Product properties , such as purity and by-product profile , must not change during process scale-up molecules were discovered and developed by large pharmaceutical houses and large companies engaged in diagnostics . 2 Typically , a CDMO will work on two types of projects : a small number of large-volume projects in the late stages ( Phase III , launch and commercial manufacture ) for large pharmaceutical houses and a large number of projects at earlier stages of development for small organisations . The technologies CDMOs use must meet the needs of all these projects .
Volume & speed
Regulatory bodies offer a set of ‘ expedited pathways ’ to drug developers to speed up clinical development . In 2020 , 68 % of all FDA approvals were designated in one or more of these categories and 58 % concerned ‘ orphan ’ diseases . These drug development projects rely on small , fast clinical trials and require small product volumes on short notice . Even at maturity , product volumes remain low ( 1-200 kg ). New APIs are developed to be highly specific for their molecular target . They act at low doses ; they are frequently highly active and toxic , calling for proper containment to handle them in a safe way . Both factors , small patient numbers and highly active ingredients lead to small product volumes .
Properties of products
Despite single , spectacularly successful large molecule therapies , the share held by small molecules manufactured by chemical synthesis has remained constant , at between two thirds and three quarters of all new molecules reaching market approval . While many statements will hold for all new development projects , we shall focus on technologies related to small molecule development . Small molecule drug candidates are identified in pre-clinical lead generation and optimisation programmes , employing methods of chemical library synthesis to create the required diversity at molecular level . The inventory of chemical transformations used for library synthesis is growing but still small . The reactions are optimised to tolerate diverse substrates rather than deliver maximum yield . They use expensive materials and hazardous reagents but avoid unusual reaction conditions , such as very low temperatures . With few exceptions , they also avoid complicated reactions , such as those introducing one or more chiral centres . Drug candidates thus identified are typically purified by chromatography . Originating from library synthesis , today ’ s small molecule drug candidates may have multi-step
syntheses and high molecular weights , but their chemical structures are typically flat ( zero to one chiral centres ) and are not complex in the sense one would call botanical masterpieces such as Artemisinin or Taxol complex . The complexity of today ’ s small molecule APIs relates to physics and solid state chemistry . Relatively large , flexible molecules allow for a large and unknown number of polymorphs ; they are hard to formulate ; and their low solubility requires new formulation methods to improve their bioavailability . 3 , 4 Chemists excelling in organic synthesis are generally not trained to tackle these problems .
Manufacturing process development
As the volume needed for clinical trials and formulation development increases , the synthetic methods are developed to provide the respective product volume within a given time in the required quality . All of the process steps applied on a small scale , such as the use of laboratory reagents or repeated chromatographic separations , must be scaled up or replaced by scalable equivalents . Product properties , such as purity and by-product profile , must not change in order to avoid time-consuming bridging studies .
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