Two-Step Synthesis of a Chiral Fluorinated Alcohol With Silica-Supported Enzyme RrADH in Batch and Continuous Flow Mode.

ObjectivesTo assess the upstream pharmaceutical supply chains of 10 high-use pharmaceuticals to detect vulnerabilities that may increase the risk of medicine shortages.DesignCohort study.SettingDutch outpatient setting in 2022.ParticipantsA total of 407...

Multi-block tensor regression for quality prediction and root cause analysis in the production of active pharmaceutical ingredients

Controlled nucleation of crystallization process as an efficient tool to tune the properties of corticosteroid API

Integration of Active Pharmaceutical Ingredient production into a pharmaceutical Lean Learning Factory

A significant number of marketed pharmaceuticals contain active pharmaceutical ingredients that are manufactured in part using biocatalysis as a key enabling technology. The utilization of biocatalysis is growing due to significant advances in technologies for enzyme discovery, supply, and improvement, as well as an increased focus on applications for chiral drugs and green chemistry. Nevertheless, there still remains a lack of clarity around quality and regulatory expectations when using biotransformations in research and manufacturing, and this lack of clarity can be a barrier to the uptake and adoption of biocatalysis. This commentary will explore and offer some rational, coherent, and achievable strategies for the use of biocatalysis in the manufacture of small molecule active pharmaceutical ingredients (APIs) based on a scientific, risk-based approach to drug quality and patient safety. We also seek to invite other interested parties to contact us with their views to add to the topics discussed here with the goal of expanding these thoughts into an industry-based white paper.

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

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

Nitrosamine impurities in angiotensin II receptor antagonists (sartans) containing a tetrazole group represent an urgent concern for active pharmaceutical ingredient (API) manufacturers and global regulators. Regarding safety, API manufacturers must develop methods to monitor the levels of each nitrosamine impurity before individual batch release. In this study, we developed and validated a sensitive, selective, and high-throughput method based on headspace gas chromatography–mass spectrometry (HS-GC–MS) for the simultaneous determination of four nitrosamines in losartan potassium API with simple sample preparation. N-Nitrosodimethylamine (NDMA, m/z 74), N-nitrosodiethylamine (NDEA, m/z 102), N-nitrosoethylisopropylamine (EIPNA, m/z 116), and N-nitrosodiisopropylamine (DIPNA, m/z 130) levels were quantified using an electron impact, single quadrupole mass spectrometer under a selected-ion-monitoring acquisition method. The method was validated according to the Q2(R1) ICH guidelines. The calibration curves of the assay ranged from 25 to 5000 ng/mL with limits of quantitation of 25 ppb for NDMA and NDEA and 50 ppb for DIPNA and EIPNA. The accuracy of the developed method ranged from −7.04% to 7.25%, and the precision %CV was ≤11.5. Other validation parameters, including specificity, stability, carryover, and robustness, met the validation criteria. In conclusion, the developed method was successfully applied for the determination of nitrosamines in losartan potassium APIs.

ABSTRACTThis paper provides the first benchmarking study of green chemistry (GC) adoption by the Indian pharmaceutical supply chain based on information from industry representatives leading such efforts. Results demonstrate that generic drug pharma and Active Pharmaceutical Ingredients (API) manufacturers in India exhibit significant interest and some advances in using GC principles. At the same time, majority (65%) of Indian companies rely on treatment and disposal of waste water instead of source reduction and one in five (20%) does not use any GC metrics. The study found that generic pharma is more advanced in adopting GC principles than API manufacturers. Regulatory risk and time pressures to deliver drugs were reported as the two most significant barriers for greater adoption of GC in India, while cost savings and environmental regulations were cited as the top two drivers. The paper concludes with some recommendations for advancing GC adoption in India.

Introduction. Earlier, the comparative analysis of the commercial and investment activities of the companies that play the key roles in the investment processes in the Russian pharmaceutical industry and operate within the four main business models (biotechnological, generic, specialized pharmaceutical companies, active pharmaceutical ingredient (API) manufacturers) has been conducted. No full assessment of the companies’ activitiesis conceivable without a financial analysis of their activities to identify the risks of investment activities. Objective of the study. A detailed comparative analysis of the financial standing of domestic pharmaceutical manufacturers operating within the selected business models for further identification of potential financial risks for investors. Research procedure and article structure. Analysis of RAS statements (forms 1 and 2) of 72 over 500 million revenue companies grouped together as selected business models for the period from 2015 to 2019. Results. The researchers provided a detailed description of the commercial activities of domestic pharmaceutical companies within the business models under consideration. The companies within various business models showed positive revenue growth rates over the past five years. All business models demonstrate consistently high business profitability and a significant share of own capital in the asset profile. Conclusion. The results of the study show the stable financial standing of the pharmaceutical companies within various business models. The biotechnology sector companies that are the most attractive for investments have the highest quality financial standing. The specialized and generic companies show similar consistently strong performance. API manufacturers that the companies with relatively small revenues are actively developing and are attractive to restrained budget investors.

This chapter looks at catalytic reactions from the stand-point of industrial development and manufacturing and not from the standpoint of academic or medicinal chemists. Catalytic reactions can be divided into two groups: heterogeneous and homogeneous reactions. Typical and very frequently applied cases of heterogeneous catalysis in active pharmaceutical ingredient (API) manufacture are hydrogenation reactions utilizing heterogeneous catalysts like palladium or platinum on carbon or Raney nickel. Heterogeneous hydrogenation catalysts are available as solids or powders; and due to their pyrophoric nature and air sensitivity, they need to be handled with caution, particularly on a large scale. The chapter discusses the production of a number of APIs for which all their synthetic routes contain one or more catalytic reaction. Continuous-flow techniques and small volume continuous manufacturing are becoming more and more recognized in API manufacture, especially for small volume products and new products under development.

The IQ Consortium reports on the current state of process analytical technology (PAT) for active pharmaceutical ingredient (API) manufacturing in branded pharmaceutical companies. The article describes the application of PAT in manufacturing and provides representative examples in four common pharmaceutical unit operations: reaction and workup, crystallization, drying, and milling.

This review gives an overview of different yeast strains and enzyme classes involved in yeast whole-cell biotransformations. A focus was put on the synthesis of compounds for fine chemical and API (= active pharmaceutical ingredient) production employing single or only few-step enzymatic reactions. Accounting for recent success stories in metabolic engineering, the construction and use of synthetic pathways was also highlighted. Examples from academia and industry and advances in the field of designed yeast strain construction demonstrate the broad significance of yeast whole-cell applications. In addition to Saccharomyces cerevisiae, alternative yeast whole-cell biocatalysts are discussed such as Candida sp., Cryptococcus sp., Geotrichum sp., Issatchenkia sp., Kloeckera sp., Kluyveromyces sp., Pichia sp. (including Hansenula polymorpha = P. angusta), Rhodotorula sp., Rhodosporidium sp., alternative Saccharomyces sp., Schizosaccharomyces pombe, Torulopsis sp., Trichosporon sp., Trigonopsis variabilis, Yarrowia lipolytica and Zygosaccharomyces rouxii.

Environmental impacts of drug products: The effect of the selection of production sites in the supply chain

A series of 1‐aryl‐2,2,2‐trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)‐alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)‐enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo‐1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium‐catalyzed cross coupling between 1‐(4‐bromophenyl)‐2,2,2‐trifluoroethanone and 4‐(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2‐trifluoro‐1‐(4′‐(methylsulfonyl)‐[1,1′‐biphenyl]‐4‐yl)ethanone has been extensively studied. Finally, the desired (R)‐2,2,2‐trifluoro‐1‐(4′‐(methylsulfonyl)‐[1,1′‐biphenyl]‐4‐yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L−1 d−1 productivity following a sequential approach.