Posted FDA 483 Violations | Week of 9/16/18

It’s 483 study time, and our GMP expert has extracted the key points in this week’s featured 483 posted by the FDA. Violations ranged from failing to provide scientific reasons for invalidating OOS results to failing to prevent colored residues on equipment.


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  • Zhejiang Huahai Pharmaceutical Co. Ltd received an 11-page 483 at the close of inspection on August 3rd 2018.
    • The firm is located in China and manufactures the API for valsartan drug products containing a carcinogenic impurity. The firm had problematic FDA inspections in 2016 and 2017. I would not be surprised to see a warning letter in their future.
    • Various firms that used the API in manufacturing of drug products have recalled them. There is not yet an import alert for the firm. I would look for that in the future as well. Observations include but are not limited to:
      • The first observation basically tells the story that the firm did not have adequate procedures to determine what testing and validation activities were necessary to support manufacturing changes made to the API. Further, the information submitted to the FDA DMF in December 2013 classifies the change as ‘minor’ although internal documentation classified it as a critical change. Personally, I’m curious if the FDA ever followed up on the changes reported to the DMF during their subsequent inspections.
      • A corrective action to a confirmed OOS for a genotoxic impurity included reprocessing of 17 batches. Corrective or preventive actions were not put in place to ensure the process was under control. The 2nd observation lists multiple examples of why their validation protocols are inadequate.
      • Observations 3 and 4 indicts the adequacy of the Quality System, again with multiple examples.
      • Management of equipment maintenance is not adequate: equipment cleaning is not adequate and colored residues are visible. Equipment is not adequately maintained and repaired when problems are identified.
      • Substances such as lubricants, heating fluids, or coolant are not always food grade lubricants and oils. They are not tested prior to release and use.
      • There are not always sound scientific reasons given for invalidating OOS results (a repeat observation).
      • The firm does not have a quality agreement with their outside laboratory that specifies equipment validation, instrument software validation, and test method validation.
      • API returned from 1 customer for OOS results was reprocessed, given a new batch number, and sold to different customers. (NOTE: it’s not clear if the new purchaser was given the complete history of the new lot)
      • Sampling plans for API raw materials include instructions obscure non-homogeneous raw material batches.
      • Ongoing stability evaluation for the API is inadequate, addressed here are forced degradation studies.
      • Critical deviations are not always investigated, and it appears that operators may write incorrect results in batch records that are not in agreement with values from the equipment.

Remember, the FDA posts just a fraction of the thousands of 483s they issue. In contrast, we have over 11,000 Form FDA 483s in our database that are keyword tagged, searchable, cross-referenced for easy comparison, and easy to copy/paste/print.


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About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence.  She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry.  At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers.  She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc.  This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends.  This was an essential service and tool within the Corporate Audit function.

Unger Consulting Inc. | | 805.217.9360

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