Quality Failures at Foreign Manufacturers Prompt Warnings and Recalls

FDA has been issuing warning letters and managing new import bans and product recalls related to a wave of potentially impure drugs and APIs from China, India, and other foreign firms. The increase in GMP-related violations, which has raised alarms about distribution of possibly harmful medicines, heightens concern about the ability of US and other established regulators to detect and address such failures, especially as drug makers increasingly rely on foreign operators for APIs and other drug components.

Most visible is a steady stream of recalls by manufacturers of valsartan, a widely used blood pressure medicine made largely with bulk ingredients from China. In June 2018, a leading Chinese manufacturer of the product, Zhejiang Huahai Pharmaceutical, informed customers that its valsartan contained traces of an impurity, N-nitrosodimethylamine (NDMA), which could cause cancer in certain amounts. Two other producers of bulk valsartan, in China and India, also disclosed a similar finding. The problem appears related to the use of a certain solvent in an updated manufacturing process, which may have been going on for several years. The lag in uncovering the situation raises questions about the conduct of pharmaceutical manufacturing operations in China, and the effectiveness of plant inspections by all parties.

These findings set off global recalls by some 50 firms that produce some 10 billion pills containing valsartan. In Europe, Novartis recalled Sandoz’ products containing valsartan, as did Teva, Stada, Dexcel Pharma, and others. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), stated in July that valsartan-containing medicines from Teva, Major Pharmaceuticals, and Solco Healthcare “did not meet our safety standards” and should be withdrawn.  In August, Torrent Pharmaceuticals recalled multiple lots of drugs containing the tainted API, as have additional pharma companies and repackagers.

The valsartan debacle comes on the heels of another major scandal in China over the production and distribution of substandard vaccines for children. Regulatory officials discovered falsified production data for DPT vaccines at Changsheng Biotechnology Co. in November 2017 but permitted the distribution of the preventive to continue for several months, until similar problems with a rabies vaccine appeared in July 2018. Additional Chinese vaccine makers have admitted to distributing faulty vaccines, igniting a call for reform. China’s National Drug Administration said it would conduct unannounced inspections of all vaccine manufacturers, in an effort to regain credibility for the regulatory regime. The vaccine problems largely affect domestic Chinese supplies but do little to raise confidence in manufacturing quality in that region.

More warnings

Perhaps due to greater attention to the quality of drugs and ingredients coming from foreign producers, FDA appears to be ramping up scrutiny of drug manufacturing operations in China and other Asian countries. FDA recently added six firms from China, India, and South Korea to its import alert roster following their refusal to admit FDA inspectors; products on the “red “list cannot be shipped to the United States.  

Recent FDA warning letters have cited drug makers in Japan and China for failure to resolve data integrity and validation issues uncovered in recent inspections. Another Chinese firm received a warning letter following its failure to address a range of manufacturing and testing issues detected in several previous inspections. FDA also released an inspection report (form 483) citing continued issues raised by recent inspections of Celltrion’s South Korean biotech manufacturing site.

Meanwhile, regulators seek to avoid enforcement actions that could lead to shortages of widely used medicines. FDA officials say they are monitoring supply situations closely in the wake of these widespread recalls and production disruptions.