warning letters to API makers yielded similar findings.

The FDA advised companies to ensure that laboratory records include complete data, with appropriate controls for computer systems. Investigators repeatedly told companies they needed to justify any deviation from required laboratory control mechanisms.

Companies highlighted in the OMQ annual report were:

Sun Pharmaceuticals, India: The FDA uncovered a litany of violations, from untested ventilation and unhygienic practices to the use of uncalibrated equipment. The FDA asked for a summary of the company’s quality system methodology, detailed and revised testing procedures and validation reports.

Chan Yat Hing Medicine Factory of Kowloon, Hong Kong: The company continually released multiple batches of drugs for distribution, despite failing to test finished batches for identity and strength of active ingredients. It also failed to ensure the identity of components including active ingredients and excipients from suppliers, or establish written procedures for production and process controls.

Sandoz International, Germany: Inspections of the company’s sites in Kalwe and Turbhe, Maharashtra, India, revealed serious documentation and data integrity lapses. Investigators discovered that staff recommended reporting an out-of-specification result to the agency, only to have the regulatory affairs department not inform the FDA until the product was approved. Investigators also noticed that “uncontrolled” Excel spreadsheets were used to record discrepancies and in-process quality data. The data were initially missing in batch records, but were later entered into the records and backdated. 

Mylan Industries, India: The FDA issued warnings about GMP compliance at three Indian plants after serious deficiencies were uncovered that should have been corrected after Mylan acquired Agila in December 2013. The concerns included lapses in clean-room practices, such as torn clothing and failure to wear sanitized gloves. Investigators also concluded that the plant’s building management and nonviable particle monitoring systems were “out of control”.

Hospira, Italy: The FDA handed Hospira in May its seventh warning letter in seven years and the second in the previous six months. The latest was for poor sterile processing, inadequate investigations into batch failures and data integrity weaknesses at its Liscate, Italy, manufacturing plant. Hospira also failed to establish and follow procedures for preventing contamination of sterile drugs, including understanding how activities in the clean room could compromise sterility.

Apotex, India: Canadian generic maker Apotix was hit with a warning letter for serious GMP lapses at its Bangalore, India, finished plant. According to the letter, Apotex failed to adequately record test results and microbiological test plates were missing for various finished drug products. The plant’s quality unit also failed to review and approve production, and control records didn’t take adequate security measures to ensure only qualified personnel made changes to master production and control records.

Micro Labs Limited, India: An inspection of Micro Labs Bangalore facility showed the manufacturer ignored poor test results. The May 2014 inspection discovered scores of laboratory test records with uninvestigated out-of-specification results.

Attix Pharmaceuticals, Canada: The Canadian drugmaker remained on import alert for failure to appropriately package drug products to avoid cross contamination. Attix failed to package beta-lactam drug products in a sterile environment, the letter says, and it didn’t use separate facilities to manufacture products and allowed personnel and materials to move freely between beta-lactam and nonbeta-lactam manufacturing areas.

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