Good Manufacturing Process Research Articles

Aflatoxin and microbial safety in commercial confectionery peanut paçoca produced in São Paulo state – Brazil

Paçoca is a typical Brazilian confectionery of Indigenous origin prepared by mixing ground roasted peanuts, sugar, and salt. A total of 52 samples of paçoca (37 pressed, 15 cooked), produced and sold in the state of São Paulo, were evaluated for aflatoxin content (AFB1, AFB2, AFG1 and AFG2), moisture content and water activity. The microbiological quality was assessed by counting mesophilic aerobic bacteria, fungal and yeast counts, most likely number of thermotolerant coliforms and Escherichia coli and Salmonella sp. The limit of quantification (LOQ) by Ultra Performance Liquid Chromatography coupled to the Mass Spectrometer (UPLC-MS/MS) ranged from 0.29 μg kg−1 for AFB1 and AFG2; 0.36 μg kg−1 for AFG1 and 0.37 μg kg−1 for AFB2. The recovery averages were 89.2, 83.5, 80.5 and 82.8% for AFB1, AFB2, AFG1 and AFG2. 71% of the samples showed aflatoxin contamination, ranging from 0.29 to 38.8 μg kg−1 (mean of 7.06 μg kg−1). Six samples (16%) exceeded the limit value tolerated by the Brazilian guideline for AFT (20 μg kg−1). The mean AFT content in cooked paçocas (19.55 μg kg−1) was higher than the levels in pressed paçocas (9.08 μg kg−1) (p < 0.05). AFB1 had a higher incidence in the two groups of paçocas (75% pressed and 60% cooked). The mean moisture content and water activity of cooked paçocas (8.86% and 0.7081) were higher than those of pressed paçocas (2.08% and 0.4863). Twenty-one samples (56%) showed fungal and yeast contamination ranging from 1.0 to 4.25 log CFU g−1. The total count of aerobic mesophilic bacteria in cooked paçocas (4.85 log CFU g−1) was also higher than in pressed paçocas (2.77 log CFU g−1) (p < 0.05). E. coli was confirmed in these samples in the range of 3.0–160 NMP g−1. Salmonella sp. was detected in 2 samples of pressed paçocas, indicating poor hygiene, inefficient heat treatment or possible cross-contamination. The results of this study demonstrate the need for greater control of the paçoca production chain through the adoption of Good Manufacturing Practices and process control, to prevent exposure of the population to aflatoxins and possible pathogenic microorganisms.

Clinically compliant cryopreservation of differentiated retinal pigment epithelial cells

Background aimsAge-related macular degeneration (AMD) is the most common cause of blindness in elderly patients within developed countries, affecting more than 190 million worldwide. In AMD, the retinal pigment epithelial (RPE) cell layer progressively degenerates, resulting in subsequent loss of photoreceptors and ultimately vision. There is currently no cure for AMD, but therapeutic strategies targeting the complement system are being developed to slow the progression of the disease. MethodsReplacement therapy with pluripotent stem cell-derived (hPSC) RPEs is an alternative treatment strategy. A cell therapy product must be produced in accordance with Good Manufacturing Practices at a sufficient scale to facilitate extensive pre-clinical and clinical testing. Cryopreservation of the final cell product is therefore highly beneficial, as the manufacturing, pre-clinical and clinical testing can be separated in time and location. ResultsWe found that mature hPSC-RPE cells do not survive conventional cryopreservation techniques. However, replating the cells 2–5 days before cryopreservation facilitates freezing. The replated and cryopreserved hPSC-RPE cells maintained their identity, purity and functionality as characteristic RPEs, shown by cobblestone morphology, pigmentation, transcriptional profile, RPE markers, transepithelial resistance and pigment epithelium–derived factor secretion. Finally, we showed that the optimal replating time window can be tracked noninvasively by following the change in cobblestone morphology. ConclusionsThe possibility of cryopreserving the hPSC-RPE product has been instrumental in our efforts in manufacturing and performing pre-clinical testing with the aim for clinical translation.

Human nasal olfactory stem cells, purified as advanced therapy medicinal products, improve neuronal differentiation.

Olfactory ecto-mesenchymal stem cells (OE-MSC) are mesenchymal stem cells derived from the lamina propria of the nasal mucosa. They display neurogenic and immunomodulatory properties and were shown to induce recovery in animal models of spinal cord trauma, hearing loss, Parkinsons's disease, amnesia, and peripheral nerve injury. As a step toward clinical practice, we sought to (i) devise a culture protocol that meets the requirements set by human health agencies and (ii) assess the efficacy of stem cells on neuron differentiation. Nasal olfactory mucosa biopsies from three donors were used to design and validate the good manufacturing process for purifying stem cells. All processes and procedures were performed by expert staff from the cell therapy laboratory of the public hospital of Marseille (AP-HM), according to aseptic handling manipulations. Premises, materials and air were kept clean at all times to avoid cross-contamination, accidents, or even fatalities. Purified stem cells were cultivated for 24 or 48 h and conditioned media were collected before being added to the culture medium of the neuroblastoma cell line Neuro2a. Compared to the explant culture-based protocol, enzymatic digestion provides higher cell numbers more rapidly and is less prone to contamination. The use of platelet lysate in place of fetal calf serum is effective in promoting higher cell proliferation (the percentage of CFU-F progenitors is 15.5%), with the optimal percentage of platelet lysate being 10%. Cultured OE-MSCs do not show chromosomal rearrangement and, as expected, express the usual phenotypic markers of mesenchymal stem cells. When incorporated in standard culture medium, the conditioned medium of purified OE-MSCs promotes cell differentiation of Neuro2a neuroblastoma cells. We developed a safer and more efficient manufacturing process for clinical grade olfactory stem cells. With this protocol, human OE-MSCs will soon be used in a Phase I clinical based on their autologous transplantation in digital nerves with a neglected injury. However, further studies are required to unveil the underlying mechanisms of action.

Production and nonclinical evaluation of an autologous iPSC–derived platelet product for the iPLAT1 clinical trial

AbstractDonor-derived platelets are used to treat or prevent hemorrhage in patients with thrombocytopenia. However, ∼5% or more of these patients are complicated with alloimmune platelet transfusion refractoriness (allo-PTR) due to alloantibodies against HLA-I or human platelet antigens (HPA). In these cases, platelets from compatible donors are necessary, but it is difficult to find such donors for patients with rare HLA-I or HPA. To produce platelet products for patients with aplastic anemia with allo-PTR due to rare HPA-1 mismatch in Japan, we developed an ex vivo good manufacturing process (GMP)–based production system for an induced pluripotent stem cell–derived platelet product (iPSC-PLTs). Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from patient iPSCs, and a competent imMKCL clone was selected for the master cell bank (MCB) and confirmed for safety, including negativity of pathogens. From this MCB, iPSC-PLTs were produced using turbulent flow bioreactors and new drugs. In extensive nonclinical studies, iPSC-PLTs were confirmed for quality, safety, and efficacy, including hemostasis in a rabbit model. This report presents a complete system for the GMP-based production of iPSC-PLTs and the required nonclinical studies and thus supports the iPLAT1 study, the first-in-human clinical trial of iPSC-PLTs in a patient with allo-PTR and no compatible donor using the autologous product. It also serves as a comprehensive reference for the development of widely applicable allogeneic iPSC-PLTs and other cell products that use iPSC-derived progenitor cells as MCB.

Target cell line characterization reveals changes in expression of a key antigen that impacts T cell dependent cellular cytotoxicity assay performance

Cell lines are important tools regularly used for in-vitro potency assays employed in Good Manufacturing Process (GMP) lot release and stability testing of different therapeutic modalities. Characterization of these cell lines is key to understanding their performance.Bispecific T cell engager (BiTE®) molecules are an exciting modality in Amgen's therapeutic product portfolio. BiTE® molecules are engineered as two linked, single chain antibody domains. One domain targets the cluster of differentiation 3 (CD3) domain of T cells, and the other domain targets a specific antigen. The mechanism of action of the BiTE® molecule is to bring T cells into close proximity of tumor cells to facilitate tumor cell killing. One BiTE® molecule in development, AMG 757, is directed against delta-like ligand 3 (DLL3), which is expressed in small cell lung cancer tumor cells. AMG 757 is a half-life extended bispecific T cell engager (HLE BiTE®) construct. The bioassay employed to demonstrate the mechanism of action of AMG 757 is a T cell dependent cellular cytotoxicity (TDCC) cell-based assay requiring two cell lines, the effector T cell line HuT-78, and engineered tumor target cells, SHP-77-Luc. During the course of development of this bioassay, characterization of the SHP-77-Luc line showed an increase in the luminescence assay signal and Maximum-to-Minimum (Max-to-Min) ratio of the dose response curve as the passage number of the cells increased. Our research revealed an increase in not only luciferase expression but also an increase in the cell surface and intracellular expression levels of DLL3 over time in culture, which ultimately resulted in the increased assay signal window.

GMP Compliant Production of a Cryopreserved Adipose-Derived Stromal Cell Product for Feasible and Allogeneic Clinical Use.

The emerging field of advanced therapy medicinal products (ATMP) holds promise of treating a variety of diseases. Adipose-derived stromal cells (ASCs) are currently being marketed or tested as cell-based therapies in numerous clinical trials. To ensure safety and efficacy of treatments, high-quality products must be manufactured. A good manufacturing practice (GMP) compliant and consistent manufacturing process including validated quality control methods is critical. Product design and formulation are equally important to ensure clinical feasibility. Here, we present a GMP-compliant, xeno-free, and semiautomated manufacturing process and quality controls, used for large-scale production of a cryopreserved off-the-shelf ASC product and tested in several phase I and II allogeneic clinical applications.

Process Analytical Technology for the Production of Parenteral Lipid Emulsions According to Good Manufacturing Practices

The good manufacturing practices (GMP) and process analytical technology (PAT) initiatives of the US Food and Drug Administration, in conjunction with International Council for Harmonisation (ICH) quality guidelines Q8, Q9, and Q10, ensure that manufacturing processes for parenteral formulations meet the requirements of increasingly strict regulations. This involves the selection of suitable process analytics for process integration and aseptic processing. In this article, we discuss the PAT requirements for the GMP-compliant manufacturing of parenteral lipid emulsions, which can be used for clinical nutrition or for the delivery of lipophilic active ingredients. There are risks associated with the manufacturing processes, including the potential for unstable emulsions and the formation of large droplets that can induce embolisms in the patient. Parenteral emulsions are currently monitored offline using a statistical approach. Inline analytics, supplemented by measurements of zeta potential, could minimize the above risks. Laser scanning technology, ultrasound attenuation spectroscopy, and photo-optical sensors combined with image analysis may prove to be useful PAT methods. In the future, these technologies could lead to better process understanding and control, thus improving production efficiency.

In vitro and in vivo assessment of a 3D printable gelatin methacrylate hydrogel for bone regeneration applications.

Bone tissue engineering (BTE) has made significant progress in developing and assessing different types of bio-substitutes. However, scaffolds production through standardized methods, as required for good manufacturing process (GMP), and post-transplant in vivo monitoring still limit their translation into the clinic. 3D printed 5% GelMA scaffolds have been prepared through an optimized and reproducible process in this work. Mesenchymal stem cells (MSC) were encapsulated in the 3D printable GelMA ink, and their biological properties were assessed in vitro to evaluate their potential for cell delivery application. Moreover, in vivo implantation of the pristine 3D printed GelMA has been performed in a rat condyle defect model. Whereas optimal tissue integration was observed via histology, no signs of fibrotic encapsulation or inhibited bone formation were attained. A multimodal imaging workflow based on computed tomography (CT) and magnetic resonance imaging (MRI) allowed the simultaneous monitoring of both new bone formation and scaffold degradation. These outcomes point out the direction to undertake in developing 3D printed-based hydrogels for BTE that can allow a faster transition into clinical use.

Generation of Tumor-Specific Cytotoxic T Cells From Blood via InVitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads.

For the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen prediction technologies provides opportunities for further development of personalized immunotherapies. In this study, we present a novel strategy to deliver in silico predicted neoantigens to autologous dendritic cells (DCs) using paramagnetic beads (EpiTCer beads). DCs pulsed with EpiTCer beads are superior in enriching for healthy donor and patient blood-derived tumor-specific CD8+ T cells compared to DC loaded with whole-tumor lysate or 9mer neoantigen peptides. A dose-dependent effect was observed, with higher EpiTCer bead per DC being favorable. We concluded that CD8+ T cells enriched by DC loaded with EpiTCer beads are tumor specific with limited tumor cross-reactivity and low recognition of autologous non-activated monocytes or CD8+ T cells. Furthermore, tumor specificity and recognition were improved and preserved after additional expansion using our Good Manufacturing Process (GMP)-compatible rapid expansion protocol. Phenotypic analysis of patient-derived EpiTCer DC expanded CD8+ T cells revealed efficient maturation, with high frequencies of central memory and effector memory T cells, similar to those observed in autologous expanded tumor-infiltrating lymphocytes. These results indicate that DC pulsed with EpiTCer beads enrich for a T-cell population with high capacity of tumor recognition and elimination, which are features needed for a T-cell product to be used for personalized adoptive cell therapy.

Cultivated Autologous Limbal Epithelial Cell Transplantation: New Frontier in the Treatment of Limbal Stem Cell Deficiency

Taking into consideration prior human experience with treating limbal stem cell deficiency (LSCD) with cultivated limbal epithelial cells (CLEC) from other countries, we have set a goal to optimize and standardize the techniques of CLEC preparation (called CALEC by our group) for the clinical trial in the United States. We performed an extensive literature review of all human trials, case series, and reports involving autologous cultivated limbal epithelial cell transplantation. Allogeneic cultivated limbal epithelial cell transplantations were reported only when combined with autologous studies. We also searched prior animal data aiding in detailing regulatory toxicology requirements. Between 1997 and 2020, the analysis of human trials revealed 21 studies on autologous grafts, and 13 studies analyzing both autologous grafts and allogeneic grafts. Of a total of 34 studies, 6 studies used good manufacturing process (GMP) facilities, and 11 studies had no animal-derived products or murine feeder layers, whereas only 1 study had both. Overall, the treatment with autologous CLEC grafts was 68.9% successful. In total there were 6 preclinical studies using rabbits, serving as surrogate studies to assess the safety and toxicity of cultivated limbal epithelial cells for human trials. Based on prior human experience, we further optimized the manufacturing conditions with GMP-grade and serum and animal-free reagents, and developed cell characterization assays for the CALEC product release. These data were used to develop a novel and consistent manufacturing process using only qualified and validated reagents for performing the first clinical trial on CALEC transplantation to treat LSCD in the United States.

Multiplex PCR for the detection of Salmonella spp. in Indonesian traditional shrimp paste (Terasi)

Terasi is a food condiment originating from Indonesia which is processed by fermenting shrimp, fish, or a mixture of both. The processing of terasi in Indonesia is still found traditionally so that it will affect the low quality of terasi which is characterized by being contaminated by pathogenic bacteria such as Salmonella. Salmonella is a bacterium that causes foodborne diseases. The purpose of this study was to evaluate the presence of Salmonella in shrimp paste using conventional method and then confirmed with molecular approach. This study used 10 samples consisting modern terasi and five traditional terasi. The isolation of Salmonella spp. carried out by using selective media, and then the isolates were characterized further using biochemical test (TSIA and LIA). The species identification of Salmonella spp. was carried out by multiplex PCR (mPCR). The isolates that were not detected by mPCR were further identified using 16s rDNA sequencing. The isolation results showed that Salmonella isolates were only detected in traditional terasi with a density range of 2.4 x 10 5 2.9 x 10 8 CFU/g. A total of 20 isolates were characterized biochemically as Salmonella, and out of 17 isolates consistently identified as Salmonella enterica serovar Typhimurium by using mPCR. The rest three isolates were further identified as Citrobacter freundii based on 16s rDNA sequencing with similarity level of 99%. The presence of Salmonella in the shrimp paste indicates that the processing of traditional shrimp paste (terasi) should be evaluated in accordance with good manufacturing process.

Analisis Daya Saing Ekspor Minyak Atsiri Nilam (Patchouli Essential Oil) Indonesia di Pasar Internasional dengan Negara Brazil, Amerika Serikat, Meksiko, dan Perancis Periode 2001-2018

Until now, the domestic patchouli essential oil industry in Indonesia is still limited to exporting unprocessed products as finished products. In addition, farmers and cooperatives understanding is still low in implementing a good plantation manufacturing process. One indicator that can be seen is the number of imports of patchouli essential oil derivative products such as semi-finished ingredients from perfume and food flavors by Indonesia in the period of October-December 2008 amounting to US$ 401 million while exports were only US$ 103 million or a deficit of three to four times of exports. The purpose of this research is to analyze the comparative competitiveness, competitive competitiveness, and specialization of Indonesian patchouli essential oil trade in the international market. Countries that are used as comparison for Indonesia (rank 7) based on the average volume of exports are Brazil (rank 1), the United States (rank 2), Mexico (rank 8) and France (rank 9). This study uses the Revealed Comparative Trade Advantage (RCTA) analysis tool to analyze comparative competitiveness, the Export Competitiveness Index (XCI) to analyze competitive competitiveness, and the Trade Specialization Index (ISP) to analyze its trade specialties. The factors that significantly influence the competitiveness and trade specialization are the export and import value of patchouli essential oil and other goods from Indonesia and competing countries, the total export and import value of patchouli essential oil. Based on the results of the RCTA, XCI, and ISP analysis, the values obtained by Indonesia were 2.013, 1.012, and 0.412, respectively. Keywords: patchouli, essential oil, competitiveness, trade specialties

Development and Validation of a Good Manufacturing Process for IL-4-Driven Expansion of Chimeric Cytokine Receptor-Expressing CAR T-Cells.

Adoptive cancer immunotherapy using chimeric antigen receptor (CAR) engineered T-cells holds great promise, although several obstacles hinder the efficient generation of cell products under good manufacturing practice (GMP). Patients are often immune compromised, rendering it challenging to produce sufficient numbers of gene-modified cells. Manufacturing protocols are labour intensive and frequently involve one or more open processing steps, leading to increased risk of contamination. We set out to develop a simplified process to generate autologous gamma retrovirus-transduced T-cells for clinical evaluation in patients with head and neck cancer. T-cells were engineered to co-express a panErbB-specific CAR (T1E28z) and a chimeric cytokine receptor (4αβ) that permits their selective expansion in response to interleukin (IL)-4. Using peripheral blood as starting material, sterile culture procedures were conducted in gas-permeable bags under static conditions. Pre-aliquoted medium and cytokines, bespoke connector devices and sterile welding/sealing were used to maximise the use of closed manufacturing steps. Reproducible IL-4-dependent expansion and enrichment of CAR-engineered T-cells under GMP was achieved, both from patients and healthy donors. We also describe the development and approach taken to validate a panel of monitoring and critical release assays, which provide objective data on cell product quality.

A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.

Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

T cell engineering strategies offer cures to patients and have entered clinical practice with chimeric antibody-based receptors; αβT cell receptor (αβTCR)-based strategies are, however, lagging behind. To allow a more rapid and successful translation to successful concepts also using αβTCRs for engineering, incorporating a method for the purification of genetically modified T cells, as well as engineered T cell deletion after transfer into patients, could be beneficial. This would allow increased efficacy, reduced potential side effects, and improved safety of newly to-be-tested lead structures. By characterizing the antigen-binding interface of a good manufacturing process (GMP)-grade anti-αβTCR antibody, usually used for depletion of αβT cells from stem cell transplantation products, we developed a strategy that allows for the purification of untouched αβTCR-engineered immune cells by changing 2 amino acids only in the TCRβ chain constant domain of introduced TCR chains. Alternatively, we engineered an antibody that targets an extended mutated interface of 9 amino acids in the TCRβ chain constant domain and provides the opportunity to further develop depletion strategies of engineered immune cells.

Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.

Quality and storage stability of tamarind juice

Abstract Tamarind is a tropical fruit with relevant importance for family agriculture, and can be used as raw material for a ready-to-drink juice; however, there are few data in the literature associated with the tamarind juice storage stability. This work aimed to evaluate the physicochemical, sensory and microbiological stability of tamarind juice throughout storage at room temperature (~28 °C) for 180 days. Two juice formulations were produced, a control (pH 2.5), and the formulation with acidity reduction (pH 3.5). Physicochemical (pH, acidity, and soluble solids), sensory and microbiological analyses were performed for both juices along storage. The results showed that both juices were stable regarding all physicochemical parameters analyzed. Furthermore, both juices kept sensory scores in the acceptance zone, despite little changes in attributes (tamarind, sour, and sweet taste) for the partially neutralized juice (pH 3.5). Microbiological results were also stable for the period analyzed, which indicated efficient good manufacturing process alongside efficient heat treatment. Therefore, both juices can be stored at room temperature without presenting quality loss.

Development of an optimized closed and semi-automatic protocol for Good Manufacturing Practice manufacturing of tumor-infiltrating lymphocytes in a hospital environment

Background aimsSeveral studies report on Good Manufacturing Process (GMP)-compliant manufacturing protocols for the ex vivo expansion of tumor-infiltrating lymphocytes (TILs) for the treatment of patients with refractory melanoma and other solid malignancies. Further opportunities for improvements in terms of ergonomy and operating time have been identified. MethodsTo enable GMP-compliant TILs production for adoptive cell therapy needs, a simple automated and reproducible protocol for TILs manufacturing with the use of a closed system was developed and implemented at the authors’ institution. ResultsThis protocol enabled significant operating time reduction during TILs expansion while allowing the generation of high-quality TILs products. ConclusionsA simplified and efficient method of TILs expansion will enable the broadening of individualized tumor therapy and will increase patients’ access to state-of-the-art TILs adoptive cell therapy treatment.

Risk-based approach for validation of technological process

Good manufacturing process is one of the most significant risk exclusion factors for patients due to lack of safety, efficacy or quality. Therefore, it is critical that the ability to continuously medicinal products of the required quality in accordance with the specifications and quality attributes has been demonstrated.The aim of our research and this publication is to formulate a practical risk-oriented approach to process validation of the pharmaceutical production, taking into account modern requirements for both the process validation itself and the quality risk management system, in terms of defining and justifying the process control strategy for the subsequent routine manufacturing commercial batches of medicinal products, that would eliminate the risk for patients associated with lack of safety, efficacy or quality of medicinal products.Materials and methods. The subject of the work is the analysis of modern requirements for validation of pharmaceutical production process and quality risk management system as processes of pharmaceutical quality system, and determination on this basis of practical model of implementation of risk-based approach to process validation (PV) – definition, justification and confirmation of effectiveness (efficiency) of control strategy of technological process of medicines production.Results and discussion. According to the requirements of current guidelines, process validation should include the collection and evaluation of data that scientifically substantiate that the process can consistently ensure proper quality product throughout the product lifecycle, starting with its development, and validation activities should be based on quality risk management principles. The model of risk-oriented definition of process control strategy is considered, which is able to provide the possibility of practical application to any groups of pharmaceutical products and processes. It can be perceived as basic and, taking into account the specifics of each company, can be modified or detailed.Conclusions. Based on the analysis of the place and role of process validation, we have proposed a comprehensive unified model for the implementation of a risk-based approach to process validation in terms of defining a process control strategy based on the principles of quality risk management recommended for the pharmaceutical industry.

A GLANCE TO THE STORY OF GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS

Good Manufacturing Process (GMP) is the magic key that opens the door of quality. GMP is an evergrowing process as the new drugs are discovering day by day, but the concept is not new; its roots are very old. Everyone in our industry should know the story of how the GMP has come to be. Most requirements were put in place as a result of tragic circumstances and to prevent future tragedies. These regulations are mandatory for drug manufacturing companies in order to manufacture quality products.&#x0D; Keywords: GMP, FDA, WHO