page 1 united states pharmacopeia prescription/non- prescription stakeholders forum 17 november 2006...

United States PharmacopeiaUnited States PharmacopeiaPrescription/Non-Prescription/Non-

Prescription Stakeholders ForumPrescription Stakeholders Forum

17 November 200617 November 2006

Presentation to CVG Discussion GroupPresentation to CVG Discussion Group

13 April 200713 April 2007

Prescription/Non-Prescription Prescription/Non-Prescription Stakeholders Forum (PNP SF)Stakeholders Forum (PNP SF)

An advisory group to the USP, enabling an An advisory group to the USP, enabling an exchange of information and perspectives exchange of information and perspectives between the USP and affected public, with the between the USP and affected public, with the goal of improving USP standards and goal of improving USP standards and informationinformation

PNP SF Member OrganizationsPNP SF Member Organizations:: Calibration & Validation GroupCalibration & Validation Group AAPSAAPS Consumer Healthcare Products AssocConsumer Healthcare Products Assoc FDAFDA Generic Pharmaceutical AssocGeneric Pharmaceutical Assoc International Pharmaceutical Excipients CouncilInternational Pharmaceutical Excipients Council International Pharmaceutical Aerosols Consortium on International Pharmaceutical Aerosols Consortium on

Regulation and ScienceRegulation and Science Midwest Compendial Discussion GroupMidwest Compendial Discussion Group New Jersey Pharmaceutical Quality Control AssocNew Jersey Pharmaceutical Quality Control Assoc Parenteral Drug AssoviationParenteral Drug Assoviation PhARMAPhARMA Western Compendial Discussion GroupWestern Compendial Discussion Group

Agenda of Nov 17, 2006 PNP SFAgenda of Nov 17, 2006 PNP SF

Residual SolventsResidual SolventsChromatographyChromatographyUniformity of Dosage UnitsUniformity of Dosage UnitsHarmonized Microbiology General Harmonized Microbiology General ChaptersChaptersUSP-NF Monograph RedesignUSP-NF Monograph RedesignRevised Rules and ProceduresRevised Rules and ProceduresSalt NomenclatureSalt Nomenclature

<467> Residual Solvents<467> Residual SolventsThe change from OVI to Residual Solvents The change from OVI to Residual Solvents became official January 1, 2007became official January 1, 2007

Tests for water-soluble and –insoluble Tests for water-soluble and –insoluble articles were revised and become official articles were revised and become official July 1, 2007July 1, 2007

USP continuing to improve solvent tests, USP continuing to improve solvent tests, e.g. comparison of “syringe” vs “transfer-e.g. comparison of “syringe” vs “transfer-line” headspace instrumentsline” headspace instruments

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

<621> Chromatography<621> ChromatographyThere are some differences between USP and There are some differences between USP and EP in allowances of parameters adjustments. EP in allowances of parameters adjustments.

USPThe amount of minor component The amount of minor component can be adjusted by +/- 30% can be adjusted by +/- 30% relative but not exceed +/- 10% relative but not exceed +/- 10% absoluteabsolute

Can be adjusted to within +/- 0.2 Can be adjusted to within +/- 0.2 units of the value or range units of the value or range specifiedspecified

Column temperature can be Column temperature can be adjusted by as much as +/- 10adjusted by as much as +/- 10oo

EP

The amount of minor solvent The amount of minor solvent component can be adjusted by component can be adjusted by +/- 30% relative or +/- 2% +/- 30% relative or +/- 2% absoluteabsolute

May vary by +/- 0.2 pH unless May vary by +/- 0.2 pH unless otherwise stated in the otherwise stated in the monograph, or +/- 1.0 pH for monograph, or +/- 1.0 pH for neutral substances neutral substances

Can be adjusted by +/- 5Can be adjusted by +/- 5oo

Attribute

Mobile Phase

pH of aqueous buffer

Temperature

<621> Chromatography<621> Chromatography

Same allowances between USP and EP for:Same allowances between USP and EP for:– Concentration of salts in buffersConcentration of salts in buffers– WavelengthWavelength– Column length (GC, HPLC)Column length (GC, HPLC)– Column inner diameter (GC, HPLC)Column inner diameter (GC, HPLC)– Film thicknessFilm thickness– Particle Size (HPLC)Particle Size (HPLC)– Flow rate (GC, HPLC)Flow rate (GC, HPLC)– Injection volumeInjection volume– Multiple adjustmentsMultiple adjustments

<621> Chromatography - Discussion<621> Chromatography - Discussion

The method may be considered changed if The method may be considered changed if many parameters are adjusted at once. many parameters are adjusted at once. The FDA acknowledges that this is a tricky The FDA acknowledges that this is a tricky issue.issue.Stakeholders enjoy the flexibility of Stakeholders enjoy the flexibility of adjustments in chromatographyadjustments in chromatographyA permanent change in the method should A permanent change in the method should be included in the Annual Reportbe included in the Annual ReportApply good science as well as compliance!Apply good science as well as compliance!

<905> Uniformity of Dosage Units<905> Uniformity of Dosage Units

Revised chapter became effective on 1 Revised chapter became effective on 1 January 2007January 2007

New calculations apply to all products New calculations apply to all products marketed in the USmarketed in the US

Are you having difficulty meeting the Are you having difficulty meeting the revised limits or changing your internal revised limits or changing your internal procedures?procedures?

This subject will be discussed at the PNP This subject will be discussed at the PNP SF in May 2007.SF in May 2007.

<905> Uniformity of Dosage Units<905> Uniformity of Dosage Units

With respect to the ICH DG pending With respect to the ICH DG pending change for CU limits to be lowered to 2%, change for CU limits to be lowered to 2%, the FDA will continue to require CU test for the FDA will continue to require CU test for all dosage forms with active content of all dosage forms with active content of <25%/25mg.<25%/25mg.

The may lead to a difference in what is The may lead to a difference in what is published in the USP and what the FDA published in the USP and what the FDA will accept.will accept.

Harmonized Microbiology General Harmonized Microbiology General ChaptersChapters

The following revisions will be postponed until The following revisions will be postponed until May 1, 2009May 1, 2009– <61> Microbiological Examination of Nonsterile <61> Microbiological Examination of Nonsterile

Products: Microbial Enumeration TestsProducts: Microbial Enumeration Tests– <62> Microbiological Examination of Nonsterile <62> Microbiological Examination of Nonsterile

Products: Tests for Specified MicroorganismsProducts: Tests for Specified Microorganisms– <1111> Microbiological Examination of Nonsterile <1111> Microbiological Examination of Nonsterile

Products: Acceptance Criteria for Pharmaceutical Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical UsePreparations and Substances for Pharmaceutical Use

Note – FDA demands that drug products are Note – FDA demands that drug products are free of all objectionable organisms (not just USP free of all objectionable organisms (not just USP specified organisms)specified organisms)

USP-NF RedesignUSP-NF RedesignUSP/NF now in 3 volumesUSP/NF now in 3 volumes

Improvements targetted for USP 32:Improvements targetted for USP 32:– General Notices improvementsGeneral Notices improvements– Monographs redesignMonographs redesign– Supporting materialsSupporting materials

Improvements targetted for USP 32:Improvements targetted for USP 32:– General ChaptersGeneral Chapters

Stimuli article in PF32 (6)Stimuli article in PF32 (6)

General Notices Project TeamGeneral Notices Project Team

General notices “say it once” reduces the General notices “say it once” reduces the length of the book, ensures consistencylength of the book, ensures consistency

But many users are unaware of General But many users are unaware of General NoticesNotices

Even experienced users have trouble Even experienced users have trouble finding informationfinding information

General Notices Project TeamGeneral Notices Project Team

Project Team will suggest:Project Team will suggest:– Reorganization and reformattingReorganization and reformatting– Focussed and compressed textFocussed and compressed text– Changes in content (addition and removal of Changes in content (addition and removal of

text, reduction in legalistic language)text, reduction in legalistic language)– Ways to encourage better awareness of Ways to encourage better awareness of

General Chapters (e.g. hyperlinks and General Chapters (e.g. hyperlinks and footnotes)footnotes)

Improvements targetted to USP 32Improvements targetted to USP 32

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

Monograph ImprovementsMonograph Improvements

New style:New style:Chromatographic system – Chromatographic system –

Mode: liquid chromatographyMode: liquid chromatographyDetector: 240-nmDetector: 240-nmColumn: 3.9-mm x 15-cm column; 4-um-L1 packingColumn: 3.9-mm x 15-cm column; 4-um-L1 packingFlow rate: about 1 mL per minuteFlow rate: about 1 mL per minuteInjection Size: about 25 uLInjection Size: about 25 uL

System Suitability – System Suitability – Sample – Standard SolutionSample – Standard SolutionSuitability Acceptance Criteria:Suitability Acceptance Criteria:

Relative standard deviation of acebutolol NMT 6.0%. Tailing factor NMT 2.0. Relative standard deviation of acebutolol NMT 6.0%. Tailing factor NMT 2.0. Calculate the percentage of each impurity eluting before the acebutolol peak Calculate the percentage of each impurity eluting before the acebutolol peak in the portion of capsules takenin the portion of capsules taken

Impurity Acceptance Criteria –Impurity Acceptance Criteria – See Acebutolol Hydrochloride See Acebutolol Hydrochloride Capsules Impurity TableCapsules Impurity Table

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

USP-NF Redesign - DiscussionUSP-NF Redesign - Discussion

Does the test used need to be indicated Does the test used need to be indicated on the label?on the label?

FDA – the test used should be indicated FDA – the test used should be indicated on the patient insert, except for OTC on the patient insert, except for OTC products where there may not be an insertproducts where there may not be an insert

Suggestions made for formatting and Suggestions made for formatting and clarityclarity

Revised Rules and ProceduresRevised Rules and Procedures

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

Other MonographsOther Monographs

SAPFA - Standards for Articles Pending FDA SAPFA - Standards for Articles Pending FDA Approval Approval SALMOUS – Standards for Articles Legally SALMOUS – Standards for Articles Legally Marketed Outside the USMarketed Outside the US

These monographs will be published on the These monographs will be published on the web, using a process similar to the monograph web, using a process similar to the monograph process.process.There is still debate about how to ensure the There is still debate about how to ensure the correctness of such submissions.correctness of such submissions.

Salt Nomenclature PolicySalt Nomenclature Policy

This topic took the form of a panel discussion This topic took the form of a panel discussion with speakers representing:with speakers representing:– USP – Legal and Expert Committee perspectivesUSP – Legal and Expert Committee perspectives– FDAFDA– Safe Medication Use Expert Committee Practitioner’s Safe Medication Use Expert Committee Practitioner’s

Perspective (nurses)Perspective (nurses)– Industry Perspective – Consumer Healthcare, GPhA Industry Perspective – Consumer Healthcare, GPhA

(Generic mfg), PhRMA (Rx mfg)(Generic mfg), PhRMA (Rx mfg)

Panel DiscussionPanel Discussion

Salt Nomenclature – USP PositionSalt Nomenclature – USP Position

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

Salt Nomenclature – USP PositionSalt Nomenclature – USP Position

According to the Expert Committee:According to the Expert Committee:– Where the strength is expressed in terms of Where the strength is expressed in terms of

the salt, the same salt name is used in the the salt, the same salt name is used in the monograph titlemonograph title

– Where the strength is expressed in terms of Where the strength is expressed in terms of the free acid or base, the same acid or base the free acid or base, the same acid or base name is used in the monograph titlename is used in the monograph title

Salt Nomenclature – CommentsSalt Nomenclature – Comments

Current USP policy results in non-uniform and inconsistent Current USP policy results in non-uniform and inconsistent nonproprietary names and titlesnonproprietary names and titlesThe current naming can result in inappropriate substitution The current naming can result in inappropriate substitution of non-equivalent drug productsof non-equivalent drug productsRecognition of salt-specific adverse effects will be lost if Recognition of salt-specific adverse effects will be lost if salt names are eliminated from the titlessalt names are eliminated from the titlesRetrospective application will cause confusion and may Retrospective application will cause confusion and may result in medical errors (labelling contributes to 30% of result in medical errors (labelling contributes to 30% of medication errors)medication errors)Does not simplify prescription writing or pharmacy record-Does not simplify prescription writing or pharmacy record-keepingkeepingMay increase drug costsMay increase drug costs

Salt Nomenclature – SuggestionsSalt Nomenclature – Suggestions

Grandfather existing productsGrandfather existing products

Consider use of salt in title and active Consider use of salt in title and active moiety in strength/dosagemoiety in strength/dosage

Address implementation, communication Address implementation, communication and timingand timing

Provide clear explanation in USP-NFProvide clear explanation in USP-NF

Involve USP at the start of the NDA review Involve USP at the start of the NDA review by FDAby FDA

Salt Nomenclature – PractitionersSalt Nomenclature – Practitioners

Include name, strength, recommended doseInclude name, strength, recommended doseDon’t include salt name unless there could be Don’t include salt name unless there could be patient impact or unless multiple salts are patient impact or unless multiple salts are availableavailableGrandfather naming of current productsGrandfather naming of current productsBe as consistent as possible in nomenclatureBe as consistent as possible in nomenclatureAvoid long names (may not fit in database and get Avoid long names (may not fit in database and get truncated)truncated)Avoid multiple expressions of product content Avoid multiple expressions of product content (e.g. Calcium Gluconate 0.465 Ca(e.g. Calcium Gluconate 0.465 Ca++++ mEq/mL, OR mEq/mL, OR 9.3 mg Ca9.3 mg Ca++++/mL OR 0.68 mOsmol/mL)/mL OR 0.68 mOsmol/mL)

Salt Nomenclature Policy - IndustrySalt Nomenclature Policy - IndustryFDA is the gatekeeper of drug product namesFDA is the gatekeeper of drug product namesUSP usually gets involved only after many years of USP usually gets involved only after many years of commercial salecommercial saleConfusion in nomenclature arises since some drugs Confusion in nomenclature arises since some drugs provide strength in terms of free acid/base, whereas provide strength in terms of free acid/base, whereas others include strength in terms of the salt formothers include strength in terms of the salt formIs it preferable for the product strength to reflect the Active Is it preferable for the product strength to reflect the Active Moiety (free acid/base) only or specific salt form?Moiety (free acid/base) only or specific salt form?Is it preferable for the product name to reflect the Active Is it preferable for the product name to reflect the Active Moiety (free acid/base) only or specific salt form?Moiety (free acid/base) only or specific salt form?

Salt Nomenclature Policy - IndustrySalt Nomenclature Policy - Industry

NAME

Salt (S)

ASStrength in terms of

Active Moiety, Name in terms of Salt

SS

Strength and Name expressed in terms of

Salt

Active Moiety (A)

AA Strength and Name expressed in terms of

Active Moiety

SAStrength in terms of

Salt, Name in terms of Active Moiety

Active Moiety (A) Salt (S)

STRENGTH

USP allows choices in 2 gridsUSP allows choices in 2 grids

NAME

Salt (S)

AS SS

(Sometimes both Strength and Name are

expressed as salt)

Active Moiety (A)

AA

(Sometimes both Strength and Name are active moiety)

SA


STRENGTH

Salt Nomenclature Policy – Industry Salt Nomenclature Policy – Industry ConcernsConcerns

No standardization at presentNo standardization at present

USP policy not consistent with FDA policy and USP policy not consistent with FDA policy and may result in change in FDA-approved namemay result in change in FDA-approved name

Should not be applied retrospectivelyShould not be applied retrospectively

Public health concerns due to potential Public health concerns due to potential inappropriate drug substitution and loss of salt inappropriate drug substitution and loss of salt informationinformation

Name should focus on the identity and strengthName should focus on the identity and strength

Salt Nomenclature - ExampleSalt 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

Salt Nomenclature PolicySalt 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


STRENGTH

Prefer the AS quadrantPrefer 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


STRENGTH

Salt Nomenclature - DiscussionSalt Nomenclature - Discussion

An extended panel discussion and Q&A An extended panel discussion and Q&A session followedsession followed

No conclusion was reached, but all agreed No conclusion was reached, but all agreed that more discussion was requiredthat more discussion was required

The panel of experts was felt to be an The panel of experts was felt to be an excellent vehicle for information sharing excellent vehicle for information sharing and discussionand discussion

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