USP30 NF25FirstSupplementRevisionCommentary PDF

COMMENTARY—1ST SUPPLEMENT TO USP30 - NF25
Revision proposals published in Pharmacopeial Forum often elicit public comments that
are forwarded to the appropriate Expert Committee for review and response. Some
revision proposals can advance to official status with necessary modifications without
requiring further public review. In such cases a summary of comments received and the
Expert Committee's responses are published in the Commentary section of USP website
at the time the revision becomes official. For those proposals that require further
revision and republication in Pharmacopeial Forum, a summary of the comments and
the Committee's responses will be included in the briefing that accompanies the
publication.
The Commentary section is not part of the official text of the monograph and is not
intended to be enforceable by regulatory authorities. Rather, it explains the basis for the
Expert Committee's response to public comments. If there is a difference between the
contents of the Commentary section and the official monograph, the text of the official
monograph prevails. In case of a dispute or question of interpretation, the language of
the official text, alone and independent of the Commentary section, shall prevail.
Where appropriate, the Commentary includes a separate discussion of proposals related

to international harmonization of the USP, the European Pharmacopoeia, and the
Japanese Pharmacopoeia in order to highlight such proposals.
The Commentary is presented in the following order: USP Monographs, Dietary

Supplement Monographs, General Chapters, NF Monographs.
USP MONOGRAPHS
Monograph/Section: Allopurinol/Multiple sections
Expert Committee: MD-GRE
No. of Commenters: 2
Comment summary #1: Commenter suggested that a proposal for Related compounds,
previously submitted by the commenter and published in PF 28(5), be reconsidered by
the Committee.
Response: Comment not incorporated. The Committee decided that it is beneficial to
have a single method for impurity analysis in the monograph, as compared to two
separate methods proposed by the commenter.
Comment summary #2: Commenter requested the Related compounds proposal be
deferred from becoming official until the required USP Reference Standards are
available for sale, and the commenter can evaluate the proposed method.
Response: Comment not incorporated. The Committee recognized that the required
USP Reference Standards will be available by the time the 1st Supplement to USP 30
becomes official. Although the Committee is not delaying approval of the monograph for
official status on this point, the Committee is willing to consider further changes to this
monograph in the future if the commenter submits a Request for Revision.
Monograph/Section: Aluminum Sulfate and Calcium Acetate for Topical Solution/Title

Expert Committee: NOM
Expert Committee-initiated change for the title: The Committee reviewed the
submitted title “Aluminum Sulfate and Calcium Acetate Powder for Topical Solution.”
The Committee noted that there are currently no USP monographs with titles like
“[Drug][Powder] for Oral Solution” or “[Drug][Powder] for Topical Solution.” Therefore,
the title was changed from “Aluminum Sulfate and Calcium Acetate Powder for Topical
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Solution” to “Aluminum Sulfate and Calcium Acetate for Topical Solution” and
corresponding changes were made in the monograph.
Monograph/Section: Amlodipine Besylate

Expert Committee: MD-CV
Comment Summary: Two commenters stated that the proposed Related compounds
test cannot detect all of the process impurities and the degradation products. One of the
commenters is developing a new method that can detect all of the impurities.
Response: Comment not incorporated at this time because the comment was not
supported by the required data. The Committee will consider publishing a revision in a
future PF upon receipt of the new method and the associated validation data.
Monograph/Section: Bismuth Subsalicylate Oral Suspension

Expert Committee: MD-CCA
Comment Summary: Commenter indicated that the proposed storage statement is
overly restricted and does not reflect the current marketed product label storage
conditions. The commenter suggested that storage conditions be modified from “Store
between 15 and 30°” to read: “Protect from freezing. Avoid excessive heat (over 40º).”
Response: The Committee decided not to incorporate the comment at this time since
the proposed change will appear in PF 33(1) and to temporarily remove the Packaging
and Storage section from the monograph.
Monograph/Section: Bismuth Subsalicylate Tablets

Comment Summary: Commenter indicated that the proposed storage statement is
overly restricted and does not reflect the current marketed product label storage
conditions. The commenter suggested that storage conditions be modified from “Store
between 15 and 30” to read: “Avoid excessive heat (over 40º).”
Response: Comment not incorporated at this time because the change proposed by the
commenter appeared as an In-Process Revision in PF 32(5).
Expert Committee-initiated Change: Because the Packaging and Storage section of
the monograph is the subject of an In-Process Revision published in PF 32(5), the
Committee decided to move the monograph into official status without the Packaging
and Storage, with that section to be made official at a later date.
Monograph/Section: Bisoctrizole
Expert Committee: MD-OOD
Comment Summary #1: Commenter suggested that the broader requirements in
General Chapter <467> Residual Solvents should be applied.
Response: Comment incorporated. The Committee decided to delete the Limit of
residual solvents according to the USP’s policy on residual solvents. The control of the
residual solvents is covered in the USP General Notices.
Comment Summary #2: Commenter suggested that a test for Residue on Ignition (ROI)
be added.
Response: Comment not incorporated at this time because the Committee reviewed the
USP 29 and found that most monographs for UV filters used in sunscreen products do
not have a ROI test.
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Comment Summary #3: Commenter suggested that a test for Loss on Drying (LOD) be
added.
Response: Comment not incorporated. The Committee determined that this test is
unnecessary because the assay is calculated on the as-is basis.
Monograph/Section: Budesonide
Expert Committee: MD-PS
Comment Summary #1: Commenter suggested the following changes:
- Change the test solution concentration in the Identification test B, Ultraviolet
Absorption <197U> from 50 µg per mL to 25 µg per mL because the
absorbance reading is too high at 50 µg per mL.
- Change the name of sodium dihydrogen phosphate, the reagent used to
prepare the Buffer solution in the Assay, to monobasic sodium phosphate,
the correct name provided in the Reagent section of USP.
Response: Comment incorporated.
- Change the limit of 21-acetate of budesonide from NMT 0.1% to NMT 0.10%
in the test for Limit of 21-acetate of budesonide.
- Add the following missing information to the Procedure in the test for Limit of
11-ketobudesonide “Maintain the column at 50o.”
- Change the column particle size from 3.5 µm to 5 µm in the Chromatographic
system section under the test for Related compounds.
- Specify the limits of the following impurities to two decimal places in the test
for Related compounds: D-homobudesonide from NMT 0.1% to NMT 0.10%,
14,15-dehydrobudesonide from NMT 0.1% to NMT 0.10%, and “any other
unknown impurity” from NMT 0.1% to NMT 0.10%.
- Add a relative retention time of 0.66 to the relative retention time of 0.61
provided for 21-dehydrobudesonide because the two epimers of this impurity
are resolved in the Related compounds procedure.
- Add the following missing information to the procedure for preparing the
Standard preparation “The proportion of acetonitrile in the Standard
preparation does not exceed 30%.”
- Change the formula provided under Procedure in the Assay to calculate
percentage of epimer A in Budesonide rather than the quantity of epimer A.
Comment Summary #3: Commenter suggested the following changes in the Limit of
21-acetate of budesonide, Limit of ketobudesonide, and Related compound procedures:
- Change the detector wavelengths in each procedure from 254 nm to 245nm.
- Develop a single procedure for determining both 21-acetate of budesonide
and ketobudesonide.
- 11-ketobudesonide could potentially co-elute with budesonide in the Related
compounds and the 21-acetate of budesonide procedures.
Response: Comment not incorporated due to the lack of supporting data. The
Committee is willing to consider revising these procedures once USP receives the
required supporting data.
Comment Summary #4: Commenter noted that 11-ketobudesonide could potentially
co-elute with budesonide in the Related compounds and in the Assay procedures.
Response: Comment not incorporated since there is a separate test for limit of 11-
ketobudesonide. Also see Response to Comment Summary #3.
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Expert Committee-initiated change: Included a chemical structure of Budesonide and

designated epimer A and epimer B in the Definition.
Expert Committee-initiated change: Added the following note “Protect all solutions
containing budesonide from light” at the beginning of the monograph and removed
similar statements from different sections of the monograph.
Expert Committee-initiated change: Deleted the Limit of methanol test since this is
manufacturer-specific test and the limit provided for this solvent is covered by the
requirements of the Residual solvents <467> General Chapter, as stated in the General
Notices.
Expert Committee-initiated change: Provided chemical names of all impurities listed
in the Table under the test for Related compounds.
Monograph/Section: Cefepime Hydrochloride/Limit of N-methylpyrrolidine; Related

compounds
Expert Committee: MD-ANT
Comment Summary #1: Commenter suggested a new column rinse solution for the
Limit of N-methylpyrrolidine test to more adequately clean the column and decrease
analysis time.
Comment Summary #2: For the Related compounds test the commenter questioned
the validity of adjusting the pH of the Mobile phase component solutions after the
addition of organic.
Response: Comment not incorporated. The Committee believes that the current Mobile
phase preparation is valid. The commenter did not supply data to support a revision.
Comment Summary #1: Commenter provided date to demonstrate that the Test
solution is stable for up to 6 hours if maintained at 5°.
Response: Comment incorporated. A Note was added to the monograph to reflect this.
Monograph/Section: Chlorhexidine Gluconate Solution /Definition and Assay

Expert Committee: MD-AA
Comment Summary: Commenter suggested changing the molecular weight of
Chlorhexidine Gluconate from 897.77 to 897.76 to be consistent with that in the USP
Dictionary.
Monograph/Section: Chlorhexidine Gluconate Oral Rinse/ Assay

Comment Summary: Commenter suggested changing the molecular weight of
Chlorhexidine Gluconate from 897.77 to 897.76 to be consistent with that in the USP
Dictionary.
Monograph/Section: Ciprofloxacin and Dexamethasone Otic Suspension/Multiple

sections
Comment Summary #1: Commenter suggested that the formula for ciprofloxacin
related compounds should include multiplication by (331.34/367.81) since the
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concentration of the Dilute standard preparation is in terms of USP Ciprofloxacin

Hydrochloride RS but L is the label claim as ciprofloxacin free base.
Comment Summary #2: Commenter suggested the limit for the 21-dehydro-17-deoxy
related compound in the test for Dexamethasone related compounds be changed from
NMT 0.6% to 1.0% and the sum of all related compounds be changed from NMT 3.0% to
3.5% to be consistent with approved specification in NDA.
Expert Committee-initiated change: In the Limit of ciprofloxacin formamide, Test
solution; Assay for ciprofloxacin, Assay preparation; and Assay for dexamethasone,
Assay preparation sections, the wording was changed from “transfer an accurately
weighted portion…” to “transfer an accurately measured volume …” to be consistent with
the term “volume” used in the corresponding formula in each section.
Monograph/Section: Desmopressin Acetate

Expert Committee: BB-PP
Comment Summary #1: One commenter suggested replacing the UV ID test with
HPLC retention time. Another commenter suggested replacing the UV ID test with an IR
ID test.
Response: Comment partially incorporated. The UV ID test was removed from the
monograph. An HPLC retention time is already included in the monograph. The
Committee determined that an additional IR ID test is not necessary at this time.
Comment Summary #2: Commenter questioned the need for a Microbial limits test for
material that may only be used in a solid oral dosage form.
Response: Comment not incorporated. The Committee decided microbial
contamination should be limited in the material because of the potential effects of
microbial contamination on the stability of the material.
Comment Summary #3: Commenter suggested raising the total aerobic microbial
count to “does not exceed 1000 cfu per g.”
Response: Comment not incorporated. The Committee decided not to raise the
aerobic microbial count limit to 1000 cfu per g due to concerns about the effect of
microbial contamination on the stability of the peptide.
Comment Summary #4: Commenter suggested changing the Water test to method Ic
to allow a smaller amount of sample to be used.
Comment Summary #5: Commenter suggested adding a lower limit of not more than
3% acetate.
Comment Summary #6: Commenter suggested that the Assay and Chromatographic
purity methods are not entirely consistent with FDA approved methods, and that a
validated method is needed.
Response: Comment not incorporated. Both the Assay and Chromatographic purity
methods had validation packages submitted with the proposed monograph.
Comment Summary #7: Commenter suggested that a 1:100 dilution of the test solution
be used in the Chromatographic purity test instead of a preparation using the reference
standard. The commenter also indicated that the reference standard needs to be
corrected for both water and acetic acid content.
Response: Comment not incorporated. The concerns raised by the commenter may be
addressed by the format of the reference standard. The Committee may recommend
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that the reference standard be packaged in such a manner that the content of water and
acetic acid do not need to be determined.
Comment Summary #8: Commenter suggested allowing an alternative method for
Amino Acid Content test.
Response: Comment incorporated. The monograph was changed to allow for other
methods of Amino Acid Analysis.
Comment Summary #9: Commenter suggested adding lower limit of not more than 3%
for acetic acid in the Acetic Acid Content test.
Comment Summary #10: Commenter suggested adding a limit test for trifluoroacetic
acid.
Response: Comment not incorporated because trifluoroacetic acid is considered a
process impurity and may not be present if other methods of synthesis are used.
Comment Summary #11: Commenter suggested adding specifications for residual
solvents.
Response: Comment not incorporated at this time.
Monograph/Section: Desmopressin Acetate Injection
Comment Summary: Commenter proposed the addition of a Chromatographic Purity
test to the monograph.
Response: The Committee believes that a Chromatographic Purity test or a Related
compounds is appropriate for this monograph and will add one as soon as one becomes
available.
Monograph/Section: Desogestrel and Ethinyl Estradiol Tablets/Multiple Sections

Comment Summary #1: Two commenters suggested the Thin-layer chromatographic
identification test use the same solvent (ether) to prepare both the test solution and
standard solution
Comment Summary #2: Commenter suggested replacing “25 Tablets” with powdered
tablets equivalent to 1.5 mg desogestrel and 0.3 mg ethinyl estradiol in the Thin-layer
chromatographic identification test to ensure the concentrations of the drug substances
in the test solution and standard solution are the same.
Comment Summary #3: Three commenters suggested revising the test for Related
compounds. One commenter suggested the test be revised for the following reasons:
the detection limits of some of the impurities are close to the specified limits; well known
degradation products of the drugs are not specified but the procedure rather specifies
process impurities; and there may be severe interference from an excipient. Another
commenter suggested that the test be revised because the procedure is inadequate in
specifying known impurities of desogestrel and ethinyl estradiol. A third commenter
suggested revising the test for the following reasons: known degradation products of the
drugs are not specified but the procedure rather specifies process impurities; excessive
baseline noise; and the system suitability requirements could not be met.
Response: Comment incorporated; the Related compounds test is not being made
official at this time because of this and several other reported deficiencies. The
Committee is willing to consider a revised Related compounds test capable of
determining the known impurities of these drugs.
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Comment Summary #4: Commenter suggested a correction to the formula in the

Assay for calculating the content of desogestrel and ethinyl estradiol.
Comment Summary #5: Commenter suggested that the test for Water be deleted.
Response: Comment incorporated. See Expert Committee-initiated change below.
Expert Committee-initiated change:
- Added an identification test that compares the retention times of peaks obtained
from standard and sample preparations in the Assay.
- Deleted the Loss on drying test and the test for Water because the total water
content is dependent upon the identity of the excipients and it would be difficult to
establish meaningful criteria that would apply to all formulations. The drug
product manufacturer should establish the limits for their product based on
scientific evaluation of their own formulation performance and stability data.
Monograph/Section: Didanosine/Related compounds and <11>

Expert Committee-initiated change: Since all the related compound USP Reference
Standards for this test were not expected to be available at the time of publication of the
First Supplement, the Committee decided not to include the related compounds section
in the monograph at this time. This section will be reviewed at a later time when all the
related compounds Reference Standards become available. Therefore, the related
compounds Reference Standards were deleted from <11> section of this monograph.
Monograph/Section: Diphenoxylate HCl and Atropine Sulfate Oral Solution and

Tablets/Assay
Comment summary: Two commenters reported a problem meeting a tailing
requirement for diphenoxylate peak, and suggested that the tailing requirement be
modified or removed from the monograph.
Response: Comment incorporated. The Committee agreed to remove the tailing
requirement for the diphenoxylate peak from the monograph, and to add a Note
suggesting that maintaining column temperature may be helpful if a significant tailing of
diphenoxylate peak is observed. Because no comments were received regarding the
tailing factor for the atropine peak, this requirement was retained. The Committee
recognizes that despite the tailing problem for one of the components, it is beneficial to
have a single Assay method for both components as proposed in these revisions.
Monograph/Section: Doxepin Hydrochloride/Related compounds

Expert Committee: MD-PP
Comment Summary #1: Two commenters requested that a Note be added to the
Related compounds test indicating the need to include both E and Z isomers responses
of doxepin in the calculation of unspecified impurity.
Comment Summary #2: Commenter indicated that there may be selectivity change
depending on the type of column and therefore provision must be made to ensure the
proper identification of Related compounds B and C.
Response: Comment incorporated. The concentration of Related compound C has
been increased by a factor of two to enable easy identification.
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Monograph/Section: Dronabinol/Related compounds

Comment summary: Commenter requested the proposal to be deferred from becoming
official until the required USP Reference Standards are available for sale, and the
Commenter can evaluate the proposed method.
Response: Comment not incorporated because the required USP Reference Standards
will be available by the time the 1st Supplement to USP 30 becomes official. Although
the Committee is not delaying approval of the monograph for official status, the
Committee is willing to consider further changes to this monograph in the future if the
commenter submits a Request for Revision.
Monograph/Section: Drospirenone
Comment Summary: Commenter suggested that known impurities should be identified
and relative response factors provided for calculating the limits in the Chromatographic
purity section.
Response: Comment not incorporated. The sponsor indicated that relative response
factors were not used when the limits were established. The Committee is willing to
consider a revised Chromatographic purity test that uses the relative response factors to
calculate the impurity limits with corresponding revised impurity limits.
Expert Committee-initiated change: Changed the title of the residual solvent test to
“Limit of 1,2-dimethoxyethane and diisopropyl ether, if present.” The residual solvent
test is manufacturer-specific, but the limits provided for the test are not covered by the
requirements of General Chapter <467> Residual Solvents.
Monograph/Section: Estradiol and Norethindrone Acetate Tablets

- Reinstate the limit of NMT 0.5% for any individual unknown impurity in the
Chromatographic purity test as published in the original proposal; and clarify that
the total limit for the combined estradiol and norethindrone acetate impurities is
NMT 1.0%.
-Delete limits erroneously included for estradiol and norethindrone acetate in the
impurity tables in the Chromatographic purity test.
- Correct all concentrations provided as µL per mL to µg per mL in the Assay.
Response: Comments incorporated.
Comment Summary #2: Commenter suggested replacing the Thin-Layer
Chromatographic Identification test with an identification test that compares the retention
times of peaks obtained from standard and sample preparations in the Assay.
Response: Comment partially incorporated. The Committee has added a second
identification test based on the retention times of the drug substances in the Assay.
Comment Summary #3: Commenter suggested replacing the test for Loss on drying
with a test for Water.
Response: Comment partially incorporated. The Committee deleted the test for Loss
on drying but concluded that the water content is dependent upon the identity of the
excipients and it thus would be difficult to establish meaningful criteria that would apply
to all formulations.
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Comment Summary #4: Commenter suggested deleting all process related impurities
that are monitored in the Chromatographic purity test.
Response: Comment not incorporated. The Committee is retaining the process related
impurities in the Chromatographic purity procedure but is willing to consider deleting
these impurities from the test in the future if related compound tests that monitor these
impurities are included in the official monographs for the two drug substances.
Expert Committee-initiated change: The Microbial limits section was deferred from
becoming official because the proposed test contains tests for the absence of
Salmonella, which is not recommended for tablets.
Monograph/Section: Famotidine Injection

Comment summary #1: Commenter reported a significant tailing when the proposed
method for Related compounds and Assay was used. No alternative procedure was
submitted with the comment.
Response: Comment not incorporated. Although the Committee is not delaying
approval of the monograph for official status, the Committee is willing to consider further
changes to this monograph in the future if a Request for Revision is submitted.
Comment Summary #2: Commenter suggested that the proposed requirements for the
Content of Benzyl alcohol be revised to include a reference to General Chapter <1>
Injections. General Chapter <1> Injections allows a wider range of benzyl alcohol
content that the currently proposed range of 90.0-110.0% of the labeled amount.
Monograph/Section: Fexofenadine Hydrochloride Tablets

Comment Summary #1: Commenter suggested the following changes in the limits of
impurities in the Related compounds test:
- Increase the limit of fexofenadine related compound A from NMT 0.35% to
NMT 0.4%.
- Increase the limit of any individual other impurity from 0.1% to 0.2%.
- Delete the requirement of NMT 0.15% for total other impurities.
Response: Comment incorporated to accommodate multiple manufacturers.
Comment Summary #2: One commenter suggested that a process impurity,
fexofenadine related compound B, could potentially co-elute with fexofenadine in the
Related compounds test and also in the Assay.
Response: Comment not incorporated since some manufacturing processes do not
produce this impurity. Although the Committee is not delaying approval of the
monograph for official status, the Committee is willing to consider further revisions to the
monograph to accommodate products that have this impurity if a Request for Revision is
submitted.
Expert Committee-initiated change: Deleted the test for Water because the total
water content is dependent upon the identity of the excipients and it would be difficult to
establish meaningful criteria that would apply to all formulations. The drug product
manufacturer should establish the limits for their product based on scientific evaluation
of their own formulation performance and stability data.
Expert Committee-initiated change: Increased the relative standard deviation
requirement for replicate injections of the Standard solution in the Related compounds
procedure from NMT 1.4% to NMT 2.0% for fexofenadine and from NMT 2.8% to NMT
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3.0% for fexofenadine related compound A to make the requirements less restrictive.
The Committee similarly increased the relative standard deviation requirement for
replicate injections of the Standard preparation in the Assay procedure from NMT 1.4%
to NMT 2.0% for fexofenadine.
Monograph/Section: Fluorometholone Acetate

Comment Summary: Commenters suggested the following changes which are based
on updated data and information:
- Change Assay limits from 98.0 – 102.0% to 98.0 – 101.0%
- Delete the absorptivity calculation requirement included in the identification test
B.
- Delete the third identification test included in the monograph -- thin-layer
identification test.
- Change the Chromatographic purity test to the improved Related compounds
test that lists in a tabular form, the related compounds of fluorometholone acetate
and provide relative response factors for the calculation of the limits of these
impurities.
- Two commenters suggested changing the Mobile phase composition from
water and acetonitrile (50:50, v/v) to water and acetonitrile (60:40, v/v), in the
Related compounds test and the Assay.
- Rename the Resolution solution in the Assay and Related compounds test,
System suitability solution and change the concentration of fluorometholone
acetate and fluorometholone from 0.5 mg per mL each to 0.03 mg per mL each.
- Under Chromatographic system in the Assay, two commenters suggested
changing the flow rate from 1.0 mL per minute to 1.5 mL per minute. One
commenter also suggested changing the resolution requirement of 4.0 between
fluorometholone and fluorometholone acetate to 10, and add column efficiency
requirement of 10,000 plates.
- Change the injection volume from 20 µL to 10 µL under Procedure in the Assay.
Response: Comment incorporated. The Committee determined after review of available
data that the changes in the chromatographic system are necessary for the separation
and quantitation of fluorometholone acetate and related compounds.
Expert Committee-initiated change: Inserted fluorometholone acetate chemical
structure and the chemical name in the monograph
Expert Committee-initiated change: Specified the use of peak height in the
calculation of levels of fluorometholone and fluorometholone diacetate as used for these
two impurities in the validation of the Related compounds test.
Monograph/Section: Fluvoxamine Maleate Tablets/Related compounds

Comment summary: Proposed related compounds test will not allow a specified
impurity to be quantified due to co-elution.
Response: Comment incorporated. The Committee has adopted a flexible monograph
approach by adding a second test.
Monograph/Section: Fosinopril Sodium

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Comment Summary #1: Commenter suggested a revision of the chemical names of

fosinopril related compound B and fosinopril related compound F in the footnotes under
Table 1.
Comment Summary #2: Commenter requested a revision to the Related compound
test method as the peak for impurity A is very broad and is difficult to quantitate and
because the LOD is same as the limits specified for impurity A. The commenter also
stated that the method is non specific with respect to the impurity F and impurity D.
Response: Comment not incorporated at this time. The commenter's suggested
method is not completely validated for all the related compounds. The Committee will
consider publishing a revision to this monograph in a future PF upon receipt of a
Request for Revision.
Comment Summary #3: Commenter is not able to meet the resolution requirement in
Test 3 for fosinopril related compound E and fosinopril related compound F. Other
commenters stated that there is no issue with this test.
Response: No change made to Test 3 at this time. However, the Committee is willing to
consider future revision and requested additional information.
Comment Summary #4: Commenter suggested revising the relative retention time
(RRT) for impurity 1 (0.12 in PF to 0.58) and impurity 2 (0.24 in PF to 0.71).
Response: Comment incorporated after confirming the RRT of these two impurities
(0.53 and 0.67). The RRT information is provided in the monograph for information
purposes only and is not a compendial requirement.
Monograph/Section: Fosinopril Sodium and Hydrochlorothiazide Tablets

Comment Summary: Commenter questioned whether the final dilution in preparing the
resolution solution for the Dissolution test is to be done using water or methanol.
Response: Comment incorporated. The language was revised to indicate that water
was used to dilute the resolution solution.
Monograph/Section: Gonadorelin Acetate/Multiple Sections

- In Limit of acetic acid and trifluoroacetic acid test, change the limit of acetic acid
from “between 8% and 12.5%” to “between 4.0% to 7.5%.”
- In Related compounds test, change the limit of any individual impurity from “not
more than 1%” to “not more than 0.5%.”
Response: Comment not incorporated. The Committee understood that both
comments related to the drug substance as it is approved for manufacture into human
drug products. According to information later received by the Committee, all human
products in the United States have been discontinued. The only FDA-approved
gonadorelin acetate products currently marketed in the United States are for veterinary
use; the proposed monograph was developed according to the tests and specifications
of a FDA-approved veterinary article. Thus, the Committee has declined to change the
limits for acetic acid and for individual impurities.
Comment Summary #2: In the Packaging and storage section, Commenter suggested
changing the storage temperature conditions from “between –25° and –10°” to “not more
than 8°; the latter temperature is similar to that stated for this article in the European
Pharmacopoeia and the commenter provided supporting stability data.
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Response: Comment partially incorporated. The Committee reviewed the submitted

data and changed the storage temperature to “not more than 8°.”
Comment Summary #3: In Identification A, Commenter suggested replacing the mass
spectrometric test with a TLC test.
Response: Comment not incorporated. The Committee declined to replace the mass
spectrometric test with a TLC test at this time, being of the opinion that a TLC test is not
sufficiently specific to identify a small peptide.
Comment Summary #4: In Water test, Commenter suggested changing the limit of
water content from “not more than 7.0%” to “not more than 7.0% for the monoacetate
form and from 4.0% to 7.0% for the diacetate form.”
Response: Comment not incorporated. This comment related to articles intended for
manufacture of human dosage forms and the human drug products have been
discontinued in the United States. As indicated below, the Committee decided to add a
Labeling statement indicating that the article be labeled for “veterinary use only.”
Comment Summary #5: In Related compounds test, Commenter suggested replacing
the proposed methods with an alternative.
Response: Comment not incorporated, as the commenter did not provide a rationale for
this replacement.
Expert Committee-initiated Change: To reflect the current regulatory status of
gonadorelin acetate in the United States, the following Labeling statement has been
added to the monograph: “Label it to indicate it is for veterinary use only.”
Monograph/Section: Human Insulin Isophane Suspension and Human Insulin Injection

Comment Summary: Commenter objected to the term Biphasic Isophane Insulin
Human Suspension in that this product is a combination product and this nomenclature
is not consistent with the current label.
Response: Comment incorporated. The Committee approved the name Human Insulin
Isophane Suspension and Human Insulin Injection.
Monograph/Section: Hydrocodone Bitartrate/ Related compounds test

Comment Summary: Commenter indicated that they encountered co-elution and
resolution problems with the proposed Related compounds test proposed in PF 30(5).
Response: The Committee decided not to make the Related compounds test section
official at this time. The Committee will work to develop a more satisfactory method for
future adoption.
Monograph/Section: Hydrocodone Bitartrate and Homatropine Methylbromide Tablets

Expert Committee-initiated change: The Committee decided to approve the
monograph as official with the exception of the dissolution section, which has not yet
been approved by the Biopharmaceutics Committee.
Monograph/Sections: Ibuprofen/ USP Reference standards; Limit of; Assay.

12
Comment Summary #1: Commenter claimed that the title “impurity C”, a specified
impurity, is already assigned to an amide in Ph. Eur. while the 4-isobutylactetophenone
(IBAP) (referred to as impurity C in the USP) is already assigned as impurity E in the
former publication. Commenter suggests harmonization with existing Ph. Eur.
monograph and name IBAP as “Related Compound E” to prevent confusion within the
industry.
Response: Comment not incorporated because it is against USP's policy to approve a
name change to a reference standard which has already appeared in the Reference
Standard Catalog.
Comment Summary #2: Commenter suggested USP harmonize with Ph. Eur. and
adopt a gradient HPLC method (in lieu of the current isocratic LC method) that would
detect potential impurities present in Ibuprofen to safeguard public safety.
Response: Comment not incorporated. The Committee suggests putting the entire
gradient HPLC method in future PF for public comments. The Committee requests that
the commenter provide chromatograms that indicate that the current USP method is
incapable of detecting these impurities.
Monograph/Sections: Ibuprofen Oral Suspension/ USP Reference standards; Limit of;

Assay
Comment Summary #1: Commenter claimed that “impurity C”, a specified impurity, is
already assigned to an amide in Ph. Eur. while the 4-isobutylactetophenone (IBAP)
(referred to as impurity C in the USP is already assigned as impurity E in the former
publication. Commenter suggests harmonization with existing Ph. Eur. monograph and
name IBAP as “Related Compound E” to prevent confusion within the industry.
Standard Catalog.
Monograph/Sections: Ibuprofen Tablets/ USP Reference standards; Limit of; Assay.

Comment Summary #1: Commenter claimed that “impurity C,” a specified impurity, is
already assigned to an amide in Ph. Eur. while the 4-isobutylactetophenone (IBAP)
(referred to as impurity C in the USP) is already assigned as impurity E in the former
publication. Commenter suggests harmonization with existing Ph. Eur. monograph and
name IBAP as “Related Compound E” to prevent confusion within the industry.
Standard Catalog.
Summary Comment #2: Commenter objected to the revision to the preparation of the
(4-IBAP) standard solution and recommended deleting the current concentration “of
about 0.12 mg per mL” as it is an approximation and could be misleading.
Monograph/Section: Irbesartan/Multiple sections

Comment Summary #1: The commenter suggested the following Assay limit of 98%-
102% be revised to 97%-102.5%.
13
Response: Comment not incorporated. The Committee will consider further revisions to
the monograph as suggested if the commenter is able to provide validation for the
suggested limits.
Comment Summary #2: Commenter suggested revising the concentration of the test
solution from 0.5 mg /ml to 1 mg/ml.
Comment Summary #3: Commenter suggested revising the calculations for the other
impurities.
Comment Summary #4: Commenter suggested deleting the preparation of the Diluted
standard solution.
Monograph/Section: Irbesartan Tablets

Comment Summary #1: Commenter suggested using tablets for preparing the sample
solution in the Assay instead of powdered tablets,
Response: Comment not incorporated. The Committee believes that grinding tablets
prior to extraction allows for a more robust procedure and the analyst should be able to
handle the extra precautions necessary.
Comment Summary #2: Commenter suggested revising the limits for the irbesartan
related compound A, and the total impurities from 0.3% and 0.6% to 0.2% and 0.5%.
Comment Summary #3: Commenter suggested revising the verbiage used in the
description of the procedure to prepare the test solution.
Response: Comment not incorporated. The Committee believes that the current USP
text conveys the intended message without any confusion to the user.
Monograph/Section: Isosorbide Mononitrate Tablets

Comment Summary: Commenter suggested revising the Isosorbide mononitrate RS
and the Isosorbide related compound A RS to Diluted Isosorbide mononitrate RS and
Diluted Isosorbide mononitrate related compound A RS.
Monograph/Section: Lidocaine and Prilocaine Cream

Comment Summary #1: Commenter suggested the following changes based on their
approved product:
- Change Assay limits from 95.0 – 105.0% to 90.0 – 110.0%.
- Change the storage requirements from "store at controlled room temperature"
to "do not store above 30o and do not freeze."
- Consider using prilocaine free base as the USP reference standard rather than
prilocaine hydrochloride.
- Revise the test of pH to include determinations on undiluted Cream.
Comment Summary #2: Commenter suggested making the following changes in the
test for Related compounds:
14
- Delete all process related impurities that are monitored in the test.
- Clarify the definitions of the following terms used in the formula for calculating
impurities: ru, rs, and L.
- Change the limit of o-toluidine from NMT 0.1% to NMT 2.0% and change the
limit of 2,6-dimethylaniline from NMT 0.1% to NMT 0.04%.
- Simplify the sample preparation procedure.
- Delete requirement to keep solutions at 10o during injection as the samples are
stable at room temperature.
- Improve the procedure to resolve prilocaine and related compound B as these
are not baseline resolved.
Response: After reviewing available data, the Committee concluded that issues related
to the impurity limits and other aspects of the Related compounds test need to be
resolved before the test is made official. Therefore, the Committee approved the
monograph as official without the Related compounds test. The limit for total impurities
in the Related compounds test is NMT 1.0.
Expert Committee-initiated change: Made editorial changes in the Identification test to
indicate that the retention times of both lidocaine and prilocaine from injections of
Standard preparation and Assay preparation are compared.
Monograph/Section: Meloxicam
Comment Summary: Commenter pointed out that the method proposed in PF used an
Intersil ODS-2 column and a mobile phase pH buffer of 9.1, and that the manufacturer’s
recommended pH range for the column is 2-8.
Response: Comment not incorporated at this time. The Committee feels that the
sponsor of the monograph had demonstrated adequately that the high pH did not affect
the stability of the column. The Committee will consider a flexible monograph approach
because the commenter has provided a fully validated proposal.
Expert Committee-initiated change: The Committee decided to approve the
monograph as official without the dissolution section which has not yet been approved
by the Biopharmaceutics Expert Committee.
Monograph/Section: Mupirocin Calcium

Comment Summary #1: Commenter recommended that the Crystallinity test be
removed as it would exclude other forms of Mupirocin.
Comment Summary #2: A commenter requested that an X-ray diffraction test be
added.
Responses: Comment not incorporated. The Committee did not incorporate the X-ray
diffraction test as it could exclude other forms of Mupirocin.
Monograph/Section: Mupirocin Cream

Comment Summary: Commenter requested that the pH range be widened.
Response: Comment not incorporated. The Committee did not find the supporting
documentation adequate to support the change.
15
Monograph/Section: Norgestimate and Ethinyl Estradiol Tablets

Comment Summary #1: Commenter suggested that the Assay limits be changed from
90.0 – 110.0% to 88.0 – 112.0%
Response: Comment not incorporated, following the Committee's review of the
available data and comments.
Comment Summary #2: Commenter suggested the following changes to the Assay:
- Change the pore size of the filter used to filter Standard preparation and Assay
preparation in the Assay from 0.2 µm to 0.45 µm.
- Change the relative standard deviation requirement for replicate injections of
(Z)-norgestimate, (E)-norgestimate, and ethinyl estradiol from 3.0% to 2.0% in
the Chromatographic system section of the Assay.
Comment Summary #3: Commenter suggested the following changes to the Assay:
- Change the detection wavelength from 230 nm to 225 nm.
- Change flow rate from 2.1 mL per minute to 1.2 mL per minute.
- Change injection volume from 25 µL to 50 µL.
Response: Comments not incorporated, following the Committee's review of the
available data and comments.
Comment Summary #4: Two commenters suggested changing the relative standard
deviation requirement for replicate injections of norgestimate and ethinyl estradiol from
3.0% to 2.0% in the Chromatographic system section of the Chromatographic purity test.
Response: Comments incorporated
Monograph/Section: Prednicarbate Cream

Comment Summary: Commenter suggested that the limit of individual unspecified
impurity in the Related compounds test for the Cream be changed from 0.1% to 0.5%
per ICH guidance (Q3B(R)). The commenter also suggested clarifying that the
specification for both prednicarbate related compound B and prednicarbate related
compound C is NMT 2.0%.
Monograph/Section: Prednicarbate Ointment

Comment Summary #1: Commenter suggested that the limit of individual unspecified
impurity in the Related compounds test for the Ointment be changed from 0.1% to 0.5%
per ICH guidance (Q3B(R)). The commenter also suggested clarifying that the
specification for both prednicarbate related compound B and prednicarbate related
compound C is NMT 2.0%.
Monograph/Section: Ondansetron/Packaging and Storage

Expert Committee-initiated change: Packaging and storage statement added.
Monograph/Section: Quinapril Tablets/Packaging and storage
16

Expert Committee-initiated change: The Committee approved the monograph as
published in PF 29(4) with the addition of a storage statement.
Monograph/Section: Ropivacaine Hydrochloride Injection

Comment Summary #1: Commenter suggested deleting references to small volume
injections in the test for Particulate matter since there are both small and large volume
presentations of the Injection.
Comment Summary #2: Commenter suggested deleting the formula for calculating the
limit of related compound A in the Limit of 2,6-dimethylaniline (ropivacaine related
compound A, base) test and instead comparing the peak response of related compound
A obtained from the Test solution with the corresponding peak in the Standard solution.
Comment Summary #3: Commenter suggested correcting the formula provided in the
Assay for calculating the concentration of ropivacaine hydrochloride in the Injection.
Monograph/Section: Topiramate
Comment Summary: The commenters suggested that the proposed related
compounds test is not adequate to reflect the products on the US market.
Response: The Committee decided to approve the monograph as official without the
Related compounds test. The Committee will revise the Related compounds test as
needed via additional In-Process Revisions.
Expert Committee-initiated Change: Because all the solvents listed are
at or below <467> limits, and the General Notices specifically refer to
Residual solvents, this requirement has been removed from the
monograph.
Monograph/Section: Vasopressin/Identification-B
Comment Summary: Commenter suggested that the monograph should allow for
either an animal bioassay or the mass spectrometry (MS) test identification test B in the
monograph.
Response: Comment not incorporated. The Committee decided that the animal assay
should be removed from the monograph as part of the USP effort to reduce animal
testing. The Committee decided that the MS test along with other tests in the
monograph is sufficient to ensure the identity and bioactivity of the molecule. The
Committee also reached consensus that MS has developed sufficiently to become a
routine release test for peptide drugs.
Monograph/Section: Verapamil Hydrochloride Injection/Multiple sections

17
Comment Summary: Commenter suggested removing the cross references to the drug
substance monograph and instead adding the tests for related compounds and Assay to
this monograph.
Monograph/Section: Verapamil Hydrochloride Tablets/ Multiple sections

Comment Summary: Commenter suggested removing the cross references to the drug
substance monograph and instead adding the tests for related compounds and Assay to
this monograph.
Monograph Name/Section: Sterile Water for Inhalation

Expert Committee: PW
Expert Committee-initiated Changes: The Committee clarified the requirements
relating to Water Conductivity, to be sure that users complete only Step 4 of Stage 2 of
Water Conductivity <645>, and do not proceed to Step 5. The Committee also
implemented changes to improve clarity or definition, eliminate errors or redundancies,
promote consistency with other portions of the USP-NF, or otherwise resolve textual
problems.
Monograph Name/Section: Sterile Water for Irrigation

problems.
Monograph Name/Section: Sterile Purified Water

problems.
REVISED MONOGRAPH TITLES: Alumina, Magnesia, and Calcium Carbonate

Tablets, Alumina, Magnesia, Calcium Carbonate, and Simethicone Tablets, Alumina,
Magnesia, and Simethicone Tablets, Calcium Carbonate, Magnesia, and Simethicone
Tablets, Dihydroxyaluminum Sodium Carbonate Tablets, Magaldrate and Simethicone
Tablets, Phenytoin Tablets, and Thiabendazole Tablets.
18
During its May 23-24, 2006 meeting, the Committee adopted the following policy
for nomenclature and labeling of chewable tablets:
(1) The format "[DRUG] Tablets" will be used for tablets that are swallowed
whole or that MAY be chewed AND for which there is no intended alternative
method of administration. When appropriate, there will also be a labeling
statement indicting that the tablets MAY be chewed.
(2) The format "[DRUG] Chewable Tablets" will be used for tablets that MUST
be chewed AND for which there is no other alternative route of
administration. There will also be a labeling statement indicating that the
tablets MUST be chewed.
In the discussion of this topic, it was noted that the main issue is when should a
product characteristic appear in the title and when should it appear in a labeling
statement. The Committee agreed that ensuring the product is dispensed and used
properly is the key consideration. One nomenclature option considered was that the
word "chewable" should be part of the labeling statement but not part of the title.
Another option was to use different nomenclature for a product that MAY be chewed vs.
a product that MUST be chewed. As shown in policy points (1) and (2) above, the
Committee agreed that the preferred nomenclature approach is to label a product that
MAY be chewed as "Tablets" with a labeling statement indicating that the tablets MAY
be chewed, while a product that MUST be chewed would be labeled "Chewable Tablets"
with a labeling statement indicating that the tablets MUST be chewed.
Therefore, based on the above chewable tablets nomenclature policy, the titles for
the monographs listed under “Revised Monograph Titles” above have been revised from
the general form [DRUG(S)] Tablets to the general form [DRUG(S)] Chewable Tablets,
with a delayed implementation date for the new titles. These monographs cover tablets
that must be chewed before being swallowed, and the Committee felt that the addition of
the term “Chewable” in these monograph titles represented a significant improvement in
that the consumer will now be provided with added information, along with the labeling
statement directing that “tablets are to be chewed before being swallowed,” to hopefully
assure that the product will be used properly to achieve the benefit of the medication.
The revised titles for the existing monographs will become official on February 1,
2010. Use of these titles would be permitted as of the August 1, 2007 official date of the
First Supplement to USP 30- NF 25, but use of these titles would not become mandatory
until February 1, 2010. The 30-months delayed implementation is intended to allow time
for product label changes to be made and for health practitioners and consumers to
become familiar with the revised terminology.
19
DIETARY SUPPLEMENTS
Monograph/Section: Asian Ginseng Capsules

Expert Committee: DSB
Comment Summary: Commenter, the sponsor of Method 1 for the test Content of
ginsenosides, observed problems of recovery in some of its soft gelatin capsule
formulations and therefore requested the deletion of Method 1 from the monograph.
Monograph/Section: Methylsulfonylmethane
Expert Committee: DSN
Comment Summary #1: Commenter suggested that a flow rate of 30 mL per minute,
an error in the PF draft, and a split ratio of 20:1 be changed to a split ratio of 2:1 and a
flow rate of 5 mL per minute in the Assay.
Response: Comment incorporated
Comment Summary #2: Commenter suggested that the Water test indicate that a
larger sample size of 500 mg may be used.
Response: Comment incorporated
Comment Summary #3: Commenter suggested that a flow rate of 30 mL per minute,
an error in the PF draft, and a split ratio of 20:1 be changed to a split ratio of 2:1 and a
flow rate of 5 mL per minute. In addition, the commenter suggested that the final
concentration of the Sensitivity check solution should be 2.0 micrograms per mL
Monograph/Section: Methylsulfonylmethane Tablets

Expert Committee: DSN
Comment Summary: Commenter suggested that a flow rate of 30 mL per minute, an
error in the PF draft, and a split ratio of 20:1 be changed to a split ratio of 2:1 and a flow
rate of 5 mL per minute in the Assay
Monograph/Section: Tomato Extract Containing Lycopene

Expert Committee: DSB
Comment Summary: Commenter suggested that in the Limits of aflatoxins test,
language be added stating: “Except to spot 20 µL of either Test solution 1 or Test
solution 2.” This recommendation was intended to make the presumed amount in the
test solution fall within the range specified by the standard solutions.
20
GENERAL CHAPTERS
Chapter Name: <11> USP Reference Standards

Expert Committee: RS
Comment Summary #1: Commenter suggested changing the phrase “Suitability for
use in nonofficial application(s) should be validated by the purchaser” to “Suitability for
use in other application(s) rests with the purchaser.”
Response(s): Comment incorporated, with additional change as follows: “Assessment
of the suitability for use in other application(s) rests with the purchaser.”
Comment Summary #2: Commenter suggested that under PROPER USE, allowance
for small sample sizes to measure loss on drying for USP reference standards should be
made. There has long been such a statement in the chapter for titrimetric water
determinations.
Expert Committee-initiated change: The scope of USP reference standard categories
was broadened to include those that may be developed to support monographs that are
developed by USP, but not published in USP-NF.
Expert Committee-initiated change: The text: “USP does not provide Certificates of
Analysis…” was changed to “USP generally does not provide Certificates of Analysis…”,
since there are a few standards currently official which require that USP provide them.
General Chapter/Section: <730> Plasma Spectrochemistry

Expert Committee: GC
Expert Committee-initiated change: A few editorial changes are made to clarify the
text. These changes include 1) spelling correction in the Fourth paragraph under
"Sample Preparation" and 2) removal of a redundant sentence in the fourth paragraph
under "Sample Introduction."
General Chapter/Section: <1065> Ion Chromatography/Apparatus

Expert Committee: GC
Comment Summary: Commenter suggested that in addition to specifying that a metal-
free tubing system should be used for trace metal analysis, the column and guard
column should also be metal-free.
Response: Comment incorporated. The Committee deleted the word tubing to indicate
that a metal-free system should by used for trace metal analysis.
General Chapter/Section: <1080> Bulk Pharmaceutical Excipients⎯Certificate of

analysis
Expert Committee: EGC
1) Under COMPENDIAL DESIGNATION, it is stated: "…the article, when stored
correctly, will comply...". Commenter recommended this be changed to "…the
article, when stored according to recommended conditions, will comply..."
2) Since this is a general information chapter, the commenter suggested the
remaining use of the term "must" throughout the chapter be changed to "should".
21
Comment Summary #2: In Expiration Date and Recommended Re-Evaluation Date,

the last paragraph refers to "long term stability data." One commenter suggested further
defining or clarifying "long term." Another commenter suggested that this section
provide further clarification by replacing the phrase "If long term stability data are not
available…" with "If data is not available from formalized stability studies…." That
commenter suggested that the purpose of the sentence is to indicate that even where
formalized stability studies have not been performed, the excipient manufacturer should
at least provide some type of statement on the Certificate of Analysis related to the
stability of the material so the user understands whether the material presents any
stability concerns.
General Chapter/Section: <1118> Monitoring Devices-Time, Temperature, and

Humidity/Data Loggers
Expert Committee: PS
Comment Summary: The commenter felt that the revision as written suggests that
radio frequency identification technology is capable of remotely monitoring temperature
and humidity of a package while in transit. The current technology only allows for the
storage of temperature and humidity data during transit, which can be downloaded to a
database once the product reaches its destination.
Response: Comment incorporated. After reviewing the comments and text in question,
the Committee agreed that the paragraph as written could be misleading about the
capabilities of radio frequency identification technology. The paragraph has been
rewritten to clarify the committee’s original intent.
General Chapter/Section: <1184> Sensitization Testing

Expert Committee: GTMDB
Number of Commenters: 2
Comment Summary #1: Several commenters suggested non-substantive, editorial
changes.
Response: Comment partially incorporated. The Committee reviewed each of these
suggestions to determine whether it offered an improvement in clarity or, eliminated an
obvious error or redundancy, or otherwise identified textual problems that were not
previously noted by USP. Where the proposed alternative language or other changes
suggested were superior to the proposal, they were adopted in substance or verbatim.
Where the suggestions did not offer any improvement, the Committee declined to accept
them. In finalizing these comments/ revisions, the Committee has taken into
consideration that this is a general information chapter.
Comment Summary #2: Commenter suggested that this chapter is beyond the scope
of the USP and does not include methods employed by a particular company and
therefore should not be included in the USP-NF.
Response: Comment not incorporated. The purpose of this chapter is clearly
informational and not prescriptive. The chapter provides a general overview of existing
methods. The comment was not supported by specifics and therefore not accepted.
Comment Summary #3: Commenter proposed that the chapter be harmonized with the
ISO standard 10993-10: Biological Evaluation of Medical Devices: Tests for Irritation and
delayed-type hypersensitivity.
Response: Comment not incorporated. The Committee determined that this
harmonization should not delay approval of the chapter as official, and instead could be
considered in a future revision.
22
General Chapter/Section: <1208> Sterility Testing-Validation Of Isolator

Systems/Multiple Sections
Expert Committee: MSA
Number of Commenters:
Comment Summary #1: Several commenters were favorable but suggested the need
for minor changes to improve or clarify the revision proposal to the General Information
Chapter.
Response: Comment partially incorporated. The Committee reviewed each of these
suggestions to determine whether it offered an improvement in clarity or, eliminated an
obvious error or redundancy, or otherwise identified textual problems that were not
previously noted by USP. Where the proposed alternative language or other changes
suggested were superior to the proposal, they were adopted in substance or verbatim.
Where the suggestions did not offer any improvement, the Committee declined to accept
them. In finalizing these comments/ revisions, the Committee has taken into
consideration that this is a general information chapter.
Comment Summary #2: Commenter objected to language in the Introductory section
on Isolators which states, ”Although a pair of sterile gloves is frequently worn under the
isolator gloves . . ." as the wearing of a second pair of non-sterile gloves should be an
option.
Response: Comment not incorporated. The text as stated is merely an observation and
does not mean that the wearing of gloves is a recommended practice.
Comment Summary #2: Commenter suggested that additional language be added to
the section on Isolator Design and Construction which states "In general, both open and
closed isolators are maintained at positive pressure relative to the surrounding
environment and overpressures of 20 to 40 Pa are typical." Commenter suggested that
this section include the statement: “The appropriate minimum pressure differential
established by a user will depend upon the isolator design."
Response: Comment partially incorporated. The Committee recognized that there are
isolators that operate typically at a higher pressure differential, and thus has changed
the statement to read “…overpressures of 20 Pa or more are typical."
Comment Summary #3: Commenter objected to the following statement in the section
on Isolator Design and Construction / Transfer Ports and Doors: "The exposed gasket
should be treated with a sporicidal agent immediately after the connection is made."
The commenter claimed that this created a requirement of having liquid sporicidal
agents within your testing isolator and exposing that environment to sporicidal agents
during testing. The commenter suggested that it would be more prudent to apply a
sporicidal agent to the gasket of each RTP connection just prior to docking.
Response: Comment incorporated. The statement was changed to read ”routinely
disinfected immediately after the connection is made, and before materials are
transferred through the RTP.”
Comment Summary #4: Commenter suggested that additional language be added to
the section on Validation of the Isolator System/ Operational Qualification / Isolator
Integrity Check which states: "To safeguard against adventitious contamination,
isolators are operated at a positive pressure differential of about 20-40 Pa during normal
operation." Commenter suggested that the section include the statement: "The
appropriate minimum pressure differential established by a user will depend upon the
isolator design."
Response: Comment partially incorporated. Original statement changed to “To
safeguard against adventitious contamination, isolators are operated at a suitable
positive pressure differential during normal operation.”
23
on Maintenance of Asepsis within the Isolator Environment: "Continuous nonviable
particulate monitoring within the isolator’s enclosure is ideal…” Commenter noted that a
previous statement within the In-process Revision stated "isolator need not meet Class 5
conditions during operation." Commenter claimed that imposition of performing non-
viable monitoring for sterility testing was unnecessary, provided little data, and imposed
additional equipment, decontamination validation of the sensor, and cost to the user.
According to the commenter, filters that are used in these isolators are extremely robust
with a long history of integrity. With the type of activity associated with testing, particles
are being generated continuously, and particle testing should be performed "at rest" and
associated with OQ validation.
Response: Comment not incorporated. The statement as it appears is only suggestive
of “ideal” scenario, and not prescriptive.
on Operational Qualification (OQ): "Gas and vapor decontamination methods require
fans in the isolator to distribute....” Commenter suggested that to meet current practices,
the sentence should indicate that fans may be required, as follows: "Gas and vapor
decontamination methods may require fans in the isolator to distribute..."
General Chapter/Section: <1217> Tablet Breaking Force

Expert Committee: PDF
No of Commenters: 2
Comment Summary #1: The third paragraph of the Introduction states that loading
occurs across the tablet diameter and fracture occurs in that plane. The commenter
suggested that clarifying language be included to better define the plane that is
referenced.
Response: Comment not incorporated. The Committee determined that the content of
the paragraph is not misleading. While any number of planes could contain the diameter
across which the loading occurs, further clarification of a particular plane is not essential
to the value of the Chapter.
Comment Summary #2: Two commenters voiced concern that the upper limits for
platen speed of 3.0 mm per second are an unnecessary restriction on available
instrumentation. One commenter described a tester that had produced data that was
“reproducible and adequate for our purposes” and operated at 3.3 mm per second.
Response: Comments incorporated. The Committee changed the text to include a
constant speed of 3.5 mm per second but only as a descriptive comment on currently
available equipment. The wording was altered to eliminate the appearance of a
specification.
Expert Committee-initiated Change: The third paragraph of the Rate and Uniformity of
Loading section was altered from the PF proposal to emphasize the need to conduct the
testing under consistent conditions if comparison of product quality is of interest. The
comparability of data from different equipment using different designs should not be
assumed.
Expert Committee-initiated Change: The Dependence of Breaking Force on Tablet
Geometry and Mass section was modified from the PF proposed text to reinforce the
notion that testing results will be meaningful only if the testing is performed in a
consistent manner, and that testing will provide the greatest benefit as a manufacturing
control if the procedure and the tablet failure can be related to the information on tablet
breaking that was part of the product development.
24
Expert Committee-initiated Change: The Committee added a statement in the Units,

Resolution, and Calibration section giving preference to the use of standard (SI) units of
force for the test results. This statement was meant to add emphasis to the caution
regarding conversion between Strong Cobb units and Newtons or kiloponds.
General Chapter: <1222> Terminally Sterilized Pharmaceutical Products-Parametric

Release
Expert Committee: MSA
Number of Commenters: 2
Comment Summary #1: Commenters suggested the need for minor changes to
improve or clarify the revision proposal to <1222>.
Response Summary: Comment partially incorporated. The Committee reviewed each
of these comments to determine whether it offered an improvement in clarity or,
eliminated an obvious error or redundancy, or otherwise identified textual problems that
were not previously noted by USP. Where the proposed alternative language or other
changes suggested were superior to the proposal, they were adopted in substance or
verbatim. Where the suggestions did not offer any improvement, the Expert Committee
declined to accept them. In finalizing these comments/ revisions, the Expert Committee
has taken into consideration that this is a general information chapter.
Comment Summary #2: Commenter suggested that the sentence in the Introduction
section that reads “The agencies would need assurance that any marketed sample of
product will be sterile and would pass the requirements for sterility as found in the
general chapter Sterility Tests 71 ” be re-written, as it could be interpreted that
Sterility Tests should still be performed for products released under Parametric Release
Comment Summary #3: Commenter suggested a change to the following sentence in
the Introduction section: ”Therefore, once a sterilization process is fully validated and
operates consistently, a combination of physical sterilization data such as accumulated
lethality or dosimetry in combination with other methods, such as biological indicators or
physicochemical integrators, ...” Commenter suggested that the term “biological
indicators or physicochemical integrators” be replaced with the term “load monitors”, to
better reflect the current definitions of indicators and integrators.
Comment Summary #4: Commenter noted that while the Introduction indicated that
"[t]here are four modes of sterilization that theoretically and practically could qualify for
parametric release, moist heat, dry heat, ethylene oxide, and ionizing radiation
sterilization," only three modes of sterilization are discussed. Commenter noted that it
was unclear as to why dry heat sterilization is not discussed.
Response: Comment not incorporated. The chapter clearly indicates that it will only
discuss “some specific modes of sterilization”
Comment Summary #5: Commenter suggested that the following sentence in the
Introduction section was misleading and should be deleted: “SAL is often used to
describe the process capability of aseptic processes...”.
Comment Summary #6: Commenter suggested that the following sentence in the
Introduction section be deleted: “Certain bioburden processes may include products that
may be inherently antimicrobial or that can withstand more lethal sterilization processes.
Products in this category will require correspondingly less rigorous control of the
manufacturing process and less restrictive in-process control points.” Commenter
25
claimed it was inappropriate to associate product characteristics with the degree of

process control.
Comment Summary #7: Commenter requested that the following statement in the
Introduction section be revised or clarified: “Generally, process resistant biological
indicators containing approximately 106 spores are used to establish the endpoint of the
sterilization process “. Commenter noted that the endpoint of the sterilization process is
not based on the BI challenge.
Response: Comment incorporated and sentence clarified
Comment Summary #8: Commenter requested that the following text in the Introduction
section be clarified: “However, a spore population of N0 can be chosen to provide an
appropriate challenge to evaluate the process. Overkill is generally defined as a process
that would produce a minimum of F0 of 12 minutes (see Critical Operating Parameters
below) and is demonstrated biologically based upon the spore log reduction of calibrated
biological indicators.”
Response: Comment incorporated and text clarified
Comment Summary #9: Commenter suggested that the phrase “relative to the
inactivation of bioburden” be removed from the General Review, Validation of
Sterilization Process section.
Comment Summary #10: Commenter objected to the sentence in the General Review,
Validation of Sterilization Process that reads: “The use of biological indicators for
establishing or periodically validating gamma radiation sterilization processes is not
required.” Commenter claimed that this statement was too restrictive and not
necessarily true, and should not be included in a general information chapter.
Response: Comment incorporated and sentence revised accordingly.
Comment Summary #11: Commenter suggested that the phrase “when using a
biological indicator microorganism with a D value of 1.0 minute” be deleted from the
footnote in the Validation of Sterilization Process section, since the D value of the BI is
not relevant to the definition of F0 .
Response: Comment incorporated and text revised accordingly.
Comment Summary #12: Commenter suggested clarification of the following sentence
in the General Review, Sterilization Microbiology Control Program section: “Monitoring
of overkill processes for bioburden is generally required only in cases where the product
is supportive of microbial growth, and, therefore, biological amplification of any
bioburden is likely.”
Comment Summary #13: Commenter objected to the term “’go-no go’ hurdles” in the
General Review, Change Control System section as unclear.
Response: Comment accepted and sentence revised accordingly. The term “’go-no go’
hurdles“ has been deleted
Comment Summary #14: Commenter objected to the use of the term “may “in the
sentence in the General Review, Release Procedures section that reads: “…results of
indicators that may have been used to demonstrate process control.” Commenter noted
that the word “may” was inappropriate since load monitors are required by current GMP
policy.
Comment Summary #15: Commenter noted that in the Modes of Sterilization, Moist
Heat Sterilization section there was no mention of dwell time as a critical parameter, and
suggested that this be added.
26
Comment Summary #16: Commenter objected to the statement in the Modes of

Sterilization, Moist Heat Sterilization section that read: “F0 is not listed as a critical
parameter…..” Commenter claimed this language was confusing and not supported in
this paragraph.
Response: Comment incorporated and text modified accordingly
Comment Summary #17: Commenter suggested with regard to the Modes of
Sterilization, Moist Heat Sterilization section generally that it is inappropriate for USP to
decide what is critical and what is secondary in this information chapter.
Response: Comment incorporated. The text has been suitably modified and is not
prescriptive.
Comment Summary #18: Commenter objected to language in the Modes of
Sterilization, Ethylene Oxide Sterilization section which suggested that the use of load
monitors is optional.
Response: Comment incorporated and text modified accordingly
Comment Summary #19: Commenter suggested that in the Modes of Sterilization,
Radiation Sterilization section, SAL be changed to PNS.
Comment Summary #20: Commenter suggested that the following text be deleted
from the Modes of Sterilization, Radiation Sterilization section: "…because the radiation
cycle is calculated on the basis of the bioburden, dosimetric release should include a
batch evaluation of the bioburden number and of its radiation resistance." Commenter
noted that the radiation dose is calculated on the basis of the bioburden, not the cycle.
27
NF MONOGRAPHS
Monograph/Section: Calcium Silicate/Multiple Sections

Expert Committee: EM1
Comment Summary: Commenter suggested that we retain the official temperature of
1300° in the Assay.
Response: Comment not incorporated. The Committee decided that the proposed
change would require additional supporting data.
Comment Summary: Commenter suggested that the specification limit be changed
from 10 µg to 50 µg in the Limit of fluoride.
Response: Comment not incorporated. The Committee decided that the proposed
change would require additional supporting data, as the commenter’s data is not
sufficient to make an adequate determination.
Monograph/Section: Coconut Oil

Expert Committee-initiated change: Add a clarification in Alkaline impurities: Change
the sentence from "Neutralize the solution if necessary with 0.01 N hydrochloric acid or
0.01 N sodium hydroxide" to "Neutralize the solution to green color if necessary with
0.01 N hydrochloric acid or 0.01 N sodium hydroxide".
Monograph: Erythritol
Comment Summary: Commenter suggested that the test for Water be changed to
Water, Method I <921>: not more than 0.5%.
Monograph/Section: Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion

Expert Committee-initiated change: Change the sentence from "Identification, Infrared
Absorption <197K>" to "Identification, Infrared Absorption <197K>⎯the test specimen
dried as specified in the Loss on drying test."
Monograph/Section: Polyethylene Oxide/Multiple Sections

Expert Committee-initiated change: Heavy metal test by ICP proposal is canceled.
Approved the other revisions as official without additional changes.
28

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COMMENTARY—1ST SUPPLEMENT TO USP30 - NF25

Where appropriate, the Commentary includes a separate discussion of proposals related

The Commentary is presented in the following order: USP Monographs, Dietary

Monograph/Section: Aluminum Sulfate and Calcium Acetate for Topical Solution/Title

Monograph/Section: Amlodipine Besylate

Monograph/Section: Bismuth Subsalicylate Oral Suspension

Monograph/Section: Bismuth Subsalicylate Tablets

Expert Committee-initiated change: Included a chemical structure of Budesonide and

Monograph/Section: Cefepime Hydrochloride/Limit of N-methylpyrrolidine; Related

Monograph/Section: Chlorhexidine Gluconate Solution /Definition and Assay

Monograph/Section: Chlorhexidine Gluconate Oral Rinse/ Assay

Monograph/Section: Ciprofloxacin and Dexamethasone Otic Suspension/Multiple

concentration of the Dilute standard preparation is in terms of USP Ciprofloxacin

Monograph/Section: Desmopressin Acetate

Monograph/Section: Desogestrel and Ethinyl Estradiol Tablets/Multiple Sections

Comment Summary #4: Commenter suggested a correction to the formula in the

Monograph/Section: Didanosine/Related compounds and <11>

Monograph/Section: Diphenoxylate HCl and Atropine Sulfate Oral Solution and

Monograph/Section: Doxepin Hydrochloride/Related compounds

Monograph/Section: Dronabinol/Related compounds

Monograph/Section: Estradiol and Norethindrone Acetate Tablets

Monograph/Section: Famotidine Injection

Monograph/Section: Fexofenadine Hydrochloride Tablets

Monograph/Section: Fluorometholone Acetate

Monograph/Section: Fluvoxamine Maleate Tablets/Related compounds

Monograph/Section: Fosinopril Sodium

Comment Summary #1: Commenter suggested a revision of the chemical names of

Monograph/Section: Fosinopril Sodium and Hydrochlorothiazide Tablets

Monograph/Section: Gonadorelin Acetate/Multiple Sections

Response: Comment partially incorporated. The Committee reviewed the submitted

Monograph/Section: Human Insulin Isophane Suspension and Human Insulin Injection

Monograph/Section: Hydrocodone Bitartrate/ Related compounds test

Monograph/Section: Hydrocodone Bitartrate and Homatropine Methylbromide Tablets

Monograph/Sections: Ibuprofen/ USP Reference standards; Limit of; Assay.

Monograph/Sections: Ibuprofen Oral Suspension/ USP Reference standards; Limit of;

Monograph/Sections: Ibuprofen Tablets/ USP Reference standards; Limit of; Assay.

Monograph/Section: Irbesartan/Multiple sections

Monograph/Section: Irbesartan Tablets

Monograph/Section: Isosorbide Mononitrate Tablets

Monograph/Section: Lidocaine and Prilocaine Cream

Monograph/Section: Mupirocin Calcium

Monograph/Section: Mupirocin Cream

Monograph/Section: Norgestimate and Ethinyl Estradiol Tablets

Monograph/Section: Prednicarbate Cream

Monograph/Section: Prednicarbate Ointment

Monograph/Section: Ondansetron/Packaging and Storage

Monograph/Section: Quinapril Tablets/Packaging and storage

Expert Committee: MD-CV

Monograph/Section: Ropivacaine Hydrochloride Injection

Monograph/Section: Verapamil Hydrochloride Injection/Multiple sections

Monograph/Section: Verapamil Hydrochloride Tablets/ Multiple sections

Monograph Name/Section: Sterile Water for Inhalation

Monograph Name/Section: Sterile Water for Irrigation

Monograph Name/Section: Sterile Purified Water

REVISED MONOGRAPH TITLES: Alumina, Magnesia, and Calcium Carbonate

Monograph/Section: Asian Ginseng Capsules

Monograph/Section: Methylsulfonylmethane Tablets

Monograph/Section: Tomato Extract Containing Lycopene

Chapter Name: <11> USP Reference Standards