USP <467> Residual Solvents and VICH GL 18

1. USP <467> Residual Solvents and VICH GL 18 CVM/GADA Quarterly Meeting January 15, 2008

2. Talk Outline • Background on USP <467> and VICH GL 18 • Information to be provided by manufacturers of APIs and Excipients • Information to be provided in ANADAs

3. USP General Chapter <467> Residual Solvents: Basics • Official on July 1, 2008 • Replaced USP <467> Organic Volatile Impurities • USP <467> based closely on ICH Q3C Guidance – Impurities: Residual Solvents (1997) • Applicable to ANADAs and NADAs. • Implemented via USP/NF General Notices • Not referenced in any USP or NF monograph, but is applicable to all USP compendial products

4. USP General Chapter <467> Residual Solvents: Basics • Three notable differences exist between USP <467> and VICH GL 18. • Residual solvent (RS) limits (2) • Option 3 for calculating acceptable RS limits • RS limits directly apply only to finished drug products (DP). • DP conformance can be based on residual solvent content of DP components [i.e., drug substance(s) and excipients]. • APIs and excipients are also within the scope of USP <467> and VICH GL 18.

5. Residual Solvent Classes in USP <467>/ VICH GL 18 • 4 Classes of RS based on toxicity: • Class 1 – Highest toxicity; should be avoided in all drugs • Class 2 – Less toxic, should be limited in all drugs • Class 3 – Low toxicity; generally deemed safe to 0.5% (5000 ppm) • Other Solvents (“Class 4”) – no adequate toxicological data is available

6. Options for Determining Compliance with RS Limits: 1 • Option 1(concentration limits, ppm) for Class 1, 2, & 3 RS • Applied to DP components (API, Excipients) • For products administered in doses of 10g or less per day • Class 1 RS limits are listed in Table 1 • Class 2 RS limits are listed in Table 2 • Class 3 RS limit is 0.5% or 5000 ppm • If DP components meet the RS limits listed in Tables, then DP meets the test criteria – valid for dose up to 10 grams per day product mass

7. Options for Determining Compliance with RS Limits: 2 • Option 2 (permitted daily exposure/PDE) for Class 2 & 3 RS • Used when Option 1 RS limits are exceeded, or daily dose exceeds 10 g • Daily Exposure is calculated, based on cumulative RS content of allcomponents • If calculated Daily Exposure is NMT PDE, DP meets Option 2 • Class 2 PDE Limits: Table 2 • Class 3 PDE Limits: 50 mg/day • Option 2 not generally applicable to Class 1 RS (no PDE established)

8. Concentration = 1000 x PDE (mg/ day) Dose (g/ day) Concentration = 1000 x 4.1 mg/ day = 410 ppm 10 g/ day Example of the use of Option 1 and Option 2 to determine RS limits: Acetonitrile • The PDE or Option 2 limit of acetonitrile is 4.1 mg/ day. • The Option 1 limit of acetonitrile is 410 ppm (based on 10 g/ day maximum daily dose).

9. Example 1 of the use of Option 1 and Option 2 to determine RS limits: Acetonitrile • Drug product 1 has max daily dose of 5.0 g. • Drug product 1 contains 2 excipients. • Only excipient 1 meets the Option 1 limit, but the drug product meets the Option 2 limit of 4.1 mg/ day and thus drug product 1 conforms.

10. Example 2 of the use of Option 1 and Option 2 to determine RS limits: Acetonitrile • Drug product 2 has max daily dose of 5.0 g. • Drug product 2 contains 2 excipients. • Drug product 2 meets neither the Option 1 or Option 2 limit.

11. Option 3 – VICH GL 18 only • Higher levels for the PDE and concentration limit can be justified based upon: • actual daily dose • target species • relevant toxicological data • consideration of consumer safety aspects • This option will be approved on a case by case basis. This option will be approved in rare instances and requires consultation with the Target Animal Divisions and the Generic Animal Drug Team. • In exceptional cases the manufacturer could provide a summary of efforts made to reduce the solvent level to meet the guideline value (including toxicological data), as well as a risk-benefit analysis to support allowing the product to be utilized with residual solvent at the higher level.

12. Options for Determining Compliance with RS Limits: 4 • The finished drug product can be tested directly for residual solvents.

13. Class 1 Solvents: General Requirements • Sponsors should avoid the use of Class 1 solvents wherever possible. • If Class 1 Solvents are used: • All Class 1 solvents likely to be present* in DP components should be identified and quantified. • DP component manufacturer (API, excipients) should report Residual Solvent concentrations to the DP manufacturer/applicant. * Likely to be present refers to solvents used or produced in the final manufacturing step and to solvents that are used or produced in earlier manufacturing steps and not removed consistently by a validated process.

14. Class 2 Solvents: General Requirements • Use of Class 2 Solvents should be limited wherever possible. • If Class 2 solvents are used: • All Class 2 solvents likely to be present in DP components should be identified. • Option 1 may be applied if all DP components are demonstrated to have RS concentrations below the Table 2 limits. • Component RS concentrations should be reported if Option 1 limits are exceeded.

15. Class 2 Solvents: General Requirements (continued) • If Class 2 solvents are used (continued): • Option 2 applies when Option 1 fails • Daily Exposure calculated to determine if DP meets the PDE limits. • Option 3 as in VICH GL 18 can be used • Option 4: the DP can be tested directly for RS

16. Class 3 Solvents: General Requirements • Class 3 Solvents are considered solvents with low toxic potential. • Loss on Drying (LOD) method can be used to demonstrate that DP component meets Option 1 limit of NMT 0.5% (5000 ppm). • All Class 3 solvents likely to be present at greater than 0.5%(5000 ppm)should be identified and reported. • USP method or other validated analytical method can be used to quantify RS • Option 2 (PDE NMT 50 mg/day for DP) can be applied.

17. Information to be provided by manufacturers of APIs and Excipients

18. Recommended Information for an API/ Excipient Manufacturer’s Statement Regarding RS • The identity and amount of all Class I solvents used or generated • The identity and amount of all Class 2 solvents “likely to be present”. • If Class 3 solvents are “likely to be present” at less than or equal to 0.5% (LOD) • If Class 3 solvents are present at greater than 0.5%, the identity of those solvents should be provided and the amount of the RS should be quantified. • All other solvents “likely to be present”

19. Recommended Information for an API/Excipient Manufacturer’s Statement Regarding RS (cont.) • The expected specifications for all solvents likely to be present in the API or excipient should be provided. • The API/Excipient vendor can provide a statement that no solvents were used (or produced) during manufacture of the ingredient if applicable. • For nonfunctional coating materials, colorants, and flavors, testing of residual solvents present in any ingredient of the component is not necessary.

20. Examples of Acceptable Statements in the Vendor COA • Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5 percent. • Only Class 2 solvents X and Y are likely to be present. (Here the excipient manufacturer would name the Class 2 solvents represented by X and Y and provide the concentrations of solvents X and Y.) • Only Class 2 solvents X and Y and Class 3 solvents are likely to be present. Residual Class 3 solvents are below 0.5 percent. Here the excipient manufacturer would name the Class 2 solvents represented by X and Y and provide the concentrations of solvents X and Y.) • No Class 1, Class 2, Class 3, or other solvents are used.

21. Residual Solvent Reporting in an ANADA

22. General guidelines • All ANADAs are required to comply with USP <467> if they are the subject of an official USP monograph. If they are not the subject of an official USP monograph, CVM recommends conformance to VICH GL 18.

23. Residual Solvents in ANADA: CVM • For all ANADAs and applicable ANADA supplements submitted after 7/1/2008, sponsors should provide information in the application to show compliance with USP <467>/ VICH GL 18, as well as verificationof any excipient manufacturer’s statements used to support compliance before approval. • For all ANADAs approved prior to 7/1/2008, ANADA sponsors should submit information demonstrating compliance with USP <467>/VICH GL 18 in an annual report. • Prior approval supplement required if RS exceed Option 1 and Option 2 limits. • For ANADAs pending in the queue, sponsors should submit information demonstrating compliance with USP <467>/VICH GL 18 as an amendment. We will not reset the clock for these amendments.

24. Residual solvents in ANADAs: CVM • Differences from USP classifications should be justified for USP compendial products. However, if there are differences in residual solvent classifications between USP <467> and VICH GL 18, CVM will continue to accept the justification that the RS limits conform to VICH GL 18.

25. Significant Differences between USP <467> and VICH GL 18 • Tetrahydrofuran (THF) • USP <467>: Class 2 solvent with a PDE of 7.2 mg/day, concentration limit of 720 ppm • VICH GL18: THF is classified as a Class 3 solvent • N-methylpyrrolidone (NMP) • Class 2 in both USP and VICH GL18 • Acceptable limits differ between the 2 guidelines • USP <467>: PDE of 5.3 mg/day, concentration limit of 530 ppm • VICH GL18: PDE of 48.4 mg/day, concentration limit of 4840 ppm

26. Residual Solvent information to be included in an ANADA • Finished product specification stating compliance with USP <467>/ VICH GL 18. • For each excipient used in the formulation, information in the submission should include: • Excipient manufacturer’s statement regarding residual solvents. • ANADA sponsor's verification of excipient manufacturer’s statement using USP method or other validated method. • For each Residual Solvent used by the API/ excipient manufacturer or used by the ANADA sponsor: • A statement that indicates which option was used to demonstrate compliance with USP <467>/ VICH GL 18 and a summary of the appropriate calculation used • The results of any Residual Solvent testing on the drug product if applicable

27. Verifying an API/ Excipient Manufacturer’s RS Statements • Residual solvents testing should be included as a part of the complete testing procedure in order to demonstrate the capability to perform the tests and to verify the excipient manufacturer’s data for each identified RS. • Once the sponsor validates and verifies the API/ excipient manufacturer’s data, the ANADA sponsor can implement a valid vendor validation program as per 21 CFR 211.84(d)(2).

28. Verification of an API/ Excipient Manufacturer’s RS Statements • Dependence by the ANADA applicant on vendor statements and/or vendor COAs that USP <467>/ VICH GL 18 is met, without verification by the applicant, does notdemonstrate compliance and will be considered a deficiency. • Exception for “solvents not used” statement • Statements of compliance with <467> should include all solvents likely to be present, including those not Class 1, 2, or 3

29. Control of Residual Solvents: Summary • Residual solvents should be controlled in all drug products. • USP <467> or VICH GL18 are applicable to generic animal drug products. • Drug product manufacturers/applicants are responsible for reporting/documenting their control measures for Residual Solvents and for verifying the Residual Solvent information that they receive from their API and excipient suppliers.