IPCA unit at Dhar, Madhya Pradesh, India issued USFDA 483 with 8 (eight) observations after inspection in June 2023. Observations include invalidation of OOS based on inconclusive hypothesis, inadequate hold time studies, inadequate dissolution methods & deployment of dissolution methods, significant scratches, dents in manufacturing equipment, inadequate cleaning of equipment, poor clean room gowns with tears, holes, stains, worn out booties, ineffective CAPAs on complaints. The audit was conducted by USFDA investigators Saleem A Akhtar, Rajiv R Srivastava, Wenzheng Zhang Read More..
Failure to thoroughly review unexplained discrepancies. Out of specification results on multiple batches of tablets were invalidated based on inconclusive hypothesis
In an OOS of a batch of tablets for dissolution test at 9 month long term stability condition, no root cause could be established in Phase 1 & Phase II investigations. Firm performed a hypothesis testing for assigning a cause for the OOS which was inconclusive. Based on inconclusive hypothesis testing, the sample was retested and OOS invalidated.
One of the three batches of tablets analysed in same sequence in HPLC was OOS for assay at the the 3rd month long term stability station. No root cause was established in Phase 1A & Phase IIA investigations. Hypothesis testing was performed for possible sample preparation error, hypothesising the analyst could have used higher pressure causing higher assay in one batch. Based on this inconclusive hypothesis, sample retested and OOS was invalidated. All the three sample preparations were by same trained analyst.
One of the three batches of tablets analysed in same sequence in HPLC was OOS for assay. No root cause was established in Phase 1A & Phase IIA investigations. It was hypothesised that the OOS could be due to error in vial filling and sample tested, and based on the inconclusive hypothesis, sample retested and OOS invalidated. No manufacturing investigation was performed.
In a Process validation exercise, for initial sample set (1x-3x) OOS was reported in two units. No root cause was established in Phase 1A & Phase IIA investigations. In Phase IIB increased sample size was used (3x-5x) as per protocol and again two units were OOS. Further an Addendum was created to the protocol and a higher size sample (5x-7x) was taken from Inprocess Bulk Containers (IBC – which is different from the equipment where initial samples were collected) and tested. The samples were collected beyond the hold time. Based on this test, the initial OOS was invalidated and batch proceeded for compression.
Hold time study data carried out during Process Validation was inadequate. Some parameters for hold time studies are not tested on samples collected from the Inprocess Bulk Containers (IBC), but these parameters are extrapolated from the sample analysis data at the completion of the stage. But the material used for drug product manufacturing is stored in IBCs. There were 12 OOS results in test related to assay between 2020 to 2023 out of which 10 were invalidated.
In the UV methods used for dissolution testing of drug product, the system suitability test (involving only one blank, one standard, one sample) do not establish the system suitability. Without demonstrating system suitability, all the dissolution data analysed by the UV method for the commercial and exhibit batches are invalid
Cleaning and maintenance of equipment are inadequate:
Significant scratches and dents were observed in product contact area in at least two manufacturing equipment, caused due to scraping of product in the past. While the Firm continued to use the equipment, no risk assessment is performed for the impact on products manufactured.
Cleaned and verified Equipment component/ part was seen to be clogged with build up of residues at various locations.
Deficiencies were observed in the deployment of Dissolution testing procedure.
Dissolution test did not start when the tablets are immersed into the dissolution media, and test was manually started after a delay during which the tablets are in contact with the dissolution media. This time is not accounted for in dissolution time.
The autosampler pulls the sample from the dissolution bowl with a delay after rinsing of the tubes during which the baskets containing the tablets do not stop and continue to rotate at the set rpm.
The rinsing volume programmed (set) for the rinsing of the sample tubes was not matching the actual rise volume measured at the end of the test.
Failure to control the laboratory test methods in the computerized system LES (Laboratory Execution System) Method creation and method builder software; It had more than 60 methods with different naming such as Trial, Test 0, 123..
Personal gowning used in the core manufacturing areas including dispensing and compression areas is in poor condition. Gowns, Arm sleeves, Booties had tears, holes, stains, worn out in numerous places.
When CAPAs for Complaints are not effective, new CAPAs are not assigned.
Leave a Comment
You must be logged in to post a comment.