european pharmacopoeia perspective on functionality...

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 Relatesto Performance and Functionality

USP Excipient Performance Chapter <1059>

Presented by Gregory E. AmidonChair, Excipients General Chapters

Outline

Overview/History of Excipient Performance TestingRegulatory Interest in Excipient Quality and PerformanceFunctionality versus PerformanceExcipient Performance Chapter <1059>Functionality Related Characteristics

Twenty Years of Functionality, Physical Testing, and Excipient Performance

1990-1995 ExcipientsSubcommitteeZak Chowhan, ChairRalph ShangrawGarnet PeckGeorge ZografiGregory E. Amidon

Advisory Panel on Physical Test

Methods (1991-5)

Gregory E. Amidon, ChairGarnet PeckDavid GrantKeith MarshallMichael BergrenZak ChowhanShigiru ItaiHans Leuenberger

1995-2000 ExcipientsSubcommitteeGregory E. Amidon, ChairDale E. WursterGarnet PeckLarry AugsburgerHarry BrittainDavid FoxStephen Byrn

Advisory PanelMembersDavid GrantKeith MarshallMichael BergrenShigiru Itai

2000-2005 Expert Committee on ExcipientTestingGregory E. Amidon, ChairDale E. Wurster, Vice ChairRichard MeuryChris MoretonDavid GrantSteven HoagRajSuryanarayanan

2005-2010 Expert Committee on Excipient Test MethodsGregory E. Amidon, ChairGarnet Peck, Vice ChairDale E. WursterRichard MeuryHarry BrittainDavid GrantSteven HoagEric Schmitt

Excipients General Chapters Committee2005-2010

Gregory E. Amidon, Chair Univ. of Michigan.Garnet Peck, Vice Chair Purdue Univ.Dale E. Wurster Univ. of IowaRichard Meury Eli LillySteven Hoag Univ. of MarylandEric 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).


“Control of the physical characteristics of the excipientsis 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 excipientsand 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.


“For an excipient, conformance to compendialspecifications 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 excipientare 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), 975–999.

A Classic Example (Magnesium Stearate)

Different Suppliers

Ref: Dansereau, R.; Peck, G.E. Drug Dev. Ind. Pharm. 1987, 13 (6), 975–999.

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 Monographs1Catherine 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; ChangquanSun; 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

INTRODUCTIONTABLETS AND CAPSULESORAL LIQUIDSSEMISOLIDS, TOPICALS AND SUPPOSITORIESAEROSOLSPARENTERALSAEROSOLS

Excipient Performance Chapter <1059> Outline

INTRODUCTIONTABLETS AND CAPSULES

DiluentBinderDisintegrantLubricantGlidant and/or Anticaking AgentColoring AgentCapsule ShellCoating AgentPlasticizer

ORAL LIQUIDSpH modifier (acidifying/alkalizing/buffering agent)SolubilizersAntimicrobial PreservativeChelating and/or Complexing AgentAntioxidantSweetening Agent

Excipient Performance Chapter Outline

SEMISOLIDS, TOPICALS AND SUPPOSITORIESSuppository BaseSuspending and/or Viscosity‐increasing AgentOintment BaseStiffening AgentEmollient

PARENTERALSPharmaceutical WaterDiluentTonicity Agent

AEROSOLSPropellant

Outline of Excipient Performance Sections

Heading Content of Section

Description Describe general purpose and use of the functional category

Functional Mechanism

Describe the mechanisms by which the 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

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

Physical Properties: The primary physical 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, (7) powder flow, (8) solubility and (9) compaction properties for tablet dosage forms.

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. 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.

Example Section

Functional Category

Description

Functional Mechanism

Physical Properties

Chemical Properties

General Chapters

Other Information

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.

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.


The Excipient Performance chapter provides an overview of the key functional categories of excipients identified in USP–NF, along with those tests that may relate to excipientperformance. 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 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).


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.


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 excipientswith desirable physicochemical properties can enhance physical and chemical stability and performance.


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 SchmittJoseph CreekmoreZak ChowhanLawrence BlockHarry BrittainRichard WendtXiaorong HeSteven EdelmuthBruno HancockGregory AmidonGarnet PeckRichard (Chris) MoretonKenneth AlexanderGary EwingRajeev GokhaleJohn LipariMatthew MullarneyJasmin MusakhanianSandeep NemaChangquan CalvinRanga VelagaletiLee Kirsch

Catherine SheehanBob Lafaver

The End

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