1. Failure to adequately investigate and document out-of-specification results according to a procedure, and implement appropriate corrective actions.
- Our investigator found that your firm repeatedly, and without justification, resampled and retested crude heparin batches when your quantitative polymerase chain reaction (Q-PCR) test for ruminant DNA exceeded your established specification limit of ≤ (b)(4) parts per million (ppm). As a result, your firm used crude heparin batches that potentially were out-of-specification (OOS) to manufacture heparin sodium API for the U.S. market.
- For example, according to your Deviation Handling Sheet No.07-2015021, you resampled and tested crude heparin batch Y102-1504005 multiple times, with the following results.
Ruminant DNA Q-PCR test results for batch Y102-1504005
- Specification (ppm)
- Value (ppm)
- Result
- Sample one
- (b)(4)
- 47.4
- OOS
- Sample two
- (b)(4)
- 343.0
- OOS
- Sample three
- (b)(4)
- 2.3
- batch released
- Similarly, your initial test results for another crude heparin batch (Y102-1503008) were also OOS. Again, you resampled without justification, and accepted the batch when you obtained results within specification.
- Disregarding the OOS results, and resampling and retesting without scientific justification, constitutes “testing into compliance.” This practice is unscientific and objectionable under CGMP.
- Your response is inadequate because you did not adequately address how you would investigate OOS lab results prior to resampling.
- For further reference regarding OOS test results, see the guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production available online at
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- Similarly, your initial test results for another crude heparin batch (Y102-1503008) were also OOS. Again, you resampled without justification, and accepted the batch when you obtained results within specification.
- Disregarding the OOS results, and resampling and retesting without scientific justification, constitutes “testing into compliance.” This practice is unscientific and objectionable under CGMP.
- Your response is inadequate because you did not adequately address how you would investigate OOS lab results prior to resampling.
- For further reference regarding OOS test results, see the guidance for industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production available online at http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf.
- In response to this letter, send us the results of your retroactive review of all Q-PCR test results for crude heparin used to manufacture API for the U.S. market. Include your detailed sampling procedure for preparing crude heparin samples for analysis.
2. Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
- During the inspection, our investigator reviewed your Q-PCR method to determine whether crude heparin batches you receive were contaminated with ruminant DNA. Our investigator identified deficiencies in your validation of your test method for detecting ruminant DNA, including failure to directly compare your Q-PCR method to FDA’s posted method: http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm350289.htm
- Although you performed a supplemental validation study for your ruminant DNA test method, you did not report a robust comparability study to the posted FDA method. You may use an alternate validated method; however, you must be able to demonstrate that the alternate method is as sensitive, or more sensitive, in detecting ruminant DNA as FDA’s posted method. We have concerns that your test method for ruminant DNA may be inadequate.
- As you have had repeated difficulty in implementing an alternate method for detecting ruminant DNA in your incoming crude heparin, we recommend that in response to this letter, you commit to implementing the FDA method and provide a timeline for full implementation.
3. Failure to adequately monitor your crude heparin suppliers.
- As part of your crude heparin supplier qualification program, you sampled material from potential suppliers and tested for ruminant DNA, among otherspecifications. If a potential supplier’s material failed testing for ruminant DNA, you did not use that supplier.
- However, when an already-qualified supplier provided material that failed ruminant DNA testing, you did not reject the material and reevaluate the raw material supplier’s qualification status.
- It is critical that your quality unit makes all supplier selection decisions, and continually evaluates the qualification status of suppliers to ensure their suitability and competence. In the event of adverse information, supplier disqualification may be necessary.
- In response to this letter, please provide a list of all of your current crude heparin suppliers and your procedure to continually monitor the acceptability of your crude heparin suppliers. Also please perform a full requalification of all current crude heparin suppliers and provide a summary report of this requalification, including a list of any suppliers that have been disqualified.
4. Failure of the quality unit to ensure that all critical deviations are investigated and resolved.
- During the inspection, our investigator reviewed the high pressure liquid chromatography (HPLC) assay of over-sulfated chondroitin sulfate (OSCS) for crude heparin batches Y102-1404007, Y102-1404008, Y102-1404009, Y102-1404010, Y102-1404011, and Y102-1404012. The investigator found that the heparin standard and system suitability tests were run in isolation, rather than contemporaneously, approximately10 hours after the initial assay was completed.
- One of your employees explained that the analyst discovered that the system suitability sequence failed during the initial sample sequence. Instead of invalidating the associated sample results, the analyst reran the system suitability sequence with the heparin standard and the OSCS control.
- Passing system suitability testing indicates that requirements for precision are satisfied and HPLC functions appropriately: in this case, detecting the contaminant OSCS in heparin. The failure of your HPLC system suitability testing calls the validity of OSCS testing performed on the same equipment into question.
- We acknowledge that your SOP Abnormal Incidents in the QC Lab, which you provided with your response, establishes procedures for handling OOS incidents in the future.
- In response to this letter, provide the results of your retrospective review of all HPLC results for OSCS. Your review should demonstrate that:
- your test results are accurate you document and investigate interrupted HPLC runsyou perform passing system suitability results in the same sequence as the evaluated samples
- For further reference regarding heparin, see the guidance for industry Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality available online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390.pdf.
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