Spain manufacturing-site findings

During the inspection, a total of nine (9) deficiencies were identified, one (1) of them were classified as critical and eight (8) as major. The deficiencies identified demonstrate significant weakness in the pharmaceutical quality system implemented at the site and raise serious concerns regarding the reliability of manufacturing, storage, documentation, cross contamination control, traceability and quality assurance oversight activities. The critical deficiency related to the repackaging, relabelling and distribution of bismuth subsalicylate originating from a Chinese manufacturing operating outside the EU GMP framework. The inspection demonstrated that OCB PHARMACEUTICAL, S.R.L. assigned new batch numbers, issued certificates of analysis containing analytical results copied from supplier documentation, removed or replaced original labels and distributed the material to pharmaceutical costumers without adequately preserving the identity of the original manufacturer and the traceability of the supply chain. These practices gave the material the appearance of being associated with OCB PHARMACEUTICAL, S.R.L. manufacturing activities, not complying with GMP Part II requirements concerning the integrity and traceability of the supply chain. Major deficiencies were identified in the effectiveness of the deviation, investigation, CAPA and risk management system; data integrity controls, personnel qualification and training; material management and traceability; contamination and cross-contamination control measures; maintenance and cleaning of facilities and equipment; documentation practices; and quality system governance. The combination of these deficiencies indicates that the quality management system is not capable of consistently ensuring the manufacture, storage and distribution of active substances in compliance with GMP Part II requirements.Particular concerns were identified regarding the design, maintenance, qualification and operation of HVAC systems and differential pressure controls, recurring environmental monitoring excursions, deficiencies in cleaning practices, uncontrolled access between classified and technical areas, inadequate investigation of contamination events and the lack of effective reassessment of cross-contamination risks following multiple significant quality incidents. These deficiencies may have compromised the effectiveness of controls intended to prevent contamination and cross-contamination of active substances manufactured at the site. In addition, deficiencies in governance and management oversight were observed. The inspection findings demonstrate that quality-related decisions were not always supported by adequate quality risk management principles and the quality unit did not exercise sufficient authority to ensure that manufacturing activities were restricted, suspended or adequately controlled when significant quality concerns were identified. Action taken/proposed by the NCA: Recall of batches already released No specific quality defects on concrete batches present in the market were detected, and thus no action/recall is deemed necessary against concrete batches released and placed on the market. Prohibition of supply Suspension of the distribution and sale of any active pharmaceutical ingredient or intermediate that has been manufactured, repackaged or relabelled in the facilities of OCB PHARMACEUTICAL, S.R.L. manufacturing site at the Canovelles. In the event that the competent authorities of the countries deem it necessary, they may use the available stock of these products for their markets upon express request. Suspension or voiding of CEP (action to be taken by EDQM) Suspension of CEP for active substances manufactured in OCB PHARMACEUTICAL, S.R.L. in Canovelles should be considered. The CEP that it has are: - Bismuth subnitrate (R0-CEP 2021-190 Rev.00) Others Action on the Manufacturing Authorisation: Temporary suspension of all manufacturing activities of active pharmaceutical ingredients and / or intermediates performed at the OCB PHARMACEUTICAL, S.R.L. manufacturing site at Canovelles. These measures will be maintained until all the deficiencies observed in the inspection have been corrected and it has been verified through a new inspection. Recommendations/proposed actions: Manufacturers of finished medicinal products using active pharmaceutical ingredients manufactured at the OCB PHARMACEUTICAL, S.R.L. site of Canovelles should not use, release for manufacture, or further process such active substances unless they perform scientifically justified testing, using suitably validated analytical methods and representative sampling plans, to demonstrate that the affected active pharmaceuticals ingredients batches do not contain traces of other bismuth salts at levels that may impact product quality, safety or compliance with the approved specifications. In case of out of specification results are detected, national competent authority (NCA) should be informed by the marketing authorization holder (MAH). This manufacturer should not be authorised in any new/ongoing marketing authorisation or variation applications for these active pharmaceutical ingredients as long as the non-compliance statement is in force. Marketing Authorisation Holders are recommended to evaluate the introduction of alternative qualified sources for active substances currently supplied by OCB PHARMACEUTICAL, S.R.L. in order to mitigate any potential supply impact resulting from the regulatory measures adopted.

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.

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

Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

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

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.