Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

International Excipient Workshop: Excipient Quality Control, Testing, and International

Harmonization
USP Headquarters, Rockville, Maryland
July 20-21, 2009

European Pharmacopoeia Perspective

on Functionality-Related Characteristics
Anne Gayot, Ph.D.
University of Lille, France

PRESENTATION NOT AVAILABLE FOR RELEASE

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

International Excipient Workshop: Excipient Quality Control, Testing, and International

Harmonization
USP Headquarters, Rockville, Maryland
July 20-21, 2009

International Harmonization:
EDQM Perspective
Susanne Keitel, Ph.D.
EDQM

PRESENTATION NOT AVAILABLE FOR RELEASE

Session III:
Excipient QBD as It Relates
to Performance and Functionality

USP Excipient Performance

Chapter <1059>

Presented by Gregory E. Amidon

Chair, Excipients General Chapters

Outline

Overview/History of Excipient Performance

Testing
Regulatory Interest in Excipient Quality and
Performance
Functionality versus Performance
Excipient Performance Chapter <1059>
Functionality Related Characteristics
 Twenty Years of Functionality, Physical
Testing, and Excipient Performance

2000-2005
1990-1995 Expert
Excipients Committee on
Subcommittee Excipient
Zak Chowhan, Chair 1995-2000
Excipients Testing
Ralph Shangraw Gregory E.
Garnet Peck Subcommittee Amidon, Chair 2005-2010 Expert
George Zografi Gregory E. Amidon, Dale E. Wurster, Committee on
Chair Vice Chair
Gregory E. Amidon Excipient Test
Dale E. Wurster Richard Meury
Garnet Peck Chris Moreton Methods
Advisory Panel on David Grant Gregory E. Amidon,
Larry Augsburger Chair
Physical Test Steven Hoag
Harry Brittain Garnet Peck, Vice
Methods (1991- Raj Chair
David Fox Suryanarayanan
5) Dale E. Wurster
Stephen Byrn
Gregory E. Amidon, Richard Meury
Chair Advisory Panel Harry Brittain
Garnet Peck Members David Grant
David Grant David Grant Steven Hoag
Keith Marshall Keith Marshall Eric Schmitt
Michael Bergren Michael Bergren
Zak Chowhan Shigiru Itai
Shigiru Itai
Hans Leuenberger

Excipients General Chapters Committee

2005-2010

Gregory E. Amidon, Chair Univ. of Michigan.

Garnet Peck, Vice Chair Purdue Univ.
Dale E. Wurster Univ. of Iowa
Richard Meury Eli Lilly
Steven Hoag Univ. of Maryland
Eric Schmitt Abbott Labs.
Harry Brittain Center for
Pharm. Physics

David Grant, deceased Univ. of Minnesota

 Regulatory Interest (1992)

FDA is checking, in particular, to assure that

physical characteristics of both active and key
inactive ingredients have been carefully
evaluated and that appropriate raw material and
in-process specifications have been established
and validated.

Ref: Quality Control Reports (Gold Sheet), 26 (6): 1 (1992).

Regulatory Interest (1994)

Control of the physical characteristics of the excipients

is also important because variations in such
characteristics may also affect the performance of the
dosage form. Changes in particle size of some
excipients, for example, may affect content uniformity.
In other cases, a changes in the supplier of an
excipient or lubricant may affect dissolution or
bioavailability.

Ref: FDA Guide to Inspections of Oral Solid Dosage Forms

Pre/Post Approval Issues for Development and Validation,
January 1994.
Regulatory Interest (1994) cont.

A major question that must be addressed is the

need for testing physical characteristics (particle
size) for each batch of excipient. For many
single source excipients, particle size is a
supplier specification and is usually tightly
controlled. Having established a specification
and not testing each lot upon receipt may be
satisfactory in such cases.

Ref: FDA Guide to Inspections of Oral Solid Dosage Forms

Pre/Post Approval Issues for Development and Validation, January
1994.

Regulatory Interest (1994) cont.

However, for multi-source excipients and where the

dosage formulator expects to shift sources of supply.
There may be differences in physical characteristics
(particle size) that may have an effect on dose
uniformity and dissolution. Examine the practices with
respect to the source of supply of the key excipients
and determine if there is justification for the lack of
testing lots of excipient for physical characteristics.

Ref: FDA Guide to Inspections of Oral Solid Dosage Forms

Pre/Post Approval Issues for Development and Validation,
January 1994.
Regulatory Interest (2004)

For an excipient, conformance to compendial

specifications alone can be inadequate for
performing its intended function in a drug
product, and/or for its suitability for use in
commercial scale manufacturing (of the drug
product), if the critical attributes of the excipient
are not similar, when obtained from multiple
sources

Rajendra Uppoor, FDA, Multisource Excipient Equivalence

FDAs Current Views, 2004 USP Annual Scientific Meeting,
September 28, 2004.

National Formulary 25 (2007)

Page 1050, General Notices and Requirements

Because of differing characteristics not

standardized by the National Formulary, all
sources or types of some excipients may not
have identical properties with respect to use in a
specific preparation. To assure interchangeability
in such instances, users may wish to ascertain
final performance equivalency or determine such
characteristics prior to use.
FDA Guidance for Industry Q8(R1) June 2009

Reference: Guidance for Industry: Q8(R1) Pharmaceutical Development (Revision 1),

Food & Drug Administration, Washington, DC, June 2009.

Approaches to Overall Pharmaceutical

Development

Reference: Appendix I. Guidance for Industry: Q8(R1) Pharmaceutical Development

(Revision 1), Food & Drug Administration, Washington, DC, June 2009.
 Why Excipient Performance Testing?
A Classic Example (Magnesium Stearate)

Surface area is
well known to
influence the
lubrication
properties of
magnesium
stearate and this
can impact
product properties
in this case
tablet tensile
strength

Ref: Dansereau, R.; Peck, G.E.

Drug Dev. Ind. Pharm. 1987, 13
(6), 975999.

A Classic Example (Magnesium Stearate)

Different Suppliers

Ref: Dansereau, R.; Peck, G.E.

Drug Dev. Ind. Pharm. 1987, 13
(6), 975999.
 Magnesium Stearate, NF Monograph

Labeling Where the labeling states the specific

surface area, it also indicates which method specified
under Specific Surface Area <846> is used.
.

Specific surface area <846> - [Note In cases

where there are no functionality-related
concerns regarding the specific surface area of
this article, this test may be omitted.] .

Microcrystalline Cellulose, NF Monograph

Labeling - The labeling

indicates the nominal loss
on drying, bulk density, and
degree of polymerization
values.... Where the particle
size distribution is stated in
the labeling, the labeling
indicates the d10, d50, and
d90 values and the range for
each.
 USP Excipient Performance
Chapter <1059>

Excipient Performance <1059> Chapter

Contributors

Gregory E. Amidon, PhD, Chair, Excipient General Chapters Expert Committee,

Garnet E. Peck, PhD, Vice Chair, Excipient General Chapters Expert Committee,
Lawrence H. Block, PhD, Chair, Excipient Monographs 2 Expert Committee,
Richard C. Moreton, PhD, Vice Chair, Excipient Monographs 2 Expert Committee,
Ashok Katdare, PhD, Vice Chair, Excipient Monographs 1 Expert Committee,
Robert Lafaver, Liaison to Excipient General Chapters & Excipient Monographs1
Catherine Sheehan,* Director, Excipients and Food Chemicals Codex, USP

Advisory Panel Members:

Eric Schmitt & Gregory Amidon, Co Chairs
Kenneth Alexander; Gary Ewing; Rajeev Gokhale; Xiaorong He; John Lipari; Lee
Kirsch; Matthew Mullarney; Jasmin Musakhanian; Sandeep Nema; Changquan
Sun; Ranga Velagaleti;
 Functionality versus Performance

Excipient function (eg: functionality) is a broad,

qualitative and descriptive term for the purpose
or role an excipient serves in a formulation.

Of greater importance, however, are the

quantitative performance requirements (eg:
critical material attributes) of excipients that must
be evaluated and controlled to ensure consistent
performance throughout the product life-cycle.

Functionality versus Performance

Not all critical material attributes of an excipient may

be identified or evaluated by specific tests and
specifications in excipient monographs.

It is important that excipient users identify and control

critical material attributes that may often go beyond
monograph specifications.

This requires a thorough understanding of the

formulation, the manufacturing processes, and the
physical and chemical properties of each ingredient.
 Excipient Performance Chapter <1059>
Outline - Sections

INTRODUCTION
TABLETSANDCAPSULES
ORALLIQUIDS
SEMISOLIDS,TOPICALSANDSUPPOSITORIES
AEROSOLS
PARENTERALS
AEROSOLS

Excipient Performance Chapter <1059>

Outline

INTRODUCTION
TABLETSANDCAPSULES
Diluent
Binder
Disintegrant
Lubricant
Glidant and/orAnticaking Agent
ColoringAgent
CapsuleShell
CoatingAgent
Plasticizer
ORALLIQUIDS
pHmodifier(acidifying/alkalizing/bufferingagent)
Solubilizers
AntimicrobialPreservative
Chelatingand/orComplexing Agent
Antioxidant
SweeteningAgent
 Excipient Performance Chapter Outline

SEMISOLIDS,TOPICALSANDSUPPOSITORIES
SuppositoryBase
Suspendingand/orViscosityincreasingAgent
OintmentBase
StiffeningAgent
Emollient
PARENTERALS
PharmaceuticalWater
Diluent
TonicityAgent
AEROSOLS
Propellant

Outline of Excipient Performance Sections

Heading Content of Section

Description Describe general purpose and use of the
functional category
Functional Describe the mechanisms by which the
Mechanism excipient functions, if known
Physical Properties Describe the relevant physical properties
Chemical Properties Describe the general chemical properties
General Chapters Identify General Test Chapters and General
Information Chapters that may be useful to
evaluation excipient performance
Other Information Provide other information
 Functional Category: Tablet and/or Capsule Diluent

Example Section Description: Components incorporated into tablet or capsule dosage forms to increase dosage form
volume or weight may be considered diluents. Sometimes referred to as fillers, they often comprise
a significant proportion of the dosage form and the quantity and type of diluent selected is often
dependent upon its physical and chemical properties. Because the diluent may comprise a large
portion of the dosage form, successful and robust manufacturing and dosage form performance is
dependent upon the measurement and control of the critical attributes.

Functional Mechanism: Among the most important functional roles diluents play is to impart
desirable manufacturing properties (eg: powder flow, tablet compaction strength, wet or dry
granule formation, homogeneity) and performance (eg: content uniformity, disintegration,
Functional Category dissolution, tablet integrity, friability, physical and chemical stability). Some diluents (eg:
microcrystalline cellulose) are occasionally referred to as dry binders because of the high degree of

Description tablet strength they impart to the final compressed tablet dosage form.

Physical Properties: The primary physical properties relevant to tablet/capsule diluents are those
Functional Mechanism properties that can have a direct effect on diluent and formulation performance. These include: (1)
particle size and size distribution, (2) particle shape, (3) bulk / tapped / true density, (4)
crystallinity, (5) moisture content, (6) specific surface area, (7) powder flow, (8) solubility and (9)
Physical Properties compaction properties for tablet dosage forms.

Chemical Properties Chemical Properties: Tablet diluents comprise a large and diverse group of materials that include
inorganics (eg: dibasic calcium phosphate, calcium carbonate), single component organic materials
(eg: lactose monohydrate, mannitol) and multicomponent or complex organics (eg:
General Chapters microcrystalline cellulose, starch). They may be soluble or insoluble in water, and they may be
neutral, acidic or alkaline in nature. These chemical properties need to be considered in selecting
diluents that will not negatively affect active ingredient physical or chemical stability and
Other Information performance. Appropriate selection of excipients with desirable physical and chemical properties
can enhance the physical and chemical stability as well as the performance of the active ingredient.
The detailed composition of an excipient may be important as excipient function may be
influenced by the presence of minor concomitant components that are essential for proper
performance. The presence of undesirable components (e.g. heavy metals, peroxides) may also
need to be controlled to assure adequate dosage form stability and performance.

General Chapters: The following General Chapters may be useful in developing tests and
specifications to assure consistent excipient performance: <616> Bulk and Tapped Density, <699>
Density, <695> Crystallinity, <696> Crystallinity Determination by Solution Calorimetry, <731>
Loss on Drying, <921> Water Determination, <776> Optical Microscopy, <786> Particle Size
Distribution Estimation by Analytical Sieving, <429> Light Diffraction Measurement of Particle
Size, <811> Powder Fineness, <846> Specific Surface Area, <1174> Powder Flow.

Excipient Performance <1059> Introduction

Typically, excipients are manufactured and supplied

to comply with compendial standards.
dosage forms development, manufacture, and
performance depends heavily upon the physical and
chemical properties of excipients.
The successful manufacture of a robust product
requires the use of well-defined excipients and
processes that together yield a consistent product.
 Excipient Performance <1059>
Introduction

An excipient may have very different functional purposes

(eg: diluent, lubricant) and required performance
characteristics (eg: particle size, size distribution, surface
area) depending on its use in a formulation, manufacturing
process, and dosage form.
The critical excipient properties that can influence dosage
form manufacturing, performance or stability should be
evaluated and controlled to ensure consistent product
performance.
Not all critical physical and chemical properties may be
identified in excipient monographs with compendial tests
and specifications.

Excipient Performance <1059>

Introduction

The Excipient Performance chapter provides an overview of

the key functional categories of excipients identified in
USPNF, along with those tests that may relate to excipient
performance.
It includes test methods that are not typically included in
compendial monographs.
Selection of tests and the identification of appropriate
specifications that are necessary to assure consistent and
reliable excipient performance can be made only with a
sound understanding of the function of the excipient, the
manufacturing process, and the performance requirements
of the dosage form.
 Functional Category:
Tablet or Capsule Diluents

Description: Components incorporated into tablet or capsule

dosage forms to increase dosage form volume or weight may
be considered diluents. Sometimes referred to as fillers, they
often comprise a significant proportion of the dosage form
and the quantity and type of diluent selected is often
dependent upon its physical and chemical properties.
Because the diluent may comprise a large portion of the
dosage form, successful and robust manufacturing and dosage
form performance is dependent upon the acquisition and
control of the critical attributes of the diluents.

Functional Category:
Tablet or Capsule Diluents

Functional Mechanism: Because tablet/capsule diluents often

comprise a large fraction of the dosage form, among the more
important functional roles is to impart desirable
manufacturing properties (eg: powder flow, tablet compaction
strength, wet granule formation, active ingredient
homogeneity) and performance (eg: content uniformity,
disintegration, dissolution, tablet integrity, friability, physical
and chemical stability).
 Functional Category:
Tablet or Capsule Diluents

Physical Properties: The primary physical and chemical

properties relevant to tablet/capsule diluents are those
properties that can have a direct effect on diluent and
formulation performance. These include: (1) particle size
and size distribution, (2) particle shape, (3) bulk / tapped /
true density, (4) crystallinity, (5) moisture content, (6)
specific surface area, and (7) powder flow.

Functional Category:
Tablet or Capsule Diluents

Chemical Properties: Tablet diluents comprise a large and

diverse group of materials that include inorganics (eg:
dibasic calcium phosphate, calcium carbonate), single
component organic materials (eg: lactose monohydrate,
mannitol) and multicomponent or complex organics (eg:
microcrystalline cellulose, starch). They may be soluble or
insoluble in water, and they may be neutral, acidic or
alkaline in nature. These chemical properties need to be
considered in selecting diluents that will not negatively
affect active ingredient physical or chemical stability and
performance. In fact, appropriate selection of excipients
with desirable physicochemical properties can enhance
physical and chemical stability and performance.
 Functional Category:
Tablet or Capsule Diluents

General Chapters:
Bulk and Tapped Density <616>,
Density <699>,
Crystallinity <695>,
Crystallinity Determination by Solution Calorimetry <696>,
Loss on Drying <731>,
Water Determination <921>,
Optical Microscopy <776>,
Particle Size Distribution Estimation by Analytical Sieving <786>,
Light Diffraction Measurement of Particle Size <429>,
Powder Fineness <811>,
Specific Surface Area <846>,
Powder Flow <1174>.

Functional Category: Lubricants

General Chapters:
<846> Specific Surface Area,
<941> X-ray Diffraction,
<731> Loss on Drying,
<429> Light Diffraction Measurement of Particle Size,
<786> Particle Size Distribution Estimation by Analytical
Sieving,
<921> Water Determination,
<695> Crystallinity,
< 696> Crystallinity Determination by Solution Calorimetry,
<776> Optical Microscopy.
Contributors to the Excipient Performance
Chapter

Eric Schmitt Catherine Sheehan

Joseph Creekmore Bob Lafaver
Zak Chowhan
Lawrence Block
Harry Brittain
Richard Wendt
Xiaorong He
Steven Edelmuth
Bruno Hancock
Gregory Amidon
Garnet Peck
Richard (Chris) Moreton
Kenneth Alexander
Gary Ewing
Rajeev Gokhale
John Lipari
Matthew Mullarney
Jasmin Musakhanian
Sandeep Nema
Changquan Calvin
Ranga Velagaleti
Lee Kirsch

The End