Bioequivalence 5

Question 1

What is the scientific framework for classifying drug substance based on?

Answer 1

aqueous solubility and intestinal permeability

Question 2

What does the biopharmaceutics classification system predict?

Answer 2

in vivo PK performance of drug products

Question 3

What are the factors that influence rate and extent of absorption?

Answer 3

aqueous solubility
dissolution rate
intestinal permeability
disintegration–>dissolution–>absorption

Question 4

What are the four BCS classes?

Answer 4

class I: high solubility, high permeability
class II: low solubility, high permeability
class III: high solubility, low permeability
class IV: low solubility, low permeability

Question 5

What is the BCS-based biowaiver applicable to?

Answer 5

immediate release
solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation

Question 6

What might BCS-based biowaivers be used for?

Answer 6

to substantiate in vivo BE
-comparison between products used during clinical development through commercialization
-post approval changes in formulation
-generic drug products

Question 7

What is solubility classification based on?

Answer 7

highest dose strength of IR product
-highly soluble when completely soluble in < 250 ml aqueous media over pH 1.2-6.8 at 37 C
-at least 3 pHs within this range, including buffers at pH 1.2, 4.5 and 6.8
-solubility at the pH of lowest solubility of the drug substance should be evaluated if it is within the specified pH range
-lowest measured solubility over the pH range of 1.2-6.8 will be used to classify the drug substance

Question 8

When can high permeability be concluded?

Answer 8

when the absolute bioavailability is > 85%

Question 9

What is another method to assess permeability?

Answer 9

in vitro methods using Caco-2 cells
-the results should be discussed in the context of available data on human PK

Question 10

Which drug is used as the standard for permeability?

Answer 10

metoprolol

Question 11

What is the extent of absorption for the four BCS classes?

Answer 11

class I: very good
class II: dissolution rate limited
class III: permeability rate limited
class IV: very poor

Question 12

Describe BCS class I.

Answer 12

well absorbed
F may be low due to 1st pass metabolism
rate limiting step is dissolution or gastric emptying
-gastric emptying rate depends on volume and motility
biowaiver probable

Question 13

Describe BCS class II.

Answer 13

absorption slower vs class I
in vivo dissolution is rate-controlling step
-dissolution profile determines concentration profile along the intestine for a greater time and absorption occurs over a longer time
drugs expected to have variable absorption
-many formulation and in vivo variables can affect dissolution profile
biowaiver unlikely

Question 14

Describe BCS class III.

Answer 14

permeability is the rate-controlling step
all of the excipients should be qualitatively the same and quantitatively similar
both the test product and reference product should display very rapid (>85% in < 15min) in vitro dissolution characteristics
biowaiver possible

Question 15

Describe BCS class IV.

Answer 15

very significant problems for effective oral delivery
dissolution profiles, solubilities can be determined
poor intestinal permeability
biowaiver not considered

Question 16

Describe the eligibility of a drug product for a BCS-based biowaiver.

Answer 16

when the drug substance in T and R are identical
T and R contain different salts provided that both belong to BCS class I
not eligible when T contains a different ester, ether, isomer, mixture of isomers, complex or derivative of a drug substance
pro drugs may be considered for a BCS-based biowaiver when absorbed as the pro-drug excipients

Question 17

What are other considerations for requesting biowaiver?

Answer 17

excipients:
-sometimes influence rate and extent of absorption
-where excipient diff exist, they should be assessed for their potential to affect in vivo absorption
exceptions (biowaivers not applicable):
-NTI drugs
-drugs for absorption in oral cavity

Question 18

What must a BCS class I drug show to qualify for BCS-based biowaiver?

Answer 18

both T and R should display either very rapid or rapid dissolution
-very rapid: >85% dissolved in < 15 min
-rapid: >85% dissolved in < 30 min
-similar in vitro dissolution characteristics under all of the defined conditions
in cases where one product has rapid dissolution and the other has very rapid dissolution, similarity of the profiles should be demonstrated

Question 19

What is the similarity factor?

Answer 19

a way to compare dissolution by looking at all points
-if > 50, the two profiles are similar

Question 20

When is the f2 test unnecessary?

Answer 20

both T and R demonstrate that > 85% of the drug dissolved in 15 minutes

Question 21

Why are dissolution studies critical in drug product development?

Answer 21

both innovator and generic companies perform these
used to assess batch-to-batch quality
provides quality assurance
assess need for further BE studies relative to minor post approval changes