May 30, 2017

After a bit of a lull, the U.S. Food and Drug Administration (FDA) issued a batch of warning letters focused on pharmaceutical manufacturing quality issues in the first quarter of 2017. Examples of quality control problems found within these FDA warning letters included unsatisfactory investigations, inadequate documentation, and poor data integrity practices.

GMP in the FDA’s Crosshairs

After an investigation that stretched from June 27, 2016, to July 15, 2016, FDA investigators inspected Trone Health Services, Inc. It issued a strong verdict in a March 22 letter. Observation includes:

Your quality unit failed to monitor and investigate error signals generated by the computerized systems that you use for high-performance liquid chromatography and gas chromatography. These signals indicated the loss or deletion of original CGMP analytical data. However, your quality unit did not comprehensively address the error signals or determine the scope or impact of lost or deleted data until after these problems were reviewed during our inspection.”

Unfortunately, reactive investigations and corrective actions after a warning letter do not meet FDA expectations for effective pharmaceutical manufacturer quality processes.

Pharmaceutical Manufacturer’s Ongoing Quality Management Problems

The FDA also investigated an API and finished drug manufacturers.  Its CGMPs are under deep scrutiny for improperly investigating out of specification (OOS) issues.

In a February warning letter, the FDA cited Wockhardt, a subsidiary of Morton Grove Pharmaceuticals, using “an unvalidated and experimental manufacturing process.”

Morton Grove is cited with performing investigations without quality unit oversight by failing to monitor production.  Product variations were identified, but the pharmaceutical manufacturer did not take adequate measures to “to address the source(s) of the variation and provide for a continued state of control.”

Such a lack of an adequate program for monitoring pharmaceutical manufacturing quality processes is an imminent safety risk.

With six previous warning letters dating back to 2013, Wockhardt faces legal action including seizure and injunction.  Executive management is being held fully responsible for all deficiencies and non-compliance.  They are expected to oversee and ensure that its global quality management and regulatory compliance system is fixed quickly.

FDA Identifies Lack of Documentation for Sterilization Process

The FDA issued a February 24 warning letter to India-based API manufacturer Megafine Pharma. A September 2016 inspection of the Gujarat, India facility identified several GMP-related problems.  Inspectors found the interior surfaces of the facility’s equipment were not as clean as required and found the facility lacked written procedures for cleaning equipment and equipment usage records.

As a result, the FDA demanded to see a plan to fix the problem and for a report on the corrective actions taken since the warning letter was issued.

After another inspection, the FDA issued a March 16 letter to drug manufacturer Opto-Pharm, citing a lack of written procedures for preventing contamination of sterile drug products.

To manufacture drugs or additives in compliance with FDA standards, all operators must be knowledgeable of the process for cleaning sterile products and other equipment.  Without the proper quality management system in place to control and distribute documentation, public safety is put at risk.


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Red Flag on Records and Data Integrity

FDA also delivered an April 3 warning letter to Pennsylvania-based Mylan Pharmaceuticals after inspecting one of the drug manufacturer’s Indian facilities.

The FDA cited Mylan for data deficiencies across operations. The extent is under review but could include “omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies.”

Extensive manual data gathering and tracking seem almost impractical in today’s pharmaceutical manufacturing environment.  Logically, the solution to correct this red flag is to implement a fully automated quality and compliance management system like AssurX.

Conclusion: FDA’s Pharmaceutical Manufacturing Quality Concerns Continue

The FDA continues to expect major improvements in pharmaceutical manufacturing quality management. While it’s anyone’s guess, given today’s federal government budget debate, it still appears likely the FDA will continue its focus on GMP and data integrity issues through 2017. If an FDA investigator finds related problems at your facility, don’t expect a lot of sympathies.