Guidance for Industry

SUPAC-MR: Modified Release Solid

Oral Dosage Forms 

Scale-Up and Postapproval Changes: Chemistry,

Manufacturing, and Controls; In Vitro Dissolution Testing

and In Vivo Bioequivalence Documentation

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 1997

CMC 8
Guidance for Industry

SUPAC-MR: Modified Release

Solid Oral Dosage Forms

Scale-Up and Postapproval Changes: Chemistry,

Manufacturing, and Controls; In Vitro Dissolution Testing

and In Vivo Bioequivalence Documentation

Additional copies are available from:

Office of Training and Communications 

Division of Communications Management

The Drug Information Branch, HFD-210

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 1997

CMC 8
i

Table of Contents

I. INTRODUCTION ..................................................... 1

II. GENERAL STABILITY CONSIDERATIONS ............................... 2

III. COMPONENTS AND COMPOSITION — NONRELEASE CONTROLLING

EXCIPIENT ......................................................... 2

A. Level 1 Change .................................................. 3

B. Level 2 Change .................................................. 4

C. Level 3 Change .................................................. 7

IV. COMPONENTS AND COMPOSITION — RELEASE CONTROLLING EXCIPIENT

................................................................... 8

A. Level 1 Change .................................................. 9

B. Level 2 Change ................................................. 10

C. Level 3 Change ................................................. 14

V. SITE CHANGES ..................................................... 15

A. Level 1 Change ................................................. 16

B. Level 2 Change ................................................ 17

C. Level 3 Change ................................................. 18

VI. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN) ................... 20

A. Level 1 Change ................................................. 20

B. Level 2 Change ................................................. 21

VII. MANUFACTURING EQUIPMENT CHANGES ............................ 22

A. Level 1 Change ................................................. 23

B. Level 2 Change ................................................ 23

VIII. MANUFACTURING PROCESS CHANGES ............................... 25

A. Level 1 Change ................................................. 25

B. Level 2 Change ................................................. 26

C. Level 3 Change ................................................ 28

GLOSSARY OF TERMS .................................................... 30

REFERENCES ............................................................ 36
ii

APPENDIX A Summary Tables of Changes for Extended Release

Solid Oral Dosage Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . .A-1

APPENDIX B Summary Tables of Changes for Delayed Release

Solid Oral Dosage Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B-1
This guidance has been prepared by the Scale-up and Postapproval Change Modified Release (SUPAC-MR) 1

Working Group operating under the direction of the Chemistry Manufacturing Controls Coordinating Committee (CMC

CC) and the Biopharmaceutics Coordinating Committee (BCC) in the Center for Drug Evaluation and Research

(CDER) at the Food and Drug Administration (FDA). This guidance represents the Agency’s current thinking on

modified release solid oral dosage forms scale-up and postapproval changes. It does not create or confer any rights for

or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach

satisfies the requirement of the applicable statute, regulations, or both.

GUIDANCE FOR INDUSTRY1

SUPAC-MR: Modified Release Solid Oral Dosage Forms 

Scale-Up and Postapproval Changes: 

Chemistry, Manufacturing, and Controls;

In Vitro Dissolution Testing and In Vivo Bioequivalence

Documentation

I. INTRODUCTION

This guidance provides recommendations to pharmaceutical sponsors of new drug applications

(NDAs), abbreviated new drug applications (ANDAs), and abbreviated antibiotic drug

applications (AADAs) who intend to change (1) the components or composition, (2) the site of

manufacture, (3) the scale-up/scale-down of manufacture, and/or (4) the manufacturing (process

and equipment) of a modified release solid oral dosage form during the postapproval period. 

The guidance defines (1) levels of change, (2) recommended chemistry, manufacturing, and

controls (CMC) tests for each level of change, (3) recommended in vitro dissolution tests and/or

in vivo bioequivalence tests for each level of change; and (4) documentation that should support

the change. This guidance specifies application information that should be provided to the Center

for Drug Evaluation and Research (CDER) to ensure continuing product quality and performance

characteristics of a modified release solid oral dose formulation for specified postapproval

changes. 

This guidance does not comment on or otherwise affect compliance/inspection documentation

that has been defined by CDER's Office of Compliance or FDA's Office of Regulatory Affairs. 

This guidance does not affect any postapproval changes other than the ones specified. For those

changes filed in a Changes Being Effected (CBE) supplement (21 CFR 314.70(c)), the FDA may,

after a review of the supplemental information, decide that the changes are not approvable. For

changes not addressed in this guidance, or for multiple changes submitted at one time or over a

short period of time, sponsors should contact the appropriate CDER review division or consult

other CDER guidances to obtain information about tests and application documentation.
2

FDA regulations at 21 CFR 314.70(a) provide that applicants may make changes to an approved

application in accordance with a guidance, notice, or regulation published in the Federal Register

that provides for a less burdensome notification of the change (for example, by notification at the

time a supplement is submitted or in the next annual report). This guidance permits less

burdensome notice of certain postapproval changes within the meaning of § 314.70(a).

For postapproval changes for modified release solid oral dosage forms that affect components and

composition, scale-up/scale-down, site change, and manufacturing process or equipment changes,

this guidance supersedes the recommendations in section 4.G of the Office of Generic Drugs

(OGD) Policy and Procedure Guide 22-90 (September 11, 1990). For all other dosage forms and

changes, this guidance does not affect the recommendations in Guide 22-90.

II. GENERAL STABILITY CONSIDERATIONS

The effect SUPAC-type changes have on the stability of the drug product should be evaluated. 

For general guidance on conducting stability studies, applicants are referred to the FDA Guideline

for Submitting Documentation for the Stability of Human Drugs and Biologics (02/87). For

SUPAC submissions, the following points also should be considered:

! In most cases (except those involving scale up), stability data from pilot scale batches will

be acceptable to support the proposed change.

! Where stability data show a trend toward potency loss or degradant increase under

accelerated conditions, it is recommended that historical accelerated stability data from a

representative prechange batch be submitted for comparison. It is also recommended that

under these circumstances, all available long-term data on test batches from ongoing

studies be provided in the supplement. Submission of historical accelerated and available

long-term data would facilitate review and approval of the supplement.

! A commitment should be included to conduct long-term stability studies through the

expiration dating period, according to the approved protocol, on the first or first three (see

text for details) production batches and to report the results in the annual reports.

III. COMPONENTS AND COMPOSITION — NONRELEASE CONTROLLING

EXCIPIENT

This section of the guidance focuses on changes in nonrelease controlling excipients in the drug

product. For modified release solid oral dosage forms, consideration should be given as to

whether the excipient is critical or not critical to drug release. The sponsor should provide

appropriate justifications for claiming any excipient(s) as a nonrelease controlling excipient in the

formulation of the modified release solid oral dosage form. The functionality of each excipient
3

should be identified. Changes in the amount of the drug substance are not addressed by this

guidance. Changes in components or composition that have the effect of adding a new excipient

or deleting an excipient are defined at level 3 (defined below), except as described below in

Section III.A.1.a. Waiver of bioequivalence testing for a change in composition which involves

only a different color, flavor or preservative may be permissible as described in 21 CFR

320.22(d)(4).

A. Level 1 Change

1. Definition of Level

Level 1 changes are those that are unlikely to have any detectable impact on

formulation quality and performance.

Examples:

a. Deletion or partial deletion of an ingredient intended to affect the

color or flavor of the drug product; or change in the ingredient of

the printing ink to another approved ingredient.

b. Changes in nonrelease controlling excipients, expressed as

percentage (w/w) of total formulation, less than or equal to the

following percent ranges:

Nonrelease Percent Excipient (w/w) Out Of

Controlling Total Target Dosage Form 

Excipient Weight

Filler ±5

Disintegrant

Starch ±3

Other ±1

Binder ±0.5

Lubricant

Ca or Mg Stearate ±0.25

Other ±1

Glidant

Talc ±1

Other ±0.1

Film Coat ±1

These percentages are based on the assumption that the drug substance in the

product is formulated to 100% of label/potency. The total additive effect of all
Example: In a product consisting of active ingredient A, lactose, microcrystalline cellulose, and magnesium 2

stearate, the lactose and microcrystalline cellulose should not vary by more than an absolute total of 5% (e.g., lactose

increases by 2.5% and microcrystalline cellulose decreases by 2.5%) relative to the target dosage form weight if it is to

stay within the level 1 range. 

4

nonrelease controlling excipient changes should not be more than 5%. The total 2

weight of the dosage form should still be within the original approved application

range.

The components (active and excipients) in the formulation should have numerical

targets that represent the nominal composition of the drug product on which any

future changes in the composition of the product are to be based. Allowable

changes in the composition should be based on the original approved target

composition and not on previous level 1 changes in the composition. For products

approved with only a range for excipients, the target value may be assumed to be

the midpoint of the original approved application range.

2. Test Documentation

a. Chemistry documentation 

Application/compendial product release requirements.

Stability: First production batch on long-term stability data reported in

annual report.

b. Dissolution documentation 

None beyond application/compendial requirements.

c. Bioequivalence documentation

None.

3. Filing Documentation

Annual report (all information including long-term stability data).

B. Level 2 Change

1. Definition of Level

Level 2 changes are those that could have a significant impact on formulation

quality and performance. 
Example: Avicel PH102 vs. Avicel PH200 3

5

Examples:

a. A change in the technical grade and/or specifications of a

nonrelease controlling excipient.3

b. Changes in nonrelease controlling excipients, expressed as

percentage (w/w) of total formulation, greater than those listed

above for a level 1 change, but less than or equal to the following

percent ranges (which represent a two-fold increase over level 1

changes):

Nonrelease Percent Excipient (w/w) Out Of

Controlling Total Target Dosage Form

Excipient Weight

Filler ±10

Disintegrant

Starch ±6

Other ±2

Binder ±1

Lubricant

Ca or Mg Stearate ±0.5

Other ±2

Glidant

Talc ±2

Other ±0.2

Film Coat ±2

These percentages are based on the assumption that the drug substance in the drug

product is formulated to 100% of label/potency. The total additive effect of all

nonrelease controlling excipient changes should not change by more than 10%. 

The total weight of the dosage form could still be within or outside the original

approved application range.

. 

The components (active and excipients) in the formulation should have numerical

targets that represent the nominal composition of the product on which any future

changes in the composition of the product are to be based. Allowable changes in

the composition are based on the original approved target composition and not on

the composition based on previous level 1 or level 2 changes. For products

approved with only a range for excipients, the target value may be assumed to be

the midpoint of the original approved application range.
6

2. Test documentation

a. Chemistry documentation

Application/compendial product release requirements and updated

executed batch records.

Stability: One batch with three months accelerated stability data reported

in prior approval supplement and long-term stability data of first

production batch reported in annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example, at 1, 2, and 4 hours and every two hours thereafter until either

80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2

hours (acid stage) followed by testing in USP buffer media, in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the application/

compendial test apparatus (three additional test conditions). If the

application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15,

30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. The above dissolution

testing should be performed using the changed drug product and the

biobatch or marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing need be performed (i.e., only in vitro release data by the
7

correlating method need to be submitted). The dissolution profiles of the

changed drug product and the biobatch or marketed batch (unchanged drug

product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.

c. Bioequivalence documentation

None. 

3. Filing Documentation

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).

C. Level 3 Change

1. Definition of Level

Level 3 changes are those that are likely to have a significant impact on

formulation quality and performance. 

Example: 

a. Changes in the nonrelease controlling excipient range beyond those

listed in Section III.B.1.b. The total weight of the dosage form may

be within or outside the approved original application range.

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements and updated 

executed batch records.

Stability:

Significant body of information available: One batch with three months'

accelerated stability data reported in prior approval supplement and longterm stability data of first three production batches reported in annual

report. 
8

Significant body of information not available: Three batches with three

months' accelerated stability data reported in prior approval supplement

and long-term stability data of first three production batches reported in

annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained using the

application/compendial test conditions for the changed drug product and

the biobatch or marketed batch (unchanged drug product). Adequate

sampling should be performed, for example, at 1, 2, and 4 hours and every

two hours thereafter, until either 80% of the drug from the drug product is

released or an asymptote is reached. 

Delayed release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained during the

buffer stage of testing using the application/compendial test conditions for

the changed drug product and the biobatch or marketed batch (unchanged

drug product). Adequate sampling should be performed, for example at

15, 30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. 

c. Bioequivalence documentation

A single-dose bioequivalence study (3). The bioequivalence study may be

waived in the presence of an established in vitro/in vivo correlation (6).

3. Filing Documentation

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).

IV. COMPONENTS AND COMPOSITION — RELEASE CONTROLLING

EXCIPIENT

This section of the guidance focuses on changes in release controlling excipients in the drug

product. For modified release solid oral dosage forms, consideration should be given as to

whether or not the excipient is critical to drug release. The sponsor should provide appropriate

justifications (i.e., mechanism of drug release and manufacturing process) for claiming any

excipient(s) as a release controlling excipient in the formulation of the modified release solid oral
Example: In a product consisting of active ingredient A, ethylcellulose and a plasticizer, the ethylcellulose and 4

plasticizer content should not vary by more than an absolute total of 5% w/w of the total release controlling excipients

(e.g., ethylcellulose content increases by 2.5% and plasticizer content increases by 2.5%) relative to the original

approved total release controlling excipient content weight in the modified release solid oral dosage form if it is to stay

within the given range allowed for level 1. 

9

dosage form. The functionality of each excipient should be identified. Changes in the amount of

the drug substance are not addressed by this guidance. Changes exceeding the ranges defined in

each of the levels below may be allowed if considered to be within normal batch-to-batch

variation and contained within an approved original application. In such situations, sponsors

should contact the appropriate CDER review division for further guidance.

A. Level 1 Change

1. Definition of Level

Level 1 changes are those that are unlikely to have any detectable impact on

formulation quality and performance.

Example:

a. Changes in the release controlling excipient(s), expressed as

percentage (w/w) of total release controlling excipient(s) in the

formulation less than or equal to 5% w/w of total release

controlling excipient content in the modified release solid oral

dosage form.

The drug substance in the product is formulated to 100% of label/potency. The

total additive effect of all release controlling excipient changes should not be more

than 5% w/w of the total release controlling excipients in the original approved

formulation. The total weight of the dosage form should still be within the 4

approved original application range.

The components (active and excipients) in the formulation should have numerical

targets that represent the nominal composition of the product on which any future

changes in the composition of the product are to be based. Allowable changes in

the composition should be based on the original approved target composition and

not on previous level 1 changes in the composition. For products approved with

only a range for excipients, the target value may be assumed to be the midpoint of

the original approved application range.
At present, there is no official CDER list of narrow therapeutic range drugs. A list was developed earlier in a 5

preliminary attempt to identify drugs where there was greater concern that deviation from the specifications and potential

changes in bioavailability could raise clinical issues. This preliminary list was not based solely on 21 CFR 320.33(c)

which is contained in a section of the regulations related to criteria and evidence to assess actual or potential

bioequivalence problems, nor does it accurately reflect the Agency's opinion on narrow therapeutic range drugs. 

Currently, the issue of narrow therapeutic range drugs is under discussion within CDER. If unsure about the

classification of a drug as a narrow therapeutic range drug, sponsors should contact the appropriate CDER review

division.

10

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements.

Stability: First production batch on long-term stability data reported in 

annual report.

b. Dissolution documentation

None beyond application/compendial requirements.

c. Bioequivalence documentation

None.

3. Filing Documentation

Annual report (all information including long-term stability data).

B. Level 2 Change

1. Definition of Level

Level 2 changes are those that could have a significant impact on formulation

quality and performance. Test documentation for a level 2 change would vary

depending on whether the product could be considered to have a narrow

therapeutic range.5
Example: Eudragit RS-100 vs. Eudragit RL-100. 6

11

Examples:

a. Change in the technical grade and/or specifications of the release

controlling excipient(s).6

b. Changes in the release controlling excipient(s), expressed as

percentage (w/w) of total release controlling excipient(s) in the

formulation, greater than those listed above for a level 1 change,

but less than or equal to 10% w/w of total release controlling

excipient content in the modified release solid oral dosage form.

The drug substance in the drug product is formulated to 100% of

label/potency. The total additive effect of all release controlling excipient

changes should not be more than 10% w/w of the total release controlling

excipient(s) in the original approved formulation. The total weight of the

dosage form could still be within or outside the approved original

application range.

The components (active and excipients) in the formulation should have

numerical targets that represent the nominal composition of the product on

which any future changes in the composition of the product are to be

based. Allowable changes in the composition are based on the original

approved target composition and not on the composition based on previous

level 1 or level 2 changes. For products approved with only a range for

excipients, the target value may be assumed to be the midpoint of the

original approved application range.

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements and updated

executed batch records.

Stability:

! Nonnarrow therapeutic range drugs: One batch with three months'

accelerated stability data reported in prior approval supplement and

long-term stability data of first production batch reported in annual

report.
12

! Narrow therapeutic range drugs: Three batches with three months'

accelerated stability data reported in prior approval supplement and

long-term stability data of first three production batches reported in

annual report.

b. Dissolution documentation

! Nonnarrow therapeutic range drugs

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example, at 1, 2, and 4 hours and every two hours thereafter until either

80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2

hours (acid stage) followed by testing in USP buffer media in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the

application/compendial test apparatus (three additional test conditions). If

the application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15,

30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. The above dissolution

testing should be performed using the changed drug product and the

biobatch or marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an 

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing should be performed (i.e., only in vitro release data by

the correlating method should be submitted). The dissolution profiles of

the changed drug product and the biobatch or marketed batch (unchanged

drug product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing
13

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.

! Narrow therapeutic range drugs

Extended release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained in

application/compendial medium for the changed drug product and the

biobatch or marketed batch (unchanged drug product). Adequate sampling

should be performed, for example at 1, 2, and 4 hours and every two hours

thereafter until either 80% of the drug from the drug product is released or

an asymptote is reached. 

Delayed release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained during the

buffer stage of testing using the application/compendial medium for the

changed drug product and the biobatch or marketed batch (unchanged drug

product). Adequate sampling should be performed, for example, at 15, 30,

45, 60, and 120 minutes (following the time from which the dosage form is

placed in the buffer) until either 80% of the drug from the drug product is

released or an asymptote is reached. 

c. Bioequivalence documentation

! Nonnarrow therapeutic range drugs: None. 

! Narrow therapeutic range drugs: A single-dose bioequivalence

study (3). The bioequivalence study may be waived in the presence

of an established in vitro/in vivo correlation (6). Changes in release

controlling excipients in the formulation should be within the range

of release controlling excipients of the established correlation.

3. Filing Documentation

Prior approval supplement (all information including accelerated stability data); 

annual report (long-term stability data).
14

C. Level 3 Change

1. Definition of Level

Level 3 changes are those that are likely to have a significant impact on

formulation quality and performance affecting all therapeutic ranges of the drug. 

Examples:

a. Addition or deletion of release controlling excipient(s) (e.g., release

controlling polymer/plasticizer).

b. Changes in the release controlling excipient(s), expressed as

percentage (w/w) of total release controlling excipient(s) in the

formulation, greater than those listed above for a level 2 change

(i.e., greater than 10% w/w of total release controlling excipient

content in the modified release solid oral dosage form). Total

weight of the dosage form may be within or outside the original

approved application range.

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements and updated

executed batch records.

Stability: Three batches with three months' accelerated stability data

reported in prior approval supplement and long-term stability data of first

three production batches reported in annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained using

application/compendial test conditions for the changed drug product and

the biobatch or marketed batch (unchanged drug product). Adequate

sampling should be performed, for example at 1, 2, and 4 hours and every

two hours thereafter until either 80% of the drug from the drug product is

released or an asymptote is reached. 

Delayed release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained during the

buffer stage of testing using the application/compendial test conditions for
15

the changed drug product and the biobatch or marketed batch (unchanged

drug product). Adequate sampling should be performed, for example at

15, 30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. 

c. Bioequivalence documentation

A single-dose bioequivalence study (3). The bioequivalence study may be

waived in the presence of an established in vitro/in vivo correlation (6). 

Changes in release controlling excipients in the formulation should be

within the range of release controlling excipients of the established

correlation.

3. Filing Documentation

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).

V. SITE CHANGES

Site changes consist of changes in location of the site of manufacture, packaging operations,

and/or analytical testing laboratory for both company-owned and contract manufacturing

facilities. They do not include any scale-up changes, changes in manufacturing (including process

and/or equipment), or changes in components or composition. New manufacturing locations

should have had a satisfactory current good manufacturing practice (cGMP) inspection.

A stand-alone packaging operations site change, using container(s)/closure(s) in the approved

application, may be submitted as a Changes Being Effected supplement. The facility should also

have a current and satisfactory cGMP compliance profile with the FDA for the type of packaging

operation in question before submitting the supplement. If the facility has not received a

satisfactory cGMP inspection for the type of packaging operation in question, a prior approval

supplement is recommended. The supplement should contain a written certification from the

packaging facility stating that it is in conformance with cGMPs. It should also contain a

commitment to place the first production batch of the product, and annual batches thereafter, on

long-term stability studies using the approved protocol in the application and to submit the

resulting data in annual reports. Where the product is available in more than one strength, size, or

container/closure system, one lot of each combination should be placed on long-term stability

studies. Bracketing or matrixing is allowed only if it has been approved previously by the FDA. 

Any changes to an approved stability protocol should have a supplemental approval prior to the

initiation of the stability study.
Common is defined as employees already working on the campus who have suitable experience with the 7

manufacturing process.

16

A stand-alone analytical testing laboratory site change may be submitted as a Changes Being

Effected supplement if the new facility has a current and satisfactory cGMP compliance profile

with the FDA for the type of testing operation in question. The supplement should contain a

commitment to use the same test methods employed in the approved application, written

certification from the testing laboratory stating that they are in conformance with cGMPs, and a

full description of the testing to be performed by the testing lab. If the facility has not received a

satisfactory cGMP inspection for the type of testing involved, a prior approval supplement is

recommended.

A. Level 1 Change

1. Definition of Level

Level 1 changes consist of site changes within a single facility where the same

equipment, standard operating procedures (SOPs), environmental conditions (e.g.,

temperature and humidity) and controls, and personnel common to both 7

manufacturing sites are used and where no changes are made to the executed batch

records, except for administrative information and the location of the facility. 

2. Test Documentation

a. Chemistry documentation

None beyond application/compendial product release requirements.

b. Dissolution documentation

None beyond application/compendial release requirements.

c. Bioequivalence documentation

None. 

3. Filing Documentation

Annual report.
17

B. Level 2 Change 

1. Definition of Level

Level 2 changes consist of site changes within a contiguous campus, or between

facilities in adjacent city blocks, where the same equipment, SOPs, environmental

conditions (e.g., temperature and humidity) and controls, and personnel common

to both manufacturing sites are used and where no changes are made to the

executed batch records, except for administrative information and the location of

the facility. 

2. Test Documentation

a. Chemistry documentation

Notification of location of new site and updated executed batch records. 

None beyond application/compendial product release requirements.

Stability: One batch with three months accelerated stability data reported

in Changes Being Effected supplement and long-term stability data of first

production batch reported in annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example at 1, 2, and 4 hours and every two hours thereafter until either

80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2

hours (acid stage) followed by testing in USP buffer media, in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the application/

compendial test apparatus (three additional test conditions). If the

application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 
18

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15,

30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. The above dissolution

testing should be performed using the changed drug product and the

biobatch or marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing should be performed (i.e., only in vitro release data by

the correlating method should be submitted). The dissolution profiles of

the changed drug product and the biobatch or marketed batch (unchanged

drug product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.

c. Bioequivalence documentation

None. 

3. Filing Documentation

Changes Being Effected supplement (all information including accelerated stability

data); annual report (long-term stability data).

C. Level 3 Change

1. Definition of Level

Level 3 changes consist of a change in manufacturing site to a different campus. A

different campus is defined as one that is not on the same original contiguous site

or where the facilities are not in adjacent city blocks. To qualify as a level 3

change, the same equipment, SOPs, environmental conditions, and controls should

be used in the manufacturing process at the new site, and no changes may be made

to the executed batch records except for administrative information, location and

language translation, where needed. 
19

2. Test Documentation

a. Chemistry documentation

Notification of location of new site and updated executed batch records. 

Application/compendial product release requirements.

Stability:

Significant body of information available: One batch with three months'

accelerated stability data reported in prior approval supplement and longterm stability data of first three production batches reported in annual

report. 

Significant body of information not available: Three batches with three

months' accelerated stability data reported in prior approval supplement

and long-term stability data of first three production batches reported in

annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained using

application/compendial test conditions for the changed drug product and

the biobatch or marketed batch (unchanged drug product). Adequate

sampling should be performed, for example at 1, 2, and 4 hours and every

two hours thereafter until either 80% of the drug from the drug product is

released or an asymptote is reached. 

Delayed release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained during the

buffer stage of testing using the application/compendial test conditions for

the changed drug product and the biobatch or marketed batch (unchanged

drug product). Adequate sampling should be performed, for example, at

15, 30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. 

c. Bioequivalence documentation

A single-dose bioequivalence study (3). The bioequivalence study may be

waived in the presence of an established in vitro/in vivo correlation (6).
20

3. Filing Documentation

Prior approval supplement (all information including accelerated stability test

data); annual report (long-term stability data).

VI. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)

Postapproval changes in the size of a batch from the pivotal/pilot scale biobatch material to larger

or smaller production batches call for submission of additional information to the application. 

Scale-down below 100,000 dosage units is not covered by this guidance. Adjustments in

parameters such as mixing times and speeds may be made to tailor the process to the

characteristics of larger or smaller scale equipment. All scale-up changes should be properly

validated and, where needed, inspected by appropriate Agency personnel.

A. Level 1 Change

1. Definition of Level

Change in batch size, up to and including a factor of ten times the size of the

pilot/biobatch, where (1) the equipment used to produce the test batch(es) may

vary in capacity, but are of the same design and operating principles; (2) the

batch(es) is manufactured in full compliance with cGMPs; and (3) the same

standard operating procedures (SOPs) and controls, as well as the same

formulation and manufacturing procedures, are used on the test batch(es) and on

the full-scale production batch(es). 

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements. Notification of

change and submission of updated executed batch records in annual report.

Stability: First production batch on long-term stability data reported in

annual report.

b. Dissolution documentation

None beyond application/compendial release requirements.

c. Bioequivalence documentation
21

None.

3. Filing Documentation

Annual report (all information including long-term stability data).

B. Level 2 Change

1. Definition of Level

Changes in batch size beyond a factor of ten times the size of the pilot/biobatch

where (1) the equipment used to produce the test batch(es) is of the same design

and operating principles; (2) the batch(es) is manufactured in full compliance with

cGMPs; and (3) the same SOPs and controls as well as the same formulation and

manufacturing procedures are used on the test batch(es) and on the full-scale

production batch(es). 

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements. 

Notification of change and submission of updated batch 

records. 

Stability: One batch with three months' accelerated stability data reported

in Changes Being Effected supplement and long-term stability data of first

production batch reported in annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example, at 1, 2, and 4 hours, and every two hours thereafter until

either 80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2
22

hours (acid stage) followed by testing in USP buffer media in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the application/

compendial test apparatus (three additional test conditions). If the

application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15,

30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. The above dissolution

testing should be performed using the changed drug product and the

biobatch or marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing should be performed (i.e., only in vitro release data by

the correlating method should be submitted). The dissolution profiles of

the changed drug product and the biobatch or marketed batch (unchanged

drug product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.

c. Bioequivalence documentation

None. 

3. Filing Documentation

Changes Being Effected supplement (all information including accelerated stability

data); annual report (long-term stability data).

VII. MANUFACTURING EQUIPMENT CHANGES

Manufacturing changes may involve the equipment used in the manufacturing process (critical

manufacturing variable). If a manufacturer wishes to use manufacturing equipment that is not

identical in every respect to the original manufacturing equipment used in the approved

application, appropriate validation studies should be conducted to demonstrate that the new
23

equipment is similar to the original equipment. For modified release solid oral dosage forms,

consideration should be given as to whether or not the change in manufacturing equipment is

critical to drug release (critical equipment variable).

A. Level 1 Change

1. Definition of Level

This category consists of (1) change from nonautomated or nonmechanical

equipment to automated or mechanical equipment to move ingredients and

(2) change to alternative equipment of the same design and operating principles of

the same or of a different capacity.

2. Test documentation

a. Chemistry documentation

Application/compendial product release requirements. Notification of

change and submission of updated executed batch records. 

Stability: First production batch on long-term stability data reported in

annual report. 

b. Dissolution documentation

None beyond application/compendial release requirements.

c. Bioequivalence documentation

None.

3. Filing Documentation

Annual report (all information including long-term stability data).

B. Level 2 Change 

1. Definition of Level

Change in equipment to a different design and different operating principles.

2. Test Documentation
24

a. Chemistry documentation

Application/compendial product release requirements. Notification of

change and submission of updated executed batch records. 

Stability:

Significant body of information available: One batch with three months'

accelerated stability data reported in prior approval supplement and longterm stability data of first three production batches reported in annual

report. 

Significant body of information not available: Three batches with three

months' accelerated stability data reported in prior approval supplement

and long-term stability data of first three production batches reported in

annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example, at 1, 2, and 4 hours and every two hours thereafter until either

80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2

hours (acid stage) followed by testing in USP buffer media, in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the application/

compendial test apparatus (three additional test conditions). If the

application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15,

30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. The above dissolution
25

testing should be performed using the changed drug product and the

biobatch or marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing should be performed (i.e., only in vitro release data by

the correlating method should be submitted). The dissolution profiles of

the changed drug product and the biobatch or marketed batch (unchanged

drug product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.

c. Bioequivalence documentation

None. 

3. Filing Documentation

Prior approval supplement with justification for change (all information including

accelerated stability data); annual report (long-term stability data).

VIII. MANUFACTURING PROCESS CHANGES

Manufacturing changes may involve the manufacturing process itself (critical

manufacturing variable). If a manufacturer wishes to use a manufacturing process that is not

identical in every respect to the original manufacturing process used in the approved application,

appropriate validation studies should be conducted to demonstrate that the new process is similar

to the original process. For modified release solid oral dosage forms, consideration should be

given as to whether or not the change in manufacturing process is critical to drug release (critical

processing variable). For purposes of categorizing the level of changes, process change may be

considered only to affect a release controlling excipient when both types of excipients (i.e.,

nonrelease and release controlling) are present during the unit operation undergoing a change.

A. Level 1 Change

1. Definition of Level

Process changes involving adjustment of equipment operating conditions such as

mixing times and operating speeds within original approved application ranges

affecting the nonrelease controlling and/or release controlling excipient(s). The
26

sponsor should provide appropriate justifications for claiming any excipient(s) as a

nonrelease controlling or a release controlling excipient in the formulation of the

modified release solid oral dosage form.

2. Test Documentation

a. Chemistry documentation

None beyond application/compendial product release requirements. 

Notification of the change and submission of the updated executed batch

records.

b. Dissolution documentation

None beyond application/compendial release requirements.

c. Bioequivalence documentation

None.

3. Filing Documentation

Annual report.

B. Level 2 Change

1. Definition of Level

This category includes process changes involving adjustment of equipment

operating conditions such as mixing times and operating speeds outside of original

approved application ranges.

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements. Notification of

change and submission of updated executed batch records. 

Stability: One batch with three months' accelerated stability data reported

in Changes Being Effected supplement and long-term stability data of first

production batch reported in annual report.
27

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, multipoint dissolution profiles should be obtained in three

other media, for example, in water, 0.1N HCl, and USP buffer media at pH

4.5, and 6.8 for the changed drug product and the biobatch or marketed

batch (unchanged drug product). Adequate sampling should be performed,

for example at 1, 2, and 4 hours and every two hours thereafter until either

80% of the drug from the drug product is released or an asymptote is

reached. A surfactant may be used with appropriate justification. 

Delayed release: In addition to application/compendial release

requirements, dissolution tests should be performed in 0.1 N HCl for 2

hours (acid stage) followed by testing in USP buffer media, in the range of

pH 4.5-7.5 (buffer stage) under standard (application/compendial) test

conditions and two additional agitation speeds using the application/

compendial test apparatus (three additional test conditions). If the

application/compendial test apparatus is the rotating basket method

(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and

if the application/compendial test apparatus is the rotating paddle method

(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. 

Multipoint dissolution profiles should be obtained during the buffer stage

of testing. Adequate sampling should be performed, for example, at 15, 30,

45, 60, and 120 minutes (following the time from which the dosage form is

placed in the buffer) until either 80% of the drug from the drug product is

released or an asymptote is reached. The above dissolution testing should

be performed using the changed drug product and the biobatch or

marketed batch (unchanged drug product).

All modified release solid oral dosage forms: In the presence of an

established in vitro/in vivo correlation (6), only application/compendial

dissolution testing should be performed (i.e., only in vitro release data by

the correlating method should be submitted). The dissolution profiles of

the changed drug product and the biobatch or marketed batch (unchanged

drug product) should be similar. The sponsor should apply appropriate

statistical testing with justifications (e.g., the f2 equation) for comparing

dissolution profiles (5). Similarity testing for the two dissolution profiles

(i.e., for the unchanged drug product and the changed drug product)

obtained in each individual medium is appropriate.
28

c. Bioequivalence documentation

None. 

3. Filing Documentation

Changes Being Effected supplement (all information including accelerated stability

data); annual report (long-term stability data).

C. Level 3 Change

1. Definition of Level

This category includes change in the type of process used in the manufacture of the

product, such as a change from wet granulation to direct compression of dry

powder.

2. Test Documentation

a. Chemistry documentation

Application/compendial product release requirements. Notification of

change and submission of updated executed batch records. 

Stability: Three batches with three months' accelerated stability data

reported in prior approval supplement and long-term stability data of first

three production batches reported in annual report.

b. Dissolution documentation

Extended release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained using

application/compendial test conditions for the changed drug product and

the biobatch or marketed batch (unchanged drug product). Adequate

sampling should be performed, for example at 1, 2, and 4 hours and every

two hours thereafter until either 80% of the drug from the drug product is

released or an asymptote is reached. 

Delayed release: In addition to application/compendial release

requirements, a multipoint dissolution profile should be obtained during the

buffer stage of testing using the application/compendial test conditions for

the changed drug product and the biobatch or marketed batch (unchanged

drug product). Adequate sampling should be performed, for example at
29

15, 30, 45, 60, and 120 minutes (following the time from which the dosage

form is placed in the buffer) until either 80% of the drug from the drug

product is released or an asymptote is reached. 

c. Bioequivalence documentation

A single-dose bioequivalence study (3). The bioequivalence study may be

waived in the presence of an established in vitro/in vivo correlation (6).

3. Filing Documentation

Prior approval supplement (all information including accelerated stability data);

annual report (long-term stability data).
30

GLOSSARY OF TERMS

The following terms and their definitions (9) are being provided to assist the reader in using this

guidance document.

Batch: A specific quantity of a drug or other material produced according to a single

manufacturing order during the same cycle of manufacture and intended to have uniform character

and quality, within specified limits (21 CFR 210.3(b)(2)).

Batch formula (Composition): A complete list of the ingredients and their amounts to be used

for the manufacture of a representative batch of the drug product. All ingredients should be

included in the batch formula whether or not they remain in the finished product (1). 

Biobatch: The lot of drug product formulated for purposes of pharmacokinetic evaluation in a

bioavailability/bioequivalency study. For modified release solid oral, this batch should be 10% or

greater than the proposed commercial production batch or at least 100,000 units, whichever is

greater. 

Bioequivalence Studies For Modified Release Drug Product: Refer to the OGD Guidance

(3). The bioequivalence study should be conducted using the reference listed drug (RLD) product

and/or the innovator drug product as the reference and the test product should be the product

(generic or innovator) which has undergone postapproval change.

Contiguous Campus: Continuous or unbroken site or a set of buildings in adjacent city blocks.

Critical Equipment Variable: A specific design, operating principle, or automation of

equipment that can affect a specific performance variable critical to the ultimate and predictable

performance of the dosage form and its drug.

Critical Manufacturing Variable: Includes those manufacturing materials (critical composition

variable), methods, equipment, and processes that significantly affect drug release, from the

formulation (e.g., coating thickness, particle size, crystal form, excipient type, concentrations and

distribution, and tablet hardness).

Critical Processing Variable: A specific step, unit process, or condition of a unit process that

can affect a specific performance variable critical to the ultimate and predictable performance of

the dosage form and its drug.

Delayed Release: Release of a drug (or drugs) at a time other than immediately following oral

administration.

Dissolution Testing: Extended release: Dissolution testing should be conducted on 12

individual dosage units for the changed drug product and the biobatch or marketed batch
31

(unchanged drug product). The potential for pH dependence of drug release from a modified

release drug product is well recognized. Multipoint dissolution profiles should be obtained using

discriminating agitation speed and medium. A surfactant may be used with appropriate

justification. Early sampling times of 1, 2, and 4 hours should be included in the sampling

schedule to provide assurance against premature release of the drug (dose dumping) from the

formulation. Differing sampling times should be justified to prevent premature drug release. See

current USP 23 NF 18, sections <711> and <724>, for general dissolution requirements. The

general dissolution conditions to be followed are shown below:

1. Apparatus: USP 23 Apparatus 1 (rotating basket) 

USP 23 Apparatus 2 (rotating paddle) 

USP 23 Apparatus 3 (reciprocating cylinder)*

USP 23 Apparatus 4 (flow-through cell)*

USP 23 Apparatus 7 (reciprocating disk)*

2. Rotation Speed: 50, 100, and 150 rpm (basket)

50, 75 and 100 rpm (paddle)

3. Temperature: 37±0.5 C

o

4. Units To Be Tested: 12

5. Dissolution Volume: 500-1000 mL

6. Dissolution Medium: Aqueous media of various pH. 

7. Sampling Schedule: Adequate sampling should be performed, for example at 1, 2, and 4

hours, and every two hours thereafter until either 80% of the drug is released or an

asymptote is reached.

8. Tolerances: As established.

9. Content Uniformity: Content uniformity testing of the proposed product lot should be 

performed as described in USP 23.

When using USP 23 Apparatus 3 (reciprocating cylinder), USP 23 Apparatus 4 (flow- *

through cell), or USP 23 Apparatus 7 (reciprocating disk) the above dissolution testing

conditions should be modified accordingly.

Delayed release: For enteric coated drug products, drug release procedures described in USP 23

NF 18, sections <711> and <724> should be followed. When the guidance refers to dissolution

testing in addition to application/compendial release requirements, the dissolution test should be

performed in 0.1N HCl for 2 hours (acid stage) followed by testing in USP buffer media, in the

range of pH 4.5-7.5 (buffer stage) under standard (application/compendial) test conditions and
32

increased agitation speeds using the application/ compendial test apparatus. For the rotating

basket method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used and for the

rotating paddle method (Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be studied. 

Multipoint dissolution profiles should be obtained during the buffer stage of testing. Adequate

sampling should be performed, for example, at 15, 30, 45, 60, and 120 minutes (following the

time from which the dosage form is placed in the buffer) until either 80% of the drug is released

or an asymptote is reached. The above dissolution testing should be performed using the changed

drug product and the biobatch or marketed batch (unchanged drug product).

Drug Product: A drug product is a finished dosage form (e.g., tablet and capsule) that contains a

drug substance, generally, but not necessarily, in association with one or more other ingredients

(21 CFR 314.3(b)). A solid oral dosage form includes but is not limited to tablets, chewable

tablets, enteric coated tablets, capsules, caplets, encapsulated beads, and gelcaps.

Drug Substance: An active ingredient that is intended to furnish pharmacological activity or

other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to

affect the structure of any function of the human body, but does not include intermediates used in

the synthesis of such ingredient (21 CFR 314.3(b)).

Enteric Coated: Intended to delay the release of the drug (or drugs) until the dosage form has

passed through the stomach. Enteric coated products are delayed release dosage forms.

Equipment: Automated or nonautomated, mechanical or nonmechanical equipment used to

produce the drug product, including equipment used to package the drug product.

Extended Release: Extended release products are formulated to make the drug available over an

extended period after ingestion. This allows a reduction in dosing frequency compared to a drug

presented as a conventional dosage form (e.g., as a solution or an immediate release dosage

form). 

Formulation: A listing of the ingredients and composition of the dosage form.

Immediate Release: Allows the drug to dissolve in the gastrointestinal contents, with no

intention of delaying or prolonging the dissolution or absorption of the drug.

In Vitro Dissolution Profile Comparison: Model Independent Approach Using Similarity

Factor: Dissolution profiles may be compared using the following equation that defines a

similarity factor (f ): 2

f2 = 50 LOG {[1+1/n 3 t=1 (Rt-Tt) ] x 100} n 2 -0.5

where LOG = logarithm to base 10, n = number of sampling time points, 3 = summation over all

time points, R = dissolution at time point t of the reference (unchanged drug product, i.e., pre- t
33

change batch), Tt = dissolution at time point t of the test (changed drug product, i.e., post-change

batch) (5 and 8). 

For comparison of multipoint dissolution profiles obtained in multiple media, similarity testing

should be performed using pairwise dissolution profiles (i.e., for the unchanged and changed

product) obtained in each individual medium. It is recommended that only one point past the

plateau of the profiles be used in calculating the f2 value. A correction for a lag time prior to

similarity testing should not be performed unless justified.

An f2 value between 50 and 100 suggests the two dissolution profiles are similar. Also, the

average difference at any dissolution sampling time point should not be greater than 15% between

the changed drug product and the biobatch or marketed batch (unchanged drug product)

dissolution profiles. An appropriate reference for this comparison should represent an average

dissolution profile derived from at least three consecutive recent batches of the unchanged drug

product (biobatch or marketed batch). Finally, the dissolution data obtained under the

application/compendial dissolution testing conditions (media, agitation, etc.), on both the changed

drug product and the biobatch or marketed batch (unchanged drug product) should be within the

application/compendial specifications. 

An f2 value less than 50 does not necessarily indicate lack of similarity. If the sponsor is of the

opinion that the differences observed related to this calculation of f2 are typical for the drug

product involved in this SUPAC situation, an appropriate justification can be submitted, but only

as part of a prior approval supplement. This justification should include additional data to support

the claim of similarity, as well as supporting statistical analysis (e.g. 90% confidence interval

analysis). If this justification is not found acceptable, the potential effect of the proposed change

on the differences in dissolution on bioavailability should be determined.

Dissolution profiles can also be compared using other model independent or model dependent

methods (5). 

In Vitro-In Vivo Correlation: A predictive mathematical model describing the relationship

between an in vitro property of an oral dosage form (usually the rate or extent of drug dissolution

or release) and a relevant in vivo response (e.g., plasma drug concentration or amount of drug

absorbed). 

For modified release dosage forms, changes in release controlling excipients in the formulation

should be within the range of release controlling excipients of the established correlation. In the

presence of an established in vitro/in vivo correlation (6), only application/ compendial dissolution

testing need be performed. Also, an established in vitro/in vivo correlation can be used for any

level of changes described in this guidance.

Justification: Reports containing scientific data and expert professional judgment to substantiate

decisions.
34

Lot: A batch or a specific identified portion of a batch, having uniform character and quality

within specified limits or, in the case of a drug product produced by continuous process, a specific

identified amount produced in a unit of time or quantity in a manner that assures its having

uniform character and quality within specified limits (21 CFR 210.3(b)(10)).

Modified Release Dosage Forms: Dosage forms whose drug-release characteristics of time

course and/or location are chosen to accomplish therapeutic or convenience objectives not offered

by conventional dosage forms such as a solution or an immediate release dosage form. Modified

release solid oral dosage forms include both delayed and extended release drug products.

Nonrelease Controlling Excipient (Non-Critical Composition Variable): An excipient in the

final dosage form whose primary function does not include modifying the duration of release of

the active drug substance from the dosage form.

Operating Principles: Rules or concepts governing the operation of the system.

Pilot Scale: The manufacture of either drug substance or drug product by a procedure fully

representative of and simulating that used for full manufacturing scale. For solid oral dosage

forms this is generally taken to be, at a minimum, one tenth that of full production, or 100,000

tablets or capsules, whichever is larger (4).

Process: A series of operations, actions and controls used to manufacture a drug product.

Ranges: The extent to which or the limits between which acceptable variation exists. 

Release Controlling Excipient (Critical Composition Variable): An excipient in the final

dosage form whose primary function is to modify the duration of release of the active drug

substance from the dosage form.

Release Mechanism: The process by which the drug substance is released from the dosage form. 

Typically the definition contains the energy source or pictorially describes the way the drug is

released.

Representative: Corresponding to or replacing some other species or the like; exemplifying a

group or kind; typical. 

Same: Agreeing in kind, amount; unchanged in character or condition. 

Satisfactory Current Good Manufacturing Practice (cGMP) Inspection: A satisfactory

cGMP inspection is one during which (1) no objectionable conditions or practices were found

during an inspection or (2) objectionable conditions were found, however, corrective action is left

to the firm to take voluntarily and the objectionable conditions do not justify further

administrative or regulatory actions.
35

Scale-up: The process of increasing the batch size.

Scale-down: The process of decreasing the batch size.

Significant Body of Information:

! Immediate Release Solid Oral Dosage Forms: A significant body of information

on the stability of the drug product is likely to exist after five years of commercial

experience for new molecular entities, or three years of commercial experience for

new dosage forms.

! Modified Release Solid Oral Dosage Forms: A significant body of information

should include, for "Modified Release Solid Oral Dosage Forms," a

product-specific body of information. This product-specific body of information

is likely to exist after five years of commercial experience for the original modified

release solid oral drug product, or three years of commercial experience for any

subsequent modified release solid oral drug product utilizing similar drug release

mechanism. 

Similar: Having a general likeness.

Technical Grade: Technical grades of excipients may differ in (1) specifications and/or

functionality, (2) impurities, and (3) impurity profiles.

Validation: Establishing through documented evidence a high degree of assurance that a specific

process will consistently produce a product that meets its predetermined specifications and quality

attributes. A validated manufacturing process is one that has been proven to do what it purports

or is represented to do. The proof of validation is obtained through collection and evaluation of

data, preferably beginning from the process development phase and continuing through into the

production phase. Validation necessarily includes process qualification (the qualification of

materials, equipment, systems, buildings, and personnel), but it also includes the control of entire

processes for repeated batches or runs. 
36

REFERENCES

1. FDA, Guideline for Submitting Documentation for the Manufacture of and Controls for

Drug Products, February 1987.

2. FDA, "Interim Policy on Exceptions to the Batch-Size and Production Condition 

Requirements for Non-Antibiotic, Solid, Oral-Dosage Form Drug Products

Supporting Proposed ANDA's" Policy and Procedure Guide #22-90,

September 13, 1990.

Office of Generic Drugs, CDER, September 13, 1990.

3. FDA, Oral Extended (Controlled) Release Dosage Forms In Vivo Bioequivalence and In

Vitro Dissolution Testing, September 1993.

4. FDA, Stability Testing of New Drug Substances and Products; ICH Guideline, Federal

Register, Vol. 59, No. 183, 48754-48759, September 1994.

5. FDA, Guidance for Dissolution Testing of Immediate Release Solid Oral Products, 1997.

6. FDA, Guidance for the Development, Evaluation and Application of In Vitro/In Vivo

Correlations for Extended Release Solid Oral Dosage Forms, 1997.

7. FDA/University of Maryland Manufacturing Research Contract Summary.

8. Moore, J. W. and H. H. Flanner, "Mathematical Comparison of Dissolution Profiles,"

Pharmaceutical Technology, 6:64-74, 1996. 

9. Skelly, J. P., et al., "Workshop Report: Scaleup of Oral Extended-Release Dosage

Forms," Pharmaceutical Research, 10(12): 1800-1805, 1993.
A-1

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

NON-RELEASE CONTROLLING COMPONENTS AND COMPOSITION

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I -COMPLETE OR PARTIAL ALL DRUGS -STABILITY 

DELETION OF COLOR/FLAVOR -APPLICATION/COMPENDIAL -CHANGE IN INKS, IMPRINTS REQUIREMENTS-UPTO SUPAC-IR LEVEL 1 -NO BIOSTUDYEXCIPIENT RANGES-NO OTHER CHANGES

II -CHANGE IN TECHNICAL ALL DRUGS -NOTIFICATION & UPDATED BATCH 

GRADE AND/OR RECORD SPECIFICATIONS -STABILITY-HIGHER THAN SUPAC-IR -APPLICATION/COMPENDIAL LEVEL 1 BUT LESS THAN REQUIREMENTS PLUS MULTI-POINT LEVEL 2 EXCIPIENT RANGES DISSOLUTION PROFILES IN THREE OTHER -NO OTHER CHANGES MEDIA (e.g., WATER, 0.1N HCL, AND USP 

BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -HIGHER THAN SUPAC-IR ALL DRUGS -UPDATED BATCH RECORD 

LEVEL 2 EXCIPIENT RANGES -STABILITY 

-APPLICATION/COMPENDIAL (PROFILE) REQUIREMENTS-BIOSTUDY OR IVIVC1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
A-2

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

RELEASE CONTROLLING COMPONENTS AND COMPOSITION

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I - 5% W/W CHANGE BASED ON ALL DRUGS -STABILITY 

TOTAL RELEASE CONTROLLING -APPLICATION/COMPENDIAL EXCIPIENT (e.g., controlled release REQUIREMENTSpolymer, plasticizer) CONTENT -NO BIOSTUDY-NO OTHER CHANGES

II -CHANGE IN TECHNICAL GRADE NON-NARROW -NOTIFICATION & UPDATED BATCH RECORD 

AND/OR SPECIFICATIONS -STABILITY -10% W/W CHANGE BASED ON -APPLICATION/COMPENDIAL TOTAL RELEASE CONTROLLING REQUIREMENTS PLUS MULTI-POINT EXCIPIENT (e.g., controlled release DISSOLUTION PROFILES IN THREE OTHER polymer, plasticizer) CONTENT MEDIA (e.g., WATER, 0.1N HCL, AND USP -NO OTHER CHANGES BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 

80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

NARROW -UPDATED BATCH RECORD 

-STABILITY -APPLICATION/COMPENDIAL (PROFILE) REQUIREMENTS-BIOSTUDY OR IVIVC1

III ->10% W/W CHANGE BASED ON ALL DRUGS -UPDATED BATCH RECORD 

TOTAL RELEASE CONTROLLING -STABILITY EXCIPIENT (e.g., controlled release -APPLICATION/COMPENDIAL (PROFILE) polymer, plasticizer) CONTENT REQUIREMENTS

-BIOSTUDY OR IVIVC1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TESTING SHOUL

1

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
A-3

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

SITE CHANGE

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I -SINGLE FACILITY ALL DRUGS -APPLICATION/COMPENDIAL REQUIREMENTS 

-COMMON PERSONNEL -NO BIOSTUDY-NO OTHER CHANGES

II -SAME CONTIGUOUS ALL DRUGS -IDENTIFICATION AND DESCRIPTION OF SITE 

CAMPUS CHANGE, AND UPDATED BATCH RECORD -COMMON PERSONNEL -NOTIFICATION OF SITE CHANGE -NO OTHER CHANGES -STABILITY

-APPLICATION/COMPENDIAL REQUIREMENTS PLUS MULTI-POINT DISSOLUTION PROFILES IN THREE OTHER MEDIA (e.g., WATER, 0.1N HCL, AND USP BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -DIFFERENT CAMPUS ALL DRUGS -NOTIFICATION OF SITE CHANGE 

-DIFFERENT PERSONNEL -UPDATED BATCH RECORD 

-STABILITY-APPLICATION/COMPENDIAL (PROFILE) REQUIREMENTS-BIOSTUDY OR IVIVC 1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
A-4

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

SCALE-UP/SCALE-DOWN

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION 

I -SCALE-UP OF BIO-BATCH(S) 10X -UPDATED BATCH RECORD -AN

OR PIVOTAL CLINICAL -STABILITY BATCH(S) (ALL DRUGS) -APPLICATION/COMPENDIAL REQUIREMENTS-NO OTHER CHANGES -NO BIOSTUDY

II -SCALE-UP OF BIO-BATCH(S) >10X -UPDATED BATCH RECORD -CH

 OR PIVOTAL CLINICAL -STABILITY SU BATCH(S) (ALL DRUGS) -APPLICATION/COMPENDIAL REQUIREMENTS-NO OTHER CHANGES PLUS MULTI-POINT DISSOLUTION PROFILES IN 

THREE OTHER MEDIA (e.g., WATER, 0.1N HCL, AND USP BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
A-5

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

MANUFACTURING - EQUIPMENT

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION 

I -EQUIPMENT CHANGES -ALTERNATE EQUIPMENT OF -UPDATED BATCH RECORD -

-NO OTHER CHANGES SAME DESIGN AND PRINCIPLE -STABILITY

(ALL DRUGS) REQUIREMENTS

-AUTOMATED EQUIPMENT -APPLICATION/COMPENDIAL 

-NO BIOSTUDY

II -EQUIPMENT CHANGES -CHANGE TO EQUIPMENT OF A -UPDATED BATCH RECORD -

-NO OTHER CHANGES DIFFERENT DESIGN AND -STABILITY S

(ALL DRUGS) REQUIREMENTS PLUS MULTIOPERATING PRINCIPLE -APPLICATION/COMPENDIAL 

POINT DISSOLUTION PROFILES IN THREE OTHER MEDIA (e.g., WATER, 0.1N HCL, AND USP BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
A-6

EXTENDED RELEASE SOLID ORAL DOSAGE FORMS

MANUFACTURING - PROCESSING

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION 

I -PROCESSING CHANGES AFFECTING -ADJUSTMENT OF EQUIPMENT -UPDATED BATCH RECORD 

THE NON-RELEASE CONTROLLING OPERATING CONDITIONS (e.g. -APPLICATION/COMPENDIAL EXCIPIENTS AND/OR THE RELEASE mixing times, operating speeds, etc.) REQUIREMENTSCONROLLING EXCIPIENTS -WITHIN APPROVED APPLICATION -NO BIOSTUDY-NO OTHER CHANGES RANGES

II -PROCESSING CHANGES AFFECTING -ADJUSTMENT OF EQUIPMENT -UPDATED BATCH RECORD 

THE NON-RELEASE CONTROLLING OPERATING CONDITIONS (e.g. -STABILITY EXCIPIENTS AND/OR THE RELEASE mixing times, operating speeds, etc.) -APPLICATION/COMPENDIAL CONTROLLING EXCIPIENTS -BEYOND APPROVED APPLICATION REQUIREMENTS PLUS MULTI-POINT -NO OTHER CHANGES RANGES DISSOLUTION PROFILES IN THREE 

OTHER MEDIA (e.g. WATER, 0.1N HCL, AND USP BUFFER MEDIA AT pH 4.5 AND 6.8) UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -PROCESSING CHANGES AFFECTING -CHANGE IN THE TYPE OF -UPDATED BATCH RECORD 

THE NON-RELEASE CONTROLLING PROCESS USED (e.g. from wet -STABILITY EXCIPIENTS AND/OR THE RELEASE granulation to direct compression) -APPLICATION/COMPENDIAL (PROFILE) CONROLLING EXCIPIENTS REQUIREMENTS 

-BIOSTUDY OR IVIVC1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TESTING SHOUL

1

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-1

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

NON-RELEASE CONTROLLING COMPONENTS AND COMPOSITION

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I -COMPLETE OR PARTIAL ALL DRUGS -STABILITY 

DELETION OF COLOR/FLAVOR -APPLICATION/COMPENDIAL -CHANGE IN INKS, IMPRINTS REQUIREMENTS-UPTO SUPAC-IR LEVEL 1 -NO BIOSTUDYEXCIPIENT RANGES-NO OTHER CHANGES

II -CHANGE IN TECHNICAL ALL DRUGS -NOTIFICATION & UPDATED BATCH 

GRADE AND/OR RECORD SPECIFICATIONS -STABILITY-HIGHER THAN SUPAC-IR -APPLICATION/COMPENDIAL LEVEL 1 BUT LESS THAN REQUIREMENTS PLUS MULTI-POINT LEVEL 2 EXCIPIENT RANGES DISSOLUTION PROFILES IN ADDITIONAL -NO OTHER CHANGES BUFFER STAGE TESTING (e.g., USP BUFFER 

MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -HIGHER THAN SUPAC-IR ALL DRUGS -UPDATED BATCH RECORD 

LEVEL 2 EXCIPIENT RANGES -STABILITY 

-APPLICATION/COMPENDIAL (PROFILE) REQUIREMENTS-BIOSTUDY OR IVIVC1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-2

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

RELEASE CONTROLLING COMPONENTS AND COMPOSITION

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I -5% W/W CHANGE BASED ON TOTAL ALL DRUGS -STABILITY 

RELEASE CONTROLLING EXCIPIENT -APPLICATION/COMPENDIAL (e.g., controlled release polymer, REQUIREMENTSplasticizer) CONTENT -NO BIOSTUDY-NO OTHER CHANGES

II -CHANGE IN TECHNICAL GRADE NON-NARROW -NOTIFICATION & UPDATED BATCH 

AND/OR SPECIFICATIONS RECORD -10% W/W CHANGE BASED ON TOTAL -STABILITYRELEASE CONTROLLING EXCIPIENT -APPLICATION/COMPENDIAL (e.g., controlled release polymer, REQUIREMENTS PLUS MULTI-POINT plasticizer) CONTENT DISSOLUTION PROFILES IN ADDITIONAL -NO OTHER CHANGES BUFFER STAGE TESTING (e.g., USP BUFFER 

MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

NARROW -UPDATED BATCH RECORD 

-APPLICATION/COMPENDIAL (PROFILE) -STABILITY REQUIREMENTS-BIOSTUDY OR IVIVC1

III >10% W/W CHANGE BASED ON TOTAL ALL DRUGS -UPDATED BATCH RECORD & STABILITY 

RELEASE CONTROLLING EXCIPIENT -APPLICATION/COMPENDIAL (PROFILE) (e.g., controlled release polymer, plasticizer) REQUIREMENTSCONTENT -BIOSTUDY OR IVIVC1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TESTING SHOUL

1

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-3

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

SITE CHANGE

LEVEL CLASSIFICATION THERAPEUTIC TEST DOCUMENTATION 

RANGE 

I -SINGLE FACILITY ALL DRUGS -APPLICATION/COMPENDIAL REQUIREMENTS 

-COMMON PERSONNEL -NO BIOSTUDY-NO OTHER CHANGES

II -SAME CONTIGUOUS ALL DRUGS -IDENTIFICATION AND DESCRIPTION OF SITE 

CAMPUS CHANGE, AND UPDATED BATCH RECORD -COMMON PERSONNEL -NOTIFICATION OF SITE CHANGE -NO OTHER CHANGES -STABILITY

-APPLICATION/COMPENDIAL REQUIREMENTS PLUS MULTI-POINT DISSOLUTION PROFILES IN ADDITIONAL BUFFER STAGE TESTING (e.g., USP BUFFER MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -DIFFERENT CAMPUS ALL DRUGS -NOTIFICATION OF SITE CHANGE 

-DIFFERENT PERSONNEL -UPDATED BATCH RECORD 

-STABILITY-APPLICATION/COMPENDIAL (PROFILE) REQUIREMENTS-BIOSTUDY OR IVIVC 1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-4

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

SCALE-UP/SCALE-DOWN

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION 

I -SCALE-UP OF BIO-BATCH(S) 10X -UPDATED BATCH RECORD -AN

OR PIVOTAL CLINICAL -STABILITY BATCH(S) (ALL DRUGS) -APPLICATION/COMPENDIAL REQUIREMENTS-NO OTHER CHANGES -NO BIOSTUDY

II -SCALE-UP OF BIO-BATCH(S) >10X -UPDATED BATCH RECORD -CH

 OR PIVOTAL CLINICAL -STABILITY SU BATCH(S) (ALL DRUGS) -APPLICATION/COMPENDIAL REQUIREMENTS-NO OTHER CHANGES PLUS MULTI-POINT DISSOLUTION PROFILES IN 

ADDITIONAL BUFFER STAGE TESTING (e.g., USP BUFFER MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TE

1PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-5

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

MANUFACTURING - EQUIPMENT

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION 

I -EQUIPMENT CHANGES -ALTERNATE EQUIPMENT OF -UPDATED BATCH RECORD 

-NO OTHER CHANGES SAME DESIGN AND PRINCIPLE -STABILITY

(ALL DRUGS) REQUIREMENTS

-AUTOMATED EQUIPMENT -APPLICATION/COMPENDIAL 

-NO BIOSTUDY

II -EQUIPMENT CHANGES -CHANGE TO EQUIPMENT OF A -UPDATED BATCH RECORD 

-NO OTHER CHANGES DIFFERENT DESIGN AND -STABILITY 

(ALL DRUGS) REQUIREMENTS PLUS MULTIOPERATING PRINCIPLE -APPLICATION/COMPENDIAL 

POINT DISSOLUTION PROFILES IN ADDITIONAL BUFFER STAGE TESTING (e.g., USP BUFFER MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION 

1 PERFORMED.

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2
B-6

DELAYED RELEASE SOLID ORAL DOSAGE FORMS

MANUFACTURING - PROCESSING

LEVEL CLASSIFICATION CHANGE TEST DOCUMENTATION FIL

I -PROCESSING CHANGES -ADJUSTMENT OF EQUIPMENT -UPDATED BATCH RECORD -ANN

AFFECTING THE NON- OPERATING CONDITIONS (e.g. -APPLICATION/COMPENDIAL RELEASE CONTROLLING mixing times, operating speeds, etc.) REQUIREMENTSEXCIPIENTS AND/OR THE -WITHIN APPROVED APPLICATION -NO BIOSTUDYRELEASE CONTROLLING RANGESEXCIPIENTS-NO OTHER CHANGES

II -PROCESSING CHANGES -ADJUSTMENT OF EQUIPMENT -UPDATED BATCH RECORD -CHA

AFFECTING THE NON- OPERATING CONDITIONS (e.g. -STABILITY SUPPRELEASE CONTROLLING mixing times, operating speeds, etc.) -APPLICATION/COMPENDIAL EXCIPIENTS AND/OR THE -BEYOND APPROVED APPLICATION REQUIREMENTS PLUS MULTIRELEASE CONTROLLING RANGES POINT DISSOLUTION PROFILES IN EXCIPIENTS ADDITIONAL BUFFER STAGE -NO OTHER CHANGES TESTING (e.g., USP BUFFER 

MEDIA AT pH 4.5-7.5) UNDER STANDARD AND INCREASED AGITATION CONDITIONS UNTIL 80% OF DRUG RELEASED OR AN ASYMPTOTE IS REACHED1

-APPLY SOME STATISTICAL TEST (F2 TEST) FOR COMPARING DISSOLUTION PROFILES2-NO BIOSTUDY

III -PROCESSING CHANGES -CHANGE IN THE TYPE OF -UPDATED BATCH RECORD -PRIO

AFFECTING THE NON- PROCESS USED (e.g. from wet -STABILITYRELEASE CONTROLLING granulation to direct compression) -APPLICATION/COMPENDIAL EXCIPIENTS AND/OR THE (PROFILE) REQUIREMENTS RELEASE CONROLLING -BIOSTUDY OR IVIVCEXCIPIENTS

1

 IN THE PRESENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION ONLY APPLICATION/COMPENDIAL DISSOLUTION TESTING SHO

1

 IN THE ABSENCE OF AN ESTABLISHED IN VITRO/IN VIVO CORRELATION. 2