India manufacturing-site findings

The inspection resulted in a critical deficiency on inadequate cleaning validation as well as eight (8) major findings. These dealt with inadequate control of identification labels inside the manufacturing area, inadequate management of visual inspection activities, sterilized product passing through an area where un-sterilized bags were waiting to be autoclaved, inadequate container closure integrity testing and delayed action to correct this very long standing issue, process validation inadequacies, deficient complaint management, deficient management of aseptic process simulations as well as insufficient qualification of manufacturers and suppliers of critical starting materials and no reassurance that primary packaging materials for ophthalmic products were free from contamination. There were also 24 other deficiencies, in addition to the critical and major findings. All these observed deficiencies raise concerns that the approach to the manufacturing of sterile products is not adequately managing inherent risks pertaining to sterile processes and is not in line with applicable EU GMP requirements. As a result of this outcome, the Inspection Review Group (IRG) at the Malta Medicines Authority has met and decided that a Statement of Non-Compliance with the principles and guidelines of EU Good Manufacturing Practice is to be issued for the site. Action taken/proposed by the NCA: Prohibition of supply No products batches manufactured at the site should be released to EEA markets until this noncompliance remains in place or is superseded by an EU GMP certificate. Others Member states should consider not initiating or authorising new marketing authorisations with this site listed as a finished product manufacturer until the recommended non-compliance statement to be issued remains in place or is not superseded with a GMP certificate. The following applications are known to be ongoing: Sodium Chloride Intravenous Infusion – 0.9% w/v, nPVC bag 0.9% w/v Czechia (RMS), Germany (CMS), Spain (CMS) & Portugal (CMS) Ref. CZ/H/1558/001/DC Timolol 5 mg/mL Eye Drops Solution 5 mg/mL, 5 ml LDPE bottle Spain , Malta, Portugal, Hungary DCP slot requested in September 2025.

During the inspection, multiple critical and major deficiencies were identified across the facility, particularly in areas directly associated with the aseptic manufacture of medicinal products. The nature and extent of these deficiencies demonstrate systemic weaknesses in contamination control, aseptic behaviour, equipment integrity, data governance, and quality control practices, which collectively pose a significant risk to the sterility, safety and overall quality of the products manufactured in Block A. Critical failures were observed in facility design and pressure cascade maintenance, including inadequate differential pressures between classified and non classified areas, reversed pressure gradients, and layout constraints that resulted in sterile API being exposed in Grade B. These issues undermine the fundamental environmental controls required for aseptic processing. Serious concerns were also identified regarding personnel behaviour and aseptic practices, with operators failing to comply with gowning requirements, aseptic discipline, RABS handling procedures, and environmental protection measures. Such behaviours directly compromise sterility assurance and indicate insufficient training and oversight. The inspection further revealed equipment in poor condition, including rusted pass box, unclean balance and step ladder, and the use of open containers for rejected materials and IPC samples within Grade B. These deficiencies represent unacceptable contamination risks within critical manufacturing areas. Significant weaknesses were found in the organisation and control of materials and GMP documentation, including the presence of operational documents, microbiology records, Petri dishes, and other materials stored in uncontrolled areas such as the expansion zone. The discovery of a deteriorated and unidentified gas cylinder connected to a pipeline used for aseptic filling further heightened concerns regarding uncontrolled substances potentially coming into contact with the product. Critical data integrity failures were identified, including missing records, inconsistent entries, unclear terminology, and analytical activities reported but not performed. These issues undermine the reliability of GMP documentation and raise concerns regarding the accuracy of batch release decisions. In the Quality Control laboratories, essential tests for APIs were not performed by the manufacturer, retention samples were improperly stored, finished product samples lacked proper identification, and sterility testing was conducted using unsuitable equipment. These deficiencies critically affect the validity of analytical results and the assurance of product quality. Major gaps were also identified in the Contamination Control Strategy (CCS), which was implemented late and failed to address several contamination risks, including API exposure in Grade B, environmental monitoring vulnerabilities, personnel limits, HEPA filter replacement rationale, and disinfectant approval. Finally, batch documentation lacked evidence of required sampling and incomplete line clearance verification, compromising batch traceability and readiness for aseptic operations. Action taken/proposed by the NCA: Others The Portuguese market is not impacted, as no medicinal products have been placed on the market by the manufacturer concerned, and alternative manufacturers with medicinal products containing the same active substance and strength are authorised in Portugal. It was decided that, for the manufacturer concerned, a Non-Compliance Report (NCR) was issued until all critical and major deficiencies have been adequately addressed and their implementation confirmed through a follow-up inspection.

Employees engaged in the manufacture and processing of a drug product lack the training and experience required to perform their assigned functions.

Changes to written procedures are not reviewed and approved by the quality control unit.

The written stability program for drug products does not include reliable, meaningful and specific test methods.

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written and followed.