Page 1 United States Pharmacopeia Prescription/Non- Prescription Stakeholders Forum 17 November 2006 Presentation to CVG Discussion Group 13 April 2007

Page 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 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

Page 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

Page 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

Page 5 Residual Solvents 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

Page 6 Residual Solvents - Discussion 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.

Page 7 Chromatography Chromatography There are some differences between USP and EP in allowances of parameters adjustments. 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 +/- 10 o 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 +/- 5 o Attribute Mobile Phase pH of aqueous buffer Temperature

Page 8 Chromatography 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

Page 9 Chromatography - Discussion 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!

Page 10 Uniformity of Dosage Units 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.

Page 11 Uniformity of Dosage Units 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.

Page 12 Harmonized Microbiology General Chapters The following revisions will be postponed until May 1, 2009 – Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests – Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms – 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)

Page 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)

Page 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

Page 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

Page 16 Monograph Improvements Current style: (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%. 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.

Page 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

Page 18 USP-NF Redesign USP is considering renumbering chapters into sensible groupings FDA has an interest in the 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.

Page 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

Page 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.

Page 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.

Page 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

Page 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)

Page 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

Page 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

Page 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

Page 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 Ca ++ mEq/mL, OR 9.3 mg Ca ++ /mL OR 0.68 mOsmol/mL)

Page 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?

Page 29 Salt Nomenclature Policy - Industry NAME Salt (S) AS Strength in terms of Active Moiety, Name in terms of Salt S Strength and Name expressed in terms of Salt Active Moiety (A)A Strength and Name expressed in terms of Active Moiety SA Strength in terms of Salt, Name in terms of Active Moiety Active Moiety (A)Salt (S) STRENGTH

Page 30 USP allows choices in 2 grids NAME Salt (S) ASAS SS (Sometimes both Strength and Name are expressed as salt) Active Moiety (A) AA (Sometimes both Strength and Name are active moiety) SASA Active Moiety (A)Salt (S) STRENGTH

Page 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

Page 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

Page 33 Salt Nomenclature Policy NAME Salt (S) Newactive Sulfate Tablets 400 mg Newactive Sulfate Tablets 500 mg Active Moiety (A) Newactive Tablets 400 mg Newactive Tablets 500 mg Active Moiety (A)Salt (S) STRENGTH

Page 34 Prefer the AS quadrant NAME Salt (S) Newactive Sulfate Tablets 400 mg Newactive Sulfate Tablets 500 mg Active Moiety (A) Newactive Tablets 400 mg Newactive Tablets 500 mg Active Moiety (A)Salt (S) STRENGTH

Page 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