[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.
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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.
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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