USFDA 483 / Jubilant Roorkee / 3006895982 /1 Aug 2022 / Yvins Dezan & Rajiv R Srivastava / Observation 1.2 & 1.3

Failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Firm (on 11/10/2020) aborted an analysis for improper peak shape during dissolution test of batches of product; recorded Analytical Interruption Report No. AIR/20/0696.

Firm (on 11/10/2020) aborted an analysis for improper peak shape during dissolution test of batches of product; recorded Analytical Interruption Report No. AIR/20/0170.

Investigation identified poor column as the root cause; Based on this samples were retested in a different column and invalidated initial results. However, review of aborted sample set revealed that the peak shape for the said peak met the system suitability criteria. Review of the retest analysis sample test revealed unknown peaks eluting closely to main peak. These peaks were not seen in the method validation report 120 / HPLC Val (Effective date 12/26/2007) Validation of HPLC Method for the Dissolution (of product..).The firm shipped tablets that contain unknown peaks to US customers.

Analytical Interruption reports (industry uses different terminologies like Laboratory Error report, Laboratory Incident reports and so on) should be handled with same amount of seriousness and attention. There should be sound rationale when invalidating a sample set, analysis or chromatogram. And appropriate CAPA should be implemented so that the incident do not recur.

·        For example if a sample set is being invalidated as cited in the 483, there should be adequate elaboration and justifications – Why a sample set is being invalidated though it has met the system suitability criteria, what impact the peak shape can have on the result. The investigation should review all previous test results of the batch (covering a reasonably sufficient number of batches / time period) for peak shape performance; is it only in the specific set (which was aborted such a discrepancy is being observed. If not, there is no sufficient rationale for aborting such a chromatographic run.

·        If indeed there is a peak shape issue which could have impacted the analysis, it shows the current system suitability criteria are relaxed or not sufficiently address the requirements for proper peak shape and consistent and reproducible results. In this case appropriate corrective action should also be implemented by revising the system suitability criteria (This also will necessitate, impact review of earlier results).

The 483 by FDA also show that extra peaks / unknown peaks observed in any test, including dissolution would need attention and resolution. It is not unusual to see that many times, for extra peaks in the dissolution attention is not given unless something is significantly different. The extra peaks even in the dissolution test need to be acknowledged, reviewed, concluded with scientific rationale through an Analytical interruption or incidence report before concluding on disposition of the batch(es). Firms should have several measures in place to prevent / avoid such deficiencies.

• During method validation establish all excipient peaks, unspecified peaks, sample matrix peaks (including in the method for dissolution, assay, uniformity of dosage units etc). Cover excipients from more than one lot / source during such method validations to cover all possible sample matrix peaks.
• In the test method identify the sample matrix peaks which can be ignored (based on method validation).
• Analyst and analytical reviewer should pay attention to unknown peaks in all chromatographic analysis (be it dissolution, assay, residual solvents, impurities/related substances). Anything out of ordinary which is not justified by method validation reports, test methods should be investigated and concluded.

Such observation will need immediate investigation as the observation raises concern on batches of drug product shipped / distributed to US customers. 

• Typically, an immediate deviation to be logged on the observation and investigation initiated to establish the root cause for the unknown peaks & corrective and preventive actions including any market action.
• If within 3 days investigation is not concluded a Field Alert Report (FAR) may be initiated; Continue investigation to make a conclusion within a reasonable time (say a week to 10 days, in this case in time for the 483 response to FDA, which is to be submitted within 15 days. In the response to 483, elaborate all actions taken). 
• If the conclusion of the investigation is that the unknown peaks are a concern and impact quality of the drug product, Market actions such as Recall will need to be initiated. Similar actions should be considered even if the investigation is inconclusive, as a matter of abundant precaution considering patient safety. 
• The investigation can look at several things, example (but not limited to):
  
  • Manufacturing investigation – see whether any contamination possible from previous product(s), equipment, manufacturing facility, laboratory, sampling and sample handling.
  • Analytical investigations covering sample matrix effect, check different lots of excipients, degradation studies for the dissolution method, establishing retention times of all specified impurities in the dissolution method.
• Make appropriate conclusions on the reasons for the unknown peaks and identify corrective actions & preventive actions for the same.
• Based on the investigation and root cause, evaluate impact on previous batches of the product and identify actions required. Evaluation of impact on other products may also need to be considered (example – if the probable reason is contamination from previous product, equipment, facility cleaning methods, effectiveness, impact will need to be reviewed).