Lessons from CDER's Quality Management Maturity Pilot Programs.

Between October 2020 and March 2022, FDA's Center for Drug Evaluation and Research (CDER) completed two pilot programs to assess the quality management maturity (QMM) of drug manufacturing establishments. Mature quality systems promote proactive detection of vulnerabilities, prevent problems before they occur, and foster a culture that rewards process and system improvements. A CDER QMM program may help to advance supply chain resiliency and robustness and mitigate drug shortages.

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue.

Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression.

Second-site mutations selected in transcriptional regulatory sequences compensate for engineered mutations in the vesicular stomatitis virus nucleocapsid protein.

The active template for RNA synthesis for vesicular stomatitis virus (VSV) and other negative-strand viruses is the RNA genome in association with the nucleocapsid (N) protein. The N protein molecules sequester the genomic RNA and are linked together by a network of noncovalent interactions. We previously demonstrated that mutations predicted to weaken interactions between adjacent N protein molecules altered the levels of RNA synthesis directed from subgenomic ribonucleoprotein (RNP) templates.

Importance of hydrogen bond contacts between the N protein and RNA genome of vesicular stomatitis virus in encapsidation and RNA synthesis.

Vesicular stomatitis virus (VSV) genomic RNA encapsidated by the nucleocapsid (N) protein is the template for transcription and replication by the viral polymerase. We analyzed the 2.9-A structure of the VSV N protein bound to RNA (T.

Mutations in the C-terminal loop of the nucleocapsid protein affect vesicular stomatitis virus RNA replication and transcription differentially.

The 2.9-A structure of the vesicular stomatitis virus nucleocapsid (N) protein bound to RNA shows the RNA to be tightly sequestered between the two lobes of the N protein. Domain movement of the lobes of the N protein has been postulated to facilitate polymerase access to the RNA template.