USP “Hot Topics” - USP <467> Residual Solvents, USP Glycerin Monograph , and More! WDCG/AOAC-SCS Joint Confere

1. USP “Hot Topics” - USP <467> Residual Solvents, USP Glycerin Monograph, and More! WDCG/AOAC-SCS Joint Conference December 4, 2008 FDA at Irvine, CA Larry A. Ouderkirk Director – Compendial Operations Staff FDA/CDER/OPS-IO Silver Spring, MD

2. Presentation Outline • USP <467> Residual Solvents (RS): Update • Updated Overview: USP <467> and ICH Q3C • CDER Residual Solvents Draft Guidance of 8/6/08 • Office of Generic Drugs (OGD) Website Update 10/28/08 • Summary and Future Plans • USP Glycerin Monograph Revision: Update • USP Revision Announcement of 11-21-08 • Additional USP Updates • New USP Certified Reference Materials (CRM) • USP-NF Monographs Redesigned for USP33/NF28 (2010) • Web-based Pharmacopeial Forum (PF) coming in 2009 (and it’s free!) • FDA Interactions with USP: FDA Staff Manual Guide Requirements • Changes to SMG and their Impact on FDA-USP Interactions

3. Overview • USP General Chapter <467> Residual Solvents – • Official on July 1, 2008 • Applies to all compendial drug products marketed in the US • NDAs, ANDAs, OTCs, and Unapproved drug products • Replaces USP <467> Organic Volatile Impurities • <467> RS implemented via USP/NF General Notices • <467> RS is not referenced in any USP or NF monograph • FD&C Act, Sec. 501 (b) – [A drug or device shall be deemed to be adulterated] If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium.

4. Overview • USP <467> is based closely on ICH Q3C Guidance for Industry – Impurities: Residual Solvents (Dec. 1997) • ICH Q3C still in effect for NDA/ANDA non-compendial DP • USP <467> RS limits are identical to those in ICH Q3C • RS limits directly apply only to finished drug products (DP) • DP itself may be directly tested, or, in most cases: • DP conformance can be based on residual solvent content of DP components [i.e., drug substance(s) and excipients]. • Therefore, in this sense, APIs and excipients are also within the “scope” of USP <467> and ICH Q3C

5. Overview: USP <467> vs. ICH Q3C Notable Differences between USP <467> and ICH Q3C : Regulatory Impact: • USP <467> – Is a mandatory drug product standard per FD&C Act. • ICH Q3C – Is a guidance/recommendation; non-enforceable (unless included in NDA or ANDA specification). Scope of Products Affected: • USP <467> – Applies to all drug products (NDAs, ANDAs, OTCs, and unapproved drugs) with USP monographs • ICH Q3C – Was applied generally to NDA/ANDA DP approved after 1997; was not made retroactive to cover pre-1997 DP Analytical: • USP <467> – Includes analytical methods (based on EP methods) • ICH Q3C – Does not include analytical methods

6. Overview: Residual Solvent Classes • <467>/Q3C list three 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 5000 ppm or 0.5% • Other Solvents (“Class 4”) – No Adequate Toxicological Data

7. RS Limits for Drug Products Determining DP Compliance with RS Limits: • Option 1 (concentration limits, ppm) for Class 1, 2, & 3 RS • Usually applied to DP components (API, Excipients) • If DP components meet the RS limits listed in Tables (valid for dose up to 10 grams per day product mass), then DP meets the test criteria* • Option 1 limits can also be applied to finished DP *Note: Use of Class 1 solvents must always be justified, even if limits are met

8. RS Limits for Drug Products Determining Compliance with RS Limits [con’t.] • Option 2 (Permitted Daily Exposure/PDE) for Class 2 & 3 RS: • Used when DP component(s) exceed Option 1 RS limits, or DP daily dose exceeds 10 g • A Daily Exposure is calculated, based on cumulative RS content of all components; If Daily Exposure NMT PDE, then DP meets Option 2 • Option 2 cannot be applied to Class 1 RS (no PDE is established) • “Option 3” – Finished drug product can be tested directly for RS: • Option 3/DP test should always be used if a solvent was used in the DP manufacturing process • DP RS levels should be below Option 1 limits • If Option 3 fails, then “other steps” should be taken by applicant to reduce RS concentration in DP

9. Class 1 Solvents – General Requirements • Class 1 Solvents (to be avoided): • Use of Class 1 solvents should be justified by applicant • Alternative solvents of lower toxicity should be evaluated • Class 1 solvents used or generated in DP components should be identified and quantified • DP component manufacturer (API, excipients) should report Class 1 solvent specifications and data to the DP manufacturer/applicant • With justification, Option 1/Table 1 concentration limits (ppm) can be applied to DP components, or finished DP • Option 2 (PDE) may not be applied to Class 1 RS

10. Class 2 Solvents – General Requirements • Class 2 Solvents (to be limited): • All Class 2 solvents likely to be present in drug product components should be identified. • Option 1 may be applied if all DP components are demonstrated to have RS concentrations below Table 2 limits. • Component RS concentrations must be reported if Table 2 limits are exceeded. • Preferred Reporting Method: Component supplier’s COA • Also acceptable: Supplier’s statement on Residual Solvents • DP Manufacturer: Is responsible for verifying the RS information supplied by the component manufacturers • Option 2 (PDE) may be applied to DP if Option 1 is not met’ • “Option 3” (direct DP testing) may also be applied

11. Class 3 Solvents – General Requirements • Class 3 Solvents (low toxicity): • All Class 3 solvents likely to be present should be identified if they exceed the Option 1 limit of NMT 5000 ppm or 0.5%. • Loss on Drying (LOD) method can be used to demonstrate that DP component meets Option 1 limit • OGD states that LOD test for Class 3 RS can be used even if Class 2 RS are also present, provided that: • Total of both Class 2 and Class 3 RS are NMT 0.5% LOD, provided that “suitable controls” are in place for Class 2 RS likely to be present • If Option 1 limit of NMT 5000 ppm/0.5% is exceeded, Option 2 (PDE NMT 50 mg/day for DP) can be applied

12. Responsibility for Reporting RS Reporting/Documentation of Solvents (all classes): • Drug product sponsors are responsible for: • Quality and safety of their drug products • Reporting all required RS information to their NDA/ANDA • Keeping comprehensive, accurate records and documentation of compliance with all applicable GMP and other regulations • DP manufacturer can test DP components for RS themselves, or • Rely on analysis or certification supplied by the API/excipient supplier, provided that: • The DP manufacturer establishes the reliability of such analyses/certification, through verification at appropriate intervals

13. Responsibility for Reporting RS • Verification of Vendor Statements: • DP Sponsor tests the components as part of a testing protocol to demonstrate capability to perform the tests and to verify the component manufacturer’s data for each identified solvent. The DP sponsor can then implement a vendor validation program per 21 CFR 211.84(d)(2), OR, • Excipient manufacturers or DP sponsors can submit evidence that the level of process understanding and control are sufficient to conclude that the acceptance criteria will always be met, provided the process is run within the range of the critical parameters (Quality by Design/Process Analytical Technology concepts).

14. CDER Draft Guidance on RS Issued by CDER on August 6, 2008 • Title: Residual Solvents in Drug Products Marketed in the US • CDER Website: http://www.fda.gov/cder/guidance/8179dft.htm • Guidances are FDA’s “current thinking” - not enforceable by law, except for those portions that reference laws/regulations (CFR, FD&C Act, etc). • Draft Guidance outlines, in general terms, how to comply with USP <467>/ICH Q3C for the following three (3) regulatory classes of drug products:

15. CDER Draft Guidance on RS • Compendial Drug Products Approved Under an NDA/ANDA • Compliance with USP <467> (per FD&C Act) is mandatory • Non-USP <467> analytical methods can be used, if validated • Annual Reports (AR) can generally be used to report <467> compliance for approved products • Analytical data can be summarized in the AR, rather than submitted in full. Complete data should be kept on file by applicant for inspection by FDA. B. Compendial Drug Products not approved under an NDA/ANDA • Includes OTCs marketed under FDA OTC monograph and Unapproved Drug Products • Compliance with USP <467> (per FD&C Act) is mandatory • Firms should also comply with cGMPs and all other applicable regulations • Documentation of compliance should be kept on file at manufacturing site

16. CDER Draft Guidance on RS • Non-compendial NDA/ANDA Drug Products • DP should conform to ICH Q3C RS limits (identical to limits in USP <467>) • For approved products, Annual Report (AR) can generally be used to report conformance • NDA/ANDA applicants and those with NDAs/ANDAs pending approval should include information indicating ICH Q3C limits are met (identical to USP <467>), as for compendial NDAs/ANDAs

17. OGD Q&A Posting on Residual Solvents • OGD ANDA RS Update: Q&A posted 10/28/08 • http://www.fda.gov/cder/ogd/index.htm#New • Posted in response to: • Industry concerns with OGD’s earlier posting of 8/21/08 • Decisions reached after FDA-Industry meeting 10/10/08. • Attempts to align FDA implementation requirements more closely with those in USP <467> and ICH Q3C • More flexible “vendor qualification” requirements to allow for Quality by Design (QbD) concept • Allows ANDAs filed 7/1/08 – 7/1/09 to “commit” to verify excipient vendor statements on RS within 6 months of ANDA approval. Verification information submitted in “Special Report” (a type of “immediate” Annual Report)

18. Control of Residual Solvents – Summary and Future Plans Summary and Future Plans • Residual Solvents should be controlled in all drug products • USP <467> or ICH Q3C are applicable to many drug product regulatory categories, as detailed in the CDER Draft Guidance • Drug product sponsors are responsible for reporting/documenting control measures for RS and for verifying the RS information they receive from their API and excipient suppliers • FDA continues to support Quality-by-Design (QbD) concepts • Comments to the Public Docket to CDER Draft Guidance are being reviewed and will be addressed. (Many of the comments were on OGD 8/21/08 Web posting.) Revised Draft Guidance may be issued next year. • Issue of NDA/ANDA policy alignment continues to be addressed by CDER Office of Pharmaceutical Science

19. USP Glycerin Monograph/DEG Glycerin and DEG – Recent History • 1990 (Nigeria) – Acetaminophen (APAP) pediatric syrup (compounded) - 40 deaths • 1990-1992 (Bangladesh) – APAP pediatric syrup (compounded) - 339 deaths (estimated) • 1995-1996 (Haiti) – APAP cough syrup - 80 deaths • 2006 (Panama) – Cough/anti-allergy syrup manufactured by Panamanian government – 46 deaths • 2007 (US) – Imported toothpaste from China labeled to contain sorbitol actually contained up to 5% DEG • Criminal charges brought against US importer and distributor by Los Angeles City Attorney’s Office

20. USP Glycerin Monograph/DEG USP Glycerin Monograph History: • Limit of DEG and Related Compounds (DEG Limit Test) • Added in late 1990s, after Haiti deaths • Gas Chromatography Method – NMT 0.1% DEG, NMT 0.1% any other impurity, NMT 1.0% total impurities (including DEG) • Glycerin Identification Test B – References the test for Limit of DEG and Related Compounds • “…the retention time of the glycerin peak in the chromatogram of the Diluted test solution corresponds to that obtained in the chromatogram of the Diluted resolution solution.”

21. USP Glycerin Monograph/DEG • 4/13/07 - FDA Letter to USP • Concern over USP Glycerin Identification Test – Detection and quantification of DEG not clearly required • Under GMPs, ID testing must be performed by manufacturers for materials acceptance • If DEG testing not part of ID test, then it may not be performed, possibly permitting acceptance of adulterated Glycerin • FDA Glycerin-DEG Guidance will reference USP monograph ID test • FDA requested USP to incorporate DEG Limit Test into the ID Test, or modify ID Test to specifically limit DEG to NMT 0.1%, per DEG Limit Test

22. USP Glycerin Monograph/DEG • FDA Guidance for Industry: Testing of Glycerin for DEG (May 2007) - Recommendations: • Firms perform glycerin ID test that includes limit test for DEG (NMT 0.1%), per cGMPs, on each container of Glycerin received • Reliance on COA is not sufficient to ensure quality of glycerin • USP monograph test or equivalent (TLC, etc.) • Drug product firms should verify chain-of-custody for glycerin • Re-packers should test glycerin for DEG • Firms should train manufacturing production staff to ensure that they understand importance of DEG testing • Pharmacies that use glycerin in compounding should test for DEG or verify that testing has been done by reliable source

23. USP Glycerin Monograph/DEG • January 2008 – USP announces revised Glycerin monograph • USP Identification Test Revised: Proposed modified USP GC test for DEG and EG • Current official GC method limits DEG to NMT 0.1% • Proposed GC method for DEG/EG had limit of NMT 0.025% • Revision posted 3-17-08 with proposed official date of 5-15-08 • April 2008 – Comments from USP stakeholders • ID GC method with lower limits not suitable as screening method; prevents use of quicker, cheaper alternative methods • Industry prefers single GC screening method for DEG/EG in ID test as a limit test, with limit of NMT 0.1%

24. USP Glycerin Monograph/DEG • USP PNP Stakeholder Forum 5/15/08 • FDA wants: • USP Glycerin ID test to detect DEG • Rugged DEG method, with adequate sensitivity • Expeditious implementation of ID test revisions to protect the public health • Recent USP Actions: • Nov. 13: USP meets with FDA to discuss Glycerin revisions • Nov. 21: USP announces intent to have Glycerin ID test with limit of NMT 0.10% limit for DEG/EG) • USP will post Revision Bulletin soon, with minimum 10-wk implementation delay (http://www.usp.org/hottopics/glycerin.html?hlc

25. USP Certified Reference Materials USP Certified Reference Materials (CRM) • USP CRM is a special class of USP Reference Standard (RS) • Dextromethorphan Hydrobromide CRM is now available • USP is ISO Guide 34 accredited as a Reference Material Producer (RMP) of Chemical CRMs. • CRM undergoes additional metrologically-based testing and statistical analysis, compared to RS. • CRM has a COA, listing a certified property value with associated uncertainty, expiration date, etc., according to ISO Guide 31. • USP CRM is can be used in the same way as a USP RS. • USP will have more CRMs available to purchase each year. • As CRMs become available, corresponding USP RS will be discontinued • Additional Information: http://www.usp.org/referenceStandards/faq.html#b

26. USP-NF Monograph Redesign USP Monograph Redesign: • All USP and NF monographs (>3000) are being redesigned (but not revised) • Concise Wording:New format reduces the number of words in descriptions of test procedures and other requirements • Cross-References:Common tests, procedures, and acceptance criteria in the drug substance and drug product are repeated where necessary to avoid the excessive cross-referencing in current monographs. • Uniform Format:The sections outlined for each monograph are made consistent throughout, as are typefaces and spacing, to make USP/NF uniform and easier to follow. • Consistent Language:Terminology is more consistent, reflecting current technical terms and language usage. • Preparation of solutions:Description of solutions is shortened to include the analyte, solvent, and concentration in SI units. When solvents are complex mixtures, additional description of component solutions is included. • Public Comment:Redesigned monographs posted to USP Website for 90-day public comment until March or April, 2009 (http://www.usp.org/monoRedesign/). • Redesigned Monographs: • Official in USP 33/NF 28 (5/1/10) • Proposed in PF 35-2 (March-April 2009)

27. Web-based Pharmacopeial Forum (PF) • Dec. 2008: New “Guideline on the Use of Accelerated Processes for Revisions to USP-NF” (Interim Revision Announcements (IRAs), Revision Bulletins, and Errata) will be posted to the USP Web site (www.usp.org ) to become effective in Jan. 2009. • 2009-2010: Approved IRAs and Errata continue to be published in PF, but will also be posted on the USP Web site. • 2009-2011: PF will continue as a paid, subscription-only publication (hard cover and electronic) • Jan. 2, 2011: PF will be converted to an on-line only, free publication that will contain only proposed revisions out for public comment. Other information currently contained in PF will be moved to the USP Web site or other USP publications. • Updated Info: http://www.usp.org/USPNF/pf/pfRedesign.html

28. FDA-USP Interactions: Update • The FDA Staff Manual Guide of May 22, 2007 • SMG 9100.1 - Development and Use of Standards • Describes FDA participation with non-governmental organizations, including voluntary standards-developing organizations (SDOs) • USP is a type of SDO • States that FDA Liaisons work with SDO committees (such as to USP Expert Committees and Advisory Panels) is part of employees’ official duties; therefore: • FDA Liaisons represent FDA and must express FDA consensus viewpoint rather than their personal scientific opinions • USP Rules & Procedures of the 2005–2010 Council of Experts (CoE) • Members of Council of Experts [Committee Chairs], Expert Committees, and ad hoc Advisory Panels serve USP as individual experts; they do not serve any outside interest.

29. FDA-USP Interactions: Update • Conflict between FDA & USP Policies over FDA interaction with USP Expert Committees (EC) & ad hoc Advisory Panels (AP) • Many FDA staff served as members of USP ECs or APs • FDA and USP agreed that FDA members of USP ECs/APs would be converted to FDA Liaisons (USP term: Government Liaison) • Government Liaison - representatives from FDA or other domestic or foreign government agencies who participate in an Expert Committee or ad hoc Advisory Panel in their capacity as government employees. • FDA Training held 9/15/08 for affected FDA staff • FDA Liaisons represent FDA viewpoints to EC or AP • Liaison’s work is part of employee’s official duties • FDA Liaisons sign special confidentiality agreements to receive briefing documents and participate in most discussions • Currently, there are 44 FDA Staff Liaisons to 33 USP ECs/APs

30. THANK YOU! Larry A. Ouderkirk Director, Compendial Operations Staff Program Activities Review Staff Standards and Technology Team Office of Pharmaceutical Science – Immediate Office FDA/CDER Silver Spring, MD Larry.Ouderkirk@fda.hhs.gov 301-796-1585