Dissolution Regulations

7/29/2019 Dissolution Regulations

1/15


2/15

New drug

Drug product

Preapproval Postapproval

Generic drug

Class 1HS/HP/RD

Class 1 HS/HPClass 2,3,4

Dissolution forBiowaivers

Lower strength

HigherStrength

BE studyDissolution

BEBA

Dissolution

BE study

Dissolution

Dissolution Testing for IR Products


3/15


NDA - If in-vivo BA of formulation established during IND period waivers of

subsequent in-vivo BE studies may be possible for BCS class 1 drugs based on

dissolution testing data

Dissolution testing development report recommendations

pH solubility profile of drug

Profiles at different agitation speeds e.g.

100-150 rpm for USP apparatus I (basket)

50-100 rpm for USP apparatus II (paddle)

Profiles generated on all strengths in at least three dissolution media

pH 1.2,4.5 and 6.8 buffer


4/15

BCS class I (HS/HP/RD) biowaivers for BE studies

Rapidly dissolving(RD)- not less than 85% of drug dissolves within 30 min

using USP I (100rpm) or USP II (50 rpm) in each media:-

0.1 N HCl/ Simulated gastric fluid USP without enzymes

pH 4.5 buffer

pH6.8 buffer/ Simulated intestinal fluid USP without enzymes



5/15

In-vivo BE Studies can be waived based on dissolution tests and in-vivo studies on

highest strength if

Drug product has same dosage form

Active and inactive ingredient in the drug product are proportionally similarwith respect to strength

If appropriate dissolution method has been established and dissolution results

indicate that dissolution characteristics of product are not dependent on product

strength then dissolution profile in one medium is sufficient to support biowaivers

If appropriate dissolution method is not available then dissolution data in three

media (pH 1.2,4.5.6.8 buffer)



6/15

ANDA

BCS based biowaivers for IR (HS/HP/RD) test products provided

reference listed drug product is also rapidly dissolving and having similar

dissolution profile that of refernce listed drug product

ANDA

FDA recommended methodavailable

USP method available

Follow FDArecommended

method

New dissolutionmethod

development

Follow USPmethod

Yes No

Yes

No



7/15

Postapproval changes

Level 1 change Dissolution testing enough (No BE)

Level 2 change - Dissolution testing enough (No BE)

Site change Level 3- Dissolution testing enough (No BE)

Level 3 changes- Dissolution testing and BE studies are necessary

However BE study may be waived with an acceptable IVIVC which must be

validated


8/15

Dissolution testing for MR Products

Drug product

Preapproval Postapproval

New drug Generic drug

Dissolutionprofile

HigherStrength

BE studyFood effect study

Dissolution

BA studiesfor eachstrength

Food effectstudiesMultiple dosestudiesDissolution

Lower strength

Dissolution profilein additional media

Beadedcapsule

Tablets


9/15

In case of MR products like beaded capsules biowaivers for lower strengths

formulation may be granted depending on BE studies on higher strength such

that the various strength varies only in no. of beads containing active moiety

Similar dissolution profile between highest and lower strengths based on the

f2 test in at least three dissolution media (Ph 1.2,4.5,6.8)

Dissolution testing for MR Products


10/15

ANDAExtended release product

USP method

Singlestrength

Multiplestrengths

Capsules Tablets

Common blend

USP methodadequately

discriminatory

USP methodonly

USP methodAdditionaldissolution

testing usingthree media

Yes No


11/15

If USP method not available then follow FDA recommended method

For capsules- if different strength s has been produced from common

blend then additional dissolution testing on highest strength only in three

different media

For tabletsadditional dissolution testing on all strength in three different

media

ANDAExtended release product


12/15

Post approval changes for MR products

Level 1 change- No BE study standard dissolution testing may be

enough

Level 2 change - Established IVIVCavailable

Dissolution profile withonly standard dissolutionmethod is recommended

Additional dissolutionprofiles besides standarddissolution method are

recommended


13/15

Established IVIVCavailable


Level 2 change related to components and composition releasecontrolling excipients

Narrow therapeutic range drug Non narrow therapeutic range drug


Single dose BE study Dissolution profile with onlystandard dissolution method

Additional dissolutionprofiles besides standard

dissolution method

Yes

NoNo Yes


14/15


Level 3 change


Single dose BE study

Dissolution profile with

only standard dissolutionmethod

No Yes


15/15

Dissolution testing and alcohol induced dose dumping

Drugs(MR) which are highly soluble in ethanol for e.g.

Office of generic drugs recommends assay

Compare dissolution performance of generic (test product) and reference

listed drug

0.1 N HCl media with differing amounts of ethanol (0%, 5%, 20%, 40%)

Documents

Dissolution Regulations