Drug Manufacturing Process Research Articles

Role of Artificial Intelligence in Pharmaceutical Drug Development

: One of the most popular sectors in the tech and healthcare industries right now is artificial intelligence. In the search and development of new drugs, artificial intelligence is essential. Drug design using computer-assisted design (CADD) has supplanted the traditional approach. Artificial intelligence is assisting businesses in the development of new drugs in a faster, more affordable, and more efficient manner, saving money and manpower in the process of creating new drug molecules to treat any disease. Quantitative structure-activity relationship (QSAR) analysis, activity scoring, in silico testing, biomarker development, and mode of action identification are all aided by artificial intelligence. It is revolutionizing these sectors by swiftly identifying potential drug candidates, efficiently conducting clinical trials, and customizing patient care. AI optimizes drug manufacturing processes, augments safety monitoring, and streamlines market analysis. In clinical trials, AI streamlines patient recruitment and ensures more precise trial designs, leading to faster and more efficient research. AI empowers personalized medicine by tailoring treatment plans and drug dosages to individual patient characteristics. AI also optimizes pharmaceutical manufacturing processes, amplifies safety monitoring by analyzing real-time data for adverse events, and supports market analysis and sales strategies. AI in the pharmaceutical industry is a multifaceted tool. Artificial Intelligence (AI) has the potential to streamline complex pharmaceutical regulatory matters. Regulatory processes like audits and dossier completion can be automated with AI tools.

Degradation of trimethoprim by advanced oxidation process using UV/TiO2 and H2O2: Kinetic and economic aspects

AbstractTrimethoprim (TMP) is an effective antibiotic for treating many different infections, but it can lead to water pollution and pose a threat of generating antibiotic‐resistant bacteria through waste in the drug manufacturing process, use, and excretion of humans as well as animals. Due to its strong and non‐selective oxidizing ability, advanced oxidation processes (AOPs) utilizing UV/TiO2 and H2O2 are more efficient in removing them than conventional wastewater treatment. This work investigates TMP degradation in different water substrates by AOPs using UV/TiO2 and H2O2. The results show that the apparent reaction rate constant to the TMP's degradation in the de‐ion water matrix is 0.0379; 0.1937; and 0.209 min−1 for UV/TiO2, UV/H2O2, and UV/TiO2/H2O2 processes. The rate of degradation of TMP in hospital wastewater is lower than that of lake water and de‐ion water. The major intermediate products obtained from the degradation of TMP in de‐ion water by UV/TiO2/H2O2 process were recognized as C14H19O4N4 (m/z: 307), C5H7ON4 (m/z: 139), and C5H6O2N4 (m/z: 155). Finally, the cost of TMP treatment in de‐ion water by several AOPs using photocatalyst and hydrogen peroxide was calculated, it is 0.88 $/m3 for UV/H2O2; 33.01 $/m3 for UV/TiO2 process, and 18.77 $/m3 for UV/TiO2/H2O2 process.

Methods comparison of two-dimensional gel electrophoresis for host cell protein characterization.

Two-dimensional electrophoresis (2DE) is a gel-based protein separation method based on size and charge which is commonly used for the characterization of host cell proteins (HCPs) during drug development in biotech and pharmaceutical companies. HCPs are a heterogenous mixture of proteins produced by host cells during a biologics drug manufacturing process. Different gel electrophoresis methods including traditional 2D SDS-PAGE with silver and SYPRO Ruby fluorescent dye staining as well as two-dimensional difference gel electrophoresis (2D-DIGE) were compared for their relative abilities to characterize HCPs. SYPRO Ruby was shown to be more sensitive than silver stain in the traditional 2D gels both with and without product protein present. Silver stain also displayed a significant preference for staining acidic proteins over basic ones while SYPRO Ruby was more consistent in imaging proteins across different isoelectric points. The non-traditional method of 2D-DIGE provides high resolution and reproducibility when comparing samples with similar protein profiles but was limited in imaging HCP spots due to its narrow dynamic range. Overall, 2DE is a powerful tool to separate and characterize HCPs and is optimized by choosing the best stain or method for each specific application. Using a combination of two or more different 2DE staining methods, when possible, provides the most comprehensive coverage to support the characterization of a complex mixture like HCPs. However, in instances where only one staining method can be used, SYPRO Ruby is shown to be the more reliable, more sensitive, and easier to use traditional staining method for most HCP-based applications.

Seaweed: a sustainable solution for greening drug manufacturing in the pursuit of sustainable healthcare

The environmental impact of drug manufacturing raises concerns about sustainability in healthcare. To address this, exploring alternative approaches to drug production is crucial. This review focuses on seaweed as a sustainable resource for greening drug manufacturing processes. Seaweed offers advantages such as renewability, abundance, and a positive environmental footprint. The review begins by providing an overview of sustainable drug manufacturing practices and the challenges faced in achieving sustainability. It then discusses seaweed as a sustainable resource, including cultivation techniques and environmental benefits. Seaweed has various applications in drug manufacturing, including extracting and purifying bioactive compounds with potential therapeutic properties. Seaweed’s role in developing green technologies, such as seaweed-based excipients, biodegradable packaging materials, and as a source of sustainable energy for drug manufacturing processes, is highlighted. The environmental and economic implications of incorporating seaweed-based solutions are discussed, emphasizing reduced carbon footprint and cost-effectiveness. Regulatory and industrial perspectives are addressed, examining challenges, and opportunities for implementing seaweed-based drug manufacturing. Collaboration between academia, industry, and regulatory bodies is crucial for successful integration. The review presents future directions and opportunities, including emerging trends and innovations in seaweed-based drug manufacturing, areas for further research, policy development, and industry engagement recommendations. Incorporating seaweed into drug production facilitates a reduction in environmental impact, promotes resource efficiency, and contributes to sustainable healthcare. This review showcases seaweed-based solutions as a means to foster a greener future for drug manufacturing, addressing environmental concerns, and promoting sustainability.

Pharmaceutical preparation, standardization and comparative study of Tinduka Ghanavati and Kulattha Guda Avaleha in context of Shwasa Roga

Ayurveda is the world's oldest medical system, which dates back to the Rigveda period BC. 5000. All the medical systems of the world have received their form of organization and developmental inspiration from this, this is an undisputed proven fact. Ayurveda has been called the science of age. Charak has described Ayurveda as eternal. The medical science of Rasashastra is also included in Ayurveda medical science. Rasashastra has been revolutionary in Ayurveda since the 8th century. This has been said to reflect the results of Rasashastra during this period. The chemical drug manufacturing process was being used in the medical world since the 8th century. Since time immemorial, humans have been engaged in research for various purposes in various areas of their lives. Research in Ayurveda is necessary and mandatory. As the struggle and difficulties in a person's life increase along with progressing on the path of salvation, he is suffering from very painful diseases due to not following the health- protecting diet and practices recommended by the famous people. Among these diseases, respiratory disease also holds an important place. This is seen more in the human community. From the study of various texts, it was found that Tindukaghanvati and Kulathaguda Avaleha are effective drug combinations for respiratory diseases. Therefore, in this research work, the study of the above mentioned Yogas on respiratory diseases was considered. The presented research work is being presented before the scholars to reestablish the principles propounded by the Acharyas. The success of the effort depends on the consent of scholars.

Sustained Efficacy, Safety, and Improved Quality of Life in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with Betibeglogene Autotemcel (Beti-cel)

Introduction: Beti-cel gene therapy addresses the underlying cause of transfusion-dependent β-thalassemia (TDT) by adding functional copies of a modified β-globin gene to autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) via a third-generation, self-inactivating lentiviral vector (LVV), BB305, which produces functional adult hemoglobin (Hb), HbA T87Q, in red blood cells (RBCs). Here, we report efficacy, safety, and quality of life (QOL) data from adult and pediatric patients treated with beti-cel who were followed for up to 9 years after treatment. These outcomes may inform patient selection for real-world treatment with beti-cel. Methods: Patients with TDT who completed either a phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel parent study and subsequently participated in the long-term, 13-year follow-up study LTF-303 (NCT02633943) were included in this analysis. Analyses were performed with data collected through January 30, 2023. Efficacy (including transfusion independence [TI], defined as a weighted average Hb ≥9 g/dL without packed RBC transfusions for ≥12 months) and safety are reported through last follow-up. QOL data are reported for studies HGB-204, HGB-207, and HGB-212 through month 36. Statistical analyses were conducted to examine key outcomes in subgroups based on patient age at enrollment (pediatric: <18 years; adult: ≥18 years). Results:As of January 30, 2023, 63 patients (median [range] age: 17 [4-35] years) had received beti-cel in a phase 1/2 or 3 study and enrolled in LTF-303, with a median (range) follow-up of 60.1 (23.8-109.5) months. Phase 3 studies used the commercial drug product manufacturing process. Ninety percent (37/41) of phase 3 patients achieved and maintained TI through last follow-up (up to 6 years; Table 1). TI rates by study, genotype, and age for phase 3 patients are also presented in Table 1. In phase 1/2 studies that used an older drug manufacturing process, 68.2% (15/22) of patients achieved TI; 14 of these patients sustained TI through last follow-up (up to 9 years). One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. Approximately 80% of pediatric and adult patients required only one mobilization cycle to achieve the drug product dose. The median percentage of drug product cells transduced with the BB305 LVV was comparable between adult and pediatric populations (78% and 80%, respectively), as were the month 6 median peripheral blood vector copy number (1.4 c/dg and 1.1 c/dg) and HbA T87Q (9.4 g/dL and 8.3 g/dL). Adult patients reported improvements in QOL up to month 36 as assessed by the Short Form-36 Health Survey Questionnaire mental and physical component summary scores, Functional Assessment of Cancer Therapy, and EuroQol ( Table 2). Pediatric Quality of Life Inventory scores will be reported at the time of presentation. Overall, 19% (12/63) of patients experienced ≥1 beti-cel-related adverse event (AE); the most common beti-cel-related AEs (occurring in ≥3 patients) were abdominal pain (experienced in 5/63 [7.9%] patients) and thrombocytopenia (3/63 [4.8%] patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. Age subgroup safety analysis as of last follow-up will be reported in the final presentation. Conclusion: Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through achievement of TI and normal or near-normal Hb. These data will inform real-world beti-cel treatment decisions for patients with TDT and providers.

Fuzzy Set Qualitative methodology for identifying the Critical Process Parameters and Quality attributes in the manufacturing of Arogyavardhini Rasa

The traditional drug manufacturing process involves numerous qualitative attributes that directly impact product quality. The Process Analytical Technology approach considers that to enhance process control, identifying critical process parameters and critical quality attributes that affect the manufacturing process is very much necessary. The Ayurvedic drug manufacturing process is more driven by fuzzy qualitative attributes. The present study was executed to identify the Critical Process Parameters and Critical Quality Attributes in the manufacturing process of a herbo-mineral formulation, viz. Arogyavardhini Rasa. Fuzzy set Qualitative Comparative Analysis (fsQCA) methodology was adopted to observe and identify the critical parameters. The study was executed in three steps, viz. Data collection, Data arrangement, and Analysis. The raw data collected was arranged and analyzed in the software R studio using the package QCA in four steps, viz. Calibration, Analysis of Necessity and Sufficiency, Truth Table construction, and Minimization. The results obtained show that Size reduction, Mardana, and Drying are the identified Critical Process Parameters that, in combination, lead to the outcome, i.e., good product quality. Thus, this study proves that Fuzzy Set Qualitative Comparative Analysis can be used as an efficient tool for the identification and measurement of the Critical Process Parameters that affect the Critical Quality Attributes and, thereby, the product quality in the manufacturing of Arogyavardhini Rasa.

Evaluation of Physico-Chemical Properties Influence on Drug Product in vitro Profiles and Solubility Profile of Fourth Generation Antibacterial Drug

Moxifloxacin hydrochloride drug substance used to treat bacterial infections in many different parts of the body and most widely used worldwide. In this study, various high-end physico-chemical techniques are used like PXRD, DSC, TGA, BET SSA and PSD analysis to check the relative differences on the product behaviour. The present work reports an impact of alteration in particle size due to compaction process where increase in particle size has been observed from 15.912 μm to 751.001 μm, decrease in specific surface area from 1.89 m2/g to 0.861 m2/g, decrease in crystallinity from 91.65% to 59.15% and impact of dehydration or loss of water from 3.776% to 1.866%, which were observed during study. All the alterations in the physico-chemical properties impacting the drug manufacturing process and on the bioperformance of the finished product. This research attempt aims to investigate the effects of these modifications on in vitro experiments conducted in the office of generic drugs (OGD) media and the equilibrium solubility profile. The in vitro studies resulted about 35% release difference observed in the initial time points, whereas solubility in water observed about 17 mg/mL difference. This research work helps to demonstrate the optimization of finished product development process to meet the biofriendly formulation.

A Review UV Method Development and Validation

Ultraviolet spectroscopy is one important and advanced analytical instrument in the Pharmaceutical industry and used for the last 35 years. The method of analysis is based on measuring the absorption of monochromatic light by colorless compounds in the near-ultraviolet path of the spectrum (200-400nm). The pharmaceutical analysis comprises the procedures necessary to determine such compounds' “identity, strength, quality, and purity”. It also includes the analysis of raw materials and intermediates during the manufacturing process of drugs. The fundamental principle of operation of a spectrophotometer covering the UV region consists that light of a definite interval of wavelength passes through a cell with solvent and falls onto the photoelectric cell that transforms the radiant energy into electrical energy measured by a galvanometer. Ultraviolet-visible spectroscopy is used to obtain the absorbance spectra of a compound in solution or as a solid.

Pharmaceutical Standardisation and Physicochemical Analysis of Krimighatini Vati

Standardization is the process for the establishment of standard for a particular or drug. Standardization in Ayurvedic formulation mainly deals with ensuring standards for the quality and purity of raw materials, quality control during the drug manufacturing process, production of a good quality finished product and storage and distribution to maintain the quality of the final product. Standard of an Ayurvedic product can be assessed only by analyzing the analytical parameters of raw drugs, drugs after preprocessing and the finished products. Krimighatini vati explained in Rasendra chintamani is an antihelminth preparation explained in Rasendra Chintamani krimirogadhikara. It contains Parada- 1part, Gandhaka- 2 parts, Ajamoda -3 parts, Vidanga bheeja- 4 parts, Palaasha bheeja- 5parts, and Kaarsakara beeja- 6 parts. It is similar to Krimimudgara rasa that is available in market but differs in proportion of Palaasha beeja and Karaskara beeja. Present study aims to standardize Krimighatini vati after preparing the medicine according to the method explained in Ayurveda samhithas. Preprocessing of the Gulika includes, Shodhana of Hingula, Gandhaka and Karaskara beeja according to the methods mentioned in Rasasastra books. Parada was extracted from Hingula by Ordhwapaathana vidhi. It was then triturated with Shuddha Gandhaka to get Kajjali. Fine powders of other drugs were mixed with Kajjali and rolled into pills with Honey. Study observed the physicochemical parameters of individual drugs and validated the Gulika by HPTLC method. Analysis of Kajjali was done using XRD so as to prove the complete formation of Kajjali. Pharmaceutical standardization helps in reproducibility of drug paving way for more studies on toxicity and efficacy of drug.

Safety and clinical outcomes in children with acid sphingomyelinase deficiency were not impacted by a change in the olipudase alfa drug manufacturing process: ASCEND-Peds 1-year subanalysis

Safety and clinical outcomes in children with acid sphingomyelinase deficiency were not impacted by a change in the olipudase alfa drug manufacturing process: ASCEND-Peds 1-year subanalysis

A GC-MS/MS Method for Trace Level Quantification of Six Nitrosamine Impurities (NDMA, NDEA, NEIPA, NDIPA, NDPA, and NDBA) in Commercially Used Organic Solvents: Dichloromethane, Ethyl Acetate, Toluene, and O-xylene

Nitrosamines, the probable carcinogens have been reported with Angiotensin II Receptor Blocker (ARB) drugs, Ranitidine, and other medicines. Solvents play a vital role in the pharmaceutical industry in the separation, purification, and cleaning process for manufacturing APIs and drug products. According to the FDA and EMA, solvents used in the drug manufacturing process are potential root causes of Nitrosamine impurities. Hence, monitoring nitrosamines in solvents is an essential step for manufacturers.A sensitive direct injection GC-MS/MS, an essential analytical tool for low-level nitrosamine quantification in solvents, was developed by utilizing multiple reactions monitoring mode (MRM) for the simultaneous determination of six nitrosamines, namely, NDMA, NDEA, NEIPA, NDIPA, NDPA and NDBA in common solvents such as dichloromethane, ethyl acetate, toluene, and o-xylene. NDMA-d6 was used as an internal standard.The FDA reported a combined direct injection method for nitrosamine impurity assay by GC-MS/MS, which had several challenges for commercial-grade solvents in terms of interferences and resolution of unknown impurities and nitrosamine peaks. A novel method was developed to optimize the critical parameters of GC-MS/MS according to the solvent samples. The method validation was performed through the following parameters, sensitivity, linearity, accuracy, precision, specificity, and stability. The quantification of nitrosamines in commercial-grade solvents ranged from 100 ppb to 8000 ppb with respect to the sample concentration of 25 mg/mL with good sensitivity in LOQ level. The quantification ranged from 5 ppb (for NDMA, NDEA, NEIPA, NDIPA, NDPA) and 13 ppb (NDBA) to 2000 ppb with respect to the sample concentration of 100 mg/mL for analytical grade solvents with good sensitivity in the proposed method. Hence, it will be useful to quantify the low-level nitrosamines in commercial-grade solvents as well as analytical-grade solvents.

Reimagining drug manufacturing paradigm in today’s pharmacy landscape

The coronavirus disease 2019 pandemic has escalated the ongoing problem of critical medication shortages, which has serious implications for the health of our patients. Currently, active pharmaceutical ingredients (APIs) are synthesized in large-scale batch operations and shipped to drug product manufacturers, where they are produced on a large scale at centralized facilities. In the centralized drug manufacturing process, the formulation components, operations, and packaging are structured to favor long-term storage and shipment of resultant medicines to the point of care, making this process vulnerable to supply chain disruptions. We propose a rethinking of the drug manufacturing paradigm with an upgraded pharmaceutical compounding-based manufacturing paradigm. This paradigm will be based on integration of continuous manufacturing of APIs and manufacturing of medicines at the point of care with application of machine learning, artificial intelligence, and 3-dimensional printing. This paradigm will support implementation of precision medicine and customization according to patients’ needs. The new model of drug manufacturing will be less dependent on the supply chain while ensuring availability of medicines in a cost-effective manner.

Fluid-fluid phase transitions in a chiral molecular model.

Molecular chirality is a fundamental phenomenon, underlying both life as we know it and industrial pharmaceutical syntheses. Understanding the symmetry breaking phase transitions exhibited by many chiral molecular substances provides basic insights for topics ranging from the origin of life to the rational design of drug manufacturing processes. In this work, we have performed molecular dynamics simulations to investigate the fluid-fluid phase transitions of a flexible three-dimensional four-site chiral molecular model developed by Latinwo et al. [J. Chem. Phys. 145, 154503 (2016)] and Petsev et al. [J. Chem. Phys. 155, 084105 (2021)]. By introducing a bias favoring local homochiral vs heterochiral interactions, the system exhibits a phase transition from a single achiral phase to a single chiral phase that undergoes infrequent interconversion between the two thermodynamically identical chiral states: the L-rich and D-rich phases. According to the phase rule, this reactive binary system has two independent degrees of freedom and exhibits a density-dependent critical locus. Below the liquid-liquid critical locus, there exists a first-order vapor-liquid coexistence region with a single independent degree of freedom. Our results provide basic thermodynamic and kinetic insights for understanding many-body chiral symmetry breaking phenomena.

Using Tiny-TIM Dissolution and In Silico Simulation to Accelerate Oral Product Development of a BCS Class II Compound.

Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro-in vivo correlation and to predict the oral bioavailability. The level C in vitro-in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro-in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process.

Data-driven approach to mitigate quality impact of hygroscopic pharmaceutical raw materials throughout the supply chain

The challenges of working with hygroscopic pharmaceutical raw materials can have a significant impact on the industry’s ability to make high-quality medicines. In order to mitigate the impact to the manufacturing process or product quality it is critical to understand the hygroscopicity of the raw materials across the entire supply chain so that the proper management strategies can be implemented, from the raw material manufacturing to the use of the raw material in the drug manufacturing process. Employing suitable controls protects these materials from physical and chemical changes due to moisture uptake such as caking or hydrolysis. We have developed a fit for purpose and data-driven approach to hygroscopicity classifications of over 200 commonly used chemicals, excipients, media and resins in drug manufacturing processes. Dynamic vapor sorption data is presented with supporting thermal gravimetric analysis and X-ray powder diffraction data where pertinent. Approximately 60% of all raw materials tested were determined to be hygroscopic. Strategies for applying this data to reduce the potential impact of hygroscopic materials on the manufacturing of pharmaceuticals are discussed with examples.

CandyCodes: simple universally unique edible identifiers for confirming the authenticity of pharmaceuticals.

Counterfeit or substandard medicines adversely affect the health of millions of people and cost an estimated $200 billion USD annually. Their burden is greatest in developing countries, where the World Health Organization estimates that one in ten medical products are fake. In this work, I describe a simple addition to the existing drug manufacturing process that imparts an edible universally unique physical identifier to each pill, tablet, capsule, caplet, etc. This technique uses nonpareils (also called sprinkles and “hundreds and thousands”), tiny inexpensive multicolor candy spheres that are normally added to other candies or desserts as decorations. If nonpareils are applied at random to a pill immediately after manufacture, the specific pattern they form is unlikely to ever be repeated by random chance; this means that the pattern (or “CandyCode”) can be used to uniquely identify the pill and distinguish it from all other pills. By taking a photograph of each CandyCoded pill after manufacture and recording the location and color of each nonpareil, a manufacturer can construct a database containing the CandyCodes of all known-authentic pills they produce. A consumer can then simply use a cellphone to photograph a pill and transfer its image to the manufacturer’s server, which determines whether the pill’s CandyCode matches a known-good CandyCode in their database (meaning that the pill is authentic) or does not have a match in the database (in which case the consumer is warned that the pill may be counterfeit and should not be consumed). To demonstrate the feasibility of using random particles as universal identifiers, I performed a series of experiments using both real CandyCodes (on commercially produced chocolate candies) and simulated CandyCodes (generated by software). I also developed a simple method for converting a CandyCode photo to a set of strings for convenient storage and retrieval in a database. Even after subjecting CandyCodes to rough handling to simulate shipping conditions, the CandyCodes were still easily verifiable using a cellphone camera. A manufacturer could produce at least 10^{17} CandyCoded pills—41 million for each person on Earth—and still be able to uniquely identify each CandyCode. By providing universally-unique IDs that are easy to manufacture but hard to counterfeit, require no alteration of the existing drug formulation and minimal alteration of the manufacturing process, and need only a cameraphone for verification, CandyCodes could play an important role in the fight against fraud in pharmaceuticals and many other products.

Review on Standardization of Ayurvedic Medicine

Standardization in Ayurvedic formulations ensures the establishment of standards for the quality and purity of raw materials, quality control during the drug manufacturing process, production of a good quality finished product, storage and distribution to maintain the quality of the final product. It is an essential tool for establishing quality control methods for Ayurvedic drugs. In Ayurveda, standardization has been well defined and documented in the classical and contemporary texts. Still, these have been written with an individualistic intent and not for industrial or commercial purposes. Careful contemplation of the classical literature of Ayurveda was done, the current guidelines of WHO on standardization of herbal drugs, latest researches on the same via the internet were explored and examined in the purview of the newest standardization procedures. In this article, an attempt has been made to bring to light the classical references related to standardization, the milestones in this on-going pursuit have been exhibited, with the use of the latest scientific methods being incorporated for a standardized Ayurvedic drug. It can be concluded from the review that standardization in Ayurveda is an on-going process where one needs to be strictly vigilant about the new scientific methods to study the fine chemical procedures and the intermediate compounds formed, but at the same time be aware of the classical. Ayurvedic methods concepts of the procedure. Asava-arista's medicinal characteristics of Ayurvedic classical dosage forms, liquid dosage forms based on self-generated alcohol with faster absorption, long shelf life, and increased market conformity have led to a continuous rise in demand. New fermentation methods and packaging innovations tend to have been embraced by many Ayurvedic processing units. The importance of standardization of such goods is underlined by these advances in manufacturing, distribution and storage. Therefore, it is of concern to examine the latest manufacturing situation and the standardization of the dosage type regarding the procedure and the consistency and effectiveness of the finished product. In addition to the effort to include criteria of consistency and standardization, the study consists of an overview and deliberates on the importance of improvements made to the conventional preparation processes, ingredients and material used in the process and the potential impact on its efficacy.

Nitrosamine impurities: from raw materials to final drug product.

Nitrosamine impurities: from raw materials to final drug product.

The risk assessment of the combined medicine in the capsule dosage form at the pharmaceutical development stage

Aim. To determine the potential risk factors associated with the critical quality indicators of the combined medicine “Neuronucleos” in the capsule dosage form for the treatment of polyneuropathies using the general risk assessment methodology while planning the drug quality at the stage of pharmaceutical development (PD). Materials and methods. The series of the combined medicine “Neuronucleos” in the capsule dosage form, critical indicators of the drug quality, the flowchart of the drug production, critical control points of the drug manufacturing process were developed. The method of causality was used. The quantitative assessment of risk factors was carriedout using the FMECA methodology. Results and discussion. The main objective of this study was to apply the Quality-by-Design (QbD) approach to PD of the combined medicine in the capsule dosage form based on uridine-5 monophosphate disodium salt (UMP), cytidine-5-monophosphate disodium salt (CMF), vitamin B6, thioctic acid and magnesium lactate dihydrate. For better patient compliance and the product quality, a target quality profile as a base for PD planning, as well as critical quality attributes (CQA) related to the product safety and efficacy were determined. The criticality of each CQA was assessed using a special scale. It was shown that “Quantitative content”, “Uniformity of dosage units”, “Dissolution”, “Impurities” were defined as the most CQA due to the minimum amount of UMF and CMF in the capsule and the possibility of their decomposition and increase in the quantity of impurities. The critical attributes of materials (CMA) were identified, and the characteristics required to control them were determined in order to ensure the expected product quality. The primary assessment of the quality indicator risks of the active ingredients was performed. It was found that the particle size affected the homogeneity, the quantitative content of API and dissolution in FPP, and it was shown that the solubility of active substances had a high risk when performing the “Dissolution” test. To determine the potential factors with a significant impact on the drug quality the maximum number of factors was found, and the Ishikawa diagram was constructed. The risk factors associated with the quality and compatibility of active substances and excipients, the quality of primary packaging, production conditions, the drug quality control and the technological process were identified. These factors are the causes of risk and can lead to a situation with negative consequences for the quality of a medicinal product. The FMECA process assessment allowed us to determine the impact of the manufacturing process on the CQA. Conclusions. At the stage of PD for the combined medicine in the capsule dosage form the potential critical indicators of the drug quality have been determined. The critical parameters of the quality of the initial components and the properties of the product have been assessed; the most probable risks for the drug quality have been identified, analyzed and assessed. Further research is advisable to focus on studying the effect of process parameters on critical parameters of the product quality and assessing risks for quality and creating a validation plan and its implementation.