Not commercially available, not documented, not qualified
Phase transformation during manufacturing and storage result in solid state impurities represented by various unwanted polymorphic forms of the drug substance (e.g. Ritonavir). Besides the requirement for analysis and specification, any polymorphic state other than that specified may already cause patent infringement
E.g. Lisinopril dihydrate polymorphs, chlorthalidon
Process impurities in drug substance and drug product
Synthesis intermediates are planned compounds produced during the synthesis of the desired substance and remain due to incomplete reaction.
Synthesis by-products are unplanned compounds generated in the reaction. Degradation products are molecules resulting from a change in the drug substance brought about over time. Such changes could occur as a result of processing or storage e.g. deamination, oxidation, aggregation, proteolysis
Interaction products occur between various involved chemicals – purposely or inadvertently
Penultimate intermediates are the last compound in the synthetic chain just proceeding the production of the ultimate desired compound
Genotoxic process impurities
Highly reactive molecules generated during various synthesis steps with a high potential of side-reactions. Analytical detection and quantification is often challenging and requires sophisticated methods and/ or derivatisation.
E.g. Hydroxymethylfurfural, formaldehyde, tetrahydrofural
Highly reactive molecules used in various synthesis steps with a high potential of side-reactions. Analytical detection and quantification is often challenging and requires sophisticated methods and/ or derivatisation.
E.g. Dibromoethane, mesylates, tosylates
Degradation products result from a change in the drug substance brought about over time. For the purpose of stability testing of the drug products, such changes could occur as a result of processing or storage at various temperature and humidity conditions.
E.g. Deamination, oxidation, aggregation, proteolysis, hydrolysis
Stereoisomeres (enantiomers and diastereoisomers) are related products similar to the drug substance with, however, potential toxicological side effects or altered physicochemical properties.
Excipient reaction products
Maillard reactions of amines and aldehydes e.g. reaction products of fluoxetine and other SSRIs with ractose; reaction of 2-hydroxymethyl-furfural with amino-groups of drug substances
Peroxides, aldehydes, heavy metals, alkaline residues.
E.g. Lactosephosphate in lactose, benzaldehyde in benzyl alcohol, etc.
Brought about as excipient impurities or during manufacturing as catalysts for oxydation and hydrolysis.
E.g. Al, As, Sn, Cd, Cr, Cu, Fe, Pb, Hg, Ni, Na, Ca
Packaging material induced impurities
Leachable and Extractables (L&E) from primary packaging material form reaction products with drug substance and/ or excipients.
E.g. alkaline oxides from glasses (Na2O, SiO2, MgO, CaO ), phtalates, styrenes, diethylhexylphthalate plasticiser from PVC, 2-mercaptobenzothiazole accelerator from rubber