Usp chemical medicines & excipients

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

Moderator:

Dr. Antony Raj Gomes

Chair, USP Medicines Compendium Expert Committee

The Medicines Compendia

Performance Based Monograph with

Reference Procedure

Antony Raj Gomas, Ph.D.

Chair, USP Medicines Compendium Expert Committee

Introduction

4

What is Medicines Compendium?

Why is it relevant?

What are the benefits to Industry and regulators?

How the Medicines compendium works?

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.

6

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 regulators, manufacturers, and other

pharmacopeias

Standards without borders

Introduction

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.

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.

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

Scientific Liaison Process

11

Scientific Liaison Process (Continued)

Scientific Review

Identification of monographs for Development, after prioritization

Preparation 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

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

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 criteria-

based 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.

14

Performance Based Monograph

Universal Tests

Description

Identification

Assay

Impurities

Specific Tests

Performance Tests

Content Uniformity

Others

Criteria for Acceptance

Drug Substance, 98% - 102%

Any Impurity NMT 0.1% (Includes both known as well as unknown)

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

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.

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.

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

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)

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.

20

Critical Characteristics of Reference Procedure

Target article

For Development

Monograph

prepared using

General Chapter

<10>

Authentic

samples of the

article

Procured from at

least 2

independent

sources

More sources are

better

Thorough

Literature Review

Pharmacopeias

Published literature

Reported synthetic

and degradation

routes

21

Monograph for development - PBM

Monograph for Development

• Prepared by Scientific Liaison

PBM

• Tests for Identification, Assay, Impurities, etc.

• Acceptance Criteria, wherever applicable

Dynamic Document

• Possibilities for changes as we go forward during method development or

• If additional information is available

22

“Proposed For Development” Monograph

List of “For

Development”

Monographs on

the MC website

23

A Typical “Proposed For Development” Monograph

Reference Procedure

24


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

25

Reference Procedure Development – In Lab Details M

eth

od

Deve

lop

me

nt

Sp

ecific

ity S

tud

ies

Me

tho

d F

ina

liza

tio

n

Me

tho

d V

alid

atio

n a

nd

Data

Pro

ce

ssin

g

Method

Validation

- Linearity

- Accuracy

- Precision

-Day 1

-Day 2

-Day 3

Data Processing

-Review of the

validation

data

-Transfer to

Scientific

Liaison

- 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

studies

- Acid

- Alkali

-Thermal

- Peroxide

- Light

- Separation of

degradation

products

(Identification,

wherever

possible)

- Loops back to

Method

development,

if needed

- Solubility

- Spectroscopic

Identification

- Assay

- Related

Substances

- Use of multi

dimension

detectors /

orthogonal

detectors

-LC-PDA-MS

-GC-MS

26

Method Development M

eth

od

Develo

pm

ent

- 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.

27

Identification - Clarithromycin

28

Method Development – Assay and Related Substances M

eth

od

Develo

pm

ent

- 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

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.

30

Specificity (Forced Degradation) Studies S

pe

cific

ity S

tud

ies

- 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

31

Method Development, Forced Degradation Studies - I

Separation of Clarithromycin &

impurities

Acid degradation of Clarithromycin drug

substance

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

33

Final Method M

eth

od F

inaliz

ation

- 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

34

Method Validation

General Chapter <10>

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.

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

37

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)

Method Validation – Quantitative Impurities Procedure - I

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)

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

40

Data Processing and Transfer

Review of the validation

data

Transfer to the Scientific

Liaison

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

42

Acceptable Procedures (Continued)

Industry Use of Medicines

Compendium Approaches

Nicholas Cappuccino, Ph.D.

Member, USP Small Molecules Expert Committee

Monograph Modernization

Todd L. Cecil, Ph.D.

Vice President, Chemical Medicines Development, USP

Monographs in USP: ~6000

Monographs needing Modernization: ~2700

Procedures to be replaced: ~2/ monograph

Modernization Scope

55

Monograph Modernization Initiative

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

CRITERIA

Non-specific ID Tests (e.g., ID by HPLC

retention time agreement

only)

Outdated Technology • Packed column GC

• Titration

• Wet chemistry

• Spectrophotometry

• TLC

Missing tests (e.g,

organic impurities)

Outdated technology

Other tests (e.g, melting point)

Safety/environmental

concerns (e.g., odor

tests, chlorinated

solvents, pyridine,

mercuric salts, etc)

MONOGRAPH TESTS

Identification

Assay

Impurities

• Organic

• Inorganic

• Residual Solvents

• Heavy Metals

Specific Tests

Status Update

Status Monographs

In USP-NF compendium 90

Modernization Underway

Awaiting bulk 6

RS Release 4

In development 335

In production 29

In Forum 78

Total 542

Yet to begin ~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.

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

Reference Procedure

58


59

Target article

For Development

Monograph

prepared using

General Chapter

<10>

Authentic

samples of the

article

Procured from at

least 2

independent

sources

More sources are

better

Thorough

Literature

Review

Pharmacopeias

Published

literature

Reported

synthetic and

degradation

routes


60

Literature Search - Pharmacopeia–USP, EP, BP, JP - Scientific Literature and Online and Paper Journals




- Specificity studies

- LC-MS Analysis for the

forced degradation studies


- Method validation

- Data processing


Pre Lab In Lab Post Lab

Reference Procedure Development – In Lab Details

61

Me

thod

Develo

pm

ent

- Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS

Specific

ity S

tudie

s

- Forced degradation studies - Acid

- Alkali -Thermal - Peroxide - Light

- Separation of degradation products (Identification,

wherever possible)

- Loops back to Method development, if needed

Meth

od F

inaliz

ation

- Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF

Me

tho

d V

alid

atio

n a

nd

Da

ta P

roce

ssin

g

Method Validation

- Linearity

- Accuracy

- Precision -Day 1

-Day 2

-Day 3

Data Processing

-Review of

the

validation

data

-Transfer to

Scientific

Liaison

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

Components of the Approach

62

Drug Product Performance and

Optimal Bioavailable Products

(OBA)

Roger Williams, M.D.

Chief Executive Officer and Chair, Council of Experts, USP

Overall Goal

Reference Procedure Approach

Drug Products—The Challenge

BCS and Determination of OBA—A Solution for

Many Medicines

Summary

Topics

65

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

Overall Goal

66

Overall Goal




Many Medicines

Summary

Topics

67

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

USP’s Medicine Compendium: Reference Procedures

Overall Goal




Many Medicines

Summary

Topics

69

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>

Drug Product Monographs: The Challenge

70

Overall Goal




Many Medicines

Summary

Topics

71

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

Drug Release – The Rate Limiting Step

Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

Volume of water (ml) required to dissolve

the highest dose strength at pH 1.2 - 8

1 10 100 1000 10000 100000

0.01

0.1

1.0

10

I

III

II

IV

Dissolution likely

to be “rate limiting”

Gastric emptying

determines on-set of

absorption

Absorption might be:

- incomplete

- sensitive to

certain excipients

Generally “problem”

molecules

Hu

ma

n P

erm

ea

bilit

y

Biopharmaceutics Classification System

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

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

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



High solubility in pH 6.8 only

– Conduct dissolution according to USP-NF <711> in pH 6.8



Low solubility in both pH values

– Product specific development needed

– Suggestions on surfactant usage could be included

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

MC Drug Product Performance Test

78

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)

What Would This ‘Further’ Look Like?

Overall Goal




Many Medicines

Summary

Topics

80

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)

The Revolution

81

Pioneers and Harmonization

New Pharmacopeial Approaches to

Excipient Monographs

Sameer Navalgund, Ph.D.

President, Analytical Research and Development

USP

Typical Excipient Monographs

Challenges involved for Excipient Monographs

USP-MC Monographs


– Critical characteristics of a Reference Procedure

– Reference Procedure Development

• Process

• Solubility

• Procedure Development

• Use of advanced technologies

Some examples

Today’s Topics for Discussion

85

“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”

Excipient – One of the Definitions

86

Definition

Identification

Assay

Impurities

Specific Tests

– Methods of analysis

– Acceptance Criteria

Additional

requirements

Typical Excipient Monographs

87

Other information

available

Nonproprietary Names

Synonyms

Empirical Formula and Molecular

Weight and structural Formula

Functional Category

Applications in Pharmaceutical

Formulation or Technology

Stability and Storage Conditions

Incompatibilities

Safety

Regulatory Status

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

Challenges Involved for Excipient Monographs

88

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

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

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

Need of a Reference Procedure - I

91

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

Need of a Reference Procedure - II

92


93

Target article

“For

Development

Monograph”

prepared using

General Chapter

<10>

Authentic

samples of the

article

Procured from at

least 2

independent

sources

More sources are

better

Thorough

Literature

Review

Pharmacopeias

Published

literature

Reported

synthetic and

degradation

routes

For Development Monograph - PBM

94

For Development Monograph

• Prepared by Scientific Liaison

PBM

• Tests for Identification, Assay, Impurities, etc.

• Acceptance Criteria, wherever applicable

Dynamic Document

• Possibilities for changes as we go forward during method development or

• If additional information is available

List of “For

Development”

Monographs on

the MC website

“Proposed For Development” Monograph

95

96

Performance Based Monograph (Aluminum Stearate)

97

Performance Based Monograph (Aluminum Stearate)

Reference Procedure


98

Literature Search - Pharmacopeia - Scientific Literature and Online and Paper Journals





- Method validation

- Data processing


Pre Lab In Lab Post Lab

Reference Procedure Development – In Lab Details

99

Meth

od D

evelo

pm

ent - Solubility

- Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS - IC

Specific

ity S

tudie

s

Meth

od F

inaliz

ation

- Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF

Meth

od V

alid

ation a

nd D

ata

P

rocessin

g

Data Processing

-Review of

the

validation

data

-Transfer to

Scientific

Liaison

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.

Method Development

100

Me

thod D

evelo

pm

ent

- Solubility

- Spectroscopic

Identification

- Assay

- Related

Substances

- Use of multi

dimension

detectors /

orthogonal

detectors -LC-PDA-MS

-GC-MS

- IC

Several criteria

– Quantification of important analytes

• 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 LC-

PDA with a full scan (200-400 nm or 200-700

nm), LC-MS/MS, IC, Corona Detector

– Use a mass spectrometric compatible mobile

phase wherever possible

Method Development – Assay and Related Substances

101

Me

thod D

evelo

pm

ent

- Solubility

- Spectroscopic

Identification

- Assay

- Related

Substances

- Use of multi

dimension

detectors /

orthogonal

detectors -LC-PDA-MS

-GC-MS

-IC

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

Final Method

102

Meth

od F

inaliz

ation

- Method

development

completed

-

- Transfer to

the Scientific

Liaison -

- If MC monograph

is common to

USP-NF, it

provides additional

new impurities for

USP-NF

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

Data Processing and Transfer

103

Sodium Bisulfite An Example

104

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

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

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

Bisulfite Identification / Assay / Impurity

107

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 LC-

MS to Identify Anions.

108

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

109

Reference Procedure Characterization (Sodium)

Resolution Solution

110

Aluminum Stearate

Potassium Stearate Other Examples

111

Resolution – Al- and K- Stearate

Fig. Lauric acid, Myristic acid, Palmitic acid, Stearic acid, Oleate acid 0.5mg/ml in methanol

Peak

Name Ret. Time Area Height

Width

(50%)

Asymmetry

(USP)

Resolution

(USP) Plates (USP)

S/N

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

112

Assay Method Development

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)

Conc.

mg/ml 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.20 0.30

PA

Resp. 0.6825 1.7723 2.9063 4.056 5.2793 6.3445 7.3218 8.3028 9.1541 9.9864 16.733 22.148

SA

Resp. 0.5742 1.4165 2.1816 3.0349 3.808 4.6371 5.4261 6.2224 6.9682 7.6548 13.142 17.763

Fig. The relationship between area responses and the concentrations

Comments: The sample concentration will be set at between 0.1~0.3mg/mL. 113

• Monographs completed so far…

1. Aluminum Stearate

2. Potassium Stearate

3. Sodium Bisulfite

4. Sodium Oleate

• Work in progress …

1. Lauryl alcohol

2. Nutmeg oil

3. Sodium Caseinate

4. Turpentine oil

USP-MC Excipients Monographs

114

Dr. Raman Mohan Singh Principal Scientific Officer & Quality Manager,

Indian Pharmacopoeia Laboratory

Indian Pharmacopoeia Commission

Sector-23, Raj Nagar, Ghaziabad-201002 email : [email protected]

web: www.ipc.gov.in

Development of Standards for

Indian Pharmacopoeia

INDIAN PHARMACOPOEIA COMMISSION

• Government of India has formed


(IPC) as an Autonomous Institution

under the Ministry of Health and

Family Welfare.

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

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

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

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.

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.

Legal requirement of Indian

Pharmacopoeia

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.

GLP REQUIREMENTS

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.

Publication of Indian Pharmacopoeia Edition Year

I 1955

II 1966

III 1985

IV 1996

Addenda 2000

2000 (Vet. Suppl)

2002

2005

V 2007

Addenda 2008

VI 2010 (Last Edition)

Addenda 2012 (Last Publication)

VII Edition 2014 (Coming Edition)

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.

IP Addendum 2012

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.

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

How it Produces

Total No. of New Monographs : 52

No. of API Monographs : 10

No. of Dosage Forms : 30

Monographs

Blood and Blood-related : 08

Product Monographs

No. of Herbs and Herbal : 04

Products Monographs

No. of Monographs Upgraded : MT 250

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.

Features: Addendum 2012

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.

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.

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.

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.

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.

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.

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.

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.

Presentation of IP 2014

IP 2014 would be presented in four volumes:

Volume 1

Volume 2

Volume 3

Volume 4

Content of Volume 1

• Notices

• Preface

• Indian Pharmacopoeia Commission

• Acknowledgements

• Introduction

• General Chapters

Content of Volume 2

• General Notices

• General Monographs on Dosage

Forms

• Monographs on Drug substances,

Dosage forms and Pharmaceutical

Aids Monographs A to M

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

Content of Volume 4

• Monographs on Veterinary Products

Non-Biological

Biological

Diagnostics

Monographs on Drug substances, Dosage forms &

Pharmaceutical aids (A to Z)

• New API’s : 204 Formulations : 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

Features of 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

NEW EDITION

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

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

List of Antiviral monographs:

1. Famciclovir

2. Famciclovir Tablet

3. Aciclovir Cream

4. Aciclovir Eye Ointment

5. Aciclovir Dispersible Tablets

6. Aciclovir Oral Suspension

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 fixed-

dose 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.

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.

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.

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.

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.

Changes

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.

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.

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.

Analytical methods are in general in harmony

with those adopted internationally for

monitoring the quality of drugs.

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.

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.

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.

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: [email protected]

Purchase of Indian Pharmacopoeia

(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 : [email protected], [email protected]

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

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.

Your Participation in the work of IP

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.

IPRS Distribution

• No. of IPRS vials Supplied to Govt. Labs = 1934

• No. of IPRS Vials Supplied to Pvt. Labs = 265

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.

IP Reference Substances

Challenges

To prepare Impurity Reference Substances

To maintain continuous Supply of IPRS

To achieve the target of 900 IPRS

By email: IPC Secretariat at [email protected]

By post:


Ministry of Health & Family Welfare

Government of India

Sector-23, Raj Nagar, Ghaziabad

(U.P.)-201002, India

Fax: 0120-2783311

How to contact IPC

Health & Medicine

Usp chemical medicines & excipients