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Background: Good manufacturing practice (GMP) is a part of quality management that maintains product quality and manages it according to the criteria of fitness for use. The heating, ventilation, and air‐conditioning (HVAC) system comprises the equipment, technology, and procedure that ensure product quality through maintaining heat, ventilation, and coolness of pharmaceutical manufacturing firms. The aim of the study was to evaluate the GMP compliance of HVAC systems and assess the opportunities and challenges of improving these systems in pharmaceutical manufacturing companies in Ethiopia. Methods: The study was conducted in eight local pharmaceutical manufacturing companies in Ethiopia from April 20 to August 30, 2021, by using a concurrent mixed‐method approach to evaluate the implementation of GMP in HVAC systems. The pharmaceutical firms were directly observed by using a structured and standard observational checklist that was adopted from the WHO minimum GMP requirements. In order to understand the challenges and opportunities, face‐to‐face interviews with key informants using a purposive sampling technique were conducted. Results: The study findings revealed that the local pharmaceutical companies applied for 67.1% of the GMP requirements of the HVAC systems. The GMP implementation status in the basic quality features of HVAC systems of local pharmaceutical companies was 75% on premises, 70.67% in HVAC system design and maintenance practices, 56.25% in product protection, 61.25% in environmental protection, and 75% in cross‐contamination prevention. The primary obstacles to implementing GMP in the HVAC systems were a shortage of skilled professionals, HVAC system spare parts, and foreign currency besides poor practice of HVAC system calibration. Conclusion: The study revealed that the local pharmaceutical manufacturing companies did not adhere to GMP standards in HVAC systems. [ABSTRACT FROM AUTHOR]

BACKGROUND: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. METHODS: Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs. RESULTS: Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. CONCLUSIONS: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.

Bakery products are in great demand among Indonesians today. Therefore, small and medium enterprises (SMEs) of bakeries have an essential role in creating products that are guaranteed to be halal and safe, following regulations in Indonesia. This research aims to design a Halal Good Manufacturing Practice (HGMP) assessment model for “X” Bakery to improve product quality. HGMP integrates the criteria of Indonesia's Halal Assurance System, called Sistem Jaminan Produk Halal (SJPH), and Good Manufacturing Practices (GMP). The Quality Function Deployment (QFD) method evaluates company performance based on HGMP criteria and translates it into technical responses. The Pareto diagram determines the priority of HGMP criteria and technical responses. The identification results show 56 valid HGMP criteria for “X” Bakery, consisting of location and environment, buildings, facilities, employees, production, and storage. Implementing the assessment model at “X” Bakery resulted in 40 HGMP criteria that needed improvement and 12 technical responses that needed to be prioritized in meeting the HGMP criteria. This HGMP assessment model is hoped to help “X” Bakery improve the quality of halal, safe, high-quality products.

Abstract Cellular senescence plays a role in the development of aging-associated degenerative diseases. Cell therapy is recognized as a candidate treatment for degenerative diseases. To achieve the goal of cell therapy, the quality and good characteristics of cells are concerned. Cell expansion relies on two-dimensional culture, which leads to replicative senescence of expanded cells. This study aimed to investigate the effect of cell culture surface modification using fibronectin (FN) and vitronectin (VN) in adipose-derived stem cells (ADSCs) during long-term expansion. Our results showed that ADSCs cultured in FN and VN coatings significantly enhanced adhesion, proliferation, and slow progression of cellular senescence as indicated by lower SA-β-gal activities and decreased expression levels of genes including p16, p21, and p53. The upregulation of integrin α5 and αv genes influences phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), and AKT proteins. FN and VN coatings upregulated AKT and MDM2 leading to p53 degradation. Additionally, MDM2 inhibition by Nutlin-3a markedly elevated p53 and p21 expression, increased cellular senescence, and induced the expression of inflammatory molecules including HMGB1 and IL-6. The understanding of FN and VN coating surface influencing ADSCs, especially senescence characteristics, offers a promising and practical point for the cultivation of ADSCs for future use in cell-based therapies.

Addressing the challenges in managing ischemic tissue repair and remodelling remains a prominent clinical concern. Current research is heavily concentrated on identifying innovative cell-based therapies with the potential to enhance revascularization in patients affected by these diseases. We have previously developed and validated a manufacturing process for human umbilical cord mesenchymal stromal cells (UC-MSCs)-based cell therapy medicinal product, according to Good Manufacturing Practices. In this study, we demonstrate that these UC-MSCs enhance the proliferation and migration of endothelial cells and the formation of capillary structures. Moreover, UC-MSCs and endothelial cells interact, allowing UC-MSCs to acquire a perivascular cell phenotype and consequently provide direct support to the newly formed vascular network. This characterization of the proangiogenic properties of this UC-MSCs based-cell therapy medicinal product is an essential step for its therapeutic assessment in the clinical context of vascular regeneration. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. We showed that Tregs could be enriched to 87– 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136–732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro , but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response. [ABSTRACT FROM AUTHOR]

Abstract Background Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) hold great therapeutic potential in regenerative medicine. Therefore, it is crucial to establish a Good Manufacturing Practice (GMP)-compliant methodology for the isolation and culture of WJ-MSCs. Through comprehensive research, encompassing laboratory-scale experiments to pilot-scale studies, we aimed to develop standardized protocols ensuring the high yield and quality of WJ-MSCs manufacturing. Methods Firstly, optimization of parameters for the enzymatic digestion method used to isolate WJ-MSCs was conducted. These parameters included enzyme concentrations, digestion times, seeding densities, and culture media. Additionally, a comparative analysis between the explant method and the enzymatic digestion method was performed. Subsequently, the consecutive passaging of WJ-MSCs, specifically up to passage 9, was evaluated using the optimized method. Finally, manufacturing processes were developed and scaled up, starting from laboratory-scale flask-based production and progressing to pilot-scale cell factory-based production. Furthermore, a stability study was carried out to assess the storage and use of drug products (DPs). Results The optimal parameters for the enzymatic digestion method were a concentration of 0.4 PZ U/mL Collagenase NB6 and a digestion time of 3 h, resulting in a higher yield of P0 WJ-MSCs. In addition, a positive correlation between the weight of umbilical cord tissue and the quantities of P0 WJ-MSCs has been observed. Evaluation of different concentrations of human platelet lysate revealed that 2% and 5% concentrations resulted in similar levels of cell expansion. Comparative analysis revealed that the enzymatic digestion method exhibited faster outgrowth of WJ-MSCs compared to the explant method during the initial passage. Passages 2 to 5 exhibited higher viability and proliferation ability throughout consecutive passaging. Moreover, scalable manufacturing processes from the laboratory scale to the pilot scale were successfully developed, ensuring the production of high-quality WJ-MSCs. Multiple freeze-thaw cycles of the DPs led to reduced cell viability and viable cell concentration. Subsequent thawing and dilution of the DPs resulted in a significant decrease in both metrics, especially when stored at 20–27 °C. Conclusion This study offers valuable insights into optimizing the isolation and culture of WJ-MSCs. Our scalable manufacturing processes facilitate the large-scale production of high-quality WJ-MSCs. These findings contribute to the advancement of WJ-MSCs-based therapies in regenerative medicine.

The medical electron linear accelerator（LINAC） has the characteristics of complex system structure, many core components and high precision control requirements, which puts forward higher requirements for product quality control and regulation. This study puts forward the main points of field inspection through the analysis of the technical characteristics and production risk of LINAC, combined with the requirements of the good manufacturing practice of medical devices. It has certain reference significance for quality management personnel and field inspectors.

Background: Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) hold great therapeutic potential in regenerative medicine. Therefore, it is crucial to establish a Good Manufacturing Practice (GMP)-compliant methodology for the isolation and culture of WJ-MSCs. Through comprehensive research, encompassing laboratory-scale experiments to pilot-scale studies, we aimed to develop standardized protocols ensuring the high yield and quality of WJ-MSCs manufacturing. Methods: Firstly, optimization of parameters for the enzymatic digestion method used to isolate WJ-MSCs was conducted. These parameters included enzyme concentrations, digestion times, seeding densities, and culture media. Additionally, a comparative analysis between the explant method and the enzymatic digestion method was performed. Subsequently, the consecutive passaging of WJ-MSCs, specifically up to passage 9, was evaluated using the optimized method. Finally, manufacturing processes were developed and scaled up, starting from laboratory-scale flask-based production and progressing to pilot-scale cell factory-based production. Furthermore, a stability study was carried out to assess the storage and use of drug products (DPs). Results: The optimal parameters for the enzymatic digestion method were a concentration of 0.4 PZ U/mL Collagenase NB6 and a digestion time of 3 h, resulting in a higher yield of P0 WJ-MSCs. In addition, a positive correlation between the weight of umbilical cord tissue and the quantities of P0 WJ-MSCs has been observed. Evaluation of different concentrations of human platelet lysate revealed that 2% and 5% concentrations resulted in similar levels of cell expansion. Comparative analysis revealed that the enzymatic digestion method exhibited faster outgrowth of WJ-MSCs compared to the explant method during the initial passage. Passages 2 to 5 exhibited higher viability and proliferation ability throughout consecutive passaging. Moreover, scalable manufacturing processes from the laboratory scale to the pilot scale were successfully developed, ensuring the production of high-quality WJ-MSCs. Multiple freeze-thaw cycles of the DPs led to reduced cell viability and viable cell concentration. Subsequent thawing and dilution of the DPs resulted in a significant decrease in both metrics, especially when stored at 20–27 °C. Conclusion: This study offers valuable insights into optimizing the isolation and culture of WJ-MSCs. Our scalable manufacturing processes facilitate the large-scale production of high-quality WJ-MSCs. These findings contribute to the advancement of WJ-MSCs-based therapies in regenerative medicine. [ABSTRACT FROM AUTHOR]

The relationship between blood establishments and advanced cellular therapies is evident in several European countries, with some involved in research and development and/or in manufacturing. The aim of the present study was to understand the advanced therapy medicinal product (ATMP) infrastructural, regulatory and logistic requirements needed for the Irish Blood Transfusion Service to support advanced therapeutics in Ireland. An online survey consisting of 13 questions was distributed in a targeted manner to the identified ATMP stakeholders in Ireland, namely those working in industry, health care, regulatory agencies or education. Subject matter experts in the field were approached and interviewed to gain further insight into the relationship between blood and tissue establishments (BTEs) and ATMPs, to explore the advantages these institutions have in development and to highlight potential challenges for implementation. In total, 84.9% of survey respondents stated that BTEs have a role in the development of advanced therapeutics. Key BTE services identified as applicable to the ATMP sector from both surveys and interviews include the provision of starting materials for research and manufacturing, donor management, use of existing quality and traceability frameworks, product logistic strategies and Good Manufacturing Practice. Challenges for BTE expansion into the sector currently include high costs associated with ATMPs, lack of expertise in these therapies, limited therapeutic populations and no national ATMP strategic plan for Ireland. Blood establishments have services and expertise that can be extended into the advanced therapy sector. The existing knowledge and skill base of BTEs in Ireland should be leveraged to accelerate the development of ATMP strategies for industry and healthcare. [ABSTRACT FROM AUTHOR]

The increasing demand of clinical-grade mesenchymal stromal cells (MSCs) for use in advanced therapy medicinal products (ATMPs) require a re-evaluation of manufacturing strategies, ensuring scalability from two-dimensional (2D) surfaces to volumetric (3D) productivities. Herein we describe the design and validation of a Good Manufacturing Practice–compliant 3D culture methodology using microcarriers and 3-L single-use stirred tank bioreactors (STRs) for the expansion of Wharton's jelly (WJ)-derived MSCs in accordance to current regulatory and quality requirements. MSC,WJ were successfully expanded in 3D and final product characterization was in conformity with Critical Quality Attributes and product specifications previously established for 2D expansion conditions. After 6 days of culture, cell yields in the final product from the 3D cultures (mean 9.48 × 108 ± 1.07 × 107 cells) were slightly lower but comparable with those obtained from 2D surfaces (mean 9.73 × 108 ± 2.36 × 108 cells) after 8 days. In all analyzed batches, viability was >90%. Immunophenotype of MSC,WJ was highly positive for CD90 and CD73 markers and lacked of expression of CD31, CD45 and HLA-DR. Compared with 2D expansions, CD105 was detected at lower levels in 3D cultures due to the harvesting procedure from microcarriers involving trypsin at high concentration, and this had no impact on multipotency. Cells presented normal karyotype and strong immunomodulatory potential in vitro. Sterility, Mycoplasma , endotoxin and adventitious virus were negative in both batches produced. In summary, we demonstrated the establishment of a feasible and reproducible 3D bioprocess using single-use STR for clinical-grade MSC,WJ production and provide evidence supporting comparability of 3D versus 2D production strategies. This comparability exercise evaluates the direct implementation of using single-use STR for the scale-up production of MSC,WJ and, by extension, other cell types intended for allogeneic therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are one of the few stem cell types used in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair, due to their unique paracrine capacity, multiple differentiation potential, active components in exosomes, and effective mitochondria donation. At present, MSCs derived from tissues such as bone marrow and umbilical cord are widely applied in preclinical and clinical studies. Nevertheless, there remain challenges to the maintenance of consistently good quality MSCs derived from different donors or tissues, directly impacting their application as advanced therapy products. In this review, we discuss the promises, problems, and prospects associated with translation of MSC research into a pharmaceutical product. We review the hurdles encountered in translation of MSCs and MSC–exosomes from the research bench to an advanced therapy product compliant with good manufacturing practice (GMP). These difficulties include how to set up GMP‐compliant protocols, what factors affect raw material selection, cell expansion to product formulation, establishment of quality control (QC) parameters, and quality assurance to comply with GMP standards. To avoid human error and reduce the risk of contamination, an automatic, closed system that allows real‐time monitoring of QC should be considered. We also highlight potential advantages of pluripotent stem cells as an alternative source for MSC and exosomes generation and manufacture. [ABSTRACT FROM AUTHOR]

DN Tofu Factory is a food industry for tofu products. The company’s main problem is a defect product in October-December 2021 with an average of 7.01%. The purpose of research was to reduce the failure of production in use of the methods of Failure Mode and Effect Analysis (FMEA) and Fault Tree Analysis (FTA). The result of DPMO (Defect per Million Opportunities) calculation is 17500 with a sigma level of 3.6084. Based on the FMEA calculations, two potential causes of failure from the highest perceived value of the RPN (Risk Priority Number), namely that workers do not use the full clothing attributes during the production process with an RPN value of 294 and workers did not pay attention to pressing time with an RPN value of 252. FTA analysis results shows two basic causes of problem, namely workers do not use PPE (Personal Protective Equipment) with a probability of 0.24 and that no tools are available to measure standard time with a probability of 0.2. The proposed improvements implemented by observing the GMP aspect (Good Manufacturing Practice) are to use digital timer, make a tool cleaning form, and make hand-washing posters, smoke free, a restriction on eating and drinking. There is a descrease in the value of DPMO to 16500 with sigma level of 3.6321 after implementation.

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.

Abstract Treatments for skin injuries have recently advanced tremendously. Such treatments include allogeneic and xenogeneic transplants and skin substitutes such as tissue-engineered skin, cultured cells, and stem cells. The aim of this paper is to discuss the general overview of the quality assurance and quality control implemented in the manufacturing of cell and tissue product, with emphasis on our experience in the manufacturing of MyDerm®, an autologous bilayered human skin substitute. Manufacturing MyDerm® requires multiple high-risk open manipulation steps, such as tissue processing, cell culture expansion, and skin construct formation. To ensure the safety and efficacy of this product, the good manufacturing practice (GMP) facility should establish a well-designed quality assurance and quality control (QA/QC) programme. Standard operating procedures (SOP) should be implemented to ensure that the manufacturing process is consistent and performed in a controlled manner. All starting materials, including tissue samples, culture media, reagents, and consumables must be verified and tested to confirm their safety, potency, and sterility. The final products should also undergo a QC testing series to guarantee product safety, efficacy, and overall quality. The aseptic techniques of cleanroom operators and the environmental conditions of the facility are also important, as they directly influence the manufacturing of good-quality products. Hence, personnel training and environmental monitoring are necessary to maintain GMP compliance. Furthermore, risk management implementation is another important aspect of QA/QC, as it is used to identify and determine the risk level and to perform risk assessments when necessary. Moreover, procedures for non-conformance reporting should be established to identify, investigate, and correct deviations that occur during manufacturing. This paper provides insight and an overview of the QA/QC aspect during MyDerm® manufacturing in a GMP-compliant facility in the Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia.

Abstract Background Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. Methods Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs. Results Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. Conclusions These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa. Graphical abstract

Risk assessment and management during the entire production process of a radiopharmaceutical are pivotal factors in ensuring drug safety and quality. A methodology of quality risk assessment has been performed by integrating the advice reported in Eudralex, ICHQ, and ISO 9001, and its validity has been evaluated by applying it to real data collected in 21 months of activities of 18F-FDG production at Officina Farmaceutica, CNR-Pisa (Italy) to confirm whether the critical aspects that previously have been identified in the quality risk assessment were effective. The analysis of the results of the real data matched the hypotheses obtained from the model, and in particular, the most critical aspects were those related to human resources and staff organization with regard to management risk. Regarding the production process, the model of operational risk had predicted, as later confirmed by real data, that the most critical phase could be the synthesis and dispensing of the radiopharmaceuticals. So, the proposed method could be used by other similar radiopharmaceutical production sites to identify the critical phases of the production process and to act to improve performance and prevent failure in the entire cycle of radiopharmaceutical products. [ABSTRACT FROM AUTHOR]

Demyelination in the central nervous system (CNS) resulting from injury or disease can cause loss of nerve function and paralysis. Cell therapies intended to promote remyelination of axons are a promising avenue of treatment, with mesenchymal stromal cells (MSCs) a prominent candidate. We have previously demonstrated that MSCs derived from human olfactory mucosa (hOM-MSCs) promote myelination to a greater extent than bone marrow-derived MSCs (hBM-MSCs). However, hOM-MSCs were developed using methods and materials that were not good manufacturing practice (GMP)-compliant. Before considering these cells for clinical use, it is necessary to develop a method for their isolation and expansion that is readily adaptable to a GMP-compliant environment. We demonstrate here that hOM-MSCs can be derived without enzymatic tissue digestion or cell sorting and without culture antibiotics. They grow readily in GMP-compliant media and express typical MSC surface markers. They robustly produce CXCL12 (a key secretory factor in promoting myelination) and are pro-myelinating in in vitro rodent CNS cultures. GMP-compliant hOM-MSCs are comparable in this respect to those grown in non-GMP conditions. However, when assessed in an in vivo model of demyelinating disease (experimental autoimmune encephalitis, EAE), they do not significantly improve disease scores compared with controls, indicating further pre-clinical evaluation is necessary before their advancement to clinical trials. [ABSTRACT FROM AUTHOR]

Ensuring the quality and safety of medicinal products is of paramount importance to the pharmaceutical industry. Good manufacturing practice (GMP) regulations are part of a pharmaceutical manufacturer's quality management system and ensure that medicinal products are manufactured, imported and controlled consistently to quality standards appropriate to their intended use. The aim of the present study is to analyze the non-compliant operations identified during GMP inspections carried out by national competent authorities (NCA) in the EU/EEC between 2013 and 2022. A retrospective analysis of non-compliance reports published in the EudraGMDP database between 2013 and 2022 was performed. Overall, 99 reports by 21 national competent authorities were analyzed presenting the results of inspections in 19 countries. A total of 1458 deficiencies were identified, of which 544 (37%) were classified as major and 127 (9%) as critical. The most common non-compliant operations were the manufacturing of active substances (49 deficiencies) and the preparation of non-sterile products (47 deficiencies). In 41 cases, the NCA recommended suspension or voiding of the certificate of suitability (CEP) and in 36 cases revocation of the GMP certificates. The observed deficiencies highlight the importance and need for continuous monitoring and improvement of manufacturers' production processes and quality management systems. [ABSTRACT FROM AUTHOR]

The key to import substitution of medicines is the organization of full-cycle production at Russian facilities, the basis of which is the organic synthesis of active pharmaceutical ingredients (APIs). This review examines the principal problems in the development of the production of APIs for medicines in Russia and the possible approaches toward addressing them under modern conditions. [ABSTRACT FROM AUTHOR]

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AbstractPurpose: The purpose of this paper is to provide a validation framework to guide future validation practitioners towards completing utility validation projects in small and medium enterprise successfully and in shorter duration compared to current practice. Design/methodology/approach: Literature review was carried out on various existing validation frameworks to analyse the positive and negative elements of the frameworks. The identified positive key elements from this analysis were incorporated to develop a comprehensive validation framework that can be used by future validation practitioners to validate utility system in manufacturing companies. Findings: The case study results proved the capability and effectiveness of the new framework as the validation of the reverse osmosis water system was completed successfully with proper documentation and within shorter period compared to previous validation projects in the case study company. Research limitations/implications: The proposed validation framework is well suited for use in small and medium enterprise companies. Further studies should be carried out to ascertain the effect of the framework. Originality/value: This paper provides a comprehensive validation framework that can guide future validation practitioners towards completing validation projects in small and medium enterprise companies successfully and in shorter period.

Introduction: In 2017 the drug chenodeoxycholic acid (CDCA) became unavailable to Dutch patients with the rare inborn error of metabolism cerebrotendinous xanthomatosis (CTX). This was a direct result of a steep price increase after CDCA was authorized in the EU as an orphan drug. As a result, Dutch health insurance companies were unable to reimburse this drug and the availability of CDCA to patients with CTX was directly at risk creating an unmet medical need. CTX is characterized by juvenile cataract, tendon xanthomas, infantile-onset diarrhea, psychomotor retardation and progressive cerebellar ataxia. Treatment with CDCA, when initiated before neurological symptoms are present, can prevent the onset of neurological complications. Methods: To assure continuation of patient treatment with a high quality product, the hospital pharmacy of the Amsterdam UMC developed CDCA capsules as a pharmacy preparation. A simple and robust formulation was developed for capsules in a broad dose range of 35-250 mg, ensuring that both pediatric and adult patients can receive an exact dose tailored to their specific needs. Capsules are prepared manually on a small scale for the individual patient. To assure the quality of the product, product validation and stability studies were performed. Results: The results show that the product complies with all specifications based on the requirements of the European Pharmacopoeia. The capsules contain the declared amount of CDCA, no degradation product or other (microbiological) impurities are formed during the production process and the capsules show a quick dissolution profile. Stability studies indicate that it is a stable product and no impurities increase or arise over time. These results show that these pharmacy preparations are of high quality and comply to Good Manufacturing Practice (GMP) requirements. Discussion: Through our research, we have demonstrated that pharmacy compounding can be a viable alternative in situations where immediate access to essential medication is crucial or when certain drugs are temporarily inaccessible. The purpose of this paper is to offer comprehensive guidance to other pharmacies to improve the availability of currently inaccessible drugs through the practice of pharmacy compounding, thereby facilitating improved patient care. [ABSTRACT FROM AUTHOR]

Treatments for skin injuries have recently advanced tremendously. Such treatments include allogeneic and xenogeneic transplants and skin substitutes such as tissue-engineered skin, cultured cells, and stem cells. The aim of this paper is to discuss the general overview of the quality assurance and quality control implemented in the manufacturing of cell and tissue product, with emphasis on our experience in the manufacturing of MyDerm®, an autologous bilayered human skin substitute. Manufacturing MyDerm® requires multiple high-risk open manipulation steps, such as tissue processing, cell culture expansion, and skin construct formation. To ensure the safety and efficacy of this product, the good manufacturing practice (GMP) facility should establish a well-designed quality assurance and quality control (QA/QC) programme. Standard operating procedures (SOP) should be implemented to ensure that the manufacturing process is consistent and performed in a controlled manner. All starting materials, including tissue samples, culture media, reagents, and consumables must be verified and tested to confirm their safety, potency, and sterility. The final products should also undergo a QC testing series to guarantee product safety, efficacy, and overall quality. The aseptic techniques of cleanroom operators and the environmental conditions of the facility are also important, as they directly influence the manufacturing of good-quality products. Hence, personnel training and environmental monitoring are necessary to maintain GMP compliance. Furthermore, risk management implementation is another important aspect of QA/QC, as it is used to identify and determine the risk level and to perform risk assessments when necessary. Moreover, procedures for non-conformance reporting should be established to identify, investigate, and correct deviations that occur during manufacturing. This paper provides insight and an overview of the QA/QC aspect during MyDerm® manufacturing in a GMP-compliant facility in the Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia. [ABSTRACT FROM AUTHOR]

The Quantum cell expansion system manufactured by Terumo-BCT is perhaps the most widely reported Good Manufacturing Practice–compliant bioreactor used for the expansion of adherent cell populations, both for research purposes and clinical cell–based therapies/trials. Although the system was originally designed for adherent cell expansion, more recently suspension cultures and extracellular vesicle manufacturing protocols have been published using the Quantum system. Cell therapy research and regenerative medicine in general is a rapidly expanding field and as such it is likely that the use of this system will become even more widespread and perhaps mandatory, for both research and development and in the clinic. The purpose of this review is to describe, compare and discuss the diverse range of research and clinical applications currently using the Quantum system, which to our knowledge has not previously been reviewed. In addition, current and future challenges will also be discussed. [ABSTRACT FROM AUTHOR]

This research aimed to build an assessment model on the Halal Good Manufacturing Practices (HGMP) in the meat industry. Data collection was used at four slaughterhouses in Indonesia. This study collected data through two closed questionnaires involving a paired matrix as a priority setting for improved policies and filling in values using a Likert scale. Integrating the Analytical Hierarchy Process (AHP) and House of Quality (HOQ) was adopted to develop a slaughterhouse assessment model. HGMP provided 54 performance indicators for slaughterhouses from 5 variables as assessment criteria. This case study found that the slaughterhouse performance in Pekanbaru had a good category than others. In addition, many defined customer and technical requirements need to be improved to meet customer needs in the Building and Facility; Equipment, Employee; Maintenance; Halal. The provision of a benchmarking matrix aims to facilitate managers to make measurable performance improvements.

Mesenchymal stromal cells (MSCs) have been considered a therapeutic strategy in regenerative medicine because of their regenerative and immunomodulatory properties. The translation of MSC-based products has some challenges, such as regulatory and scientific issues. Quality control should be standardized and optimized to guarantee the reproducibility, safety, and efficacy of MSC-based products to be administered to patients. The aim of this study was to develop MSC-based products for use in clinical practice. Quality control assays include cell characterization, cell viability, immunogenicity, and cell differentiation; safety tests such as procoagulant tissue factor (TF), microbiological, mycoplasma, endotoxin, genomic stability, and tumorigenicity tests; and potency tests. The results confirm that the cells express MSC markers; an average cell viability of 96.9%; a low expression of HLA-DR and costimulatory molecules; differentiation potential; a high expression of TF/CD142; an absence of pathogenic microorganisms; negative endotoxins; an absence of chromosomal abnormalities; an absence of genotoxicity and tumorigenicity; and T-lymphocyte proliferation inhibition potential. This study shows the relevance of standardizing the manufacturing process and quality controls to reduce variability due to the heterogeneity between donors. The results might also be useful for the implementation and optimization of new analytical techniques and automated methods to improve safety, which are the major concerns related to MSC-based therapy. [ABSTRACT FROM AUTHOR]

Background: Xeno-free generation of human embryonic stem cells (hESCs) is important to prevent potential animal contaminations in culture for advanced cellbased therapeutic applications. Xeno-free production of hESCs is the first step for manufacturing clinical-grade hESC lines. Objective: To produce new hESC lines in xeno-free condition. Materials and Methods: This lab resources report was conducted at Stem Cell Biology Research Center, Yazd, Iran from 2019-2022. 4 new hESC lines from 11 (10 fresh and 1 frozen) donated surplus discarded human embryos were established. In this study, we report the xeno-free derivation of new Yazd hESC lines (Yazd4-7), without using immunosurgery, by culturing intact zona-free blastocysts obtained from discarded embryos onto the YhFF#8 cells as a feeder layer in a microdrop culture system. The pluripotency gene expression profile of the cell lines was assessed by reverse transcription polymerase chain reaction and the expression of specific surface markers was detected using immunofluorescent staining. In vitro differentiation was induced using embryoid body formation and gene expression profile of 3 germ layers and germ cells. Reverse transcriptase polymerase chain reaction was investigated to prove their pluripotent capacity. Results: In sum, we have been able to generate 4 new hESC lines (Yazd4-7) from 11 discarded embryos in xeno-free culture conditions using a micro drop culture system and YhFF#8 as a human source feeder layer. Conclusion: The outcome of this work can be the foundation for the future allogeneic cell-based therapeutic application using clinical grade good manufacturing practicederived hESC derivatives. [ABSTRACT FROM AUTHOR]

Government campaigns to replace off-patent brand pharmaceuticals with low cost generic products in national health insurance systems have apparently increased their production in the last two decades in Japan. The contamination of a batch of generic itraconazole tablets with the sleep inducer rilmazafone caused significant adverse events and related accidents in 2020, amidst increasing use of the generic products in healthcare. Investigations revealed many Good Manufacturing Practice (GMP) violations and other evidence of poor quality management in the manufacturing/marketing authorization holder (MAH). Urgent inspection of other MAHs found multiple cases of GMP noncompliance that resulted in temporary administrative suspension. Various quality issues, including nonconformity in stability monitoring, in these generic MAHs resulted in prolonged suspension of product shipments and shortages in medical institutions. These problems highlighted long-standing issues in quality management by MAHs and inspections by authorities, which had been neglected during rapid production expansion. This review introduces these manufacturing control and management problems and their countermeasures, and discusses the impact of habitual inadequate development processes that disregard the quality-by-design (QbD) perspective as the root cause of the issues. [ABSTRACT FROM AUTHOR]

Medications that are no longer covered by a patent and that are made by companies other than the original inventor are known as generics. In recent years, the use of generic medications has grown, principally as a cost-cutting tool in the delivery of healthcare. The typical price difference between generic and brand-name medications is 20 to 90%. The principal objective of laws governing pharmaceuticals in the US, Europe, and Japan is to protect public health. Good Manufacturing Practice (GMP) requirements in the United States, European Union, and Japan are designed to ensure that products are consistently produced and controlled according to quality standards. In the US, GMP regulations are enforced by the Food and Drug Administration (FDA). The EU has GMP guidelines that are enforced by national authorities, and Japan has its own GMP regulations that are enforced by the Ministry of Health, Labor, and Welfare. These regulations cover a wide range of areas including facilities, equipment, production processes and record keeping, which are put in place to ensure product quality and safety. Adhering to GMP requirements is essential for ensuring that products are manufactured to the highest standards and meet the expectations of consumers and regulatory authorities. Overall, the GMP requirements in these regions play a vital role in maintaining the safety and quality of products and are crucial for the pharmaceutical and food industries. [ABSTRACT FROM AUTHOR]

The development of medicinal products often continues throughout the different phases of a clinical study and may require challenging changes in raw and starting materials at later stages. Comparability between the product properties pre- and post-change thus needs to be ensured. Here, we describe and validate the regulatory compliant change of a raw material using the example of a nasal chondrocyte tissue-engineered cartilage (N-TEC) product, initially developed for treatment of confined knee cartilage lesions. Scaling up the size of N-TEC as required for the treatment of larger osteoarthritis defects required the substitution of autologous serum with a clinical-grade human platelet lysate (hPL) to achieve greater cell numbers necessary for the manufacturing of larger size grafts. A risk-based approach was performed to fulfill regulatory requirements and demonstrate comparability of the products manufactured with the standard process (autologous serum) already applied in clinical indications and the modified process (hPL). Critical attributes with regard to quality, purity, efficacy, safety and stability of the product as well as associated test methods and acceptance criteria were defined. Results showed that hPL added during the expansion phase of nasal chondrocytes enhances proliferation rate, population doublings and cell numbers at passage 2 without promoting the overgrowth of potentially contaminant perichondrial cells. N-TEC generated with the modified versus standard process contained similar content of DNA and cartilaginous matrix proteins with even greater expression levels of chondrogenic genes. The increased risk for tumorigenicity potentially associated with the use of hPL was assessed through karyotyping of chondrocytes at passage 4, revealing no chromosomal changes. Moreover, the shelf-life of N-TEC established for the standard process could be confirmed with the modified process. In conclusion, we demonstrated the introduction of hPL in the manufacturing process of a tissue engineered product, already used in a late-stage clinical trial. Based on this study, the national competent authorities in Switzerland and Germany accepted the modified process which is now applied for ongoing clinical tests of N-TEC. The described activities can thus be taken as a paradigm for successful and regulatory compliant demonstration of comparability in advanced therapy medicinal products manufacturing. [ABSTRACT FROM AUTHOR]

Risk assessment and management during the entire production process of a radiopharmaceutical are pivotal factors in ensuring drug safety and quality. A methodology of quality risk assessment has been performed by integrating the advice reported in Eudralex, ICHQ, and ISO 9001, and its validity has been evaluated by applying it to real data collected in 21 months of activities of 18F-FDG production at Officina Farmaceutica, CNR-Pisa (Italy) to confirm whether the critical aspects that previously have been identified in the quality risk assessment were effective. The analysis of the results of the real data matched the hypotheses obtained from the model, and in particular, the most critical aspects were those related to human resources and staff organization with regard to management risk. Regarding the production process, the model of operational risk had predicted, as later confirmed by real data, that the most critical phase could be the synthesis and dispensing of the radiopharmaceuticals. So, the proposed method could be used by other similar radiopharmaceutical production sites to identify the critical phases of the production process and to act to improve performance and prevent failure in the entire cycle of radiopharmaceutical products.

Abstract Background Afghanistan, a low-income landlocked country, is continuously suffering from domestic war and conflicts; the country struggles to provide quality healthcare services, including affordable medicinal products in the required quantity. Moreover, the quality standards of domestic pharmaceutical companies have not been established yet. One of the internationally recognized guidelines for monitoring manufacturing processes in pharmaceutical companies is Good Manufacturing Practice (GMP), recommended by World Health Organization (WHO). Therefore, this study aimed to assess whether a pharmaceutical company in Kabul, Afghanistan adheres to the GMP standards established by WHO. Method A descriptive cross-sectional study was conducted to assess the WHO-delineated GMP compliance of 25 pharmaceutical companies in Kabul, Afghanistan. The inspection checklist was developed by Afghanistan's National Medicine and Healthcare Products Regulatory Authority (NMHRA) using the WHO-delineated GMP guidelines. In addition, direct observation, interviews with respective delegates, and documentation reviews were conducted to collect research data. Result Only 38.33% (1.14 ± 1.08) of GMP contents were complied. Personnel 66.67% (2 ± 1.15) and materials 58.67% (1.76 ± 1.11) were the most commonly complied components, whereas the product recall 12.98% (0.39 ± 0.85), quality assurance 16.44% (0.49 ± 0.81) and quality control laboratory 28.35% (0.85 ± 1.12) were the least complied ones. Conclusion None of the GMP components was fully adhered to by the pharmaceutical companies in Kabul, Afghanistan. Quality control and assurance should be implemented immediately, including validation and qualification practices.

Abstract Background Flumazenil (FMZ) is a functionally silent imidazobenzodiazepine which binds to the benzodiazepine binding site of approximately 75% of the brain γ-aminobutyric acid-A receptors (GABAARs). Positron Emission Tomography (PET) imaging of the GABAARs with [11C]FMZ has been used to evidence alterations in neuronal density, to assess target engagement of novel pharmacological agents, and to study disorders such as epilepsy and Huntington’s disease. Despite the potential of FMZ PET imaging the short half-life (t 1/2) of carbon-11 (20 min) has limited the more widespread clinical use of [11C]FMZ. The fluorine-18 (18F) isotopologue with a longer t 1/2 (110 min) is ideally suited to address this drawback. However, the majority of current radiochemical methods for the synthesis of [18F]FMZ are non-trivial and low yielding. We report a robust, automated protocol that is good manufacturing practice (GMP) compatible, and yields multi-patient doses of [18F]FMZ. Results The fully automated synthesis was developed on the Trasis AllinOne (AIO) platform using a single-use cassette. [18F]FMZ was synthesized in a one-step procedure from [18F]fluoride, via a copper-mediated 18F-fluorination of a boronate ester precursor. Purification was performed by semi-preparative radio-HPLC and the collected fraction formulated directly into the final product vial. The overall process from start of synthesis to delivery of product is approximately 55 min. Starting with an initial activity of 23.6 ± 5.8 GBq (n = 3) activity yields of [18F]FMZ were 8.0 ± 1 GBq (n = 3). The synthesis was successfully reproduced at two independent sites, where the product passed quality control release criteria in line with the European Pharmacopoeia standards and ICH Q3D(R1) guidelines to be suitable for human use. Conclusion Reported is a fully automated cassette-based synthesis of [18F]FMZ that is Good Manufacturing Practice (GMP) compatible and produces multi-patient doses of [18F]FMZ.

Purpose: The purpose of this paper is to provide a validation framework to guide future validation practitioners towards completing utility validation projects in small and medium enterprise successfully and in shorter duration compared to current practice. Design/methodology/approach: Literature review was carried out on various existing validation frameworks to analyse the positive and negative elements of the frameworks. The identified positive key elements from this analysis were incorporated to develop a comprehensive validation framework that can be used by future validation practitioners to validate utility system in manufacturing companies. Findings: The case study results proved the capability and effectiveness of the new framework as the validation of the reverse osmosis water system was completed successfully with proper documentation and within shorter period compared to previous validation projects in the case study company. Research limitations/implications: The proposed validation framework is well suited for use in small and medium enterprise companies. Further studies should be carried out to ascertain the effect of the framework. Originality/value: This paper provides a comprehensive validation framework that can guide future validation practitioners towards completing validation projects in small and medium enterprise companies successfully and in shorter period. [ABSTRACT FROM AUTHOR]

Meugang is a tradition of consuming meat as a form of joy for the people of Aceh in welcoming the month of Ramadan or Eid. The quality and safety of meat is determined by the implementation of good methods of processing meat products in Slaughterhouse. The government has set standard rules that need to be carried out in the management of Slaughterhouse to produce safe, healthy, whole and halal fresh meat products through Regulation of the Minister of Agriculture of the Republic of Indonesia number II of 2020 concerning Certification of Veterinary Control Numbers of Animal Products Business Units. This study was intended to examine good manufacturing procedure in the animal product production chain in the Ruminant Slaughterhouse Business Unit (RPH-R) Aceh Barat district. The results showed that overall meat processing activities in RPH-R had a total of 22 major deviations and 23 minor deviations. This amount does not meet the Veterinary Control Number Level for the RPH-R Business Unit. The number of deviations is very large and the presence of microbial contamination in the meat samples is very worrying, so the relevant parties are advised to improve the implementation of animal slaughtering activities at the RPH-R Aceh Barat in accordance with the standard regulations that have been set. [ABSTRACT FROM AUTHOR]

This research aimed to build an assessment model on the Halal Good Manufacturing Practices (HGMP) in the meat industry. Data collection was used at four slaughterhouses in Indonesia. This study collected data through two closed questionnaires involving a paired matrix as a priority setting for improved policies and filling in values using a Likert scale. Integrating the Analytical Hierarchy Process (AHP) and House of Quality (HOQ) was adopted to develop a slaughterhouse assessment model. HGMP provided 54 performance indicators for slaughterhouses from 5 variables as assessment criteria. This case study found that the slaughterhouse performance in Pekanbaru had a good category than others. In addition, many defined customer and technical requirements need to be improved to meet customer needs in the Building and Facility; Equipment, Employee; Maintenance; Halal. The provision of a benchmarking matrix aims to facilitate managers to make measurable performance improvements. [ABSTRACT FROM AUTHOR]

Recent years have witnessed the introduction of ex vivo expanded dermal fibroblasts for several cell therapy and tissue-engineering applications, including the treatment of facial scars and burns, representing a promising cell type for regenerative medicine. We tested different in-house produced human platelet lysate (HPL) solutions against fetal bovine serum as supplements for in vitro fibroblast expansion by comparing cell yield, molecular marker expression, extracellular matrix (ECM) generation, genomic stability and global gene expression. Our in-house produced HPL supported fibroblast growth at levels similar to those for FBS and commercial HPL products and was superior to AB human serum. Cells grown in HPL maintained a fibroblast phenotype (VIM+, CD44+, CD13+, CD90+), ECM generation capacity (FN+, COL1+) and a normal karyotype, although gene expression profiling revealed changes related to cell metabolism, adhesion and cellular senescence. The HPL manufacturing process was validated within a GMP compliant system and the solution was stable at −80ºC and −20ºC for 2 years. Dermal fibroblasts expanded in vitro with HPL maintain a normal karyotype and expression of fibroblast markers, with only minor changes in their global gene expression profile. Our in-house produced GMP-HPL is an efficient, safe and economical cell culture supplement that can help increase the healthcare activity of blood transfusion centers through the re-use of transfusional plasma and platelets approaching their expiration date. Currently, our HPL solution is approved by the Spanish Agency of Medicines and Medical Devices and is being used in the manufacture of cell therapy products.Abbreviations: AB plasma: plasma group AB; ABHS: AB Human Serum; ABHS+GF: AB Human Serum supplemented with growth factors; ANOVA: Analysis of variance; ATMPs: Advanced Therapies for Medicinal Products; CPE: cytopathic effect; DEGs: Differentially expressed genes; DMEM: Dulbecco’s modified Eagle’s Medium; ECM: Extracellular matrix; ELISA: enzyme-linked immunosorbent assay; FBS: Fetal bovine serum; FDR: False discovery rate; FGF: Fibroblast growth factor; GMP: Good manufacturing practice; HPL: Human platelet lysate; HPL-CM: commercial human platelet lysate; MSCs: mesenchymal stem cells; NEAA: non-essential amino acids; P/S: penicillin/streptomycin; PBS: phosphate buffered saline; PC: leukodepleted platelet concentrate; PCR: polymerase chain reaction; PDGF: Platelet-derived growth factor; PDGFRA: Platelet-derived growth factor receptor alpha; qPCR: quantitative polymerase chain reaction; RNA: Ribonucleic acid; RT: Room temperature; TAC: Transcriptome analysis console; TGF-β: Transforming growth factor beta