FDA inspectors last month spent two weeks inspecting the plant of the Chinese API maker after learning its valsartan contained an impurity that is a suspected carcinogen.
Inspectors had been in the plant twice before, including last year, but this was the first visit to list observations that strike at the heart of the manufacturing changes made by Zhejiang Huahai Pharmaceutical (ZHP) that are suspected of producing the impurity that resulted in a global recall of its valsartan.
In an 11-observation, highly redacted Form 483 posted today, the FDA berated the management for making the process changes without thoroughly testing them. It also documents that the changes in producing the API were made in 2011, much earlier than originally suggested.
It says Huahai did not conduct and document a formal risk assessment for the change "to evaluate the potential impact of proposed changes on the quality of the intermediates or the final API for this critical change to your validated manufacturing process..."
The plant did use an outside firm to “conduct a lab-scale research project and then used the results from that to validate the commercial scale change.” Many of the other 10 observations hark back to the processes change, saying it did not perform enough investigations, or provide adequate documentation for the changes.
It said that in 2016 and 2017 the plant initiated 17 out-of-spec inventions for an impurity and attributed 13 to lab errors, five to production errors and two to a combo of the two. ZHP reprocessed all 17 batches.
The FDA acknowledged last month that it was a U.S. drugmaker that first alerted the agency that the valsartan API it got from the Chinese ingredient maker contained a potentially dangerous impurity. In the process of investigating, the FDA learned something it hadn’t known: that a combination of manufacturing conditions could lead to formation of the N-nitrosodimethylamine impurity in an API. The FDA had twice before inspected the plant and issued Form 483's but those did not criticize the process changes.
The discovery has led to a global recall of more than half of all valsartan products on the market (PDF), but the FDA said patients can still find untainted products (PDF) from other producers. While the levels of NDMA in ZHP’s valsartan API were trace amounts, they were considered unacceptable, the FDA has said.
Regulators also started looking into the chemical class of “genotoxic impurities,” into which valsartan falls, and last week said it uncovered a second and unexpected cancer-causing impurity in three batches of the blood pressure medicine valsartan that were sold by Torrent Pharmaceuticals. The regulatory agency said the newest impurity to be found was N-Nitrosodiethylamine (NDEA), which is a known animal and suspected human carcinogen. The products tested were included in Torrent’s recall last month.