Good Manufacturing Practice Requirements Research Articles

Análisis de buenas prácticas de fabricación en plantas procesadoras de leche de cabra en Cariri

The growing demand for safe food has resulted in a need for industries to adapt to established standards to ensure quality products that do not pose risks to consumers' health. There are several factors that can influence the quality of the milk and can make it an inappropriate product for human consumption, such as physical, chemical or biological factors that may contaminate the milk due to failures in obtaining, processing or shipping it. Thus, it is essential that food producing / industrializing establishments obtain excellent percentages of conformities about GMP's, which are measures that must be implemented by food industries in order to guarantee the necessary requirements for food production safe. The present work aimed to evaluate the application of Good Manufacturing Practices (GMP), in caprine milk processing units, in the Cariri region of Paraíba. Four processing units were visited, called A, B, C and D, and were checked for compliance with GMP standards. From the observational analysis carried out, it was found that, of the four establishments studied, only processing plants A and C were classified in group 1, being considered of low risk to food security, plants B and D, in turn, were classified in group 2, which offered a medium risk to food security. Non-conformities were observed in all five items on the list, in all establishments, being described flaws in buildings, lack of products related to personal hygiene, presence of pests within the industry, and mainly, non-compliance with some Operations Procedures Standardized. The present study demonstrated that plants B and D should improve their levels in relation to GMP's, both to meet the requirements of current legislation and to offer safer products to their consumers, in view of the large number of non-conformities observed in these establishments. It is also necessary to have a more effective inspection of the competent bodies to ensure that the establishments are adapted to all GMP's requirements, thus avoiding the risk of transmitting foodborne illnesses to consumers, waste of raw materials as well as financial losses for the establishment.

Are radiopharmaceuticals self-sterilizing? Radiation effect of gallium-68 and lutetium-177 on bacillus pumilus and staphylococcus succinus.

For radiopharmaceuticals, aseptic preparation in combination with filtration is the most commonly used sterilizing method. In general, the production of radiopharmaceuticals needs to fulfil the requirements of good manufacturing practice. In the scope of this work, we focused on the positron emitter gallium-68 and on the therapeutically used beta- and gamma-emitter lutetium-177, as they are routinely used for in-house synthesis of radiopharmaceuticals in nuclear medicine departments. Our hypothesis is, that radiopharmaceuticals might be self-sterilizing due to a high radioactivity concentration and high-energy radionuclides in the preparation for intravenous injections. Incubation with gallium-68 and lutetium-177 for both 30 minutes and 5 hours post-dispensing did not cause any significant effect on bacteria growth. As the theoretical dose is only 0.1-0.6 % of the Ph. Eur. recommended dose of 25 kGy, we conclude that the beta and positron energy of lutetium-177 and gallium-68 as used for standard radiopharmaceutical in-house production is not sufficient to decrease the number of colony forming units compared to the control values. Based on these findings, gallium-68 and lutetium-177 labeled radiopharmaceuticals are not self-sterilizing under the tested conditions with respect to bacillus pumilus and staphylococcus succinus. Consequently, strict aseptic preparation conditions in addition to end-sterilization of the radiopharmaceutical e.g. through membrane filtration are strongly advised for in-house productions.

Risk assessment in development of technical requirements for designing fermentation equipment in accordance with requirements of good manufacturing practice

The object of research is the risks arising at the stage of cultivation of biological agents in fermentation equipment. The starting point of the life cycle of equipment, including fermenters, is the terms of reference, which defines all the necessary requirements that must be taken into account in the design, manufacture, installation and qualification. One of the most important and important stages of the equipment life cycle is the formation of a holistic and complete technical specification, which would allow taking into account all critical process parameters already at the stage of developing the design of the fermenter in accordance with the requirements of good manufacturing practice. It is important to note that the regulatory documents of the pharmaceutical industry (good manufacturing practices, good engineering practices, etc.) do not form specific requirements for equipment and processes, but only define general approaches to ensuring the quality system. The study used the principles of risk management, which are advisable to use throughout the entire life cycle of the equipment. The analysis of the stages of sanitary preparation (washing, disinfection and rinsing), sterilization of the fermenter and the cultivation process made it possible to determine the risks arising at the corresponding stages of production and ways to solve them. The approach to the analysis of critical parameters proposed in this work can be used to improve the development of technical specifications for a fermenter. Thanks to this, at the initial stages, a comprehensive approach to risk management is provided, which in turn will prevent the negative impact of external factors on the final product. Another aspect of using the research results is the possibility of forming fermenter validation protocols. The results obtained in this work can also be used in the development and scaling of the cultivation process for the production of active pharmaceutical ingredients in biopharmaceutical production.

MSC Manufacturing for Academic Clinical Trials: From a Clinical-Grade to a Full GMP-Compliant Process.

Following European regulation 1394/2007, mesenchymal stromal cell (MSCs) have become an advanced therapy medicinal product (ATMP) that must be produced following the good manufacturing practice (GMP) standards. We describe the upgrade of our existing clinical-grade MSC manufacturing process to obtain GMP certification. Staff organization, premises/equipment qualification and monitoring, raw materials management, starting materials, technical manufacturing processes, quality controls, and the release, thawing and infusion were substantially reorganized. Numerous studies have been carried out to validate cultures and demonstrate the short-term stability of fresh or thawed products, as well their stability during long-term storage. Detailed results of media simulation tests, validation runs and early MSC batches are presented. We also report the validation of a new variant of the process aiming to prepare fresh MSCs for the treatment of specific lesions of Crohn’s disease by local injection. In conclusion, we have successfully ensured the adaptation of our clinical-grade MSC production process to the GMP requirements. The GMP manufacturing of MSC products is feasible in the academic setting for a limited number of batches with a significant cost increase, but moving to large-scale production necessary for phase III trials would require the involvement of industrial partners.

Theoretical justification of selecting a method for cultivation of mammal cells as a basis for designing membrane bioreactors in accordance with the requirements of good manufacturing practice

The object of research is technological cultivation systems, the central element of which are bioreactors, which ensure efficient metabolism of mammalian cells (Metazoa). Fundamental differences in the phenotypic characteristics of mammalian cells from microorganisms and the special phase-hydrodynamic state of the cultivation system form special requirements for the design and operation of bioreactors. One of the most problematic areas in the process of using cell cultures to obtain medicinal products of biological origin is to ensure the correct cultivation conditions in order to obtain the maximum amount of the target product. The quality assurance system for drug production is based on good manufacturing practice, which puts forward a number of general requirements for the organization of production of drugs of specified quality, efficacy and safety. The study analyzed the phenotypic characteristics of mammalian cells. The analysis of industrial cultivation systems is carried out and a new classification is proposed, which takes into account the phase-hydrodynamic state of the culture and the specifics of the hydrodynamics of the bioreactor. The analysis made it possible to determine membrane cultivation systems as the most promising. The choice of this cultivation system has a number of features, in particular, the provision of favorable conditions during a long process of cultivation of support-dependent cells. This system guarantees a constant and efficient supply of nutrients, including dissolved oxygen, and the removal of waste products. A wide range of materials for the manufacture of membranes allows to use an individual approach to different types of cell lines. Due to this, it is ensured that high cultivation rates are obtained - the density of cells on the growth surface, the provision of the necessary substances during the entire cultivation process without negative mechanical effects on the cells. The modular design of the membrane elements allows for scalability of the cultivation process from laboratory development to industrial cultivation. The results obtained in this work can be the initial data in the study of hydrodynamic and mass transfer characteristics and in the development or construction of new bioreactors, which will reduce the stage of laboratory development and accelerate the introduction of innovative drugs.

Maintenance Factors Affecting Increased Lutetium-177 Production

Abstract With lutetium (Lu-177) demand forecasted to increase following the conclusion of clinical trials and product registration in key jurisdictions, manufacturers are seeking to improve their production outputs. Naturally, the question falls to operation and maintenance of these production centers to ensure reliable supply to market. Maintenance in the radiopharmaceutical industry is a complex environment with many competing interactions between radiation safety and good manufacturing practice (GMP) requirements. With the view of doubling lutetium production by the end of 2020 and plans for continued increases over the coming years, a key question was whether the plant reliability could accommodate this increase sustainably. As plant use increases the potential frequency of failure as well as the impact of outages increases, it results in a general increase in risk. Since its development by the aviation industry in 1960s, the reliability centered maintenance (RCM) concept has seen adoption by many industries. The International Atomic Energy Agency (IAEA) developed a technical document on RCM applications in nuclear industry in May 2007 while the International Society of Pharmaceutical Engineers (ISPE) refers to the concept in their own baseline guides as well as other risk-based methods in line with international standards. Blame for reliability issues often falls at the feet of the equipment design with suggestions that wholesale redesign of equipment will solve reliability issues. Careful review of existing strategies against these baseline guidelines tells a different story with clear gaps between existing maintenance strategies and current best practice. This document details the results of that investigation, providing information on the gaps found and the systems implemented to bring maintenance strategies back in alignment with current best practice. The article also offers commentary on situations requiring compromises between those best practices defined by IAEA and ISPE.

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [177Lu]Lu-PSMA-617.

In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of 177Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding 177Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.

Rapid generation of monocyte-derived antigen-presenting cells with dendritic cell-like properties.

One of the major challenges in cellular therapy is the establishment and validation of simple and fast production protocols meeting good manufacturing practice (GMP) requirements. Dendritic cells (DCs) are of particular therapeutic interest, due to their critical role in T cell response initiation and regulation. Conventional wisdom states that DC generation from monocytes is a time-consuming protocol, taking up to 7-9 days. This study systematically screened and validated numerous culture components and conditions to identify the minimal requirements, which can give rise to functional monocyte-derived antigen-presenting cells (MoAPCs) in less than 48 h (36 h MoAPC). A total of 36 h MoAPCs were evaluated in terms of surface marker expression, endocytic capability, and induction of antigen-specific T cell expansion via flow cytometry. Screening of media compositions, glucose concentrations, and surface marker kinetics, particularly DC-SIGN as a DC-specific marker, allowed the generation of DC-like APCs in 36 h (36 h MoAPCs). A total of 36 h MoAPCs displayed a similar phenotype to 48 h MoAPC and standard 7 d MoDCs in terms of HLA-DP,DQ,DR, CD83, and DC-SIGN expression, while CD1a was preferentially expressed in standard MoDCs. Functional evaluation revealed that 36 h MoAPCs displayed reduced endocytosis capabilities and IL-12p70 production. However, 36 h MoAPCs were able to induce T cell expansion both in an allogenic and antigen-specific setting. Our results indicate that mature 36 h MoAPCs possess DC-like capabilities by inducing antigen-specific T cell responses. This study has important implications for the generation of DC-based cellular therapies, allowing a more cost and time-efficient generation of APCs.

Constraints of Small and Medium Food Industry to Take Advantage of Domestic Market Opportunities during the Covid-19 Pandemic

The small and medium-sized food industry (SMFI) has a great opportunity to meet domestic market demand during the Covid-19 pandemic but there are various obstacles. This paper aims to present the constraints faced by SMFIs, especially concerning raw materials and marketing, in taking advantage of domestic market opportunities, and proposes alternative solutions. The study was conducted on four SMFIs that produce functional food in Malang Regency. Data were collected through in-depth interviews. The results showed that the demand for functional foods such as garlic, ginger, turmeric and fruits increased during the Covid-19 pandemic, which seemed to be related to public awareness about increasing immunity. However, the obstacles faced by SMFIs were the high price of raw materials due to limited supply, and limited marketing because they did not have distribution licenses from BPOM. Information about the process and BPOM’s distribution permit requirements was very limited for SMFI managers, and large capital was needed to fulfill the requirements of Good Manufacturing Practices. Therefore, SMFIs should have long-term cooperation with farmers to ensure the availability of raw materials; build networks and maintain cooperation with customers; and utilize credit for MSMEs in the economic recovery program provided by the government to meet the GMP requirements in BPOM’s distribution permit. The government should conduct intensive outreach to SMFI managers about the process and requirements for distribution permits from BPOM, credit facilities, and other policies related to economic recovery during the Covid-19 pandemic.
 Keywords: small and medium food industry, domestic market, Covid-19 pandemic, BPOM

Karakteristik dan Pemenuhan CPPOB Pelaku UMKM Online Produk Olahan Beku Daging Sapi dan Ayam di DKI Jakarta

Online trading system impacts small and medium entreprsises (SMEs) to easily sell food products andmake the sales of processed food and beverage product in Indonesia continues to grow, however theirawareness to implement food safety standards is still considered as low. This research was aimed todetermine the characteristic and Good Manufacturing Practices (GMP) fulfillment of online SMEswith frozen processed beef and chicken products that is included in medium risk registration categorieswith BPOM MD authorization. Research methods include sample selection of 24 SMEs respondentsin DKI Jakarta with snowball sampling method, questionnaire distribution, field observations anddata processing using descriptive analysis. Analysis of GMP fulfillment by MSMEs is based on eightrequirements refer to Ministry of Industry Regulation Number 75/M-IND/PER/7/2010 concerning GMPguidelines. Results showed that 41.7% the leader had bachelor degree and 54.2% total assets under5 million rupiah with annual turnover under 50 million rupiah. Most of them had IUMK (62.5%),production room located in household kitchen (54.2%) and selling online through social media (95.8%).79.2% of respondents slightly understand about GMP and food safety concept. The most uncompliedfrom eight requirements of GMP was application of lamp protectors in the production room (91.7%).

A flexibilização de requisitos brasileiros de Boas Práticas de Fabricação durante a pandemia da COVID-19 sob uma perspectiva comparada

Introduction: The risk of drug shortages due to the COVID-19 pandemic required from national health authorities to take quick actions in order to avoid it and, at the same time, preserve the maintenance of a minimum standard of quality, safety and efficacy of medicines, as National Health Regulatory Agency (Anvisa) did by publishing RDC nº 392/2020. Objective: To carry out a comparative analysis between the exceptionalities listed in article 7 of RDC nº 392/2020 with the requirements of good manufacturing practices (GMP) exceptionally relaxed by foreign health authorities due to COVID-19, showing, whenever necessary, the impact of these requirements on the quality of medicines made available to the population. Method: A selective search was made for documents related to the temporary flexibility of GMP requirements for medicines and pharmaceutical ingredients during the COVID-19 pandemic at the electronic addresses on the internet of some health authorities. Such requirements were critically compared with those listed in article 7 of RDC nº 392/2020. Results: Exceptionalities were presented in a Table, detailing the topics and subtopics found in the analyzed documents of MHRA, EMA and Anvisa. More similarities were verified than differences between the flexible requirements, perhaps because RDC nº 392/2020 was prepared considering the documents referenced here from MHRA and EMA. Conclusions: Despite the mistakes pointed out and the criticisms made to RDC nº 392/2020, the merit of Anvisa cannot be diminished, as it was shown that regardless of the territory in which the regulatory agencies are located, there is considerable convergence among Brazilian expectations and those of the other health authorities consulted.

Crossing the hurdles of translation—a robust methodology for synthesis, characterization and GMP production of cross‐linked high molecular weight hyaluronic acid particles (cHA)

AbstractHyaluronic acid (HA) is one of the most widely used extracellular matrix substrate in tissue engineering, drug delivery, and other clinical applications, due to its unique physiochemical properties and ubiquitous biological presence. In the past decade, there has been a surge in research paradigms involving HA products to evaluate their commercial feasibility. Numerous papers and reviews have reported procedures for chemical modifications and cross‐linking of HA, but the intricacies of their scale‐up in the production processes are often not discussed. Protected by confidentiality agreements with industry partners, information on these procedures is exclusive and not accessible within an academic setting. Establishing translatable synthetic protocols of HA would address this significant gap in the field and facilitate their use in other applications. The current method details a reproducible and robust method for producing particles that are composed of high molecular weight hyaluronic acid (cHA) and cross‐linked via a 4‐arm polyethylene glycol amine linker using 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methyl‐morpholinium chloride chemistry. A critical analysis of previously reported procedures for their advantages and limitations (reaction parameters, molar equivalents, and reagents used for cross‐linking), forms the basis for this procedure and its subsequent adaptation to good manufacturing practices requirements. As a component of a Class III medical device, the reported cHA is in the form of non‐sized particles.

Automated GMP-Compliant Production of [68Ga]Ga-DO3A-Tuna-2 for PET Microdosing Studies of the Glucagon Receptor in Humans.

Introduction: [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 (previously published as [68Ga]Ga-DO3A-VS-Cys40-S01-GCG) has shown high-affinity specific binding to the glucagon receptor (GCGR) in vitro and in vivo in rats and non-human primates in our previous studies, confirming the suitability of the tracer for drug development applications in humans. The manufacturing process of [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 was automated for clinical use to meet the radiation safety and good manufacturing practice (GMP) requirements. Methods: The automated synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler, Eurotope, Germany), disposable cassettes for 68Ga-labeling, and pharmaceutical-grade 68Ge/68Ga generator (GalliaPharm®) used in the study were purchased from Eckert & Ziegler. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, and pH, as well as product purification step, were investigated and optimized. Process optimization was conducted with regard to product quality and quantity, as well as process reproducibility. The active pharmaceutical ingredient starting material DO3A-VS-Cys40-Tuna-2 (GMP-grade) was provided by Sanofi Aventis. Results: The reproducible and GMP-compliant automated production of [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 with on-line documentation was developed. The non-decay-corrected radiochemical yield was 45.2 ± 2.5% (n = 3, process validation) at the end of the synthesis with a labeling synthesis duration of 38 min and a quality controlincluding release procedure of 20 min. The radiochemical purity of the product was 98.9 ± 0.6% (n = 17) with the total amount of the peptide in the preparation of 48 ± 2 µg (n = 3, process validation). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity tests met the acceptance criteria. The product was stable at ambient temperature for at least 2 h. Conclusion: The fully automated GMP-compliant manufacturing process was developed and thoroughly validated. The resulting [68Ga]Ga-DO3A-VS-Cys40-Tuna-2 was used in a clinical study for accurate quantification of GCGR occupancy by a dual anti-diabetic drug in vivo in humans.

Human-Induced Pluripotent Stem Cell Culture Methods Under cGMP Conditions.

The discovery of induced pluripotent stem cells (iPSCs) revolutionized the approach to cell therapy in regenerative medicine. Reprogramming of somatic cells into an embryonic‐like pluripotent state provides an invaluable resource of patient‐specific cells of any lineage. Implementation of procedures and protocols adapted to current good manufacturing practice (cGMP) requirements is critical to ensure robust and consistent high‐quality iPSC manufacturing. The technology developed at Allele Biotechnology for iPSC generation under cGMP conditions is a powerful platform for derivation of pluripotent stem cells through a footprint‐free, feeder‐free, and xeno‐free reprogramming method. The cGMP process established by Allele Biotechnology entails fully cGMP compliant iPSC lines where the entire manufacturing process, from tissue collection, cell reprogramming, cell expansion, cell banking and quality control testing are adopted. Previously, we described in this series of publications how to create iPSCs using mRNA only, and how to do so under cGMP conditions. In this article, we describe in detail how to culture, examine and storage cGMP‐iPSCs using reagents, materials and equipment compliant with cGMP standards. © 2020 The Authors. Basic Protocol 1: iPSC Dissociation Support Protocol 1: Stem cell media Support Protocol 2: ROCK inhibitor preparation Support Protocol 3: Vitronectin coating Basic Protocol 2: iPSC Cryopreservation Basic Protocol 3: iPSC Thawing

Validation of the framycetin sulfate determination technique by HPLC in a Framidex medicinal preparation

A method for determination of framycetin sulfate in a Framidex preparation (eye and ear drops) by HPLC-UV (λ = 365 nm) using 2, 4-dinitrofluorobenzene as a derivatizing agent has been developed The characteristics of analytical methods determined for the purpose of their validation and relevant criteria for the validity of validated methods with the goal of the quality control of drugs (pharmaceutical substances and drugs) are presented. According to the results of an intralaboratory experiment on the validation assessment of the method by the parameters of the specificity, limit of determination (LOD), linearity, precision and laboratory accuracy, it is shown that the LOD decreases by an order of magnitude, the correlation coefficient is not less than 0.99 correctness (average value — 97.5 – 102.5%; variation coefficient — not more than 2.0%; the confidence range should include 100% of values), convergence (variation coefficient — not more than 1.5%), intermediate precision (variation coefficient — not more than 1.5%). It is shown that the obtained values of metrological characteristics do not exceed the validation criteria and the developed method matches all the well-known requirements of GMP (Good Manufacturing Practice).

Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.

Assessing the Correlation Between GMP Deviations and Potential Quality Defects of Medicinal Products: the Result of the Survey of Qualified Persons

Introduction. One of the key issues in the field of assessing the conformity of drug manufacturers with the requirements of good manufacturing practice (GMP) is a systematic methodology for classifying revealed deficiencies (deviations, non-conformities) by their level of criticality. Today the information included into regulatory documents regarding the definitions of critical, major and minor (other) deficiencies is not always sufficient for the use in GMP inspection practice, as well as in quality management systems of the pharmaceutical manufacturers. In terms to study approaches to the classification of GMP deviations applied in the practice of the Qualified persons of drug manufacturers in the Russian Federation, a survey was conducted in the form of a questionnaire. This work became a logical continuation of a previous study among employees of the pharmaceutical inspectorate of the Russian Federation.Aim. To identify the correlation between the classification of critical and major GMP deviations and potential class I and II quality defects of medicinal products.Materials and methods. The study was based on a survey of Qualified persons of drug manufacturers (56 respondents) using a questionnaire specially designed. The main hypothesis of the study is that specialists (Qualified persons) who make decisions on the classification of GMP deviations are guided by potential quality defects that may be caused by the indicated deviations. In the framework of the study, authors used the model of gradation of quality defects of the medicinal products into 3 classes (class I, II and III) according to the rate of their significance as indicated in the PIC/S and EMA guidelines. At the same time, for GMP deviations a three-level gradation system is also used: Critical, Major and Minor (Other). In designing of questionnaires for the survey, the focus was made on examples of quality defects of classes I and II and, accordingly, Critical and Major GMP deviations.Results and discussion. The results of the processing and analysis of questionnaires summarize the opinion of the majority of respondents about the direct relationship between product quality defects of the high risk (class I) and critical GMP deviations. Respondents also expressed the opinion that deviations that could trigger the occurrence of the class II quality defects in most cases will be classified as critical. The results obtained during the study also indicate the similarity of existing approaches of the classification of GMP deviations (deficiencies) between QPs of the drug manufacturers and pharmaceutical inspectors.Conclusion. The results of the study show that for the purpose of classifying (determining the criticality) of GMP deviations (deficiencies) , it is possible to use the rating system for the quality defects of medicinal products by the rate of their significance for the patient which is presented in EU regulatory documents and PIC/S guidelines. The results of the study also will facilitate the drawing of conclusions that today, not only from the position of regulatory authorities, but also for the pharmaceutical industry, there is a need to develop methodological guidelines with a focus on a risk-based classification of GMP deviations (deficiencies). These guidelines should take into account the potential impact of the mentioned GMPdeviations on the occurrence of the quality defects of medicinal products and, as a result, threats to the life and health of patients.

An Update on the Progress of Isolation, Culture, Storage, and Clinical Application of Human Bone Marrow Mesenchymal Stem/Stromal Cells.

Bone marrow mesenchymal stem/stromal cells (BMSCs), which are known as multipotent cells, are widely used in the treatment of various diseases via their self-renewable, differentiation, and immunomodulatory properties. In-vitro and in-vivo studies have supported the understanding mechanisms, safety, and efficacy of BMSCs therapy in clinical applications. The number of clinical trials in phase I/II is accelerating; however, they are limited in the size of subjects, regulations, and standards for the preparation and transportation and administration of BMSCs, leading to inconsistency in the input and outcome of the therapy. Based on the International Society for Cellular Therapy guidelines, the characterization, isolation, cultivation, differentiation, and applications can be optimized and standardized, which are compliant with good manufacturing practice requirements to produce clinical-grade preparation of BMSCs. This review highlights and updates on the progress of production, as well as provides further challenges in the studies of BMSCs, for the approval of BMSCs widely in clinical application.

Scientific substantiation of HACCP system implementation in juice production

The purpose of the study is to substantiate the scientific implementation of a safety management system based on HACCP principles in the production of juice. Research Methods: Integral Risk Analysis, Decision Tree to Identify Critical Control Points. On the basis of theoretical data and research of the production process, an analysis of hazardous factors affecting the safety of the finished product is made. Based on the requirements of good hygiene and manufacturing practices (GMP and GHP), 13 prerequisite programs have been developed for the enterprise. The prerequisite programs specify which operational records should be maintained by the enterprise. According to the normative documents, which establish requirements for the HACCP system at the Ukrainian enterprises. Obligations in Ukraine are regulated by the provisions of the Code for the Association of Ukraine with the European Union and that it is consolidated on the basis of legislation and regulatory acts. The HACCP group at the enterprise, juice description, identification of specific consumer groups, development and validation of the block diagram, analysis of dangerous factors, establishment of critical control points, establishment of critical limits, monitoring systems, corrective actions, validation and verification procedures, and document management. The description of the juice includes the composition; structure and physicochemical characteristics; microbiological and chemical criteria; type of processing, method of consumer and transport packaging; type of marking; storage and transportation conditions; expiration date; method of consumption, marketing method; information about the intended consumer consumption (use). The production flowchart is based on the technological instructions of the enterprise and tested. Hazardous factors analysis includes biological, chemical and physical factors. 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Solid Phase 11C-Methylation, Purification and Formulation for the Production of PET Tracers.

Routine production of radiotracers used in positron emission tomography (PET) mostly relies on wet chemistry where the radioactive synthon reacts with a non-radioactive precursor in solution. This approach necessitates purification of the tracer by high performance liquid chromatography (HPLC) followed by reformulation in a biocompatible solvent for human administration. We recently developed a novel 11C-methylation approach for the highly efficient synthesis of carbon-11 labeled PET radiopharmaceuticals, taking advantage of solid phase cartridges as disposable "3-in-1" units for the synthesis, purification and reformulation of the tracers. This approach obviates the use of preparative HPLC and reduces the losses of the tracer in transfer lines and due to radioactive decay. Furthermore, the cartridge-based technique improves synthesis reliability, simplifies the automation process and facilitates compliance with the Good Manufacturing Practice (GMP) requirements. Here, we demonstrate this technique on the example of production of a PET tracer Pittsburgh compound B ([11C]PiB), a gold standard in vivo imaging agent for amyloid plaques in the human brains.