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A question of quality
What exactly did Ranbaxy do to get slapped with a $500m fine? TOI-Crest lists the faulty manufacturing practices US authorities uncovered at one of its key plants.
Ranbaxy, it now appears, gave US authorities a seven-year itch. US Food and Drug Administration (FDA) inspectors first noted allegations about Ranbaxy's faulty manufacturing practices as early as 2006. This was soon followed by a whistleblower's lawsuit in 2007 alleging that the company defrauded US federal medical programmes by misrepresenting information on manufacturing procedures.
Soon, three of Ranbaxy's manufacturing plants - Dewas (in Madhya Pradesh), Paonta Sahib and Batamandi (both in Himachal Pradesh) - came under FDA scrutiny.
In one key unit, Dewas, FDA investigators Thomas J Arista and Robert D Tollefsen, after an inspection in early 2008, found massive deviations from the prescribed US current good manufacturing practice (CGMP) and regulations in the manufacture of sterile and non-sterile finished products. Violations of statutory requirements were also documented with respect to the manufacturing and control of what are called 'active pharmaceutical ingredients' (APIs). Despite explanations by Ranbaxy executives the inspectors came to a conclusion that the company failed to adequately address multiple and serious deficiencies.
"If you wish to continue to ship your products to the United States, it is your firm's responsibility to ensure compliance with all US standards for current good manufacturing practice, " reads the FDA's warning letter, dated September 16, 2008, to Ranbaxy.
But the export of drugs did not stop. Under the circumstances, the FDA did not refuse shipments of Ganciclovir, an important API for antiviral drugs, stating that Ranbaxy was its sole source supplier and that this drug was important enough to have a sufficient supply maintained.
The FDA's specific concerns about Dewas were about five broad areas of manufacturing. These included problems with what is called a 'beta-lactam containment program', inadequacies in batch production and control records, failure investigations, and with quality control programmes and aseptic operations. Three of these were critical to pushing the FDA to recommend action.
BETA-LACTAM CONTAINMENT CONTROL PROGRAMME
This was the real deal-breaker, apparently. Ranbaxy's 'interim controls' for the containment of beta-lactam antibiotics such as penicillins, cephalosporins, and penems were found to be grossly inadequate. Specifically, the FDA noted a failure in operations related to the manufacturing, processing, and packaging of penicillins as they were not adequately separated from non-penicillin products. During the inspection, investigators observed inadequate containment practices regarding the handling and movement of company staff, equipment, and materials. They objected to staff members of penicillin beta-lactam and non-penicillin beta-lactam units eating together in the same mess hall, said sources. In addition, staff working in the cephalosporin API dispensing area were also observed with powder on their gowns and were seen coming in direct contact with the outer surface of a bulk material bag that was then placed on transport equipment that could enter non beta-lactam areas.
Inspectors also pointed to operators and transport equipment (forklifts) being used to convey beta-lactam and non-beta-lactam materials to their respective manufacturing blocks in very close proximity to other personnel moving about freely on the campus.
The company's response on the issue lacked data to assure the USFDA that all gown parts could be adequately decontaminated, and even SOPs (Standard Operating Procedures) provided by them had no instructions on how such decontamination would be done.
Besides, FDA inspectors expressed concern that with the available facilities it could be difficult to detect beta-lactam contamination on porous surface materials such as operator gowns, corrugated cardboard boxes, and other types of materials mentioned in these reports.
PRODUCTION RECORDS INADEQUACIES
USFDA inspectors found that batch production and control records failed to include complete information relating to the production and control of each batch produced. For instance, production records failed to document weight or measure of excipients (usually an inert substance used as the 'vehicle' for the main ingredient of a drug) dispensed and used in production. Records also lacked second person verification to ensure that these weights or measures were correct. Records for sterile finished products also lacked complete information. For example, records did not document the name or initials of the individual operators who executed the manufacturing instructions, nor the individuals who performed the visual inspection of vials. These are meant to help pinpoint problems in the chain in retrospect, if discovered.
QUALITY CONTROL UNIT ISSUES
As per the USFDA's inspection report Ranbaxy's Quality Control Unit (QCU) failed to ensure that its organisational structure, procedures, processes, resources, and activities were adequate to ensure that APIs and drug products, sterile and non-sterile, meet their intended specifications for quality and purity. This is a serious charge, according to industry experts. The QCU here was not independent and did not properly discharge its quality assurance and quality control responsibilities, FDA inspectors found. They also stated that Ranbaxy's response failed to adequately address the need for corrections to prevent reoccurrence.
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