Usp NF 2022 Issue 3

Commentary
USP–NF 2022 Issue 3
June 1, 2022
In accordance with USP’s Rules and Procedures of the Council of Experts (“Rules”), and
except as provided in Section 9.02 Accelerated Revision Processes, USP publishes proposed
revisions to the United States Pharmacopeia and the National Formulary (USP–NF) for public
review and comment in the Pharmacopeial Forum (PF), USP’s free bimonthly journal for public
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Committee (EC) deems appropriate, the proposal may advance to official status or be re-
published in PF for further notice and comment, in accordance with the Rules. In cases when
proposals advance to official status, a summary of comments received and the appropriate
Expert Committee's responses, as well as Expert Committee-initiated changes, are published
in the Proposal Status/Commentary section of USPNF.com at the time the official revision is
published.
The Commentary is not part of the official text and is not intended to be enforceable by
regulatory authorities. Rather, it explains the basis of Expert Committees’ responses to public
comments on proposed revisions. If there is a difference or conflict between the contents of the
Commentary and the official text, the official text prevails.
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Commentary for USP–NF 2022, Issue 3

Comments were received for the following when they were proposed in Pharmacopeial
Forum:
General Notices to USP-NF

0.1 N Sodium Hydroxide VS Reagent
Methanol Reagent
General Chapters
<206> Aluminum
<211> Arsenic
<241> Iron
<251> Lead
<261> Mercury
<291> Selenium
<771> Ophthalmic Products - Quality Tests
<781> Optical Rotation
<857> Ultraviolet-Visible Spectroscopy
<1857> Ultraviolet-Visible Spectroscopy - Theory and Practice
Monographs
Amantadine Hydrochloride Tablets
Amiloride Hydrochloride Tablets
Argatroban Injection
Candesartan Cilexetil
Candesartan Cilexetil Tablets
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets
Chlordiazepoxide Hydrochloride Capsules
Choline Bitartrate
Colistin Sulfate
Cranberry Fruit Juice
Cranberry Fruit Juice Concentrate
Doxycycline
Enzacamene
Etravirine
Etravirine Tablets
Fluticasone Propionate
Fosamprenavir Calcium
Latanoprost
Menthol
Molindone Hydrochloride
Naloxone Hydrochloride
Pramipexole Dihydrochloride
Primidone Tablets

Propionic Acid
Propranolol Hydrochloride Injection
Rivaroxaban
Saquinavir Mesylate
Siler Root
Siler Root Dry Extract
Siler Root Powder
Streptococcus thermophilus
Sodium Propionate
Tamsulosin Hydrochloride Capsules
Tiotropium Bromide
Zinc Acetate
No comments were received for the following proposals:
Monographs
Codeine
Cranberry Fruit Dry Juice
Diphenhydramine Hydrochloride Oral Powder
Emedastine Ophthalmic Solution
Emedastine Difumarate
Erythromycin Ethylsuccinate Injection
Erythromycin Ethylsuccinate Oral Suspension
Ethionamide
Fish Oil Omega-3 Acid Ethyl Esters Concentrate
Fish Oil Containing Omega-3 Acids
Fish Oil Containing Omega-3 Acids Capsules
Fish Oil Containing Omega-3 Acids Delayed-Release Capsules
Fumaric Acid
Insulin Glargine
Insulin Glargine Injection
Krill Oil
Krill Oil Capsules
Krill Oil Delayed-Release Capsules
Lactiplantibacillus Plantarum
Ligilactobacillus Salivarius
Liotrix Tablets
Neomycin Sulfate and Dexamethasone Sodium Phosphate Cream
Neomycin Sulfate and Flurandrenolide Cream
Neomycin Sulfate and Flurandrenolide Lotion
Neomycin Sulfate and Hydrocortisone Acetate Cream
Neomycin Sulfate and Hydrocortisone Acetate Lotion
Neomycin And Polymyxin B Sulfates Cream
Neomycin And Polymyxin B Sulfates and Gramicidin Cream

Neomycin And Polymyxin B Sulfates, Gramicidin, And Hydrocortisone Acetate Cream
Nystatin
Omega-3-Acids Ethyl Esters
Omega-3 Free Fatty Acids
Omega-3 Acids Triglycerides
Trichlormethiazide
Zinc Sulfate
General Notices
Monograph/Section(s): General Notices and Requirements/Section 2.20 Official Articles
Expert Committee: Council of Experts
No. of Commenters: 10
The following is Commentary in response to a proposed revision to General Notices. This

revision will be official on December 1, 2022.
Revision language:
Revise Section 2.20 Official Articles to add the following language at the end of the
second paragraph: “For a biologic product licensed under the Public Health Service Act,
the official title shall be the title specified in the relevant monograph plus any prefix
and/or suffix designated by the FDA unless otherwise specified in the applicable
monograph.”
This revision was initially proposed in 2017 after the U.S. Food and Drug Administration’s (FDA)
issuance of its final guidance, Nonproprietary Naming of Biological Products in January 2017.
The final guidance indicated FDA’s thinking that biological products licensed under the Public
Health Service Act (PHS Act) bear a nonproprietary name that includes an FDA-designated
suffix. This guidance also referenced FDA’s intent to continue its practice of designating the
names of biological products with a prefix, where necessary. In 2019, FDA issued an additional
draft guidance document, Nonproprietary Naming of Biological Products: Update.
To understand the impact of this revision, USP has held ongoing scientific engagements,
conducted two Comment rounds in Pharmacopeial Forum, and hosted a stakeholder
roundtable. The proposal received varied stakeholder comments expressing both support and
opposition.
The purpose of this revision is to clarify the continued application of USP public quality
standards to biologic products that may be assigned an FDA-designated prefix and/or suffix,
including originator biological products, related biological products, biosimilar products, and
interchangeable products and is not intended to comment on FDA’s biological product naming
policy. This revision will help provide clarity to stakeholders with respect to FDA’s naming
convention and official titles of USP monograph standards.

Section 2.20 Official Articles:
Comment Summary #1: Commenters indicated disagreement with FDA’s guidance,
Nonproprietary Naming of Biological Products but expressed appreciation for USP’s proposal to
minimize confusion.
Response: Comment partially incorporated. The Council of Experts determined the revision is
necessary to clarify the continued application of USP public quality standards to biological
products and to prevent confusion and potential compliance issues for industry.
Comment Summary #2: Commenters suggested not to align USP naming of biological
products regulated under the Public Health Service Act with the FDA guidance, Nonproprietary
Naming of Biological Products.
Response: Comment not incorporated. The Council of Experts determined the revision is
Comment Summary #3: The commenter suggested that USP monographs for biological
products are not beneficial to public health and may impede or delay innovation.
Comment Summary #4: Commenters requested cancellation of the proposed revision because
they do not support the use of prefixes and/or suffixes for biological products regulated under
the Public Health Service Act, per the FDA guidance, Nonproprietary Naming of Biological
Products.
Reagents
Reagent: Methanol
Expert Committee: USP Headquarters
Comment Summary #1: The commenter requested clarity on the definition of “Anhydrous
Application” stated in the text.
Response: Comment incorporated. USP changed the wording of the heading from “For
Anhydrous Applications” to “Applications Requiring Anhydrous Methanol”.
Reagent: 0.1 N Sodium Hydroxide VS

Expert Committee: USP Headquarters

Comment Summary #1: The commenter noted that the standardization procedure listed in the
text is for potentiometric endpoint not for visual endpoint.
Response: Comment incorporated. USP updated the section title to read “Standardization with
potentiometric endpoint”.
General Chapters
General Chapter/Sections: <206> Aluminum

Expert Committee: General Chapters–Chemical Analysis
Comment Summary #1: For procedures describing ICP-OES, commenter recommended,
a. including some text to describe the instrument qualification process before testing (e.g.,
calibration procedure, criteria, etc.).
b. including additional concentrations over the working range of the standardization
solutions to help the reader demonstrate linearity before continuing the procedure.
Response:
a. Comment not incorporated. ICP-OES Instrument qualification is covered in chapter
<730>.
b. Comment not incorporated. It has been established in the literature as well as empirical
evidence that the use of three standards in ICP-OES is the optimal number of
standards for the technique. Adding more levels can in many cases provide false
interpretation of the linearity of the analysis. Please see the following reference from
Internationally recognized expert in Atomic Spectroscopy (1) Boumans, P.W.J.M.,
Inductively Coupled Plasma Emission Spectroscopy, Part I, John Wiley and Sons,
1987, p. 18ff.
2) (https://www.perkinelmer.com/CMSResources/Images/46-
74353FAR_LinearRangeStudyoftheOptimaSimultaneousICP-OES.PDF)
REQUIREMENTS FOR PROCEDURE VALIDATION

Comment Summary #1: In the SPECIFICITY subsection, commenter recommended including
a list of some components that could be responsible for interfering with assessing the element.
Response: Comment not incorporated. This chapter is intended for use for any material and
any potential interference must be therefore evaluated on a case-by-case basis. As such, it is
not possible for USP to generalize the list of interferences.
Comment Summary #2: Commenter recommended tightening ranges for the acceptance
criteria for ACCURACY, PRECISION, and INTERMEDIATE PRECISION.
Response: Comment not incorporated. The acceptance criteria presented have been shown
to be adequate for the purpose (ppb concentrations), in particular at working ranges close to
LOD and LOQ.

Comment Summary #3: Commenter recommended that the proposed ICP-MS and ICP-OES
procedures, that are the same procedures as those currently in <233>, are not to be added to
the six element-specific chapters as this approach will not benefit excipient monographs for
following reasons:
a) The addition of the ICP-MS and ICP-OES procedures, which are already described in
<233>, is redundant. Even if the ICP-MS and ICP-OES procedures are added to the
element-specific chapters they will be still considered as alternative procedures because
they are not referenced in excipient monographs and cannot be used without being
validated.
Response: Comment not incorporated. The procedures in these element specific chapters
modernize these chapters by including instrumental procedures and make the stakeholders
aware of the availability of these procedures as an alternative along with validation requirements
necessary for their use as an alternative . This addition would also allow one to directly
reference these procedures in future monographs.
Alternate procedures should be validated and show comparable results per GNs section 6.30
Alternative and Harmonized Methods and Procedures. In this case, the required validation
criteria is set forth in the element specific chapters. Users are not required to use ICP –
OES/MS based procedures but may choose to as long as they meet the validation
requirements. Inclusion of these procedures in element specific chapters eliminates the
potential for redundant testing.
Comment Summary #4: Commenter stated that users can use the procedures listed in <233>
per General Notices section 6.30. Alternative and Harmonized Methods and Procedures if they
prefer using ICP-MS and ICP-OES technology for analysis of elemental impurities.
Response: Comment not incorporated. The procedures in these element specific chapters are
included to inform the stakeholders of the availability of these procedures as an alternative and
provide validation requirements necessary for their use as an alternative. Alternative procedures
should be validated per General Notices section 6.30 Alternative and Harmonized Methods and
Procedures. In this case, the required validation criteria is set forth in the element specific
chapters. Users are not required to use ICP – OES/MS based procedures but may choose to as
long as they meet the validation requirements. Inclusion of these procedures in element specific
chapters eliminates the potential for redundant testing.
Comment Summary #5: Commenter stated that because the limits for elemental impurities in
excipient monographs are associated with the existing wet chemistry procedures, the
methodology and the existing limits cannot be changed unless validation and sample evaluation
work are conducted and demonstrate that the current and any alternative procedures produce
comparable results. There may be some cases in which the current limits have to be revised to
reflect results obtained by ICP-MS and ICP-OES technology.
Response: Comment not incorporated. These procedures are stand-alone procedures and not
referenced in monographs. If a user decides to go with the instrumental procedure and fails to
meet the limits given in the monograph, they may reach out to USP with data and request a
change in monograph limits.

PROCEDURES
Comment Summary #1: The name for some procedures is not included in the text of all six
chapters as is done for other Procedures. Therefore, the commenter recommended adding a
line in each chapter as suggested below:
<206> Aluminum -- Procedure 1: Atomic Absorption Spectroscopy
<211> Arsenic – Procedure 1: Colorimetry
Procedure 2: Colorimetry
<241> Iron – Procedure 1: Chemical method
<251> Lead – Procedure 1: Chemical method
<261> Mercury –Procedure 1: Titration
Procedure 2: Atomic Absorption Spectroscopy
Procedure 3: Atomic Absorption Spectroscopy
<291> Selenium – Procedure 1: Spectroscopy
Response: Comment incorporated. The name of the procedures has been added for all six
chapters for consistency.
Comment Summary #2: ICP Procedures -Standardization

Standardization solution 1, Standardization solution 2, and Blank
In all six chapters, the order of the text may lead users to run the standards and blank in the
order given. Some software will not allow this and the blank needs to be run first. Therefore,
suggest change to:
Blank, Standardization solution 1, and Standardization solution 2
Response: Comment not incorporated. The format reflects the standard convention used by
USP. The specific analysis sequence should be that used in the validation of the method.
REQUIREMENTS FOR PROCEDURE VALIDATION:

Comment Summary #1: Commenter requested clarification as to why the sentence ”The
following validation requirements do not apply when the monograph prescribes Procedure 2 or
Procedure 3,” cannot apply to ICP validation. The listed validation requirements are a suitable
approach to validating the ICP methods and are not out of alignment with General Notices or
<1225> Validation of Compendial Procedures, therefore, suggest delete sentence and replace
with wording clear for the intent.
Response: Comment incorporated. Section has been revised to provide greater clarity. The
validation requirements section was revised to clarify that the criteria are applicable for primary
and alternative methods.
Comment Summary #2: Commenter expressed that a switch from an existing wet chemistry
sample preparation procedures to one that uses ICP-OES or ICP-MS with complete digestion
may lead to varying results as is common when comparing results generated from different
procedural approaches as is the case at times when comparing results from leaching methods
to results from total digestion methods. Commenter recommended considering this
variance/bias in results based on the procedures used and provide comments on potential
method-to-method variability when these ICP-OES and ICP-MS procedures are included in
General Chapters that allow the flexibility of multiple test method approaches.

Response: Comment not incorporated. These procedures are stand-alone procedures and not
referenced in monographs. If a user decides to go with the instrumental procedure and fails to
meet the limits given in the monograph, they may reach out to USP with data and request a
change in monograph limits.
General Chapter/Sections: <211> Arsenic

Please see commentary for <206> for comments related to all six of the elemental chapters.
Comment Summary #1: The proposed procedures are exclusively ICP-AES and ICP-OES or
ICP-MS, hence, well-known and already established procedures such AAS (e.g., with flame,
graphite furnace or hydride generation) are not mentioned, even as a possible alternative.
Commenter recommended introducing following statement from chapter <233> in chapters
〈211〉 Arsenic, 〈241〉 Iron, 〈251〉 Lead and 〈261〉 Mercury. This should make possible the
determination of those elements by means of other analytical procedures (when fit for purpose),
e.g., AAS:
“Any alternative procedure that has been validated and meets the acceptance criteria
that follow is considered to be suitable for use”.
Response: Comment incorporated. Introductory statement is included.
General Chapter/Sections: <241> Iron

e.g., AAS:
Response: Comment incorporated.
General Chapter/Sections: <251> Lead


e.g., AAS:
General Chapter/Sections: <261> Mercury

graphite furnace or hydride generation) are not mentioned, even as a possible alternative. We
would like to recommend introducing following statement from chapter <233> in chapters 〈211〉
Arsenic, 〈241〉 Iron, 〈251〉 Lead and 〈261〉 Mercury. This should make possible the
e.g., AAS:
General Chapter/Sections: <291> Selenium

Comment Summary #1: Commenter recommended omission of this chapter due to USP’s
decision to remove all tests for elements that are part of USP <232>/ICH Q3D elemental
impurities list from drug substance monographs.
Response: Comment not incorporated. There may be other potential users of chapter <291>
therefore, USP intends to evaluate the impact of omitting this chapter before reaching a decision
on its omission.
General Chapter/Sections: <771> Ophthalmic Products – Quality Tests / Multiple Sections

Expert Committee: General Chapters – Dosage Forms
Comment Summary #1: The commenter suggested that all the arrows in Figure 1 should be
pointing inward to the area of the eye rather than outward to the label.

Comment Summary #2: Under OPHTHALMIC DOSAGE FORMS, last sentence, the
commenter suggested changing from “For multidose products, a suitable antimicrobial
preservative or packaging system is required to maintain sterility over the shelf life of the
product.” to “For multidose products, a suitable antimicrobial preservative or packaging system
is required to maintain antimicrobial effectiveness over the shelf life of the product.”
Comment Summary #3: Under “Solutions”, first sentence, the commenter suggested changing
from “Included in this section are those solid products that, when reconstituted according to
instructions in the labeling, result in a solution.” to “Included in this section are solutions
and those solid products that, when reconstituted according to instructions in the labeling, result
in a solution.”
Comment Summary #4: Under “Suspensions”, first sentence, the commenter suggested
changing from “Included in this section are those solid products that, when reconstituted
according to instructions in the labeling, result in a suspension.” to “Included in this section are
suspensions and those solid products that, when reconstituted according to instructions in the
labeling, result in a suspension.”
Comment Summary #5: Under “Inserts”, third sentence, the commenter suggested changing
from “Inserts can be classified as erodible (soluble) or nonerodable (insoluble).” to “Inserts can
be classified as erodible (soluble, biodegradable) or nonerodable (insoluble,
nonbiodegradable).”
Response: Comment incorporated. The text was modified to be in accordance with the
information in the USP General Chapter <1151> Pharmaceutical Dosage Forms.
Comment Summary #6: Under ANTIMICROBIAL PRESERVATIVES, last sentence, the

commenter suggested changing from “Acceptance criteria for antimicrobial preservative content
in multiple-unit products should be established.” to “Acceptance criteria for antimicrobial
preservative content in multi-dose products should be established.”
Comment Summary #7: Under CONTAINER-CLOSURE INTEGRITY, last sentence, the

commenter suggested changing from “Validation of container integrity must demonstrate no
penetration of microbial contamination or of chemical or physical impurities (see Package
Integrity Evaluation—Sterile Products <1207>).” to “Validation of container integrity must
demonstrate no penetration of microbial contamination or of chemical or physical impurities prior
to opening (see Package Integrity Evaluation—Sterile Products <1207>).”
Response: Comment not incorporated. The topic is covered by the USP General Chapter
<1207> Package Integrity Evaluation – Sterile Products.

Comment Summary #8: Under VISCOSITY, first sentence, the commenter suggested
changing from “An increase in viscosity increases the residence time of a formulation in the
eye.” to “An increase in viscosity increases the residence time of a formulation on or in the eye.
Response: Comment not incorporated. The text was modified to better describe the drug
products.
Comment Summary #9: The commenter proposed adding additional thresholds for reporting,
identifying and qualifying leachables for topical ophthalmic drug products into <771>, in
accordance with perspectives provided by FDA during various workshops.
Response: Comment not incorporated. The FDA has not published a formal guidance
document establishing the thresholds for leachables and extractables for ophthalmic products.
USP intends to update the chapter to reflect these thresholds after such publication by FDA.
Comment Summary # 10: Commenter requested clarification regarding the tests and
acceptance criteria for a packaging system to maintain sterility over the shelf life of the product.
Response: Comment not incorporated. Both whole product and package system are tested.
This information is included in the section Container Closure Integrity.
Comment Summary #11: Under Universal Tests, Identification, it is stated that the most widely
used identification methods are HPLC <621> and TLC <201>. The commenter suggested
updating the text to cover more state of art procedures.
Response: Comment incorporated. All the references of analytical procedures were removed to
allow for the use of any appropriate and validated analytical technique.
Comment Summary #12: In the Introduction, Figure 1, the commenter suggested adding the
word “route” after each entry. The commenter indicated the figure is intended to portray some of
the routes of administration to the eye. However, because the term “route” is not consistently
used, it appears as if some of the entries (i.e., Sub-Tenon, Superior rectus, Inferior rectus
muscle) are intended to portray the anatomy of the eye. The word “muscle” should either be
added after “superior rectus” or deleted from the “inferior rectus” entry. The commenter also
suggested considering pointing the arrows at the injection site rather than away from the
injection site.
Response: Comments incorporated.
Comment Summary #13: Under Suspensions, Paragraph 2, final sentence, the commenter
suggested the following editorial change: The drug particle size is often reduced to levels of <10
μm in an attempt to avoid excessive lacrimation is desirable to reduce irritation. While
lacrimation typically results from irritation of the eye, the goal is to reduce irritation whether or
not lacrimation occurs.
Response: Comment incorporated. The text was simplified.
Comment Summary #14: The commenter suggested to add the words “lacrimal punctum” to
the arrow in the Figure 2. This would be consistent with the Figure 1 entries.

Comment Summary #15: Under Drug Product Quality, introductory paragraph, sentence 1,
item 2, the commenter suggested changing “e.g., dissolution or drug release…” To “i.e.,
dissolution or drug release...”
Comment Summary #16: Under Universal Tests, pH, Sentence 4 – the commenter noted that
the acceptance criteria for pH is a range, not a single value. The acceptable range should be
based upon drug product stability data but may not always reflect maximum product stability
because there may be other factors to consider such as patient acceptability. The commenter
suggested the following editorial changes: “The pH value range of the formulation should be the
one where the drug product is the most stable based on drug product stability data.”
Comment Summary #17: Under Antimicrobial Preservatives, Sentence 1, item 2, the

commenter recommended that item 2 be revised. It is the radiopharmaceutical drug product that
would contain a radionuclide, not the antimicrobial agent. Item 2 should read: The substance
antimicrobial agent radiopharmaceutical drug product contains a radionuclide with a physical
half-life of <24 h.”
Comment Summary #18: Under Container-Closure Integrity, Sentence 1, the commenter

suggested the following editorial changes: “The packaging system should be closed or sealed in
such a manner as to prevent contamination or loss of contents and should provide evidence of
being incorporate a tamper evident design.”
Comment Summary #19: Under Specific Tests, Resuspendability/Redispersibility, the

commenter recommended adding the following text as the final sentence in this subsection to
be consistent with expectation that an applicant provide a one-time quantitative demonstration
of dose homogeneity: “Quantitative demonstration of the active ingredient’s redispersibility
during product development is also recommended.”
General Chapter/Sections: <857> Ultraviolet-Visible Spectroscopy /Multiple Sections

GENERAL COMMENTS/INTRODUCTION
Comment Summary #1: The commenter requested clarification for the rationale replacing “cell”
with “cuvette” throughout the chapter.
Response: Comment incorporated. With increasing use of UV-Vis with biosystems, the
terminology use was changed to avoid the overlap of terms in disciplines (e.g., biological cell
vs. sample cell).

Comment Summary #2: The commenter requested further clarification as to whether the plate
readers with monochromators could be used, as multichannel plate reader (which are excluded
from the scope of the chapter) is a plate reader that has a specific wavelength selection and do
not have a monochromator detector.
Response: Comment partially incorporated. The EC revised the entry to incorporate additional
text in the introduction to clarify the exclusion: " Chromatographic detectors and any type of
multichannel plate reader systems (i.e., filter or monochromator systems) are specifically
excluded from this chapter.”
PRINCIPLES OF MEASUREMENT
Comment Summary #1: The commenter stated that the equation that describes the incident
and transmitted radiation is incorrect and suggested it should be established at the same
wavelength.
Response: Comment not incorporated. The commenter did not correctly identify the
designation of the variables. The "naught" variable designation is intended to refer to the
radiation intensity, not the radiation wavelength variable. It denotes the difference between
incident radiation and transmitted radiation, not the wavelength.
Comment Summary #2: The commenter suggested including content for cuvettes handling and
cuvette verification procedures.
Response: Comment not incorporated. The EC, stating that precautions and additional
analytical considerations are included in Chapter <1857>, determined that there is no need for
such added text.
QUALIFICATION OF UV-VIS SPECTROMETERS

Comment Summary #1: The commenter, referring to the Control of Wavelengths and
Absorbance, requested that the precision acceptance criteria for be revised to percent relative
standard deviation (%RSD) instead of standard deviation.
Response: Comment not incorporated. The EC, noting that USP Chapter <1225> states that
the evaluation of precision can be reported by calculating "…statistically valid estimates of
standard deviation or relative standard deviation", determined that the current text is suitable.
Comment Summary #2: The commenter requested clarification regarding the removal the
reference to deuterium lines and xenon line in the text and Table 2 of the proposed revision.
Response: Comment incorporated. The EC determined that the removal of the deuterium line
reference in the text for wavelength accuracy was an editorial error, and the deleted text has
been reinstated. The appropriate xenon line for wavelength accuracy was included in the body
text and Table 2 of the balloted document.
Comment Summary #3: The commenter, referring to Control of wavelengths subsection, noted
that the language under the control of wavelengths in the body text, Table 1 and Table 3 exhibit
discrepancies. Hence, the commenter requested that USP address this discrepancy by aligning

the statement under Table 3 with the wavelength ranges in Table 1, to clarify the operational
range that can be claimed on the system.
Response: Comment incorporated. The text before Table 1 was revised to clarify the
requirement stating that “the wavelengths selected for qualification must bracket the intended
range for use.”
Comment Summary #4: The commenter, stating that diode array instruments it is not clear
how many replicates are needed to assess accuracy, requested clarification.
Response: Comment incorporated. The EC revised the entry to include, “For diode array
instruments, only one wavelength accuracy measurement is required (no replicate
measurements are required), and no precision determination needs to be performed, due to the
non-mechanical design of the monochromator.”
Comment Summary #5: The commenter, referring to Establishment of acceptance limits

(absorbance) -choice if standard stating that the temperature controls may be important when
measuring standards, noted that is provided.
Response: Comment not incorporated. The EC determined that the current text is suitable,
noting that the discussion on the impact of temperature on the measurement is discussed in
Chapter <1857> and a reference was provided under the Control of Absorbance section.
Comment Summary #6: The commenter requested that the Control of Absorbance using
metal-on-fused-silica and neutral density glass should be listed as alternatives for qualification
as these reference materials may be challenging to acquire.
Response: Comment not incorporated. The chapter indicates that the listed entries in Table 4
are provided as options and are not requirements.
Comment Summary #7: The commenter requested an additional reference material of nicotinic
acid at a level of 36 mg/L be included for Control of Absorbance at 1 – 3 AU.
Response: Comment incorporated. The reference material has been included in Table 4 and in
the text under Control of Absorbance.
Comment Summary #8: The commenter, noting that the neutral density glass filters in the
range of 0-1 AU had been removed from Table 4, requested adding them again.
Response: Comment incorporated. The EC, noting that the neutral density glass filters were
inadvertently removed, re-added those entries to the Table 4.
Comment Summary #9: The commenter expressed concern over the use of certified nicotinic
acid solutions to qualify the Control of Absorbance at 213 and 261 nm with certified set of
sealed nicotinic acid standards (with concentrations from 6 mg/L to 48 mg/L to cover our
intended absorbance working range 0 – 2 A. The commenter expressed the inability to meet the
requirements, even while assessing the impact of the spectral bandwidth and temperature of the
measurement.

Response: Comment not incorporated. The EC noting that the use of certified nicotinic acid is
well established standard used for the control of absorbance at 213 nm and 261 nm, determined
that the current content is suitable.
Comment Summary #10: The commenter, referring to Control of wavelength – Wavelength

precision, which requires the standard deviation of the mean value of the six wavelength
measurements, indicated that the terms “standard deviation of the mean” is confusing and
requested replacing it with “standard deviation”.
Response: Comment incorporated. The EC revised the text.
Comment Summary #11: The commenter, referring to the control of absorbance section, noted
that the new absorbance precision specifications represent tighter specifications due to the
increased number of significant figures in the specification and requested to revert to previous
specifications. Another commenter referring to the same topic requested a justification for
establishing tighter acceptance limits.
Response: Comment not incorporated. The EC, noting that the UV-Vis spectrometers intended
for compendial applications must meet these requirements, determined that the specifications
are suitable. The EC also noted that for at least the last 20 years, numerous manufacturers of
UV-Vis spectrometers have typically met these updated specifications indicated in the chapter.
Comment Summary #12: The commenter, referring to the Estimation of the Limit of Stray Light
Section, requested adding “while doing this measurement with Acetone, “Air” or “Empty cuvette”
should be used as reference” reasoning that “Air” is the “Appropriate” reference for Acetone
measurement.
Response: Comment incorporated. The EC revised the entry to state: “If measurements are
being performed in the 250–330 nm region, on a spectrometer using individual sources for the
UV and visible regions of the spectrum, then an additional PQ verification using acetone should
be performed, using air as reference.”
Comment Summary #13: The commenter, referring to Table 5 in the Estimation of Stray Light
section, requested that the EC reexamine the necessity of 4 standards for verification of stray
light under the rationale that the 190nm to 330nm spectral range is enough as most of the UV
applications falls under UV region.
Response: Comment not incorporated. The EC, stating that the selection of materials listed are
options for Estimation of the Limit of Stray Light based on the spectrum region of interest, and
not all are required, determined that the entries are suitable.
Comment Summary #14: The commenter, referring the Table 5 in the Estimation of Stray Light
section, suggest revising the header of the table to add “for Procedure B” at the end and remove
“For procedure B” from the first row of Column 1 and 2. Additionally, the commenter suggested
that the table be moved after Procedure B subsection.
Response: Comment not incorporated. The EC, stating that the materials listed in the table are
options applicable for Estimation of the Limit of Stray light by both Procedure A and Procedure
B, determined that the current Table 5 content is suitable.

Comment Summary #15: The commenter suggested including a spectral range assessment
for Estimation of the Limit of Stray Light above 400 nm.
Response: Comment not incorporated. The EC, stating that there are no available standard
procedures for Estimation of the Limit of Stray Light above 400 nm, and are not currently
required by any pharmacopeia, determined that the current text is suitable.
Comment Summary #16: The commenter, referring to Estimation of the Limit of Stray Light,
recommended adding that getting absorbance maxima of greater than 2 (or transmittance of
less than 1%) is important (Irrespective of its wavelength) reasoning that this peak value may
change due to resolution selection of the instrument.
Response: Comment not incorporated. The EC, stating that the wavelengths listed in Table 5
are recommended, and the acceptance criteria for Procedure B includes a maximum
absorbance of greater than 2.0 AU, determined that the current text is suitable.
Comment Summary #17: The commenter, referring to Table 5 in Estimation of the Limit of
Stray Light - measurement of stray light with Aqueous sodium iodide or potassium iodide (10
g/L)- requested that recommended the spectral range should be changed to 200 nm to 270 nm
reasoning that the peak value is expected near 220 which may shift depending on the resolution
selection of the instrument.
Response: Comment not incorporated. The EC, stating that 210 nm is acceptable lower
wavelength limit for the specified range determined that the current content is suitable.
Comment Summary #18: The commenter, noting that a sentence has been added in the
Performance Qualification section about trending and statistical evaluation as being necessary,
requested additional clarification on requirements for the statistical evaluation.
Response: Comment partially incorporated. The EC added language that includes a
recommendation for statistical evaluation and trend analysis that can used to confirm ongoing
fitness for purpose but is not a requirement.
Comment Summary #19: The commenter, referring to the second paragraph of the
Performance Qualification section, recommended an alternative verbiage.
Response: Comment partially incorporated in line with response to Comment 18.
General Chapter/Sections: <781> Optical Rotation /Multiple Sections

Expert Committee: General Chapters–Physical Analysis
GENERAL COMMENTS
Comment Summary #1: The commenter requested to revise the measurement temperature
from 25ºC to 20ºC.
Response: Comment not incorporated. Monograph requirements are established upon a
measurement temperature of 25ºC. To change this requirement, USP must acquire data to

revise individual monographs accordingly. USP intends to review this revision process and
consider this work for the future.
INTRODUCTION
Comment Summary #1: The commenter recommended simplifying and clarifying the equations
for specific rotation such that there is a distinction between the calculation for a neat liquid and a
solution, and the circumstance in which density should be applied.
Response: Comment not incorporated. The text was revised to include three equations, one
for a neat, undiluted liquid, one for a sample solution where the concentration is reported in
g/mL, and another for a sample solution where the concentration is reported in g/g.
Comment Summary #2: The commenter suggested describing the formal units for optical
rotation.
Response: Comment not incorporated. The units of optical rotation are included as (º)*mL*dm-
1*g-1, which is typically expressed as (º).
Comment Summary #3: The commenter suggested that the notation for specific rotation
should include the dependence on both the wavelength and temperature.
Response: Comment incorporated. Text to clarify the dependence of specific rotation on
temperature is included, such that the notation is described accurately.
QUALIFICATION OF POLARIMETERS
Comment Summary #1: The commenter suggested that traceability of a temperature reading
device, per general notices 6.80.30, should claim traceability to a metrological institute, e.g.
NIST or equivalent.
Response: Comment not incorporated. The existing language in the Operational
Qualification/Temperature Control section states: “The OQ of a polarimeter's temperature
control is performed by demonstrating that the operating temperature is within ±0.5° C to a
temperature recorded on a temperature reading device that is traceable to a National Institute of
Standards and Technology (NIST) standard or equivalent (see General Notices, 6.80.30.
Temperature Reading Devices).”
Comment Summary #2: The commenter indicated that the Operational Qualification of the
wavelength accuracy and bandwidth was inadequate, as the procedure proposed is also
impacted by other conditions as temperature, path length, and light emission intensity. In
addition, the commenter indicated that the procedure requirements may not be applicable to
polarimeters employing atomic emission lamps.
Response: Comment incorporated. The section has been revised such that the wavelength
and the bandwidth of the polarimeter is reported for polarimeters employing bandpass filters,
whereas polarimeters employing alternative sources only need report the source wavelength.
Comment Summary #3: The commenter suggested that the wording stating the “wavelength
accuracy and bandwidth of the light source” is misleading, as the wavelength accuracy and
bandwidth are dependent on the interference filters.

Response: Comment incorporated. The section has been revised such that the wavelength
and the bandwidth of the polarimeter is reported for polarimeters employing bandpass filters.
Comment Summary #4: The commenter requested the minimum Operational Qualification of
Optical Rotation accuracy of ± 0.005° be implemented, or at least an accuracy of ± 0.01° for the
entire measuring range of the polarimeter.
Response: Comment not incorporated. Not all polarimeters manufactured and currently used
in industry report optical rotation to the third decimal place. The European Pharmacopeia
(Ph.Eur.) also requires an operational accuracy of 0.01°. The requirement is harmonized with
the Ph.Eur., where the accuracy of the optical rotation is qualified using a certified reference
material with a stated expanded uncertainty ± 0.01° or better.
Comment Summary #5: The commenter suggested removing the Wavelength Accuracy and
Bandwidth section, as the procedure for Accuracy of Optical Rotation implies wavelength
accuracy.
Response: Comment partially incorporated. The section for Wavelength Accuracy and
Bandwidth simply requires reported the determined operating wavelength and bandwidth.
Comment Summary #6: The commenter suggested an accuracy of ±0.005° is excessive for
the reference material because the polarimeter is only capable of reporting a result of ±0.01°,
and the NIST Sucrose SRM reports an uncertainty of ±0.007°.
Response: Comment incorporated. The section has been revised such that the optical rotation
is qualified using a certified reference material with a stated expanded uncertainty ± 0.01° or
better. This adjustment allows for the use of the NIST Sucrose SRM.
Comment Summary #7: The commenter requested a modified limit for the certified optical
rotation reference material of ±0.010⁰.
Response: Comment partially incorporated. The section has been revised such that the optical
rotation is qualified using a certified reference material with a stated expanded uncertainty ±
0.01° or better.
Comment Summary #8: The commenter suggested the proposed repeatability requirement
does not allow for instances where the polarimeter manufacturer does not provide repeatability
specifications.
Response: Comment not incorporated. The EC has concluded that repeatability and precision
requirements are available for polarimeters currently in market.
PROCEDURES
Comment Summary #1: The commenter suggested that the specific size of the measurement
cell could be variable as long as the % volume is appropriate for the sample size being
measured. A 2.0 or 5.0-dm measurement cell could also be appropriate.
Response: Comment not incorporated. USP monograph requirements are established on the
1.0-dm cells.

Comment Summary #2: The commenter suggested that the difference between the USP and
Ph. Eur. operating temperatures of 25°C and 20°C, respectively, is double the work for
companies, and requests the USP harmonize with the Ph.Eur.
Response: Comment not incorporated. USP monograph requirements are established at 25°C.
USP will engage in harmonization efforts, but each monograph requirements would need to be
revised, as well. To change this requirement, USP would require validated results. USP invites
sponsors to submit validation package for monographs for harmonizing the operating
temperature to 20°C.
General Chapter/Sections: <1857> Ultraviolet-Visible Spectroscopy – Theory and Practice

/Multiple Sections
THEORY
Comment Summary #1: Several commenters, referring to the first and second sentence of the
second paragraph of the “Theory” section, commented that they contained an error using the
term “chromosomes” instead of “chromophores”.
Response: Comment incorporated. The text has been revised.
Comment Summary #2: The commenter requested a rationale for removing the Derivative
Spectroscopy section.
Response: Comment not incorporated. The EC, stating that only two known USP monographs
employ the use of UV-Vis first derivative spectroscopy and that the deleted content in this
section did not support these monograph procedures, determined that the deletion was
appropriate. The EC further noted that the content of this section is widely available in
textbooks.
UV-VIS SPECTROMETERS
Comment Summary #1: The commenter, referring to the first sentence of the first paragraph of
Spectral Bandwidth—Effect on Resolution and Signal-to-Noise Ratio section, recommended
revising the sentence “to read “Spectral bandwidth (SBW) is important to ensure adequate peak
resolution.”
Comment Summary #2: The commenter, referring to the sentence “If access to a variable-
bandwidth instrument is available, then the optimum setting can be defined as the largest
bandwidth at which no significant reduction in peak intensity is observed”, recommended
revising it to replace “the largest bandwidth” with “the narrowest bandwidth”.
Response: Comment partially incorporated. The EC revised the entry to replace the “largest
bandwidth” with "narrowest slit width".
Comment Summary #3: The commenter, referring to the sentence “Custom-built systems do
not have additional shuttering, stray light filtering, and other capabilities that are found in

commercially designed spectrometers” in the Alternative UV-Vis Detector Spectrometer
Configurations section, suggested revising the sentence to “Custom-built systems may not have
additional shuttering, stray light filtering, and other capabilities that are found in commercially
designed spectrometers,” reasoning that these capabilities are often built into custom systems.
Response: Comment incorporated. The EC revised the text .
Comment Summary #4: The commenter, referring to the excerpt starting with the second
sentence until the end of last paragraph of Optimum Working Photometric Range subsection,
recommended revising the entry to: “The use of shorter path length cuvettes may be successful
to reduce a measured solution absorbance when ratio dilution with solvent is not possible. Ratio
dilution with solvent may increase error associated with the measurement or alter the solution
chemistry of the sample,” reasoning that it is common practice to perform ratio dilution,
especially if other size cuvettes are not readily available.
stating that while it is understood ratio dilution is common practice, the intention of <1857> is to
provide best practices, and that the best practice here is to use shorter pathlength cuvettes as
opposed to performing ratio dilutions.
ANALYTICAL CONSIDERATIONS
Comment Summary #1: The commenter noting that a section titled “Temperature Coefficients
and Effects” has been added on the temperature dependence of absorbance due to variations
in sample concentration, stated that it is unclear on whether the additional temperature
monitoring is required for qualification or not. Further, the commenter noted that USP <857>
has no further information on limits for temperature control and most UVs have no way of
adjusting temperature so this would be based on room temperature only, which will be very hard
to control when a qualification is happening. The commenter requested a reference table for
standard accuracy at different temperatures should be included, reasoning that actual
implementation needs further clarification.
stating that USP <1857> does not provide mandatory requirements for temperature control, but
gives to the reader additional information and best practices on temperature control need when
measuring liquid reference materials at higher concentrations.
Comment Summary #2: The commenter, referring to the third column header of Table 2 -
190L1-noted that it is unclear why “190” was included and recommended either removing “190”
or clarifying why it is necessary, possibly as a footnote to Table 2.
Response: Comment incorporated. The text has been revised.
Comment Summary #3: The commenter, referring to the first sentence of the Sample-Based
Factors section and some other places noting that “Spectrophotometry” has been replaced with
“spectroscopy” in the proposed text, suggested revising the sentence to replace UV-Vis
spectroscopy with UV-Vis spectrometry. The commenter provided as rationale that
“spectroscopy” refers to the theoretical study whereas “spectrometry” is the method used to
acquire quantitative measurement of the spectrum.

Comment Summary #4: The commenter, referring to a new added paragraph in Solution
Preparation subsection of Sampling Factors section and stating that the added section appears
to be redundant and unnecessary, recommended that this paragraph be removed.
stating that redundancy in communicating best practices and providing information is valuable to
reinforce particularly important messages.
Comment Summary #5: The commenter, referring to entries “It is preferable to use a single
cuvette for all measurements of both the reference and samples, and where possible, never
move the cuvette if you can move the solution” in the third paragraph and “whenever possible,
measure standards and samples at the same time and under the same conditions to minimize
the potential for bias in the fourth paragraph of the “CUVETTE” section,” stated that these two
statements are opposite and asked for clarification.
noting that both measurement procedures, using single cuvette or two cuvettes, are discussed
in the chapter and analytical considerations for both are discussed.
Comment Summary #6: The commenter, referring to the last paragraph of “CUVETTES”
section, suggested revising the sentence to replace “spectroscopic” term with “spectrometric”
term. The commenter’s rationale was to align with the expected update to replace
“spectrophotometry” with to “spectrometry” in the rest of the text.
Monographs
Monograph/Section: Amantadine Hydrochloride Tablets/Multiple Sections

Expert Committee: Small Molecules 1
Comment Summary #1: The commenter noted their approved dissolution method and/or
tolerances are different from what is proposed in the monograph.
Response: Comment not incorporated. The commenter did not provide data to support their
comment. As appropriate, a second dissolution test can be added in the future upon receipt of
the supporting data.
Comment Summary #2: The commenter recommended removing the reporting threshold from
the test for Organic Impurities as it will vary based on product-specific factors.
Response: Comment not incorporated. Based on comments received on a proposed policy for
reporting thresholds, USP determined that before the removal of any reporting thresholds from
monographs can occur, further stakeholder engagement is needed. USP intends to conduct
further stakeholder engagement on this issue.

EC-initiated Change #1: Change from “Any individual unspecified degradation product” to “Any
unspecified degradation product” in the Organic Impurities test to be consistent with ICH
terminology.
Monograph/Section(s): Amiloride Hydrochloride Tablets /Organic impurities

Comment Summary #1: The commenter requested removing the reporting threshold as it will
vary based on product-specific factors.
reporting thresholds, USP determined that before the removal of any reporting thresholds from
Comment Summary #2: The commenter recommended tightening the limits for Amiloride acid,
Amiloride methyl ester, and 5-Hydroxyamiloride hydrochloride to align with ICH Q3B guidelines
Response: Comment not incorporated. The limit of NMT 1.0% for each of those specified
impurities is consistent with what has been approved by the US FDA. The EC will consider
future revisions to the monograph upon receipt of supporting data.
Comment Summary #3: The commenter noted the impurity of “Chloropyrazine methyl
carboxylate” was misspelled as “Amiloride ethyl ester.” The commenter recommended changing
the text to “Amiloride methyl ester”.
Response: Comment partially incorporated. “Amiloride ethyl ester” has been replaced by
“Amiloride related compound A” to be consistent with current naming practice. The
corresponding footnote reflects the correct chemical structure.
Comment Summary #4: The commenter suggested revising “Any other unknown impurity” to
“Any unspecified degradation product” to align with ICH Q3B guidelines.
Response: Comment not incorporated. The “any other unknown impurity” of NMT 0.5% limit is
consistent with what has been approved by the US FDA. The EC will consider future revisions
to the monograph upon receipt of supporting data.
Monograph/Section: Argatroban Injection/Multiple Sections

Comment Summary #1: The commenter recommended that USP work with the approved
manufacturers to ensure that the marketed products will be able to meet the requirements in the
proposed monograph to avoid a drug shortage.
Response: Comment incorporated. USP reached out to approved manufacturers. The EC
evaluated the information received and made additional changes to this monograph as
summarized below. The EC will consider future revisions to the monograph upon receipt of
additional supporting data.

Comment Summary #2: The commenter recommended that this monograph be developed in
conjunction with a monograph for Argatroban in Sodium Chloride Injection.
Response: Comment not incorporated. This comment was outside of the scope of this specific
standard, however, we note that a monograph proposal for Argatroban in Sodium Chloride
Injection was developed and published in PF46(1).
Comment Summary #3: The commenter recommended revising the proposed Definition to
accommodate other FDA approved products.
Response: Comment incorporated. The Definition was revised by not specifying water as an
inactive ingredient and removing “in Water for Injection.” (Please also see the additional change
listed in EC-initiated Change #1.)
Comment Summary #4: The commenter recommended revising the acceptance criteria for
Dehydroargatroban and Total degradation products in the test for Organic Impurities to
accommodate other FDA-approved applications.
Response: Comment incorporated. The acceptance criterion for Dehydroargatroban was
widened from NMT 0.3% to NMT 1.5%, and a footnote was added to Table 2 for Total
degradation products to exclude Dehydroargatroban in the Total degradation products.
Comment Summary #5: The commenter recommended removing the reporting threshold from
the test for Organic Impurities as it will vary based on product-specific factors.
reporting thresholds, USP determined that before the removal of reporting thresholds from
Comment Summary #6: The commenter recommended adopting flexible approach and
revising the acceptance criterion for pH in the Specific Tests section to accommodate other
FDA-approved applications.
Response: Comment incorporated. Based on information received by USP from manufacturers,
the acceptance criterion for the test of pH was revised from 6-8 to 6-8.5 including an additional
note “this pH test is applicable to formulations which contain sorbitol.”
Comment Summary #7: The commenter indicated that it’s not suitable to include the test for
Osmolality and Osmolarity <785> in this monograph as a public standard and recommended
deleting it.
Comment Summary #8: The commenter commented that the acceptance criteria are not
included in Bacterial Endotoxins Test <85> in the Specific Tests section.
Response: Comment not incorporated. The monograph refers to the general chapter Bacterial
Endotoxin Test <85> for the requirements; no change is needed.

EC-initiated Change #1: The term “argatroban” was revised to “Argatroban” in the first
sentence of the Definition to be consistent with the current USP practice.
Monograph/Sections: Candesartan Cilexetil/ Organic Impurities

Comment Summary #1: The commenter recommended removing the reporting threshold as it
will vary based on product-specific factors.
EC-initiated Change #1: To align the chemical information between the monograph and the
associated labels and certificates of reference standards, alternative chemical names were
included for USP Candesartan Cilexetil Related Compound A RS, USP Candesartan Cilexetil
Related Compound B RS, USP Candesartan Cilexetil Related Compound D RS and USP
Candesartan Cilexetil Related Compound F RS in the section USP Reference Standards <11>.
Monograph/Sections: Candesartan Cilexetil Tablets/Organic Impurities

monographs can occur, further stakeholder engagement is needed. USP intends to do further
stakeholder engagement is needed. USP intends to do further stakeholder engagement on this
issue.
Comment Summary #2: The commenter indicated that process impurities should not be listed
in a public standard for drug products and recommended the removal of one of the process
impurities, Candesartan cilexetil related compound A from Table 3
Response: Comment not incorporated. The designation of process impurities included Table 3
and the associated footnote are part of the official text outside of the scope of the proposed
revisions. The EC will consider future revisions to this monograph upon receipt of supporting
information.
EC-initiated Change #1: To align the chemical information between the monograph and the
associated labels and certificates of reference standards, alternative chemical names were
included for USP Candesartan Cilexetil Related Compound A RS, USP Candesartan Cilexetil
Related Compound B RS, USP Candesartan Cilexetil Related Compound D RS and USP
Candesartan Cilexetil Related Compound F RS in the section USP Reference Standards <11>.

Monograph/Sections: Chlordiazepoxide and Amitriptyline Hydrochloride Tablets/Organic
Impurities
Comment Summary #2: The commenter requested changing the acceptance criterion for 2-
Amino-5-chlorobenzophenone from what was proposed for consistency with what has been
approved.
Response: Comment incorporated by retaining the currently official acceptance criterion for 2-
Amino-5-chlorobenzophenone.
Comment Summary #3: The commenters requested revising several of the acceptance
criteria, removing the reference to cyclobenzaprine, and replacing the proposed analytical
procedure with a different analytical procedure which is more robust.
Response: Comment partially incorporated by retaining the currently official test for Organic
Impurities instead of using the proposed procedure. The EC will consider future revisions to the
monograph.
EC-initiated Change #1: The relative retention times for Chlordiazepoxide and Amitriptyline are
explicitly stated within the System suitability section of the revised Assay.
EC-initiated Change #2: The references to USP Amitriptyline Related Compound A RS, USP
Amitriptyline Related Compound B RS, USP Cyclobenzaprine Hydrochloride RS, and USP
Nortriptyline Hydrochloride RS are removed from the USP Reference Standards <11> section
as they are no longer needed.
Monograph/Sections: Chlordiazepoxide Hydrochloride Capsules/Organic Impurities

stakeholder engagement on this issue.

Comment Summary #2: The commenter requested changing the acceptance criterion for 2-
Amino-5-chlorobenzophenone from what was proposed for consistency with what has been
approved.
Response: Comment incorporated by retaining the currently official acceptance criterion for 2-
Amino-5-chlorobenzophenone.
EC-initiated Change: The reference to USP Chlordiazepoxide Related Compound A RS is

removed from the Sensitivity solution and the Signal-to-noise ratio requirement.
Monograph/Section(s): Colistin Sulfate/Organic Impurities

Expert Committee: Biologics Monographs 4
Comment Summary #1: The commenter recommended removing the reporting threshold in the
test for Organic Impurities as ICH Q3A limits (including reporting threshold) will vary based on
product-specific factors because of the different Maximum Daily Doses (MDD) for different
products using the drug substance.
Response: Comment not incorporated. Colistin Sulfate as a fermentation product is out of the
scope of ICH Q3A.
Monograph/Section(s): Cranberry Fruit Juice and Cranberry Fruit Juice Concentrate /

Identification, Composition and Specific Tests
Expert Committee: Botanical Dietary Supplements and Herbal Medicines
Number of Commenters: 9
Identification
Comment Summary #1: The commenter asked if USP plans to include pictures of the
reference profile under Identification B. HPTLC for Articles of Botanical Origin <203> and
Identification C. HPLC Profile of Flavonoids. It could be helpful to see a characterized profile to
interpret acceptance.
Response: Comment incorporated. The HPLC chromatograms of the USP Cranberry Fruit
Juice Dry Extract RS will be provided in this reference material's corresponding CoA. HPTLC
images of the USP Cranberry Fruit Juice Dry Extract RS will be available in the Supporting
Information of the Dietary Supplements Compendium (DSC), which is an online publication.
Comment Summary #2: The commenter indicated that some peak descriptions under
Identification C. HPLC Profile of Flavonoids are rather empirical (without scale / unit) as ‘no
peak’, ‘minor’, etc. Is it possible to describe some scaled specifications (e.g., ratio between
peaks, or peak % on total area basis calculation)?
Response: Comment not incorporated. The area ratio of peonidins (Σ peonidin-3-O-galactoside
and peonidin-3-O-arabinose) and cyanidins (Σ cyanidin-3-O-galactoside and cyanidin-3-O-
arabinoside) (ranging between 0.5 and 1.9), was proposed in the monograph; area ratios
between other compounds largely varied and thus could not be proposed as characteristic
ratios.

Comment Summary #3: The commenter asked to confirm that the acceptance criteria under
Identification B. HPTLC for Articles of Botanical Origin <203> correctly specifies that there
should not be any band of procyanidin B2/B1 because cranberry juice is a source of that
procyanidin.
Response: Comment not incorporated. Although procyanidin B2 and B1 could be minor
components in Cranberry Fruit Juice, these bands are not detected by HPTLC under the
conditions proposed in the monograph. Detection of these bands could indicate adulteration
with grape seed extract.
Comment Summary #4: Regarding authenticity, the commenter proposed that the monograph
include reference to the utility of MALDI-TOF MS (Feliciano et al., 2012 and AOAC Official First
Action Status-in press), an advanced analytic platform for identification of A-type
proanthocyanidins (PACs) in Cranberry. The DMAC method cannot differentiate Cranberry
(PACs) from those of potential adulterants (i.e., grape seed extract and peanut skin).
Response: Comment not incorporated. USP is currently evaluating MALDI-TOF MS and other
HR-MS techniques for PAC characterization and detection of adulteration for a possible new
USP General Chapter and future monograph modernization. The commenter’s recommendation
will be considered as this chapter is developed.
Comment Summary #5: The commenter suggested that another authenticity method is needed
since DMAC (4-dimethylaminocynnamaldehyde) does not distinguish the type of PACs (A vs. B-
type) from different plant sources. MALDI-TOF should be included or referenced as the method
for authenticity testing in any product in which PAC content is of interest.
Response: Comment not incorporated. USP is currently evaluating MALDI-TOF MS and other
HR-MS techniques for PAC characterization and detection of adulteration for a possible new
USP General Chapter and future monograph modernization. The commenter’s recommendation
will be considered as this chapter is developed.
Comment Summary #6: The commenter indicated that under Identification B. HPTLC for
Articles of Botanical Origin <203>, different amounts of the supernatant of Standard solution C
(1.5 mL) and Sample solutions (150 μL for Cranberry Fruit Juice Concentrate and 1 mL for
Cranberry Fruit Juice) are put on the cartridges and asked if the same volume of Standard
solution C (1.5 mL) could be used in both cases to avoid mistakes in the procedure.
Response: Comment not incorporated. The sample preparation concentration and the amount
Fruof sample loaded on the cartridges depend on the ingredient type because the concentration
of polyphenols differs considerably among the different ingredients. These volumes are based
on optimization and validation.
Comment Summary #7: Under Identification B. HPTLC for Articles of Botanical Origin <203>,
the commenter indicated that the precondition with SPE cartridge, according to L1 definition, the
diameter should be 1.5 to 10 mm. The diameter of the Phenomenex cartridge is 55 mm thus, in
our opinion should be L2 type.
Response: Comment incorporated. It was confirmed that the SPE cartridge corresponds to L2
according to our USP Chromatography Column database.

Comment Summary #8: The commenter stated that in some places under Identification B.
HPTLC for Articles of Botanical Origin <203>, the term "orange-brick band" in contrast to "brick-
orange band" was used?
Response: Comment incorporated. The color of the band was changed to brick-orange where
applicable.
Comment Summary #9: Under Identification B. HPTLC for Articles of Botanical Origin <203>,
the commenter asked if the term "below" instead of "before" was correct in the following
statement: "The occurrence of a yellow-green band near the sample application and before
cyanidin-3-O-glucoside might indicate the presence of peanut skin extract."
Response: Comment incorporated. The statement was corrected as follows: "The occurrence
of a yellow-green band between the sample application and cyanidin-3-O-glucoside might
indicate the presence of peanut skin extract."
Composition
Comment Summary #1: Under Composition. Content of Dextrose and Fructose, for the HPLC
determination of dextrose and fructose, the commenter suggested that due to the known
thermosensitivity of RI detectors, a fixed column temperature (instead of ambient temperature)
should be proposed. It is also recommended to keep the connection between the column and
the detector as short as possible.
Response: Comment incorporated. RI detectors usually require 5°C above room temperature;
therefore, a temperature of 30°C has been incorporated.
Comment Summary #2: The commenter indicated no description/acceptance of organic acids

in juice. It is recommended to use the same as for concentrate.
Response: Comment not incorporated Both monographs, Cranberry Fruit Juice and Cranberry
Fruit Juice Concentrate include organic acid content specifications.
Comment Summary #3: The commenter suggested that the monograph for Cranberry Fruit
Juice be revised to include a method for quantification of proanthocyanidins.
Response: Comment not incorporated. The commenter did not provide data to support the
inclusion of such a method. USP will consider introducing limits for PAC content in this
monograph upon receiving supporting information.
Comment Summary #4: The commenter inquired why is there no quantitation (by DMAC) of
proanthocyanidins in Cranberry Fruit Juice.
Response: Comment not incorporated. The commenter did not provide data to support
quantitation (by DMAC) of proanthocyanidins (PACs) in Cranberry Fruit Juice. USP will consider
introducing limits for PAC content in this monograph upon receiving supporting information.
Comment Summary #5: The commenter stated that for Cranberry Fruit Juice Concentrate, the
DMAC test under Composition. Content of Proanthocyanidins, the acceptance NLT 0.6% looks
too high, suggesting a lower limit of 0.5% instead.

Response: Comment not incorporated. The data received for Cranberry Fruit Juice
Concentrate for Dietary Supplements support a specification that is not lower than 0.6% PACs.
Further revisions may be considered upon receipt of supporting data.
Comment Summary #6: The commenter proposed that to consider the solids content, which
can differ (notably for concentrate), the %PAC calculation based on the DMAC test should be
done on a dry matter basis (or solid content basis based on RI analysis) instead of % calculation
on the raw material basis
Response: Comment not incorporated. The %PAC calculation in Cranberry Fruit Juice
Concentrate is expressed in % w/w, so the weight of the material (instead of the solid content) is
accounted for.
Specific tests
Comment Summary #1: The commenter stated that the solids content is defined as 7.5 ± 0.5%
for Cranberry Fruit Juice and 50 ± 0.5% for Cranberry Fruit Juice Concentrate, requesting an
increase in both ranges.
Response: Comment not incorporated. The specifications and CoAs received from different
manufacturers support a limit of soluble solids of 7.5 ± 0.5% and 50 ± 0.5% for Cranberry Fruit
Juice and Cranberry Fruit Juice Concentrate, respectively.
Monograph/Sections: Choline Bitartrate/Multiple Sections

Expert Committee: Non-Botanical Dietary Supplements
EC-initiated Change #1: The EC decided to add an additional note to the Related Compounds
procedure to help users distinguish, identify, and address artifact and impurity peaks in the
HPLC-CAD chromatograms.
EC-initiated Change #2: Instructions for the Standard response line in the test procedure for
the Limit of Total Amines contain error in representation of the accurate cumulative
concentrations after each addition of the Standard solution, which should be calculated by
taking into account the accurate total volume of the solution in the vessel. Instructions to
calculate the correct and accurate cumulative concentrations have been added to the text.
Monograph/Section: Doxycycline/Multiple Sections

Comment Summary #1: The commenter requested removing the reporting threshold from the
test for Organic Impurities as it will vary based on product-specific factors.

Comment Summary #2: The commenter requested including <197K> in Identification A and
allowing the flexibility of using either <197A> or <197K> as in the Doxycycline Hyclate
monograph.
Response: Comment not incorporated. The EC will consider future revisions to this monograph
upon receipt of the necessary supporting data.
Comment Summary #3: The commenter recommended using the same USP standard of
doxycycline, in the tests for Assay and Organic Impurities in both Doxycycline and Doxycycline
Hyclate monographs.
Response: Comment not incorporated. Based on the supporting data, the EC determined the
use of USP Doxycycline Monohydrate RS is suitable for the tests in Doxycycline monograph.
Comment Summary #4: The commenter indicated there are slight differences in the relative
retention times and relative response factors for Organic Impurities test between Doxycycline
and Doxycycline Hyclate monographs and recommended using the same values of relative
retention times and relative response factors in both monographs.
Response: Comment not incorporated. The EC determined the relative retention times and
relative response factors are consistent with the validation data.
Monograph/Section(s): Enzacamene/Organic Impurities

EC-initiated Change #1: Change from “Any individual unspecified impurity” to “Any unspecified
impurity” in Table 2 of the Organic Impurities section to be consistent with ICH terminology.
Monograph/Section: Etravirine/ Organic Impurities

Expert of Committee: Small Molecules 1
Monograph/Section: Etravirine Tablets/ Organic Impurities

Expert of Committee: Small Molecules 1
stakeholder engagement on this issue

Monograph/Sections: Fluticasone Propionate/Impurities
Expert Committee: Small Molecules Monographs 5
Comment Summary #1: The commenter recommended revising the limit for any unspecified
impurity in the test for Organic Impurities to be consistent with ICH Q3A guidelines.
Response: Comment not incorporated. The comment is outside the scope of the revision. The
EC will consider future revisions to the monograph upon receipt of supporting data.
Comment Summary #2: The commenter requested removing the “reporting threshold” in the
test for Organic Impurities.
further stakeholder engagement.
Comment Summary #3: The commenter recommended replacing fluticasone propionate with
fluticasone propionate related compound D in the preparation of the Sensitivity solution in the
test for Organic Impurities to avoid possible interference resulting from system carryover from
previous injections of higher concentration sample solutions.
Response: Comment not incorporated. The EC will consider future revisions to the monograph
upon receipt of supporting data.
Comment Summary #4: The commenter recommended decreasing the concentration of the
Sensitivity stock solution to permit a different final dilution in the preparation of the Sensitivity
solution in the test for Organic Impurities.
Response: Comment not incorporated. USP General Notices and Requirements permits
changes in solution preparations, as discussed in Section 6.50.20.1. Adjustments to Solutions,
provided that the change does not increase the error of the measurement.
Comment Summary #5: The commenter recommended adding a Residue on Ignition test with
appropriate limits to control inorganic impurities.
EC will consider future revisions to the monograph upon receipt of supporting data.
Monograph/Section(s): Fosamprenavir Calcium/Multiple sections

Comment Summary #1: The commenter recommended a change in reagent form used to
prepare the Buffer in the Assay section.
Response: Comment not incorporated. The EC determined that the preparation listed matches
what is in the submission the developed monograph is based off. Further revisions will be
considered upon receipt of supporting data.

Comment Summary #2: The commenter recommended revising the Assay calculation to
include the correction for water.
Response: Comment not incorporated. The EC determined that the calculation is calculated
against the USP RS that is already corrected for water and assigned a value.
Comment Summary #3: The commenter recommended the Standard solution in the Organic
Impurities test be identical to that in the Assay.
Response: Comment not incorporated. The EC determined that the concentration in the
Standard solution for the Organic Impurities test is based on the unspecified impurity level to
evaluate response.
Comment Summary #4: The commenter noted that two different impurities in Table 1 and
Table 3 are given the same name of Fosamprenavir pyrophosphate and recommended the
name(s) be changed so they are different.
Response: Comment incorporated. One of the impurities is a dimer and the name was
corrected accordingly, Fosamprenavir pyrophosphate appears in Table 1 and Bisfosamprenavir
pyrophosphate appears in Table 3.
EC-initiated Change #1: Change from the “Any individual unspecified impurity” to “Any
unspecified impurity” in Table 1 and Table 3 of the Organic Impurities section to be consistent
with ICH terminology.
Monograph/Sections: Latanoprost/Organic Impurities

monographs can occur, further stakeholder engagement. USP intends to conduct further
stakeholder engagement on this issue.
Comment Summary #2: The commenter recommended revising the limit of “Any unspecified
impurity” from 0.1% to 0.10% to be in line with ICH Q3A.
Response: Comment not incorporated. The comment is outside of the scope of the revision.
The EC will consider a future revision to the monograph upon receipt of the supporting data.

Monograph/Section(s): Menthol/Assay and Related Compounds
Comment Summary #1: The commenter proposed implementation of an internal standard in
Assay and Related Compounds.
Response: The proposed revision included an internal standard.
Comment Summary #2: The commenter proposed determining %RSD based on ratio of
Amenthol/Ainternal standard in System suitability
Response: Comment not incorporated. The proposed revision included an internal standard
and determination of %RSD using the ratio of Amenthol/Ainternal standard in System suitability; no
additional revision was needed.
Comment Summary #3: The commenter asked whether it is possible to perform GC using
helium as the carrier gas if the conditions are appropriately converted.
Response: Comment not incorporated. The proposed GC system using helium as a carrier gas
exhibited poor peak response.
Comment Summary #4: The commenter proposed indicating relative retention time (RRT) for
the internal standard in Assay, and also asked the “Related compounds” section can be placed
before “Limit of nonvolatile residue”.
Response: Comment incorporated to include RRT of internal standard (0.27). No need to re-
place the sections as the current order of the sections is aligned with USP style.
Comment Summary #5: The commenter questioned whether the proposed Assay method
works because the test by commenter’s lab using the proposed method found two out of
specifications among 16 runs.
Response: Comment not incorporated. After examining experimental details and data, no
issues were found in the method. No further actions are required.
Monograph/Section: Molindone Hydrochloride/Organic Impurities

Comment Summary #1: The commenter recommended removing the reporting threshold in the
Monograph/Sections: Naloxone Hydrochloride/Organic Impurities


Comment Summary #2: The commenters indicated that the acceptance criteria for all specified
impurities and Total impurities are different from what have been approved by the FDA.
Response: Comment partially incorporated. There are five specified impurities included in
Table 3. USP received information from manufacturers for four specified impurities and Total
impurities with higher approved limits. The acceptance criteria were widened from NMT 0.10%
to NMT 0.15% for each of these four specified impurities (10α-Hydroxynaloxone,
Noroxymorphone, 10β-Hydroxynaloxone and 2,2’-Bisnaloxone) and from NMT 0.5% to NMT
0.8% for Total impurities.
Comment Summary #3: The commenter indicated that their specification includes an
additional specified impurity “10-Ketonaloxone” with an acceptance criterion at NMT 0.15% and
a wider acceptance criterion for Total impurities at NMT 1.0%.
Response: Comment not incorporated. Based on the available information, the EC determined
that it’s not necessary to add the specified impurity “10-Ketonaloxone” to Table 3 and the
revised acceptance criterion for Total impurities at NMT 0.8% is adequate.
Monograph/Section(s): Pramipexole Dihydrochloride/Limit of Pramipexole Related

Compound D
Comment Summary #1: The commenter requested that USP not change the reference
standard concentrations in the procedure for the Limit of Pramipexole Related Compound D, as
they believe that the USP Pramipexole Related Compound D RS was always a dihydrochloride
sale.
Response: Comment not incorporated. USP Pramipexole Related Compound D RS has
changed salt forms over time, necessitating the updates to the test.
Monograph/Sections: Primidone Tablets/Organic Impurities

Comment Summary #1: The commenter recommended removing the “reporting threshold” as
it will vary based on product-specific factors.
Monograph/Section: Propionic Acid / Organic Impurities

Expert Committee: Simple Excipients

Comment Summary #1: The commenter suggested changing the “NMT 0.15%” requirement
for any unidentified individual impurity to “NMT 0.2%” with supporting data.
Response: Comment incorporated. The available data supported this change.
Monograph/Sections: Propranolol Hydrochloride Injection/Organic Impurities

Monograph/Section(s): Rivaroxaban/Multiple Sections

Comment Summary #1: The commenter recommended harmonizing the Enantiomeric Purity
test procedure with the corresponding test in the European Pharmacopeia 10.7 monograph for
Rivaroxaban and including a limit of NMT 0.5% for the Rivaroxaban R Isomer.
Response: Comment not incorporated. The EC determined that the proposed procedure and
the acceptance criterion are consistent with a US FDA approved application.
Comment Summary #2: The commenter recommended harmonizing the Identification test B
with the corresponding test in the European Pharmacopeia 10.7 monograph and include the
reference to the Enantiomeric Purity test instead of the Assay test for the retention time
agreement.
Response: Comment not incorporated. The EC determined that the proposed Identification test
B is consistent with an FDA approved application and will consider a future revision as
appropriate.
Comment Summary #3: The commenter recommended harmonizing the acceptance criterion
for Water Determination <921>, Method I, Method Ic with the corresponding limit of NMT 0.5%
in the European Pharmacopeia monograph.
Response: Comment not incorporated. The EC determined that the proposed acceptance
criterion for water determination is consistent with an FDA approved application.
Comment Summary #4: The commenter indicated that the proposed procedures for Organic
Impurities and the Enantiomeric Purity tests are not suitable for their drug substance because
the in-house impurities are either coeluting or closely eluting and one of in-house impurities is
not soluble in the diluent.
Response: Comment not incorporated. The EC will consider future revision to the monograph
upon receiving the necessary supporting information.

Comment Summary #5: The commenter indicated that the Injection volume under the Assay
and Organic Impurities test procedures is below the suggested injection precision of the general
analytical instruments.
Response: Comment not incorporated. The EC determined that the proposed Injection volume
is consistent with validation data and is suitable for its intended use.
Comment Summary #6: The commenter indicated that the peak response of rivaroxaban is
low due to the proposed low Injection volume in the tests for Assay and Organic Impurities.
Response: Comment not incorporated. The EC determined that the proposed Injection volume
is consistent with validation data and is suitable for its intended use.
Comment Summary #7: The commenter requested replacing the proposed procedures for
Assay and Organic Impurities tests with their in-house test procedures as they are fully
validated and are specific for all known impurities for rivaroxaban.
Response: Comment not incorporated. The EC determined that the proposed methods are
consistent with validation data and are suitable for their intended use.
Organic Impurities test as it will vary based on product-specific factors.
reporting thresholds, USP determined that before removal of reporting thresholds from
Comment Summary #9: The commenter requested replacing the proposed procedures for
Assay and Organic Impurities tests with their in-house test procedures as they provide higher
peak response due to larger injection volume.
Response: Comment not incorporated. The proposed methods are fully validated and are
consistent with a US FDA approved application.
Comment Summary #10: The commenter requested replacing the proposed Enantiomeric
purity test procedure with their in-house test procedure for better resolution.
Response: Comment not incorporated. The proposed method is fully validated and is
consistent with a US FDA approved application.
Monograph/Section: Saquinavir Mesylate/Organic Impurities


Monograph/Section(s): Siler Root/Multiple Sections

Comment Summary: The commenter indicated that the USP convention is not to italicize the
botanical family name, the Siler Root family monographs should be corrected in this regard.
Response: Comment incorporated. The monographs of Siler Root, Siler Root Powder and Siler
Root Dry Extract are corrected consistent with the USP convention.
Monograph/Section(s): Siler Root Powder/Multiple Sections

Comment Summary: The commenter indicated that the USP convention is not to italicize the
botanical family name, the Siler Root monograph should be corrected in this regard.
Monograph/Section(s): Siler Root Dry Extract/Multiple Sections

Comment Summary #1: The commenter indicated that the USP convention is not to italicize
the botanical family name, the Siler Root monograph should be corrected in this regard.
Monograph/Section(s): Sodium Propionate / Organic Impurities

Expert Committee: Simple Excipients
EC-initiated Change #1: A note of “The peak eluting at RRT 0.3 is sodium ion peak. This
peak, and the peaks eluting before it, are exclusive from integration. These peaks are not from
organic impurities of sodium propionate” was added in the Analysis section of the test to offer
clarity.
Monograph/Sections: Streptococcus thermophilus

Expert Committee: Non-Botanical Dietary Supplements
Comment Summary # 1: The commentor questioned the basis for providing Food Chemical
Codex (FCC) as a source method for testing Listeria.

Response: Comment not incorporated. The EC concluded that referencing FCC is acceptable,
noting that FCC is an official publication of USP and the method for Listeria in FCC is based on
AOAC Official Method 999.06 Listeria in Foods. USP-NF does not currently have a method to
test Listeria and efforts are underway to revise <2022> Microbiological Procedures for the
Absence of Specified Microorganisms- Nutritional and Dietary Supplements, to include testing
method for Listeria and other pathogens.
Comment Summary #2: The commentor requested justification for the wide differences among
the sample test quantities in the test for Contaminants, Contaminant microorganisms.
Response: The monograph references <64> Probiotic tests for specified microorganisms which
in turn references <2022>Microbiological Procedures for the Absence of Specified
Microorganisms- Nutritional and Dietary Supplements, that has a requirement for testing 10g of
samples. The different sample quantities required in the monograph is based on the sponsor
provided documents. Per General Notices and Requirements, 3.10. Applicability of Standards,
“Where the requirements of a monograph differ from the requirements specified in
these General Notices or an applicable general chapter, the monograph requirements apply and
supersede the requirements of the General Notices or applicable general chapters, whether or
not the monograph explicitly states the difference”.
Monograph/Section: Tamsulosin Hydrochloride Capsules/Organic Impurities

Comment Summary #1: The commenter requested removing the ‘reporting
threshold’ because it will vary based on product-specific factors.
Comment Summary #2: The commenter requested removing “methoxy tamsulosin”,

“ethoxyphenoxy ethyl bromide”, and “desethoxy tamsulosin” from Table 13 in the Organic
Impurities section as they are sufficiently controlled in the drug substance.
Response: Comment incorporated. The impurities were moved to the System suitability section
where a ‘Note’ was included with associated relative retention times.
Comment Summary #3: The commenter requested aligning the acceptance criteria for ‘Any
unspecified impurities’ with ICH Q3B.
Response: Comment incorporated. The criterion for ‘Any unspecified impurities’ was changed
from NMT 0.6% to NMT 0.63%. This is based on the following calculation: 0.005 mg (5ug
[identification threshold]) /0.8 mg (MDD) = 0.00625 x 100 = 0.63%.
Comment Summary #4: The commenter requested widening the acceptance criteria for ‘Total
impurities’ for consistency with what has been approved.

Response: Comment incorporated. The criterion for ‘Total impurities’ was changed from NMT
0.9% to NMT 2.0% consistent with a US FDA approved application.
Monograph/Sections: Tiotropium Bromide/Multiple sections

Expert Committee: Small Molecules Monographs 5
Comment Summary #1: The commenter recommended revising the second of three chemical
names proposed in the Chemical Information to align the usage of alpha- and beta- with current
chemical nomenclature conventions.
Response: Comment partially incorporated. The second chemical name, which is based on an
older chemical nomenclature scheme, is not included in the monograph.
Comment Summary #2: The commenter requested removing the “reporting threshold” in the
test for Organic Impurities.
Comment Summary #3: The commenters recommended not proceeding with the proposed
LC-MS test for the Limit of Tiotropium Related Compound G and Tiotropium Related Compound
H, citing tailing of the tiotropium peak that leads to an elevated baseline and potentially
interferes with the accurate quantitation of tiotropium related compound G. A commenter also
suggested that the analytical method may suffer from poor precision.
Response: Comment not incorporated. The analytical method satisfied all validation
requirements for accuracy and precision over the range of 25% to 150% of the impurity
acceptance criterion, i.e., NMT 0.10% each of tiotropium related compound G and tiotropium
related compound H. Additionally, the compendial test procedure permits users to optimize
method performance for their instrumentation. The EC will consider future revisions to the
monograph upon receipt of the necessary supporting data.
Comment Summary #4: The commenters requested revising the acceptance criteria for Water
Determination to accommodate both the anhydrous and monohydrate forms of tiotropium
bromide.
Response: Comment incorporated. The acceptance criteria for Water Determination were
widened from the range 2.6%-3.4% to the limit NMT 4.0%, thereby accommodating both the
anhydrous and monohydrate forms of tiotropium bromide.
EC-initiated Change #1: The UNII codes for tiotropium bromide (anhydrous) and for tiotropium
bromide monohydrate are added to the Chemical Information in the monograph.
Monograph/Sections: Zinc Acetate /Multiple Sections


Comment Summary #1: The commenter recommended USP to tighten the acceptance criteria
for ‘Arsenic’ and ‘Lead’ to be consistent with ICH Q3D guidelines.
EC will consider future revisions to the monograph upon the receipt of supporting data.
Comment Summary #2: The commenter recommended USP to include tests for ‘Aluminum’
and ‘Iron’ with acceptance criteria consistent with what have been approved by the FDA and
recommend USP to contact the FDA approved applicants to obtain the relevant information.
Response: Comment partially incorporated. USP was not able to obtain any additional
supporting information from FDA approved applicants. The EC will consider future revisions to
the monograph upon the receipt of supporting data.

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Commentary

USP–NF 2022 Issue 3

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Commentary for USP–NF 2022, Issue 3

General Notices to USP-NF

Commentary for USP–NF 2022, Issue 3

No comments were received for the following proposals:

Commentary for USP–NF 2022, Issue 3

The following is Commentary in response to a proposed revision to General Notices. This

Commentary for USP–NF 2022, Issue 3

Reagent: 0.1 N Sodium Hydroxide VS

Commentary for USP–NF 2022, Issue 3

General Chapter/Sections: <206> Aluminum

Comment Summary #1: For procedures describing ICP-OES, commenter recommended,

REQUIREMENTS FOR PROCEDURE VALIDATION

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

Comment Summary #2: ICP Procedures -Standardization

REQUIREMENTS FOR PROCEDURE VALIDATION:

Commentary for USP–NF 2022, Issue 3

General Chapter/Sections: <211> Arsenic

General Chapter/Sections: <241> Iron

General Chapter/Sections: <251> Lead

Commentary for USP–NF 2022, Issue 3

General Chapter/Sections: <261> Mercury

General Chapter/Sections: <291> Selenium

General Chapter/Sections: <771> Ophthalmic Products – Quality Tests / Multiple Sections

Commentary for USP–NF 2022, Issue 3

Comment Summary #6: Under ANTIMICROBIAL PRESERVATIVES, last sentence, the

Comment Summary #7: Under CONTAINER-CLOSURE INTEGRITY, last sentence, the

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

Comment Summary #17: Under Antimicrobial Preservatives, Sentence 1, item 2, the

Comment Summary #18: Under Container-Closure Integrity, Sentence 1, the commenter

Comment Summary #19: Under Specific Tests, Resuspendability/Redispersibility, the

General Chapter/Sections: <857> Ultraviolet-Visible Spectroscopy /Multiple Sections

Commentary for USP–NF 2022, Issue 3

QUALIFICATION OF UV-VIS SPECTROMETERS

Commentary for USP–NF 2022, Issue 3

Comment Summary #5: The commenter, referring to Establishment of acceptance limits

Commentary for USP–NF 2022, Issue 3

Comment Summary #10: The commenter, referring to Control of wavelength – Wavelength

Commentary for USP–NF 2022, Issue 3

General Chapter/Sections: <781> Optical Rotation /Multiple Sections

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

General Chapter/Sections: <1857> Ultraviolet-Visible Spectroscopy – Theory and Practice

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

Monograph/Section: Amantadine Hydrochloride Tablets/Multiple Sections

Commentary for USP–NF 2022, Issue 3

Monograph/Section(s): Amiloride Hydrochloride Tablets /Organic impurities

Monograph/Section: Argatroban Injection/Multiple Sections

Commentary for USP–NF 2022, Issue 3

Commentary for USP–NF 2022, Issue 3

Monograph/Sections: Candesartan Cilexetil/ Organic Impurities

Monograph/Sections: Candesartan Cilexetil Tablets/Organic Impurities

Commentary for USP–NF 2022, Issue 3