Guidance for Industry

Immediate Release Solid Oral

Dosage Forms

Scale-Up and Postapproval

Changes: Chemistry,

Manufacturing, and Controls, In

Vitro Dissolution Testing, and

In Vivo Bioequivalence

Documentation
Center for Drug Evaluation and Research (CDER)

November 1995

CMC 5
TABLE OF CONTENTS

I. PURPOSE OF GUIDANCE ........................................ 1

II. DEFINITION OF TERMS ......................................... 3

III. COMPONENTS AND COMPOSITION .............................. 6

IV. SITE CHANGES ............................................... 13

V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN) .............. 16

VI. MANUFACTURING ............................................. 18

VII. IN VITRO DISSOLUTION ........................................ 23

VIII. IN VIVO BIOEQUIVALENCE STUDIES ............................. 23

IX. REFERENCES ................................................ 25

APPENDIX A: NARROW THERAPEUTIC RANGE DRUGS . . . . . . . . . . . . . . . A-1
 This guidance has been prepared by the Immediate Release Scale-up and Post 1

Approval Change (SUPAC) Expert Working Group of the Chemistry Manufacturing

Controls Coordinating Committee (CMC CC) of the Center for Drug Evaluation and

Research at the Food and Drug Administration. This guidance is an informal

communication under 21 CFR 10.90(b)(9) that reflects the best judgment of CDER

employees at this time. It does not create or confer any rights, privileges or benefits for

or on any person, nor does it operate to bind or obligate FDA in any way. For additional

copies of this guidance contact the Consumer Affairs Branch (formerly the Executive

Secretariat Staff), HFD-8, Center for Drug Evaluation and Research, 7500 Standish

Place, Rockville, MD 20855 (Phone: 301-594-1012). An electronic version of this

guidance is also available via Internet by connecting to the CDER file transfer protocol

(FTP) server (CDVS2.CDER.FDA.GOV).

 GUIDANCE FOR INDUSTRY1

IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS

SCALE-UP AND POSTAPPROVAL CHANGES:

CHEMISTRY, MANUFACTURING, AND CONTROLS,

IN VITRO DISSOLUTION TESTING,

AND IN VIVO BIOEQUIVALENCE DOCUMENTATION

I. PURPOSE OF GUIDANCE

This guidance provides recommendations to sponsors of new drug applications

(NDA's), abbreviated new drug applications (ANDA's), and abbreviated

antibiotic applications (AADA's) who intend, during the postapproval period, 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 an immediate release oral formulation. 

This guidance is the result of: 1) a workshop on the scale-up of immediate

release drug products conducted by the American Association of

Pharmaceutical Scientists in conjunction with the United States Pharmacopoeial

Convention and the Food and Drug Administration (FDA); 2) research

conducted by the University of Maryland at Baltimore on the chemistry,

manufacturing and controls of immediate release drug products under the

FDA/University of Maryland Manufacturing Research Contract; 3) the drug

categorization research conducted at the University of Michigan and the

University of Uppsala on the permeability of drug substances; and 4) the Scale-
 See Workshop Report: Scale-up of Immediate Release Oral Solid Dosage Forms, 2

Pharmaceutical Research, 10 (2): 313-316, Skelly et al; and Federal Register. Vol. 59,

No. 183, Thursday, September 22, 1994, pages 48754-59.

2

Up and Post Approval Changes (SUPAC) Task Force which was established by

the Center for Drug Evaluation and Research (CDER) Chemistry, Manufacturing

and Controls Coordinating Committee to develop guidance on scale-up and

other postapproval changes. 

The guidance defines: 1) levels of change; 2) recommended chemistry,

manufacturing, and controls tests for each level of change; 3) in vitro dissolution

tests and/or in vivo bioequivalence tests for each level of change; and 4)

documentation that should support the change. For those changes filed in a

“changes being effected supplement” [21 CFR 314.70(c)], the FDA may, after a

review of the supplemental information, decide that the changes are not

approvable. This guidance thus sets forth application information that should be

provided to CDER to assure continuing product quality and performance

characteristics of an immediate 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 changes

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

over a short period of time, or where the number of batches needed for stability

testing is not specified, sponsors should contact the appropriate CDER review

division or consult other CDER guidances/guidelines to obtain information about

tests and application documentation.

21 CFR 314.70(a) provides that applicants may make changes to an approved

application in accordance with a guideline, 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 immediate release dosage forms that affect

components and composition, scale-up, site change, and manufacturing

process or equipment changes, this guidance supersedes the recommendations

in section 4.G of the Office of Generic Drugs 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. DEFINITION OF TERMS2
3

 

A. 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)].

B. Contiguous Campus

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

C. Dissolution Testing

Case A: Dissolution of Q = 85% in 15 minutes in 900 milliliters (mL)

of 0.1N hydrochloride (HCl), using the United States

Pharmacopeia (USP) <711> Apparatus 1 at 100 revolutions

per minute (rpm) or Apparatus 2 at 50 rpm.

Case B: Multi-point dissolution profile in the application/compendial

medium at 15, 30, 45, 60, and 120 minutes or until an

asymptote is reached for the proposed and currently

accepted formulation.

Case C: Multi-point dissolution profiles performed in water, 0.1N HCl,

and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate

profiles) for the proposed and currently accepted

formulations. Adequate sampling should be performed at

15, 30, 45, 60, and 120 minutes until either 90% of drug

from the drug product is dissolved or an asymptote is

reached. A surfactant may be used with appropriate

justification. 
4

D. Drug Product

A drug product is a finished dosage form (e.g., tablet, capsule, or

solution) 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 tablets, chewable tablets, capsules, and soft

gelatin capsules.

E. 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)].

F. Equipment

Automated or non-automated, mechanical or non-mechanical equipment

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

the drug product.

G. Formulation

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

H. Justification

Reports containing scientific data and expert professional judgment to

substantiate decisions.

I. New Drug Substance

Any substance that, when used in the manufacture, processing, or

packing of a drug, causes that drug to be a new drug, but does not

include intermediates used in the synthesis of such substance [21 CFR

310.3(g)].

J. Operating Principle

Rules or concepts governing the operation of the system.
5

K. 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 (see the FEDERAL REGISTER of Thursday,

September 22, 1994, 59 FR 48754-59).

L. Process

A series of operations and/or actions used to produce a desired result.

M. Ranges

The extent to which or the limits between which acceptable variation

exists. 

N. Same

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

O. Scale-up

The process of increasing the batch size.

P. Scale-down

The process of decreasing the batch size.

Q. Similar

Having a general likeness.

R. Significant body of information

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. 
6

S. 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 the production phase.

Validation necessarily includes process qualification (the qualification of

materials, equipment, systems, buildings, and personnel), but it also

includes the control of the entire processes for repeated batches or runs. 

III. COMPONENTS AND COMPOSITION 

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

product. Changes in the amount of 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.

A. Level 1 Changes

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 excipients, expressed as percentage (w/w) of

total formulation, less than or equal to the following percent

ranges:
7

EXCIPIENT PERCENT EXCIPIENT

(w/w) OUT OF TOTAL

TARGET DOSAGE

FORM WEIGHT

Filler ±5

Disintegrant

Starch ±3

Other ±1

Binder ±0.5

Lubricant

Calcium (Ca) or

Magnesium (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 excipient changes should not be

more than 5%. (Example: In a product consisting of active

ingredient A, lactose, microcrystalline cellulose and magnesium

stearate, the lactose and microcrystalline cellulose should not vary

by more than an absolute total of 5% (e.g. lactose increases 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). 
8

The components (active and excipients) in the formulation should

have numerical targets which 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 approved target composition

and not on previous Level 1 changes in the composition.

2. Test Documentation

a. Chemistry Documentation

Application/compendial release requirements and stability

testing.

Stability testing: one batch on long-term stability data

reported in annual report.

b. Dissolution Documentation

None beyond application/compendial requirements.

c. In Vivo Bioequivalence Documentation

None.

3. Filing Documentation

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

B. Level 2 Changes

1. Definition of Level

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

formulation quality and performance. Tests and filing

documentation for a Level 2 change vary depending on three

factors: therapeutic range, solubility, and permeability.

Therapeutic range is defined as either narrow or non-narrow. A list

of narrow therapeutic range drugs is provided in Appendix A. Drug

solubility and drug permeability are defined as either low or high. 

Solubility is calculated based on the minimum concentration of

drug, milligram/milliliter (mg/mL), in the largest dosage strength,

determined in the physiological pH range (pH 1 to 8) and
9

temperature (37 + 0.5 C). High solubility drugs are those with a o

dose/solubility volume of less than or equal to 250 mL. (Example: 

Compound A has as its lowest solubility at 37 + 0.5 C, 1.0 mg/mL o

at pH 7, and is available in 100 mg, 200 mg and 400 mg strengths. 

This drug would be considered a low solubility drug as its

dose/solubility volume is greater than 250 mL (400 mg/1.0

mg/mL=400 mL). Permeability (Pe, centimeter per second) is

defined as the effective human jejunal wall permeability of a drug

and includes an apparent resistance to mass transport to the

intestinal membrane. High permeability drugs are generally those

with an extent of absorption greater than 90% in the absence of

documented instability in the gastrointestinal tract, or those whose

permeability attributes have been determined experimentally). 

Examples:

a. Change in the technical grade of an excipient. (Example:

Avicel PH102 vs. Avicel PH200.)

b. Changes in excipients, expressed as percent (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):

EXCIPIENT PERCENT EXCIPIENT (w/w)

OUT OF TOTAL TARGET

DOSAGE FORM WEIGHT

Filler ±10

Disintegrant

Starch ±6

Other ±2
10

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 excipient changes

should not change by more than 10%. 

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 approved target composition and not on

the composition based on previous Level 1 or Level 2 changes.

2. Test Documentation

a. Chemistry Documentation

Application/compendial release requirements and batch

records.

Stability testing: 1 batch with 3 months accelerated stability

data in supplement and 1 batch on long-term stability. 

b. Dissolution Documentation

Case A: High Permeability, High Solubility Drugs
11

Dissolution of 85% in 15 minutes in 900 mL of

0.1N HCl. If a drug product fails to meet this

criterion, the applicant should perform the

tests described for Case B or C (below).

Case B: Low Permeability, High Solubility Drugs

Multi-point dissolution profile should be

performed in the application/compendial

medium at 15, 30, 45, 60 and 120 minutes or

until an asymptote is reached. The dissolution

profile of the proposed and currently used

product formulations should be similar.

Case C: High Permeability, Low Solubility Drugs

Multi-point dissolution profiles should be

performed in water, 0.1 N HCl, and USP buffer

media at pH 4.5, 6.5, and 7.5 (five separate

profiles) for the proposed and currently

accepted formulations. Adequate sampling

should be performed at 15, 30, 45, 60, and

120 minutes until either 90% of drug from the

drug product is dissolved or an asymptote is

reached. A surfactant may be used, but only

with appropriate justification. The dissolution

profile of the proposed and currently used

product formulations should be similar.

c. In Vivo Bioequivalence Documentation

None: if the situation does not meet the description in 

Case A, Case B or Case C, refer to Level 3 changes.

3. Filing Documentation

Prior approval supplement (all information including accelerated

stability data); annual report (long-term stability data).
12

C. Level 3 Changes

1. Definition of Level

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

impact on formulation quality and performance. Tests and filing

documentation vary depending on the following three factors: 

therapeutic range, solubility, and permeability. 

Examples: 

a. Any qualitative and quantitative excipient changes to a

narrow therapeutic drug beyond the ranges noted in Section

III.A.1.b.

b. All other drugs not meeting the dissolution criteria under

Section III.B.2.b.

c. Changes in the excipient ranges of low solubility, low

permeability drugs beyond those listed in Section III.A.1.b.

d. Changes in the excipient ranges of all drugs beyond those

listed in Section III.B.1.b.

2. Test Documentation

a. Chemistry Documentation

Application/compendial release requirements and batch

records.

Significant body of information available:

One batch with three months accelerated

stability data reported in supplement; one

batch on long-term stability data reported in

annual report.

Significant body of information not available:

Up to three batches with three months

accelerated stability data reported in
13

supplement; one batch on long-term stability

data reported in annual report.

b. Dissolution Documentation

Case B dissolution profile as described in Section III.B.2.b.

c. In Vivo Bioequivalence Documentation

Full bioequivalence study. The bioequivalence study may be

waived with an acceptable in vivo/in vitro correlation has

been verified.

3. Filing Documentation

Prior approval supplement (all information including accelerated

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

IV. SITE CHANGES

Site changes consist of changes in location of the site of manufacture for both

company-owned and contract manufacturing facilities and do not include any

scale-up changes, changes in manufacturing (including process and/or

equipment), or changes in components or composition. Scale-up is addressed in

Section V of this guidance. New manufacturing locations should have a

satisfactory current Good Manufacturing Practice (CGMP) inspection.

A. Level 1 Changes

1. Definition of Level

Level 1 changes consist of site changes within a single facility

where the same equipment, standard operating procedures

(SOP's), environmental conditions (e.g., temperature and humidity)

and controls, and personnel common to both manufacturing sites

are used, and where no changes are made
14

to the manufacturing batch records, except for administrative

information and the location of the facility. Common is defined as

employees already working on the campus who have suitable

experience with the manufacturing process.

2. Test Documentation

a. Chemistry Documentation

None beyond application/compendial release requirements.

b. Dissolution Documentation

None beyond application/compendial release requirements.

c. In Vivo Bioequivalence Documentation

None.

3. Filing Documentation

Annual report.

B. Level 2 Changes

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, SOP's, 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 manufacturing batch records, except for administrative

information and the location of the facility. 

2. Test Documentation

a. Chemistry Documentation

Location of new site and updated batch records. None

beyond application/compendial release requirements.
15

One batch on long-term stability data reported in annual

report.

b. Dissolution Documentation

None beyond application/compendial release requirements.

c. In Vivo Bioequivalence Documentation

None.

3. Filing Documentation

Changes being effected supplement; annual report (longterm stability test data).

C. Level 3 Changes

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, SOP's, environmental conditions, and controls should

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

changes may be made to the manufacturing batch records except

for administrative information, location and language translation,

where needed. 

2. Test Documentation

a. Chemistry Documentation

Location of new site and updated batch records. 

 Application/compendial release requirements.
16

Stability:

Significant body of data available:

One batch with three months accelerated

stability data reported in supplement; one

batch on long-term stability data reported in

annual report.

Significant body of data not available:

Up to three batches with three months

accelerated stability data reported in

supplement; up to three batches on long- term

stability data reported in annual report.

b. Dissolution Documentation

Case B: Multi-point dissolution profile should be

performed in the application/compendial

medium at 15, 30, 45, 60 and 120 minutes or

until an asymptote is reached. The dissolution

profile of the drug product at the current and

proposed site should be similar.

c. In Vivo Bioequivalence Documentation

None.

3. Filing Documentation

Changes being effected supplement; annual report (long-term

stability data).

V. 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 in the application. Scale-down below 100,000 dosage units is not

covered by this guidance. All scale-up changes should be properly validated

and, where needed, inspected by appropriate agency personnel. 

A. Level 1 Changes
17

1. Definition of Level

Change in batch size, up to and including a factor of 10 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 (are) manufactured in full compliance with

CGMP's; and 3) the same standard operating procedures (SOP's)

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 release requirements. Notification

of change and submission of updated batch records in

annual report.

One batch on long-term stability reported in annual report.

b. Dissolution Documentation

None beyond application/compendial release requirements.

c. In Vivo Bioequivalence

None.

3. Filing Documentation

Annual report (long-term stability data).

B. Level 2 Changes

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 (are) manufactured in full compliance with CGMP'S;

and 3) the same SOP's and controls as well as the same
18

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 release requirements. Notification

of change and submission of updated batch records. 

Stability testing: One batch with three months accelerated

stability data and one batch on long-term stability. 

b. Dissolution Documentation

Case B testing.

c. In Vivo Bioequivalence

None.

3. Filing Documentation

Changes being effected supplement; annual report (long-term

stability data).

VI. MANUFACTURING

Manufacturing changes may affect both equipment used in the manufacturing

process and the process itself.

A. Equipment

1. Level 1 Changes

a. Definition of Change

This category consists of: 1) change from non-automated

or non-mechanical 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.
19

b. Test Documentation

i. Chemistry Documentation

Application/compendial release requirements.

Notification of change and submission of updated

batch records. 

Stability testing: One batch on long-term stability. 

ii. Dissolution Documentation

None beyond application/compendial release

requirements.

iii. In Vivo Bioequivalence Documentation

None.

c. Filing Documentation

Annual report (long-term stability data).

2. Level 2 Changes

a. Definition of Level

Change in equipment to a different design and different

operating principles.

b. Test Documentation

i. Chemistry Documentation

Application/compendial release requirements.

Notification of change and submission of updated

batch records. 
20

Stability testing:

Significant body of data available:

One batch with three months

accelerated stability data reported in

supplement; one batch on long-term

stability data reported in annual report.

Significant body of data not available:

Up to three batches with three months

accelerated stability data reported in

supplement; up to three batches on

long-term stability data reported in

annual report.

ii. Dissolution Documentation

Case C dissolution profile.

iii. In Vivo Bioequivalence Documentation

None.

c. Filing Documentation

Prior approval supplement with justification for change;

annual report (long-term stability data). 

B. Process

1. Level 1 Changes

a. Definition of Level

This category includes process changes including changes

such as mixing times and operating speeds within

application/validation ranges.

b. Test Documentation
21

i. Chemistry Documentation

None beyond application/compendial release

requirements.

ii. Dissolution Documentation

None beyond application/compendial release

requirements.

iii. In Vivo Bioequivalence Documentation

None.

c. Filing Documentation

Annual report.

2. Level 2 Changes

a. Definition of Level

This category includes process changes including changes

such as mixing times and operating speeds outside of

application/validation ranges.

b. Test Documentation

i. Chemistry Documentation

Application/compendial release requirements.

Notification of change and submission of updated

batch records. 

Stability testing: One batch on long-term stability.

ii. Dissolution Documentation

Case B dissolution profile.

iii. In Vivo Bioequivalence Documentation

None.
22

c. Filing Documentation

Changes being effected supplement; annual report (longterm stability data).

3. Level 3 Changes

a. 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.

b. Test Documentation

i. Chemistry Documentation

Application/compendial release requirements. 

Notification of change and submission of updated

batch records. 

Stability testing:

Significant body of data available:

One batch with three months

accelerated stability data reported in

supplement; one batch on long-term

stability data reported in annual report.

Significant body of data not available:

Up to three batches with three months

accelerated stability data reported in

supplement; up to three batches on

long-term stability data reported in

annual report.

ii. Dissolution Documentation

Case B dissolution.

iii. In Vivo Bioequivalence Documentation
23

In vivo bioequivalence study. The bioequivalence

study may be waived if a suitable in vivo/in vitro

correlation has been verified.

c. Filing Documentation

Prior approval supplement with justification; annual report

(long-term stability data). 

VII. IN VITRO DISSOLUTION

See current United States Pharmacopeia/National Formulary, section <711>, for

general dissolution specifications. All profiles should be conducted on at least 12

individual dosage units.

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

similarity factor (f ): 2

 

 

 

f2 = 50 LOG {[1+1/n (R -T ) ] x 100}

n 2 -0.5 

t=1 t t

 

where Rt and Tt are the percent dissolved at each time point. An f2 value

between 50 and 100 suggests the two dissolution profiles are similar.

VIII. IN VIVO BIOEQUIVALENCE STUDIES

Below is a general outline of an in vivo bioequivalence study. It is intended as a

guide and the design of the actual study may vary depending on the drug and

dosage form.

A. Objective: 

To compare the rate and extent of absorption of the drug product for

which the manufacture has been changed, as defined in this guidance, to

the drug product manufactured prior to the change.

B. Design: 

The study design should be a single dose, two-treatment, two-period

crossover with adequate washout period between the two phases of the

study. Equal numbers of subjects should be randomly assigned to each

of the two dosing sequences.
24

C. Selection of Subjects: 

The number of subjects enrolled in the bioequivalence study should be

determined statistically to account for the intrasubject variability and to

meet the current bioequivalence interval.

D. Procedure: 

Each subject should receive the following two treatments:

Treatment 1: Product manufactured with the proposed change.

Treatment 2: Product manufactured prior to the proposed change.

Following an overnight fast of at least 10 hours, subjects should receive

either Treatments 1 or 2 above with 240 mL water. Food should not be

allowed until 4 hours after dosing. Water may be allowed after the first

hour. Subjects should be served standardized meals beginning at 4

hours during the study.

E. Restrictions:

Prior to and during each study phase, water may be allowed ad libitum

except for 1 hour before and after drug administration. The subject

should be served standardized meals and beverages at specified times.

No alcohol or xanthine- or caffeine-containing foods and beverages

should be consumed for 48 hours prior to each study period and until

after the last blood sample is collected.

F. Blood Sampling:

Blood samples should be collected in sufficient volume for analysis of

parent drug and active metabolite(s), if any. The sampling times should

be such that it should be able to capture the Cmax and Tmax during the

absorption period. Sampling should be carried out for at least three

terminal elimination half-lives for both parent drug and active

metabolite(s). Whole blood, plasma or serum, whichever is appropriate

for the analytes, should be harvested promptly and samples should be

frozen at -20 C or -70 C to maintain sample stability. o o

G. Analytical Method:
25

The assay methodology selected should ensure specificity, accuracy,

interday and intraday precision, linearity of standard curves, and

adequate sensitivity, recovery, and stability of the samples under the

storage and handling conditions associated with the analytical method.

H. Pharmacokinetic Analysis:

From the plasma drug concentration-time data, AUC , AUC , C , 0-t 0-inf max

Tmax, K and t should be estimated. el 1/2

I. Statistical Analysis:

Analysis of variance appropriate for a crossover design on the

pharmacokinetic parameters using the general linear models procedures

of SAS or an equivalent program should be performed, with examination

of period, sequence and treatment effects. The 90% confidence intervals

for the estimates of the difference between the test and reference least

squares means for the pharmacokinetic parameters (AUC , AUC , 0-t 0-inf

Cmax) should be calculated, using the two one-sided t-test procedure.

IX. REFERENCES

A. Code of Federal Regulations 210.3(b)(2) and (10), 310.3(b) and (g), and

320.1(a) and (e).

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

C. Federal Register. Vol. 59, No. 183, Thursday, September 22, 1994,

pages 48754-59.

D. “Guideline for Industry: Stability Testing of New Drug Substances and

Products,” U.S. Department of Health and Human Services, Food and

Drug Administration, September 1994.

E. “Guideline for Submitting Documentation for the Manufacture of and

Controls for Drug Products,” U.S. Department of Health and Human

Services, Food and Drug Administration, February 1987.

F. Policy and Procedure Guide #22-90: “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”,
26

U.S. Department of Health and Human Services, Center for Drug

Evaluation and Research, Office of Generic Drugs, September 13, 1990.

G. Workshop Report: Scale up of Immediate Release Oral Solid Dosage

Forms, Pharmaceutical Research, 10 (2): 313-16, Skelly et al.

SUBMITTED BY:

_____________________________________

Allen Rudman

Chair, SUPAC Working Group

APPROVED BY:

______________________________________

Roger L. Williams,M.D.

Chair, CMC CC
A-1

Appendix A

Narrow Therapeutic Range Drugs

Aminophylline Tablets, ER Tablets

Carbamazepine Tablets, Oral Suspension

Clindamycin Hydrochloride Capsules

Clonidine Hydrochloride Tablets

Clonidine Transdermal Patches

Dyphylline Tablets

Disopyramide Phosphate Capsules, ER Capsules

Ethinyl Estradiol/Progestin Oral Contraceptive Tablets

Guanethidine Sulfate Tablets

Isoetharine Mesylate Inhalation Aerosol

Isoproterenol Sulfate Tablets

Lithium Carbonate Capsules, Tablets, ER Tablets

Metaproterenol Sulfate Tablets

Minoxidil Tablets

Oxtriphylline Tablets, DR Tablets, ER Tablets

Phenytoin, Sodium Capsules (Prompt or Extended), Oral Suspension

Prazosin Hydrochloride Capsules

Primidone Tablets, Oral Suspension

Procainamide Hydrochloride, Capsules, Tablets, ER Tablets

Quinidine Sulfate Capsules, Tablets, ER Tablets

Quinidine Gluconate Tablets, ER Tablets

Theophylline Capsules, ER Capsules, Tablets, ER Tablets

Valproic Acid Capsules, Syrup

Divalproex, Sodium DR Capsules, DR Tablets

Warfarin, Sodium Tablets

ER - Extended Release

DR - Delayed Release