Impurities in Drug Substances

and Drug Products- A USP

Approach Approach
MODULE II MODULE II
97
Contents Module II
Monographs
USP monograph USP monograph
Pending monograph
General Revision Process
Impurities in Monographs (USP & Pending)
Flexible monographs
Case studies (Examples) Case studies (Examples)
98
Monographs
USP Monographs
For articles approved by FDA for marketing in US
Pending Monographs Pending Monographs
For articles that are tentatively approved by FDA or
under FDA review under FDA review
Monograph development process is the
f b h same for both.
99
Outline
Monographs
USP monograph USP monograph
Pending monograph
General Revision Process
Impurities in Monographs (USP & Pending)
Flexible monographs
Case studies (Examples) Case studies (Examples)
100
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
3
RS 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
Approved Not Approved Next
steps?
7
101
official six months after publication unless otherwise indicated.
Commentary generated.
Outline
Monographs
USP monograph USP monograph
Pending monograph
General Revision Process
Impurities in Monographs (USP & Pending)
Flexible monographs
Case studies (Examples) Case studies (Examples)
102
Impurities in USP Monographs
Based on the sponsors 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 as Drug substances contain process impurities as well as
some degradants
Drug products contain mainly degradants Drug products contain mainly degradants
May include process impurities if they are also degradants
Di ti ti b t i iti d d d t Distinction between process impurities and degradants
become more important when dealing with drug
products. p
104
Outline
Monographs
USP monograph USP monograph
Pending monograph
General Revision Process
Impurities in Monographs (USP & Pending)
Flexible monographs
Case studies (Examples) Case studies (Examples)
105
Flexible Monograph Approach
Need-based flexibility to account for different routes of
synthesis, hydrates, solvates, polymorphs, or formulations
Enables multiple procedures preparations and/or acceptance Enables 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 profiles impurity 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
f 4.10.10. 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 in procedures. 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 appropriate such 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
107
Flexible Monographs: Examples
Emtricitabine
Lopinavir Lopinavir
Paclitaxel
Levofloxacin Levofloxacin
Lamivudine
Fluconazole Injection Fluconazole Injection
Famciclovir
A d And many more
108
Outline
Monographs
USP monograph USP monograph
Pending monograph
General Revision Process
Impurities in Monographs (USP & Pending)
Flexible monographs
Case studies (Examples) Case studies (Examples)
109
Possible Scenarios Regarding Impurities
Sponsor impurity limits are different from USP
Monograph or Pharmacopeial Forum (PF) proposal
limits limits
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 PF Specific impurities of interest are not included in PF
proposal or USP monograph
Multiple scenarios
Resolution of each case with examples
110
Monograph Limits are Different from FDA Approved Limits
Two possible scenarios:
Monograph or PF proposal Limits are wider than FDA Monograph or PF proposal Limits are wider than FDA
approved limits
This does not pose any compliance issue- no resolution
necessary necessary
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
111
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 0.1
Any unspecified degradation 0.1 y g
product
Total 0.35
112
Levetiracetam Tablets
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 th Levetiracetam 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 p
approved limit
The limit for Any individual unspecified degradation product should
be tightened to 0 10% to be consistent with ICH Q3B guidelines
113
be tightened to 0.10% to be consistent with ICH Q3B guidelines
Levetiracetam Tablets
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
Levetiracetam Tablets
PF36(1) proposal was balloted with the following changes PF36(1) proposal was balloted with the following changes
Official in USP34 Supplement 2
Name Limit
NMT %
Levetiracetam acid 0.3
Any individual unspecified 0.1 y
degradation product
Total 0.6
115
Specific Impurities Not Included
Possible scenarios Possible scenarios
Specific impurities come from a different synthetic route
M h t h id d th ifi Monograph sponsor may not have considered the specific
impurities
116
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
117
Trimpramine Maleate
P blished in PF 32(6) for p blic comments Published in PF 32(6) for public comments
Name RRT Acc Criteria Name RRT Acc Criteria
NMT%
Iminodibenzyl 0.49 0.20
Imipramine 0 72 0 20 Imipramine 0.72 0.20
Trimipramine Related
compound A
0.80 0.20
T i i i 1 0 NA Trimipramine 1.0 NA
Any unspecified impurity -- 0.10
Total --- 0.50
118
Trimpramine Maleate
USP received the following comment from an USP 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:
Commenters in-house procedure does not monitor
Trimipramine Related Compound A
119
Trimpramine Maleate
Resolution Steps Resolution Steps
Commenter was asked to evaluate the PF 32(6) procedure
Results of the evaluation indicated PF 32(6) procedure to be Results 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
120
Trimpramine Maleate
Official Monograph in USP34 Supplement 2
Name RRT Acc Criteria
NMT%
Trimipramine N-oxide 0.32 0.15
Iminodibenzyl 0.49 0.20
Desmethyltrimipramine 0 68 0 15 Desmethyltrimipramine 0.68 0.15
Imipramine 0.72 0.20
Trimipramine Related
compound A
0.80 0.20
compound A
Trimipramine 1.0 NA
Trimipramine diamine 2.4 0.30
121
Any unspecified impurity -- 0.10
Total --- 1.0
Galantamine Hydrobromide
Published in PF32(3) [Mar-Apr 2007] for public comments
Name RRT RRF Acc
Criteria Criteria
NMT%
6b -hexahydrogalantamine 0.65 0.96
6 octahydrogalantamine 0.82 0.81 0.35 6 octahydrogalantamine 0.82 0.81 0.35
Galantamine hydrobromide 1.00 1.0
6 -hexahydrogalantamine 1.16 0.95
Tetrahydrogalantamine 2 05 1 2 0 40 Tetrahydrogalantamine 2.05 1.2 0.40
Individual unspecified
impurity
1.0 0.10
Total impurities 1 0
122
Total impurities 1.0
Galantamine Hydrobromide
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
impurities impurities
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
123
Galantamine Hydrobromide
Evaluation indicated that all impurities can be separated without any coelution
issues.
124
Reprinted with permission
Galantamine Hydrobromide
Monograph revised in December 2008 via revision bulletin
I it t bl i d t i l d ll th th i iti ith Impurity table revised to include all the three impurities with
appropriate limits
Note added to identify one additional impurity (Narwedine))
from naturally derived material
125
Galantamine Hydrobromide
Official monograph has the following impurities table
Name RRT RRF Acc
Criteria Criteria
NMT%
N-Desmethylgalantamine 0.29 1.2 0.6
O Desmethylgalantamine 0 35 1 1 0 20 O-Desmethylgalantamine 0.35 1.1 0.20
6 hexahydrogalantamine (also known
as N-galantamine oxide
0.65 0.96 0.20
6 octahydrogalantamine 0 82 0 81 0 35 6 octahydrogalantamine 0.82 0.81 0.35
Galantamine hydrobromide 1.00 1.0
6hexahydrogalantamine (also
known as epigalantamine)
1.16 0.95 0.20
known as epigalantamine)
Narwedine 1.64 1.9 0.15
Tetrahydrogalantamine 2.05 1.2 0.40
126
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
Carbaoxypydilphenyl
methylpiperazine
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
127
Miratazpine Orally Disintegrating Tablets
USP received the following comments from an approved application
holder
The monograph does not monitor two other known degradants
Procedure in PF proposal unsuitable Procedure 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 p
are not required per ICH Q3B guidelines
The procedure takes too long-requires 140 minutes
128
Miratazpine Orally Disintegrating Tablets
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.
129
Miratazpine Orally Disintegrating Tablets
Gradient elution procedure published in PF 37(2) Mar-Apr 2011
Name Relative Acc Name Relative
retention
time
Acc.
Criteria
NMT %
Mirtazapine Related
Compound B
0.23 0.5
Compound B
Miratzapine Related
compound C
0.51 0.5
Mirtazapine Related 0.62 0.5
compound A
Mirtazapine 1.0 __
Mirtazapine Related
compound D
1.3 0.5
compound D
Ind. Unsp. degradant --- 0.5
Total --- 3.0
130
Revised monograph official in
USP35 Supplement 1
Risperidone
Background:
Monograph became official in USP US30 S2 Monograph became official in USP US30 S2
Name RRT Limit
E-oxime 0.60 0.20
Z-oxime 0.67 0.20
9-hydroxyrisperidone 0.76 0.20
5 fl ororisperidone 0 94 0 20 5-fluororisperidone 0.94 0.20
Risperidone 1.0 --
6-methylrisperidone 1.2 0.20
Any individual unsp
impurity
-- 0.10
Total -- 0.30
131
Risperidone
USP received the following comments from an approved application
holder
The monograph does not include two known process impurities from a
different manufacturing process different manufacturing process
The procedure is not selective for the two known process impurities
132
Risperidone
Th l t d th USP h d The company evaluated the USP monograph procedure
D&H
G
133
Risperidone
The company evaluated the USP monograph procedure
Retention time data with USP monograph procedure Retention time data with USP monograph procedure
Name RRT Limit
E-oxime 0.60 0.20
Z-oxime 0.67 0.20
9-hydroxyrisperidone 0.76 0.20
5 fl ororisperidone(D)/ 0 94 0 20 5-fluororisperidone(D)/
Impurity H
0.94 0.20
Risperidone/Impurity G 1.0 --
6 th l i id 1 2 0 20 6-methylrisperidone 1.2 0.20
Any individual unsp
impurity
-- 0.10
134
Total -- 0.30
Risperidone
The company developed an alternative procedure.
H
D
H
G
135
Risperidone
Retention time data with alternative procedure Retention time data with alternative procedure
Name RRT Limit
E-oxime 0.52 0.20
Z-oxime 0.64 0.20
9-hydroxyrisperidone 0.76 0.20
Imp rit H 0 90 Impurity H 0.90
5-fluororisperidone(D) 0.94 0.20
Risperidone 1.0 --
Impurity G 1.08
6-methylrisperidone 1.2 0.20
Any individual -- 0.10
136
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 formulations
Enables multiple procedures preparations and/or acceptance Enables 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 profiles impurity profiles
hydrate-specific water limits/ranges
polymorph-specific crystallinity requirement
May need procedure-specific USP Reference Standards
138
Emtricitabine (Pending Monograph)
There is no Official USP monograph for Emtricitabine at There is no Official USP monograph for Emtricitabine at
this point.
Two ANDA holders submitted tentatively approved Two ANDA holders submitted tentatively approved
specifications.
The monograph was processed as Pending monograph g g g
and posted on the USP Website.
Flexible Monograph approach was used to address
diff t i it fil d li it different impurity profiles and limits.
139
Lopinavir (Official and Pending Monograph)
The innovator sponsored the monograph and was processed
and became Official in USP-NF and became Official in USP NF.
An ANDA holder (not fully approved) sponsored the second
submission with different specifications including different p g
impurity profile/limits.
The monograph was processed as Pending monograph and
t d th USP W b it posted on the USP Website.
140
Lopinavir (Official and Pending Monograph)
Typical comment/query:
From innovator sponsor: The specifications (e.g. impurity
profile/limits) for Pending monograph are different than those in profile/limits) for Pending monograph are different than those in
Official USP monograph.
Request for revision: Change specifications in Pending q g p g
monograph to be consistent with those in Official USP
monograph.
From Generic sponsor: The specifications (e g impurity From 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!
141
Lopinavir (Official and Pending Monograph)
Response:
The specifications in Official USP monographs reflect those fully
approved by FDA and published in USP NF approved 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 be USP 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 pp
USP will evaluate and consolidate the two specifications in a
single monograph as appropriate.
142
Flexible Monograph: Paclitaxel
LabelingThe 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 li sources)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 cell Procedure 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.
143
Flexible Monograph - Inorganic Impurities
Manufacturing process leads to specific inorganic
impurities p
Galantamine Hydrobromide ( Pd)
PF 33(3) proposal included a test for Limit for Pd PF 33(3) proposal included a test for Limit for Pd.
An approved manufacturer commented as follows:
Our process does not use Pd in the process Our process does not use Pd in the process.
Resolution:
EC made the test optional with the following note EC made the test optional with the following note
Limit of Palladium [Note-Perform the test if Pd is known process
impurity]
144
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 it Authorized 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 p
stability, 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[NOTEPerform this test only if acetic acid
is a known organic manufacturing process impurity.]
Limit of 2-propanol [NOTEPerform this test only if 2-propanol
is a known organic manufacturing process impurity.]
146
.
Flexible Monograph: Organic Impurities
Simple example
I iti b t d b t t b tifi d Impurities can be separated but cannot be quantified
Pharmacopeial Forum 31(3) [May-June 2005]
147
Flexible Monograph: Citalopram Hydrobromide
USP received the following comments from an approved application USP received the following comments from an approved application
holder
Not suitable for monitoring two additional process impurities- chloro and
bromo analogs g
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
148
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 p
the analyst to choose the appropriate procedure based on the
knowledge of manufacturing process.
149
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
150
Flexible Monograph: Levofloxacin
O i I iti P d 1 (S 1)
Name
Relative Retention
Time
Relative Response
Factor
Acceptance
Criteria (NMT (%)
Organic Impurities: Procedure 1 (Sponsor 1)
N-Desmethyl
Levofloxacin
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 3 9-Desfluoro
levofloxacin
0.73 1.0 0.3
Levofloxacin 1.0 - -
D I 1 23 1 0 0 8 D-Isomer 1.23 1.0 0.8
Any unknown impurity - 1.0 0.1
151
Total impurities - _ 0.5
(Do not include
D-Isomer)
Flexible Monograph: Levofloxacin
Relative Acceptance Criteria
Organic Impurities: Procedure 2 (Sponsor 2)
Name Retention
Time
(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 10 Any other impurity - 0.10
Total impurities - 0.50
152
Flexible Monograph: Levofloxacin
Organic impurities, Procedure 3 (Sponsor 2)
Acceptance criteria: NMT 1.0% for D-Ofloxacin (D-isomer)
153
Flexible Monograph: Levofloxacin (Comparison)
Name
Acceptance Criteria
NMT (%) Sponsor 1
Acceptance Criteria
NMT (%) Sponsor 2
N-Desmethyl Levofloxacin
(Levofloxacin related compound A)
0.3 0.20
Diamine derivative 0 3 NA Diamine derivative 0.3 NA
Levofloxacin N-Oxide 0.3 NA
9-Desfluoro levofloxacin 0 3 NA 9 Desfluoro levofloxacin 0.3 NA
Levofloxacin - -
D-Isomer 0.8 1.0
Levofloxacin related compound B NA 0.13
Any unknown impurity 0.1 0.10
154
Total impurities 0.5
(Do not include
D Isomer)
0.5
(Do not include
D Isomer)
Flexible Monograph: Levofloxacin
A note was added to specify that the currently official Organic A 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 impurity levofloxacin 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
Name
p ( ( )
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 for Request 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. p
The third sponsor submitted Procedure 4 for different impurity
profile/limits.
Flexible monograph approach was used to accommodate these Flexible monograph approach was used to accommodate these
different impurity profiles/limits.
158
Flexible Monograph: Fluconazole Injection
(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 Impurities
Acceptance 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
( )
Flexible Monograph: Fluconazole Injection
Sponsor 2 Organic imp rities Proced re 3
Name
Relative 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 0.2 Epoxyfluconazole 2.6 0.2
Any other impurity NA 0.2
Total impurities NA 0.5
160
Flexible Monograph: Fluconazole Injection
Sponsor 3 Organic impurities Procedure 4
Name
Relative
Retention
Time
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
161
Any other impurity NA 0.1
Total impurities NA 0.5
Flexible Monograph: Fluconazole Injection
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) [ NOTEOn 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 is epoxyfluconazole are potential impurities. Procedure 4 is
recommended if fluconazole bromohydrine and epoxyfluconazole are
potential impurities. ]
162
Flexible Monograph: Fluconazole Injection
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 y
impurity (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 pp
limit for this sponsor.
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Flexible Monograph: Famciclovir
First generic company submitted data for a tentatively First generic company submitted data for a tentatively
approved drug.
The monograph was processed and posted on USP The monograph was processed and posted on USP
Website as Pending.
The sponsor obtained full FDA approval.
Need to advance to Official USP monograph.
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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 it monograph 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
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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 - 0.5
D 0.60 0.2 0.2
E 0.10 - 0.1
F 0.10 - -
G 0.20 - -
H 0.15 - -
I 0.10 0.15 0.1
G 0.10 - - G 0.10
K - - 0.1
L - - 0.1
M - - 0.1
N - - 0.4 N 0.4
O - - 0.2
P - - 0.07
Any unspecified
impurity 0.10 0.05 0.06
166
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
NA
R
NA
NA 5
167
Resolution Process in Case of Discrepancy
1. Evaluate the issue
If the discrepancy is in the monograph/ proposal limits contact the If 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 Briefing Column 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-
2011 2011
Make adjustments per <621>
If the adjustments resolve the issue, perform verification as needed
168
If the issues persist, contact the Scientific Liaison with the Evaluation
Study data
169
170