Write a short note on: [Marks 5]

• a) SUPAC IR
• b) SUPAC MR
• c) SUPAC SS
SUPAC ( Scale Up and Post Approval Changes)
 SUPAC involves the scale up process and the changes made after the
approval in the composition, manufacturing process, manufacturing
equipment and the changes in the site.
• This guidance provide recommendations to sponsors of New Drug
Applications (NDA's), Abbreviated New Drug Applications (ANDA's),
and Abbreviated Antibiotic Drug Applications (AADA's) who intend,
during the post-approval period, to change the components or composition,
the site of manufacture, the scale-up/scale-down of manufacture; and/or
the manufacturing (process and equipment) of an immediate release oral
formulation.
• The guidance thus sets forth application information that should be
provided to CDER (Center for Drug Evaluation and Research) to assure
continuing product quality and performance characteristics of an
immediate release solid oral dose formulation for specified post-approval
changes.
• The guidelines define:
1) Level 1/2/3 changes
• It includes:
a) Level 1 or minor changes along with its definition and examples
b) Level 2 or moderate changes along with its definition and examples
c) Level 3 or major changes along with its definition and examples
2) Test documentation - It includes:
a) Chemistry documentation
b) Dissolution documentation
c) In vivo bioequivalence documentation (in case SUPAC IR): bioequivalence
documentation (in case SUPAC MR).
In case of SUPAC SS, test documentation includes:
a) Chemistry documentation
b) In vitro release documentation
c) In vivo bioequivalence documentation

3) Filing documentation
• The documentation includes data such as:
• a) Annual report (all information including long-term stability data
• b) Prior approval supplement: (all information including accelerated
stability data
• c) Changes being effected supplement
• d) Prior supplement approval justification for change
The FDA has issued following guidance for SUPAC, designated as:
• i) SUPAC IR (for immediate release tablets, chewable tablets, capsules
and soft gelatin)
• ii) SUPAC-MR (for modified release solid oral dosage form)
• iii)SUPAC SS (for non-sterile semisolid dosage form including creams,
gels, ointments, lotions).
A) For SUPAC-IR:

a) For Components and Composition

b) For Site Changes
c) Changes in Batch Size
d) Manufacturing- 1. Equipment 2. Process
• a) For components and composition:
• This section of guidance focuses on the 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 changes.
 Level 1 changes for components
Test documentation
and composition of excipients

Level 1 changes are those that are a. Chemistry documentation:

unlikely to have any detectable Application/compendial
impact on formulation quality and release requirements and
performance. stability testing.
Examples: Stability testing: one batch on
long-term stability data
a. Deletion or partial deletion of an
reported in annual report.
ingredient intended to affect the
color or flavor of the drug product; b. Dissolution documentation:
or change in the ingredient of the None beyond application
printing ink to another approved /compendial requirements.
ingredient.
c. c. In vivo bioequivalence
b. Changes in excipients, expressed documentation: None.
as percentage (w/w) of total
formulation, less than or equal to the
following percent ranges the total
additive effect of all excipient
changes should not be more than 5%

Filing documentation: Annual report (all information including long-term

stability data).
Level 2 changes for components
Test documentation
and composition of excipients

Level 2 changes are those that could a. Chemistry documentation:

have a significant impact on Application/compendial release
formulation quality and requirements and batch records
performance, Tests and filing
Stability testing: 1 batch with 3
documentation for a Level 2 change
months accelerated stability data in
vary depending on three factors
supplement and I batch on long-term
therapeutic range, solubility, and
stability.
permeability.
b. Dissolution documentation:
Examples:
Case A High permeability. High
a. Change in the technical grade of an
solubility drugs. Dissolution of 85%
excipient. (Example: PH102 vs.
in 15 minutes in 900 mL of 0.1N
Avicel PH200.) Avicelb.
HCl. If a drug product fails to meet
b. Changes in excipients, expressed as
this criterion, the applicant should
percent (w/w) of total formulation,
perform the tests described for Case
greater than those listed above for
B or C (below).
a Level 1 change but less than or
equal to the following percent Case B Low permeability, High
ranges (which represent a two fold solubility drugs. Multi-point
increase over Level 1 changes): The dissolution profile should be
total additive effect of all excipient performed in the
changes should not change by more application/compendia medium at
than 10%. 15, 30, 45, 60 and 120 minutes or
until an asymptote is reached. The
dissolution profile of the proposed
and currently used product
formulations should be similar.
Case C High permeability, Low
solubility drugs. Multi-point
dissolution profiles should be
performed in water, 0.1 N HCl, and
USP buffer media at pH 4.5, 6.5,
and 7.5 (five separate profiles) for
the proposed and currently accepted
formulations. Adequate sampling
should be performed at 15, 30, 45,
60, and 120 minutes until either
90% of drug from the drug product
is dissolved or an asymptote is
reached. A surfactant may be used,
 but only with appropriate
justification. The dissolution profile
of the proposed and currently used
product formulations should be
similar.
c. In vivo bioequivalence
documentation: None.
If the situation does not meet the description
in Case A, Case B or Case C, refer to Level
3 changes.

Filing documentation Prior approval supplement (all information including accelerated

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

Level 3 changes for components

Test documentation
and composition of excipients

Level 3 changes are those that are likely a. Chemistry documentation:

to have a significant impact on Application/compendial release
formulation quality and requirements and batch records Stability
performance. Tests and filing testing:
documentation vary depending on the
i) Significant body of information available
following three factors: therapeutic
One batch with three months accelerated
range, solubility. and permeability.
stability data reported in supplement; one
Examples: batch on long-term stability data reported
in annual report.
a. Any qualitative and quantitative excipient
changes to a narrow therapeutic drug ii) Significant body of information not
beyond the ranges noted in Section available Up to three batches with three
III.A.1.b. months accelerated stability data reported in
supplement; one batch on long-term
b. All other drugs not meeting the
stability data reported in annual report.
dissolution criteria under Section Ⅲ.Β.2.6.
b. Dissolution documentation: Case B
c. Changes in the excipient ranges of low
dissolution testing.
solubility, low permeability drugs beyond
those listed in Section III.A.1.b. c. In vivo bioequivalence documentation:
Full bioequivalence study. The
d. Changes in the excipient ranges of all
bioequivalence study may be waived with
drugs beyond those listed in Section
an acceptable in vivo/in vitro correlation has
III.B.1.b.
been verified.
Filing documentation Prior approval supplement (all information including accelerated
stability data); annual report (long-term stability data).

• b) 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 for site Test documentation

Level 1 changes consist of site changes a. Chemistry documentation: None beyond

within a single facility where the same application / compendial release
equipment, Standard Operating requirements.
Procedures (SOP's), environmental
b. Dissolution documentation None beyond
conditions (e.g., temperature and humidity)
application/compendial release
and controls, and personnel common to both
requirements,
manufacturing sites are used, and where no
changes are manufacturing except for c. In vivo bioequivalence documentation:
made to the batch records, administrative None,
information and the location of the
facility.

Filing documentation Annual Report

Level 2 changes for site Test documentation

 Level 2 changes consist of site changes a. Chemistry documentation Location
within a contiguous campus, or between of new site and updated batch
facilities in adjacent city blocks, where records. None beyond
the same equipment, SOP's, application/compendial release
environmental conditions (e.g., requirements. One batch on long-
temperature and humidity) and controls, term stability data reported in annual
and personnel common to both report.
manufacturing sites are used, and where b. Dissolution None documentation
no changes are made to the manufacturing beyond application/compendial
batch records except for administrative release requirements
information and the location of the c. In Vivo bioequivalence
facility. documentation: None

Filing documentation Changes being effected supplement; annual report (long-term

stability data).

Level 3 changes for site Test documentation

Level 3 changes consist of a change in a. Chemistry documentation Location

manufacturing site to a different campus. of new site and updated batch
records. Application/compendial
A different campus is defined as one that is
release requirement.
not on the same original contiguous site or
Stability testing is carried out for
where the facilities are not in adjacent
significant body of data available
city blocks.
and significant body of data not
To qualify as a Level 3 change, the same available:
equipment, SOP's, environmental
conditions, and controls should be used in
the manufacturing process at the new site, b. Dissolution documentation Case B
and no changes may be made to the dissolution testing
manufacturing batch records except for
administrative information, location and
language translation, where needed. c. In vivo bioequivalence documentation:
None.

Filing documentation Changes being effected supplement; annual report (long-term

stability data)

c) Changes in batch size:

 • Post-approval 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 in this guidance.
• All scale-up changes should be properly validated and, where needed, inspected by
appropriate agency personnel.

Level 1 changes in batch size Test documentation

Change in batch size, up to and including a a. Chemistry documentation Application/

factor of 10 times the size of the compendial release requirements.
pilot/biobatch, Notification of change and submission of
updated batch records in annual report.
where:
One batch on long-term stability reported in
1) The equipment used to produce the test annual report.
batch(es) is of the same design and
operating principles;
b. Dissolution- None
2) The batch(es) is (are) manufactured in
full compliance with CGMP's; and
3) The same standard operating procedures c. In vivo bioequivalence - None.
(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).

Filing documentation Annual report (long-term stability data)

Level 2 changes in batch size Test documentation

Changes in batch size beyond a factor of a. Chemistry documentation:

ten times the size of the pilot/biobatch, Application/ compendial release
requirements. Notification of
where:
change and submission of updated
1) The equipment used to produce the batch records.
test batch(es) is of the same design Stability testing: One batch with
and operating principles; three months accelerated stability
2) The batch(es) manufactured (are) data and one batch on long-term
full in compliance with CGMP'S; stability
and b. Dissolution documentation: Case B
3) 3) The same SOP's and controls as testing.
well as the same formulation and c. In vivo bioequivalence: None.
 manufacturing procedures are used
on the test batch(es) and on the full-
scale production batch(es).
Filing documentation Changes being effected supplement; annual report (long-term
stability data).

d) Manufacturing: Manufacturing changes may affect both equipment used in the

manufacturing process and the process itself.
i) For Equipment:

Level 1 changes for manufacturing

Test documentation
equipment

This category consists of: i. Chemistry documentation

Application/compendial release
1) Change from non-automated or non-
requirements.
mechanical equipment to automated or
mechanical equipment to move Notification of change and submission of
ingredients; and updated batch records.
2) Change 10 alternative equipment of the Stability testing: One batch on long-term
same design and operating principles of the stability.
same or of a different capacity.
ii. Dissolution documentation - None
beyond application/compendial
requirements. release
iii. In vivo bioequivalence
documentation: None.

Filing documentation Annual report (long-term stability data)

Level 2 changes for manufacturing

Test documentation
equipment

Change in equipment to a different i. Chemistry documentation

design and different operating Application/compendial release
principles requirements. Notification of change
 and submission of updated batch
records.
Stability testing is carried out for
significant body of data available
and significant body of data not
available:
ii. Dissolution documentation Case C
dissolution profile.
iii. In vivo bioequivalence
documentation: None.

Filing documentation: Prior approval supplement with justification for change; annual
report (long-term stability data).

ii) For Process

Level 1 changes for manufacturing

Test documentation
process

This category includes process changes i. Chemistry documentation None beyond

including changes such as mixing times application compendial release
and operating speeds within requirements.
application/validation ranges.
ii. Dissolution documentation: None
beyond application/compendial
requirements. release
iii. In vivo bioequivalence documentation-
None.

Filing documentation- Annual Report

Level 2 changes for manufacturing

Test documentation
process
 This category includes process changes i. Chemistry documentation
including changes such as mixing times Application/compendial release
and operating speeds outside of requirements. Notification of change and
application/validation ranges. 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.

Filing documentation Changes being effected supplement; annual report (long-term

stability data).

Level 3 changes for manufacturing

Test documentation
process

This category includes change in the type of i. Chemistry documentation Application/

process used in the manufacture of the compendial release requirements.
product, such as a change from wet Notification of change and submission of
granulation to direct compression of dry updated batch records.
powder..
Stability testing is carried out for significant
body of data available and significant body
of data not available:
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.

Filing documentation Prior approval supplement with justification; annual report (long-
term stability data).

In vitro dissolution: Dissolution profiles may be compared using the following

equation that defines a similarity factor (f2)
where R, and T, are the percent dissolved at each time point. An f value between
50 and 100 suggests the two dissolution profiles are similar.

In vivo bioequivalence studies: Below is a general outline of an in vivo

bioequivalence study.
It is intended as a guide and the design of the actual study may vary depending
on the drug and dosage form.
A. Objective: To compare the rate and extent of absorption of the drug product
for which the manufacture has been changed, as defined in this guidance, to the
drug product manufactured prior to the change.

B. Design: The study design should be a single dose, two-treatment, two-period

crossover with adequate washout period between the two phases of the study.
Equal numbers of subjects should be randomly assigned to each of the two dosing
sequences.
C. Selection of subjects: The number of subjects enrolled in the bioequivalence
study should be determined statistically to account for the intrasubject variability
and to meet the current bioequivalence interval.
D. Procedure: Each subject should receive the following two treatments:
Treatment 1: Product manufactured with the proposed change.
Treatment 2: Product manufactured prior to the proposed change. Following an
overnight fast of at least 10 hours, subjects should receive either Treatments 1 or
2 above with 240 mL water. Food should not be allowed until 4 hours after
dosing. Water may be allowed after the first hour. Subjects should be served
standardized meals beginning at 4 hours during the study.

E. Restrictions: Prior to and during each study phase, water may be allowed ad
libitum except for 1 hour before and after drug administration. The subject
should be served standardized meals and beverages at specified times. No
alcohol or xanthine- or caffeine-containing foods and beverages should be
consumed for 48 hours prior to each study period.

F. Blood sampling: Blood samples should be collected in sufficient volume for

analysis of parent drug and active metabolite(s), if any. The sampling times
should be such that it should be able to capture the Cmax and Tmax during the
absorption period. Sampling should be carried out for at least three terminal
elimination half-lives for both parent drug and active metabolite(s). Whole blood,
plasma or serum, whichever is appropriate for the analytes, should be harvested
promptly and samples should be frozen at - 20 °C or -70 °C to maintain sample
stability.

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 K el and t1/2should 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% 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.

B) For SUPAC-MR:
A) For non-release controlling excipients: This section of guidance focuses
on changes in non-release controlling excipients in the drug product. For
modified release solid oral dosage forms, consideration should be given as
to whether the excipient is critical or not critical to drug release.
  The sponsor should provide appropriate justifications for claiming any
excipient(s) as a non-release controlling excipient in the formulation of the
modified release solid oral dosage form.
 The functionality of each excipient should be identified. Changes in the
amount of the drug substance are not addressed by this guidance.
Changes in components or composition that have the effect of adding a
new excipient or deleting an excipient are defined at level 3; except for
Waiver of bioequivalence testing for a change in composition which
involves only a different color, flavor or preservative may be
permissible.

Level 1 changes for for

components and composition of
Test documentation
excipients: non-release controlling
excipients

Level 1 changes are those that are unlikely a. Chemistry documentation:

to have any detectable impact on Application/compendial product release
formulation quality and performance. requirements.
Examples: Stability First production batch on long-
term stability data reported in annual
a. Deletion or partial deletion of an
report.
ingredient intended to affect the color or
flavor of the drug product; or change in the
ingredient of the printing ink to another
b. Dissolution documentation: None,
approved ingredient.
beyond application/compendial
requirements.
b. Changes in non release controlling
excipients, expressed as percentage (w/w)
c. Bioequivalence documentation : None.
of total formulation, less than or equal to the
following percent ranges: The total additive
effect of all non release controlling
excipient changes should not be more than
5%.

Filing documentation- Annual report (all information including long-term stability data).
 Level 2 changes for for
components and composition of
Test documentation
excipients: non-release controlling
excipients

Level 2 changes are those that could have a a. Chemistry documentation:

significant impact on formulation quality Application/compendial product release
and performance. Example: Avicel PH102 requirements and updated executed batch
vs. Avicel PH200. records.
Examples: Stability: One batch with three months
accelerated stability data reported in prior
a. A change in the technical grade and/or
approval supplement and long-term
specifications of a non-release controlling
stability data of first production batch
excipient.
reported in annual report,
b. Changes in non release controlling
excipients, expressed as percentage (w/w)
of total formulation, greater than those listed b. Dissolution documentation- dissolution
above for a level 1 change, but less than or test is carried out for extended release and
equal to the following percent ranges (which delayed release solid dosage forms.
represent a two-fold increase over level I
changes): The total additive effect of all
nonrelease controlling excipient changes c. Bioequivalence documentation-None.
should not change by more than 10%.

Filing documentation Prior approval supplement (all information including accelerated

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

Level 3 changes for for

components and composition of
Test documentation
excipients: non-release controlling
excipients

Level 3 changes are those that are likely to a. Chemistry documentation: Application /
have a significant impact on formulation compendial product release requirements
quality and performance. and updated executed batch records.
Example:
a. Changes in the non-release Stability testing is carried out for significant
controlling excipient range beyond body of data available and significant body
those listed in Level 2b. of data not available
b. The total weight of the dosage form
b. Dissolution documentation
may be within or outside the
dissolution test is carried out for
 approved original application extended release and delayed release
range. solid dosage forms.
c. Bioequivalence documentation: A
single-dose bioequivalence study. The
bioequivalence study may be waived in
the presence of an established in vitro/in
vivo correlation.

Filing documentation Prior approval supplement (all information including accelerated

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

B) For release controlling excipients:

 This section of the guidance focuses on changes in release controlling
excipients in the drug product.
 For modified release solid oral dosage forms, consideration should be
given as to whether or not the excipient is critical to drug release.
 The sponsor should provide appropriate justifications (i.e., mechanism
of drug release and manufacturing process) for claiming any excipient(s)
as a release controlling excipient in the formulation of the modified release
solid oral dosage form.
 The functionality of each excipient should be identified.
 Changes in the amount of the drug substance are not addressed in this
guidance.
 Changes exceeding the ranges defined in each of the levels below may be
allowed if considered to be within normal batch-to-batch variation and
contained within an approved original application.

Level 1 changes for for

components and composition of
Test documentation
excipients: Release controlling
excipients
Level 1 changes are those that are unlikely a. Chemistry documentation
to have any detectable impact on Application/compendial product release
formulation quality and performance. requirements, Stability: First production
batch on long-term stability data reported
Example:
in annual report.
a. Changes in the release controlling
b. Dissolution documentation None beyond
excipient(s), expressed percentage (w/w) of
application compendial requirements.
total release controlling excipient(s) in the
formulation less than or equal to 5% w/w c. Bioequivalence documentation None.
of total release controlling excipient content
in the modified release solid oral dosage
form.

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

Level 2 changes for for

components and composition of
Test documentation
excipients: Release controlling
excipients

Level 2 changes are those that could have a a. Chemistry documentation

significant impact on formulation quality Application/compendial product release
and performance. requirements and updated executed batch
records.
Example: Eudragit RS-100 vs. Eudragit RL-
100,
Examples: Stability: Stability testing is carried out for
Non-narrow and Narrow drugs
a. Change in the technical grade and/or
therapeutic range
specifications of the release controlling
excipient(s).
b. Changes in the release controlling b. Dissolution documentation: dissolution
excipient(s), expressed As percentage (w/w) testing is carried out for extended release
of total release controlling excipient(s) in and delayed release solid dosage forms.
the formulation, greater than those listed
above for a level 1 change, but less than or
equal to 10% w/w of total release C. Bioequivalence documentation:
controlling excipient content in the bioequivalence documentation is carried out
modified release solid oral dosage form. for Non-narrow and therapeutic range drugs.
Narrow

Filing documentation Prior approval supplement (all information including accelerated

stability data); annual report (long-term stability data).
 Level 3 changes for for
components and composition of
Test documentation
excipients: Release controlling
excipients

Level 3 changes are those that are likely to a. Chemistry documentation

have a significant impact on formulation Application/compendial product release
quality and performance affecting all requirements and updated executed
therapeutic ranges of the drug. batch records.
Examples: Stability: Three batches with three
months' accelerated stability data
reported in prior approval supplement
a. Addition or deletion of release controlling and long. term stability data of first
excipient(s) (e.g release controlling three production batches reported in
polymer/plastic sizer). annual report.

b. Changes in the release controlling

excipient(s), expressed as percentage (w/w)
b. Dissolution documentation
of total release controlling excipient(s) in
dissolution testing is carried out for
the formulation, greater than those listed
extended release and delayed release
above for a level 2 change (ie, greater than
solid dosage forms.
10% w/w of total release controlling
excipient content in the modified release
solid oral dosage form). Total weight of the
c. Bioequivalence documentation: A
dosage form may be within or outside the
single-dose bioequivalence study. The
original approved application range.
bioequivalence study may be waived in
the presence of an established in vitro/in
vivo correlation. Changes in release
controlling excipients in the formulation
should be within the range of release
controlling excipients of the established
correlation.

Filing documentation Prior approval supplement (all information including accelerated

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

C) SUPAC SS:
a) For components and composition of excipients: (Level 1 to Level 3)
 This section of guidance focuses on qualitative and quantitative changes in
excipients in the drug product.
  The chronology of changes in components and composition should be
provided. Changes in components or composition that have the effect of
adding a new excipient or deleting an existing excipient are defined at
Level 3 changes.
 These changes generally result in the need to change the labeling.

Level 1 changes for components

Test documentation
and composition of excipients

Level I changes are those that are unlikely a) Chemistry documentation:

to have any detectable impact on Application/compendial product release
formulation quality and performance. requirements stability testing. and
Examples: Stability testing First production batch on
long-term stability reported in annual report.
a) Deletion or partial deletion of an
ingredient intended to affect the color, b) In vitro release documentation: None.
fragrance, or flavor of the drug product.
c) In vivo bioequivalence documentation:
b) Any change in an excipients upto 5% of None
approved amount of that excipient. The total
additive effect of all excipient changes
should not be more than 5%. Changes in the
composition should be based on the
approved target composition and not on
previous level 1 changes in the composition.
A change in diluent (q.s. excipient) due to
component and composition changes in
excipient may be made and is excluded from
the 5% change limit.
c) Change in a supplier of a structure
forming excipient that is primarily a single
chemical entity (purity ≥ 95%) or change in
a supplier or technical grade of any other
excipient.

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

Level 2 changes for components

Test documentation
and composition of excipients
Level 2 changes are those that a could have a) Chemistry documentation Application/
a significant impact on formulation compendial product release requirements
performance. quality and executed batch records. Stability testing:
One batch with three months accelerated
Examples:
stability data reported in changes being
a) Changes of >5% and <10%, of approved effected supplement and long-term stability
amount of an individual excipient. The total data of first production batch reported in
additive effect of all excipient changes annual report. and
should not be more than 10%. Changes in
b) In vitro release documentation: The in
the composition should be based on the
vitro release rate of a lot of the
approved target composition and not on
new/modified formulation should be
previous level 1 or level 2 changes in the
compared with that of a recent lot of
composition. Changes in diluent (q.s.
comparable age of the pre-change
excipient) due to component and
formulation of the product. The median in
composition changes in excipients are
vitro release rates (as estimated by the
acceptable and are excluded from the 10%
estimated slope from each cell) of the two
change limit.
formulations should be demonstrated to be
b) Change in supplier of a structure forming within the acceptable limits using the testing
excipients (not covered under level 1). procedure described below.

c) Change in the technical grade of structure

forming excipient.
b) In vivo bioequivalence documentation:
d) Change in particle distribution of the size None.
drug substance, if the drug is in suspension.

Filing documentation Changes being effected supplement (all information including

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

Level 3 changes for components

Test documentation
and composition of excipients

Level 3 changes are those that are likely to a) Chemistry documentation

have a significant impact on formulation Application/compendial product release
performance. quality and requirements and executed batch records
of significant body of information
Examples:
available and significant body of
a) Any qualitative and quantitative information not available.
changes in an excipient beyond the
b) In vitro release documentation:
ranges noted in level 2 change.
b) Change in crystalline form of the The in vitro release rate of the
drug substance, if the drug is in new/modified formulation should be
suspension. established as a point of reference.
Under this level 3 change, in vitro
 release documentation is not required,
but sponsors are encouraged to develop
this information for use in subsequent
changes under this guidance.
c) In vivo bioequivalence
documentation: Full bioequivalence
study on the highest strength, with in
vitro release/other approach on the
lower strength(s).

Filing documentation Prior approval supplement (all information including accelerated

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

b) For components and composition of Preservative: (Level 1 to Level 3)

 For semi-solid products, any change in the preservative may affect the
quality of the product.
 If any qualitative or quantitative changes are made in the formulation,
additional testing should be performed.
 No change in the vitro release documentation or in vivo bioequivalence
documentation is needed for preservative changes.

Level 1 changes for components and

Test documentation
composition of preservatives

Quantitatively 10% or less change in the Application/compendial product release

approved amount of preservative. requirements.
Preservative effectiveness test
carried out at lowest specified
preservative level.

Filing documentation- Annual report

Level 2 changes for components and

Test documentation
composition of preservatives
Quantitatively greater than 10% and up to Application/compendial product release
20% change in the approved amount of requirements.
preservative.
Preservative effectiveness test at lowest
specified preservative level.

Filing documentation Changes being effected supplement.

Level 3 changes for components and

Test documentation
composition of preservatives

Quantitatively greater than 20% change in the a) Application/compendial product

approved amount of preservative (including release requirements.
deletion) or use of a different preservative.
b) Preservative effectiveness test at
lowest specified preservative level.
c) Analytical method for
identification and assay for new
preservative.
d) Validation studies to show that the
new preservative does not interfere
with application/compendia test.
e) Executed batch records.
f) Stability testing One batch with
three months accelerated stability
data reported in prior approval
supplement and long-term stability
data of first production batch reported
in annual report.

Filing documentation Prior approval supplement (all information including accelerated

stability data); annual report (long-term stability data)
c) Manufacturing- 1) Equipment 2) Process- (Level 1 to Level 2)
 Manufacturing changes may affect both equipment used in the
manufacturing process and the process itself.
1) Equipment

Level 1 changes for

Test documentation
manufacturing: equipment

Change from non-automated or non- a) Chemistry documentation Application/

mechanical equipment automated. or to compendial product release requirements.
mechanical equipment to transfer
Notification of change and submission of
ingredients.
updated executed batch records.

Stability testing First production batch on

Change to alternative equipment of the same long-term stability reported in annual report.
design and operating principles.
b) In vitro release documentation: None.

c) In vivo bioequivalence documentation:

None.

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

Level 2 changes for

Test documentation
manufacturing: equipment

Change in equipment to a different design or a) Chemistry documentation: - a

different operating principle. Application/ compendial product release
requirements.
Change in type of mixing equipment, such
as high shear to low shear and vice versa. Notification of change and submission of
updated executed batch record of significant
body of information available and
significant body of information not
available.
b) In vitro release documentation: The in
vitro release rate of a lot of the
new/modified formulation should be
compared with that of a recent lot of
comparable age of the pre-change
formulation of the product. The median in
vitro release rates (as estimated by the
 estimated slope from each cell) of the two
formulations should be demonstrated to be
within the acceptable limits using the testing
procedure described below.
c) In vivo bioequivalence Documentation:
None

Filing documentation Changes being effected supplement (all information including

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

2) Process

Level 1 changes for

Test documentation
manufacturing: Process

Process changes, including changes such as a) Chemistry documentation: None

rate of mixing, mixing times, operating beyond application/compendial product
speeds, and holding times within approved release requirements.
application ranges.
Also, order of addition of components
(excluding actives) to either oil or water
phase.
b) In vitro release documentation: None.
c) In-vivo bioequivalence documentation:
None

Filing documentation- Annual report

Level 2 changes for

Test documentation
manufacturing: Process

Process changes, including changes such as a) Chemistry documentation: Application/

rate of mixing, mixing times, rate of compendial product release requirements.
cooling, operating speeds, and holding Notification of change and submission of
times outside approved application ranges updated executed batch records of
for all dosage forms. significant body of information available
and significant body of information not
Also, any changes in the process of
available.
combining the phases.
b) In vitro release documentation: The in
vitro release rate of a lot of the
 new/modified formulation should be
compared with that of a recent lot of
comparable age of the pre-change
formulation of the product. The median in
vitro release rates (as estimated by the
estimated slope from each cell) of the two
formulations should be demonstrated to be
within the acceptable limits using the testing
procedure described below.
c) In vivo bioequivalence documentation:
None

Filing documentation Changes being effected supplement (all information including

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

d) Changes in batch size (Level 1 to Level 2)

 This guidance recommends that the minimum batch size for the NDA
pivotal clinical trial batch or the ANDA/ AADA biobatch be at least 100
kg or 10% of a production batch, whichever is larger.
 Deviations from this recommendation should be discussed with an
appropriate agency review division. All scale changes should be properly
validated and may be inspected by appropriate agency personnel.

Level 1 changes for Batch size Test documentation

Change in batch size, up to and including a a) Chemistry documentation: Application/

factor of ten times the size of the pivotal compendial product release requirements.
clinical trial/biobatch, where: Notification of change and submission of
updated executed batch records in annual
1) The equipment used to produce the test
report.
batch(es) are of the same design and
operating principles;

2) The batch(es) is manufactured in full Stability testing First production batch on

compliance with cGMPs; and long-term stability reported in annual report.

b) In vitro release documentation: None.

3) The same Standard Operating Procedures c) In vivo bioequivalence documentation:
(SOPs) and controls, as well as the same None.
formulation and manufacturing procedures,
are used on the test batch(es) and on the full-
scale production batch(es).

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

Level 2 changes for Batch size Test documentation

Changes in batch size from beyond a factor a) Chemistry documentation: Application/

of ten times the size of the pivotal where: compendial product release requirements.
clinical trial/biobatch,
Notification of change and submission of
1) The equipment used to produce the test updated executed batch records
batch(es) are of the same design and
accelerated Stability testing: One batch with
operating principles;
three months’ stability data reported in
2) The batch(es) is manufactured in full change being effected supplement and long-
compliance with eGMPs; and term stability data of fire production batch
reported in annual report.
3) The same standard operating procedures
(SOPs) and controls, as well as the same b) In vitro release documentation The in
formulation and manufacturing procedures, vitro release rate of a lot of the
are used on the test batch(es) and on the full- new/modified formulation should be
scale production batch(es). compared with that of a recent lot of
comparable age of the pre-change
formulation of the product. The median in
vitro release rates (as estimated by the
estimated slope from each cell) of the two
formulations should be demonstrated to be
within the acceptable limits using the testing
procedure described below.

c) In vivo bioequivalence documentation:

None
 Filing documentation Changes being effected supplement (all information including
accelerated stability data); annual report (long-term stability data).

e) Site Changes (Level 1 to Level 3)

 Manufacturing site changes consist of changes in location in the site of
manufacture, packaging/filling operations, and/or testing for both company
owned and contract manufacturing facilities and do not include any other
level 2 or 3 changes, i.e. 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 within the past two years.

Level 1 changes for Manufacturing

Test documentation
Site

Level 1 changes consist of site changes a) Chemistry documentation: None

within a single facility where the same beyond application/ compendial product
equipment, Standard Operating Procedures release requirements.
(SOPs), environmental conditions (e.g.,
b) In vitro release documentation: None.
temperature and humidity) and controls, and
personnel common to both manufacturing c) In vivo bioequivalence documentation:

sites are used, and where no changes are None.

made manufacturing batch except for to the

records, administrative information and the
location of the facility.

Filing documentation- Annual report.

Level 2 changes for Manufacturing

Test documentation
Site
Level 2 changes consist of site changes a) Chemistry documentation Location of
within contiguous campus, or between new site and updated executed batch
facilities in adjacent city blocks, where records. None beyond application/
similar equipment, Standard Operating compendial product release requirements.
Procedures, (SOPs), environmental
Stability testing First production batch on
conditions (e.g., temperature and humidity)
long-term stability reported in annual report.
and controls, and personnel common to both
manufacturing sites are used, and where no b) In vitro release documentation: None.
changes are made to the manufacturing
batch records, except for administrative c) In VIVO bioequivalence
information and the location of the facility. documentation: None.

Filing documentation Changes being effected supplement, annual report (long-term

stability data)

Level 3 changes for Manufacturing

Test documentation
Site

Level 3 changes consist of a site change in a) Chemistry documentation:

manufacturing site to a different campus. Location of new site and updated
executed batch records significant body
A different campus is defined as one that is
of information available and significant
not on the same original contiguous site or
body of information not available.
where the facilities are not in adjacent city
blocks. Application/ compendial product release
requirements.
Any change to a new contract manufacturer
also constitutes a level 3 change. b) In vitro release documentation: The
in vitro release rate of a lot of the
new/modified formulation should be
compared with that of a recent lot of
comparable age of the pre-change
formulation of the product. The median
in vitro release rates (as estimated by the
estimated slope from each cell) of the
two formulations should be
demonstrated to be within the acceptable
limits using the testing procedure
described below.
c) In vivo bioequivalence
documentation: None.

Filing documentation Changes being effected supplement (all information including

accelerated stability data); annual report (long-term stability data).
In vitro release test:
 In vitro release is one of several standard methods which can be used to
characterize performance characteristics of a finished topical dosage
form, i.e., semisolids such as creams, gels, and ointments.
 Important changes in the characteristics of a drug product formula or the
thermodynamic properties of the drug(s) it contains should show up as a
difference in drug release. Release is theoretically proportional to the
square root of time (√t) when the formulation in question is in control
of the release process because the release is from a receding boundary.
 In vitro release method for topical dosage forms is based on an open
chamber diffusion cell system such as a Franz cell system, fitted usually
with a synthetic membrane.
 The test product is placed on the upper side of the membrane in the open
donor chamber of the diffusion cell and a sampling fluid is placed on the
other side of the membrane in a receptor cell.
 Diffusion of drug from the topical product to and across the membrane
is monitored by assay of sequentially collected samples of the receptor
fluid.
 The in vitro release methodology should be appropriately validated.
Sample collection can be automated.
 Aliquots removed from the receptor phase can be analyzed for drug content
by High Pressure Liquid Chromatography (HPLC) or other analytical
methodology.
 A plot of the amount of drug released per unit area (mcg/cm²) against the
square root of time yields a straight line, the slope of which represents the
release rate.
 This release rate measure is formulation-specific and can be used to
monitor product quality.
 The release rate of the bio batch or currently manufactured batch should be
compared with the release rate of the product prepared after a change as
defined in this guidance.
In vivo bioequivalence studies:
The design of in vivo bioequivalence studies for semisolid dosage forms varies
depending on the pharmacological activity of the drug and dosage form. A brief
general discussion of such tests follows:
Objective: To document the bioequivalence of the drug product for which the
manufacture has been changed, as defined in this guidance, compared to the
drug product manufactured prior to the change or compared to the Reference
Listed Drug (RLD).
Design: The study design is dependent on the nature of the active drug. The
bioequivalence study can be a comparative skin blanching study as in
glucocorticoids or a comparative clinical trial or any other appropriate validated
bioequivalence study (e.g., dermato pharmacokinetic study) for the topical
dermatological drug product.
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 sample sunder the storage and
handling conditions associated with the analytical method.

Platform Technology
Q. What is platform technology? Explain with examples. [Marks 3/5]
Ans.:
 Platform technology is a common or standard method, equipment,
procedure or work practice that may be applied for research,
development or manufacture of different products.
 It is considered as a valuable tool to improve safety, efficacy, efficiency,
productivity and quality of drug product development.
 Platform technology when combined with risk-based approach is the
most systematic method to take advantage of prior knowledge for a given
new molecule.
 It allows a constant development through addition of data for each new
molecule produced using this approach, thereby increasing the robustness
of the platform.
 Platform technology is widely used in biopharmaceutical industry to
manufacture clinical and commercial biopharmaceutical products.
 The use of platform technologies emerged in biopharmaceutical product
development programs during 1990's and primarily focused on
monoclonal antibody production processes.
Following are some examples of platform technologies:
i. Effervescent technology: This technology is used to manufacture fast
dissolving effervescent tablets; and is applied to several molecules to provide
quick relief and taste masking effects.
ii. Inhalational technology: The technology is applied to treat respiratory tract
diseases, and includes MDIs (Metered Dose Inhalers), DPIs (Dry Powder
Inhalers), autohalers and nasal sprays.
The technology is advantageous and supplies a high concentration of drug in the
airways and reduces systemic side effects. The inhalational technology is applied
in the production of variety of inhalers of salbutamol.
iii. Liposomal technology: This technology is used to improve delivery of
drugs, to reduce the toxicity of drugs and to optimize pharmacokinetic
parameters and pharmacological effect.
iv. Microsphere technology: The technology is applied to develop
differentiated formulations for targeted delivery.
Microsphere technology is aimed for a site-specific action; and offers various
advantages like reducing side effects and the need to take repeated injections.
v. Nanotechnology: The technology involves reducing the particle size of drug
(to nanosize) and delivering the same to specific types of cancer cells for the
treatment of cancer.
The technology applied in the development and manufacturing of various drugs
like paclitaxel, fenofibrate, sirolimus, etc.
vi. Orally disintegrating tablet technology:
 The technology is applied to design a drug delivery system for rapid
disintegration of the product.
 The technology offers greater patient compliance and convenient dosing
for all ages of patients.
 Some other examples of platform technology are hot melt extrusion
technology, magnetic targeted carriers, multi-unit pellet system
technology, sprinkle technology, stem-cell based products, sustained
release formulation technology, etc.

Thank You..