Establishing Impurity Specifications

1. Establishing Impurity Specifications Antony Fake PhD WHO Medicines Prequalification Programme

2. Abbreviations • API – Active Pharmaceutical Ingredient • FPP – Finished Pharmaceutical Product • LOD – Loss on Drying • PDE – Permitted daily exposure • TDI – Total daily intake • TTC – Threshold of Toxological Concern

3. Impurities • Impurities are unwanted chemicals present in the API or FPP arising from normal manufacture. • They are not chemicals accidently or maliciously introduced. • Impurities have no therapeutic value and are potentially harmful. Therefore they need to be controlled.

4. Impurities (2) Question: If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph can we accept the specifications?

5. Impurity (3) Question: If a manufacturer controls impurity content in accordance with a pharmacopoeial monograph can we accept the specifications? Unfortunately no, monographs are developed based upon how the API was prepared historically. A particular manufacturer's manufacturing method may lead to unexpected impurities, due to a different route of synthesis, different reagents, etc.

6. Overview Setting an impurity limit • What are the potential impurities? • What impurities actually occur? • When to specify impurities. • Setting limits for impurities.

7. What are the potential impurities?

8. What are the potential impurities? • The first step in setting impurity specifications is to consider 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.

9. What are the potential impurities? (2) API SM Potential Impurities Reaction intermediate Final API FPP

10. What are the potential impurities? (2) API SM Potential Impurities Residue of the API SM Residue of the intermediate Reaction intermediate Final API FPP

11. What are the potential impurities? (2) SM impurities API SM Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reaction intermediate Final API FPP

12. What are the potential impurities? (2) SM impurities API SM Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reagents Solvents Catalysts Reaction intermediate Reagents Solvents Catalysts Final API Solvents FPP

13. What are the potential impurities? (2) SM impurities API SM Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Reagents Solvents Catalysts By-products Reaction intermediate Reagents Solvents Catalysts By-products Final API Solvents FPP

14. What are the potential impurities? (2) SM impurities API SM Potential Impurities Residue of the SM Residue of the intermediate Impurities in the SM Reagents Solvents Catalysts Reaction by-products Degradation products Reagents Solvents Catalysts By-products Reaction intermediate Reagents Solvents Catalysts By-products Degradation Final API Solvents FPP

15. What are the potential impurities? (2) SM impurities API SM 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 Reagents Solvents Catalysts By-products Reaction intermediate Reagents Solvents Catalysts By-products Degradation Final API Excipient-API interactions Solvents FPP

16. What are the potential impurities? (2) SM impurities API SM 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 Reagents Solvents Catalysts By-products Reaction intermediate Reagents Solvents Catalysts By-products Degradation Final API Excipient-API interactions Solvents? Container-API interactions FPP

17. What are the potential impurities? (3) • It is essential to have a detailed knowledge of the preparation of the API and the controls place upon the API starting materials, reaction intermediates, reagents and solvents. • It is essential to know how the API degrades. • Similarly, the manner of preparation of the FPP is important. Are there solvents involved, heat, water etc?

18. What are the potential impurities? (4) • Most of the potential impurities arise during the preparation of the API and its subsequent degradation. • The focus of FPP impurities is usually limited to degradation products, or occasionally API-Excipient and API-API interactions (isoniazid/rifampicin). • Typically FPP impurity specifications only control for API degradation products. • Consequently, there is a large focus on the control of impurities in the API.

19. What are the potential impurities? (5) Determining most of the potential impurities does not require a great deal of chemistry knowledge. Impurities can be divided into: • Impurities introduced during manufacture • API degradation products • API reaction by-products

20. What are the potential impurities? (6) What impurities are introduced during manufacture? • These can be determined from the detailed manufacturing process description. • They are the solvents, reagents, catalysts, residue starting material, reaction intermediates used in manufacture.

21. What are the potential impurities? (7) What are the possible degradation impurities? • These can be determined from the results of stress studies. • Significant degradation products should be identified and treated as potential impurities.

22. What are the potential impurities? (8) What are the possible reaction by-products? • Here some chemistry knowledge would be helpful. Advice: • Look for areas of functionality, particularly C-O, C-N, and double bonds. • Consider all the impurities specified in relevant pharmacopoeial monographs. • Remember, it is the applicant's job to do this not yours.

23. What are the potential impurities? (9) At C-O bonds oxidation, reduction, cleavage, addition and elimination can readily occur.

24. What are the potential impurities? (10) Additions to double bonds within the molecule may occur unintentionally, and even if intentional are not 100% specific.

25. What are the potential impurities? (11) Stereochemical impurities can arise.

26. What are the potential impurities? (12) Certain chemical structures "alert structures" are considered to be genotoxic.

27. What are the potential impurities? (13) • Genotoxins must be considered carefully due to their toxicity at even very low levels. • The most common situation that arises is the use of the reagents methylsulphonic acid or toluene sulphonic acid. • In the presence of alcohols like methanol or ethanol they can form sulphonate esters. These esters are genotoxic. • Remember, if the impurity and the API share the same alert structure then the impurity does not need to be controlled as a genotoxin.

28. What impurities actually occur?

29. What impurities actually occur? Chance of an impurity occurring Chance Enantiomers Step impurity is introduced API SM Step 1 Step 2 Step 3 Final API

30. What impurities actually occur? (2) • 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. • 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. • 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

31. What impurities actually occur? (3) Analytical methods • 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. • 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.

32. When to specify impurities.

33. When to specify impurities The ICH divides impurities into • Organic impurities (process- and drug-related) • Residual solvents • Inorganic impurities

34. When to specify impurities (2) Organic impurities • Any impurity routinely observed in batch data or long-term stability trials should be controlled by the impurity specifications. • 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. • Impurities above the ICH identification threshold need to be identified and individually specified in the specifications.

35. When to specify impurities (3) • Regardless of the related substance requirements of an applicable pharmacopoeial monograph, a test for any unspecified impurity and total impurities should be included.

36. When to specify impurities (4) Genotoxins • 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. • 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. • 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.

37. When to specify impurities (5) Residual solvents • The absence of specific test should be demonstrated on at least 3 production batches or 6 pilot scale batches.

38. When to specify impurities (6) Metal residues: EMEA/CHMP/SWP/4446/2000

39. Setting limits for impurities

40. Setting limits for impurities • The limits must be qualified as safe. • The limits should realistically reflect batch and stability data.

41. Setting limits for impurities (2) Organic Impurities An organic impurity above the applicable ICH qualification threshold needs to be qualified.

42. Setting limits for impurities (3) If the impurity limit is greater than the ICH qualification threshold then it should be qualified: • Through toxicological trials. • 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. • 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.

43. Setting limits for impurities (4) • The limit for any unspecified impurity should be at the ICH identification threshold. • The limit for total impurity content should reflect batch data. • These concepts are applicable to synthetic APIs, but could be used on a case by case basis for semi-synthetic APIs.

44. Setting limits for impurities (5) Genotoxins:EMEA/CHMP/QWP/251344/2006 • Are considered unsafe at any level. • A limit for a genotoxin with an understood toxicity can be calculated based upon the known PDE. • A limit for a genotoxin without sufficient toxicity information must determine based upon a TTC of 1.5ug/day. Max limit = TTC/maximum dose. • Levels above this limit need to justified toxicologically. • Limits for genotoxins like aflatoxins, N-nitroso-, and azoxy-compounds are considered so toxic they must be justified using toxicological study data. TTC = Threshold of Toxological Concern

45. Setting limits for impurities (6) Residual solvents ICH limits apply – Q3C(R4) • Class I solvents – See table 1, Q3C(R4) • Class III solvents – 5000 ppm is acceptable without further justification; might be controlled by LOD (0.5%) • Class III solvent limits above 5000 ppm are permissible, but it would tend to indicate poor manufacturing control.

46. Setting limits for impurities (7) Class II solvents – 2 methods for calculating limits • Option 1 – Table of Q3C(R4) - predefined limits. Good for APIs and FPPs • Option 2 – A limit based upon the calculated total exposure to the solvent in the FPP.

47. Setting limits for impurities (8) For instance: Acetonitrile • The option 1 limit is 410 ppm based on a PDE of 4.1 mg/day. • The option 2 limit allows potentially a limit higher than 410 ppm. • Option 2 permits up to 4.1 mg of acetonitrile in the FPP. • The limit of 410 ppm may be exceeded in the API provided the total amount of residual acetonitirile in the FPP does not exceed 4.1 mg.

48. Setting limits for impurities (9) This can lead to API manufacturers justifying limits like this: Acetonitrile (PDE 4.1 mg/day) in zidovudine (300 mg per day) Using the ICH formula: Max limit = 1000 x 4.1/0.3 = 13,660 ppm (seems a little excessive).

49. Setting limits for impurities (10) BUT "provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing standards." – ICHQ3C(R4) Basically, we might accept 1000 ppm (i.e. >410 ppm) if supported by batch data, but not 20 times this value. Also, option 2 applies to the total amount of solvent in the FPP. If the amount of solvent in the API is excessive it may cause problems for the setting FPP limits.

50. Setting limits for impurities (9) Metal residues: EMEA-CHMP-SWP-4446-2000