Impurities in Drug Substance & in Drug Product

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Impurities in Drug Substance & in Drug Product

  1. 1. IMPURITIES IN DRUG SUBSTANCES & DRUG PRODUCTS
  2. 2. IMPURITIES IN DRUG SUBSTANCES TOPICS TO BE COvERED:          Introduction Classification of Impurities Rationale for the Reporting and Control of Impurities Analytical Procedure Identification, Reporting and Qualification of Impurities Listing of Impurities in Specification Illustration of Reporting Impurity Results for Identification and Qualification in an Application Decision Tree for Identification and Qualification More on Residual Solvents 2
  3. 3. INTRODUCTION Objective:  The objective of the guideline makes recommendation to applicant on reporting, identifying and qualifying information on impurities in new drug substance. What is impurity?  Any component of the new drug substance that is not the chemical entity defined as the new drug substance. or  Any component that is not the drug substance or an excipient. 3
  4. 4. ClASSIfICATION Of IMPURITIES Impurities can be classified into the following categories: 1. Organic impurities (process- and drug-related) 2. Inorganic impurities 3. Residual solvents 4
  5. 5. 1. ORGANIC IMPURITIES: Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include: Starting materials By-products Intermediates Degradation products Reagents, ligand and catalysts 5
  6. 6. 2. INORGANIC IMPURITIES: Inorganic impurities can result from the manufacturing process. They are normally known and identified and include: Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal) 6
  7. 7. 3. 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. Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances. 7
  8. 8. RATIONAlE fOR THE REPORTING AND CONTROl Of IMPURITIES  Organic Impurity: The actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substance should be summarised.  Inorganic Impurity: Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures. Carry-over of catalysts to the new drug substance should be evaluated during development  Residual Solvent: The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents. 8
  9. 9. ANAlyTICAl PROCEDURE  Analytical Procedures should be validated and demonstrate that it is suitable for the detection and quantification of the impurities.  Reference standards used in the analytical procedures for control of impurities should be evaluated and characterised according to their intended uses. 9
  10. 10. IDENTIfICATION, REPORTING AND QUAlIfICATION Of IMPURITIES  Quantitative results should be presented numerically, and not in general terms such as “complies”, “meets limit” etc.  Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).  Results should be rounded using conventional rules. 10
  11. 11. IDENTIfICATION, REPORTING AND QUAlIfICATION Of IMPURITIES (CONTD.) Thresholds: Maximum Daily Dose ≤ 2g/day Reporting Threshold 0.05% > 2g/day 0.03% Identification Threshold 0.10% or 1.0 mg per day intake (whichever is lower) 0.05% Qualification Threshold 0.15% or 1.0 mg per day intake (whichever is lower) 0.05%  Any impurity at a level greater than (>) the identification threshold should be identified.  Any impurity at a level greater than (>) the reporting threshold (and total impurities observed in these batches of the new drug substance should be reported.  All impurities at a level greater than (>) the reporting threshold should be summed and reported as total impurities.  All impurities at a level greater than (>) the qualification threshold should be qualified. 11
  12. 12. LISTING OF IMPURITIES IN SPECIFICATION     The specification for a new drug substance should include a list of impurities. The selection of impurities in the new drug substance specification should be based on the impurities found in batches manufactured by the proposed commercial process. Specified impurities can be identified or unidentified. In summary, the new drug substance specification should include, where applicable, the following list of impurities:  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 12
  13. 13. DEFINITION  Impurity Profile: A description of the identified and unidentified impurities present in a new drug substance.  Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance.  Identified Impurity: An impurity for which a structural characterisation has been achieved.  Unidentified Impurity: An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). 13
  14. 14. DEFINITION (CONTD.)  Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified.  Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification.  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. 14
  15. 15. ILLUSTRATION OF REPORTING IMPURITy RESULTS FOR IDENTIFICATION AND QUALIFICATION Example 1: 0.5 g Maximum Daily Dose  Reporting threshold = 0.05%  Identification threshold = 0.10%  Qualification threshold = 0.15% "Raw" Result (%) 0.044 0.0963 0.12 0.1649 Reported Calculated Total Result Daily Intake (%) (TDI) (mg) of Reporting the impurity threshold (rounded result =0.05% in mg) Not reported 0.10 0.12 0.16 Action Identification Qualification (Threshold (Threshold 0.10% 0.15% exceeded?) exceeded?) 0.2 None None 0.5 0.6 0.8 None Yes Yes None None Yes 15
  16. 16. ILLUSTRATION OF REPORTING IMPURITy RESULTS FOR IDENTIFICATION AND QUALIFICATION (CONTD.) Example 2: 0.8 g Maximum Daily Dose  Reporting threshold = 0.05%  Identification threshold = 0.10%  Qualification threshold = 1.0 mg TDI “Raw” Result (%) 0.066 0.124 0.143 Reported Calculated Total Result Daily Intake (%) (TDI) (mg) Reporting of the impurity threshold (rounded result =0.05% in mg) 0.07 0.12 0.14 0.6 1.0 1.1 Action Identification Qualification (Threshold (Threshold 1.0 0.10% mg TDI exceeded?) exceeded?) None yes yes None None Yes 16
  17. 17. DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF IMPURITy Is impurity greater than identification threshold? Yes No Yes Structure identified Any known human relevant risks? No No Reduce to NMT(≤) Identification threshold Yes No further action Yes No Consider…… Yes No Reduce to NMT(≤) Qualification threshold Yes Greater than Qualification threshold No Reduce to safe level
  18. 18. DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF IMPURITy (CONTD.) Consider patient population and duration of use and consider conducting:  Genotoxicity studies (point mutation, chromosomal aberration)  General toxicity studies (one species, usually 14 to 90 days)  Other specific toxicity endpoints, as appropriate Yes Any clinically relevant adverse effects? No
  19. 19. MORE ON RESIDUAL SOLvENTS  ICH Q3C, recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of patients.  It recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.  Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.  Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.
  20. 20. MORE ON RESIDUAL SOLvENTS (CONTD.) CLASSIFICATION SOLvENTS: Solvent OF RESIDUAL Concentration limit (ppm) Concern Benzene Carbon tetrachloride 2 4 1,2-Dichloroethane 1,1-Dichloroethene 1,1,1-Trichloroethane 5 8 1500 Carcinogen Toxic and environmental hazard Toxic Toxic Environmental hazard
  21. 21. MORE ON RESIDUAL SOLvENTS (CONTD.) CLASSIFICATION SOLvENTS: Solvent Acetonitrile Chlorobenzene Cyclohexane Dichloromethane Hexane Methanol N-Methylpyrrolidone Tetrahydrofuran Toluene Xylene OF PDE (mg/day) 4.1 3.6 38.8 6.0 2.9 30.0 5.3 7.2 8.9 21.7 RESIDUAL Concentration limit (ppm) 410 360 3880 600 290 3000 530 720 890 2170
  22. 22. MORE ON RESIDUAL SOLvENTS (CONTD.) CLASSIFICATION SOLvENTS: Acetic acid Acetone Anisole 1-Butanol 2-Butanol Butyl acetate tert-Butylmethyl ether Dimethyl sulfoxide Ethanol Ethyl acetate Ethyl ether Ethyl formate Formic acid OF RESIDUAL Heptane Isobutyl acetate Isopropyl acetate Methyl acetate 3-Methyl-1-butanol Methylethyl ketone Methylisobutyl ketone 2-Methyl-1-propanol Pentane 1-Pentanol 1-Propanol 2-Propanol Propyl acetate
  23. 23. MORE ON REsidual sOlvENts (cONtd.) ICH Q3C defines options for the definition of acceptance criteria for class 2 solvents OptiON 1: ⇒ tabulated limits, calculated on the basis of a TDI (Tolerable Daily Intake) of 10 g of the product OptiON 2: ⇒ Products that are administered in doses greater than 10 g per day should be considered under Option 2
  24. 24. MORE ON REsidual sOlvENts (cONtd.) ExaMplE fOR OptiON 2: Concentration (ppm) = Component Amount in formulation 1000 x PDE dose Acetonitrile content Daily exposure Drug substance 0.3 g 800 ppm 0.24 mg Excipient 1 0.9 g 400 ppm 0.36 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 728 ppm 3.64 mg PDE (Permitted Daily Exposure) limit : 4.1 mg/day, limit: 410 ppm
  25. 25. iMpuRitiEs iN dRuG pROducts tOpics tO bE cOvEREd:        Introduction Rationale for the Reporting and Control of Degradation Products Analytical Procedure Reporting Degradation Products Content of Batches Listing of Degradation Products in Specifications Qualification of Degradation Products Decision Tree for Identification and Qualification of a Degradation Products 25
  26. 26. iNtROductiON Objective:  The objective of the guideline makes recommendation to applicant on the content and qualification of impurities in new drug products produced from chemically synthesised new drug substance. What is 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. 26
  27. 27. RatiONalE fOR tHE REpORtiNG aNd cONtROl Of dEGRadatiON pROducts  The applicant should summarize the degradation products observed during manufacture and/or stability studies of the new drug product. This summary should be based on sound scientific appraisal of potential degradation pathways in the new drug product and impurities arising from the interaction with excipients and/or the immediate container closure system.  A rationale should be provided for exclusion of those impurities that are not degradation products (e.g., process impurities from the drug substance and impurities arising from excipients). The impurity profiles of the batches representative of the proposed commercial process should be compared with the profiles of batches used in development and any differences discussed. 27
  28. 28. RatiONalE fOR tHE REpORtiNG aNd cONtROl Of dEGRadatiON pROducts  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.  When identification of a degradation product is not feasible, a summary of the laboratory studies demonstrating the unsuccessful efforts to identify it should be included in the registration application. 28
  29. 29. aNalytical pROcEduRE  Analytical Procedures should be validated and demonstrate that it is suitable for the detection and quantification of the degradation products.  In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products. As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.  The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold. 29
  30. 30. REpORtiNG dEGRadatiON pROducts cONtENt Of batcHEs     Analytical results should be provided in the registration application for all relevant batches of the new drug product used for clinical, safety, and stability testing, as well as batches that are representative of the proposed commercial process. Quantitative results should be presented numerically, and not in general terms such as “complies”, “meets limit” etc. Any degradation product at a level greater than (>) the reporting threshold, and total degradation products observed in the relevant batches of the new drug product, should be reported with the analytical procedures indicated. Below 1.0%, the results should be reported to the number of decimal places (e.g., 0.06%) in the applicable reporting threshold; at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%). 30
  31. 31. listiNG Of dEGRadatiON pROducts iN spEcificatiON         The specification for a new drug product should include a list of degradation products. The selection of degradation products in the new drug product specification should be based on the degradation products found in batches manufactured by the proposed commercial process. Specified degradation product can be identified or unidentified. In summary, the new drug product specification should include, where applicable, the following list of degradation products: 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 31 Total degradation products.
  32. 32. dEfiNitiON      Degradation Profile: A description of the degradation products observed in the drug substance or drug product. Development Studies: Studies conducted to scale-up, optimise, and validate the manufacturing process for a drug product. Identification Threshold: A limit above (>) which a degradation product should be identified. Identified Degradation Product: A degradation product for which a structural characterisation has been achieved. New Drug Substance: The designated therapeutic moiety that has not been previously registered in a region or member state (also referred to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or salt of a previously approved substance. 32
  33. 33. dEfiNitiON (cONtd.)       Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. Qualification Threshold: A limit above (>) which a degradation product should be qualified. Reporting Threshold: A limit above (>) which a degradation product should be reported. Specified Degradation Product: A degradation product that is individually listed and limited with a specific acceptance criterion in the new drug product specification. A specified degradation product can be either identified or unidentified. Unidentified Degradation Product: A degradation product for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). Unspecified Degradation Product: A degradation product that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new 33 drug product specification.
  34. 34. THRESHOLDS FOR DEGRADATION PRODUCTS IN NEW DRUG PRODUCTS Reporting Thresholds: Maximum Daily Dose1 Threshold2,3 ≤ 1g 0.1% >1g 0.05% Identification Thresholds: Maximum Daily Dose1 Threshold2,3 < 1 mg 1.0% or 5 µg TDI, whichever is lower 1 mg - 10 mg 0.5% or 20 µg TDI, whichever is lower >10 mg - 2 g 0.2% or 2 mg TDI, whichever is lower > 2g 0.10% 34
  35. 35. THRESHOLDS FOR DEGRADATION PRODUCTS IN NEW DRUG PRODUCTS (CONTD.) Qualification Thresholds: Maximum Daily Dose1 < 10 mg 1.0% or 50 µg TDI, whichever is lower 10 mg - 100 mg 0.5% or 200 µg TDI, whichever is lower >100 mg - 2 g 0.2% or 3 mg TDI, whichever is lower >2g  Threshold2,3 0.15% Notes: 1. The amount of drug substance administered per day 2. Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic. 3. Higher thresholds should be scientifically justified. 35
  36. 36. ILLUSTRATION OF REPORTING DEGRADATION PRODUCTS RESULTS FOR IDENTIFICATION AND Maximum Daily Dose Example 1: 50 mg QUALIFICATION Reporting threshold: 0.1% Identification threshold: 0.2% Qualification threshold: 200 μg 'Raw' Result (%) 0.04 0.2143 0.349 0.550 Reported Result Total Daily Intake (TDI) of the Degradation (%) Product (Reporting (rounded result Threshold in μg) = 0.1%) Not reported 0.2 0.31 0.61 Action Identification Qualification Threshold Threshold 0.2% 200 μg TDI exceeded? exceeded? 20 None None 100 150 300 None Yes Yes None None1 Yes1 36
  37. 37. ILLUSTRATION OF REPORTING DEGRADATION PRODUCTS RESULTS FOR IDENTIFICATION AND QUALIFICATION Example 2: 1.9 gram Maximum Daily Dose Reporting threshold: 0.05% Identification threshold: 2 mg Qualification threshold: 3 mg 'Raw' Result (%) 0.049 0.079 0.183 0.192 Reported Total Daily Result Intake (TDI) of the Degradation (%) Product (Reporting Threshold (rounded result in mg) = 0.05%) Not reported 0.08 0.181 0.191 Action Identification Qualification Threshold Threshold 2 mg TDI 3 mg TDI exceeded? exceeded? 1 None None 2 3 4 None Yes Yes None None1, 2 Yes1 37
  38. 38. DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A DEGRADATION PRODUCT Is degradation product greater than identification threshold? Yes No Yes Structure identified Any known human relevant risks? Reduce to safe level No No Reduce to NMT(≤) Identification threshold Yes No further action Yes No Consider…… Yes No Reduce to NMT(≤) Qualification threshold Yes Greater than Qualification threshold No 38
  39. 39. DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A DEGRADATION PRODUCT (CONTD.) Consider patient population and duration of use and consider conducting:  Genotoxicity studies (point mutation, chromosomal aberration)  General toxicity studies (one species, usually 14 to 90 days)  Other specific toxicity endpoints, as appropriate Yes Any clinically relevant adverse effects? No 39
  40. 40. REFERENCE  ICH Guidelines- Q3A(R2): Impurities in New Drug Substances  ICH Guidelines- Q3B(R2): Impurities in New Drug Products  ICH Guidelines- Q3C(R5): Impurities: Guidelines for Residual Solvents  CPMP/ICH/2737/99 : Impurities in New Drug Substances  CPMP/ICH/283/95 : Impurities: Guidelines for Residual Solvents  ANDAs: Impurities in New Drug Substances, June 2009, Revision 1 40
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