EMA (Europe) Findings

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product manufacturer until the recommended non-compliance statement to be issued remains in place or is not superseded with a GMP certificate.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batches manufactured at the site should be released to EEA markets until this non-compliance remains in place or is superseded by an EU GMP certificate.

The GMP inspection has been performed on February 10–12, 2026 and April 22-23, 2026. This manufacturer, a hospital pharmacy, is producing multiple type of products: medicinal products for human use with a marketing authorization, advanced therapy medicinal products (ATMPs, investigational) and human investigational medicines. It concerns sterile production of registered products and ATMPs and non-sterile production of registered products. In addition, the activities of investigational medicinal products are manufacturing of tablets/capsules, and relabeling and repackaging. All of the clinical studies are performed in the Netherlands, except one study is performed in Europe (M22BOL EU CT 2023-505039-11-00). The outcome of the inspection was GMP non-compliant, which is based on one (1) critical deficiency, seven (7) major deficiencies and fourteen (14) other deficiencies. In summary the main inspection findings were as follows: Critical deficiency: 1) The execution of the Out-of-Specification (OOS) process is inadequate. In practice, multiple batches of registered finished products were released even though they did not comply with the specified limits for moisture content or assay. An Advanced Therapy Medicinal Product (ATMP) was released despite a failed sterility test which was performed as an in-process control. In addition, the procedure for OOS is not unambiguous and can lead to batch certification and release without thorough investigation of sufficient justification. Major deficiencies: 1) The control of aseptic practices for both the registered product and the ATMP manufacturing process is insufficient e.g. Annex1 gap assessment and the contamination control strategy are incomplete. Regarding ATMP production multiple aspects are not under control. 2) Aseptic process simulation is inadequate for both the registered product and the ATMP process, including the additional media fill. 3) The design, investigation and trending of microbiological test results are insufficient for example multiple microbial exceedances on the hands of the operators in class A handling the ATMP product. 4) Operator behaviour in the cleanroom and gowning procedures for Grade B areas are inadequate. 5) The Pharmaceutical Quality System (PQS) is insufficient. This is shown by deficiencies identified in the management of deviations, CAPAs, changes, complaints, self-inspections, and the Product Quality Reviews (PQRs) that were assessed. 6) The approach to Computerized System Validation (CSV) and data integrity is inadequate. 7) Good Documentation Practices (GDocP) are not sufficiently adhered to, as demonstrated for example by the backlog of revisions for multiple documents. In conclusion: the impact of the GMP non-compliance on registered products, ATMPs and most of the investigational medicinal products is exclusively national, except for one clinical study (EU CT 2023-505039-11-00)(see paragraph: suspension of clinical trials). Action taken/proposed by the NCA: Suspension of clinical trials For the EU only one product is impacted: M22BOL study (EU CT 2023-505039-11-00). The activities relabeling and repackaging of DS-8201a (trastuzumab deruxtecan). All the other products are solely present on the Dutch market. Impact: The impact of the inspection findings for EU CT 2023-505039-11-00, where a registered product will be relabeled and repacked by NKI/AVL, will be limited. This is an existing and released medicinal product. The critical shortcoming plus four major shortcomings regarding sterile manufacturing and aseptic production do not affect this investigational medicinal product. However, major shortcomings regarding the Quality Management system, Computer System Validation and Good Documentation practice could affect this investigational medicinal product. Recommendations: Up to this moment, four patients out of the expected total amount of 72 patients have been treated since the start of the clinical trial May, 2, 2024. Those four patients were treated in the Netherlands. It is up to the concerned Member States to make a decision regarding their market taking into account the legal frameworks. Others Withdrawal of GMP certificates NL/H 24/2051740A, NL/H 24/2051740B, NL/H 24/2051740C and NL/H 24/2051740D. A re-inspection will be performed on the basis of the company's plan of action to address the deficiencies (currently not scheduled yet). After a positive result following the re-inspection an new GMP-certificate will be issued and this non-compliance statement will be withdrawn.

The GMP inspection has been performed on February 10–12, 2026 and April 22-23, 2026. This manufacturer, a hospital pharmacy, is producing multiple type of products: medicinal products for human use with a marketing authorization, advanced therapy medicinal products (ATMPs, investigational) and human investigational medicines. It concerns sterile production of registered products and ATMPs and non-sterile production of registered products. In addition, the activities of investigational medicinal products are manufacturing of tablets/capsules, and relabeling and repackaging. All of the clinical studies are performed in the Netherlands, except one study is performed in Europe (M22BOL EU CT 2023-505039-11-00). The outcome of the inspection was GMP non-compliant, which is based on one (1) critical deficiency, seven (7) major deficiencies and fourteen (14) other deficiencies. In summary the main inspection findings were as follows: Critical deficiency: 1) The execution of the Out-of-Specification (OOS) process is inadequate. In practice, multiple batches of registered finished products were released even though they did not comply with the specified limits for moisture content or assay. An Advanced Therapy Medicinal Product (ATMP) was released despite a failed sterility test which was performed as an in-process control. In addition, the procedure for OOS is not unambiguous and can lead to batch certification and release without thorough investigation of sufficient justification. Major deficiencies: 1) The control of aseptic practices for both the registered product and the ATMP manufacturing process is insufficient e.g. Annex1 gap assessment and the contamination control strategy are incomplete. Regarding ATMP production multiple aspects are not under control. 2) Aseptic process simulation is inadequate for both the registered product and the ATMP process, including the additional media fill. 3) The design, investigation and trending of microbiological test results are insufficient for example multiple microbial exceedances on the hands of the operators in class A handling the ATMP product. 4) Operator behaviour in the cleanroom and gowning procedures for Grade B areas are inadequate. 5) The Pharmaceutical Quality System (PQS) is insufficient. This is shown by deficiencies identified in the management of deviations, CAPAs, changes, complaints, self-inspections, and the Product Quality Reviews (PQRs) that were assessed. 6) The approach to Computerized System Validation (CSV) and data integrity is inadequate. 7) Good Documentation Practices (GDocP) are not sufficiently adhered to, as demonstrated for example by the backlog of revisions for multiple documents. In conclusion: the impact of the GMP non-compliance on registered products, ATMPs and most of the investigational medicinal products is exclusively national, except for one clinical study (EU CT 2023-505039-11-00)(see paragraph: suspension of clinical trials). Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. NL/H 24/2051740C, NL/H 24/2051740D Including the GMP certificates of Louwesweg 6, Amsterdam e.g. NL/H 24/2051740A and NL/H 24/2051740B. A re-inspection will be performed on the basis of the company's plan of action to address the deficiencies (currently not scheduled yet). After a positive result following the re-inspection a new GMP certificate will be issued and this non-compliance statement will be withdrawn. Suspension of clinical trials For the EU only one product is impacted: M22BOL study (EU CT 2023-505039-11-00). The activities are relabeling and repackaging of DS-8201a (trastuzumab deruxtecan). All the other products are solely present on the Dutch market. Impact: The impact of the inspection findings for EU CT 2023-505039-11-00, where a registered product will be relabeled and repacked by NKI/AVL, will be limited. This is an existing and released medicinal product. The critical shortcoming plus the four major shortcomings regarding sterile manufacturing and aseptic production do not affect this investigational medicinal product. However, major shortcomings regarding the Quality Management System, Computer System Validation and Good Documentation practice could affect this investigational medicinal product. Recommendations: Up to this moment, four patients out of the expected total amount of 72 patients have been treated since the start of the clinical trial May, 2, 2024. Those four patients were treated in the Netherlands. It is up to the concerned Member States to make a decision regarding their market taking into account the legal frameworks.

The GMP inspection has been performed on February 10–12, 2026 and April 22-23, 2026. This manufacturer, a hospital pharmacy, is producing multiple type of products: medicinal products for human use with a marketing authorization, advanced therapy medicinal products (ATMPs, investigational) and human investigational medicines. It concerns sterile production of registered products and ATMPs and non-sterile production of registered products. In addition, the activities of investigational medicinal products are manufacturing of tablets/capsules, and relabeling and repackaging. All of the clinical studies are performed in the Netherlands, except one study is performed in Europe (M22BOL EU CT 2023-505039-11-00). The outcome of the inspection was GMP non-compliant, which is based on one (1) critical deficiency, seven (7) major deficiencies and fourteen (14) other deficiencies. In summary the main inspection findings were as follows: Critical deficiency: 1) The execution of the Out-of-Specification (OOS) process is inadequate. In practice, multiple batches of registered finished products were released even though they did not comply with the specified limits for moisture content or assay. An Advanced Therapy Medicinal Product (ATMP) was released despite a failed sterility test which was performed as an in-process control. In addition, the procedure for OOS is not unambiguous and can lead to batch certification and release without thorough investigation of sufficient justification. Major deficiencies: 1) The control of aseptic practices for both the registered product and the ATMP manufacturing process is insufficient e.g. Annex1 gap assessment and the contamination control strategy are incomplete. Regarding ATMP production multiple aspects are not under control. 2) Aseptic process simulation is inadequate for both the registered product and the ATMP process, including the additional media fill. 3) The design, investigation and trending of microbiological test results are insufficient for example multiple microbial exceedances on the hands of the operators in class A handling the ATMP product. 4) Operator behaviour in the cleanroom and gowning procedures for Grade B areas are inadequate. 5) The Pharmaceutical Quality System (PQS) is insufficient. This is shown by deficiencies identified in the management of deviations, CAPAs, changes, complaints, self-inspections, and the Product Quality Reviews (PQRs) that were assessed. 6) The approach to Computerized System Validation (CSV) and data integrity is inadequate. 7) Good Documentation Practices (GDocP) are not sufficiently adhered to, as demonstrated for example by the backlog of revisions for multiple documents. In conclusion: the impact of the GMP non-compliance on registered products, ATMPs and most of the investigational medicinal products is exclusively national, except for one clinical study (EU CT 2023-505039-11-00)(see paragraph: suspension of clinical trials). Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. NL/H 24/2051740C, NL/H 24/2051740D Including the GMP certificates of Louwesweg 6, Amsterdam e.g. NL/H 24/2051740A and NL/H 24/2051740B. A re-inspection will be performed on the basis of the company's plan of action to address the deficiencies (currently not scheduled yet). After a positive result following the re-inspection a new GMP certificate will be issued and this non-compliance statement will be withdrawn. Suspension of clinical trials For the EU only one product is impacted: M22BOL study (EU CT 2023-505039-11-00). The activities are relabeling and repackaging of DS-8201a (trastuzumab deruxtecan). All the other products are solely present on the Dutch market. Impact: The impact of the inspection findings for EU CT 2023-505039-11-00, where a registered product will be relabeled and repacked by NKI/AVL, will be limited. This is an existing and released medicinal product. The critical shortcoming plus the four major shortcomings regarding sterile manufacturing and aseptic production do not affect this investigational medicinal product. However, major shortcomings regarding the Quality Management System, Computer System Validation and Good Documentation practice could affect this investigational medicinal product. Recommendations: Up to this moment, four patients out of the expected total amount of 72 patients have been treated since the start of the clinical trial May, 2, 2024. Those four patients were treated in the Netherlands. It is up to the concerned Member States to make a decision regarding their market taking into account the legal frameworks.

The GMP inspection has been performed on February 10–12, 2026 and April 22-23, 2026. This manufacturer, a hospital pharmacy, is producing multiple type of products: medicinal products for human use with a marketing authorization, advanced therapy medicinal products (ATMPs, investigational) and human investigational medicines. It concerns sterile production of registered products and ATMPs and non-sterile production of registered products. In addition, the activities of investigational medicinal products are manufacturing of tablets/capsules, and relabeling and repackaging. All of the clinical studies are performed in the Netherlands, except one study is performed in Europe (M22BOL EU CT 2023-505039-11-00). The outcome of the inspection was GMP non-compliant, which is based on one (1) critical deficiency, seven (7) major deficiencies and fourteen (14) other deficiencies. In summary the main inspection findings were as follows: Critical deficiency: 1) The execution of the Out-of-Specification (OOS) process is inadequate. In practice, multiple batches of registered finished products were released even though they did not comply with the specified limits for moisture content or assay. An Advanced Therapy Medicinal Product (ATMP) was released despite a failed sterility test which was performed as an in-process control. In addition, the procedure for OOS is not unambiguous and can lead to batch certification and release without thorough investigation of sufficient justification. Major deficiencies: 1) The control of aseptic practices for both the registered product and the ATMP manufacturing process is insufficient e.g. Annex1 gap assessment and the contamination control strategy are incomplete. Regarding ATMP production multiple aspects are not under control. 2) Aseptic process simulation is inadequate for both the registered product and the ATMP process, including the additional media fill. 3) The design, investigation and trending of microbiological test results are insufficient for example multiple microbial exceedances on the hands of the operators in class A handling the ATMP product. 4) Operator behaviour in the cleanroom and gowning procedures for Grade B areas are inadequate. 5) The Pharmaceutical Quality System (PQS) is insufficient. This is shown by deficiencies identified in the management of deviations, CAPAs, changes, complaints, self-inspections, and the Product Quality Reviews (PQRs) that were assessed. 6) The approach to Computerized System Validation (CSV) and data integrity is inadequate. 7) Good Documentation Practices (GDocP) are not sufficiently adhered to, as demonstrated for example by the backlog of revisions for multiple documents. In conclusion: the impact of the GMP non-compliance on registered products, ATMPs and most of the investigational medicinal products is exclusively national, except for one clinical study (EU CT 2023-505039-11-00)(see paragraph: suspension of clinical trials). Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. NL/H 24/2051740A, NL/H 24/2051740B Including the GMP certificates of the Plesmanlaan 121, Amsterdam e.g. NL/H 24/2051740C and NL/H 24/2051740D. A re-inspection will be performed on the basis of the company's plan of action to address the deficiencies (currently not scheduled yet). After a positive result following the re-inspection a new GMP certificate will be issued and this non-compliance statement will be withdrawn. Suspension of clinical trials For the EU only one product is impacted: M22BOL study (EU CT 2023-505039-11-00). The activities are relabeling and repackaging of DS-8201a (trastuzumab deruxtecan). All the other products are solely present on the Dutch market. Impact: The impact of the inspection findings for EU CT 2023-505039-11-00, where a registered product will be relabeled and repacked by NKI/AVL, will be limited. This is an existing and released medicinal product. The critical shortcoming plus the four major shortcomings regarding sterile manufacturing and aseptic production do not affect this investigational medicinal product. However, major shortcomings regarding the Quality Management System, Computer System Validation and Good Documentation practice could affect this investigational medicinal product. Recommendations: Up to this moment, four patients out of the expected total amount of 72 patients have been treated since the start of the clinical trial May, 2, 2024. Those four patients were treated in the Netherlands. It is up to the concerned Member States to make a decision regarding their market taking into account the legal frameworks.

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.