FDA Inspection Notes 10 Problems With Biocon's Manufacturing Facility

The FDA’s Office of Surveillance has released its findings from an inspection of Biocon’s troubled manufacturing facility in Bangalore, India.

The FDA inspectors listed 10 observations made during the agency’s inspection conducted during May and June of 2017:

• Inadequate investigation of unexplained discrepancies among batches. The report notes that Biocon did not properly investigate the presence of visible particulate material that had been observed in an injectable drug since August 2015. The drug in question continues to be sold in Uruguay, Russia, and the Dominican Republic.
• Inadequate validation of sterilization processes. Procedures designed to prevent microbiological contamination of drugs do not include validation of sterilization processes. Aseptic personnel are not tracked, there are no requirements for qualifying personnel during microbiological growth media fills, the process used to sterilize gloves has not been validated, filling times are not tracked during microbiological growth media fills, and the procedure used to validate the HVAC system does not take into account microbial levels.
• Deficient monitoring of environmental conditions. Aseptic operators are held to lower qualifications than necessary, there are no specified locations for environmental monitoring, and a protocol for microbiological monitoring of controlled environments is not followed.
• No establishment of procedures designed to prevent microbiological contamination of sterile drug products. Validation of the effectiveness of disinfectants is not performed, there are no disposal records for expired cleanroom garments, and staff were observed picking up cleaning cloths that had been dropped on the floor.
• Incomplete laboratory records. An FDA microbiologist reported different readings on equipment from those reported by the facility’s microbiologist, and not all internal records can be reconciled. Data from the leak testing of sterile gloves is not documented.
• Deficient procedures for cleaning and maintaining equipment. The firm lacks a scientific rationale for its disinfecting practices, numerous surfaces are not routinely disinfected, and inquiries into microorganisms found during previous investigations were delayed by months.
• Lack of authority in the quality control unit. The facility’s quality control department lacks the authority or responsibility to approve or reject drug products or components. The inspectors noted that vendor qualification procedures are not enforced for sterile gloves and that expired materials are in unrestricted use.
• Lack of training for employees who manufacture and process drugs. The FDA inspectors found that colony growth on the facility’s environmental and personnel monitoring plates are often enumerated incorrectly, and that personnel with administrator rights to critical information technology systems do not have documented training.
• Lack of scientifically sound laboratory controls. The firm lacks procedures adequate to assure the identity, strength, quality, and purity of drug products. The firm’s bacterial endotoxin testing for finished products is deficient and could lead to false negative results. The pH testing protocol of samples is also deficient.
• Labeling procedures are not followed. Rejected labels can be found in an unsecured waste bin, rather than under lock and key.

The extensive, 8-page report comes on heels of similarly critical assessment from the French National Agency for Medicines and Health Products Safety (ANSM), which noted 35 problems at the facility, 11 of which were deemed major deficiencies. The ANSM recommended to the European Medicines Agency that no batch of any of the 3 biosimilars addressed in its findings be supplied to the European marketplace, and that the marketing authorizations for the products be revoked until ANSM can verify that all of its recommendations have been implemented.

Biocon’s trastuzumab biosimilar, MYL-1401O, which the company developed in collaboration with Mylan, is among the drugs identified in ANSM’s report as being affected by the deficiencies. The FDA’s Oncologic Drugs Advisory Committee voted unanimously to recommend approval of MYL-1401O in its July 13, 2017 meeting, during which no mention of the facility’s issues was made. With regulatory action for MYL-1401O expected in September, the inspection report raises the question of whether approval of the drug could be delayed until Biocon takes corrective action in its facility.