USFDA 483 / Lupin, Pithampur, India / FEI 3007549629/ Inspection Mar 21 – Mar 29, 2023 / FDA Inspectors – Eileen A Liu, Yvins Dezan / Observation 1

Investigations of a failure of a batch or any of its components to meet any of its specifications did not extend to other drug products that may have been associated with the specific failure or discrepancy.

Specifically,

During stability studies in September 2021 sample of drug product batch at 9 Month Long term Condition did not comply with specification limit – Out of specification (OOS-IO-153-21-0027). Investigation did not identify any laboratory error, hence OOS result stood valid. Manufacturing investigation concluded that surface imperfections and aberrations of material (of container closure system?) led to product loss under conditions of stability study, at specific orientation. (However, this batch of material underwent a successful incoming material inspection when they were received at the warehouse and was released by QA in September 2020; No issues of surface imperfections and aberrations were reported at that time).

The Firm performed impact assessment and the OOS batch and other batches were recalled. The investigation further identified the material was used for manufacture of more batches of drug product. These batches were in the US market and within expiry at the time of the investigation. No adequate justification for allowing the above impacted batches to remain in the US market until expiration.

When an OOS investigation identifies a root cause, whether this cause could be impacting other batches and products should be assessed. When root cause is deficiencies with an input material (e.g. Container closure system-Packing Materials, Excipients, API etc.) the impact assessment should consider all other potential batches in which the specific batch of input material is used; all the more so when it is a stability OOS.

It will be prudent to go one more step to look at whether previous batches of the input material could also have similar concerns. When issues are with input material, support from vendor should be ensured in the investigations and impact assessment. If investigation with vendor is able to identify the root cause for the issue with specific input material batch, it can also help in narrowing down and focus of the investigation by the Firm (drug product manufacturer)  – whether such an issue could be impacting limited number of vendor supplied batches, and consequently drug product batches. This will help the Firm in avoiding spreading out investigation / impact assessment to large number of batches.

The scope of assessment should cover all Batches within expiry which could be having a potential impact; followed by appropriate remedial actions (such as recall). If assessment concludes the potential impact is only on a smaller subset of batches out of all batches considered for impact evaluation, the rationale should be scientifically sound, justified and documented.

For deficiencies in input material, CAPAs should be established by vendor (to prevent recurrence) and also by the Firm (to ensure adequate measures to detect the deficiency / discrepancy in advance – during incoming material inspection).

Open up the OOS investigation, list out all batches which could be potentially impacted; Extend investigation to potential impact due to earlier batches (of input material).

Make an assessment of potential impact, affected batches (Firm can look at data from stability studies, investigation analysis of representative set of batches). If it is identified there could be other batches which are impacted (and within expiry) initiate recall.

Review whether an effective CAPA is implemented for the cause by vendor as well as by the Firm. If not, take up with the vendor to establish root cause for the deficiency and adequate CAPAs to prevent recurrence / and early detection of deficiencies at the Firm.

Review the OOS / failure investigation procedures to address investigation and Impact assessment elaborately with sufficient rationale. Train and coach personnel.