Ajaz S. Hussain, Ph.D.Office of Pharmaceutical Sciences

CDER, FDA17 September 2003

Quality by Design: Next Steps to Realize Opportunities?

Outline• “Quality by Design” (QbD)

– What is QbD from a pharmaceutical science perspective?

– How is/should QbD be achieved?– When is/should QbD achieved?– How is/should level of QbD be evaluate and

measured?– How should QbD communicated?– What is the relationship between QbD and Risk?– What are/should be the regulatory benefits of QbD?– What steps should FDA take to realize the benefits

of QbD?

What is QbD from a pharmaceutical science

perspective?

• Traditional– Dosage form

• Immediate release– Direct compression– Wet granulation– Dry granulation

• Buccal tablets• Sub-lingual tablets• Capsules

– Hard gelatin– Soft gelatin

Product Design

Process Design

Design features of these conventional products and processes have essentially been defined over the last several decades and toady we often do not consider these as a “design” issue. Thinking or rethinking in terms of Quality by Design offers significant opportunities.

“Dosage form Design”

• “A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance.”– DOSAGE FORM DESIGN: A PHYSICOCHEMICAL

APPROACH. Michael B. Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.), Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington, Kentucky, U.S.A.)

MODERN TABLET FORMULATION DESIGN AND MANUFACTURE

Larry L. Augsburger and Mark J. Zellhofer • “Tablet dosage forms have to satisfy a unique design

compromise. The desired properties of rapid or controlled disintegration and dissolution of the primary constituent particles must be balanced with the manufacturability and esthetics of a solid compact resistant to mechanical attrition.”

• “The objective of preformulation studies is to develop a portfolio of information about the drug substance to serve as a set of parameters against which detailed formulation design can be carried out. Preformulation investigations are designed to identify those physicochemical properties of drug substances and excipients that may influence the formulation design, method of manufacture, and pharmacokinetic-biopharmaceutical properties of the resulting product.”

Design Features: TABLET FORMULATION

Larry L. Augsburger and Mark J. Zellhofer

• Optimal drug dissolution and, hence, availability from the dosage form for absorption consistent with intended use (i.e., immediate or extended release).

• Accuracy and uniformity of drug content.• Stability, including the stability of the drug substance,

the overall tablet formulation, disintegration, and the rate and extent of drug dissolution from the tablet for an extended period.

• Patient acceptability. As much as possible, the finished product should have an attractive appearance, including color, size, taste, etc., as applicable, in order to maximize patent acceptability and encourage compliance with the prescribed dosing regimen.

• Manufacturability. The formulation design should allow for the efficient, cost-effective, practical production of the required batches.

Achieving Quality by Design?

IntegrityUniformity

Weight Control

In vitroDissolution

ChemicalPurity

API, Excipients, Manufacturing Process

PharmaceuticsProfile

API Particle Size

API Salt Selection

ChemicalCompatibility

DegradationPathway

Prediction

Material PropertyCharacterization

Process Simulation

Design

Christopher Sinko, Ph.D.Christopher Sinko, Ph.D.Pfizer Global Research & DevelopmentPfizer Global Research & Development

Example Attribute: Bioavailability• Objective: Maximize & reproducible

– Absorption mechanism (passive, active, site specific)

– Physico-chemical attributes (solubility, dissolution rate, salt selection, particle size, morphic form, stability of drug substance ….)

– Formulation design (disintegrating agent, wetting agent, solubilizer, pH modifiers, absorption enhancers,..)

– Process design (wet/dry granulation, lubrication, compaction,….)

– Specifications and controls on all critical variables

BA Data from pre-CAN andExp Toxicology Studies

Simulations Using DissolutionAbsorption Model**

BA is expected tobe significantlyPS Dependent**

Tablet Content Uniformity Model

BA is expected to be

PS Independent**

In vivo studies in animals

PS Analysis

Drug Substance

Delump(e.g. pass

through20 mesh)

Is desired PS readily achievable?

Consistent with Model ?

NoYes

ImproveModel

No

Yes

Recommend Appropriate PS

In-process Sample

Done

PS Reduction** At expected dosing range in humans integrating data from pre-clinical studies.

Christopher Sinko, Ph.D.Christopher Sinko, Ph.D.Pfizer Global Research & Pfizer Global Research & DevelopmentDevelopment

Formulation & Process Design

• Starting at small scale – pilot – clinical/prod.• Need tools to screen/evaluate various design

prototypes– In Vitro Dissolution Test

• bio-studies to ensure relevance of in vitro dissolution test• Relevance based on physico-chemical aspects of the drug

and formulation

• Observations (personal)– Often a dissolution test is used to screen/evaluate

experimental formulations without sufficient considerations or verification of its in vivo predictability (relevance)

August 2000 FDA Guidance

BCS Applications

PRE-CLINICALPHASE IPHASE IIPHASE III

CLINICAL-TRIAL-FORMULATION

MARKETEDFORMULATION

POST-APPROVALCHANGES

MULTI-SOURCEPRODUCTS

POST-APPROVALCHANGES

INITIAL CLASSIFICATIONCLASS CONFIRMEDPRODUCT CONFORMS TOBCS SPECIFICATION

EQUIVALENCE IN VITRO

EQUIVALENCE IN VITRO - LEVEL 3

EQUIVALENCE IN VITRO

EQUIVALENCE IN VITRO - LEVEL 3

Dissolution Test & Bioequivalence: Risk Assessment

Dissolutiongenerally

“over-discriminating”

Dissolution failsto signal

bio-in-equi~ 30% (?)

NO YES

NO

YES

Bio

eq

uiv

ale

nt

Dissolution Specification

Why?

False Positives and False Negatives!!!

15 min 30 min 45 min AUC CmaxRef 95 96 98 100 100B 96 97 97 104 95C 62 84 92 84 55D 82 94 95 88 87E 103 103 103 112 120F 13 35 53 100 102

Test/Ref. Mean

I. J. MacGilvery. Bioequivalence: A Canadian Regulatory Perspective. In, Pharmaceutical Bioequivalence. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York, (1992)).

Appropriate Specification or “Over-discrimination”

All Bioequivalent to RLDDISSOLUTION OF GENERIC & RESEARCH TABLETS

TIME IN MINUTES

0 5 10 15 20 25 30 35

% D

RU

G R

EL

EA

SE

D

0

10

20

30

40

50

60

70

80

90

100

110

ANDA1ANDA2ANDA3ANDA4ANDA5

ANDA6ANDA7ANDA8ANDA874-217 UMAB-SLOWUMAB-MEDIUMUMAB-FAST

Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate

Acceptance Criteria

0 10 20 30 40 50

% D

rug

Dis

solv

ed

0102030405060708090

100110

USP Specification

Product A

Product B

Time in Minutes

Product B was notbioequivalent to

Product A

Log(AUCinf): CI 94.6 - 123.6

Log(AUC): CI 89.1 - 130.0

Cmax: CI 105.3 - 164.2

(weak acid, rapid dissolution in SIF)

Time in Hours

0 1 2 3 4 5 6

Dru

g C

on

cen

trat

ion

in

Pla

sm

a (n

g/m

l)

0

200

400

600

800

1000

1200

1400

1600

1800Capsule (Ref.)

Tablet 1(wet-granulation - starch)

Tablet 2(direct compression -

calcium phosphate)

USP Paddle 50rpm, Q 70% in 30 min

Failure to Discriminate Between Bio-in-equivalent Products: Inappropriate Test Method?

NDA #X: Bioequivalent?• Drug X (100 mg dose, volume

required to dissolve the dose at pH 8, lowest solubility, is 230 ml, extent of absorption from a solution is 95%)

• Weak base exhibits a sharp decline in solubility with increasing pH above 3

• Clinical-trial formulation: Wet granulation, drug particle size (D50%) 80 microns, lactose MCC, starch, Mg-stearte, silicon dioxide. Tablet weight 250 mg. Dissolution in 0.1 N HCl 65% in 15 min and 100 % in 20 minutes. Disintegration time 10 minutes.

• The company wants to manufacture the product using direct compression.

• To-Be-Marketed formulation: Direct compression, drug particle size (D50%) 300 microns, dicalcium phosphate, MCC, Mg-stearate, silicon dioxide. Tablet weight 500 mg. Dissolution in 0.1 N HCl - 85% in 15 min., and 95% in 20 min. Disintegration 1 min.

• Clincal product exhibits poor dissolution in pH 7.4 media (about 30% in 60 minutes). Data for T-b-M not available.

Failure of Dissolution Tests to Signal Bio-in-equivalence

• Inappropriate “acceptance criteria”– One point specification

– Set “too late”

• Inappropriate test method– media composition (pH,..)

– media volume

– hydrodynamics

• Excipients affect drug absorption• Other reasons

aaps Annual Meeting 20

ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION

What specific test conditions and acceptance criteria are appropriate? [IR]

dissolution significantlyaffect BA?

Develop test conditions and acceptance distinguish batches with unacceptable BA

YES

NO

YES

NOYES

NO

Do changes informulation or

manufacturing variables affect dissolution?

Are these changes controlledby another procedure

and acceptancecriterion?

Adopt appropriate test conditionsand acceptance criteria without

regard to discriminating power, topass clinically acceptable batches.

Adopt test conditions and acceptance criteria which can distinguish

these changes. Generally, single point acceptance criteria are acceptable.

Average # of BE Studies: At a Major Pharmaceutical Company

mean ~ 24 mean ~ 7

In Vivo BE* for Justifying Changes During Development

Capsule Tablet(WG)

FilmCoat

SiteChange

Changein DrugManuf.

Solvent-Coat

SiteChange

Tablet(DC)

Multi-StrengthScale-up

Multi-Strength

BE Study

Failed BE

To-Be-Marketed

Approval

*Generally 3-6 clinical bioequivalence tests are conducted in a NDA

                              

Tablet Formulation

Is Dissolution Rate Limiting?

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0 4 8 12 16 20 24

Time

Con

cent

rati

on

Capsule

Solution

Metoprolol IR Tablets:In Vitro - In Vivo Relationship

TIME IN MINUTES

0 5 10 15 20 25 30 35

% D

RU

G R

ELE

ASED

01020304050

6070

8090

100110

Rapid

Slow

FDA-UMAB (931011)

RATIO (T/R) OF % DISSOLVED AT 10 MINUTES

0.2 0.4 0.6 0.8 1.0 1.2

AU

C, A

ND

Cm

ax R

ATIO

S (

T/R

)

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

SO

LUTIO

N

FDA-UMAB (931011)

AUC

Cmax

Metoprolol IR Tablets: Experimental & Simulation Data

RATIO (T/R) OF % DISSOLVED AT 10 MINUTES

0.2 0.4 0.6 0.8 1.0 1.2

AU

C,

AN

D C

ma

x R

AT

IOS

(T

/R)

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2AUC

Cmax

Plot 1 Regr

FD

A-U

MA

B (

931

011

)

SO

LU

TIO

N

T 8

5%

~

30

min

in v

itro

0.1 0.2 0.3 0.4 0.5

0.0

0.5

1.0

1.5

2.0

0.0

0.5

1.0

1.5

2.0

0.75 0.80

0.85

0.90

0.95

0.70 0.75

0.80 0.85

0.90

0.95

Mean Intestinal Transit Time = 3.33 h

Mean Intestinal Transit Time = 1.67 h85%

DISSOLUTION

TIME

(h)

Gastric Emptying Half-Time (h)

Cumulative Dissolution and Disintegration Data: Critical Formulation Variables

Time in Minutes

0 5 10 15 20 25 30 35

% D

ru

g D

issolv

ed

0

20

40

60

80

100

120

Corresponding Disintegration Time

Data

MCC(-)SSG(+)MgS(-)

MCC(-)SSG(+)[MgS(-)]

PARETO PLOT

DISINTEGRANT

DILUENT*DISINTEGRANT

OBSERVED DISSOLUTION

0 20 40 60 80 100

PR

ED

ICT

ED

DIS

SO

LU

TIO

N

0

20

40

60

80

100

Dissolution predominantly effected by disintegrant leveland by interaction terms involving disintegant and dilutent

and dilutent and mg stearate.

An hypothetical case study: Critical Formulation variables?

Unpublished Data from DPQR/CDER/FDA

What is QbD?

• Design decisions based on through formulation and process understanding as these relate to the intended use

• What is the relationship between QbD and Risk?– Within a given quality system and for a

product: inverse relationship between level of QbD and Risk

QbD Questions (Contd.)• How is/should QbD be achieved?

– In a structured manner guided by scientific information/knowledge gathered during pre-formulation, development, scale-up, and in production

• When is/should QbD achieved?– Ideally for clinical trial material (all major/critical aspects),

fine-tune over the life-cycle• How is/should level of QbD be evaluate and

measured?– Established relationships (preferably – quantitative

/mathematical) between product & process variables and quality attributes (as in draft PAT Guidance)

• How should QbD communicated?– As part of the original submission (e.g., CTD-Q; P2 –

Pharmaceutical Development) and/or– Post-approval (supplement or comparability

protocol)

QbD Questions (Contd.)

• What are/should be the regulatory benefits of QbD?

– Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance

– Risk-based regulatory approaches recognize• the level of scientific understanding of how

formulation and manufacturing process factors affect product quality and performance and

• the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product

– Example: Customized SUPAC [SUPAC –C]

What steps (is) should FDA (taking) take to realize the

benefits of QbD?

• Start to build elements of “Pharmaceutical Development” in all relevant guidance documents (e.g., Draft Drug Product Guidance)

• Support development of ICH guideline on “Pharmaceutical Development”

• Train FDA staff on how to evaluate the knowledge content of “Pharmaceutical Development Reports”

What steps (is) should FDA (taking) take to realize the

benefits of QbD?• While the ICH process on Pharmaceutical

Development is ongoing– Focus on SUPAC-C concept– Work with/within the draft Comparability

Protocol Guidance• Is this format too restrictive?

– In addition to Comparability Protocol concept develop additional guidance on SUPAC-C

• Appendix to Comparability Protocol?• Planned revisions of current SUPAC guidance?• Independent SUPAC-C guidance?

SUPAC-C: Quality Risk Classification (based on SUPAC and GAMP-4)

High

Medium

Low

Low

Med

ium

Hig

h

Risk LikelihoodIm

pact

on

Qu

alit

y

Level 3

Level 2

Level 1

Quality by design +Systems approach

Quality Risk Priority

3

2

1

Low

Med

ium

Hig

h

Probability of DetectionR

isk

Cla

ssif

icat

ion High

Medium

Low

Quality by design +Systems approach

Level of QbD: Metrics• Achievement of pre-determined product and process

performance characteristics that are adequate for the intended on every batch and in an established cycle time

• Performance characteristics are selected or developed through scientific studies – to identify target characteristics– of all relevant sources of variability in the target characteristics – to evaluate the effectiveness of testing/controls strategies to

mitigate the risk of variability• Metrics

– Right-first-time – Process Time/Cycle time – Ability to reliably predict impact of changes

“Quality by Design” (QbD)• What is QbD from a pharmaceutical science

perspective? • How is/should QbD be achieved?• When is/should QbD achieved?• How is/should level of QbD be evaluate and

measured?• How should QbD communicated?• What is the relationship between QbD and Risk?• What are/should be the regulatory benefits of QbD?• What steps should FDA take to realize the benefits

of QbD?