Guidance for Industry on Scale-Up

and Post approval

Changes for Immediate Release Solid
Oral
Dosage Forms

by
P.NADANASABAPATHI
Jr Research Associate
Apex Laboratories P Ltd
 PURPOSE OF GUIDANCE
• This guidance provides recommendations to
sponsors of NDA's, ANDA's, and AADA's who
intend, during the post approval period, to
changes
• the components or composition;
• the site of manufacture
• scale-up/scale-down of manufacture; and/or
• manufacturing (process and equipment) of an
immediate release oral formulation.
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
4)documentation that should support the
change.
 DEFINITION OF TERMS
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
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.
 D. Drug Product
• A drug product is a finished dosage form (e.g., tablet, capsule, or
solution) that contains a drug substance,
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.
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
 J. Operating Principle
• Rules or concepts governing the operation of the system.
K. Pilot 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.
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.

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.
 COMPONENTS AND COMPOSITION
CHANGES

• 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
Level 1 Changes - unlikely to have any detectable
impact on formulation quality and performance.

• Deletion or partial deletion of an ingredient which

affect the color or flavor of the drug product; or
change in the ingredient of the printing ink to
another approved ingredient.
• Changes in excipients, expressed as percentage
(w/w) of total formulation, less than or equal to
the following percent ranges:
EXCIPIENT % EXCIPIENT
Filler ±5

Starch ±3
Disintegrants
Other ±1

Binder ±0.5

(Ca) or
Lubricant
(Mg) Stearate ±0.25
Other ±1

Talc ±1
Glidant
Other ±0.1

Film Coat
±1
 Test Documentation
Chemistry Documentation
• Application/ compendial release equirements
and stability testing.
• Stability testing: one batch on long-term stability
data reported in annual report.
Dissolution Documentation
• None beyond application/compendial
requirements.
In Vivo Bioequivalence Documentation
• Annual report (all information including long-term
stability data).
 Level 2 Changes - a significant impact on
formulation quality and performance.
• Level 2 change vary depending on three factors:
therapeutic range, solubility, and permeability.
• Therapeutic range is defined as either narrow or non-
narrow.
• Drug solubility and drug permeability are defined as
either low or high.
• High solubility drugs are those with a dose/solubility
volume of less than or equal to 250 mL.
• Permeability is defined as the effective human jejunal
wall permeability of a drug and includes an apparent
resistance to mass transport to the intestinal membrane.
Changes
• Change in the technical grade of an
excipient.
• 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.
 EXCIPIENT % EXCIPIENT

Filler ±10
Starch ±6
Disintegrants
Other ±2
Binder ±1
(Ca) or
Lubricant
(Mg) Stearate ±0.5
Other ±2
Talc ±2
Glidant
Other ±0.2
Film Coat ±2

The total additive effect of all excipient changes

should not change by more than 10%.
 Test Documentation
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.
Dissolution Documentation
• Case A: High Permeability, High Solubility Drugs
• Case B: Low Permeability, High Solubility Drugs
• Case C: High Permeability, Low Solubility Drugs
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.
Filing Documentation
• Prior approval supplement (all information including accelerated
stability data); annual report (long-term stability data).
 Level 3 Changes- 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.
• Any qualitative and quantitative excipient changes to a
narrow therapeutic drug beyond the ranges
• All other drugs not meeting the dissolution criteria under
Case A,B,C.
• Changes in the excipient ranges of low solubility, low
• permeability drugs beyond those listed in Table 1.
• Changes in the excipient ranges of all drugs beyond
those listed in Table2.
 Test Documentation
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.
one batch on long-term stability data reported in annual report.
Dissolution Documentation
• Case B dissolution profile.
In Vivo Bioequivalence Documentation
• Full bioequivalence study. The bioequivalence study may be waived
with an acceptable in vivo/in vitro correlation has been verified.
Filing Documentation
• Prior approval supplement (all information including accelerated
stability data); annual report (long-term stability data).
 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..
• New manufacturing locations should have a
satisfactory current Good Manufacturing
Practice (CGMP) inspection.
 Level 1 Changes- site changes within a single facility
here 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,.
Test Documentation
Chemistry Documentation
• None beyond application/compendial release requirements.
Dissolution Documentation
• None beyond application/compendial release requirements.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Annual report.
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
Test Documentation
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.
Dissolution Documentation
• None beyond application/compendial release requirements.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Changes being effected supplement; annual report (long term
stability test data).
 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.
Test Documentation
Chemistry Documentation
• Location of new site and updated batch records.
Application/compendial release requirements.
Stability:
Significant body of data available:
• One batch with three months accelerated stability; 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, up
to three batches on long- term stability data reported in annual report.
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..
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Changes being effected supplement; annual report
 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.
Level 1 Changes- in batch size, up to and
including a factor of 10 times the size of the
pilot/biobatch,
• the equipment used to produce the test
batch(es) is of the same design and operating
principles,
• the batch(es) is (are) manufactured in full
compliance with CGMP's,
• 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)
 Test Documentation
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.
Dissolution Documentation
• None beyond application/compendial release
requirements.
In Vivo Bioequivalence
• None.
Filing Documentation
• Annual report (long-term stability data).
Level 2 Changes- Changes in batch size
beyond a factor of ten times the size of the
pilot/bio batch,
• the equipment used to produce the test
batch(es) is of the same design and
operating principles,
• the batch(es) is (are) manufactured in full
compliance with CGMP'S, and
• the same SOP's and controls as well as
the sameformulation and manufacturing
procedures are used on the testbatch(es)
and on the full-scale production batch(es).
 Test Documentation
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.
Dissolution Documentation
• Case B testing.
In Vivo Bioequivalence
• None.
Filing Documentation
• Changes being effected supplement; annual report (long-
term stability data).
 MANUFACTURING -changes may affect
both equipment used in the manufacturing
process and the process itself.
Level 1 Changes consists of:
• change from non-automated or non-
mechanical equipment to automated or
mechanical equipment to move ingredients,
• change to alternative equipment of the same
design and operating principles of the same
or of a different capacity.
 Test Documentation
Chemistry Documentation
• Application/compendial release requirements.
Notification of change and submission of updated
batch records.
• Stability testing: One batch on long-term stability.
Dissolution Documentation
• None beyond application/compendial release
requirements.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Annual report (long-term stability data).
• Level 2 Changes in equipment to a different design and different operating
principles.
Test Documentation
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; up to three
batches on long-term stability data reported in annual report.
Dissolution Documentation
• Case C dissolution profile.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Prior approval supplement with justification for change, annual report (long-
term stability data).
 Process
• Level 1 Changes- includes process changes including
changes such as mixing times and operating speeds within
application/validation ranges.
Test Documentation
Chemistry Documentation
• None beyond application/compendial release requirements.
Dissolution Documentation
• None beyond application/compendial release requirements.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Annual report.
• Level 2 Changes - includes process changes
including changes such as mixing times and operating
speeds outside of application/validation ranges.
Test Documentation
Chemistry Documentation
• Application/compendial release requirements. Notification
of change and submission of updated batch records.
Stability testing: One batch on long-term stability.
Dissolution Documentation
• Case B dissolution profile.
In Vivo Bioequivalence Documentation
• None.
Filing Documentation
• Changes being effected supplement; annual report
(longtermstability data).
• Level 3 Changes - 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.
Test Documentation
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; 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; up to three
batches on long-term stability data reported in annual report.
Dissolution Documentation
• Case B dissolution.
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.
Filing Documentation
• Prior approval supplement with justification; annual report (long-term stability
data).
 IN VITRO DISSOLUTION
• 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 Σn t=1 (Rt-T ) 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.
 IN VIVO BIOEQUIVALENCE
STUDIES
• 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.
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.
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
 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.
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.
 Restrictions:
• Prior to and during each study phase, water may be allowed ad
libitum except for 1 hour before and after drug administration. The
subjectshould 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.
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
 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.
Pharmacokinetic Analysis:
• From the plasma drug concentration-time data, AUC0-t, AUC0-
inf, Cmax, Tmax, Kel and t1/2 should be estimated.
Statistical Analysis:
• Analysis of variance appropriate for a crossover design on the
pharmaco-kinetic 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 (AUC0-t, AUC0-inf, Cmax)
should be calculated, using the two one-sided t-test procedure.