pharmaceutical nomenclature issues and challenges moheb m. nasr, ph.d. acting director office of new...

Pharmaceutical NomenclatureIssues and challenges

Moheb M. Nasr, Ph.D.Acting Director

Office of New Drug Chemistry (ONDC)OPS, CDER, FDA

Advisory Committee for Pharmaceutical Sciences (ACPS)

October 22, 2003

ACPS, October 22, 2003 2

Pharmaceutical Nomenclature Issues and

challenges

FDA Perspective

Orally Disintegrating Tablets (ODT)

Topical Dosage Form Classification - an

Update

Committee Discussions

Dan Boring, R.Ph.,Ph.D.

Frank Holcombe, Jr., Ph.D.

Lucinda Buhse, Ph.D.


Issues and challenges

z Impact on regulatory decisions, marketing, drug development, and the public

z Nomenclature development (scientific and regulatory challenges)y How to do it right the first time?y Is a new dosage form needed or is it just a minor

modification in an existing dosage form that can be handled by labeling?

y How to establish definitions and criteria for new dosage forms?

y Do we need to have that many dosage forms?


Issues and challenges

z Coordination with different organizations and stakeholders

z Definitions (descriptive and quantifiable attributes)

z Refinement and/or replacement of older dosage forms

z Pharmaceutical equivalence issues


Questions for ACPS

1. What are the factors that the Agency should consider in determining (a) whether a new dosage form name is warranted and (b) how such a dosage form should be defined?

2. Is it reasonable or useful to include a quantifiable attribute when defining a dosage form or distinguishing between closely related dosage forms where appropriate? Can such an approach be viewed as too arbitrary in some cases and too rigid in other cases?


Questions for ACPS

3. Is the proposed criterion, i.e., an in vitro disintegration time of less than 60 seconds, reasonable for defining an orally disintegrating tablet?

4. Has the update on topical dosage forms presented today addressed the questions/comments raised by the ACPS at the March 2003 meeting?

FDA Perspective on Dosage Form Nomenclature

Dr. Dan Boring, R.Ph., Ph.D.Review Chemist; Labeling Expert

ONDC, OPS


Nomenclature ofPharmaceutical Dosage

Forms

z Issues and challengesy Scientificy Regulatoryy Marketingy Legaly Healthcare providery Patient


What is an Established Name?

z The FD&C Act states “drug” only z Drug substance and/or drug product?z At CDER, an established name for both

drug substance and drug productz In general, an established name for a drug

product is:[(drug substance) (release characteristic)

(route of administration) (dosage form)]z Today’s focus is on dosage form


Definition ofa Pharmaceutical Drug

Product

z Drug Product is defined as a finished dosage form such as tablet, capsule or solution

z What is a dosage form?z A dosage form could be defined as the

physical form of a drug product at the point that it is introduced into the body, or, where final preparation is required before introduction into the body, the physical form of the drug product in the package that bears instructions for final preparation (private communication)

z Dosage forms are non-proprietary


Stakeholders

z Innovators y Research, development, marketing, legal

z FDAy OND, ONDC, ODS, COS, NSC

z USPy Expert Comm on Nomenclature and

Labelingz Healthcare providers and patients

y Not direct participants


FDA Nomenclature Issues

z New drugsy No USP monograph existsy Is a new name necessary? y Is it nomenclature or labeling?

z Generic drugsy Compliance with USP monograph?y Is a compendial name being developed?y Will name allow proper product selection for

substitution? y Name definition should not allow generic manufacturers

to substitute a new dosage form for a RLDz OTC drugs

y Product selection by patient


Nomenclature Assessment Factors

z Name must clearly identify the productz Name promotes accurate recognition without

risk of medication errorsz Name meets database, indexing and listing

needsz Name consistent with precedents (i.e.,

systems)z Name should not provide an advantage

through exclusive proprietary technology


Challenges

z Will a new name serve long-term needs?

z Is an older term still accurate?z Is a developing new term appropriate?z Can objective standards be developed

to define a new dosage form? z How should name development be

coordinated (innovator, FDA, USP)?z Global harmonization?z Implementation?


New Dosage Forms and Drug Delivery

Systems

z Orally disintegrating tablets

z Tablets for suspensionz Liposomesz Microspheresz Films?z Iontophoretic systems?

DefiningOrally Disintegrating

Tablets

Frank Holcombe, Jr. Ph.D.Associate Director for Chemistry

Office of Generic Drugs, OPS


Current Definitions of ODT

z FDA definition“A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”

z USP Stimuli proposal“A solid oral dosage form that disintegrates rapidly in the mouth”


Desired Characteristics and Benefits of ODT

z Oral disintegrationz Rapid disintegrationz No chewing or liquids necessaryz Provides improved route of

administration and increased compliance for certain patient populations


Issues Concerning ODT

z Limited experience – similarity of all initial products

z Expansion in product variations due to changes in y Technologiesy Formulationsy Additional drug productsy Target market population



z Format of suitable definition y Should address both the desired

characteristics and control of extent of product range

y Must address:x Method of administrationx Objective criteria (limits for

disintegration time)



z Disintegration evaluationy In-vivo testing (subjective,

objective)y In-vitro testing (objective)

x Variety of methodsx Results may be method dependent


In-vitro Testing Methods

z Applicant in-house methods (proprietary)

z FDA laboratory method (static)

z USP Chapter <701> Disintegration (dynamic)


In-vitro Testing Results

z Static: 1-78 secz Dynamic: 1-69 secz Most products in 1 to 30 sec rangez No data correlating in-vivo and in-

vitro disintegration times


In-vitro Testing ResultsDisintegration Time

0

10

20

30

40

50

60

70

80

90

1 2 3 4 6 7 8 9 10 11 12 13 16 17 18 19 20 21 22 23 27 29

Sample Number

Tim

e (

seco

nd

s)

DPA Method - Static

USP Method


FDA Proposal

z A revision of the ODT definition to include in-vitro disintegration method and acceptance criteria (USP <701>, < 60 sec) Objective:

To provide criteria (based on original expectations) for distinguishing orally disintegrating tablets from other tablet forms

Topical Dosage Form Classification – an Update

Lucinda Buhse, Ph.D. Acting Director

Division of Pharmaceutical AnalysisOffice of Testing and Research, OPS


Decision Tree on Topical Dosage Form Nomenclature(ACPS, March 2003)

GelYes

Is itan emulsion in

a liquid preparation oran emulsion or suspension

in a semisolidpreparation?

Yes

A topicaldosage form

for dermatologicalapplication

Yes toboth

Yes

Doesit contain

> 50% of volatilesas measured by

LODc?

No

No

Yes

Is it apourable liquid

with a viscosity of 30,000 cpsd?

Lotion

Doesit contain

sufficientb quantitiesof a gelling agent to

form a 3Dmatrix?

Paste

Doesit contain

a large proportion(20-50%) of

dispersedsolids?

No Yes

No

Does itcontain (1) 50

of hydrocarbons orPEGe as the vehicle and(2) < 20% of volatiles

as measured byLODc?

Ointment

Cream

No toeitheror both

Solution,aerosol, powder,or suspensiona

No


Advisory Committee Input

z No need to include appearance and feel (e.g., greasy, non-greasy)

z Definitions should be based on the vehiclez Ointments and suspensions could be classified as

lotions (an overused term)z Do not make cream a default definition and do not

separate creams using hydrophilic-vs-hydrophobicz Use detailed rheological evaluation (e.g., yield

values) to distinguish gels and/or lotions from creams

z Reconsider criteria used to classify gels


CDER Activities

z Evaluation of ACPS inputz Consultations with Dr. Arthur Kibbez Analysis of liquid/semi-solid

borderline products based on more extensive rheological evaluation

z Examination of optical properties and compositions of gels


05

101520253035404550

0 200 400 600 800 1000 1200 1400

Shear Stress (D/cm2)

Shea

r Rat

e(1/

sec)

Rheological Evaluation

Sample Yield Value(D/cm2)

1 5029 9062 12561 16036 19550 20051 525 4 60032 660

Con

form

s to

co

ntai

ner

Doe

s no

t con

form

to

con

tain

er


Decision Tree on Topical Dosage Form Nomenclature10/14/03

Is iteither a liquida

(as supplied andduring use) or a

semisolidb?

Yes

A topical dosage form fordermatological application

Yes

Doesit contain 50%

of volatilesd?Paste

Does itcontain a large

proportion (20-50%)of dispersed

solids?

No Yes

No

No

Yes toboth

(2)

(1)Gel

Doesit contain

(1) 50% ofhydrocarbons, waxes,or PEGf as the vehicle

and (2) 20% ofvolatilesd?

Ointment

Cream

No to eitheror both

Is it(1) a liquida or (2)

a semisolidb?

(2)(3)

Aerosol orpowder

Lotion

Suspension

Is it(1) clear and

homogeneous, or isit (2) an emulsionc or (3)

a liquid containingundisolved

solids?

(2)(1)

Solution

(1)

Is it(1) a solution or

colloidal dispersione

stiffened with agelling agent, or (2)

an emulsionc?


Questions for ACPS

1.What are the factors that the Agency should consider in determining (a) whether a new dosage form name is warranted and (b) how such a dosage form should be defined?

2. Is it reasonable or useful to include a quantifiable attribute when defining a dosage form or distinguishing between closely related dosage forms where appropriate? Can such an approach be viewed as too arbitrary in some cases and too rigid in other cases?


Questions for ACPS

3. Is the proposed criterion, i.e., an in vitro disintegration time of less than 60 seconds, reasonable for defining an orally disintegrating tablet?

4. Has the update on topical dosage forms presented today addressed the questions/comments raised by the ACPS at the March 2003 meeting?

pharmaceutical nomenclature issues and challenges moheb m. nasr, ph.d. acting director office of new...

Documents

dosage form slide

dosage form nomenclature

finished dosage form

existing dosage form

new dosage forms

topical dosage forms

related dosage forms

solution z