EMA (Europe) Data integrity findings

During the inspection of the manufacturing site, in the frame of EDQM’s inspection progamme, 21 deficiencies against EU GMP were identified. One deficiency was classified as critical due to inadequate control of contamination and cross-contamination risk in shared facilities. The risk assessments and contamination control strategy for Workshop 2 and the dispensing area were insufficiently robust, specific, justified, and effectively implemented, notably for exposed product operations, gowning, area and equipment cleanliness, material entry, dispensing activities, and the use of shared equipment for potentially highly potent products. Furthermore, absence of contraindications between APIs manufactured in the shared facility was not evaluated consistently. These represent a potential risk to patient safety. Five deficiencies were classified as major and were related to the following areas: cleaning validation and cleaning procedures, preventive maintenance and equipment condition, data integrity, change control management, and batch release and compliance to CEP. In addition, 15 other deficiencies were found (i.e. records, quality system, personnel training, calibration, labelling management, equipment qualification). Action taken/proposed by the NCA: Requested Variation of the marketing authorisation(s) For medicinal products containing APIs manufactured by LIANYUNGANG GUIKE PHARMACEUTICAL CO. LTD. in Workshop 2, assessment of the MA to remove or substitute this manufacturer of active substances and intermediates should be considered. In addition, no new MAs should be granted for products relying on this API source while the statement of non-compliance remains in force. Recall of batches already released If there are alternative suppliers and there is no risk of shortage, recall of medicinal product should be evaluated by the involved NCAs following assessment conducted in conjunction with MAHs. Prohibition of supply Due to the nature of the non-compliance, prohibition of supply is recommended, unless there are no alternative suppliers and there is a risk of shortage. Suspension or voiding of CEP (action to be taken by EDQM) The EDQM had taken the decision to suspend all granted CEPs from LIANYUNGANG GUIKE PHARMACEUTICAL CO. LTD. CEP 2013-019 Atracurium besilate CEP 2021-236 Cisatracurium besilate CEP 2017-271 Entecavir monohydrate (intermediate)

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.

An inspection performed by AIFA between 22 and 24 June 2026 identified serious and systemic deficiencies affecting the Pharmaceutical Quality System and the implementation of EU GMP requirements applicable to aseptic preparation of parenteral nutrition products. Twelve major deficiencies were identified. • Pharmaceutical Quality System deficiencies. • Inadequate documentation and data integrity controls. • Deficiencies in computerized systems validation and electronic data management. • Inadequate Contamination Control Strategy. • Deficiencies in aseptic process simulation (APS/media fill). • Deficiencies in environmental and microbiological monitoring. • Inadequate qualification and validation activities. • Deficiencies in personnel training, supplier qualification and quality control oversight. Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. IT/265/H/2024 Regulatory Action Taken A Statement of Non-Compliance with GMP has been issued. Suspension of the manufacturing authorization No. aM-194/2024. While a state of non-compliance with GMP requirements was identified, the Inspection Team also took into account the nature of the medicinal products manufactured at the site, which are intended for patients receiving parenteral nutrition and therefore constitute essential and potentially life-sustaining therapies. Based on the inspection findings, no evidence emerged indicating an immediate and concrete risk to patient health associated with batches already manufactured and distributed. Consequently, following a risk-benefit assessment, which was considered favourable to the continued use of the medicinal products already supplied, the Inspection Team does not consider it necessary, based on the information currently available, to recommend the recall of batches already manufactured and distributed. Others The site manufactures sterile parenteral nutrition preparations exclusively on a medical prescription basis pursuant to Article 5 of Directive 2001/83/EC, as transposed into Italian legislation by Legislative Decree No. 219/2006. Parenteral nutrition preparations are supplied exclusively to the Italian market on a medical prescription basis (Article 5 of Directive 2001/83/EC). No actions for other countries are needed.

During the visit, critical and major deficiencies in compliance with EU Good Manufacturing Practices (GMP) were observed in the authorised facilities in building 3. In general, these deficiencies were related to an non-existent Pharmaceutical Quality System and, consequently, affecting all the site’s authorised activities: poor or non-existent supplier approval, control and release of raw materials, facility maintenance and cleaning, access control, management of planned changes and deviations, personnel qualification and training, qualification/calibration control and equipment management, manufacturing operations, prevention of cross-contamination, comply with procedures, management of documentation and data integrity, among others. Furthermore, the inspection revealed an insufficient and ineffective monitoring of the company's review quality system activities, as deficiencies identified in previous inspections have not been addressed. These deficiencies pose a risk to the quality and safety of the veterinary medicinal products manufactured. It should be noted that the company has a history of non-compliance with EU GMP Guidelines according to previous inspection reports. The manufacturing authorisation (MIA) had been suspended in September 2022, following the inspection on November 2021, but suspension was lifted after the inspection on July 2023. In addition, the last day of inspection (June 17th) an adjacent building belonging to the company LABORATORIOS EURISKO, S.L. (located in the "El Molí" Industrial Park, building 1B) was inspected. This building was not declared in the Site Master File, and it is not authorised for the manufacture and/or storage of medicinal products and active substances. In building 1B inspectors found a large quantity of veterinary medicinal products in their final packaging (liquids for internal use and powders for oral solution), intermediates (bulk solution), active substances, starting materials, samples, and other non-medicinal products, such as supplements, as well as production equipment and manufacturing documentation (including delivery notes, invoices, and production records) related to veterinary medicines and active substances. All these materials, documents, and equipment were outside the control of the quality system, poorly identified, and managed in a manner that did not ensure their proper traceability, integrity, or preservation. It was demonstrated that unauthorised manufacturing activities of veterinary medicinal products were being carried out in building 1B without meeting any of the applicable quality requirements and controls and necessary guarantees, in compliance with Good Manufacturing Practices (GMP). It was also detected that distribution activities of active substances were being performed without registration in the applicable API Register. The unauthorised manufacturing activity performed in building 1B had not been detected in previous inspections, although it has been ongoing for several years, as evidenced by the documentation reviewed. Furthermore, based on the labelling of medicinal products and available customer invoices, it is evident that most part of the products are intended for export, for which the company lacks the required authorisations. Action taken/proposed by the NCA: Suspension of the manufacturing authorisation No. 6558 in Full Recall of batches already released Recall of any medicinal product manufactured at LABORATORIOS EURISKO, S.L. is proposed. Prohibition of supply Taking into account the deficiencies identified during the inspection it is concluded that all the products manufactured by LABORATORIOS EURISKO, S.L. are affected by the GMP non-compliance. During the inspection, veterinary medicinal products containing the following actives substances with the pharmaceutical form liquids for internal use and powders for oral solution were found: Norfloxacin, Ciprofloxacin, Enrofloxacin, Kanamycin, Cephalexin, Tylosin, Doxycycline, Neomycin, Gentamicin, Erythromycin, Amoxicillin, Ivermectin, Amprolium, Albendazole, Sulfachloropyridazine, Acetylsalicylic acid, Florfenicol, Ampicillin and Piperazine (non-exhaustive list). In building 3 one pilot batch STI15012025 and the three validation batches STI18122025A, STI18122025B and STI18122025C of Norfloxacin were legally manufactured since 2023. The pilot batch was released on 03/11/2025 destined for Bangladesh and the three validation batches were released on 01/03/2026 destined for Bangladesh, too. Veterinary medicinal products manufactured in the unauthorised facility were intended for distribution and export to Greece, Lebanon, Bangladesh, Siria, Oman and Yemen. The reviewed documentation indicates that exports of medicinal products to these countries have been carried out. Other destinations countries cannot be ruled out. The reviewed documentation during the inspection indicates that the company has distributed and export active substances (Kanamycin, Cephalexin, Tylosin, Amoxicillin and Piperazine) to the following countries: Greece, Lebanon, Oman and Yemen. Other destination countries cannot be ruled out.

An onsite GMP inspection was conducted following an application received by the company (Zenzi Pharmaceutical Industries Private Limited), to assess compliance with EU GMP guidelines. The company was previously granted EU GMP certificate DK/H/10000/726 dated 01/05/2023 following an EU GMP inspection conducted on 10/02/2023 (last day of the inspection). Since this inspection the business in the EU shifted from Dune Medicare ApS, Denmark to Forza Advance Limited, Malta with respect to responsibility for EU Batch Release. Three years since the last GMP inspection elapsed on 10/02/2026. During the onsite inspection performed between 26th – 31st March 2026, the inspectors observed 2 Critical, 7 Major and a total of 17 Other issues. The first critical finding related to the Pharmaceutical Quality System (PQS). The management and documentation of the PQS was found to be severely lacking in various aspects. The Quality Assurance department was also not adequately resourced. Senior management leadership and active participation was not ensuring an effective PQS. The headcount at QA was a total of 6 personnel shared between the inspected Oral Solid Dosage Block and a Sterile Injectable block (out of this inspection’s scope). From the inspection findings and observations made it was clear that the QA department was not able to maintain an adequate PQS and could not respond to the inspection requests effectively. Control of documentation was not in place to ensure that documents are current, effectively updated and securely distributed. High-level documents were not current at the time of their effectiveness, nor identified for revision at the time of the inspection. The management of change control, deviations, risk assessments and good documentation practices within the organisation were also found to be severely lacking. The second critical finding related to Data Integrity violations which were observed during the inspection. Various Logbooks/Registers were present in various forms other than hard bound, ranging from clipped with different paper and ink, stapled and loose papers in plastic folders. Evidence of reissued parts of logbooks replacing original parts were observed during the inspection. This raised serious concerns related to integrity and reliance on logbooks’ content. Other data integrity concerns included backdating practices which were observed three times on two occasions during the course of the inspection. Audit trail was disabled from chromatographic sequences in QC analysis. The password complexity policy for software was not enforced with high protection requirements. Deliberate false information was given to the inspector for the password length setting set by IT administrator in the Agilent Open Labs software. Sequence files for HPLC and GC were in folders with read/write access allowing renaming and deleting of data by analysts. Sequence files whose analysis was reviewed complete in one month showed modified dates in another month. Seven “Major” findings were identified related to supplier qualification, training and medical examination of employees, temperature mapping, primary and secondary packaging operations, Quality Control operations, sampling, and storage of API not in accordance with the product labelling. 17 findings which were classified as “Others” were also identified. 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 Good Manufacturing Practice laid down in Directive (EU) 2017/1572 is to be issued for the site. Action taken/proposed by the NCA: Others Member states should consider whether review of any current active marketing authorisations is necessary and 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.

Critical and major GMP deficiencies were identified during the inspection of the manufacturing site in the frame of EDQM's inspection programme. These included significant failures in quality management oversight, data integrity, materials management, equipment cleaning and maintenance, and facility conditions. The deficiencies demonstrated a lack of effective quality system and inadequate control over GMP-relevant operations. Critical data integrity issues were observed, undermining the reliability of manufacturing and quality control data. Due to the systemic nature of the deficiencies, it cannot be ensured that active substances manufactured at the site comply with EU GMP requirements. No specific evidence of defective batches placed on the market was identified during the inspection. Action taken/proposed by the NCA: Suspension or voiding of CEP (action to be taken by EDQM) The EDQM AdHoc Committee decided to suspend the following CEPs: CEP 2019-123 / Clopidogrel hydrogen sulfate, CEP 2020-318 / Levetiracetam, CEP 2023-153 / Rosuvastatin calcium, CEP 2024-419 / Thioctic acid. Furthermore, the EDQM AdHoc Committee decided to remove Cadchem Laboratories Limited as intermediate manufacturer from CEP 2017-247, CEP 2014-176, CEP 2021-052 and CEP 2025-295.