The document summarizes a presentation on the USP Medicines Compendium. It discusses the development of reference procedures for inclusion in the compendium. Reference procedures are developed by USP laboratories to test pharmaceutical substances and products regardless of manufacturer. They are optimized to separate components and identify impurities using analytical tools like HPLC-MS. The presentation covers topics like the development process, forced degradation studies to identify degradation products, and validation of the reference procedures.

1. General Session I: Chemical
Medicines and Excipients
Tuesday, April 16, 2013 (11:00 a.m. to 1:30 p.m.)
IPC–USP Science & Standards Symposium
Partnering Globally for 21st Century Medicines

2. Moderator:
Dr. Antony Raj Gomes
Chair, USP Medicines Compendium Expert Committee

3. The Medicines Compendia
Performance Based Monograph with
Reference Procedure
Antony Raj Gomas, Ph.D.
Chair, USP Medicines Compendium Expert Committee

4. Introduction

What is Medicines Compendium?

Why is it relevant?

What are the benefits to Industry and regulators?

How the Medicines compendium works?
4

5. Introduction
USP Medicines Compendium –

Public quality standards for medicines (Documentary and reference
standards)

Medicines includes chemical and biological drug substances and
products; excipients

Approved for marketing by national regulatory authorities outside of the
U.S.

Does not include foods, traditional medicines/dietary supplements.
5

6. Introduction
Why is USP publishing the MC?

Part of global public health mission

Availability of public standards - ensure medicines are of good
quality.

Check on substandard, spurious, fake, falsified and/or counterfeit
medicines.

USP’s global presence

National pharmacopeia of the United States

Work globally—with
pharmacopeias

Standards without borders
regulators,
manufacturers,
and
other
6

7. USP MC – Scientifically Unique
The MC offers an innovative approach to creating public monographs with reference
materials. The process starts with a For Development Monograph that includes a
Performance Based Monograph (PBM). This monograph provides tests for critical quality
attributes and acceptance criteria, but does not give specific step-by-step
procedures. Instead, it gives criteria for an acceptable procedure. The information in the
PBM allows manufacturers to consider how they wish to develop their own acceptable
procedures.
The MC also incorporates Reference Procedures, which are developed by USP laboratories.
This Reference Procedure is a procedure that can be used to test articles from multiple
sources. An MC Reference Procedure is developed in a manner that identifies impurities
associated with a product, regardless of the manufacturer’s process. The Reference
Procedure in a MC monograph is developed by USP staff, collaborating with donors of
information and materials.
7

8. USP MC – Scientifically unique
Manufacturers also may submit information and materials to support more optimized
controls for the medicines and their ingredients. These procedures are called Acceptable
Procedures and are incorporated into the MC monograph.
MC monographs are accompanied by validation data and reference materials, including
Certified Reference Materials for assays and Reference Standards for impurities
The MC is produced by a unique online-only process, including online commenting. The
online-only approach enables anyone to freely access MC standards, and speeds standards
development.
8

9. Identification and Prioritization of Candidates
Identification

Approved by non-US national regulatory authorities
Prioritize

Public Health Impact

Exposure to the population

Disease burden

Essential Medicines List
9

10. Scientific Liaison Process

11. Scientific Liaison Process (Continued)
Scientific Review
Identification of
Preparation
monographs for Development, after prioritization
of Monographs for Development
Review
laboratory results of Reference Procedure development
Identify
the Reference Materials for development from the monographs
Evaluation
of laboratory results of Reference Material development
Monograph Logistics
Draft
Reference Procedure in MC format
Complete
Reference Material data summary (recommend content and uncertainty values)
Prepare
Reference Procedure development data summary report (validation data) for posting with the
Proposed
Standard for Comment
Prepares
for Expert Committee Review
Reference
Procedure (in MC format) with validation data
Reference
Material data summary
Other Acceptable
Procedures with validation data
11

12. Topics

USP-MC Monographs

What is a Reference Procedure?

Critical characteristics of a Reference Procedure

Reference Procedure Development
– Process
– Solubility
• Dissolution of solid oral drug products
– Procedure Development
– Forced Degradation Studies
– Use of advanced technologies
12

13. 
The MC Monograph
MC monograph typically contains…

Tests, Procedures, and Acceptance Criteria

Tests are consistent with USP-NF (Identification, Assay, Impurities, Performance Tests,



Specific Tests)
Tests are grouped into one of three separate sections

Performance Based Monograph (Core section)

Reference Procedures (containing monograph specific procedures for Assay and
Impurities)

Acceptable Procedures (containing procedures meeting requirements of a criteriabased procedure, but not those of a reference procedure)
Procedures differ from USP-NF and include both

Reference Procedures and

Criteria-based Procedures
Acceptance Criteria are based upon the ICH Q6A, Q3A, and Q3B limits.
13

14. Performance Based Monograph

Universal Tests


Identification

Assay


Description
Impurities
Specific Tests


Content Uniformity


Performance Tests
Others
Criteria for Acceptance


Any Impurity NMT 0.1% (Includes both known as well as unknown)


Drug Substance, 98% - 102%
Drug Product, 95% - 105%
Criteria-based Procedures for Assay and Impurities

Procedure Performance Measures (Precision, accuracy, others)

Procedure Criteria of Acceptance (% RSD, Bias, R2, others)

Elemental Impurities
14

15. Need of a Reference Procedure

Analytical procedures for pharmaceutical products and components
are typically derived from an understanding of the manufacturing
process, i.e., what’s likely to be present.

These procedures are optimized to be as fast and simple as possible.

Where a party other than the manufacturer wishes to test a
component or product, this type of detailed information is not
available.
15

16. Need of a Reference Procedure

To complicate matters further, the global pharmaceutical marketplace
includes components and products processed from different starting
materials, having different manufacturing processes, and formulated
using different excipients and strengths.

This diversity leads to vast array of specific tests and procedures to
analysis nearly identical substances.

The goal of establishing a single reference procedure for each test in
a pharmacopeia has therefore been a difficult one.
16

17. MC Approach – Reference Procedure

The MC approach deviates from tradition by developing reference
procedures from a different perspective:
– Rather than adapting a procedure that has been optimized to be
fast and inexpensive by using a single manufacturer’s data;
– USP labs develop and implement a procedure that is optimized to
find all significant components in a substance through separation
and multidimensional detection.
– A Reference procedure is developed using a battery of analytical
tools that are appropriate for the molecule and matrix.
– HPLC / UHPLC + Photodiode Array (PDA) and Mass
Spectroscopic (MS) detection in series
– Evaporating Light Scattering Detector (ELSD), Corona Detector
17

18. Reference Procedure

Detailed procedural outline of the experimental details that are to be completed
without significant modification.

The amount of modification allowed is included in the General Notices and
referenced general Chapters.
Reference Procedures can be

Chapter Based



Uniformity of Dosage Units <905>: Meets the requirements
Monograph Specific
Reference Procedures

Identification

Residual Solvents

Assay and Impurities (As per the requirements)
18

19. Reference Procedure (Continued)
Reference Procedures should

Effectively measure a critical parameter of the monograph article

Adequately describe the solutions, conditions, and calculations necessary to
make a meaningful measurement

Provide a validated and verifiable procedure that is source independent.

Validated according to <10>

Verifiable according to <10> for a manufacturers article

Source independence is an approximation, but should, in the best case,
provide the ability to quantify the critical parameter measured by the Test
regardless of the source of that material.
19

20. Critical Characteristics of Reference Procedure
Target article
For Development
Monograph
prepared using
General Chapter
<10>
Authentic
samples of the
article
Thorough
Literature Review
Pharmacopeias
Procured from at
least 2
independent
sources
More sources are
better
Published literature
Reported synthetic
and degradation
routes
20

21. Monograph for development - PBM
Monograph for
Development
PBM
Dynamic
Document
• Prepared by Scientific Liaison
• Tests for Identification, Assay, Impurities, etc.
• Acceptance Criteria, wherever applicable
• Possibilities for changes as we go forward during
method development or
• If additional information is available
21

22. “Proposed For Development” Monograph

List of “For
Development”
Monographs on
the MC website
22

23. A Typical “Proposed For Development” Monograph
Reference Procedure
23

24. Reference Procedure Development
Literature Search
- Pharmacopeia–USP, EP, BP, JP
- Scientific Literature and Online
and Paper Journals
Procurement
- Drug substance, Drug products,
Impurities by Standards Acquisition
department
- Pharmacopeial impurities by
Analytical Development department
- Method Development by
multi-source materials
- Specificity studies
- LC-MS Analysis for the
forced degradation studies
- Method finalization
- Method validation
- Data processing
Share the Method
validation data with the
Scientific Liaison
24

25. - Method
development
completed
- Transfer to
the Scientific
Liaison
- If MC monograph
is common to
USP-NF, it
provides
additional new
impurities for
USP-NF
Method Validation and Data Processing
- Forced
degradation
studies
- Acid
- Alkali
-Thermal
- Peroxide
- Light
- Separation of
degradation
products
(Identification,
wherever
possible)
- Loops back to
Method
development,
if needed
Method Finalization
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
-LC-PDA-MS
-GC-MS
Specificity Studies
Method Development
Reference Procedure Development – In Lab Details
Method
Validation
- Linearity
- Accuracy
- Precision
-Day 1
-Day 2
-Day 3
Data Processing
-Review of the
validation
data
-Transfer to
Scientific
Liaison
25

26. Method Development
Method Development
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
-LC-PDA-MS
-GC-MS

Solubility
– Different pH buffer solutions (1.2, 4.5, 6.8)

Spectroscopic Identification
– FT-IR, Specific Optical Rotation, etc.

Assay
– Chromatography

Related Substances
– Chromatography

Use of multi dimension detectors / orthogonal detectors
– LC-PDA-MS, ELSD, Corona, etc.
26

27. Identification - Clarithromycin
27

28. Method Development
Method Development – Assay and Related Substances
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
-LC-PDA-MS
-GC-MS

Several criteria
– Quantification of important analytes
–
–
–
–
• Active substances, impurities, other components
The most prevalent method is chromatographic separation
with spectroscopic or spectrometric detection.
The procedure is adjusted to achieve acceptable separation
of the primary peak from other peaks.
Use a multi-dimensional detector such as LC-PDA with a full
scan (200-400 nm or 200-700 nm)
Use a mass spectrometric compatible mobile phase
28

29. Use of MS compatible mobile phases

Routine use of MS detector to evaluate a sample for non-chromophoric
species.

Procedure development with mass spec-compatible mobile phases.

The resolving power of these mobile phases may be less than phosphate
buffers, but the information obtained from the MS is considered more
important that the pure separation.

When Liquid chromatography cannot be used or where adequate separation
cannot be accomplished with a mass spec-compatible buffer, then it will be
important to consider likely interferences to a procedure and ensure that the
procedure can adequately quantify the analyte of interest even in the
presence of these interferences.
29

30. Specificity Studies
Specificity (Forced Degradation) Studies
- Forced
degradation
studies
- Acid
- Alkali
-Thermal
- Peroxide
- Light
- Separation of
degradation
products
(Identification,
wherever
possible)
- Loops back to
Method
development,
if needed



Forced degradation studies
– Acid
– Alkali
– Thermal
– Peroxide
– Light (UV & Fluorescence)
• Solution
• Solid
Separation of degradation products
– Identification, wherever possible
Loops back to Method development, if needed
30

31. Method Development, Forced Degradation Studies - I
Separation of Clarithromycin &
impurities
Acid degradation of Clarithromycin drug
substance
31

32. Method Development, Forced Degradation Studies - II
Acid degradation of Clarithromycin drug substance
Easier quantification and basic identification information with full scan PDA and MS
Detection of co-eluting species
32

33. Method Finalization
Final Method
- Method
development
completed
- Transfer to
the Scientific
Liaison
- If MC monograph
is common to
USP-NF, it
provides
additional
new impurities
for USP-NF

Forced degradation completed
– Non-targeted screening
– Unequivocal separation

Method development completed

Internal Review

Method of analysis is transferred to the Scientific
Liaison

Types of Reference Standards
– Process impurities (Known / Unknown)
– Degradation products
33

34. Method Validation
General Chapter <10>
34

35. Method Validation – Assay - I
Assay:

Precision and Accuracy: six independent weighings, two injections per
sample

Calculation and Acceptance Criteria: Calculate % RSD and calculated
predicted content of the Precision measures using the calibration curve
from the Range requirement*

Ruggedness: Precision and Accuracy assessments over 3 day

Range: six independent weighings at 80%, 90%, 100%, 110%, and
120%. The precision and accuracy is determined for each concentration*
*the Precision and Accuracy is then compared to defined acceptance criteria of the Test to determine the
probability of the procedure returning a passing value if it was 100%. The probability must be greater than
0.95.
35

36. Method Validation – Impurity Limit Procedure

Precision: six independent weighings spiked at the limit, two injections per
sample

Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount calculated
in <10> (for a 0.1% impurity, NMT 5.7%; for an 0.05% impurity, NMT 6%; etc)

Limit of Detection: five injections each of; one sample spiked at the limit; and
one sample spiked at (limit - %RSD above)

Acceptance criteria: the mean value of the second standard must pass the
limit test

Specificity: each impurity must be quantifiable to within the LOD
36

37. Method Validation – Quantitative Impurities Procedure - I

Precision: six independent weighings spiked at the limit, two injections per
sample

Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount
calculated in <10> (for a 0.1% impurity, NMT 2.8%; for an 0.05% impurity,
NMT 3%; etc)

Ruggedness: Precision and Accuracy assessments over 3 day

Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount
calculated in <10> (for a 0.1% impurity, NMT 5.7%; for an 0.05% impurity,
NMT 6%; etc)
37

38. Method Validation – Quantitative Impurities Procedure - II

Accuracy: six independent solutions spiked at 50%, 75%, 100%, 125% and
150% of the limit for each specified impurity

Calculation and Acceptance Criteria: Calculate Spike Recovery and each
concentration: between 100-%RSD to 100+%RSD (for a 0.1% impurity;
97%-103%;this is under consideration for a change to 94%-106%)

Specificity: Resolution of NLT 1.5 between all impurities (where unattainable,
meeting Accuracy is sufficient)
38

39. Method Validation – Assay - II

Specificity: Resolution of NLT 1.5 between main and all impurities

Process Impurities: evaluation of candidate material at 120% to 200% of the
analytical concentration identification (of presence) of impurity peaks at
0.01% or greater

Degradation Products: Target 30% reduction in active content using Acid,
Base, Heat, Light (UV and ambient), Peroxide, others as appropriate:
identification (of presence) of impurity peaks at 0.10% or greater

Un-retained and non-eluted Impurities: HPTLC with attention to the Origin
and Solvent front

Ancillary Data

FT-IR Spectrum, Water Determination, Enantiomeric purity, Solubility in pH
1.2 and 6.8 buffers
39

40. Data Processing and Transfer

Review of the validation
data

Transfer to the Scientific
Liaison
40

41. Acceptable Procedures
Acceptable Procedures
Provided
by any manufacturer with validation package

Not a direct comparison to a Reference Procedure but to the PBM
requirements / pre-established criteria appropriate to the Test
Any
procedure that meets the performance requirements of PBM is
considered “equivalent” and published as `acceptable procedure’
There
can be multiple acceptable procedure for one monograph
41

42. Acceptable Procedures (Continued)
42

44. Industry Use of Medicines
Compendium Approaches
Nicholas Cappuccino, Ph.D.
Member, USP Small Molecules Expert Committee

54. Monograph Modernization
Todd L. Cecil, Ph.D.
Vice President, Chemical Medicines Development,
USP

55. Modernization Scope

Monographs in USP: ~6000

Monographs needing Modernization: ~2700

Procedures to be replaced: ~2/ monograph
55

56. Monograph Modernization Initiative
MONOGRAPH TESTS
Identification
CRITERIA
Non-specific ID Tests
(e.g., ID by HPLC
retention time agreement
only)
Assay
Outdated Technology
•
•
•
•
•
Packed column GC
Titration
Wet chemistry
Spectrophotometry
TLC
Impurities
• Organic
• Inorganic
• Residual Solvents
• Heavy Metals
Missing tests (e.g,
Specific Tests
Other tests
organic impurities)
Outdated technology
(e.g, melting point)
Safety/environmental
concerns (e.g., odor
tests, chlorinated
solvents, pyridine,
mercuric salts, etc)
STRATEGIES
By Monograph
• Individual
• Families
• Therapeutic
Category
• Drug Substances,
Dosage Forms
By Test
• ID
• Assay
• Impurities
• Specific Test(s)
• Other
By Technology
Platform
• Gas chromatography
• Titrations
• Spectrophotometry
• Wet chemistry
• Other
TACTICS
Sources of Data
• Manufacturers
• USP Labs
• FDA CRADA
• Other
Pharmacopeias
General Chapters
• Route of
administration
• Monograph-specific
procedures
• Performance-based
procedures
PRIORITIZATION
• USP model
(default)
• OTC drug
substances a priority
in FY13
• Input from FDA
Task Group (high
priority items) and
FDA CRADA labs

57. Status Update
Status
Monographs
In USP-NF compendium
90
Awaiting bulk
RS Release
Modernization Underway
6
4
In development 335
In production
In Forum
78
Total
Yet to begin
29
542
~2000
To accelerate from current rate of 150/year to over 300/year, USP
has been adding internal laboratory capacity to develop needed
procedures from scratch.

58. Reference Procedure

USP’s Reference Procedure approach deviates
from ‘tradition’ developing a monograph’s
specification from a different perspective:
– Rather than adapting a procedure that has been optimized to be
fast and inexpensive
– Our labs develop and implement a procedure that is optimized to
find all significant components in a substance through separation
and multidimensional detection
– A Reference Procedure is developed using a battery of analytical
tools that are appropriate for the molecule (ingredient) and matrix
(drug product).
– HPLC / UHPLC + Photodiode Array (PDA) and Mass
Spectroscopic (MS) detection in series
– Evaporating Light Scattering Detector (ELSD), Corona Detector
– The approach includes forced degradation studies and validation,
which is publicly available
58

59. Critical Characteristics of Reference Procedure
Target article
For Development
Monograph
prepared using
General Chapter
<10>
Authentic
samples of the
article
Thorough
Literature
Review
Procured from at
least 2
independent
sources
Pharmacopeias
More sources are
better
Reported
synthetic and
degradation
routes
Published
literature
59

60. Reference Procedure Development
Pre Lab
Literature Search
- Pharmacopeia–USP, EP, BP, JP
- Scientific Literature and Online
and Paper Journals
Procurement
- Drug substance, Drug products,
Impurities by Standards Acquisition
department
- Pharmacopeial impurities by
Analytical Development department
In Lab
- Method Development by
multi-source materials
- Specificity studies
- LC-MS Analysis for the
forced degradation studies
- Method finalization
- Method validation
- Data processing
Post Lab
Share the Method
validation data with the
Scientific Liaison
60

61. - Acid
- Alkali
-Thermal
- Peroxide
- Light
- Separation of
degradation
products
(Identification,
wherever possible)
- Loops back to
Method
development,
if needed
- Method
development
completed
- Transfer to
the Scientific
Liaison
- If MC monograph
is common to
USP-NF, it
provides additional
new impurities for
USP-NF
Method Validation and Data Processing
-LC-PDA-MS
-GC-MS
- Forced
degradation
studies
Method Finalization
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
Specificity Studies
Method Development
Reference Procedure Development – In Lab Details
Method Validation
- Linearity
- Accuracy
- Precision
-Day 1
-Day 2
-Day 3
Data Processing
-Review of
the
validation
data
-Transfer to
Scientific
Liaison
61

62. Components of the Approach

1. Not Less Than 2 sources

2. 5 Modules across 4 Regions

3. Family approach

4. Target of 200 – 300 monographs/yr

5. Reach beyond standard technology

6. Respect industry resources
62

64. Drug Product Performance and
Optimal Bioavailable Products
(OBA)
Roger Williams, M.D.
Chief Executive Officer and Chair, Council of Experts,
USP

65. Topics

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for
Many Medicines

Summary
65

66. Overall Goal

Manufacturers
–
–
–
–

Strong discovery and development
Good registration processes
Well manufactured, safe and effective drug products
Interchangeable in global commerce
Pharmacopeias
– Fully harmonized ingredient and product monographs
– Modern, relevant, timely and free with validation
66

67. Topics

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for
Many Medicines

Summary
67

68. USP’s Medicine Compendium: Reference Procedures

Begins with PBM

Non-optimized Reference-Procedures, and Acceptable
Procedures

Suitable for All Ingredients and Products in Global
Markets

Requires a ‘Module’—about six staff and highly
sophisticated analytical equipment

Each Module produces about 60 monographs with 2-3
reference materials a year

Working Together: A Full Cohort of Monographs (Timely,
Relevant, Free, Fully Harmonized) for All Medicine
Ingredient and Products

69. Topics

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for
Many Medicines

Summary
69

70. Drug Product Monographs: The Challenge

Global Sources Make Product Performance
Measures difficult
– Different regulatory expectations
– Different reference producs (US: Reference Listed
Drugs
– Different patient expectations

Many countries have no bioavailability or
bioequivalence (BA/BE) requirements

USP’s Medicine Compendium attempts to
address through general application in
monographs and General Chapter <12>
70

71. Topics

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for
Many Medicines

Summary
71

72. BCS Concept
 Published by Amidon and co-workers
1995
 Biopharmaceutics Classification
System is a scientific framework for
classifying drug substances based on
their aqueous solubility and intestinal
permeability
 The aim is to optimize the development
of oral dosage forms relying only on
rate limiting factors for absorption

73. Drug Release – The Rate Limiting Step
Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

74. Biopharmaceutics Classification System
Human Permeability
10
I
Gastric emptying
determines on-set of
absorption
II
Dissolution likely
to be “rate limiting”
1.0
III
IV
Absorption might be:
- incomplete
- sensitive to
certain excipients
0.1
Generally “problem”
molecules
0.01
1
10
100
1000
10000
Volume of water (ml) required to dissolve
the highest dose strength at pH 1.2 - 8
100000

75. Medicines Compendium, General Chapter <12>
 Drug
Product Performance
 Non-solution orally administered immediate release drug
products
 A partial solution for “well-behaved” IR drug products
 Creates a default characterization for most IR drug
products
 Linked to the BCS classification of the drug substance

76. Chapter Details
 Determine
the Solubility of the Drug Substance
 Aqueous media at pH 1.2 and pH 6.8
 Maximum unit dose in 250 mL media
 Room temperature, gentle stirring
 High or low solubility
 Determine
Dissolution Conditions
 4 cases possible
 Conduct dissolution tests

77. Dissolution Cases
 High
solubility in both pH 1.2 and 6.8
– Conduct dissolution according to USP-NF <711> in each pH 1.2 and 6.8
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 30 minutes
 High
solubility in pH 1.2 only
– Conduct dissolution according to USP-NF <711> in pH 1.2
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 15 minutes
 High
solubility in pH 6.8 only
– Conduct dissolution according to USP-NF <711> in pH 6.8
– App. 1@100 rpm or App. 2@50 rpm in 900 mL
– Q=85% in 15 minutes
 Low
solubility in both pH values
– Product specific development needed
– Suggestions on surfactant usage could be included

78. MC Drug Product Performance Test
PERFORMANCE TESTS
• Dissolution <711>
Medium, Apparatus, Time, and Acceptance criteria: See MC
general chapter Assessing Drug Product Performance <12>.
Standard solution: USP Metamizole Sodium CRM in an
appropriate diluent
Sample solution: Pass a portion of the solution under test through a
suitable filter, and dilute with an appropriate diluent to obtain a
concentration approximately the same as that of the Standard
solution.
Instrumental conditions: Proceed as directed in the Assay or in an
alternatively validated procedure.
• Uniformity of Dosage Units <905>: Meets the requirements
78

79. What Would This ‘Further’ Look Like?

Pharmaceutically equivalence

Highly soluble drug substance (API)

Then optimally bioavailable (OBA)
– All O-BA are also BE
– No comparator product; no comparison studies
– Registration only
– No regulatory review
– Only pharmacopoeial monographs
– Periodic inspection to assure conformity
– Label OBA

All others: in vivo studies and Comparator
Pharmaceutical Product (CPP—also US Reference
Listed Drug)

80. Topics

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for
Many Medicines

Summary
80

81. The Revolution

Up to 70% Ingredients

No Comparative BE Studies—Ever

A Label that Says OBA (and USP and MC)

OBA Medicines Fully Interchangeable Globally

Part of Fully Harmonized Monograph
– PBM and Reference Procedures in Monograph
– Good for all pharmacopeias—USP and MC and others

Achieves Stated Goals (see First PPT)
81

82. Pioneers and Harmonization

84. New Pharmacopeial Approaches to
Excipient Monographs
Sameer Navalgund, Ph.D.
President, Analytical Research and Development
USP

85. Today’s Topics for Discussion

Typical Excipient Monographs

Challenges involved for Excipient Monographs

USP-MC Monographs

What is a Reference Procedure?
– Critical characteristics of a Reference Procedure
– Reference Procedure Development
•
•
•
•

Process
Solubility
Procedure Development
Use of advanced technologies
Some examples
85

86. Excipient – One of the Definitions

“An excipient is an inactive substance used
as a carrier for the active ingredients of a
medication.”

In addition excipients can be used to aid the process by
which a product is manufactured.

In general, the active substances may not be easily
administered and absorbed by the human body; they
need to be put in some appropriate form. In such cases,
the active substance is dissolved or mixed with an
excipient.

Excipients are also sometimes used to bulk up
formulations with very potent active ingredients, to allow
for convenient and accurate dosage”
86

87. Typical Excipient Monographs

Definition

Identification

Assay



Other information
available
Nonproprietary Names

Synonyms
Impurities

Empirical Formula and Molecular
Weight and structural Formula
Specific Tests

Functional Category
– Methods of analysis
– Acceptance Criteria



Applications in Pharmaceutical
Formulation or Technology

Stability and Storage Conditions

Incompatibilities

Safety

Regulatory Status
Additional
requirements
87

88. Challenges Involved for Excipient Monographs

Multiples
– Different Starting Materials
– Different Sources of Starting Materials
– Use of natural products
• Inherent variability
– Manufacturing Processes
– Polymeric products
• Nature and extent of polymerization
• Degree of polymerization
• Use of higher temperatures for polymerization
– Isolation
– Characterization
88

89. USP-MC Monograph
 MC



monograph typically contains…
Tests, Procedures, and Acceptance Criteria
Tests are consistent with USP-NF (Identification, Assay, Impurities,
Performance Tests, Specific Tests)
Tests are grouped into one of three separate sections
• Performance Based Monograph (Core section)
• Reference Procedures (containing monograph specific procedures for
Assay and Impurities)
• Acceptable Procedures (containing procedures meeting requirements of a
criteria-based procedure, but not those of a reference procedure)

Procedures differ from USP-NF
 Includes both
• Reference Procedures and
• Criteria-based Procedures
89

90. What is a Reference Procedure?

The MC approach deviates from tradition by
developing reference procedures from a different
perspective:
– Rather than adapting a procedure that has been optimized
to be fast and inexpensive by using a single manufacturer’s
data
– Our labs develop and implement a procedure that is
optimized to find all significant components in a substance
through separation and multidimensional detection
– A Reference procedure is developed using a battery of
analytical tools that are appropriate for the molecule and
matrix
– HPLC / UHPLC / IC + Photodiode Array (PDA) and Mass
Spectroscopic (MS) detection in series, Evaporating Light
Scattering Detector (ELSD), Corona Detector
90

91. Need of a Reference Procedure - I

Analytical procedures for excipients are typically
derived from an understanding of the
manufacturing process, i.e., what’s likely to be
present
 These procedures are optimized to be as fast
and simple as possible
 Where a party other than the manufacturer
wishes to test a component or product, this type
of detailed information is not available
91

92. Need of a Reference Procedure - II

To complicate matters further, the global
pharmaceutical marketplace includes
components and products processed from
different starting materials and having different
manufacturing processes
– Many excipients are polymeric in nature, adding
additional complexity

This diversity leads to vast array of specific tests
and procedures to analysis nearly identical
substances
 The goal of establishing a single reference
procedure for each test in a pharmacopeia has
therefore been a difficult one
92

93. Critical Characteristics of Reference Procedure
Target article
“For
Development
Monograph”
prepared using
General Chapter
<10>
Authentic
samples of the
article
Thorough
Literature
Review
Pharmacopeias
Procured from at
least 2
independent
sources
Published
literature
More sources are
better
Reported
synthetic and
degradation
routes
93

94. For Development Monograph - PBM
For
Development
Monograph
PBM
• Prepared by Scientific Liaison
• Tests for Identification, Assay, Impurities, etc.
• Acceptance Criteria, wherever applicable
• Possibilities for changes as we go forward
during method development or
Dynamic
Document • If additional information is available
94

95. “Proposed For Development” Monograph

List of “For
Development”
Monographs on
the MC website
95

96. Performance Based Monograph (Aluminum Stearate)
96

97. Performance Based Monograph (Aluminum Stearate)
Reference Procedure
97

98. Reference Procedure Development
Pre Lab
In Lab
Post Lab
Literature Search
- Pharmacopeia
- Scientific Literature and Online
and Paper Journals
Procurement
- Drug substance, Drug products,
Impurities by Standards Acquisition
department
- Pharmacopeial impurities by
Analytical Development department
- Method Development by
multi-source materials
- Method finalization
- Method validation
- Data processing
Share the Method
validation data with the
Scientific Liaison
98

99. - Method
development
completed
- Transfer to
the Scientific
Liaison
- If MC monograph
is common to
USP-NF, it
provides additional
new impurities for
USP-NF
Method Validation and Data
Processing
-LC-PDA-MS
-GC-MS
- IC
Method Finalization
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
Specificity Studies
Method Development
Reference Procedure Development – In Lab Details
Data Processing
-Review of
the
validation
data
-Transfer to
Scientific
Liaison
99

100. Method Development
Method Development
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors
-LC-PDA-MS
-GC-MS
- IC

Solubility
– Different solvents and solutions

Spectroscopic Identification
– FT-IR, NIR, Specific Optical Rotation, etc.

Assay
– Chromatography

Related Substances
– Chromatography

Use of multi dimension detectors /
orthogonal detectors
– LC-PDA-MS, ELSD, Corona, etc.
100

101. Method Development
Method Development – Assay and Related Substances
- Solubility
- Spectroscopic
Identification
- Assay
- Related
Substances
- Use of multi
dimension
detectors /
orthogonal
detectors

Several criteria
– Quantification of important analytes
–
–
-LC-PDA-MS
-GC-MS
-IC
–
–
• Main substances, impurities, other
components
The most prevalent method is
chromatographic separation with
spectroscopic or spectrometric detection.
The procedure is adjusted to achieve
acceptable separation of the primary peak
from other peaks.
Use a multi-dimensional detector such as LCPDA with a full scan (200-400 nm or 200-700
nm), LC-MS/MS, IC, Corona Detector
Use a mass spectrometric compatible mobile
101
phase wherever possible

102. Method Finalization
Final Method
- Method
development
completed
- Transfer to
the Scientific
Liaison
- If MC monograph
is common to
USP-NF, it
provides additional
new impurities for
USP-NF

Non-targeted screening

Unequivocal separation

Method development completed

Internal Review

Method of analysis is transferred to
the Scientific Liaison

Types of Reference Standards
– Process impurities (Known / Unknown)
– Degradation products
102

103. Data Processing and Transfer

Review of the validation data

Transfer to the Scientific Liaison

Science Review

Review by the Expert Committee

Presented on the website for 90 day comment
period

Ballot by the Expert Committee
103

104. Sodium Bisulfite
An Example
104

105. Sodium Bisulfite
 Sodium Bisulfite consists predominantly of the sodium
salts of Bisulfite.
 The molecular formula is NaHSO3
 The molecular weight is 104.6.
 A common reducing agent
 Readily reacts with dissolved oxygen
 The related compound
 Sodium metabisulfite
 is used in almost all commercial wines to
prevent oxidation and preserve flavor.
 Sodium bisulfite is sold by some home
winemaking suppliers for the same purpose. In
fruit canning, sodium bisulfite is used to prevent
browning (caused by oxidation) and as an
antimicrobial agent.
105

106. Bisulfite Identification / Assay / Impurity
Bisulfite Identification/Assay/Impurity
Ion Chromatograph + Electrical Conductivity Detector
Chromatographic conditions:
Column: IonPac AS17-C RFIC 4.0 X 250 mm
Guard column: IonPac AG17-C 4.0 X 50 mm
Detector Cell Temperature: 35º
Column temperature: 30º
Flow rate: 1.0 mL/min
Suppressor Current: 109 mA
Injection volume: 10 µL
Mobile phase: Gradient of Potassium hydroxide (KOH) by
IC Eluent generator
106

107. Bisulfite Identification / Assay / Impurity
Ion Chromatograph with Mass Spectrometry
Chromatographic conditions:
Parameters:
Column: IonPac CS16 RFIC 5 X 250 mm
Guard column: IonPac CG16 5 X 50 mm
Detector Cell Temperature: 35º
Column temperature: 40º
Flow rate: 1.0 mL/min
Suppressor Current: 88 mA
Injection volume: 25 µL
Run time: 30 min
Mobile Phase: 30 mM of Methanesulfonic acid
107

108. Challenges & trouble -shooting
HPLC-UV or HPLC-CAD
The HPLC method is not appropriate with CN-column, Ion pair reagent and
UV detector.
Attempted the CAD detector, but since the very big background noises
brought about by the CN-column bleeding and the Ion pair reagent, so the
CAD detector didn’t work for the sulfite
Titration:
The commercial Sodium Bisulfite usually contains the Sodium metabisulfite.
Attempted to use non-aqueous potentiometric titration to differentiate the
bisulfite from metabisulfite, but can’t find a suitable organic solvent.
Ion chromatography:
An IC method was developed to evaluate the Sodium Identification / Assay
/ Purities with Cation mode
An IC method was developed to evaluate the Bisulfite Identification /
Assay / Purities with Anion mode
Unique Innovation: IC-Inhibitor combined with LCMS to Identify Anions.
108

109. Resolution solution: Mixed impurities at 5 μg/mL at 1% level
109

110. Reference Procedure Characterization (Sodium)
Resolution Solution
110

111. Aluminum Stearate
Potassium Stearate
Other Examples
111

112. Resolution – Al- and K- Stearate

S/N
Peak
Name
Ret. Time
Area
Height
Width
(50%)
Asymmetry
(USP)
Resolution
(USP)
Plates (USP)
LA
6.307
0.7219
4.8
0.138
1.03
7.85
11490
648.2
MA
8.367
10.6437
60.29
0.171
1.04
6.58
13223
8173.3
PA
10.507
23.2015
108.35
0.212
1.04
1.7
13560
14663.7
OA
11.123
23.4109
105.14
0.216
1.09
3.74
14638
14227.6
SA
12.473
21.8556
102.54
0.209
1.07
n.a.
19659
13872.5
Fig. Lauric acid, Myristic acid, Palmitic acid, Stearic acid, Oleate acid 0.5mg/ml in methanol
112

113. Assay Method Development
Conc.
mg/ml
0.01
0.02
0.03
0.04
PA
Resp.
0.6825 1.7723 2.9063
SA
Resp.
0.05
0.5742 1.4165 2.1816 3.0349
4.056
0.06
0.07
0.08
0.09
0.10
0.20
0.30
5.2793 6.3445 7.3218 8.3028 9.1541 9.9864 16.733 22.148
3.808
4.6371 5.4261 6.2224 6.9682 7.6548 13.142 17.763
Linear Range Selection:
Sample solution
10, 20, 30, 40, 50, 60, 70, 80,
90, 100, 200, 300 μg/ml of
Potassium Stearate in methanol.
Diluent: Acetonitrile :
Tetrahydrofuran : 60 mM Acetic
Acid= 60: 5: 35)
Fig. The relationship between area responses and the concentrations
113
Comments: The sample concentration will be set at between 0.1~0.3mg/mL.

114. USP-MC Excipients Monographs
•
Monographs completed so far…
1.
4.
Aluminum Stearate
Potassium Stearate
Sodium Bisulfite
Sodium Oleate
•
Work in progress …
1.
Lauryl alcohol
Nutmeg oil
Sodium Caseinate
Turpentine oil
2.
3.
2.
3.
4.
114

116. Development of Standards for
Indian Pharmacopoeia
Dr. Raman Mohan Singh
Principal Scientific Officer & Quality Manager,
Indian Pharmacopoeia Laboratory
Indian Pharmacopoeia Commission
Sector-23, Raj Nagar, Ghaziabad-201002
email : ipclab@vsnl.net
web: www.ipc.gov.in

117. INDIAN PHARMACOPOEIA COMMISSION
•
Government of India has formed
Indian Pharmacopoeia Commission
(IPC) as an Autonomous Institution
under the Ministry of Health and
Family Welfare.

118. It has become fully operational w.e.f. 1st January, 2009

119. Vision
To promote the highest standards
of drugs for use in humans and
animals within practical limits of
the technologies available for
manufacture and analysis

120. Mission
To promote public health in India
by bringing out authoritative and
officially accepted standards for
quality of drugs including APIs,
excipients, dosage forms and
medical devices for use by
health professionals, patients
and consumers

121. MANDATES OF THE COMMISSION
• Publication of Indian Pharmacopoeia at
regular and shorter intervals.
• Publication of National Formulary of India.
• Providing Reference Substances to the
stakeholders.
• National Coordination Centre (NCC) for
running of the Pharmacovigilance Programme
of India (PvPI).
• Providing training to the Stakeholders.

122. Legal requirement of Indian
Pharmacopoeia
As per the Drugs and Cosmetics Act 1940, the
Indian Pharmacopoeia is the legally recognized
book of Standards for the quality of drug
substances and preparations included therein.

123. GLP REQUIREMENTS
 As per Schedule - L1 of Drugs and Cosmetics
Act 1940 and Rules 1945 (Rules 74, 78 and
150E).
In the said rules, after Schedule L, the following
shall be inserted, namely:- SCHEDULE L-I
 These rules may be called the Drugs and
Cosmetics (Third Amendment) Rules, 2008.
 Effective from 1st November, 2010.

124. 
Provisions in Schedule L1 are legal
requirement and are to be complied with
strictly therefore clarifications may be sought
from Indian Pharmacopoeia for the
provisions which are relevant.

IP is a official compendia of the drugs
statutory recognized by the Govt. of India
plays an important role to control spurious,
counterfeit and substandard drugs in India
and also contribute for implementation of the
Good Laboratory Practices.

125. Publication of Indian Pharmacopoeia
Edition
I
II
III
IV
Addenda
V
Addenda
VI
Addenda
VII Edition
Year
1955
1966
1985
1996
2000
2000 (Vet. Suppl)
2002
2005
2007
2008
2010 (Last Edition)
2012 (Last Publication)
2014 (Coming Edition)

126. IP Addendum 2012
 This Addendum has the same authority as the
Indian Pharmacopoeia 2010. The General
Notices, Monographs, Appendices and other
portions of the Indian Pharmacopoeia that are
amended by this Addendum supersede the
original matter to that extent.
 This Addendum amends as well as adds new
materials to the Indian Pharmacopoeia 2010. The
General Notices and Appendices included in the
Indian Pharmacopoeia 2010 apply to the contents
of this Addendum as well unless specifically
stated otherwise.

127. How it Produces

Letters or e-mails related to IP 2010 amendments,
corrections received from various manufacturers
and users.

Most of the queries are sorted out at Secretariat
level.
Typographical mistakes
Printing mistakes
Based on other related pharmacopoeia/ literature.

Queries related to technical debate sent to Subject
Experts or concerned committees for their opinion.

128. How it Produces

Incorporation of suggestions after reviewing
by Subject Experts.

Harmonization of different views of various
companies on a specific query.

Working group of 03 Experts:
 Mr. J L Sipahimalani
 Mr. R. Raghunandanan
 Mr. R. Sridharan

129. Features: Addendum 2012
 Total No. of New Monographs
 No. of API Monographs
 No. of Dosage Forms
:
52
:
10
:
30
:
08
:
04
:
MT 250
Monographs
 Blood and Blood-related
Product Monographs
 No. of Herbs and Herbal
Products Monographs
 No. of Monographs Upgraded

130. Features: Addendum 2012
 Added API monographs whose formulation monographs
was already in IP-2010 and formulation monographs whose
API monographs was given in IP 2010.
 Added 6 New Appendices related to Blood Products.
 Added New General Chapter on Analytical Method
Validation.
 Added 11 new HPLC Chromatogram of Herbal Products.
 Added 4 new IR Spectra in IR Spectra bank.
 Extensively worked on the harmonization of existing IP
Monographs in IP-2010 as per other International
Pharmacopoeias.

131. Presentation of Indian Pharmacopoeia-2010
Introduction
The Indian Pharmacopoeia is presented in three volumes.
 Volume I contains the Notices, Preface, the Structure of the
IPC, Acknowledgements, Introduction, and the General
Chapters.
 Volume II contains the General Notice, General Monographs
on Dosage Forms, Monographs on drug substances, dosage
forms and pharmaceutical aids (A to M).
 Volume III contains Monographs on drug substances, dosage
forms and pharmaceutical aids (N to Z) followed by
Monographs on Vaccines and Immunosera for Human use,
Herbs and Herbal products, Blood and blood-related products,
Biotechnology products and Veterinary products.

132. Introduction
 General chemical tests for identification of an
article have been almost eliminated and the
more specific infrared and ultraviolet
spectrophotometric tests have been given
emphasis. The concept of relying on published
infrared spectra as a basis for identification has
been continued.

133. Introduction

The use of chromatographic methods has been greatly extended
to cope with the need for more specificity in assays and in
particular, in assessing the nature and extent of impurities in
drug substances and drug products. Most of the existing Assays
and Related substances tests are upgraded by liquid
chromatography method in view to have more specificity and to
harmonise with other International Pharmacopoeias.

The test for pyrogens involving the use of animals has been
virtually eliminated. The test for bacterial endotoxins introduced
in the previous edition is now applicable to more items. The test
for abnormal toxicity is now confined to certain vaccines.

134. General Notices
 General Notices mentioned in all three volumes of
IP- 2010 with blue pages to make it user friendly
which have common terms & definitions used in the
monograph/ appendices.
 The General Notices provide the basic guidelines for
the interpretation and application of the standards,
tests, assays, and other specifications of the Indian
Pharmacopoeia (IP), as well as to the statements
made in the monographs and other texts of the
Pharmacopoeia.

135. General Notices
 The active pharmaceutical ingredients (drug
substances),
excipients
(pharmaceutical
aids),
pharmaceutical preparations (dosage forms) and other
articles described in the monographs are intended for
human and veterinary use (unless explicitly restricted
to one of these uses).
 The requirements given in the monographs are not
framed to provide against all possible impurities,
contaminants or adulterants; they provide appropriate
limitation of potential impurities only.

136. General Notices
136
Alternative Methods. The tests and assays described are the
official methods upon which the standards of the Pharmacopoeia
are based. Alternative methods of analysis may be used for control
purposes, provided that the methods used are shown to give results
of equivalent accuracy and enable an unequivocal decision to be
made as to whether compliance with the standards of the
monographs would be achieved if the official methods were used.
Automated procedures utilizing the same basic chemistry as the test
procedures given in the monograph may also be used to determine
compliance. Such alternative or automated procedures must be
validated.
In the event of doubt or dispute, the methods of analysis of the
Pharmacopoeia are alone authoritative and only the result obtained
by the procedure given in this Pharmacopoeia is conclusive.

137. Monographs
General monographs
General monographs on dosage forms include
requirements of general application and apply to
all preparations within the scope of the
Introduction section of the general monograph,
except where a preamble limits the application.
The
requirements
are
not
necessarily
comprehensive for a given specific preparation;
additional requirements may sometimes be given
in the individual monograph for it.

138. Monographs
 Individual Monographs: The terms used in
the individual monograph are defined in
General Notices.
 Reagent , Solutions & indicators given in the
individual monographs are italicized which are
available in Appendices.
 Storage & Labelling: The conditions given in
the individual monographs are well defined in
the General Notices.

139. Presentation of IP 2014
IP 2014 would be presented in four volumes:
Volume 1
Volume 2
Volume 3
Volume 4

140. Content of Volume 1
•
•
•
•
•
•
Notices
Preface
Indian Pharmacopoeia Commission
Acknowledgements
Introduction
General Chapters

141. Content of Volume 2
• General Notices
• General Monographs on Dosage
Forms
• Monographs on Drug substances,
Dosage forms and Pharmaceutical
Aids Monographs A to M

142. Content of Volume 3
• General Notices
• Monographs on Drug substances, Dosage forms
and Pharmaceutical aids Monographs N to Z
• Monographs on Vaccines and Immunosera for
Human Use
• Monographs on Herbs and Herbal Products
• Monographs on Blood and Blood-related Products
• Monographs on Biotechnology Products
• Index

143. Content of Volume 4
• Monographs on Veterinary Products
 Non-Biological
 Biological
 Diagnostics

144. Features of NEW EDITION
Monographs on Drug substances, Dosage forms &
Pharmaceutical aids (A to Z)
• New API’s
Formulations
: 204
: 169
Vaccine & immunosera for human use
: 05
Monographs on Herbs & Herbal products
: 30
Biotechnology Products
: 06
Monographs on Veterinary products
:
Chemical
: 39
Vet Vaccines
: 16
Diagnostics
: 01

145. NEW EDITION
Vet. Appendices
: 06
Vet. General Chapter
: 10
Vet. Surgical materials monograph : 07
Radiopharmaceutical Monographs : first time
being introduced in this edition.
General Monograph
: 01
Monographs
: 19

146. Specific features
Adding:
(i) 480 new monographs.
(ii) 32 new General Chapters.
(iii) About 200 new IR spectra’s.
(iv) Introducing first time 19 Radiopharmaceutical
Monographs & 1 General Chapter.
(v) Separate Veterinary Volume for easy access .
(vi) 11 New Anticancer monographs
(vii) 06 New Antiviral Monographs

147. List of Anticancer monographs:
1.
Bortezomib
2.
Carboplatin
3.
Docetaxel Anhydrous
4.
Gemicitabine Hydrochloride
5.
Lapatinib Ditosylate
6.
Mitomycin
7.
Sorafenib Tosylate
8.
Premetrexed Disodium
9.
Erlotinib Hydrochloride
10. Fludarabine Phophate
11. Bicalutamide

148. List of Antiviral monographs:
1. Famciclovir
2. Famciclovir Tablet
3. Aciclovir Cream
4. Aciclovir Eye Ointment
5. Aciclovir Dispersible Tablets
6. Aciclovir Oral Suspension

149.  The scope of the Pharmacopoeia has been
extended to include products of biotechnology,
indigenous herbs and herbal products, Veterinary
vaccines and additional antiretroviral drugs and
formulations, inclusive of commonly used fixeddose combinations.
 Standards for new drugs and drugs used under
National Health Programmes are added in this
edition and drugs as well as their formulations not
in use now a days are ommited from this edition.

150. Format
 In an effort to make the pharmacopoeia more
user-friendly,
design of the texts of the
monographs and of the test methods are kept
same however they are upgraded.
 Cross-referencing has been avoided to make each
monograph complete in itself thus making it
convenient to the analyst performing the tests and
to the ones checking the results of analysis.

151. Basis of Pharmacopoeial requirement
 As in the past, this compendium provides a publicly
available statement concerning the quality of a product
that can be expected and demonstrated at any time
throughout the accepted shelf-life of the article.
 The standards laid down represent the minimum with
which the article must comply and it is incumbent on
the manufacturer to ensure that the article is
manufactured in accordance with Good Manufacturing
Practices (GMPs).
 It is essential that sufficiently stringent limits are
applied at the time of release of a batch of a material or
product so that the pharmacopoeial standards are met
until its expiry date under the storage conditions
specified.

152.  It must be noted that a valid interpretation of
any requirement of the Pharmacopoeia should
be done in the context of the monograph as a
whole, the relevant general monograph, where
appropriate, the specified tests and methods of
analysis including any reference to the
relevant General Notices.
 Familiarity with the General Notices will
facilitate the correct application of the
requirements.

153. Changes
 Keeping in view the essential requirement under the
Drugs and Cosmetics Act, 1940 and Rules there in the
information on category of a drug, dosage and usual
available strengths of dosage forms has been re-kept in
this edition.
 General chemical tests for identification of an article
have been almost eliminated and the more specific
infrared and ultraviolet spectrophotometric tests have
been given emphasis. The concept of relying on
published infrared spectra as a basis for identification
has been continued.

154.  The use of chromatographic methods has been
greatly extended to cope with the need for more
specificity in assays and in particular, in assessing
the nature and extent of impurities in ingredients
and products.
 Most of existing Assays and Related substances
tests are upgraded by liquid chromatographic
method in view to harmonize with other
international Pharmacopoeias.

155.  The test for pyrogens involving the use of
animals has been virtually eliminated.
 The test for bacterial endotoxins introduced
in the previous editions is now applicable to
more items.
 The test for abnormal toxicity is now
confined to certain vaccines.

156. General Chapters
 Volume I is devoted mainly to test methods
that are applicable to all the articles of the
pharmacopoeia and general information
pertaining to the quality requirements of
medicinal substances.
 It also includes reference data such as
reference spectra, typical chromatograms etc.
 The test methods reflect the sophistication of
analytical methodology and instrumentation.

157.  Analytical methods are in general in harmony
with those adopted internationally
monitoring the quality of drugs.
for
 The steps taken for harmonization have been
initiated by the need to cope with the
increasing demand for drugs manufactured in
the country to globally accepted standards.

158.  The trend towards controlling the microbial
quality of all medicinal products has been
recognized and the requirement regarding
limits of bacterial contamination even of
products for oral administration and topical
application so that adequate controls are
exercised by manufacturers by the adoption of
GMPs has been continued.

159. General Monographs

The General Monographs for dosage forms of active
pharmaceutical ingredients (APIs) are grouped together
at the beginning of Volume II.

They are followed by the monographs for the APIs,
pharmaceutical aids and individual dosage forms, all in
alphabetical order. Monographs for other articles of a
special nature such as vaccines and immunosera for
human use, herbs and herbal products, blood and blood
related products & biotechnology products are given in
separate sections in Volume III.

Veterinary Monographs are given in Volume IV.

160. Purchase of Indian Pharmacopoeia
IP-2014 & Addendum-2012 can be procured from the office of the
Secretary-cum-Scientific Director,IP Commission at IPC Campus,
Rajnagar, Sector 23, Ghaziabad – 201 002 (UP),India or from our
distribution network (see website:www.ipc.gov.in).
Other Distribution Centres:
(1) M/s Educational BookCentre
133, Gala Complex, Din Dayal Upadhyay Road,
Mulund (W),
Mumbai-400080.
Phone :- + 91-22-2560 3324 Fax:- 91-22- 25685341
E-mail: ebc@vsnl.net

161. (2) M/s Educational Book Agency (India),
5-D , Kamla Nagar ,
New Delhi-110 007.
Phone : 23844216, 41530228
Fax: 011-23842077, Mobile:- 9811672690
E-Mail : eba@airtelmail.in, ebaindia200@yahoo.co.in
Web: indianpharmacopoeia.in
(3) M/s Pharma Book Syndicate,
4-3-375, Ansuya Bhawan Opp.Lane to Central Bank,
Bank Street, Hyderabad-500095.
Phone:- 23445666, 23445622, 23445644,
Fax:- 040- 23445611
E-mail : info@ pharmabooksyndicate.com

162. Your Participation in the work of IP
Interested parties can participate in the following ways:
 Submit draft monographs along with supporting
documents.
The Indian Pharmacopoeia encourages you to submit draft
monographs. Your draft may be the starting point for an
official public standard.
 Propose Revisions to Existing General Chapters and
Monographs
You can propose revisions to the general chapters and
monographs in the current official edition of the Indian
Pharmacopoeia.

163. IP Chemical Reference Substance
Current Status
 Total candidate materials received till date
= 400 Nos.
 Total IPRS available for distribution
= 253 Nos.
 IPRS under process of filling and Labeling = 25 Nos.
 IPRS under characterization
= 25 Nos.
 Candidate materials under review
= 71 Nos.
 IPRS available for distribution till Mar. 2013= 253 Nos.

164. IPRS Distribution
• No. of IPRS vials Supplied to Govt. Labs
= 1934
• No. of IPRS Vials Supplied to Pvt. Labs
= 265

165. IP Reference Substances
 IPC has proposed to provide IPRS as complementary
to all regulatory / pharmacopoeial bodies for
harmonization among SAARC, SEARO & ASEAN
Countries as presented by the Scientific Director, IPC
during his visit at FIP Conference Amsterdam,
Netherland.
 IPC is also going to include 50 New drug
monographs in IP-2014 which are not available in
any other Pharmacopoeia like EP/BP/USP with
validated protocol and IPRS.

166. Challenges
 To prepare Impurity Reference Substances
 To maintain continuous Supply of IPRS
 To achieve the target of 900 IPRS

167. How to contact IPC
By email: IPC Secretariat at ipclab@vsnl.net
By post:
Indian Pharmacopoeia Commission
Ministry of Health & Family Welfare
Government of India
Sector-23, Raj Nagar, Ghaziabad
(U.P.)-201002, India
Fax: 0120-2783311