Module 4 Dissolution method assessment – IVIVC(R).pdf

USP’s Perspective on Drug Product

USP s Perspective on Drug Product

Performance Test

Definitions

•

Biopharmaceutics

– the science that examines the interrelationship of the

physicochemical properties of the drug, dosage form and the route of administration on the rate and extent of systemic drug absorption

absorption

– based on in vitro and in vivo studies

•

In vitro–in vivo correlation, IVIVC

t bli h t f ti l l ti hi b t bi l i l – establishment of a rational relationship between a biological

property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage formg

In Vitro – In Vivo Correlation

• Early practice was to develop dissolution requirements based on the in vitro performance of clinically successful formulationsp y

• Similarity in dissolution behavior has long been sought from the

perspectives of both bioavailability and quality control considerations

• The goal of the pharmaceutical scientist is to find a relationship between an in vitro characteristic of a dosage form and its in vivo performance

<1088> - In Vitro In Vivo Evaluation of Dosage Forms

• In Vitro evaluation

i di t l

– immediate release – modified release • In Vivo evaluation

– Characterization of Drug Substance properties • Physicochemical

• PharmacokineticPharmacokinetic • Disposition

• Pharmacodynamic

Characterization of Dosage Form properties – Characterization of Dosage Form properties

<1088> - In Vitro - In Vivo Evaluation of Dosage Forms

• In Vitro-In Vivo Correlations

C l ti L l

– Correlation Levels

– Developing a Correlation

• Establishment of Dissolution Specification Ranges – Convolution

In Vitro – In Vivo Correlation?

Oral Bioavailability

F

= F

* F

* F

= F

* (1 - E

) * (1 – E

)

• F_abs - fraction of drug absorbed in the system

• F – fraction of the drug absorbed which is not eliminatedF_g fraction of the drug absorbed which is not eliminated through the gut

Parameters to be Correlated

• In vivo taken form human PK-studies

O l i f ki ti b

– Overlapping of kinetic sub-processes

– Apparent in vivo dissolution needs to be deconvoluted • at least distribution and elimination taken into

account

In Vivo

Parameters to be Correlated

• In vitro taken from dissolution experiments

E i t l d i d t i i d t

– Experimental design determines primary data

• closed models (paddle) provide cumulative profiles • Open models (flow-through cell) provide fractionated

profiles

In Vitro – In Vivo Correlation

• The biological properties most commonly used are one or more pharmacokinetic parameters obtained following the more pharmacokinetic parameters obtained following the administration of the dosage form

– AUC C

– Cmax

• The physicochemical property most commonly used is a dosage form's in vitro dissolution behavior

– % drug released under a given set of conditions

Determining the Fraction Absorbed

• Model dependent methods

– Wagner Nelson – Loo-Riegelman

• Model independent methods

In Vivo

IVIVC Correlation Levels according to Chapter <1088>

• Level A

Hi h t t f l ti

– Highest category of correlation

– Represents a point-to-point relationship between in vitro dissolution and the in vivo input rate of the drug from the dosage form

IVIVC Correlation Levels

• Level A – Advantages:

– A point-to-point correlation is developedA point to point correlation is developed

• All in vitro dissolution data and all the in vivo plasma drug concentration profile data are used

An in vitro dissolution curve can serve as a surrogate for in vivo – An in vitro dissolution curve can serve as a surrogate for in vivo

performance

• A change in manufacturing site, method of manufacture, raw material supplies minor formulation modification and even material supplies, minor formulation modification, and even product strength using the same formulation can be justified without the need for additional human studies

A truly meaningful (in vivo indicating) quality control procedure – A truly meaningful (in vivo indicating) quality control procedure,

Level A IVIVC Example

Dissolution profiles for two

diff t t bl t f l ti

Bioavailability from two

different tablet formulations

8

L

different tablet formulations different tablet formulations

6 8 ra ti on ( ng/ m L Formulation 1 Formulation 2 60 80 100 eased (% ) Formulation 1 Formulation 2 2 4 m a C o n cen tr 20 40 60 rc e nt dr ug r e l 0

0 2 4 6 8 10 21

Pl

as

m

0

0 1 2 3 4

Pe

IVIVC Correlation Levels

• Level B

Utili th i i l f t ti ti l t l i

– Utilizes the principles of statistical moment analysis

– Compares the mean in vitro dissolution time, MDT, to either the mean residence time, MRT (mean time that the drug molecules

t i th b d ) th i i di l ti ti

stay in the body), or the mean in vivo dissolution time – Utilizes all of the in vitro and in vivo data

– Not considered to be a point-to-point correlation because it does not reflect the actual in vivo plasma level curve

– Cannot rely upon a Level B correlation alone to justify

formulation modification, manufacturing site change, excipient source change, batch-to-batch quality, etc.

Level B Correlation

In Vitro - In Vivo Correlation of Mean Dissolution Times

2 5 2 2.5 1 1.5 Tvi v o [h] 0.5 MD T R R T1 T1 -0.5

0 T2T2

IVIVC Correlation Levels

• Level C

R l t di l ti ti i t (t50% t90% t ) t

– Relates one dissolution time point (t50%, t90%, etc.) to one pharmacokinetic parameter such as AUC, Cmax, or Tmax – Single point correlation

– Does not reflect the complete shape of the plasma level, which is the critical factor that defines the performance of finished drug products

– Has limited usefulness in predicting in vivo drug performance – Cannot be used to justify formulation modification,

Level C Correlation

Level C Correlation

In Vitro – In Vivo Correlation

• Immediate release and rapidly dissolving drug products

Diffi lt t bt i IVIVC d t l ti hi f di l ti – Difficult to obtain an IVIVC due to relationship of dissolution

and absorption in vivo

• Rapid dissolution - may only obtain one or two dissolution l ithi h t ti i d ( <30 i ) l

samples within short time period (e.g.; <30mins) unless

e.g.; profiling with the use of fiber-optics

In Vitro – In Vivo Correlation

• Extended release drug products

IVIVC k b t f ER d d t h i i

– IVIVC works best for ER drug products where in vivo drug release is rate limiting step by design

– Need to compare at least two formulation variables to set specification ranges

• More rapid drug release • Less rapid drug release

• Alternatively target vs. upper/lower side batches

In Vitro – In Vivo Correlation

• IVIVC is drug formulation dependent under specificIVIVC is drug formulation dependent under specific dissolution conditions

• Generic drug products containing same pharmaceutical • Generic drug products containing same pharmaceutical

Lack of In Vitro-In Vivo Correlation

• May not be able to obtain an IVIVC for your drug product where :

S t i d b ti i th t li iti t f b ti

– Systemic drug absorption is the rate-limiting step for absorption • Variations in drug dissolution/release are not reflected in

variations in drug absorption

• Dissolution is not rate limiting step

– Drug dissolution test is not discriminatingg g

Lack of In Vitro-In Vivo Correlation

• Bioindicative dissolution method needed

Dissolution media do not reflect physiological conditions in the GI • Dissolution media do not reflect physiological conditions in the GI

tract

– pH in different regions of GI tract

C f G

– Contents of GI tract • Liquids and solids • Fed or fasted state

• Normal digestive enzymes • Water content

• Other factors affecting systemic drug absorptionOther factors affecting systemic drug absorption – GI transit time