Impurities in Drugs author: srikanth N http://stabilitystudies.blogspot.com http://stabilitystudies.blogspot.in Drug Substance and Drug Product Impurities in Drugs author: srikanth N http://stabilitystudies.blogspot.in

http://stabilitystudies.blogspot.com Impurity Any component of the new drug substance that is not the chemical entity defined as the new drug substance http://stabilitystudies.blogspot.in

Type of Impurities http://stabilitystudies.blogspot.in Impurity Process Degradation Contamination Enantiomeric Polymorphic http://stabilitystudies.blogspot.in

Types of Impurities Each type of Impurity can be classified as follows. http://stabilitystudies.blogspot.in

Types of impurities Volatile Non-Volatile Organic Identified Un-identified Inorganic Residual solvents Volatile Non-Volatile http://stabilitystudies.blogspot.in

Reagents, catalysts and Ligands Organic Impurities Organic Impurities Starting Materials By-Products Intermediates Degradation Products Reagents, catalysts and Ligands http://stabilitystudies.blogspot.in

Inorganic impurities Inorganic Impurities Reagents,ligands and catalysts Heavy Metals or Other residual salts Inorganic salts Other materials (filter aids, charcoal) http://stabilitystudies.blogspot.in

control organic impurity Control of organic impurities API Synthesis Raw materials, by-products, related intermediates Solvents, reagents, ligands and catalysts API Purification Carbon Related? Polymorph or chiral or solvents Packaging and storage Degradants http://stabilitystudies.blogspot.in

Residual solvents Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance http://stabilitystudies.blogspot.in

Solvent as an impurity Solvents Used as vehicle during synthesis may remain as residue Dissolution during purification/crystallization may remain as residue Used during granulation/coating/any other operation http://stabilitystudies.blogspot.in

Drug substance Drug Substance Manufacturing Starting Material Reaction By-products Unreacted Intermediates Reagents, Ligands and catalysts Packaging and storage Degradation Products http://stabilitystudies.blogspot.in

Impurities in specification Organic Impurities Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than () the identification threshold Total impurities Residual Solvents Inorganic Impurities http://stabilitystudies.blogspot.in

Listing in specification Listing of impurities % of Impurity Listing in specification > 1.0% 1.3 %( one digit after decimal place) < 1.0% 0.18% (Two digits after decimal Place) http://stabilitystudies.blogspot.in

Others Enantiomeric Impurity: A compound with the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image. Polymorphic Forms: Different crystalline forms of the same drug substance. These can include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms. http://stabilitystudies.blogspot.in

Types Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance. Actual Impurity: An impurity that is actually appear in the new drug substance. http://stabilitystudies.blogspot.in

Qualification Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. Qualification Threshold: A limit above (>) which an impurity should be qualified. Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B. http://stabilitystudies.blogspot.in

Thresholds Max daily Dose Reporting threshold Identification Threshold Qualification Threshold ≤ 2 g / day 0.05% 0.10% or 1.0 mg per day whichever is lower 0.15% or 1.0 mg per day intake, whichever is lower > 2 g / day 0.03% http://stabilitystudies.blogspot.in

Drug product In the Drug product specification, only degradation products are to be incorporated as impurities. The degradation products include Degradation products of the drug substance or Reaction products of the drug substance with an excipient and/or Immediate container closure system http://stabilitystudies.blogspot.in

Rationale for the reporting and control of degradation products The applicant should summarise the degradation products observed during manufacture and/or stability studies of the new drug product. Any degradation product observed in stability studies conducted at the recommended storage condition should be identified when present at a level greater than (>) the identification thresholds http://stabilitystudies.blogspot.in

Analytical procedures Validated analytical procedures should be used to analyze the impurities. As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation. When an analytical procedure reveals the presence of other peaks in addition to those of the degradation products (e.g., the drug substance, impurities arising from the synthesis of the drug substance, excipients and impurities arising from the excipients), these peaks should be labeled in the chromatograms and their origin(s) discussed in the validation documentation. http://stabilitystudies.blogspot.in

Listing in the specification Each specified identified degradation product Each specified unidentified degradation product Any unspecified degradation product with an acceptance criterion of not more than () the identification threshold Total Degradation products. http://stabilitystudies.blogspot.in

Def’s Degradation Product: An impurity resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system. Degradation Profile: A description of the degradation products observed in the drug substance or drug product. http://stabilitystudies.blogspot.in

Identification thresholds http://stabilitystudies.blogspot.com Identification thresholds Max Daily Dose * Threshold < 1mg 1.0% or 5 µg TDI, whichever is lower 1mg-10 mg 0.5% or 20 µg TDI, whichever is lower > 10 mg 0.2 % or 2mg TDI, whichever is lower > 2 g 0.10% * Per Day http://stabilitystudies.blogspot.in