Documentation and records Findings

The batch production and control records are deficient in that they do not include documentation of the accomplishment of each significant step in processing and packing.

The written MDR procedure does not include documentation and recordkeeping requirements for all information that was evaluated to determine if an event was reportable.

Batch production and control records do not include complete information relating to the production and control of each batch.

The inspection resulted in a critical deficiency related to contamination risk in the Fluid Bed Coating (FBC) equipment due to an observed pool of liquid and residue in a section of the inlet air plenum of a fully cleaned FBC. The flaws were due to common design between FBCs (inclination of plenum not allowing gravity draining) and inadequate cleaning procedure. In addition, there was no detectability of a failure in HEPA filter integrity through real-time monitoring of pressure differential before and after the supply air HEPA filter of the Air Handling Units of the FBCs. There were eleven (11) major findings relating to: Inadequate Master Batch Record instructions and production documentation; Deficient process validation, including insufficient coverage of process, demonstration of its reproducibility and pellet homogeneity; Incomplete cleaning validation; Differential pressure excursions; Deficient warehouse, sampling and dispensing controls; Inadequate vendor qualification; Inadequate identification testing of incoming starting materials, Excipient risk assessments, Out-of-Specification handling, Equipment qualification and Pest control. Action taken/proposed by the NCA: Revocation of the marketing authorisation(s) Member states should consider not initiating or authorising new marketing authorisations with this site listed as an intermediate product manufacturer until the recommended non-compliance statement to be issued remains in place or is not superseded with a GMP certificate. Prohibition of supply No products batches manufactured at the site should be released to EEA markets until this non-compliance remains in place or is superseded by an EU GMP certificate.

Your firm failed to determine actual yield and percentages of theoretical yield at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product [21 CFR 211.103]. Specifically, in addition to the deficiencies noted in the visual inspection reject rate calculations, our review of the data collected during the inspection revealed that the acceptable yield range established in your batch records permits yields as low as (b)(4) , allowing up to (b)(4) of a batch to be rejected without triggering an investigation, yet the batch can still be released for distribution. Furthermore, although (b)(4) meets the definition of particulate matter as “mobile undissolved particles, other than air bubbles, unintentionally present in solutions” in SOP-061 (Visual Inspection Finished Product, Rev. 23), it was classified as a “minor” defect in ISSUE-2025-0011, without scientific justification or a clear procedural basis in SOP-061. By classifying (b)(4) as a minor defect rather than as particulate matter, (b)(4) rejects are counted only as part of the minor reject rate limit, bypassing both the major defect category trigger and the separate particulate category trigger entirely. Additionally, certain “cosmetic” defects are allowed to be returned to the batch, despite SOP-061 containing no definition, criteria, or examples of what constitutes a “cosmetic” defect, nor does it specify which cosmetic defect may be returned to the batch and which must be rejected.

Batch production and control records do not include in-process results for each batch of drug product produced.