Module 2 USP Impurities_0501

Impurities in Drug Substances and Drug Products- A USP

ApproachApproachMODULE IIMODULE II

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Contents – Module II

MonographsUSP monograph–USP monograph

–Pending monographGeneral Revision ProcessImpurities in Monographs (USP & Pending)Flexible monographsCase studies (Examples)Case studies (Examples)

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Monographs

USP Monographs

– For articles approved by FDA for marketing in US

Pending MonographsPending Monographs

– For articles that are tentatively approved by FDA or under FDA reviewunder FDA review

Monograph development process is the f b hsame for both.

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Outline



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Documentary Standards Setting Process

Monograph development is initiated

Manufacturer submits proposal USP initiates development

1

Scientific Liaison performs technical review and drafts monograph,

USP evaluates procedures requiring RS prior to publication and

2

3RS collaborative testing (optional)

Proposal is published for 90-day public comment period

3

4

Scientific Liaison and Expert Committee reviews comments

Expert Committee ballots to adopt proposal

5

6

Monograph is published in compendium (USP-NF, FCC) or on web site (Pending Monograph). USP-NF text becomes ffi i l i th ft bli ti l th i i di t d

ApprovedNot ApprovedNext steps?

7

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official six months after publication unless otherwise indicated. Commentary generated.

Outline



102

Impurities in USP Monographs

Based on the sponsor’s NDA/ANDA

Limits of Specified impurities are consistent with FDA approved limits

Limits of unspecified and total impurities are consistent with FDA approved limits

Procedures are based on the approved NDA/ANDA methods

103

Impurities in USP Monographs

Drug substances contain process impurities as well asDrug substances contain process impurities as well as some degradants

Drug products contain mainly degradantsDrug products contain mainly degradants– May include process impurities if they are also degradants

Di ti ti b t i iti d d d tDistinction between process impurities and degradants become more important when dealing with drug products.p

104

Outline



105

Flexible Monograph Approach

Need-based flexibility to account for different routes of synthesis, hydrates, solvates, polymorphs, or formulationsEnables multiple procedures preparations and/or acceptanceEnables multiple procedures, preparations, and/or acceptance criteria within a single monograph Uses of the flexible approach

– multiple formulation-specific dissolution procedures – multiple organic impurity procedures based on different

impurity profilesimpurity profiles– hydrate-specific water limits/ranges– polymorph-specific crystallinity requirement

May need procedure-specific USP Reference Standards

106

Flexible Monographs: General Notices 4.10.10

f4.10.10. Applicability of Test Procedures A single monograph may include several different tests, procedures, and/or acceptance criteria that reflect attributes of different manufacturers' articles. Such alternatives may be presented for different polymorphic forms, impurities, hydrates, and dissolution cases. Monographs indicate the tests, procedures, and/or acceptance criteria to be used and the required labeling.▲A test in a monograph may contain and require multiple procedures. However, multiple procedures may be included inprocedures. However, multiple procedures may be included in particular monographs specifically for the purpose of assuring the availability of an appropriate procedure for a particular product. In such cases, a labeling statement to indicate the appropriatesuch cases, a labeling statement to indicate the appropriate application of the procedure(s) will be included in the monograph. A labeling statement is not required if Test 1 is used. ▲USP34

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Flexible Monographs: Examples

Emtricitabine

LopinavirLopinavir

Paclitaxel

LevofloxacinLevofloxacin

Lamivudine

Fluconazole InjectionFluconazole Injection

Famciclovir

A dAnd many more

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Outline



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Possible Scenarios Regarding Impurities

Sponsor impurity limits are different from USP Monograph or Pharmacopeial Forum (PF) proposal limitslimits– Monograph or PF proposal Limits are wider than FDA

approved limits

– Monograph or PF limits are tighter than FDA approved limits

Specific impurities of interest are not included in PFSpecific impurities of interest are not included in PFproposal or USP monograph– Multiple scenarios

Resolution of each case with examples

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Monograph Limits are Different from FDA Approved Limits

Two possible scenarios:– Monograph or PF proposal Limits are wider than FDAMonograph or PF proposal Limits are wider than FDA

approved limits

• This does not pose any compliance issue- no resolution necessarynecessary

– Monograph or PF proposal limits are tighter than FDA– Monograph or PF proposal limits are tighter than FDA approved limits

• This does pose a compliance issue

• Following example demonstrates the resolution

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Levetiracetam Tablets

New monograph proposal published in Pharmacopeial Forum 36(1)New monograph proposal published in Pharmacopeial Forum 36(1) for Public comments

Name Limit NMT %

Levetiracetam acid 0.1Any unspecified degradation 0.1y gproductTotal 0.35

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USP received the following comment from an approved application holder

Levetiracetam acid limit in PF proposal is tighter than FDA approved limit

USP received the following comments from FDA

L ti t id li it h ld b th t f thLevetiracetam acid limit should be same as that of the levetiracetam drug substance (0.3%)

Total impurities limit in the PF proposal is different from the p p papproved limit

The limit for Any individual unspecified degradation product should be tightened to 0 10% to be consistent with ICH Q3B guidelines

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be tightened to 0.10% to be consistent with ICH Q3B guidelines


Resolution steps:

Contacted all the approved applicants

Highest approved limit for Levitiracetam acid NMT 0.3%

Highest limit for Total impurities NMT 0.6%

Confirmed the above with FDA

Expert Committee decided to widen the limits of levetiracetam acid and Total Impurities to be consistent with FDA approved limits.p pp

Expert Committee did NOT tighten the limit for “Any individual unspecified degradation product” from 01% to 0.10% because many approved applications have 0.1% limit.pp

114


PF36(1) proposal was balloted with the following changesPF36(1) proposal was balloted with the following changes

Official in USP34 Supplement 2Name Limit

NMT %Levetiracetam acid 0.3Any individual unspecified 0.1ydegradation productTotal 0.6

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Specific Impurities Not Included

Possible scenariosPossible scenariosSpecific impurities come from a different synthetic route

M h t h id d th ifiMonograph sponsor may not have considered the specific impurities

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Specific Impurities Not Included

Information USP needs to know:Information USP needs to know:

Regulatory status of the article as this is very important to decide the path

Has the company evaluated the USP monograph or PF procedure

Provide supporting data for revision request

Several examples to demonstrate resolution pathways

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Trimpramine Maleate

P blished in PF 32(6) for p blic commentsPublished in PF 32(6) for public comments

Name RRT Acc CriteriaName RRT Acc Criteria NMT%

Iminodibenzyl 0.49 0.20Imipramine 0 72 0 20Imipramine 0.72 0.20Trimipramine Related compound A

0.80 0.20

T i i i 1 0 NATrimipramine 1.0 NAAny unspecified impurity -- 0.10Total --- 0.50

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Trimpramine Maleate

USP received the following comment from anUSP received the following comment from an approved application holder

PF proposal does not include three additional impurities.

Request USP to include their in-house procedure

USP observations:

Commenter’s in-house procedure does not monitor Trimipramine Related Compound A

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Trimpramine Maleate

Resolution StepsResolution Steps

Commenter was asked to evaluate the PF 32(6) procedure

Results of the evaluation indicated PF 32(6) procedure to beResults of the evaluation indicated PF 32(6) procedure to be suitable to monitor all the impurities

Commenter provided the evaluation study report

Expert committee decided to include the new impurities with FDA approved limits

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Trimpramine Maleate

Official Monograph in USP34 Supplement 2

Name RRT Acc Criteria NMT%

Trimipramine N-oxide 0.32 0.15Iminodibenzyl 0.49 0.20Desmethyltrimipramine 0 68 0 15Desmethyltrimipramine 0.68 0.15Imipramine 0.72 0.20Trimipramine Relatedcompound A

0.80 0.20compound A Trimipramine 1.0 NATrimipramine diamine 2.4 0.30

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Any unspecified impurity -- 0.10Total --- 1.0

Galantamine Hydrobromide

Published in PF32(3) [Mar-Apr 2007] for public comments

Name RRT RRF Acc CriteriaCriteria NMT%

6b -hexahydrogalantamine 0.65 0.96 —

6 β –octahydrogalantamine 0.82 0.81 0.356 β octahydrogalantamine 0.82 0.81 0.35

Galantamine hydrobromide 1.00 1.0 —6α -hexahydrogalantamine 1.16 0.95 —

Tetrahydrogalantamine 2 05 1 2 0 40Tetrahydrogalantamine 2.05 1.2 0.40

Individual unspecified impurity

— 1.0 0.10

Total impurities 1 0

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Total impurities — — 1.0


USP received the following comment from a DMF holder

Their manufacturing process introduces three additional impurities

DMF holder has an in-house method which can monitor all the impuritiesimpurities

Users reported that the procedure in PF33(2) [Mar-Apr 2007] does not monitor 3 additional known process impurities.

Regulatory Status: DMF has been cited in six approved ANDAs

USP requested the DMF holder to evaluate the PF33(2) procedure

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Evaluation indicated that all impurities can be separated without any coelution

issues.

124Reprinted with permission


Monograph revised in December 2008 via revision bulletin

I it t bl i d t i l d ll th th i iti ithImpurity table revised to include all the three impurities with appropriate limitsNote added to identify one additional impurity (Narwedine))from naturally derived material

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Official monograph has the following impurities table

Name RRT RRF Acc CriteriaCriteria NMT%

N-Desmethylgalantamine 0.29 1.2 0.6

O Desmethylgalantamine 0 35 1 1 0 20O-Desmethylgalantamine 0.35 1.1 0.20

6β –hexahydrogalantamine (also known as N-galantamine oxide

0.65 0.96 0.20

6 β–octahydrogalantamine 0 82 0 81 0 356 β octahydrogalantamine 0.82 0.81 0.35

Galantamine hydrobromide 1.00 1.0 —

6α–hexahydrogalantamine (also known as epigalantamine)

1.16 0.95 0.20known as epigalantamine)

Narwedine 1.64 1.9 0.15

Tetrahydrogalantamine 2.05 1.2 0.40

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Individual unspecified impurity — 1.0 0.10

Total impurities — — 1.0

Miratazpine Orally Disintegrating Tablets

Published in PF 33(6) Nov-Dec 2007

Name Retention time

Relative retention time

Acc. Criteria NMT %time NMT %

Acyclomirtazapine 39.6 0.64 0.2

Carbaoxypydilphenylmethylpiperazine

42.8 0.69 0.2

Mirtazapine Related compound A

55.0 0.88 0.2

Mirtazapine 62.0 1.0 __

Mirtazapine N-oxide -- 1.26 0.2

Ind. Unsp. degradant --- --- 0.2

Total --- --- 0.5

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USP received the following comments from an approved application holder

The monograph does not monitor two other known degradants

Procedure in PF proposal unsuitableProcedure in PF proposal unsuitable

An unknown peak ( ~9%) elutes at 30 min (artifact from excipient)

The monograph has specified limits for known process impurities which g p p p pare not required per ICH Q3B guidelines

The procedure takes too long-requires 140 minutes

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Resolution:

PF 33(6) proposal was adopted without Organic Impurities procedure.

The commenter has a validated gradient elution procedure which can monitor the necessary degradants in 30 minutes.

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Gradient elution procedure published in PF 37(2) Mar-Apr 2011

Name Relative AccName Relative retention time

Acc. Criteria NMT %

Mirtazapine Related Compound B

0.23 0.5Compound B

Miratzapine Related compound C

0.51 0.5

Mirtazapine Related 0.62 0.5compound A

Mirtazapine 1.0 __

Mirtazapine Related compound D

1.3 0.5compound D

Ind. Unsp. degradant --- 0.5

Total --- 3.0

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Revised monograph official in USP35 Supplement 1

Risperidone

Background:Monograph became official in USP US30 S2Monograph became official in USP US30 S2

Name RRT LimitE-oxime 0.60 0.20Z-oxime 0.67 0.209-hydroxyrisperidone 0.76 0.205 fl ororisperidone 0 94 0 205-fluororisperidone 0.94 0.20Risperidone 1.0 --6-methylrisperidone 1.2 0.20Any individual unsp impurity

-- 0.10

Total -- 0.30

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Risperidone

USP received the following comments from an approved application holder

The monograph does not include two known process impurities from a different manufacturing processdifferent manufacturing process

The procedure is not selective for the two known process impurities

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Risperidone

Th l t d th USP h dThe company evaluated the USP monograph procedure

D&H G

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Risperidone

The company evaluated the USP monograph procedure

Retention time data with USP monograph procedureRetention time data with USP monograph procedure

Name RRT LimitE-oxime 0.60 0.20Z-oxime 0.67 0.209-hydroxyrisperidone 0.76 0.205 fl ororisperidone(D)/ 0 94 0 205-fluororisperidone(D)/ Impurity H

0.94 0.20

Risperidone/Impurity G 1.0 --6 th l i id 1 2 0 206-methylrisperidone 1.2 0.20Any individual unsp impurity

-- 0.10

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Total -- 0.30

Risperidone

The company developed an alternative procedure.

HD

H

G

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Risperidone

Retention time data with alternative procedureRetention time data with alternative procedure

Name RRT LimitE-oxime 0.52 0.20Z-oxime 0.64 0.209-hydroxyrisperidone 0.76 0.20Imp rit H 0 90Impurity H 0.905-fluororisperidone(D) 0.94 0.20Risperidone 1.0 --Impurity G 1.086-methylrisperidone 1.2 0.20Any individual -- 0.10

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Any individual unspecified impurity

0.10

Total -- 0.30

Risperidone

Resolution:

Replace the existing monograph procedure.ep ace t e e st g o og ap p ocedu e

Include the two new impurities which form critical pair for ensuring the system suitability

Introduce resolution requirement between the two critical pairs: D&H impurities; risperidone and impurity G

Expert Committee after reviewing the data recommended publishing the proposal in a future PF

Revision proposal will appear in a future PF once all the required new impurity ref std bulks arrive at USP

137

Flexible Monograph Examples

Need-based flexibility to account for different routes of synthesis, hydrates, solvates, polymorphs, or formulationsEnables multiple procedures preparations and/or acceptanceEnables multiple procedures, preparations, and/or acceptance criteria within a single monograph Uses of the flexible approach

– multiple formulation-specific dissolution procedures – multiple organic impurity procedures based on different

impurity profilesimpurity profiles– hydrate-specific water limits/ranges– polymorph-specific crystallinity requirement

May need procedure-specific USP Reference Standards

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Emtricitabine (Pending Monograph)

There is no Official USP monograph for Emtricitabine atThere is no Official USP monograph for Emtricitabine at this point.

Two ANDA holders submitted tentatively approvedTwo ANDA holders submitted tentatively approved specifications.

The monograph was processed as Pending monograph g g gand posted on the USP Website.

Flexible Monograph approach was used to address diff t i it fil d li itdifferent impurity profiles and limits.

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Lopinavir (Official and Pending Monograph)

The innovator sponsored the monograph and was processed and became Official in USP-NFand became Official in USP NF.

An ANDA holder (not fully approved) sponsored the second submission with different specifications including different p gimpurity profile/limits.

The monograph was processed as Pending monograph and t d th USP W b itposted on the USP Website.

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Typical comment/query:

From innovator sponsor: The specifications (e.g. impurity profile/limits) for Pending monograph are different than those inprofile/limits) for Pending monograph are different than those in Official USP monograph.

– Request for revision: Change specifications in Pending q g p gmonograph to be consistent with those in Official USP monograph.

From Generic sponsor: The specifications (e g impurityFrom Generic sponsor: The specifications (e.g. impurity profile/limits) in USP monograph (USP-NF) are different than those posted on the USP website.

– Request for revision: Change specifications in Official USP monograph to be consistent with those in Pending monograph!

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Response:

The specifications in Official USP monographs reflect those fully approved by FDA and published in USP NFapproved by FDA and published in USP-NF.

The specifications in Pending monographs reflect those tentatively approved or under review by FDA and posted on USP website.pp y p

USP does not change specifications in USP monograph to reflect those in corresponding Pending monograph. On the other hand, USP does not change specifications in Pending monograph to beUSP does not change specifications in Pending monograph to be consistent with Official USP monograph.

Once specifications in Pending monograph get full FDA approval, p g g p g ppUSP will evaluate and consolidate the two specifications in a single monograph as appropriate.

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Flexible Monograph: Paclitaxel

Labeling—The labeling indicates the type of process used to produce the material and the Related compounds test with which the material complies.

Organic Impurities—

Procedure 1 (for material labeled as isolated from natural ) If th t i l li ith thi d th l b lisources)—If the material complies with this procedure, the labeling

indicates that it meets Organic Impurities, Procedure 1.

Procedure 2 (for material labeled as produced by a semi-synthetic process)—If the material complies with this procedure, the labeling indicates that it meets Organic Impurities, Procedure 2.

Procedure 3 (for material labeled as produced by a plant cellProcedure 3 (for material labeled as produced by a plant cell fermentation process)—If the material complies with this procedure, the labeling indicates that it meets Organic Impurities, Procedure 3.

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Flexible Monograph - Inorganic Impurities

Manufacturing process leads to specific inorganic impuritiesp

Galantamine Hydrobromide ( Pd)PF 33(3) proposal included a test for Limit for PdPF 33(3) proposal included a test for Limit for Pd.

An approved manufacturer commented as follows:

Our process does not use Pd in the processOur process does not use Pd in the process.

Resolution:

EC made the test optional with the following noteEC made the test optional with the following note

Limit of Palladium – [Note-Perform the test if Pd is known process impurity]

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Flexible Monograph– Residual Solvents

Manufacturing process leads to specific residual solvents with limits higher than <467>

Rocuronium Bromide

USP32 S1 included a test for Limit of 2-propanol

A th i d di h bli h d N b 01 2007 d itAuthorized pending monograph was published on November 01, 2007 and it had a test for Limit of Acetic acid

When the sponsor of the Authorized pending monograph received full approval, the authorized pending monograph and the USP 32 S1 monograph were reconciled.

145

Flexible Monograph: Special Situations

Issue during reconciliation:

Authorized Pending monograph sponsor uses acetic acid to improve the g g p p pstability, but does not use isopropyl alcohol in the manufacturing process.

Sponsor of the USP 32 S1 monograph does not use acetic acid to stabilize the drug substance.g

The revision bulletin published with the following texts:

Definition: Modified to include “ on 2-propanol or acetic acid free basis”Limit of acetic acid—[NOTE—Perform this test only if acetic acidis a known organic manufacturing process impurity.]

Limit of 2-propanol —[NOTE—Perform this test only if 2-propanolis a known organic manufacturing process impurity.]

146.

Flexible Monograph: Organic Impurities

Simple example

I iti b t d b t t b tifi dImpurities can be separated but cannot be quantifiedPharmacopeial Forum 31(3) [May-June 2005]

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Flexible Monograph: Citalopram Hydrobromide

USP received the following comments from an approved applicationUSP received the following comments from an approved application holder

Not suitable for monitoring two additional process impurities- chloro and bromo analogsg

Isocratic procedure in the proposal required 70 min for chloro analog and 80 min for bromo analog

Band broadening makes the quantification very difficult if not impossible

User developed and validated an alternative gradient elution Procedure

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Flexible Monograph: Citalopram Hydrobromide

Revision proposal published in PF32(6) [Nov-Dec 2006] with

“flexible monograph approach”flexible monograph approach

Official monograph in USP34-NF30 contains the following:

Two procedures included in the monograph with direction to p g pthe analyst to choose the appropriate procedure based on theknowledge of manufacturing process.

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Flexible Monograph: Levofloxacin

Official USP monograph based on NDA with one organic impurity procedure.The second sponsor submitted two procedures for different impurity profile.Using a flexible monograph approach, Organic Impurities, Procedure g g p pp , g p ,2 and Procedure 3 were added to the monograph.Flexible monograph approach addressed different impurities from different synthetic route and the corresponding limits.y p g

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O i I iti P d 1 (S 1)

NameRelative Retention

TimeRelative Response

FactorAcceptance

Criteria (NMT (%)

Organic Impurities: Procedure 1 (Sponsor 1)

N-DesmethylLevofloxacin

0.47 1.0 0.3

Diamine derivative 0.52 0.9 0.3

Levofloxacin N-Oxide 0.63 1.1 0.3

9-Desfluoro 0 73 1 0 0 39-Desfluoro levofloxacin

0.73 1.0 0.3

Levofloxacin 1.0 - -

D I 1 23 1 0 0 8D-Isomer 1.23 1.0 0.8

Any unknown impurity - 1.0 0.1

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Total impurities - _ 0.5 (Do not include

D-Isomer)


Relative Acceptance Criteria

Organic Impurities: Procedure 2 (Sponsor 2)

Name RetentionTime

(NMT (%)

Levofloxacin related compound A (N D th l L fl i )

0.9 0.20(N-Desmethyl Levofloxacin)

Levofloxacin 1.0 -

Levofloxacin related compound B 2.9 0.13

A th i it 0 10Any other impurity - 0.10

Total impurities - 0.50

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Organic impurities, Procedure 3 (Sponsor 2)

Acceptance criteria: NMT 1.0% for D-Ofloxacin (D-isomer)

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Flexible Monograph: Levofloxacin (Comparison)

NameAcceptance Criteria NMT (%) Sponsor 1

Acceptance Criteria NMT (%) Sponsor 2

N-Desmethyl Levofloxacin (Levofloxacin related compound A)

0.3 0.20

Diamine derivative 0 3 NADiamine derivative 0.3 NA

Levofloxacin N-Oxide 0.3 NA

9-Desfluoro levofloxacin 0 3 NA9 Desfluoro levofloxacin 0.3 NALevofloxacin - -D-Isomer 0.8 1.0Levofloxacin related compound B NA 0.13

Any unknown impurity 0.1 0.10

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Total impurities 0.5 (Do not include

D Isomer)

0.5 (Do not include

D Isomer)


A note was added to specify that the currently official OrganicA note was added to specify that the currently official Organic Impurity procedure is now designated as Procedure 1 and Organic Impurities, Procedures 2 and Procedure 3 are recommended if levofloxacin related compound B is a potential organic impuritylevofloxacin related compound B is a potential organic impurity.

LABELING: If a procedure for Organic Impurities other than Procedure 1 is used, then the labeling states with which Organic Impurities procedure the article complies.

155

Potential Flexible Monograph: Lamivudine

R id l S l t

Acceptance Criteria (NMT (%)

Residual Solvents

Namep ( ( )

Alcohol 0.2

Isopropyl acetate 0.2

Methanol 0.1

Triethylamine 0.1

Total residual solvents 0.3

156

Potential Flexible Monograph: Lamivudine

Generic sponsor obtained approval for Lamivudine (methanol solvate).)Request to add “content of methanol” for the Lamivudine, methanol solvate.Request to add the acceptance criteria of 2 0%-3 0% for methanol forRequest to add the acceptance criteria of 2.0% 3.0% for methanol for (Lamivudine, methanol solvate).Considering the request for revision as flexible monograph.

157

Flexible Monograph: Fluconazole Injection

Published in PF 34 (1) [Mar.–Apr. 2008] as proposed new monograph based on approved ANDA with organic impurities, Procedure 1 and pp g p ,Procedure 2.The second sponsor submitted Procedure 3 for different impurity profile/limits.pThe third sponsor submitted Procedure 4 for different impurity profile/limits.Flexible monograph approach was used to accommodate theseFlexible monograph approach was used to accommodate these different impurity profiles/limits.

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(Sponsor 1)(Sponsor 1)

Procedure 1: For Nonpolar Impurities Acceptance criteria :p

Largest unknown nonpolar impurity: NMT 0.1%

Total unknown nonpolar impurities: NMT 0.5%

Procedure 2: For Polar ImpuritiesAcceptance criteria

Largest unknown polar impurity: NMT 0.1%

Total unknown polar impurities: NMT 0 5%Total unknown polar impurities: NMT 0.5%

Total unknown polar and nonpolar impurities: NMT 1.0%

(sum of results from Procedure 1 and Procedure 2)

159

( )


Sponsor 2 Organic imp rities Proced re 3

NameRelative Retention Time Acceptance Criteria,

NMT (%)

Sponsor 2, Organic impurities, Procedure 3

Bistriazole ketone 0.13 0.2

Fluconazole isomer 0.5 0.2

Epoxyfluconazole 2.6 0.2Epoxyfluconazole 2.6 0.2

Any other impurity NA 0.2

Total impurities NA 0.5

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Sponsor 3 Organic impurities Procedure 4

Name Relative

RetentionTime

Acceptance Criteria,NMT (%)

Sponsor 3, Organic impurities, Procedure 4

Aminofluconazole quaternary salt

0.57 0.1

Fluconazole isomer 0.68 0.1

Fluconazole diol 0.91 0.1

Fluconazole 1.0 -

Fluconazole bromohydrine 2.58 0.1`

Epoxyfluconazole 2.59 0.1

A h i i NA 0 1

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Any other impurity NA 0.1

Total impurities NA 0.5


Labeling: Label to indicate the vehicle used. If a test for Organic Impurities other than Procedure 1 and Procedure 2 is used, then the p ,labeling states with which Organic Impurities test the article complies

IMPURITIES Organic Impurities

[ NOTE On the basis of the synthetic route perform either (a)[ NOTE— On the basis of the synthetic route, perform either (a) Procedure 1 and Procedure 2 or (b) Procedure 3 or (c) Procedure 4. Procedure 3 is recommended if bistriazole ketone and epoxyfluconazole are potential impurities Procedure 4 isepoxyfluconazole are potential impurities. Procedure 4 is recommended if fluconazole bromohydrine and epoxyfluconazole are potential impurities. ]

162


Comment received:

The limit for any unspecified impurity according to ICH Q3 (B) based on the Maximum Daily Dose of 400 mg for the drug product is 0.2%.The commenter requested to revise the limit for any other individual q yimpurity (unspecified) in Procedure 4 from 0.1% to 0.2%The Expert Committee did not approve the request because the limit of 0.1% in the proposed procedure is consistent with FDA approved p p p pplimit for this sponsor.

163

Flexible Monograph: Famciclovir

First generic company submitted data for a tentativelyFirst generic company submitted data for a tentatively approved drug.

The monograph was processed and posted on USPThe monograph was processed and posted on USP Website as Pending.

The sponsor obtained full FDA approval.

Need to advance to Official USP monograph.

164

Flexible Monograph: Famciclovir

Two additional submissions: Second generic and the innovator.

The second generic company can use the existing organic impurity procedure in Authorized Pending

h b t ith diff t i it li itmonograph but with different impurity limits.

Innovator has different impurity profile/limits but cannot use existing procedure (Flexible monograph approach)use existing procedure (Flexible monograph approach)

Need to consolidate these specifications from three sponsors in one single monograph! p g g p

165

Famciclovir (Impurity Profile Comparison)

I it N ( i 1) ( i 2) (I t )Impurity Name (generic 1)Limits, NMT (%)

(generic 2)Limits, NMT (%)

(Innovator)Limits, NMT (%)

A 0.05 - -B 0.50 - -C 0.20 - 0.5D 0.60 0.2 0.2E 0.10 - 0.1F 0.10 - -G 0.20 - -H 0.15 - -I 0.10 0.15 0.1G 0.10 - -G 0.10K - - 0.1L - - 0.1M - - 0.1N - - 0.4N 0.4O - - 0.2P - - 0.07

Any unspecified impurity 0.10 0.05 0.06

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p y

Total impurities 1.0 0.50 0.8

Famciclovir (Impurity Profile Comparison)

Additional impurities by Procedure 2 from Innovator only:

Impurity Name (Generic 1)Limits NMT

(Generic 2)Limits NMT (%)

(Innovator)Limits NMT

(PPM)( )

Q NA NA 10

NAR NA NA 5

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Resolution Process in Case of Discrepancy

1. Evaluate the issueIf the discrepancy is in the monograph/ proposal limits contact theIf the discrepancy is in the monograph/ proposal limits, contact the Scientific Liaison

If the discrepancy is regarding the procedure, do the following:

– Evaluate what is not working.2. Confirm correct column and parameters have been used

Column information is available in Pharmacopeial Forum BriefingColumn information is available in Pharmacopeial Forum Briefing

Information is also available form the on-line USP-NF

USP chromatography column data base freely available online in mid-20112011

Make adjustments per <621>

If the adjustments resolve the issue, perform verification as needed

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If the issues persist, contact the Scientific Liaison with the Evaluation Study data

169

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