United States Pharmacopeia Prescription/Non- Prescription Stakeholders Forum 17 November 2006

1. United States PharmacopeiaPrescription/Non-Prescription Stakeholders Forum17 November 2006 Presentation to CVG Discussion Group 13 April 2007

2. Prescription/Non-Prescription Stakeholders Forum (PNP SF) An advisory group to the USP, enabling an exchange of information and perspectives between the USP and affected public, with the goal of improving USP standards and information

3. PNP SF Member Organizations: Calibration & Validation Group AAPS Consumer Healthcare Products Assoc FDA Generic Pharmaceutical Assoc International Pharmaceutical Excipients Council International Pharmaceutical Aerosols Consortium on Regulation and Science Midwest Compendial Discussion Group New Jersey Pharmaceutical Quality Control Assoc Parenteral Drug Assoviation PhARMA Western Compendial Discussion Group

4. Agenda of Nov 17, 2006 PNP SF • Residual Solvents • Chromatography • Uniformity of Dosage Units • Harmonized Microbiology General Chapters • USP-NF Monograph Redesign • Revised Rules and Procedures • Salt Nomenclature

5. <467> Residual Solvents • The change from OVI to Residual Solvents became official January 1, 2007 • Tests for water-soluble and –insoluble articles were revised and become official July 1, 2007 • USP continuing to improve solvent tests, e.g. comparison of “syringe” vs “transfer-line” headspace instruments

6. <467> Residual Solvents - Discussion • Class 2 solvents can exceed the ICH limits and still be used in secondary manufacturing IF the solvent evaporates in processing OR the total solvent is below the limit in the drug product • It is very challenging to validate residual solvent methods since they are used in thousands of materials. It may be more appropriate to verify the methods and make adjustments for your material as required. • However, the wording of the residual solvent methods does not allow for adjustments. • Note – many companies have internal, validated alternate methods.

7. <621> Chromatography • There are some differences between USP and EP in allowances of parameters adjustments. EP The amount of minor solvent component can be adjusted by +/- 30% relative or +/- 2% absolute May vary by +/- 0.2 pH unless otherwise stated in the monograph, or +/- 1.0 pH for neutral substances Can be adjusted by +/- 5o • USP • The amount of minor component can be adjusted by +/- 30% relative but not exceed +/- 10% absolute • Can be adjusted to within +/- 0.2 units of the value or range specified • Column temperature can be adjusted by as much as +/- 10o Attribute Mobile Phase pH of aqueous buffer Temperature

8. <621> Chromatography • Same allowances between USP and EP for: • Concentration of salts in buffers • Wavelength • Column length (GC, HPLC) • Column inner diameter (GC, HPLC) • Film thickness • Particle Size (HPLC) • Flow rate (GC, HPLC) • Injection volume • Multiple adjustments

9. <621> Chromatography - Discussion • The method may be considered changed if many parameters are adjusted at once. The FDA acknowledges that this is a tricky issue. • Stakeholders enjoy the flexibility of adjustments in chromatography • A permanent change in the method should be included in the Annual Report • Apply good science as well as compliance!

10. <905> Uniformity of Dosage Units • Revised chapter became effective on 1 January 2007 • New calculations apply to all products marketed in the US • Are you having difficulty meeting the revised limits or changing your internal procedures? • This subject will be discussed at the PNP SF in May 2007.

11. <905> Uniformity of Dosage Units • With respect to the ICH DG pending change for CU limits to be lowered to 2%, the FDA will continue to require CU test for all dosage forms with active content of <25%/25mg. • The may lead to a difference in what is published in the USP and what the FDA will accept.

12. Harmonized Microbiology General Chapters • The following revisions will be postponed until May 1, 2009 • <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests • <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms • <1111> Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use • Note – FDA demands that drug products are free of all objectionable organisms (not just USP specified organisms)

13. USP-NF Redesign • USP/NF now in 3 volumes • Improvements targetted for USP 32: • General Notices improvements • Monographs redesign • Supporting materials • Improvements targetted for USP 32: • General Chapters • Stimuli article in PF32 (6)

14. General Notices Project Team • General notices “say it once” reduces the length of the book, ensures consistency • But many users are unaware of General Notices • Even experienced users have trouble finding information

15. General Notices Project Team • Project Team will suggest: • Reorganization and reformatting • Focussed and compressed text • Changes in content (addition and removal of text, reduction in legalistic language) • Ways to encourage better awareness of General Chapters (e.g. hyperlinks and footnotes) • Improvements targetted to USP 32

16. Monograph Improvements • Current style: • Chromatographic system (see Chromatography 621) – The liquid chromatography system is equipped with a 240-nm detector and a 3.9-mm x 15-cm column that contains 4-um packing L1. The flow rate is about 1 mL per minutes. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 6.0%. • Procedure – Separately inject equal volumes (about 35 uL) of the Standard solution, Test solution, and Diluent chromatograms for about two times the retention time of acebutolol, and measure the responses for all the peaks, disregarding any peaks corresponding to those obtained from the diluent.

17. Monograph Improvements • New style: Chromatographic system – Mode: liquid chromatography Detector: 240-nm Column: 3.9-mm x 15-cm column; 4-um-L1 packing Flow rate: about 1 mL per minute Injection Size: about 25 uL System Suitability – Sample – Standard Solution Suitability Acceptance Criteria: Relative standard deviation of acebutolol NMT 6.0%. Tailing factor NMT 2.0. Calculate the percentage of each impurity eluting before the acebutolol peak in the portion of capsules taken Impurity Acceptance Criteria – See Acebutolol Hydrochloride Capsules Impurity Table

18. USP-NF Redesign • USP is considering renumbering chapters into sensible groupings • FDA has an interest in the <1000 vs. >1000 chapters, since the former are enforceable and the latter are not • Industry is very concerned that the renumbered chapters will cause confusion in established products and methods • USP will consider listing “old” and “new” chapter numbers, and will not make any sudden decisions on the matter • Concern about the review process for new format chapters – what is the process if transcription errors occur? The changes will NOT go through PF since the meaning will be the same.

19. USP-NF Redesign - Discussion • Does the test used need to be indicated on the label? • FDA – the test used should be indicated on the patient insert, except for OTC products where there may not be an insert • Suggestions made for formatting and clarity

20. Revised Rules and Procedures • “Intent to Comment” form will no longer be included in PF – since there is a longer comment period (90d), less of a need for extensions • Can still request extensions. The wording about 90d will be softened in the next USP • Proposals will not be reprinted in PF unless they are substantially changed. Comment summaries will now be published in the Commentary section of USP-NF or Supplement. They will be printed in aggregate, without identification of who made the comments. It will be indicated whether the comment was included or not, and why. • Discussion – perhaps consider putting Commentary on the web to avoid confusion as to what is official text.

21. Other Monographs • SAPFA - Standards for Articles Pending FDA Approval • SALMOUS – Standards for Articles Legally Marketed Outside the US • These monographs will be published on the web, using a process similar to the monograph process. • There is still debate about how to ensure the correctness of such submissions.

22. Salt Nomenclature Policy • This topic took the form of a panel discussion with speakers representing: • USP – Legal and Expert Committee perspectives • FDA • Safe Medication Use Expert Committee Practitioner’s Perspective (nurses) • Industry Perspective – Consumer Healthcare, GPhA (Generic mfg), PhRMA (Rx mfg) • Panel Discussion

23. Salt Nomenclature – USP Position • US Adopted Names are jointly sponsored by USP, AMA, APhA, membership includes FDA • USP uses USAN for titles of drug substance monographs • USP Nomenclature Expert Committee sets the title of the drug product according to established naming conventions • FDA has strict rules about using the “established name”, “official name” or “common or usual name” for a drug, otherwise it is misbranded • FDA recommends that drug name and strength match (i.e. if name includes salt, strength should include the salt)

24. Salt Nomenclature – USP Position • According to the Expert Committee: • Where the strength is expressed in terms of the salt, the same salt name is used in the monograph title • Where the strength is expressed in terms of the free acid or base, the same acid or base name is used in the monograph title

25. Salt Nomenclature – Comments • Current USP policy results in non-uniform and inconsistent nonproprietary names and titles • The current naming can result in inappropriate substitution of non-equivalent drug products • Recognition of salt-specific adverse effects will be lost if salt names are eliminated from the titles • Retrospective application will cause confusion and may result in medical errors (labelling contributes to 30% of medication errors) • Does not simplify prescription writing or pharmacy record-keeping • May increase drug costs

26. Salt Nomenclature – Suggestions • Grandfather existing products • Consider use of salt in title and active moiety in strength/dosage • Address implementation, communication and timing • Provide clear explanation in USP-NF • Involve USP at the start of the NDA review by FDA

27. Salt Nomenclature – Practitioners • Include name, strength, recommended dose • Don’t include salt name unless there could be patient impact or unless multiple salts are available • Grandfather naming of current products • Be as consistent as possible in nomenclature • Avoid long names (may not fit in database and get truncated) • Avoid multiple expressions of product content (e.g. Calcium Gluconate 0.465 Ca++ mEq/mL, OR 9.3 mg Ca++/mL OR 0.68 mOsmol/mL)

28. Salt Nomenclature Policy - Industry • FDA is the gatekeeper of drug product names • USP usually gets involved only after many years of commercial sale • Confusion in nomenclature arises since some drugs provide strength in terms of free acid/base, whereas others include strength in terms of the salt form • Is it preferable for the product strength to reflect the Active Moiety (free acid/base) only or specific salt form? • Is it preferable for the product name to reflect the Active Moiety (free acid/base) only or specific salt form?

29. Salt Nomenclature Policy - Industry

30. USP allows choices in 2 grids

31. Salt Nomenclature Policy – Industry Concerns • No standardization at present • USP policy not consistent with FDA policy and may result in change in FDA-approved name • Should not be applied retrospectively • Public health concerns due to potential inappropriate drug substitution and loss of salt information • Name should focus on the identity and strength

32. Salt Nomenclature - Example API: Newactive Sulfate Dosage Form: Tablets Product is formulated with 500 mg Newactive Sulfate to provide 400 mg of the Newactive free-base equivalent

33. Salt Nomenclature Policy

34. Prefer the AS quadrant

35. Salt Nomenclature - Discussion • An extended panel discussion and Q&A session followed • No conclusion was reached, but all agreed that more discussion was required • The panel of experts was felt to be an excellent vehicle for information sharing and discussion