Production Of Active Pharmaceutical Ingredients Research Articles

A total productive maintenance & reliability framework for an active pharmaceutical ingredient plant utilising design for Lean Six Sigma

This research investigates the requirement for and relationship and implementation of a total productive maintenance (TPM) and Reliability Centred Maintenance (RCM) strategy within an Active Pharmaceutical Ingredient (API) Plant. This research aimed to study the tools and techniques of TPM and Reliability Engineering and then deploy a designed model to an API plant. A case study involving Design for Lean Six Sigma phases of Define, Measure, Analyse, Design, and Verify was utilised to build an API site TPM pilot program. Data was collected using interviews across Company 'X's local and Global Engineering teams. Process runtime, downtime and plant availability metrics were compiled and a new design for Total Productive Maintenance and Reliability was proposed and verified. A maintenance framework was designed to optimally incorporate Total Productive Maintenance, Reliability and Operational Excellence with an emphasis on Overall Equipment Efficiency (OEE) realizing a 33 % reduction in planned maintenance activities, a 70 % reduction in Corrective Maintenance, Cleaning for Maintenance was reduced by 50 %, the pilot maintenance area of the centrifuge has its OEE increased by 20 % and plant availability increased by two hundred and 6 h. This research highlights the importance of Total Productive Maintenance as a key component of an effective maintenance strategy and its potential to transform maintenance practices. Based on this research and results, TPM is recommended to be applied to any API manufacturing organization. A limitation of the study is that it is a single-site case study. The novelty of this research is based upon the emphasis on Reliability Engineering to remove non-value add Maintenance time from the manufacturing schedule. The Total Productive Maintenance & Reliability model designed and implemented in this research is unique in the literature and can be leveraged by engineering professionals and academics to understand the benefits of TPM.

The effects of particle shape, orientation, and Reynolds number on particle-wall collisions

Crystallisation is an important unit operation used in the production of Active Pharmaceutical Ingredients (APIs). Crystallisation is typically carried out using seed crystals in a process called secondary nucleation that allows for greater control of crystal quality attributes. The mechanism of secondary nucleation is still not well understood. Particle attrition is one proposed mechanism. This work examines the conditions under which particle-wall collisions occur. This is done through the simulation of free-moving particles in an impinging jet flow using an immersed-boundary lattice Boltzmann method (IB-LBM) CFD solver. Particle Reynolds numbers from 100 to 400 are examined. Particle shapes with aspect ratios from 1:1 to 8:1 are used to represent the crystal habits of APIs.Particles that start in their low-drag or high-drag orientation maintain this orientation on approach to the target surface. All other intermediate initial orientations examined cause particles to rotate toward and overshoot their high-drag form before adopting their high-drag form in proximity to the target surface. Particles in their low-drag form remain in their initial orientation due to the symmetry of the computational domain. In this orientation, a collision is most likely to occur, and the minimum critical Reynolds number at which a particle-wall collision will occur can be determined. This value is shown to increase with increasing particle frontal length. Pointed or rounded leading edges are shown to improve a particle's ability to pierce the boundary layer adjacent to the target surface and reduce this value. In cases where a Reynolds number of 400 is insufficient to cause a particle-wall collision, the particles’ minimum distances from the target surface are reported. Using the minimum critical Reynolds number values obtained, the approach velocities required for particles to collide with a wall are shown to be larger than the impeller tip speeds typically used during crystallisation operations. This work provides for the first time the conditions under which particle-wall collisions occur for varying shape and orientation, their behaviour on approach, and the associated impact velocities.

The Transfer Pricing Implications of GILTI for Transfer Pricing in the Pharmaceutical Sector

Pharmaceutical multinationals generate substantial profits from their ownership of valuable intangible assets including patents and marketing intangibles. Their production activities are often vertically integrated with the production of active pharmaceutical ingredients occurring in Western Europe with the fill and finish function occurring in India. The transfer pricing challenges have led to numerous litigations where tax authorities have accused multinationals of shifting profits to tax havens. This article discusses the transfer pricing issues in litigations involving Canada, India and the United States, noting how the applications of market-based approaches versus profits-based approaches lead to very different results.

SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening.

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source.

Enantioselective Transformations in the Synthesis of Therapeutic Agents.

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008-2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.

P-460 The Impact of Assisted Reproductive Technologies on Climate Change : The French Case

Abstract Study question How much tons of carbon dioxide equivalent (tCO2e) are generated by Assisted Reproductive Technologies in France in a year ? Summary answer It is estimated that Assisted Reproductive Technologies generated 55 691 tons of carbon dioxide equivalent in France in 2022. What is known already Since the 1800s, human activities have been the main driver of climate change, primarily due to burning fossil fuels (coal, oil and gas). Created in 1988, the Intergovernmental Panel on Climate Change (IPCC) provides regular assessments of the scientific basis of climate change, its impacts and future risks, and options for adaptation and mitigation. On December 12th 2015, 196 Parties adopted The Paris Agreement at COP 21 (Paris), a legally binding international treaty on climate change, aiming to limit global warming to well below 2 degrees Celsius. The French health sector is only beginning to measure it's carbon emission footprint. Study design, size, duration This study was conducted in Poissy/Saint-Germain-En-Laye Hospital during the year 2022 in the Department of reproductive medicine and biology. Greenhouse gas emissions were classified into three scopes. Scope 1 emissions are direct emissions divided into four categories : stationary combustion, mobile combustion, fugitive emissions, process emissions. Scope 2 emissions are indirect emissions from the generation of purchased energy. Scope 3 emissions are all indirect emissions, including both upstream and downstream emissions (separated into 15 categories). Participants/materials, setting, methods Every couple that required IVF or ICSI (including donors) during the year 2022 was included in this study. Number of personnel, transportation of patients, total medication prescribed, electricity consumption and medical furnitures were considered for the calculus of total emissions. Emission factors to calculate carbon emission were taken on the Ecological Transition Agency (ADEME) database. Extrapolation to all of France's ART clinics was possible using the BioMedical Agency (ABM) 2020 report on ART activities. Main results and the role of chance Assisted Reproductive Technologies generated 55 691 tons of carbon dioxide equivalent (tCO2e) in France in 2022 from 30 963 ICSI and 15 674 IVF procedures. We estimate that every oocyte retrieval procedure generated 1.19 tCO2e (ICSI and IVF). Department of Reproductive Medicine and Biology of Poissy/Saint-Germain-En-Laye (PSGEL) generated 796 tCO2e from 666 oocyte retrieval procedures (449 ICSI, 217 IVF), representing 1.43% of all IVF and ICSI in France. Electricity consumption at PGSEL generated 1 051 tCO2e based on a total of 14 200 kw/h (average price of 0.1740 euros) in 2022. Drugs prescriptions (758 069 euros) and Furniture (194 648 euros) at PGSEL generated respectively 409.584 tCO2e and 61.314 tCO2e in 2022 . 32 members of medical and non-medical at PGSEL staff generated 320 tCO2e in 2022. Transportation of patients to PGSEL generated 4.44 tCO2e in 2022. This is the first study to report an estimation of the carbon emission footprint of French ART. Limitations, reasons for caution Not all data was available (CO2 emissions created by the manufacture of active pharmaceutical ingredients in Asia) or taken into account (waste management, anesthesia type, hospital construction, etc). Fertility preservation procedures were not considered in our calculations. Results are therefore an under-estimation of real CO2 emissions. Wider implications of the findings French Healthcare was responsible for 46 MtCO2e (8% of national total) in 2021. The biggest impact we can have in ART to lower our carbon footprint is optimise the pharmaceutical supply chain of drug manufacturing and use recycled materials for drug packaging (plastic, glass, aluminium, steel) as much as possible. Trial registration number not applicable

Heterogeneous Catalysis under Continuous Flow Conditions

Abstract: Heterogeneous catalysis using continuous flow processing is one of the most demanding subjects from the viewpoint of manufacturing industrial-scale organic compounds. An amalgamation of the two areas of technology, i.e., heterogeneous catalysis and flow chemistry, has opened new avenues for green synthetic chemistry. These processes are particularly convenient in terms of short diffusion paths and improved mixing due to the sensing of high local concentration of catalytic species on solid catalytic surface when the liquid/ gaseous reagents pass through the column, ultimately resulting in quicker and more efficient reaction with increased reaction rates and higher turnover numbers. It imparts several key benefits over conventional batch systems, such as time and energy-saving methodologies, better productivity, reproducibility, economic viability, waste reduction, and ecofriendly nature. Also, it eradicates the need for any intermediate isolation, separation of catalysts, and use of excess reagents. The present review article focuses on heterogeneous catalysis under continuous flow conditions. Various key reactions, for instance, carbon-carbon bond formation, hydrogenation, condensation, and oxidation, are presented well, along with their recent developments in the manufacturing of active pharmaceutical ingredients and platform chemicals. Asymmetric catalysis has also been discussed with its applications in the synthesis of complex organic molecules. It is anticipated that the review article will proliferate significant interest in modernizing chemical syntheses through continuous flow processes.

Organisational and methodological challenges of CAR-T manufacturing in the Russian Federation

Despite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry.

PharmaBlock expands research in Pennsylvania

PharmaBlock, a pharmaceutical research and manufacturing services firm, has opened an R&D site in West Chester, Pennsylvania. With 2,800 m 2 of laboratory space, the facility includes process and analytical labs, as well as manufacturing suites with flow chemistry, micropacked bed hydrogenation, and solid-state chemistry capabilities. PharmaBlock says the site will enhance its production of clinical- stage active pharmaceutical ingredients (APIs) for the US market. The company plans to add reactors ranging from 500 to 2,000 L for API production in West Chester next year.

Flamma launches investment campaign

Flamma , a pharmaceutical contract development and manufacturing firm based in Bergamo, Italy, has announced a three-year, $200 million investment program. The company says it will improve a manufacturing site it acquired in Bulciago, Italy, and expand manufacturing of active pharmaceutical ingredients (APIs) at its China location from 200 m 3 to 400 m 3 . It will also add highly potent API manufacturing at its plant in Malvern, Pennsylvania, and technologies including flow chemistry at its headquarters. The company says the expansion supports a strategy of securing domestic supply chains with the ability to transfer projects in China to Europe while pursuing API production for the Chinese market in China.

Chemometrics-Assisted UV-Vis Spectrophotometry for Quality Control of Pharmaceuticals: A Review

Spectroscopic method in the UV-Vis region is considered the most molecular spectrometric method for content determination of a single component. However, a lot of pharmaceutical dosage forms comprise two or more components which lead to peak overlapping. Moreover, in the chemical stability test, active pharmaceutical ingredient (API) was also found along with the degradation products, impurities, and adulterant compounds. UV-Vis spectroscopy is one of the methods of choice for the determination or quantification of a single component in pharmaceutical preparations. The pharmaceutical products typically contain two or more APIs having chromophoric agents capable of absorbing UV-Vis beams and the absorbance values are summative from the absorption of each UV-Vis active compound according to the additive nature of Lambert-Beer law. The main problem for the simultaneous determination of API along with impurities and the degradation products in pharmaceutical preparations is the presence of overlapping peaks of UV-Vis spectra. The chemometrics-assisted spectroscopy is one of the analytical efforts to solve these problems. This review highlighted the application of chemometrics in combination with UV-Vis spectroscopy for the assay of API, impurities, adulteration issues and degradation products present in pharmaceutical dosage forms.

Membrane-Based Solvent Exchange Process for Purification of API Crystal Suspensions.

Bottom-up approaches to producing aqueous crystal suspensions of active pharmaceutical ingredients (APIs), such as anti-solvent crystallisation, are gaining interest as they offer better control over surface properties compared to top-down approaches. However, one of the major challenges that needs to be addressed is the removal of organic solvents after the crystallisation step due to strict limitations regarding human exposure. Within this work, we investigated a process concept for the removal of solvent (i.e., ethanol) from the API crystal suspension using membrane-based diafiltration. A four-stage diafiltration process successfully reduced the ethanol concentration in the API (here, naproxen) crystal suspension below 0.5 wt% (the residual solvent limit as per ICH guidelines) with a water consumption of 1.5 g of added water per g of feed. The solvent exchange process had no negative influence on the stability of the crystals in suspension, as their size and polymorphic form remained unchanged. This work is a step towards the bottom-up production of API crystal suspension by applying solvent/anti-solvent crystallisation. It provides the proof of concept for establishing a process of organic solvent removal and offers an experimental framework to serve as the foundation for the design of experiments implementing a solvent exchange in API production processes.

Competition And Vulnerabilities In The Global Supply Chain For US Generic Active Pharmaceutical Ingredients.

The US supply of generic drugs is heavily dependent on the global supply chain for sources of generic active pharmaceutical ingredients (APIs) for the US pharmaceutical market. Data from Clarivate Analytics' Cortellis Generics Intelligence database were analyzed to perform a systematic examination of generic APIs produced globally for the US market during 2020-21. We identified a total of 565 facilities producing 1,379 unique generic APIs across forty-two countries. India, China, and Italy were the top producers; 14percent of APIs were manufactured in the US. About a third of APIs were manufactured by a single facility, and another third were manufactured by two or three facilities. More than one in every five APIs reflected markets in which current Food and Drug Administration standards would have failed to detect low competition because there were three or fewer API manufacturers despite there being four or more manufacturers of finished generic drugs. Monitoring the API supply is crucial to identifying vulnerabilities in the US pharmaceutical supply chain and identifying drugs that could represent potential priorities for domestic production. Incentives in the US may be needed to support API production to safeguard against supply-chain disruptions.

Separation and identification of degradation impurities of esomeprazole sodium.

Drug impurities are important factors that affect drug safety and efficacy. The aim of this study is to separate and confirm the structure of two degradation impurities of esomeprazole sodium, designated X and Y. The impurities X and Y were successfully isolated using preparative HPLC by developing separation methods with the help of ACD/Labs AutoChrom software. There was a steady increase in X and Y impurities in forced esomeprazole sodium degradation. Impurity X was confirmed as 6-methoxy-1h-benzo[d]imidazole-2-yl-4-amino-3,5-dimethylpyridinecarboxylate and impurity Y as 6-methoxy-1h-benzo[d]imidazole-2-yl-4-hydroxy-3,5-dimethylpyridinecarboxylate using nuclear magnetic resonance spectrometry, infrared spectroscopy, and high-resolution mass spectrometry. These findings provide a comprehensive understanding of the impurity profile of esomeprazole sodium because these impurities are reported for the first time. Based on our results, active pharmaceutical ingredient manufacturers can further control process parameters to reduce impurity generation, and drug production manufacturers can optimize the packaging and storage conditions of esomeprazole sodium.

Scalability of U-Shape Magnetic Nanoparticles-Based Microreactor–Lipase-Catalyzed Preparative Scale Kinetic Resolutions of Drug-like Fragments

The production of active pharmaceutical ingredients (APIs) and fine chemicals is accelerating due to the advent of novel microreactors and new materials for immobilizing customized biocatalysts that permit long-term use in continuous-flow reactors. This work studied the scalability of a tunable U-shape magnetic nanoparticles (MNPs)-based microreactor. The reactor consisted of a polytetrafluoroethylene tube (PTFE) of various inner diameters (ID = 0.75 mm, 1.50 mm, or 2.15 mm) and six movable permanent magnets positioned under the tube to create reaction chambers allowing the fluid reaction mixture to flow through and above the enzyme-loaded MNPs anchored by permanent magnets. The microreactors with various tube sizes and MNP capacities were tested with the preparative scale kinetic resolution of the drug-like alcohols 4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-2-ol (±)-1a and 4-(3,4-dihydroquinolin-1(2H)-yl)butan-2-ol (±)-1b, utilizing Lipase B from Candida antarctica immobilized covalently onto MNPs, leading to highly enantioenriched products [(R)-2a,b and (S)-1a,b]. The results in the U-shape MNP flow reactor were compared with reactions in the batch mode with CaLB-MNPs using similar conditions. Of the three different systems, the one with ID = 1.50 mm showed the best balance between the maximum loading capacity of biocatalysts in the reactor and the most effective cross-section area. The results showed that this U-shaped tubular microreactor might be a simple and flexible instrument for many processes in biocatalysis, providing an easy-to-set-up alternative to existing techniques.

Development and Validation of SI/RS-UHPLC-PDA Method for Olmesartan Medoxomil and Metoprolol Succinate-Related Substance.

Olmesartan medoxomil (OLM) and metoprolol succinate (MPS) in fixed-dose combination (FDC) tablet formulation prescribed extensively. Stability indicating (SI) method for impurities and related substance (RS) test quantitates the amount of these analytes in formulation; the manuscript presents SI/RS-ultra-high performance liquid chromatography-photodiode array (UHPLC-PDA) method for OLM and MPS and their impurities. Well-resolved separation of all analytes was achieved with gradient elution on a Shimadzu on Shimpack GIST-C18 (100 mm x 2.1 mm, 2 µm) column maintained at 25°C. Mobile phase-A consist of 0.1% orthophosphoric acid in water and mobile phase-B was acetonitrile at a flow rate of 0.4 mL/min, data integrated at 225 nm and 16 min of short runtime for satisfactory elution of all peaks. The proposed SI/RS-UHPLC-PDA method was developed and validated as per International Conference on Harmonisation (ICH) of Technical Requirements guidelines. The system suitability test complied by all eluted peaks of the interest with acceptable linearity, recovery, and precision. Specificity, robustness, and method sensitivity parameters were determined; all the parameters were found to be within the limits. All the impurities and stress-degraded peaks were well resolved. The proposed method was found to be simple, fast, linear, and accurate. Further, the method is precise, robust, and specific; suitable for routine IPQC during active pharmaceutical ingredient manufacturing, stability and impurity profiling studies of the titled bulk analytes. Furthermore, the method can be extended to assess the levels of impurities formed during life cycle of new FDCs of titled analytes.

Sustainable production of active pharmaceutical ingredients from lignin-based benzoic acid derivatives via “demand orientation”

Catalytic production of several representative active pharmaceutical ingredients (APIs) from lignin.

Brazilian national production of active pharmaceutical ingredients: regulatory and strategic framework.

Active Pharmaceutical Ingredient (API) is any component of the final pharmaceutical product that serves as the active ingredient. The goal of the API Manufacturing is to produce APIs that are competitively priced and meet the quality standards with the least possible impact on the environment. The global API market is expected to experience massive growth in the coming years reaching the size of USD 355.94 billion. The global Pharmaceutical Industry is facing a new scenario in 2023 after responding to the COVID-19 pandemic. In this new panorama, rethinking the pharmaceutical production and market is necessary. Despite Brazil's prominence in terms of worldwide pharmaceutical spending, only 5% of the APIs required by local pharmaceutical companies are produced domestically. Therefore, Brazil is an untapped field for APIs' manufacturing and faces a scenario of health vulnerability associated with the reliance on foreign API imports to ensure the viability of national Pharmaceutical Production and Services. Huge investments are required to boost the growth of the API Manufacturing sector. Herein is presented a critical analysis of the current regulatory and strategic status of Brazilian national production and/or acquisition of APIs, which represent the key starting materials for the Pharmaceutical Industry.

The pros and cons of reshoring to address the problems of shortages in global pharmaceutical value chains: the case of antibiotics

PurposeAntibiotics shortages have become an increasingly common problem in Europe because of several reasons, including the offshoring of the production of active pharmaceutical ingredients for many of these products to low production cost countries, such as China and India. The problem has deteriorated because of the Covid-19 crisis that has put most global value chains (GVCs) under great stress. This situation has boosted extensive discussions among academics, practitioners and policymakers on possible changes to the configuration of GVCs. This paper aims to focus specifically on antibiotics supply chains from the perspective of a small country (Sweden), and analyse the pros and cons of backshoring and nearshoring alternatives, as a means to reduce drug shortages.Design/methodology/approachThis work adopts a systemic perspective to capture the implications of reshoring for the different stakeholders involved in the antibiotics field. The present meso-analysis, focusing at the industry level, is based on multiple sources of primary data collected between 2014 and 2021, including participation in policy-related projects and interviews with over 100 representatives of key stakeholders in the antibiotics field.FindingsThis paper shows how reshoring can address the problems of drug shortages and reduce availability risk in antibiotics’ GVCs. However, the authors show that no simple and best solution exists because both alternatives of reshoring, i.e. backshoring and nearshoring, entail pros and cons for different stakeholders. The authors conclude with implications for policymakers and managers.Research limitations/implicationsThe analysis of pros and cons of both backshoring and nearshoring for various stakeholders offers relevant implications for research on operations and supply management, international business and economics/political science.Originality/valueThis paper looks at reshoring as a policy-driven decision and provides an innovative systemic perspective to analyse the implications for different stakeholders of two reshoring options concerning the antibiotics supply chain.

Continuous-Flow Chemistry and Photochemistry for Manufacturing of Active Pharmaceutical Ingredients

An active pharmaceutical ingredient (API) is any substance in a pharmaceutical product that is biologically active. That means the specific molecular entity is capable of achieving a defined biological effect on the target. These ingredients need to meet very strict limits; chemical and optical purity are considered to be the most important ones. A continuous-flow synthetic methodology which utilizes a continuously flowing stream of reactive fluids can be easily combined with photochemistry, which works with the chemical effects of light. These methods can be useful tools to meet these strict limits. Both of these methods are unique and powerful tools for the preparation of natural products or active pharmaceutical ingredients and their precursors with high structural complexity under mild conditions. This review shows some main directions in the field of active pharmaceutical ingredients' preparation using continuous-flow chemistry and photochemistry with numerous examples of industry and laboratory-scale applications.