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Introduction: USP Mission

Interpretation of the New USP General Chapter <467> Residual Solvents Chair: USP Residual Solvents Project Team Thomas E. Chapman, Ph.D. Allergan Inc. USP-WCDG August 1 st , 2008. Introduction: USP Mission.

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Introduction: USP Mission

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  1. Interpretation of the New USP General Chapter <467> Residual Solvents Chair: USP Residual Solvents Project TeamThomas E. Chapman, Ph.D.Allergan Inc.USP-WCDG August 1st, 2008

  2. Introduction: USP Mission • “The United States Pharmacopeia promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other health care technologies, and related practices used to maintain and improve health and promote optimal health care delivery.”

  3. History: Residual Solvents “…..residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.” ICH, USP, EP [Note: “residual solvents” refers to the amount not removed during the purification of the product”]

  4. Residual Solvents • Residual solvents are one of the three main types of impurities in pharmaceutical articles, the other two being organic and inorganic impurities. • Therefore, standards to control the strength, quality, and purity of official pharmaceutical articles in the United States Pharmacopeia (USP) and the National Formulary (NF) frequently include a test for residual solvents, together with procedures for the test and acceptance criteria.

  5. Residual Solvents • The implementation of modern standards to control these types of impurities has occupied regulatory agencies, pharmaceutical manufacturers, and pharmacopeias for many years. • Substantial progress in the overall effort came with development of the ICH Q3C Guideline in 1997 (Impurities: Guideline for Residual Solvents) and subsequent adoption of this Guideline as a FDA guidance.

  6. ICH Q3C and EP • ICH Q3C • Published in July 1997 • Revised in 2002 • EP adopts the ICH Q3C guideline in 1999. • General Chapter 5.4. An introductory paragraph and reproduces the ICH Guideline • Chapter 2.4.24 Identification and control of residual solvents (Test methods for Class 1, 2 and 3 Residual Solvents)

  7. <467> Organic Volatile Impurities • Individual monographs specify which <467> method to follow. • Residual solvents controlled: Chloroform (60 ppm), Dioxane (380 ppm), Methylene Chloride (600 ppm) and Trichloroethylene (80 ppm) • Four methods: I, IV, V, and VI • Standards: reagent grade solvents • Direct injection or Headspace (Method IV) • Column: G27 (Method I), G43 (Methods IV and V), various supports and coatings (Method VI) • Dissolving solvent: “water or the solvent specified in the monograph”

  8. USP: Residual Solvents • USP incorporates ICH Q3C classification and evaluation system and EP procedures • USP was not consistent with Q3C Impurity guideline (1997) • First proposal to amend General Chapter <467> and General Notices published in PF 29(4), 2003

  9. USP: Residual Solvents General Notices and Requirements statement: ….”all drug substances, excipients, and products are subject to relevant control of residual solvents”…….. Monograph Changes • <467>OVI: Removed

  10. USP 29-NF 24 General Notices Text “ Residual solvents – The requirements are stated in Residual solvents <467> together with information in Impurities in Official Articles <1086>. Thus all drug substances, excipients, and products are subject to relevant control of residual solvents, even when no test is specified in the individual monograph. The requirements have been aligned with the ICH guideline on this topic. If solvents are used during production, they are of suitable quality. In addition, the toxicity and residual level of each solvent are taken into consideration, and the solvents are limited according to the principles defined and the requirements specified in Residual solvents <467>, using the general methods presented therein or other suitable methods. (Official July 1, 2008)

  11. Residual Solvents <467>: Main Points • Driving force: Safety of the patient; recommends use of less toxic solvents • Testing is to be performed only for solvents “likely to be present” • used or produced in the final manufacturing step • used in previous steps and not removed by a validated procedure • The limits for acceptable concentrations listed in the Chapter are for drug products, not for its components.

  12. Residual Solvents <467>: Main Points, continued • The concentration in the drug product may be • calculated from the contributions of components • determined experimentally; mandatory if • solvents are used in its manufacture • cumulative calculation exceeds limits • Manufacturers of drug products may rely on data provided by the suppliers of components • Provides unambiguous identification and quantification methods

  13. Residual Solvents <467>: Main Points, continued • Includes options to allow use of materials that exceed the limits established. • “The procedures described in this general chapter are to be applied wherever possible. Otherwise, manufacturers may select the most appropriate validated analytical procedure for a particular application.” (ICH and EP take similar approach) (see <1225>Validation of Compendial Procedures). • Submission of alternative methods is not required

  14. Risk-based classification of solvents Three classes of solvents: Class 1 – Unacceptable toxicities; should be avoided, unless their use can be strongly justified in a risk- based assessment. Class 2 – Less severe toxicities; should be limited. Class 3 – Less toxic; should be used where practical. • [Note: Other solvents may be used but only after approval from a regulatory agency.]

  15. Establishing Exposure Limits (Appendix 3 in the General Chapter) • Permitted Daily Exposure (PDE) derived from the No-observed-effect level (NOEL) in animal studies. • For Class 1 solvents, exposure limits were determined using a large safety factor (10,000 to 100,000) • For Class 2 solvents, PDE was calculated from NOEL, weight adjustments, and correction factors (e.g. extrapolating between species and accounting for variability between individuals)

  16. Limits of Residual Solvents • Class 1: concentration limits, in ppm, are provided in a Table. They should not be exceeded “unless otherwise stated in the individual monograph.” • Class 2: concentration limits are to be calculated from PDE with the formula: Concentration (ppm) = 1000 PDE/dose, where PDE is in mg/day and dose is in g/day A table is provided, to be used when the daily dose is 10 g or less, or when the daily dose is not known or fixed. • Class 3: PDE is 50 mg/day (“unless otherwise stated in the individual monograph.”), corresponding to a concentration of 0.5% for daily doses of 10 g or less

  17. Limit of Residual Solvents: Class 1 • Class 1 Residual Solvents (Table 1): Should not be used in the manufacturing of drug substances, excipients or drug products because of unacceptable toxicities or deleterious environmental effects of the residual solvents. • However if their use is unavoidable, their levels should be restricted as shown in Table 1.

  18. Table 1. Class 1 Residual Solvents

  19. Limit of Residual Solvents: Class 2 • Class 2: 26 solvents • Class 2 Residual Solvents: should be limited in drug substances, excipients, and drug products because of their inherent toxicities. • Their levels should be restricted as shown in Table 2. Concentration limits (ppm) vary between 50 (methylbutylketone) and 3880 (cyclohexane). • When Class 2 residual solvents are used (or produced) in the manufacturing or purification process, they shouldbe identified and quantified

  20. Table 2. Class 2 Residual Solvents

  21. Options for Determining Levels of Class 2 Residual Solvents in Drug Products Option 1: All the components of the drug product (drug substances and excipients) meet the concentration limits (ppm) listed in Table 2, and the daily dose does not exceed 10 g: drug product passes. Option 2: At least one of the components of the drug product exceeds the concentration limits (ppm), or the daily dose exceeds 10 g: the daily exposure to a solvent (calculated as the sum of the components contributions) should be less than the PDE (mg).

  22. Example 1: Option 1 and Option 2, with acetonitrile • PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). • 5.0 g drug product/day. Composed of two excipients • Excipient 1 meets Option 1 limit of 410 ppm. • Drug substance, excipient 2, and drug product do not meet Option 1 limit of 410 ppm. • Drug product however, does meet Option 2 limit of 4.1 mg/day.

  23. Example 2: Option 1 and Option 2, with acetonitrile • PDE acetonitrile = 4.1 mg/day, thus Option 1 limit is 410 ppm (from Table 2). • 5.0 g drug product/day. Composed of two excipients • Drug product does not meet Option 1 limit (410 ppm) or Option 2 limit (4.1 mg/day). • Manufacturer could test to see if manufacturing reduced the level of acetonitrile in the drug product below 410 ppm; if so it passes.

  24. Limit of Residual Solvents: Class 3 • Class 3: 28 solvents • Less toxic and of lower risk to human health • Unless otherwise stated in the individual monograph, PDE is nmt 50 mg/day, corresponding to a concentration limit of 5000 ppm for daily doses not greater than 10 g of product. • Use Loss on Drying in NMT 0.5%. • If the monograph allows for a concentration resulting in more than 50 mg/day, Class 3 solvents must be identified and quantified.

  25. Table 3. Class 3 Residual Solvents

  26. Analytical Procedures (ICH, EP) • ICH: “Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure . . .” • EP: “. . . The methodology in the general analytical method (2.2.24) is to be applied wherever possible. Otherwise an appropriate validated method is to be employed.”

  27. Analytical Procedures (USP) • USP: • “. . . The procedures described in . . . This general chapter are to be applied whenever possible. Otherwise manufacturers may select the most appropriate validated analytical procedure for a particular application . . .”

  28. Identification, Control, and Quantitation of Residual Solvents • Class 1 and Class 2 Residual Solvents • Procedure A-Identification and Limit Test • Procedure B-Confirmatory Test • Procedure C-Quantitative Test • Class 3 Residual Solvents • LOD, followed if necessary by Gas Chromatography analysis if it exceeds 0.5%

  29. Rationale for Two Procedures • Procedure A and B are orthogonal approaches • Co-elutions occur in both procedures, but • Co-eluting peaks in Procedure A are resolved in Procedure B, and vice versa • Final quantification by Procedure C

  30. Decision Tree yes no yes no

  31. Decision Tree, continued no no yes yes yes no

  32. USP Method Specifics: Procedure A • Headspace • G43 capillary GC column: 6% cyanopropyl phenyl-94% dimethylpolysiloxane • 0.32 mm x 30m, 1.8 µm • 0.53 mm X 30m, 3.0 µm • Split ratio: 1:5 • Oven 40oC: 20 mins • 10oC/min to 240oC, 20 mins • Injector temp: 140oC • FID temp: 250oC

  33. USP Method Specifics Head Space Operating Parameters

  34. USP Method Specifics: Procedure A, Continued • System Suitability: • Class 1 Standard Solution • Signal-to-Noise (S/N): 1,1,1 trichloroethane NLT 5 • Class 1 System Suitability Solution • Signal-to-Noise (S/N): All peaks NLT 3 • Class 2 Mixture A Standard Solution • Resolution: Acetonitrile and methylene chloride NLT 1.0.

  35. USP Method Specifics: Procedure A,continued • Procedure: • Class 1 Standard Solution • Class 2 Mixture A Standard Solution • Class 2 Mixture B Standard Solution • Test Solution • If a peak response of any peak in the Test Solution is greater or equal to a corresponding peak in either the Class 1 Standard Solution, Class 2 Mixture A, or B Standard Solutions, proceed to Procedure B to verify the identity of the peak, otherwise the article meets the requirements of this test.

  36. USP Method Specifics: Procedure B • Only run Procedure B, to confirm procedure A • If the peak response(s) in the Test Solution in the peaks identified in Procedure A is/are greater than or equal to a corresponding peak(s) in either the Class 1 Standard Solution, Class 2 Mixture A, or B Standard Solutions, proceed to Procedure C to quantify the peak(s), other wise the article meets the requirements of this test.

  37. Preparations for Procedure C • Same as for Procedure A (If results from Procedure A are inferior to B, use Procedure B conditions ), plus • Standard solution(s) – for each peak identified and verified by Procedures A and B by dilution of the respective USP Residual Solvent Reference Standard • Spiked Test Solution – mixture of Test Solution and Standard solution

  38. Method Specifics: Procedure C, continued Calculate the ppm of each residual solvent: =5(C/W)[ru/(rst-ru)] C= Concentration in ppm of USP Standard W=Weight in g of test article ru =peak response of RS in the Test Solution rst =peak response of RS in the Spiked Test Solution (allows for recovery issues).

  39. Residual Solvents Class 1 – Procedure A

  40. Residual Solvents Class 1 – Procedure B

  41. Residual Solvents Class 2A – Procedure A • 1 Methanol 8 Methylcyclohexane • 2 Acetonitrile 9 1,4-Dioxane • 3 Dichloromethane 10 Toluene • 4 Trans-1,2-Dichloroethene 11 Chlorobenzene • 5 Cis-1,2-Dichloroethene 12 Ethylbenzene • 6 Tetrahydrofuran 13 m-xylene, p-xylene • 7 Cyclohexane 14 o-xylene

  42. Regulatory Aspects-1 21 Code of Federal Regulations Parts 210 and 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS 21 CFR 211. 194 (a) (2) - A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. (If the method employed is in the current revision of the United States Pharmacopeia, National Formulary, AOAC INTERNATIONAL, Book of Methods, or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice). The suitability of all testing methods used shall be verified under actual conditions of use. http://www.fda.gov/cder/dmpq

  43. Regulatory Aspects-2 FDA Statement-OGD • All drug substances, excipients, and products are subject to relevant control of residual solvents, even when no test is supplied in the individual monograph. • Starting July 1, 2008: • Any new ANDA must provide information and data as necessary to demonstrate control of residual solvents prior to approval or tentative approval. • ANDA’s currently under review but not approved by July 1, 2008, must also contain this information and data. • Residual Solvent information and data for approved products should be submitted in the next annual report for the ANDA. http://www.fda.gov/cder/ogd/ResidualSolvents.pdf

  44. Regulatory Aspects-3 FDA Statement OGD-Continued • Ensure that all Drug Substance and excipients must have limits (ppm) that fall within ICH Q3C (option 1) limit or , • Ensure that all Drug Substances and excipients weighted by their amount in the drug product, result in a cumulative daily exposure for residual solvents (PDE) that falls within the ICH Q3C (option 2) limit or , • Ensure via direct testing of the drug product, that the total Daily Exposure falls within ICH Q3C (option 2) limit. http://www.fda.gov/cder/ogd/ResidualSolvents.pdf

  45. Regulatory Aspects-4 FDA Statement OGD-Continued • Sponsors include a commitment to re-assess suppliers if a new vendor is chosen. • Although above statements are for compendial materials in the USP, the OGD expects ANDA’s for products not official in the USP to contain information and data that assures safe levels of residual solvents in the drug product consistent with USP <467>. http://www.fda.gov/cder/ogd/ResidualSolvents.pdf

  46. Supplier/End-User • USP <467> Limits in Excipients • Limits are not specifications for each excipient. • If C of A states levels well below ICH Q3C, FDA expects if this is tested by end-user that specifications will be set there too. • Some excipients used as drug products. • Manufacturer of drug product has to calculate, based upon limit and PDE.

  47. Supplier • Generally, Class 1 Solvents such as benzene are no longer being used in producing excipients. • Many produced with Class 2 or 3. • Eliminating or lowering solvent levels may change quality and performance for certain functions. • Take advantage of USP calculation option, i.e PDE rather than limit (ppm).

  48. Supplier and C of A • Need information exchange between user and supplier. • However there are confidentiality concerns. • Trust needed between two parties • A supplier audit may be needed, GMP concern for regulatory department and FDA. • Not just rely on C of A. • The C of A may not specify what residual solvents are present or cite meets ICH Q3C guidelines. • Screening then needed

  49. Contract Lab • Perform Residual Solvent testing per USP. • Can also screen with GC/MS • Co-elution not a problem • Use qualifier ions in SIM mode • Release testing: • GC/MS, however is not the USP <467> method, and as such would have to be validated if it is to be used as a release assay.

  50. Future of <467> • USP may revise the chapter in response to additional comments received regarding the analytical method. • USP has not discussed separating methods in <467> to a separate chapter. (Similar to Ph Eur) http://www.usp.org/USPNF/notices/faq.html

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