scholarly journals Automated synthesis of [18F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Alexander Wurzer ◽  
Daniel Di Carlo ◽  
Michael Herz ◽  
Antonia Richter ◽  
Stephanie Robu ◽  
...  
Keyword(s):  
Quality Control ◽  
Large Scale ◽  
Isotopic Exchange ◽  
Selection Process ◽  
Radiochemical Yield ◽  
Anhydrous Acetonitrile ◽  
Optimum Process ◽  
Automated Synthesis ◽  
Scale Production ◽  
Automated Production

Abstract Introduction The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.

The Research of Production Process Statistical Steady-State Based on the Hypothesis Test

2011 ◽  
Vol 314-316 ◽  
pp. 2433-2438
Author(s):  
Wei Zhi Wang
Keyword(s):  
Quality Control ◽  
Steady State ◽  
Production Process ◽  
Quantitative Method ◽  
Large Scale ◽  
Hypothesis Test ◽  
Influence Factors ◽  
Normal Operation ◽  
Scale Production ◽  
Large Scale Production

By only applying a after the event exam in the quality control of the batch production is not enough to meet the needs of modern large-scale production. To a certain extent, modern quality control is a dynamic process of the steady-state judge and adjustment. A simple and reliable steady-state judge rule and method is the premise to guarantee the normal operation. This paper provides a quantitative method to evaluate production process steady-state by analyzing influence factors based on mathematical statistics. The method is both suitable for simple production process and complex production process with sub-processes.

Fully-Automated Synthesis of 177Lu Labelled FAPI Derivatives On The Module Modular Lab-Eazy

2021 ◽  
Author(s):  
Kurtulus Eryilmaz ◽  
Benan KILBAS
Keyword(s):  
Quality Control ◽  
Chromatographic Analysis ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated System ◽  
Automated Synthesis ◽  
Modular Approach ◽  
Stability Studies ◽  
European Pharmacopoeia ◽  
First Time

Abstract Backround: To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively employed. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield (85–90%). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals were accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template.

Liposomes

2017 ◽  
pp. 52-87
Author(s):  
Mangal Shailesh Nagarsenker ◽  
Megha Sunil Marwah
Keyword(s):  
Quality Control ◽  
Large Scale ◽  
Clinical Success ◽  
Scale Production ◽  
Large Scale Production ◽  
Diagnostic Applications ◽  
Set Up ◽  
Insight Into ◽  
Characterisation Techniques

The science of liposomes has expanded in ambit from bench to clinic through industrial production in thirty years since the naissance of the concept. This chapter makes an attempt to bring to light the impregnable contributions of great researchers in the field of liposomology that has witnessed clinical success in the recent times. The journey which began in 1965 with the observations of Bangham and further advances made en route (targeting/stealthing of liposomes) along with alternative and potential liposome forming amphiphiles has been highlighted in this chapter. The authors have also summarised the conventional and novel industrially feasible methods used to formulate liposomes in addition to characterisation techniques which have been used to set up quality control standards for large scale production. Besides, the authors have provided with an overview of primary therapeutic and diagnostic applications and a brief insight into the in vivo behaviour of liposomes.

Raman spectroscopy in pharmaceutical research and industry

2018 ◽  
Vol 3 (8) ◽  
Author(s):  
Nathalie Jung ◽  
Maike Windbergs
Keyword(s):  
Drug Delivery ◽  
Raman Spectroscopy ◽  
Quality Control ◽  
Drug Delivery Systems ◽  
Large Scale ◽  
Pharmaceutical Research ◽  
Delivery Systems ◽  
Scale Production ◽  
Non Invasive ◽  
Large Scale Production

Abstract In the fast-developing fields of pharmaceutical research and industry, the implementation of Raman spectroscopy and related technologies has been very well received due to the combination of chemical selectivity and the option for non-invasive analysis of samples. This chapter explores established and potential applications of Raman spectroscopy, confocal Raman microscopy and related techniques from the early stages of drug development research up to the implementation of these techniques in process analytical technology (PAT) concepts for large-scale production in the pharmaceutical industry. Within this chapter, the implementation of Raman spectroscopy in the process of selection and optimisation of active pharmaceutical ingredients (APIs) and investigation of the interaction with excipients is described. Going beyond the scope of early drug development, the reader is introduced to the use of Raman techniques for the characterization of complex drug delivery systems, highlighting the technical requirements and describing the analysis of qualitative and quantitative composition as well as spatial component distribution within these pharmaceutical systems. Further, the reader is introduced to the application of Raman techniques for performance testing of drug delivery systems addressing drug release kinetics and interactions with biological systems ranging from single cells up to complex tissues. In the last part of this chapter, the advantages and recent developments of integrating Raman technologies into PAT processes for solid drug delivery systems and biologically derived pharmaceutics are discussed, demonstrating the impact of the technique on current quality control standards in industrial production and providing good prospects for future developments in the field of quality control at the terminal part of the supply chain and various other fields like individualized medicine. On the way from the active drug molecule (API) in the research laboratory to the marketed medicine in the pharmacy, therapeutic efficacy of the active molecule and safety of the final medicine for the patient are of utmost importance. For each step, strict regulatory requirements apply which demand for suitable analytical techniques to acquire robust data to understand and control design, manufacturing and industrial large-scale production of medicines. In this context, Raman spectroscopy has come to the fore due to the combination of chemical selectivity and the option for non-invasive analysis of samples. Following the technical advancements in Raman equipment and analysis software, Raman spectroscopy and microscopy proofed to be valuable methods with versatile applications in pharmaceutical research and industry, starting from the analysis of single drug molecules as well as complex multi-component formulations up to automatized quality control during industrial production.

scholarly journals A Proposal for Six Sigma Integration for Large-Scale Production of Penicillin G and Subsequent Conversion to 6-APA

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Anirban Nandi ◽  
Sharadwata Pan ◽  
Ravichandra Potumarthi ◽  
Michael K. Danquah ◽  
Indira P. Sarethy
Keyword(s):  
Quality Control ◽  
Quality Assurance ◽  
Six Sigma ◽  
Mass Production ◽  
Large Scale ◽  
Penicillin G ◽  
Scale Production ◽  
Large Scale Production ◽  
Subsequent Conversion ◽  
Six Sigma Methodology

Six Sigma methodology has been successfully applied to daily operations by several leading global private firms including GE and Motorola, to leverage their net profits. Comparatively, limited studies have been conducted to find out whether this highly successful methodology can be applied to research and development (R&D). In the current study, we have reviewed and proposed a process for a probable integration of Six Sigma methodology to large-scale production of Penicillin G and its subsequent conversion to 6-aminopenicillanic acid (6-APA). It is anticipated that the important aspects of quality control and quality assurance will highly benefit from the integration of Six Sigma methodology in mass production of Penicillin G and/or its conversion to 6-APA.

Large scale production of human lymphoblastoid (namalva) interferon. III. quality control and safety tests.

1983 ◽  
Vol 5 (8) ◽  
pp. 493-496
Author(s):  
Arye Lazar ◽  
Dino Marcus ◽  
Shaul Reuveny ◽  
Haim Grosfeld ◽  
Abraham raub ◽  
...  
Keyword(s):  
Quality Control ◽  
Large Scale ◽  
Scale Production ◽  
Large Scale Production

scholarly journals Fully-automated synthesis of 177Lu labelled FAPI derivatives on the module modular lab-Eazy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Kurtulus Eryilmaz ◽  
Benan Kilbas
Keyword(s):  
Quality Control ◽  
Chromatographic Analysis ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated System ◽  
Automated Synthesis ◽  
Modular Approach ◽  
Stability Studies ◽  
European Pharmacopoeia ◽  
First Time

Abstract Background To the best of our knowledge, manually production of [177Lu]Lu-FAPI radiopharmaceutical derivatives has been only described in literature. In this work, a fully-automated [177Lu]Lu-FAPI synthesis has been well designed for the first time using commercially available synthesis module. In addition to the development of an automated system with disposable cassette, quality control (QC) and stability studies were comprehensively presented. Results A fully automated synthesis of [177Lu]Lu-FAPI derivatives was achieved on the Modular Lab Eazy (ML Eazy) with high radiochemical yield ([177Lu]Lu-FAPI-04; 88% ± 3, [177Lu]Lu-FAPI-46; 86% ± 3). Chromatographic analysis indicated the formation of radiosynthesis with an absolute radiochemical purity (99%). Stability experiments clarified the durability of the products within 4 days. All obtained specifications are consistent to European Pharmacopoeia. Conclusion A fully automated synthesis of [177Lu]Lu-FAPI radiopharmaceuticals was accomplished regarding quality control standards and quality assurance by using commercially available a modular approach namely ML Eazy with disposable customized cassette and template. Graphical abstract

scholarly journals Robust and Facile Automated Radiosynthesis of [18F]FSPG on the GE FASTlab

2021 ◽  
Author(s):  
Richard Edwards ◽  
Hannah E. Greenwood ◽  
Graeme McRobbie ◽  
Imtiaz Khan ◽  
Timothy H. Witney
Keyword(s):  
Large Scale ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Automated Synthesis ◽  
Molar Activity ◽  
Positron Emission ◽  
Optimized Protocol ◽  
Cancer Types ◽  
Automated Procedures ◽  
Phosphate Buffered Saline

Abstract Purpose (S)-4-(3-18F-Fluoropropyl)-ʟ-Glutamic Acid ([18F]FSPG) is a radiolabeled non-natural amino acid that is used for positron emission tomography (PET) imaging of the glutamate/cystine antiporter, system xC-, whose expression is upregulated in many cancer types. To increase the clinical adoption of this radiotracer, reliable and facile automated procedures for [18F]FSPG production are required. Here, we report a cassette-based method to produce [18F]FSPG at high radioactivity concentrations from low amounts of starting activity. Procedures An automated synthesis and purification of [18F]FSPG was developed using the GE FASTlab. Optimization of the reaction conditions and automated manipulations were performed by measuring the isolated radiochemical yield of [18F]FSPG and by assessing radiochemical purity using radio-HPLC. Purification of [18F]FSPG was conducted by trapping and washing of the radiotracer on Oasis MCX SPE cartridges, followed by a reverse elution of [18F]FSPG in phosphate-buffered saline. Subsequently, the [18F]FSPG obtained from the optimized process was used to image an animal model of non-small cell lung cancer. Results The optimized protocol produced [18F]FSPG in 38.4 ± 2.6 % radiochemical yield and >96 % radiochemical purity with a molar activity of 11.1 ± 7.7 GBq/μmol. Small alterations, including the implementation of a reverse elution and an altered Hypercarb cartridge, led to significant improvements in radiotracer concentration from <10 MBq/ml to >100 MBq/ml. The improved radiotracer concentration allowed for the imaging of up to 20 mice, starting with just 1.5 GBq of [18F]Fluoride. Conclusions We have developed a robust and facile method for [18F]FSPG radiosynthesis in high radiotracer concentration, radiochemical yield, and radiochemical purity. This cassette-based method enabled the production of [18F]FSPG at radioactive concentrations sufficient to facilitate large-scale preclinical experiments with a single prep of starting activity. The use of a cassette-based radiosynthesis on an automated synthesis module routinely used for clinical production makes the method amenable to rapid and widespread clinical translation.

Large-Scale Processing Machinery for Fabrication of Composite Hulls and Superstructure

1991 ◽  
Vol 7 (04) ◽  
pp. 220-226
Author(s):  
John F. Raymer
Keyword(s):  
Quality Control ◽  
Composite Materials ◽  
Large Scale ◽  
Selection Process ◽  
Mechanical Systems ◽  
Production Engineering ◽  
Processing Machinery ◽  
The World ◽  
Fiber Reinforcements ◽  
Efficient Manufacturing

Large-scale mechanical systems for impregnating and positioning composite materials are now permitting efficient manufacturing of composite hulls up to 60 m (200 ft) and greater. Recreational, commercial, and military vessels fabricated from composite materials are gaining acceptance around the world; however, processing of thermosetting resins and fiber reinforcements in quantities exceeding 90 000 kg (200 000 lb) per unit presents a new set of challenges to production engineers responsible for maintaining quality control. Impregnation systems are currently being used at several mine-hunter production shipyards worldwide. Large-to-medium sized recreational yachts are also in production with impregnation systems. This paper reviews some past and current impregnator installations, the selection process used for choosing the systems, and production engineering factors.

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