[Federal Register Volume 60, Number 230 (Thursday, November 30, 1995)]
[Notices]
[Pages 61638-61643]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-29218]



      

[[Page 61637]]

_______________________________________________________________________

Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval 
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution 
Testing; In Vivo Bioequivalence Documentation; Guidance; Notice

  Federal Register / Vol. 60, No. 230 / Thursday, November 30, 1995 / 
Notices  
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[[Page 61638]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95D-0349]


Immediate Release Solid Oral Dosage Forms; Scale-Up and 
Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro 
Dissolution Testing; In Vivo Bioequivalence Documentation; Guidance

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guidance entitled ``Immediate Release Solid Oral Dosage Forms; Scale-Up 
and Postapproval Changes: Chemistry, Manufacturing, and Controls; In 
Vitro Dissolution Testing; In Vivo Bioequivalence Documentation.'' The 
guidance sets forth application information that should be provided to 
the Center for Drug Evaluation and Research (CDER) to assure continuing 
product quality and performance characteristics of immediate release 
solid oral dose formulations for specified changes. The guidance 
fulfills a commitment made in the President's National Performance 
report, ``Reinventing Drug and Medical Device Regulations,'' April 
1995, to reduce through guidance the number of manufacturing changes 
that require preapproval by FDA. The guidance provides recommendations 
to sponsors of new drug applications (NDA's), abbreviated antibiotic 
applications (AADA's), and abbreviated new drug applications (ANDA's) 
who intend, during the postapproval period, to change the components or 
composition of the drug, site of manufacture, scale-up/scale-down of 
manufacture, and/or manufacturing process or equipment. The guidance 
was prepared by the Immediate Release Scale-Up and Postapproval Change 
Expert Working Group of the Chemistry Manufacturing Controls 
Coordinating Committee (CMC CC) at CDER.

DATES: Written comments may be submitted at any time.

ADDRESSES: Submit written requests for single copies of the guidance 
``Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval 
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution 
Testing; In Vivo Bioequivalence Documentation'' to the Consumer Affairs 
Branch (HFD-8) (previously the CDER Executive Secretariat Staff), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855. Send two self-addressed 
adhesive labels to assist that office in processing your requests. An 
electronic version of the guidance document is also available via 
Internet. Requesting persons should connect to the CDER FTP server 
(CDVS2.CDER.FDA.GOV) using the FTP protocol. The guidance is available 
in WordPerfect Versions 5.2 and 6.0. Submit written comments on the 
guidance to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. 
Requests and comments should be identified with the docket number found 
in brackets in the heading of this document. A copy of the guidance and 
received comments are available for public examination in the Dockets 
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

FOR FURTHER INFORMATION CONTACT: Allen Rudman, Center for Drug 
Evaluation and Research (HFD-645), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-0375.

SUPPLEMENTARY INFORMATION: FDA is publishing a guidance entitled 
``Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval 
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution 
Testing; In Vivo Bioequivalence Documentation.'' The guidance specifies 
application information that sponsors should provide to CDER to assure 
continuing product quality and performance characteristics of immediate 
release solid oral dose formulations for changes made in NDA's, AADA's, 
and ANDA's. The guidance fulfills a commitment made in the President's 
National Performance report, ``Reinventing Drug and Medical Device 
Regulations,'' April 1995, to reduce through guidance the number of 
manufacturing changes that require preapproval by FDA.
    The 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 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-Up and Post Approval Changes (SUPAC) Task Force which was 
established by the Center for Drug Evaluation and Research Chemistry, 
Manufacturing, and Controls Coordinating Committee to develop guidance 
on scale-up and other postapproval changes.
    The guidance describes: (1) The levels of change that may be made 
in the components or composition of the drug, site of manufacture, 
scale-up/scale-down of manufacture, and manufacturing process and 
equipment; (2) the 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) filing 
documentation.
     The regulations in Sec. 314.70(a) (21 CFR 314.70(a)) state 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 
Sec. 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.
    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 
behalf of any person, nor does it operate to bind or obligate FDA in 
any way. Different approaches may be followed, but the applicant is 
encouraged to discuss significant variations in advance with FDA review 
divisions to preclude spending time and effort in preparing a 
submission that FDA may later determine to be unacceptable.
    Interested persons may, at any time, submit written comments on the 
guidance to the Dockets Management Branch (address above). Two copies 
of any comments are to be submitted, except that individuals may submit 
one 

[[Page 61639]]
copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. The guidance and received 
comments may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday.
    The text of the guidance follows:

Immediate Release Solid Oral Dosage Forms; Scale-up and Postapproval 
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution 
Testing; In Vivo Bioequivalence Documentation; Guidance

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 dosage 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-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'' (Sec. 314.70(c) (21 CFR 314.70(c))), 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 recommended 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.
     The regulations in Sec. 314.70(a) state 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 
Sec. 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 Terms \1\

     \1\See Workshop Report: Skelly, et al., ``Scale-up of Immediate 
Release Oral Solid Dosage Forms,'' Pharmaceutical Research, 
10(2):313-316; and the Federal Register of September 22, 1994, 59 FR 
48754-59.
---------------------------------------------------------------------------

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 percent in 15 minutes in 900 
milliliters (mL) of 0.1N hydrochloride (HCl), using the United 
States Pharmacopeia (U.S.P.) <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 U.S.P. 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 percent of drug from the drug 
product is dissolved or an asymptote is reached. A surfactant may be 
used with appropriate justification.

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.

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 September 
22, 1994, 59 FR 48754-48759).

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.

[[Page 61640]]


R. Significant body of information

    A significant body of information on the stability of the drug 
product is likely to exist after 5 years of commercial experience 
for new molecular entities, or 3 years of commercial experience for 
new dosage forms.

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 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 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:

                                                                        
------------------------------------------------------------------------
                                             PERCENT EXCIPIENT (w/w) OUT
                 EXCIPIENT                   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 drug product is formulated to 100% of label/
potency. The total additive effect of all excipient changes should 
not be more than 5 percent. (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 percent (e.g., 
lactose increases 2.5 percent and microcrystalline cellulose 
decreases by 2.5 percent) relative to the target dosage form weight 
if it is to stay within the Level 1 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 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 
(mg)/mL), in the largest dosage strength, determined in the 
physiological pH range (pH 1 to 8) and temperature 
(370.5 deg.C). High solubility drugs are those with a 
dose/solubility volume of less than or equal to 250 mL. (Example: 
Compound A has as its lowest solubility at 370.5  deg.C, 
1.0 mg/mL 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 percent 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 versus 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 twofold increase over Level 1 changes):

                                                                        
------------------------------------------------------------------------
                                             PERCENT EXCIPIENT (w/w) OUT
                 EXCIPIENT                   OF TOTAL TARGET DOSAGE FORM
                                                       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 percent of label/
potency. The total additive effect of all excipient changes should 
not change by more than 10 percent.
    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 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: One 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
    Dissolution of 85 percent in 15 minutes in 900 mL of 0.1N HCl. 
If a drug product fails to meet this description, the applicant 
should perform the tests described for Case B or Case 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 drug product formulations should be 
similar.
    Case C: High Permeability, Low Solubility Drugs

[[Page 61641]]

    Multi-point dissolution profiles should be performed in water, 
0.1N HCl, and U.S.P. 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 percent 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 drug 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).

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 cases 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 3 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 3 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 dissolution profile as described in Section III.B.2.b.
    c. In Vivo Bioequivalence Documentation
    Full bioequivalence study. The bioequivalence study may be 
waived when 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 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.
    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 (long-term 
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.
    Stability:
    Significant body of information available:
    One batch with 3 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 3 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

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 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.

[[Page 61642]]

    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 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 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.
    Stability testing: One batch with 3 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 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.
    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.
    Stability testing:
    Significant body of information available:
    One batch with 3 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 3 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 Change

    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
    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.
    c. Filing Documentation
    Changes being effected supplement; annual report (long-term 
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 drug 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 information available:
    One batch with 3 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 3 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
    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 (f2):
    f2 = 50 LOG {[1+1/n nt=1 (Rt-
Tt) 2]-0.5 x 100}
    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 before 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.

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: Drug product manufactured with the proposed change.
    Treatment 2: Drug product manufactured prior to the proposed 
change.
    Following an overnight fast of at least 10 hours, subjects 
should receive either Treatments 1 or 2 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.

[[Page 61643]]


E. Restrictions:

    Before 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 before 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  deg.C or 
-70  deg.C to maintain sample stability.

G. Analytical Method:

    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, AUC0-t, 
AUC0-inf, Cmax, Tmax, Ke1 and t1/2 should 
be estimated.

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 
percent confidence intervals for the estimates of the difference 
between the test and reference least squares means for the 
pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) should 
be calculated, using the two one-sided t-test procedure.

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

    Dated: November 22, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-29218 Filed 11-29-95; 8:45 am]
BILLING CODE 4160-01-F