NF IVIV

Question 0

Standardised conditions 3

Answer 0

Temperature
Solid-liquid interface
Media composition

Question 1

Biopharmacuetical def of dissolution

Answer 1

amount of active ingredient (in solid dosage form) the is dissolved per unit time (under standardised conditions)…

Question 2

Two main purposes of dissolution testing

Answer 2

QC and predict PK in vivo

Question 3

Dissolution QC purposes 4

Answer 3

Batch reproducibility
Shelf life stability
Batch release
Assures changes to manufacturing process do not impact performance (requires BE study)

Question 4

Predict PK in vivo purposes

Answer 4

Guide formulation selection, design and scale-up during

development

– set specifications for API form and particle size

– Guide bioequivalence strategy

– Biowaiver

– In vitro-in vivo correlations

Question 5

The main factors influencing dissolution

Answer 5

Testing Conditions
Drug Formulation
Drug properties

Question 6

Condition factors influencing dissolution 3

Answer 6

Apparatus
Method parameters
Dissolution medium

Question 7

Formulation actors influencing dissolution 3

Answer 7

Compositon
Manufacturing process
M/r?

Question 8

Drug properties influencing dissolution5

Answer 8

Solubility in dissolution medium
Hydrophilic/hydrophobic
Shape/size
Crystalline/amorphous
Polymorphs present?

Question 9

Phycoco,logical conditions affecting dissolution

Answer 9

Properties of GI fluids (composition, pH)

� Gastric emptying (especially for non

disintegrating systems)

� Intestinal transit time

� GI motility and hydrodynamic patterns

� GI enzymes

� Fasted state/ Fed

Question 10

The media considerations

Answer 10

Buffers
Media proposed by pharmacopeia
Bio relevent media

Question 11

Hydrodynic conisidrations 5

Answer 11

Design if apparatus
Agitation intensity
Flow volume
Viscosity if medium
Formulation/drug location

Question 12

pH of fasted/fed small intestine

Answer 12

Fasted 6.8

Fed 5

Question 13

Bio relevant media types

Answer 13

Milk (fed stomach)

Fasted/fed state simulated gastric/intestinal/colonic fluid

Question 14

Two closed testing apparatus

Answer 14

USP apparatus I (rotating basket)

USP apparatus II (rotating paddle)

Question 15

Advantages of closed system ap 3

Answer 15

Simple
Robust
Adequately standardised
(Per infant incubation of dosage form in the SAME medium)

Question 16

Disadvantages of closed app 3

Answer 16

Homogenising
Dispersion
agglomeration

Question 17

Open system appparatus

Answer 17

USP AP III (cylinder bio-dis)

USP AP IV (flow through cell)

Question 18

Advantages of open systems 3

Answer 18

Multiple pH levels/sequential changes
Residence time in GI
Hydrodynamics in GI

Question 19

Ap IV can be used for

Answer 19

Specific dosage forms

Multi particulate or suspensions

Question 20

FDA definition of IVIVC

Answer 20

Mathematic model describing the relationship between in vitro property and relevant in vivo response

Generally:
In vitro: rate/extent of dissolution/release
In vivo: plasma drug conc/amount absorbed

Question 21

BA

Answer 21

Rate and extend to which an active drug is absorbed from the drug product and becomes available at the site of caution

Question 22

BE

Answer 22

Absence if significant difference in BA in pharmaceutical alternatives
(Administered at same molar dose + similar conditions)

Question 23

Which level can be used to justify changes

Answer 23

Level a

Question 24

What sort of change can be justified?

Answer 24

``` Manufacturing site Method Raw materials Minor formulation Strength ```

Question 25

Level a usually plots

Answer 25

Release v absorption

Question 26

Level b usually plots

Answer 26

Mean dissolution time V Mean residence time OR mean in vivo dissolution time

Question 27

Weakest correlation

Answer 27

Level c

Question 28

Level c usually plots

Answer 28

Dissolution time point Vs AUC tmax or Cmax

Question 29

Level c is a ... point relationship that .... reflect the entire shape of the curve

Answer 29

Single point | Does not

Question 30

Levee c is useful.,.

Answer 30

In early stages of formulation development when pilot forms selected

Question 31

Multiple level c can be used to justify a biowaiver?

Answer 31

Yes

Question 32

Multiple level c relates

Answer 32

One or more PK parameters to amount dissolved at several time points (at least three)

Question 33

Development of level a correlation

Answer 33

1 develop formulations with different release rates 2 perform in vivo dissolution studies (determine in vivo plasma concentration profiles) 3 estimate absorption time course for each 4 establish model between IVIV variables 5 predict plasma concentration using model

Question 34

How to determine the internal predictability?

Answer 34

Use IVIVC to predict each formulations plasma concentration | Compare observed and predicted using % predicted error

Question 35

Ideal %PE

Answer 35

<15%

Question 36

Equation for %PE

Answer 36

%PE = (AUCobeserved - AUCpredicted/AUCobservered) x100

Question 37

For external predictability PE must be

Answer 37

<10

Question 38

5 applications of IVIVC

Answer 38

•in place of additional bioavailability studies • assist in validating or setting dissolution specifications (based on the performance of the biobatch in-vivo) • Biowaiver - new formulation (the mechanism of drug release should remain the same;) • Biowaivers - manufacturing site, equipment, manufacturing process, and formulation composition. • IVIVC: reduce the number of human studies during the formulation development, shortens time, economizes the resources and leads to improved product quality

Question 39

Limitations

Answer 39

first-pass metabolism in the GI tract Site-dependent absorption • absorption rate-limited * food effects, disease state, healthy volunteers * inter- and intra-subject variability

Question 40

Bio classes where IVIVC expected

Answer 40

I (high high) - if dissolution is rate limiting step | II (high perm, low sol)