The past week saw three enforcement actions in the area of data integrity, two from Europe and one from the FDA. The Eudra GMP postings of non-compliance identified two new reports regarding API manufacturing sites in China. The national inspectorates involved were the Polish authorities and the French authorities. These are summary reports of non-compliance rather than a complete inspection report and do not have the granularity of an FDA warning letter or form 483. The FDA posted a warning letter issued to a clinical investigator that also falls into the area of data integrity deficiencies. I cover all three below.
- The Polish authorities inspected Chengdu Okay Pharmaceutical Co. Ltd. (Sichuan Province, China) and determined that they do not comply with EU GMPs. The inspection was conducted October 28, 2015 and results were posted February 21, 2016. Data integrity issues are front and center at this API manufacturer. Twenty one (21) deficiencies were identified. Five (5) were identified as ‘critical’ and ten (10) were classified as ‘major’. The translation provided was difficult to understand in parts, but it appears that the critical deficiencies were observed primarily in the QC area. Those associated with data integriy include, but were not limited to:
- Lack of records to support impurity calculation in a reference standard used to qualify an in-house standard. Integrity of the data could not be guaranteed.
- Impurities and active ingredient content were incorrectly calculated.
- Data supporting the conditions used for HPLC analysis were not confirmed.
- Documentation and control of computerized systems were deficient as follows:
- When the method used was changed, the previous method was not retained
- The HPLC system could be accessed without a login or password. Thus, actions conducted within the system are not attributable to a specific individual.
- The firm did not have a procedure describing access control for the HPLC system. This, combined with the preceding item, point to a failure to ensure that only authorized individuals have access to the system.
- The firm did not have a list of personnel authorized to access the HPLC system.
- One computer station held two different HPLC software.
- The presented means of measuring pH were inadequate to explain the results in the batch record.
- Some HVAC qualification data were falsified.
- The French authorities determined that Dongying Tiandong Pharmaceutical Co., Ltd (Shandong Province China) was not operating in compliance with the EU GMPs. The inspection was conducted December 9, 2015 and the summary report was posted February 25, 2016. The firm manufactures non-sterile APIs including heparin sodium and enoxaparin sodium. Ten (10) deficiencies were identified, two (2) were classified critical and three (3) were classified major.
- CRITICAL: PCR results obtained from the approved suppliers of Crude Heparin appeared to be manipulated. No evidence was available to support that the samples retested for the presence of ruminant DNA came from the same batch tested initially. Remember that heparin is isolated from porcine intestines, so the presence of ruminant DNA suggests cross contamination or possibly purposeful adulteration.
- CRITICAL: Documentation was not available to support the traceability of the supply chain. Supply chain knowledge is key in ensuring that only raw materials and components from qualified vendors are used.
- MAJOR: Includes failure to appropriately manage OOS events; when new suppliers were added there was no delivery document available nor was the testing systematically recorded in the logbook; and finally, the NMR spectrum used to identify enoxaparin sodium and heparin sodium included an additional peak that as not identified or investigated.
Proposed actions include possible withdrawal of the current GMP certificate and removal of the site from MAs. Further, consideration should be given to recall of existing product and finally the site should not be named in any MA while the non-compliant designation remains in effect.
- The FDA issued a warning letter to Gregory J. Tracey MD (Hoboken NJ) on December 16, 2015 that was posted this past week on the FDA website. Briefly, he failed to ensure that only patients who met the inclusion criteria were enrolled in the clinical study. Patients were required to have a negative serum pregnancy test; if positive, they were to be excluded from the trial. Based on the warning letter, it seems that in multiple instances Dr. Tracey signed off on laboratory results that showed a positive serum pregnancy test prior to enrollment and did not disqualify the individual from enrollment. Further the checklist showed the box was checked ‘no’ for whether the subject had a positive serum pregnancy tests at screening or check in. The warning letter states “…you signed a statement that you had reviewed the subject’s inclusion/exclusion criteria and source documentation for the study; that you acknowledged having reviewed those records in order to determine the subject’s eligibility to receive study drug; and that you had determined that the subject was eligible to receive study drug. However, as noted above, your determination that Subject 1214 was eligible to receive study drug was contrary to the protocol, because the records that you had signed indicated that Subject 1214 had a positive serum pregnancy test at screening, at rescreening, and at check-in.” The patient received two doses of the drug, did not return to the clinic and withdrew from the study. At the study withdrawal evaluation , another blood test was conducted and again the result was a positive HCG test.