Good Manufacturing Practice Requirements Research Articles

Optimization of the Production Process of Clinical-Grade Human Salivary Gland Organoid-Derived Cell Therapy for the Treatment of Radiation-Induced Xerostomia in Head and Neck Cancer.

Head and neck cancer is a common cancer worldwide. Radiotherapy has an essential role in the treatment of head and neck cancers. After irradiation, early effects of reduced saliva flow and hampered water secretion are seen, along with cell loss and a decline in amylase production. Currently, there is no curative treatment for radiation-induced hyposalivation/xerostomia. This study aimed to develop and optimize a validated manufacturing process for salivary gland organoid cells containing stem/progenitor cells using salivary gland patient biopsies as a starting material. The manufacturing process should comply with GMP requirements to ensure clinical applicability. A laboratory-scale process was further developed into a good manufacturing practice (GMP) process. Clinical-grade batches complying with set acceptance and stability criteria were manufactured. The results showed that the manufactured salivary gland-derived cells were able to self-renew, differentiate, and show functionality. This study describes the optimization of an innovative and promising novel cell-based therapy.

Ensuring the quality of 3D printed medicines: Integrating a balance into a pharmaceutical printer for in-line uniformity of mass testing

Semi-solid extrusion (SSE) 3D printing has great potential to be integrated in a clinical setting, with the use of pre-filled and disposable pharma-ink syringes meeting regulatory good manufacturing practice (GMP) requirements. Uniformity of mass testing is a critical quality attribute and is carried out by weighing a specific amount of dosage units in a single batch and finding the average mass to evaluate any deviations. However, this test for small batches of 3D printed medicines may require weighing the entire manufactured batch. To overcome this limitation, an in-line analytical balance was implemented inside a GMP pharmaceutical 3D printer, with a specialised software-controlled weighing system for the automated mass uniformity testing of the entire printed batch. Three different dose batches (n = 28) of hydrocortisone pharma-ink were 3D printed and subjected to in-line mass uniformity testing. The developed software was capable of registering the weights of all individual printlets and accurately detecting any deviations within the accepted limits. Only one printlet was outside the accepted weight range, a result of the first print often being imperfect due to the semi-solid nature of the pharma-ink. The weight results were compared against an external analytical balance, and no significant differences were found. This study is the first to integrate an analytical balance inside a pharmaceutical printer, automating the dosage form mass uniformity testing which can save time, labour, and resources, whilst improving the quality control testing of 3D printed pharmaceuticals.

Advances in High-Performance Liquid Chromatography (HPLC) Method Development and Validation: A Comprehensive Review

High-Performance Liquid Chromatography (HPLC) stands as the cornerstone technique for the detection, separation, and quantification of drugs in various matrices. Method optimization necessitates a thorough investigation of multiple chromatographic parameters, encompassing sample pretreatment, mobile phase composition, column selection, and detector configuration. This article aims to comprehensively address the processes of method development, optimization, and validation within the realm of HPLC. The inherent advantages of HPLC, including its rapidity, specificity, accuracy, precision, and automation feasibility, render it an indispensable tool for analyzing a wide spectrum of drugs in complex multi-component dosage forms. Furthermore, HPLC method development and validation hold paramount importance across the spectrum of drug discovery, development, and manufacturing, as well as in diverse human and animal studies. The validation of analytical methods during drug development and manufacturing is imperative to ensure their fitness for the intended purpose. Adhering to Good Manufacturing Practice (GMP) requirements, pharmaceutical industries must establish comprehensive validation policies outlining the validation procedures. This article primarily delves into the optimization of HPLC conditions, emphasizing the critical role of method refinement in ensuring robust and reliable analytical methods.

ETİBARLI İSTEHSALAT TƏCRÜBƏSİNƏ DAİR XÜSUSİ TƏLƏBLƏRİN HAZIRLANMASININ ZƏRURİLİYİ

The article investigates existing international and regional requirements on various areas of Good Manufacturing Practice for the production of medicinal products, emphasizes the im-portance of preparing national requirements - annexes to the basic requirements of Good Manu-facturing Practice in the mentioned area, and gives relevant proposals on the relevant topic.

Overview of Good Manufacturing Practices Requirements for Herbal Medicines in India and Europe

Over the past three decades, the usage of herbal medicines and supplements has grown significantly, with at least 80% of people turning to them for some aspect of primary healthcare. Although the efficacy of many herbal products has been proved, therapies utilising these compounds have showed promising potential. Since safety is still a major concern when using herbal remedies, it is crucial that the proper regulatory agencies put in place the necessary safeguards to protect public health by ensuring that all herbal medications are secure and of high enough quality. In addition to outlining some significant difficulties in conducting an efficient safety review of herbal medicinal products, this review examines toxicity-related issues and significant safety concerns resulting from their use. Good Manufacturing Practices are designed to promote human health and, as a result, quality of life. Ensure the applicability of the principles offered and demonstrate the advantages resulting from this applicability in order to accomplish the objectives specified.

Assisting Food Household Industries in Implementation of Good Manufacturing Practice (GMP) on Frozen Meat Kebab in Sidoarjo District

Background: Good Manufacturing Practice (GMP) is a reference that explains the procedures to produce processed food so that it is of high quality, safe, and suitable for public consumption. The Food Safety Facilitator's role is to help register the processed products of SME (Small Medium Enterprise) X to obtain an NIE( Nomor Izin Edar) number. Objectives: The SME assistance aims to improve the implementation of GMP so that it can meet the GMP level that meets the requirements of the Regulation of the Head of the Food and Drug Administration on Guidelines for Inspection of Processed Food Production Facilities. Methods: Initial observations were made with a form based on the standards of the Food and Drug Administration to determine the score and value of SME X, then mentoring and training were carried out to correct GMP non-conformities. Results: The first observation of SME X showed that there were aspects that did not comply with the GMP requirements. With several non-conformities obtained, SME X received a grade of D or very poor, so it needs improvement to get an NIE number from BPOM. The results of the final inspection indicated an improvement in the score from D (very poor) to B (good) so that SME X could obtain the NIE number. Conclusions: Assistance and training to SMEs contributed to the improvement of SMEs' GMP implementation scores so that SME X was able to obtain a distribution license number for its food products

Magistral Phage Preparations: Is This the Model for Everyone?

Phage therapy is increasingly put forward as a promising additional tool to help curb the global antimicrobial resistance crisis. However, industrially manufactured phage medicinal products are currently not available on the European Union and United States markets. In addition, it is expected that the business purpose-driven phage products that are supposed to be marketed in the future would mainly target commercially viable bacterial species and clinical indications, using fixed phage cocktails. hospitals or phage therapy centers aiming to help all patients with difficult-to-treat infections urgently need adequate phage preparations. We believe that national solutions based on the magistral preparation of personalized (preadapted) phage products by hospital and academic facilities could bring an immediate solution and could complement future industrially manufactured products. Moreover, these unlicensed phage preparations are presumed to be more efficient and to elicit less bacterial phage resistance issues than fixed phage cocktails, claims that need to be scientifically substantiated as soon as possible. Just like Belgium, other (European) countries could develop a magistral phage preparation framework that would exist next to the conventional medicinal product development and licensing pathways. However, it is important that the current producers of personalized phage products are provided with pragmatic quality and safety assurance requirements, which are preferably standardized (at least at the European level), and are tiered based on benefit-risk assessments at the individual patient level. Pro bono phage therapy providers should be supported and not stopped by the imposition of industry standards such as Good Manufacturing Practice requirements. Keywords: antimicrobial resistance; antibiotic resistance; bacterial infection; bacteriophage therapy; magistral preparation.

Penerapan Kebijakan Pengawasan Obat Tradisional dalam Perspektif Kesehatan Masyaraat

Traditional medicine is one part of Indonesia's rich culture that has been used by the community for a long time. However, issues surrounding the safety and efficacy of traditional medicines often arise as a concern in the public health domain. This research uses qualitative research methods. The data collection technique was carried out by literature study and from interviews with traditional medicine users, traditional healthcare practitioners, and health officials. Thus, this can assist researchers in understanding their perceptions, experiences, and viewpoints regarding traditional medicine supervision. The data that has been collected is then analyzed using three stages, namely data reduction, data presentation and conclusion drawing. This is done to ensure that the implementation of legal supervision of traditional medicines is carried out through various stages. The process begins with the granting of production licenses to producers after fulfilling predetermined requirements. After that, the Food and Drug Monitoring Agency (BPOM) is responsible for supervising the production process directly on site. Supervision of the production process is carried out at least once a year. However, if there are violations of either CPOTB (Good Traditional Medicine Manufacturing Practice) or GMP (Good Manufacturing Practice) requirements, the inspection will be more intensive. The inspection is carried out until the manufacturer corrects and improves production activities in accordance with applicable standards.

Good Manufacturing Practice (GMP) in Tofu MSMEs in North Aceh

This study examined tofu MSMEs in Lhokseumawe City and the North Aceh District. Observations indicate discrepancies between tofu production and the GMP requirements for Good Manufacturing Practices. The amount that the tofu sector has adopted appropriate food production procedures by the Regulation of the Ministry of Sector of the Republic of Indonesia Number 75/M-IND/PER/7/2010 is determined using a GMP approach. This research is anticipated to improve the product safety of the tofu industry and provide recommendations for improvement. In this study, data collection techniques included candid interviews related to the GMP aspect questionnaire consisting of 11 inspection aspects, direct field observation of 21 MSMEs by marking the location conditions, production equipment, and materials used, and following the processing process, followed by a search for deviations from GMP aspects and comparison with the literature review, documentation of the necessary data related to GMP assessment, and a search for relevant literature. According to the evaluation, 12 MSMEs with a value range of 41% to 60% fell into the category of not meeting the requirements. The second criterion is extremely inadequate, ranging from 21% to 40% for five MSMEs. Additionally, the criteria for sufficient completion with a range of values between 61% and 80% for up to 4 MSMEs led to an evaluation of 11 GMP aspects in 21 MSMEs. Know on the location aspect with a percentage of 71% in the sufficient category, building aspects with a percentage of 11% in the critical category, aspects of sanitation with a percentage of 40% in the category of very less fulfilling, aspects of machinery and equipment with a percentage of 80% in the category of sufficiently fulfilling, aspects of materials with a percentage of 100% in the category of fulfilling, and aspects of supervision with a percentage of 40% in the category of fulfilling.

NMR as powerful technology for noninvasively monitoring cell health and expansion during bioprocessing

Over the last decades, the success of advanced cell therapies and the increasing production volumes of vaccines, proteins, or viral vectors have raised the need of robust cell-based manufacturing processes for ensuring product quality and satisfying good manufacturing practice requirements. The cultivation process of cells needs to be highly controlled for improved productivity, reduced variability, and optimized bioprocesses. Cell cultures can be easily monitored using different technologies, which could deliver direct or indirect assessment of the cells' viability. Among these techniques, nuclear magnetic resonance (NMR) spectroscopy is a powerful technology that permits the evaluation and the identification of key endogenous metabolites. NMR can provide information on the cell metabolic pathways, on the bioprocesses, and is also capable to quickly test for impurities. In this study, NMR was successfully used as a technology for monitoring cell viability and expansion in different supports for cell growth (including bioreactors), to predict the bioprocess output and for the early identification of key metabolites linked to cell starvation. This investigation will allow the timely control of culture conditions and favor the optimization of the bioprocesses.

GMP AUDIT CHECKLIST – A VALUABLE MANAGEMENT TOOL IN PHARMACEUTICAL INDUSTRY

Internal audit is an effective independent activity within a pharmaceutical industry quality management system. It ensures a thorough analyses and evaluation of the company activities and helps prevent, predict and detect mistakes and weaknesses in order to minimize losses. Internal audits help the organization achieve its goals and ensures all the involved parties that a program complies with regulatory and Good Manufacturing Practice (GMP) requirements. A successful audit, is carried out by quality auditor or audit team members, chosen carefully and properly trained. The auditor should gain as much information in advance before the auditing process begins that should help him to design tools useful in achieving the desired results. There are several sections recommended to be included in the GMP audit checklist: Quality management, Personnel, Facility and Equipment System, Documentation, Production System, Packaging and Labelling System, Storage System, and Laboratory Control System. A quality management system (QMS) is a formalized collection of processes, procedures, and documented policies, therefore the auditor looks to find out if the system complies with GMP requirements. As for the personnel, GMP audit checklist cover all the necessary procedures to ensure that the organization’s hiring and supervising practices are in compliance to GMP requirements, such as competences, trainings, dressing, and hygiene of the employees. Documentation ensures traceability of all development, manufacturing and testing activities, so the auditor needs to verify major types of documents that should be kept and recorded. The checklist includes questions addressing review of the layout, construction, size, location of the facility and main areas such as production area, storage, and laboratory, as well as the installation, operation, instructions, maintenance and cleaning of the equipment used in the manufacture. The production and process audit checklist include organization’s various stages of manufacturing such as weighing or measuring of raw materials, appropriate storage conditions for intermediates, In-Process sampling and controls, contamination control, process validation. Checklist points for internal audit of Packaging and Labelling System include elements ensuring the security and quality of packaging and as well elements that relate to labelling such as documentation, storage of starting materials and finished products, packaging and labelling operations. Internal auditing of storage system should prevent occurrence of mix-ups, damage, physical, chemical or microbial contamination. As for the Laboratory Control System, the GMP checklist questions aim to ensure that pharmaceutical products meet safety, efficacy, purity, and stability standards. The checklist is a good and critical tool to assist in conducting an in-depth and consistent audit and will serve as guideline for evaluation of compliance to standards and documentation, as well as for the effectiveness of the audited process.

Embedding MSCs in Si-HPMC hydrogel decreased MSC-directed host immune response and increased the regenerative potential of macrophages.

Embedding mesenchymal stromal cells (MSCs) in biomaterial is a subject of increasing interest in the field of Regenerative Medicine. Speeding up the clinical use of MSCs is dependent on the use of non-syngeneic models in accordance with Good Manufacturing Practices (GMP) requirements and on costs. To this end, in this study, we analyzed the in vivo host immune response following local injection of silanized hydroxypropyl methylcellulose (Si-HPMC)-embedded human MSCs in a rat model developing colorectal damage induced by ionizing radiation. Plasma and lymphocytes from mesenteric lymph nodes were harvested in addition to colonic tissue. We set up tests, using flow cytometry and a live imaging system, to highlight the response to specific antibodies and measure the cytotoxicity of lymphocytes against injected MSCs. We demonstrated that Si-HPMC protects MSCs from specific antibodies production and from apoptosis by lymphocytes. We also observed that Si-HPMC does not modify innate immune response infiltrate in vivo, and that in vitro co-culture of Si-HPMC-embedded MSCs impacts macrophage inflammatory response depending on the microenvironment but, more importantly, increases the macrophage regenerative response through Wnt-family and VEGF gene expression. This study furthers our understanding of the mechanisms involved, with a view to improving the therapeutic benefits of biomaterial-assisted cell therapy by modulating the host immune response. The decrease in specific immune response against injected MSCs protected by Si-HPMC also opens up new possibilities for allogeneic clinical use.

Systematic approach to cross-contamination risk management in the production of medicinal products

Introduction. Good Manufacturing Practice (GMP) requires drug manufacturers to apply risk management principles in their operations. One of the main risks to the quality and safety of pharmaceuticals is cross-contamination. The introduction of a systematic approach to contamination risk management requires manufacturers to make a comprehensive assessment of both production processes and the organization of production sites (premises, equipment, systems, etc.). Therefore, the transition to the current GMP requirements for operating production sites may require significantly higher financial and labor costs than for projected production facilities.Aim. Development of a scientifically based program and methodology for cross-contamination risk management for existing pharmaceutical industries, taking into account compliance with the harmonized GMP requirements of the Russian Federation and the EAEU and world practice.Materials and methods. In the course of the study, methods of risk management, analysis and systematization of data and a process approach were used.Results and discussion. The key aspects of the organization of the co-manufacturing of medicines are outlined. A step-by-step approach to risk management, involving a preliminary assessment of the conformity of a production organization with GMP requirements is described. The proposed scheme is aimed at ensuring the continuous functioning of the cross-contamination risk management process.Conclusion. The presented risk management methodology aims to conduct a proper assessment of the risks of cross-contamination for multiproduct pharmaceutical enterprises. This technique allows to identify areas that need improvement to ensure compliance of manufacturing sites with GMP requirements, which ultimately contributes to improving the quality of medicines.

Characterisation of a simple ‘hanging bag’ photobioreactor for low‐cost cultivation of microalgae

AbstractBACKGROUNDMicroalgae are a diverse group of photosynthetic microorganisms of significant interest to the biotechnology industry, either as a sustainable source of natural compounds, or as light‐driven cell factories to produce recombinant metabolites and proteins. Their ability to utilise light, CO2, and basic nutrients leads to a simple and low‐cost phototrophic cultivation process. This is particularly relevant to low‐ and middle‐income countries, all of which require a cultivation system that is cheap, technically simple to operate, readily scalable, and can meet basic Good Manufacturing Practice requirements. A disposable ‘hanging bag’‐type photobioreactor operated as a bubble column fits these criteria.RESULTSIn this study, the characterisation and design modifications to improve the performance of a 15 L hanging bag is reported. The bubble behaviour using different sparger designs was investigated together with gas hold‐up, mixing time, and mass transfer coefficient of CO2. A gas flow rate of 5 L min−1 using a new sparger design and a modified height‐to‐diameter ratio of the bag led to a two‐fold improvement in algal biomass productivity when culturing the green microalga Chlorella sorokiniana. The cultivation of a luciferase‐expressing Chlamydomonas reinhardtii strain in the modified hanging bag also demonstrated an 11% increase in luciferase content.CONCLUSIONThis is the first attempt to characterise this simple hanging bag system that brings the industry‐favoured single‐use bag concept into the research field of photobioreactor technology. The hanging bag with modified sparger and dimensions improves microalgal biomass productivity and demonstrates the potential of simple and low‐cost systems for microalgal cultivation. © 2021 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

Risk Assessment of RYR Food Supplements: Perception vs. Reality.

Thirty-seven red yeast rice (RYR) food supplements were screened for their mycotoxin and natural statin content. Products included pure RYR capsules and multi-ingredient formulations with standardized amounts of monacolin K (MK), marketed both online and retail in the European Union. In terms of mycotoxins, citrinin (CIT) was found in all the monitored products. As CIT content ranged from 100 to 25100 μg/kg, only four products were compliant with maximum EU levels in force until April 2020, while a single product was compliant with the limit of 100 μg/kg introduced after that date. Four contaminated products were labeled as “citrinin free”. In terms of natural statins, nine products had a lower content vs. label statements (from −30 to −83%), while for 24 a larger MK amount (from 10 to 266%) was noticed. Three products had a negligible MK content and only 19 offered a daily dosage exceeding 10 mg as dictated by the health claim granted by EFSA in the EU. No sample had label values compliant with pharmaceutical Good Manufacturing Practices requirements (95–105% content of active constituent). Variable, but small amounts of simvastatin (0.1–7.5 μg per daily dose) were found in 30 samples. These results suggest that limited efficacy and reported safety issues may stem from an under-regulated and undercontrolled market, weakening both effectiveness and risk assessment evaluations.

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.

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.