Scale up and post approval changes.pptx

Scale Up and Post
Approval Changes
(SUPAC)
Prepared by: Jagruti Kachchhi
M.Pharm, Pharmaceutical Quality
Assurance (Semester - 1)
Course Name: Product
Development and Technology
Transfer
Course code: MQA104T

Smt. B N B Swaminarayan Pharmacy College, Salvav, Vapi 2

INTRODUCTION
• Scale up is defined as
"process of increasing batch
size."
• The scale up process and the changes made
after approval in composition, manufacturing
process, manufacturing equipments and
change of site together known as Scale up
and post approval changes or SUPAC.

Purpose of the guidelines
The Manufacturing process
or equipment
Composition
or component
The site of manufacture
The batch size
NDA
ANDA
AADA
Smt. B N B Swaminarayan Pharmacy College, Salvav, Vapi
4

SUPAC Documents
• A series of documents issued by USFDA (CDER -
Center for drug evaluation and research) to help
applicants with post approval changes.
• Currently finalized SUPAC Guidelines are:-
1. SUPAC-IR (Immediate release) - Nov 1995
2. SUPAC-IR Question and Answers- Feb 1997
3. SUPAC-ATLS (Analytical Testing Laboratories) -
Apr 1998
4. SUPAC-MR (Modified Release) - Sep 1997
5. SUPAC-SS (Non-sterile semisolid) - May 1997

SUPAC Guidelines - define
• Minor changes
• Moderate changes
• Major changes
• Annual report
• Changes being affected supplement
• Prior approval supplement
• Application/ Compedial tests
• In - vitro dissolution test
• In - vivo test
Filing
Level of
changes
Tests

SUPAC - IR
means
Scale - Up and Post- Approval
Changes - Immediate Release
Solid Dosage Form

Components and composition
changes
• Level 1 changes:
• Those changes that are unlikely to have any detectable
impact on formulation quality and performance.
• Eg., Change in the color, flavor; Change in the excipients
express as %w/w of total formulations, less than or equal to
the following range:
Excipients %w/w of total dosage form
Filler +/- 5
Binder +/- 0.5

 Test documentation:
• Chemistry documentation
 Application/ compendial product release requirements
Stability testing (1 batch long term)
• Dissolution documentation
 None
• In vivo bioequivalence documentation
 None
Filing documentation:
• Annual reports (All information including long term
stability data)

• Changes are those that could have significant
impact on the formulation quality and performance.
• Ex., Changes in the technical grade of excipients (
Avicel pH 102 vs. Avicel pH 200), Changes in
excipients are expressed as %w/w of total
formulations are as follow:
Excipients %w/w of total dosage form
Filler +/- 10
Binder +/- 10

Test documentation:
 Level 1 + 1 batch with 3 months accelerated stability
study
 Case A- High permeability, high solubility
 Case B- Low permeability, high solubility
 Case C- High permeability, low solubility drugs
None
• As per level 1 + accelerated stability study

• Level 3 changes are those that are likely to have
significant impact on formulation quality and
performance.
• Example:
1. Any qualitative or quantitative excipient changes
to a narrow therapeutic drug beyond the range
for level 1
2. All other drug not meeting the dissolution
criteria as level 2

 Level 1 + 1 month accelerated stability study of 1
batch (SBOIA) or 3 batches (SBOINA)
 Case B- Low permeability, high solubility
 Full bioequivalence study except IVIVC verified.
• Prior approval supplement, annual report.

Manufacturing site change
• It includes the change in location of the site of
manufacturing facilities for both company owned
and contract manufacturer.
• It do not include Scale up.
• Level 1 change:
Change Test documentation Filing documentation
Site change within a
single facility where
same equipment, SOP,
environmental conditions
and common personnel.
Chemistry, dissolution
documentation are
according to compendial
release requirements.
In vivo bioequivalence
not required.
Annual report
14

• Level 2 change:
• Level 3 change:
Site change within a
contiguous campus or
between facilities in
adjacent city blocks.
Level 1+ 1 batch long
term stability in
chemistry
documentation
Annual report
Site change to a different
campus.
Chemistry
documentation: 1 batch
for accelerated stability + 1
batch for long term
stabilityfor SBOlA
Dissolution test for case B
drugs
Annual report
15

Change in batch size
• Post approval changes in the batch size of a batch
from the pivotal/ pilot scale biobatch material to
larger or smaller production.
• Scale down below 100000 dosage units is not
covered by this guideline.
• Scale up changes should be properly validated and
if needed, inspected by appropriate agency
personnel.

• Level 1 change:
• Level 2 change:
Changes in batch size
upto and including
factor of 10 times the size
of pilot batch where
equipment, manufacturer
and SOP are same.
Same as level 2 of site
change requirements
change requirements
Changes in batch size
beyond the factor of 10
As per level 1 + 1 batch
with 3 months accelerated
stability + case B
dissolution testing
Annual report

Manufacturing equipment
changes
• Level 1 change:
Change from non
automated to automated
or vice versa to move
ingredients.
Change to alternative
equipment of same design
and the operating principle
of same or different
capacity.
As per level 1 of batch
size change
As per level 1 of batch
size change
18

• Level 2 change:
Change in equipment to
different design
As per level 3 of the site
change except case C
dissolution instead of Case
B.
change

Manufacturing process changes
• Level 1 change:
Change in process like
mixing time, operating
speed within application/
validation range.
As per level 1 of site
change
As per level 1 of site
change

• Level 2 change:
• Level 3 change:
Process changes like
mixing time, operating
speed outside the
application/ validation
range.
As per level 2 changes in
the site change
As per level 2 changes in
the site change
Change in the type of
process used in the
manufacturer of the
product, such as change
from Wet granulation to
direct compression.
As per the level 3 changes
of components and
composition changes.
As per the level 3 changes
of components and
composition changes.
21

SUPAC - MR
means
Scale - Up and Post - Approval
Changes- Modified Release
Solid Dosage Form

Components and composition- Non
release controlling excipient:
• Level 1 change:
• Deletion or partial deletion of ingredients intended
to affect the color or flavor of the drug product or
change in printing ink to another approved
ingredient.
• Change in non release controlling excipients,
expressed as %w/w of total formulations, less than
or equal to the following changes:
23

Non release controlling excipient %w/w of total formulations
Filler +/-5
Disintegrants
Starch +/-3
Other +/-1
Binder +/-0.5
Lubricant
Ca or Mg stearate +/-0.25
Other +/- 1
Glidant +/-1
24

 Application/ compendial product release requirements
Stability testing (1st production batch long term)
 None
 None
Annual reports (All information including long term stability
data)

• Level 2 change:
• A change in the technical grade or specifications of
non release controlling excipients.
• Changes in non release controlling excipient
expressed as %w/w of total formulations. (Two folded
increase over level 1 changes).
• Chemistry documentation: Application/compendial
product release requirements and updated executed
batch records.
• Stability: 1 batch with 3 month accelerated stability
data reported in prior approval supplement and long
term stability data.

• Dissolution documentation:
• Extended release
 Multipoint dissolution profile in 0.1N HCl and
USP buffer media at pH 4.5 and 6.8 for the changes
drug product and the bio batch or marketed batch
(unchanged drug product).
 Adequate sampling at 1, 2 and 4 hours and every
two hours there after until either 80% of the drug
from the drug product is released or an asymptote is
reached. Surfactant may be used with appropriate
justification.

• Delayed release:
 D.T. performed in 0.1 N HCl for 2 hours (acid
stage) followed by USP buffer media with range of
pH 4.5 - 7.5 (buffer stage) under standard test
conditions and two additional agitation speed.
Apparatus -1: 50, 100 and 150 rpm
Apparatus -2: 50, 75 and 100 rpm
Adequate samplingat 15, 30, 45, 60 and 120 min
until 80% of the drug releases from drug product or
an asymptote is reached.
• Bioequivalence documentation: None

• Prior approval supplement (accelerated stability
data) annual report (long term stability data).
• Level 3 change:
• Changes are as level 2 changes. The total weightof
the dosage form may be within or outside the
approved original application range.

• Chemistry documentation: Application/compendial
product release requirements and updated executed
batch records.
Stability: 1 batch with 3 month accelerated stability
data reported in prior approval supplement and long
term stability data of first 3 production batches reported
in annual report.
• Dissolution documentation: Same as level 2 changes
• Bioequivalence documentation: A single dose
bioequivalence study. It may be in presence of an
established IVIVC.
Filing documentation: Same as level 2 change

Components and composition-
Release controlling excipient:
• The sponsor should provide appropriate
justifications. ( i.e., Mechanism of drug release &
manufacturing process) for claiming any excipientas
a release controlling excipient in the formulation of
modified relea e solid oral dosage form.
• Level 1 Change:
• Same as non release controllingexcipient.

• Level 2 change:
• Same as non release controlling excipient.
• Test documentation for a level 2 changes would
vary depending on whether the product could be
considered to have a narrow therapeutic range.
a) Chemistry documentation: Same as non release
controlling excipient.

• Stability:
 Non narrow therapeutic range drugs: 1 batch with 3
months accelerated stability data reported in prior
approval supplement & long term stability data of first
production batch reported in annual report.
• Narrow therapeutic range drugs: 3 batches with 3
months accelerated stability data reported in prior
approval supplement and long term stability data of first
three production batches reported in annual report.
b) Dissolution documentation: Same as non release
controlling excipient for both non narrowed and narrow
therapeutic range drugs.

C) Bioequivalence documentation:
• Non narrow therapeutic range: None
• Narrow therapeutic range drug: Same as non release
controlling excipient.
 Filing documentation:
• Prior approval supplement (accelerated stability data)
annual report (long term stability data).
• Level 3 change:
• Affecting all the therapeutic ranges.
• Same as non release controlling excipient.

• Same as immediate release solid oral dosage form.
Manufacturing equipment &
process changes
• Same as immediate release solid oral dosage form.
• Same as immediate release solid oral dosage form .

SUPAC - SS
means
Scale - Up and Post Approval
Changes- Non Sterile Semisolid
Dosage form

• Level 1 change:
Components and composition
1. Deletion / partial
deletion of color,
fragrance and flavor of
drug.
2. Upto 5% change in
approved amount of
excipient.
3. Change in supplier of
structure forming &
technical grade of
excipient (purity > 95%)
1. Chemistry
documentation
:Application/ compendial
product release
requirements
Stability:- First production
batch on long term
stability reported in annual
report.
2. In vivo bioequivalence
documentation: None
Annual report
( All information including
long - term stability data)
37

1. Changes of 5 to 10% of
approved amount of
individual excipient
(Diluent - 10%)
2. Change in technical
grade of structure forming
excipients
3. Change in particle size
distribution of drug
substance , if is in
suspension.
1. Chemistry
documentation:
Application/ compendial
product release
requirements & executed
batch records
Stability: 1 batch with 3
months accelerated
stability data reported in
changes being affected
supplement & long term
stability data of first
production batch required
in annual report
2. In vitro release
documentation test
Changes being affected
supplement (All
information including
accelerated stability data)
Annual report (Long term
stability data)
38

• Level 3 change:
Any quantitative and
qualitative change in
excipients (>10%)
Change in crystalline
form of drug substance,
if it is in suspension
Chemistry
documentation: 3
batches with 3 months
accelerated stability study
& 1st 3 production
batches on long term
stability study
In vitro release
documentation
In vivo bioequivalence
documentation
Prior approval supplement
(All information including
Annual report ( long term
stability data)

Preservative:
• Level 1 change:
<10% change in the
approved amount of
preservative
product release
requirements
Preservative effectiveness
test as lowest specified
preservative level.
Annual report

• Level 2 change:
• Level 3 change:
10-20% change in
approved amount of
preservative
Same as level 1 Changes being affected
supplement
>20% Change in approved
amount of preservative,
deletion of preservative or
use of a different
preservative
Additionally executed
batch records.
For new preservative,
analytical method for
assay, identification and
validation studies.
1 batch for 3 months
accelerated stability
study.
Annual report
Prior approval supplement
41

Manufacturing equipment:
• Level 1 change:
In corporation of
automated or
mechanical equipment in
place of non-automated or
non- mechanical
equipment to transfer
ingredients.
Alternative equipment of
same design and operating
principles.
product release
requirements.
Stability: First production
batch on long term
stability study.
Annual report
long- term stability data)

• Level 2 change:
Equipment of a different
design or different
operating principles.
Type of mixing
equipment. Ex, High
shear to low shear or vice
versa.
Compendial product
Executed batch Records.
In vitro release test.
Changes being affected
supplement (All
information including
Annual report
(Long term stability data)

Manufacturing process:
• Level 1 change:
Process changes within
approved application
range requirements.
Order of additional
components.
product release
requirements.
Annual report

• Level 2 change:
Process changes outside
the approved
application ranges.
Process of combining
phases.
Same as level 2 change of
manufacturing equipment
Same as level 2 change of
manufacturing equipment

Batch size: (Scale up and scale down)
• Level 1 change:
Changes in the batch size
<10 times the size of
pivotal clinical trials.
Compendial product
Executed batch Records.
Stability: First production
batch on long term
stability study
Annual report

• Level 2 change:
>10 times the size of
pivotal clinical trial or
biobatch
Compendial product
Executed batch records.
Stability: 1 batch for 3
month accelerated stability
study and first batch on
long term stability study.
Same as level 2 of
manufacturing equipment.

• Level 1 change:
• Level 2 change:
Within a single facility Compendial product release
requirements
Annual report
Within same contiguous
campus or between
facilities in adjacent city
blocks
• Same as level 1
• Executed batch Records
• location of new site
• 1st production batch on
long term stability study
Changes being effected
supplement
Annual report
( All information including

• Level 3 change:
Change in manufacturing
site to different campus
contract manufacturer
• Compendial product
• Executed batch
Records.
• Location of new site.
• In vitro release test
Changes being effected
supplement (including
Annual report (All
information including long
term stabilitydata)

In vitro release testing
• In vitro surrogate tests are often used to assure that
product quality and performance are maintained
over time and in the presence of change.
• In vitro release testing are used to assure consistent
delivery of the active components from semi solid
products.

In vitro release testing

• Sample applications - to prevent solvent
evaporation and compositional changes.
• Sampling time - At least 5 times over an
appropriate time period.
• Sample analysis - Specific and sensitive analytical
procedure required.
• In vitro release rate - A plot of the amount of
drug released per unit membrane area(mcg/cm)
vs. square root of time gives straight line. The
slope of the line represents the release rate of
product.

In vivo Bioequivalence studies
• In vivo bioequivalence studies are performed for
new drug ti establish essential pharmacokinetic
parameters including rate of absorption, extent
of absorption, rate of excretion, metabolism and
elimination half life after a single and multiple
dose administration.
• In vivo bioequivalence studies are conducted in
the usual manner as discussed for bio-
availability studies. i.e., The pharmacokinetic
and pharmacodynamic methods.

Limitations of SUPAC
• SUPAC has not been updated(1995/97 for main
guidelines).
• It does not discuss multiple of changes.
• Does not cover modified equipment.
• Must be used in conjunction with other reference.
Ex, Excipient handbook

REFERENCE
• https://www.fda.gov
• Shah V P, skelly J P, Barr W H,Malinowski H, and
Amidon G L. "Scale up of controlled release
product - Preliminary considerations",
Pharmaceutical technology.1992; 16(5): 35-40.

Scale up and post approval changes.pptx

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