The US Food and Drug Administration (FDA) visited the facility in Jinan, Shandong in January 2017 and found significant deviations from current good manufacturing practice (cGMP) for active pharmaceutical ingredients (API), resulting in a warning letter issued late last month.
“Your site is a contract testing lab that analyzes samples of heparin and heparin-related drugs for the presence of over-sulfated chondroitin sulfate (OSCS) using Nuclear Magnetic Resonance (NMR) spectroscopy,” the Agency states. “You failed to routinely establish system suitability when testing samples for OSCS.”
The company was also pulled up on its failure to investigate equipment failure during a system suitability test for detection of OSCS carried out in December last year.
“System suitability testing determines whether requirements for precision are satisfied and ensures the NMR spectrometer is fit for the intended testing before analyzing samples,” the letter says. “It is critical that your system be demonstrated as suitable for detecting OSCS contamination in heparin to avoid the possibility of samples erroneously passing when an instrument is not working properly.”
In 2008, more than 100 people died after suffering allergic reactions to heparin that had been made using API contaminated by OSCS.
Back then heparin API cost $12,000 a kilo and OSCS, which has similar chemical properties and was not detectable using analytical tests employed at the time, cost $20 a kilo.
At the time, then FDA commissioner Andrew von Eschenbach told a Senate Committee starting materials used by API supplier Scientific Protein Laboratories-Changzhou (SPL-CZ) had been bulked up with OSCS at an earlier point in the supply chain for economic reasons.
The tragedy prompted the FDA to ask manufacturers of heparin drugs and APIs to “audit and qualify their crude heparin suppliers to ensure conformance to appropriate quality standards.”
Shandong Analysis and Test Center was also found to have failed to prevent unauthorised access or changes to data, and failed to provide adequate controls to prevent manipulation and omission of data.
“During our inspection, we requested that you display original electronic data for analysis of heparin and heparin-related drug samples. Your analyst was unable to retrieve requested data, and explained that he deletes older data to make space for newly acquired data.”
The company also refused to provide the FDA during the inspection with data related to testing performed as a third-party, claiming it needed to obtain consent from several of its customers.
“When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs manufactured, processed, packed, or held in the facility may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection.”