The US Food and Drug Administration (FDA) has issued a Warning Letter to Mylan for its manufacturing plant in Morgantown, West Virginia for cGMP violations for finished pharmaceuticals following an inspection from March 19, 2018, to April 12, 2018. The company was cited for several quality-control issues, cleaning practices, investigations into out-of-specification (OOS) results and variations, and change-management practices.

The agency cited the company for several issues. It said that the company’s cleaning validation and verification program for manufacturing equipment was inadequate to prevent cross contamination. It noted many recurring incidents in which visible drug residues were found on non-dedicated equipment after the equipment was deemed clean by multiple staff. It also cited cleaning-swab failures related to detergent residue across numerous pieces of non-dedicated equipment and surfaces. Overall, the agency said that the company’s cleaning program was insufficient due to instances showing a lack of procedures, consistency in following cleaning protocols, documentation, verification, and validation.

The agency also cited the firm for inadequate investigations into out-of-specification (OOS) results and process deviations, noting that root causes did not consistently include scientifically supported conclusions.

The agency also said that changes in blend size, formulation, and manufacture of the company’s drug products were not evaluated consistently, appropriately, or thoroughly before execution. It also noted that the company failed to use its change-management system for significant changes and that numerous batches with major process changes were not included in its stability program. Overall, the agency said that the company’s rigorous oversight of manufacturing changes continues to be a major factor in the unexpected variation observed in the company’s drug products.

Overall, the agency said the company’s quality unit “is not fully exercising its authority and/or responsibilities” and that the company’s quality systems are not adequate. It cited prior cGMP violations at the Morgantown facility and other facilities in the company’s network. This included the citing of three facilities in 2015 for among other things, inadequate controls for manufacturing sterile drugs; failure to establish scientifically sound and appropriate laboratory controls; and failure to thoroughly investigate unexplained discrepancies. The agency also cited the firm in 2017 for, among other things, invalidating numerous initial OOS assay results without sufficient investigations to determine the root cause of the initial failure.

In response, the FDA is requiring the company to do several things. With respect to its cleaning program, the agency is requesting that the company provide evidence of a validated program in which cleaning procedures used to remove active ingredients and detergents from production equipment can consistently meet predetermined and scientifically sound specifications. It also is requiring the company to provide validation and verification relating to the number, location, timing, and frequency of cleaning swabs on equipment and to provide a retrospective investigation into all cleaning-swab failures and identify the root cause of the failures. It is also asking the company to update its cleaning training programs for its production and quality assurance employees.

With respect to its findings on OOS results, the agency is requiring the company to provide a retrospective, independent review of all OOS (raw materials, in-process testing, and finished testing) results obtained for drug products currently within expiry and to provide a corrective action preventive action plan (CAPA) plan that identifies manufacturing root causes and specifies meaningful improvements. It is also asking the company to provide a retrospective, independent evaluation of the adequacy of major manufacturing investigations (e.g., deviations, rejects) performed for products currently within expiry and a comprehensive, independent assessment of its overall system for investigations of deviations, atypical events, complaints, OOS results, and failures.

With respect to change-management issues, the FDA is requiring the company to provide a comprehensive, independent evaluation of its change-management system as well as an independent, retrospective review of any changes that may have significantly increased variation in manufacturing for all batches within expiry.

Source: FDA