USP General Notices &General Chapters An Overview Dr.A.Amsavel

USP General Notices &General Chapters An Overview
USP sections, General Notices, Legal recognition, Definition
Monograph, Reagents, Description & solubility, Tests & procedures, Reagents & Solutions, Packaging and storage, storage conditions, General Chapters , Universal tests, specific tests , frequently used GCs.

1. Dr. A. Amsavel, M.Sc., B.Ed., Ph.D.

2. History of USP
USP was established by Dr. Lyman Spalding with 10 physician
in Jan 1820.
Federal Food & Drugs Act recognized the USP & NF in 1906
and enforced by FDA in 1938.and enforced by FDA in 1938.
USP is private non-profit Organisation
Objective :
Compendialstandard setting and revision
To set standards for Drug Substance & Drug Product on
Strength, purity, quality packing, labeling etc

3. Major Sections of USP-NF
Preface: By-laws, changes from previous USP
General Notices: Definitions and assumptions
USP Monographs :Drug substance, product standards
General Chapters: General test methods, informationGeneral Chapters: General test methods, information
Reagents: Materials used in Monographs
Reference Tables: Description, solubility, etc.
NF Monographs: Excipients
Dietary Supplement Monographs :Substance and product
standards

4. General Notices
Most of persons DO NOT READ this Important Document.
General Notice Applies to all the Articles of USP & to meet
Regulatory requirement
It is Guidance to Monograph and General Chapters
Major Content in General Notices
Official status and legal recognition
Conformance to standards
Monographs and general chapters
Monographs Components: “How-To” Manual
Testing Practices And Procedures & Test Results
Terms & Definitions
Preservation, Packaging, Storage, And Labeling

5. Legal Recognition
In USA, USP-NF is recognized by the Laws and regulations
(FDCA).
If drug is not comply with compendialidentity standards or be
deemed adulterated, misbranded or both. (FDA 21CFR§299.5 deemed adulterated, misbranded or both. (FDA 21CFR§299.5
a, b & c)
Also to packed and labeled as per compendialstandard
Enforcement of USP standards is the responsibility of FDA
and other government authorities in the U.S. and elsewhere.
USP has no role in enforcement

6. Conformance To Standards
Applicability of Standards:
Monograph & "Applicable General Chapters“ are standards
& Requirement
<1> -<999> : CompendialRequirements
<1000> -<1999>: Informational
<2000> -<2999>: Dietary ingredients & supplements
General Chapters below 1000 is Requirement as like Monograph.
Discrete sections of text that standardise the use of common tests and
procedures for compendialtopics. These chapters are often referenced
in individual monographs.

7. Monograph as Legal Standard
According to the U.S. Federal Food, Drug and cosmetic act,
assays and specifications in USP-NFconstitute Legal
standards.
USP-NFmonograph as public standards.
Monographs Available in USP:
Drug substances
Dosage forms, including combinations
Excipients
Dietary supplements and botanicals
Compounded preparation
Medical Devices,
Vitamins, minerals

8. Drug substance Monographs-Contents
Monographs consists Article's name, definition,
specification, Acceptance criteria and other requirements
related to packaging, storage, and labeling.
Official Title (USAN-United States Adopted Name)
Graphic Formula
Chemical Formula
Molecular weight
Chemical name(s)
CAS number

9. Monograph-Example
Everything following in“is OFFICIAL
Description and
Solubility is provided Solubility is provided
separately in USP
Packaging & Storage:
Labelling:
Case-by-case
Ref: USP NF-42

10. Drug Substance Monograph: Tests
Examples of Specific Tests & Procedures
Identification
pH
Water or Loss on DryingWater or Loss on Drying
Organic volatile impurities
Related compounds or chromatographic purity
Specific rotation
Assay
Other tests based on product requirement
Implied test: Residual Solvents & Elemental Impurities

11. Monograph-Test Procedures:
Test Procedures:
Test procedures are specific to the article as necessary to
determine if it meets the attributes of identity, strength,
quality and purity.quality and purity.
In general, test procedures start with Identification (ID) and
end with Assay.
Often the actual test procedures are described in the GENERAL
CHAPTERSsection.

12. Description and Solubility
Provided in the reference table “Description and Relative Solubility“.
It may indirectly assist in the preliminary evaluation of an article, It
is not intended to serve as a standard or test for purity.
Descriptive Term
Parts of Solvent Requiredfor
1 Part of Solute1 Part of Solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1,000
Very slightly soluble
From 1,000 to 10,000
Greater than or equal to
Practically insoluble, or Insoluble 10,000

13. Impurities : Additional Tests
Impurities and Foreign SubstancesGC <1086>
Tests for the presence of foreign substances and impurities are provided
to limit such substances to amounts that are unobjectionable under
conditions in which the article is customarily employed
Objectives of the Pharmacopoeia is to assure the user of official articles of Objectives of the Pharmacopoeia is to assure the user of official articles of
their identity, strength, quality and purity it is manifestly impossible to
include in each monograph a test for every impurity, contaminant or
adulterant that might be present including microbial contamination.

14. Other impurities : GC <466>
Any unlabeled impurity present of >0.1% is variance to standard.
Sum of impurity < 2.0%
Exclusions are fermentation, semi synthetic, biological,
radiopharmaceuticals & BT derived productsradiopharmaceuticals & BT derived products
The presence of any unlabeled other impurity in an official
substance is a variance from the standard if the content is
0.1% or greater. The sum of all Other Impurities combined
with the monograph-detected impurities may not exceed
2.0% (see Ordinary Impurities (466))

15. Testing practices and procedures
Appropriate safety protocols should be followed
Analytical procedures may be omitted, but must pass if tested
Automated and manual methods can be interchanged
Alternative methods may be used, if validated the method, but
still must pass USP still must pass USP
Harmonised method can be interchangeable with Ph.Eur/JP
In the event of dispute, result of USP is conclusive
Sample sizes may change if equivalent accuracy maintained
For water, Purified Water is to be used unless otherwise specified
Each article must Pass all Compendialtests

16. Testing practices
Adjustments to Solutions:
When a specified concentration is stated in a procedure, a solution
of other normality or molaritymay be used.
Provided allowance is made for the difference in concentration Provided allowance is made for the difference in concentration
and that the change does not increase the error of measurement.
Proportionately larger or smaller quantities than the
specified weights and volumes of assay or test substances and
Reference Standards may be taken, provided the measurement is
made with at least equivalent accuracy

17. Can I use In-House Test method instead of USP
“Compliance may be established also by the use of alternative
methods,
Any alternatives or automated methods shall be validated..”
However…where a difference appears, or in the event of
dispute, only the result obtained by the procedure given in this
Pharmacopoeia is conclusive.”

18. Compendial Test Vs Release Test
“Compendialstandards define what is an acceptable product
and give test procedures to comply.
These standards apply at any time in the life of the article
from production to consumption.
The manufacturer’s …assure that the article will indeed
comply with compendialstandards until its expiration date,
when stored as directed.”

19. Reagents, Indicators and Solutions
Defines suitable grades for reagents and methods of
preparation for solutions in the tests and assays
Reagents
Indicators
Buffer SolutionsBuffer Solutions
Colorimetric solutions (CS)
Test solution (TS)
Volumetric solutions (VS)
RS refers to a USP Reference Standard .
"Use ACS reagent grade", it is intended that a grade meeting the corresponding
specifications of the current edition of Reagent Chemicals,

20. Test Apparatus
Glassware size is a suggestion
Clear containers can be used; for light sensitive articles if
rendered opaque
Equivalent instruments may be used
Concentrations may be altered to obtain on-scale Concentrations may be altered to obtain on-scale
measurements
Centrifuge is assumed to have 8 inch radius and spun at a speed
to separate within 15 minutes.
Chromatographic columns sizes default to ID
“…another instrument of equivalent or greater sensitivity and
accuracy may be used”
Changes in concentration are allowed if accuracy is equivalent:
UV-Vis, HPLC, GC, MS

21. USP General Notice: Terms & Definition
Important definitions must know:
1.Calculate on dried, anhydrous, solvent free basis. If not specified, it
is “as-is” basis
2.About : within 10% weight or volume 2.About : within 10% weight or volume
3.Concomitantly: measurements performed in immediate
succession
4.Accurately weighed / measured: For Quantitative
5.Negligible : Quantity not exceeding 0.50 mg.
6.Temperature : Measure at 25°C; moderate heat: Not exceeding
45°C
7.Vacuum : (NMT 20mmHg or 2.67kPas)

22. USP General Notice: Terms & Definition
8.Transfer : A Quantitatively manipulation.
9.Drying to constant weight : Should not differ more than 0.50mg at two
consecutive weighings
10.Ignite to constant weight: at 800 ±25°, 15 minutes/not differ more
than 0.50mg in consecutive weighingsthan 0.50mg in consecutive weighings
11.Indicator: Approx 0.2ml or 3 drops
12.MeasurmentGravimetric/volumetric tests: 25.0mL or 25.0mg (one
decimal):
13.Desiccator: Tightly closed container with suitable desiccant such as
anhydrous calcium chloride, magnesium perchlorate, phosphorus
pentoxide, or silica gel .

23. Definitions
Specific gravity: measured at 25°C
Time limit: for test & assays 5 minutes
Odour: Odourless, practically odourlessor faintly
characteristic odour.characteristic odour.
Examine after exposure to 15minutes in air or freshly opened
package of test of 25g keep in 100ml evaporating dish for 15
minutes and examine.
Light protection: low-actinic or light resistant container-amber or
opaque by wrapping or coating

24. Definitions
If the measurement is stated to be "accurately measured“
or "accurately weighed," follow the statements
Percentage measurement:
W/W if a mixture of weights or semisolidsW/W if a mixture of weights or semisolids
W/V if a mixture of solutions or suspensions of solids with a liquid
W/V if mixture of gases in liquids
V/V if a mixture of liquids

25. Significant Figures and Tolerances
Interpretation of Requirements (Rounding rules)
Calculated results are to be rounded off to the number of
places in agreement with the limit (99.0-101.0)
Sig. Digit (+1) less than 5 –truncated 99.4499 = 99.4Sig. Digit (+1) less than 5 –truncated 99.4499 = 99.4
Sig. Digit (+1) greater than 5 –rounded up 99.4836 = 99.5
Sig. Digit (+1) equal to 5 –rounded up 99.4500 = 99.5

26. Rounding Rules (USP42)

27. Packaging, Storage And Labelling
Packaging and Storage Requirements (659) & Labeling (7)
Containers:
Tight (Protects from air & moisture)
Light -Resistant
Well closed (Protects from extraneous solids)Well closed (Protects from extraneous solids)
Hermetic (impervious to air or other gases)
Primary packaging component: A Packaging component that is in direct
contact with product
Secondary packaging component: A Packaging component that is in direct
contact with a Primary packaging component

28. Storage Temperature
Freezer: Temperature between -25°C and -10°C
Cold: Any temperature not exceeding 8°C
Refrigerator: A cold place with temp between 2°C and 8°C
Cool : Temp between 8°C and 15°CCool : Temp between 8°C and 15°C
Note: An article for which storage in a cool place is specified
may be stored in a refrigerator unless directed otherwise
Room Temperature: Ambient
Warm: Temp 30°C to 40°C
Excessive heat : more than >40°C
Protection from Freezing

29. Storage Temperature
Controlled Room Temperature:
Temperature between 20 °C and 25°C, excursion
permitted 15-30°C, spike allowed to 40°C for NMT 24hrs.
(mean kinetic temp (MKT) of NMT 25°C)
Controlled cold Temperature: Controlled cold Temperature:
2-8°C , excursion permitted 0-15°C, spike allowed to 25°C
for NMT 24hrs. (MKT of NMT 8°C)
Dry place:
Does not exceed 40% average % RH at 25°C or RH at
specific temp.

30. Low-Density Polyethylene
Primary bag test requirement:
Infrared Spectroscopy: Spectrum matches at the same wavelengths as the
spectrum of USP Low-Density Polyethylene RS.
Differential Scanning Calorimetry: Thermogramshould ne similar to USP
RS. Endothermdoes not differ by more than 8.0°C
Heavy Metals: Should meet the requirements Physicochemical Tests, Heavy Metals: Should meet the requirements Physicochemical Tests,
Heavy Metals.
Nonvolatile Residue:
Sample Preparation: 20.0 mLof Extracting Medium for portion of 60 cm2,
regardless of thickness.
Does not exceed 12.0 mg in water extract at a temperature of 70°C
Does not exceed 75.0 mg in alcohol extract at a temperature of 70°C
Does not exceed 350.0 mg in hexanes extract at a temperature of 50°C

31. Guide to General Chapter
Chart-1 for API
Universal test
Description
Identification
TLC,IR, UV
<191, 197,201, 851 etc>
Specific test
Physicochemical characterisation
LOD, MR, SOR,pH, PSD, BD&TD etc
Equipment<191, 197,201, 851 etc>
Assay
<11,621,541,851 etc>
Impurities
Organic (627,851 etc)
Inorganic (231, 232 etc)
Residual solvent (467, 731)
Limit test
<31 > Volumetric apparatus
<1251> Weighing & AB
<1051> Cleaning if GW
Thermal & Spectroscopy
Water content

32. Most Used General Chapters
1.<11> USP Reference standards
2.<621> Chromatography
3.<197> SpectrophotometricIdentification Tests
4.<791> pH
5.<731> Loss on drying5.<731> Loss on drying
6.<905> Uniformity of dosage units
7.<232&233>Elemental Impurities:Limits& Procedure
8.<191> Identification tests--General
9.<467> Residual solvent
10.<921> Water determination

33. Frequently Referred General Chapters
<201> TLC identification test
<541> Titrimetry(assay test)
<851> Spectrophotometry& light scattering (assay &id)
<466> Ordinary impurities
<781> Optical rotation<781> Optical rotation
<281> Residue on ignition
<741> Melting range or temperature
<786> Particle size distribution by sieving
<1251> Weighing & analytical balance
<645> Water conductivity
<643> TOC
<616> BD and TD of powder

34. General Chapters: QMS & GMP
<1121> Nomenclature
<1078> Principles of GMP for Bulk Pharmaceutical & Excipients
<1029>Good Documentation Guidelines
<724> Drug Release
<1010> Analytical Data Interpretation & Treatment
<1225> Validation of CompendialMethods
<1058> Analytical Instrument Qualification
<1226> Verification of compendialprocedures.
<1224> Transfer of Analytical procedures.
(1467) Residual Solvents—Verification of CompendialProceduresand
Validation of Alternative Procedures

35. General Chapters: GxP& MB
<1177> Good Packaging Practices
<1079>Good Storage & Distribution Practices for Drug Products
<1080>Bulk Pharmaceutical Excipients—Certificate of Analysis
<1117> Microbiological Best Laboratory Practices
<1111>Microbiological Examination of NonsterileProducts
<1072> Disinfectant & Antiseptic
<85> Bacterial EndotoxinsTest
<71> Sterility Tests
<61&61> Microbiological Examination

36. General Chapters:
<1644> Theory and Practice of Electrical Conductivity
<1231> Water for Pharmaceutical purposes
<1195> Significant Change Guide for Bulk Pharmaceutical Excipients
<671> Containers—Performance Testing <671> Containers—Performance Testing
<1210>Statistical Tools for Procedure Validation
<1051> Cleaning Glass Apparatus
<1097> Bulk Powder Sampling Procedure


37. T h a n k YouT h a n k You