Impurity in Drug Substance & Product
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CCK Discussion Forum on Impurity Emergence: A Wake Up Call for Drug Safety & Quality - 13 Oct 2019 at ICCBS, University of Karachi. Session largely participated by qualified and experienced pharmaceutical professionals having diversified educational background and experience.
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Impurity in Drug Substance & Product
- 1. Impurity in Drug Substance & Product CCK- Forum Sunday, Oct 13th Karachi Lecture 1
- 3. Acknowledgment and thanks to Anthony Fake, Theo Dekker, Rutendo Kawana & Lynda Paleshnuik of World Health Organization
- 4. Most Common Abbreviations Used • API – Active Pharmaceutical Ingredient • FPP – Finished Pharmaceutical Product • LOD – Loss on Drying • PDE – Permitted daily exposure • TDI – Total daily intake • TTC – Threshold of Toxicological Concern
- 5. Focus • Impurities and brief explanation – already given • What are potential impurities • What impurities actually occur • When to specify impurities • Setting Impurities limits
- 6. What • are the potential impurities? What • impurities actually occur? When • to specify impurities. Let us unfold .... Setting impurity limits
- 7. What are the potential impurities?
- 8. What are the potential impurities?
- 9. What potential impurities might be present, based upon all available information. This step is often poorly performed by applicants. There is a tendency to skip this step in discussions and just adopt pharmacopoeial specifications if a monograph exists. What are the potential impurities?
- 10. What potential impurities might be present, based upon all available information. This step is often poorly performed by applicants. There is a tendency to skip this step in discussions and just adopt pharmacopoeial specifications if a monograph exists. What are the potential impurities?
- 11. What potential impurities might be present, based upon all available information. This step is often poorly performed by applicants. There is a tendency to skip this step in discussions and just adopt pharmacopoeial specifications if a monograph exists. What are the potential impurities?
- 12. API SM Reaction intermediate Final API FPP Potential Impurities
- 13. API SM Reaction intermediate Final API FPP Potential Impurities Residue of the API SM Residue of the intermediate
- 14. API SM Reaction intermediate Final API FPP SM impurities Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM
- 15. API SM Reaction intermediate Final API FPP Reagents Solvents Catalysts Solvents SM impurities Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reagents Solvents Catalysts
- 16. API SM Reaction intermediate Final API FPP Reagents Solvents Catalysts Solvents By-products By-products SM impurities Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Reagents Solvents Catalysts
- 17. API SM Reaction intermediate Final API FPP Reagents Solvents Catalysts Solvents Degradation By-products By-products SM impurities Reagents Solvents Catalysts Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Degradation products
- 18. API SM Reaction intermediate Final API FPP Reagents Solvents Catalysts Solvents Degradation By-products By-products SM impurities Excipient-API interactions Reagents Solvents Catalysts Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Degradation products Excipient-API interactions
- 19. API SM Reaction intermediate Final API FPP Reagents Solvents Catalysts Solvents? Degradation By-products By-products SM impurities Container-API interactions Excipient-API interactions Reagents Solvents Catalysts Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Degradation products Excipient-API interactions Container closure interactions
- 20. It is essential to have a detailed knowledge of the Preparation of the API & the Controls placed upon the API Starting Materials Reaction Inter- mediates Reagents Solvents
- 21. It is essential to know How the API degrades
- 22. Similarly, the manner of preparation of the FPP is important Are there solvents involved, heat, water etc?
- 23. Most of the potential impurities arise during the preparation of the API and its subsequent degradation
- 24. The focus of FPP impurities is usually limited to degradation products, or occasionally API-Excipient and API- API interactions
- 25. Typically FPP impurity specifications only control for API degradation products
- 27. Consequently, there is a large focus on the control of impurities in the API
- 28. Impurities introduced during manufacture API degradation products API reaction by- products Determining most of the potential impurities does not require a great deal of chemistry knowledge. Impurities can be divided into:
- 29. These can be determined from the detailed manufacturing process description They are the solvents, reagents, catalysts, residue starting material, reaction intermediates used in manufacture What impurities are introduced during manufacture?
- 30. These can be determined from the results of stress studies. Significant degradation products should be identified and treated as potential impurities. What are the possible degradation impurities?
- 31. Genotoxins must be considered carefully due to their toxicity at even very low levels
- 32. The most common situation that arises is the use of the reagents methylsulphonic acid or toluene sulphonic acid
- 33. In the presence of alcohols like methanol or ethanol they can form sulphonate esters. These esters are genotoxic
- 34. Remember, if the impurity and the API share the same alert structure then the impurity does not need to be controlled as a genotoxin
- 35. What impurities actually occur?
- 36. API SM Step 1 Step 3 Final API Step 2 Chance Chance of an impurity occurring Step impurity is introduced Enantiomers
- 37. Investigation of batch analysis and long- term stability data is required. Impurities present at levels greater than the ICH reporting threshold should be reported by the manufacturer.
- 38. Potential impurities can be excluded by either testing the final API or FPP, or a relevant proceeding molecule. Some pharmacopoeial impurities may not be present if a different manner of preparation, (reagents, synthesis) is used.
- 39. For degradants, look to long-term stability data. The presence of an impurity under accelerated conditions does not mean it will appear under long-term conditions
- 40. If you are looking for an impurity using a test method that can not detect the impurity then you are wasting your time. Demonstrated specificity and appropriate LOD/LOQs are important, especially for genotoxins. Analytical methods
- 41. It is important for the manufacturer to detail the methods used. This is often not clear in submitted dossiers if different test methods have been used at different times. Analytical methods
- 42. When to specify impurities?
- 43. Organic impurities (process- and drug-related) Residual solvents Inorganic impurities PLEASE Remember
- 44. Any impurity routinely observed in batch data or long-term stability trials should be controlled by the impurity specifications Organic Impurities
- 45. Impurities observed below the ICH identification threshold need not be individually specified in the specifications. They can be controlled under the limit for any unspecified impurity Organic Impurities
- 46. Impurities above the ICH identification threshold need to be identified and individually specified in the specifications Organic Impurities
- 47. If a genotoxin is formed or is likely to be formed during manufacture or storage then a limit for this impurity should be included in specifications GENOTOXINS
- 48. If batch data (6 pilot or 3 production) demonstrate that levels of the impurity are at or below 30% of the allowable limit then non- routine testing may be adopted. It should still be specified
- 50. For instance, if methylsulphonic acid and methanol were used in the last step, but methane methylsulphonate was not detected then it may be appropriate to test once annually.
- 51. For instance, if methylsulphonic acid and methanol were used in the last step, but methane methylsulphonate was not detected then it may be appropriate to test once annually. If methylsulphonic acid and methanol were used in the first of three steps, but methane methylsulphonate was not detected then it may be appropriate to specify the test is to be applied when there is a change in manufacture.
- 52. Setting limits for impurities?
- 53. The limits must be qualified as safe. The limits should realistically reflect batch and stability data.
- 54. Through toxicological trials. By comparison to levels found in an innovator or prequalified FPP. By comparison to a limit previously approved in a prequalified FPP. This is a last resort. If the impurity is greater than the ICH qualification threshold then it should be qualified:
- 55. If the impurity is greater than the ICH qualification threshold then it should be qualified:
- 56. By comparison to a limit specified in the Ph.Int., Ph.Eur., or USP for a specific impurity. It could even be in a monograph for another substance. A statement in a monograph of "any other impurity NMT 0.5%" can not be used as justification for an impurity limit, as it is not specific If the impurity is greater than the ICH qualification threshold then it should be qualified:
- 57. The limit for any unspecified impurity should be at the ICH identification threshold. The limit for total impurity content should reflect batch data.
- 58. These concepts are applicable to synthetic APIs, but could be used on a case by case basis for semi-synthetic APIs.
- 59. • Are considered unsafe at any level. • A limit for a genotoxin with an understood toxicity can be calculated based upon the known PDE. Genotoxins
- 60. Wrap up
- 61. Any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient of the product Impurity
- 62. Any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient of the product Impurity An impurity for which structural characterisation has been achieved Identified Impurity
- 63. Any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient of the product Impurity An impurity defined only by qualitative properties e.g. Rt Unidentified Degradation Product An impurity for which structural characterisation has been achieved Identified Impurity
- 65. Impurity Thresholds Maximum daily dose Reporting threshold Identification threshold Qualification threshold <= 2g/day 0.05% 0.10% or 1mg/day intake 0.15% or 1mg/day intake >= 2g/day 0.03% 0.05% 0.05%
- 66. If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph, Can we accept the specifications? Yes/No
- 67. Unfortunately NO Monographs are developed based upon how the API was prepared historically. If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph, Can we accept the specifications?
- 68. Remember A particular manufacturing method may lead to unexpected impurities, due to a different route of synthesis, different reagents, etc. If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph, Can we accept the specifications?
- 71. Preparation and potency determination/specification of primary and secondary (working) standards, with CoAs Analytical methods with validation Impurities to be characterised and limits set Synthesis/ degradation according to Q3A(R) Residual solvents according to Q3C Requires justification for proposed specifications
- 72. Impurities Moisture content (or LOD: moisture + residual solvents) Identification (at least one specific, e.g. IR spectrum) Appearance/description Typical set of specifications
- 73. Residual solvent(s) Inorganic impurities, including catalysts Related organic substances (synthesis degradation) specified unspecified total organic impurities Impurities Additional parameters important for specific API such as particle size, polymorphic form, microbial limits Assay
- 74. • The current monograph always applicable • Additional critical specifications that are not included in monograph e.g. – Particle size & polymorphic form – Synthesis related impurities resulting from specific process which may be additional to monograph – Residual solvents (specific to process) CEP normally states tests additional to the monograph – e.g. residual solvents & impurities
- 75. 1.5 ug/day Intake of genotoxic impurity is considered as acceptable risk Maths
- 76. Thank You