What Impact should ICH Q8 have on ICH Q6A Decision Trees?

Ajaz S. Hussain, Ph.D.

Deputy Director, OPS/CDER/FDA

Outline

• An overview of ICH Q6A dissolution decision trees– Relationship between disintegration and dissolution

test?– Mechanistic basis? Causal link?– Appropriate test conditions and acceptance criteria?

• How ICH Q8 may help improve regulatory decisions?– Case example #1 DOE– Case example #2 New technology

• Summary of an QbD approach

ICH Q6A: Decision Tree #7 (1)

Modified release?

High solubility?

Rapid dissolution?

Relationship betweenDisintegration - Dissolution?

No

Yes

Yes

Generally single-point dissolution acceptance criteria

with a lower limit

Generally disintegrationacceptance criteria with

an upper limit

Establish drug releaseacceptance criteria:

ER: Multiple time pointMR: Two stage, parallel

or sequential

Yes

No

No

No

Yes

Test – Test Empirical Relationship

1/Disintegration Time (min.)

0.04 0.06 0.08 0.10 0.12 0.14 0.16

% D

isso

lved

in 1

0 m

inut

es.

0

10

20

30

40

50

60

70

80

90

100

1/Disintegration Time (min.)

0.04 0.06 0.08 0.10 0.12 0.14 0.16

% D

isso

love

d in

15

min

utes

.

0

10

20

30

40

50

60

70

80

90

100

• Disintegration time (DT) vs. % Dissolved at 10 and 15 minutes

Disintegration - Dissolution Relationship: Issues

Total Dissolution = Ft + Fl + Fs + Fs*

Disintegration DisintegrationTime (DT)

TabletSurface (t)

LargeFragments (l)

SmallFragments (s)

Ft Fl Fs Fs*

After DTPrior to DT

10# screen

Fraction dissolved

Note: Disintegration and dissolution process in a dissolution apparatus may differ from that in a disintegration apparatus (different hydrodynamics and other conditions)

Mechanistic Understanding in ICHQ6A?

• For example – “Particle size distribution testing may also be proposed in place of dissolution testing when development studies demonstrate that particle size is the primary factor influencing dissolution; justification should be provided.”

• ICHQ6A 3.3.2.3 Parenteral Drug Products

• Mechanistic understanding – identification and scientific justification of causal physical or chemical relationships between pharmaceutical materials and/or process factors – Note – establishment of “correlation” between two

characteristics may not always be causal

7

ICH Q6A [EVENT] 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

NO

YES

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.

In absence of Pharmaceutical Development Information: Difficult to answer ….

• Do changes in formulation or manufacturing variables affect dissolution?– Are these changes controlled by another procedure

and acceptance criterion?

• Adopt test conditions and acceptance criteria which can distinguish these changes. – Generally, single point acceptance criteria are

acceptable. (tradition – risk based?)

• Discriminating test conditions? What should the test discriminate?

                              

Tablet Formulation

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

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(-)]

Drug M, IR Tablet

Pharmaceutical Development Information: Improves our ability to answer…

• Do changes in formulation or manufacturing variables affect dissolution? – Yes, formulation composition and excipient functionality &

variability; are these “critical”?

• Are these changes controlled by another procedure and acceptance criterion?– Raw material certificate of analysis and weighing before

charging – are these controls adequate?

• Adopt test conditions and acceptance criteria which can distinguish these changes. – Test does distinguish these changes at 10 or 15 minutes;

should the acceptance criterion be set at 10 minutes?

Need for a Comprehensive Control Strategy

Process Understanding

API

API SynthesisAPI

Mill/Blend

LOD

KEY:Green = strongYellow = moderateRed = weak

Solid = positiveDashed = negative

TotalImpurities

Blend Humidity ParticleSize

DryerPressure

NaOHAdded

API

Dissolution

Bulk Volume

MagnesiumStearate Attribute

Drug Product

MillingParameters

G.P. Migliaccio, FDA Science Forum 2005

Raw material variability: Certificate of analysis adequate?

NIR Differentiation of Hydration-magnesium stearate

G.P. Migliaccio, FDA Science Forum 2005

Percent Dissolved Plot

0

10

20

30

40

50

60

70

80

90

100

110

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10

Dissolution Time (Hours)

% o

f L

abel

Cla

im

D1-1D1-2D1-3D1-4D1-5D1-6

Vessel

DPA/FDAUnpublished data

Understanding and controlling critical variables

Controlling Dissolution Rate: Options

Drug Substance

Formulation

Process

Product NIRDissoTest

BioPK/PD

Dissolution = f (Ex1, Ex2, P1, P2, PS…)

Real Time Release(Stability?)

Stability

“Market Standard”

What should the acceptance criteria be?

• In the previous discussion we did not answer the question “should the acceptance criterion be set at 10 minutes?”

• In QbD framework a design specification in vivo) is declared upfront, its suitability for the intended use justified and product/process designed with adequate controls

Design Specification

• Current/Reactive: “dissolution significantlyaffect BA?”

• QbD/Proactive: “Dissolution in vivo not rate limiting by design” or is “X ±Y by design”– Dissolution in vivo not rate limiting by design, i.e., sufficiently

rapid such that blood levels from a tablet are essentially equivalent to that after administration of drug in a aqueous solution

• Highly soluble drugs (e.g., control of critical variables using conventional formulation and manufacturing unit operations)

• Low solubility drugs (e.g., novel technologies such as nanotechnology)

– BA/BE studies conducted during development would then be used to test a “design specification” hypothesis

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 24Time

Con

cen

trat

ion

CapsuleSolution

Theoretical & Experimental Justification

RATIO (T/R) OF % DISSOLVED AT 10 MINUTES(10 min selected for graphical clarity only)

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)

Drug M, IR Tablet

Pharm Res. 1999 Feb;16(2):272-80

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(-)]

Drug M, IR Tablet: For BA/BE what are the critical variables?What should the specification be? Is a routine QC dissolution test necessary?

??

All “BE”

Key Questions

• What is the intended use?• What design specification delivers it?

– IR tablet with rapid in vivo dissolution (~30 minutes)– What in vitro test system will be used for product development?– What is the in vitro acceptance criteria? (e.g., target 85% in 15

minutes and not slower than current regulatory standard of 85% in 30 minutes)

• How is the design specification justified?– Phase I, relative BA with aqueous solution as ref.

• What is the product design strategy?– Pre-formulation characterization – solubility, permeability,

stability, compatability,..particle size needed for rapid dissolution– IR Tablet with a “super disintegrant”

Key Questions

• What manufacturing science information is available to justify the design/selection of manufacturing process?

• What are the critical variables with respect to manufacture-ability, stability, bioavailability?

• What should be the regulatory specifications and control strategy to reliably deliver (state of control) the product quality and performance over the intend life-cycle of the commercial product?

In Vitro Acceptance Criteria: Product Optimization and also possibly for QC testing

• Operating characteristics?• Although the test involves

three stages, the behavior is dominated by the first and second stage.

• In the figure (right) it can be observed that when the mean value is Q-0.6*standard deviation (10%) and less, the probability of acceptance (Pa) is insignificant, and when the mean value is Q+0.6*standard deviation and more, the Pa is almost 1. Statistical Properties of the Dissolution Test of

USP. Carlos D. Saccone, Julio Tessore, Silvino A. Olivera, and Nora S. Meneces. Dissolution Technologies AUGUST 2004

Specifications - Standards and Continuous Improvement

CurrentRegulatoryAcceptance

RangeAlert

Action

OOSE.g., USP - Stage 2

Ensuring design specification are accepted as regulatory specifications

• Characterize dissolution variability in acceptable clinical lots (base on clinical S&E)– Clinical lot should be in the state of control (e.g., from

beginning to end of production, stratified sampling) with respect to critical variables (design specifications)

– Gauge R&R type study to characterize “total” variability

– Estimate of variability used to set “action” or “alert” limits within the design specification

– Design specification (test method, and acceptance criteria = current public standard) then can be the regulatory specification

Summary

• ICH Q8 has the potential to enhance utility of many aspects of ICH Q6A– Opportunity to convert the current “event” driven

(reactive) decision process to an hypothesis based decision process

– Design specifications – beginning with the end in mind – can focus attention on design process to exceed current regulatory standards or expectations without the need for such standards to be “tightened” based on process capability

– Improved confidence in critical variables, their control strategy and achieving a state of statistical process control provide an effective means for continuous improvement within a companies quality system