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Scale Up and Post Approval changes
(SUPAC)
1
Prepared By :
Charmi shah
2308212170009
Introduction
Purpose of Guidelines
Level of changes
Requirements for post approval changes
Limitations of SUPAC
References
CONTENTS
2
What is SUPAC?
3
Technology transfer of a pharmaceutical product from research to the production
floor with simultaneous increase in production outputs is commonly known as scale
- up.
In simple terms, the process of increasing batch size is termed as scale- up.
Conversely, scale- down refers to decrease in batch size in response to reduced
market requirements.
The scale-up process and the changes made after approval in the composition,
manufacturing process, manufacturing equipment, and change of site have
become known as Scale-Up and Post approval Changes, or SUPAC.
Hence while making such a changes from lab scale to pilot scale or to plant scale,
submission of all this data including excipients, their purpose and quantities to FDA
is necessary for getting the marketing approval.
Purpose of Guidelines
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 post
approval period, to change:
1. The components or composition
2. The site of manufacture
3. The scale-up/scale-down of manufacture
4. The manufacturing (process and equipment) of an immediate release
oral formulation.
4
 A series of documents were issued by US FDA (CDER) to help applicants with
post-approval changes. Currently finalized SUPAC guidance are as below :
 SUPAC-IR(immediate release) -Nov 1995.
 SUPAC-IR Ques and Answers- Feb 1997.
 SUPAC –MR(modified release)- Sep 1997.
 SUPAC SS(non sterile semisolid)- May 1997. (CDER- Centre for Drug
Evaluation and Research)
5
SUPAC Guideline: Defines
• Minor change
• Moderate change
• Major change
Level of
changes
• Application/Compendial Test
• Invitro Dissolution / Release
• In vivo
Test
documentation
• Annual report
• Change being effected supplement
• Prior approval supplement
Fillings
6
LEVEL CHANGES
Level 1 Those change that are unlikely to have any detectable impact on
formulation quality and performance.
E.g. Changes in the colour, flavours changes in the excipient
express as the percentage (w/w)of total formulation, less than or
equal to the following range.
Level 2 Changes are those that could have significant impact on the
formulation quality and performance.
E.g. changes in the technical grade of excipient changes
expressed as percent level 2 change.
Level 3 Those that are likely to have significant impact on formulation
quality and performance.
E.g Any qualitative or quantitative excipient changes to a narrow
therapeutic drug beyond the range for level 1 all other drug not
meeting the dissolution criteria as per level 2.
7
Requirements for Post Approval Changes
A. Components and composition of drug product
B. Change in batch size
C. Manufacturing equipment change
D. Manufacturing site change
8
A)Components and Composition of Drug Product
1. SUPAC-IR:
Focus on changes in the amount of excipients in the drug product.
2. SUPAC-MR:
Excipient critical or non critical to the drug release.
9
(A)Components
and composition
of drug product
In general, mainly focus on change in ingredients in
drug products. Change in adding or deleting an
excipient are describe in level 3. Adding or deleting
of ingredients must be filled as prior approval
supplement.
The exception to this applied to colors, which can
be removed or reduce from formulation and filled
in an annual report.
Case A: High permeability, High solubility drugs
Case B: Low permeability, High solubility drugs.
Case C: High permeability, Low solubility drugs
10
Component and Composition IR
Level Classification Excipients
range %w/w of
total
formulation
Test
Documentation
Filling
1 Deletion/partial deletion of
ingredient (colour, flavour,
etc)
Filler ±5
Starch ±3
Stability application/
Annual compendial
requirements report
Annual
repórt
Changes in excipients less
than or equal to.
Lubricant
Ca/Mg. stearate
±0.25
2 Change in technical grade
of excipients
Filler±10 Stability application/
compendial requirements
Depends on solubility,
therapeutic range and
permeability Case A,B,C
Prior
approval
supplement
Changes in excipients
greater than level 1
Starch (±)6 Annual
repórt
11
12
Level classification Excipients
range %w/w
of total
formulation
Test Filling
3 Higher than level 1
and 2 excipient
changes
- Stability
application/
compendial
requirements
Case B
Biostudy /
IVIVC
Prior approval
supplement
Annual repórt
SUPAC MR: Component and composition
13
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
1 Deletion or partial deletion
of an ingredient up to
SUPAC-IR Level 1.
Stability
Application/compendial
requirements.
Annual report
2 Change in technical grade of
excipients
Stability
Application/compendial
requirements.
Prior approval
supplement
LEVEL CLASSIFICATION TEST
DOCUMENTATION
FILING
3 Higher than SUPAC-
IR Level 1 and Level
2 excipient
Stability
application/compendia
l requirements.
Prior approval
supplement
14
B)
Change in
batch size
Change in batch size from pivotal/pilot scale
bio batch to larger or smaller production
batches tends to change the operating
parameter.
Therefore, all the parameters, such as mixing
time, speed, etc., are adjusted according to
the equipment (large or small) used in the
process. Below 100,000 dosage unit are not
covered by this guidance.
15
Change in batch IR
Level Classification Test Filling
1 Change in batch size up
to 10 times more of pilot
batch
Update batch record/
Application/ compendial
Requirements/stability
Annual report
2 Change in batch size
beyond 10 times more of
pilot batch
No other changes
Application/compendial
Requirements, stability
Updated batch record
Multipoint dissolution
profile with three buffer
until 80% drug released
Annual report
Changes
being effected
supplement
16
17
C)
Manufacturing
Equipment
change
Any change in manufacturing equipment other than that used in
the approved application requires appropriate validation studies
to demonstrate that the new equipment is similar to the original
equipment.
Equipment should be same design and operating principle
according to SUPAC IR.
Change in V-blender from one manufacturer to another
manufacturer would not represent a change in operating
principle, and hence be considered to be the same under
SUPAC-IR, whereas a change in equipment from one class (V-
blender) to a different class (ribbon blender) would be
considered a change in design and operating principle and
would be considered different under SUPAC-IR.
18
Equipment IR
Level Classification Test Filling
1 Alternate equipment of
same design and
principles Automated
Update batch record/
Application/compendial
Requirements/stability
Annual report
2 Change to equipment
of different design and
principles
Application/compendial
Requirements, stability
Updated batch record
Multipoint dissolution
profile with three buffer
until 80% drug released
Annual report
Changes being
effected
supplement
D)
Manufacturing
site change
•The sponsor of an ANDA must include in its application
the site of manufacture, where the drug product will be
produced, tested, packaged, or labelled.
•A change in any of these sites can adversely affect the
identity, strength, quality, purity, or potency of the
finished product.
•Therefore, any site change under SUPAC-IR calls for
the new site to be in compliance with good
manufacturing practice (cGMP) regulations.
19
Manufacturing site changes IR
Level Classification Test Filling
1 Site change in
single facility No
change in
SOP/equipment's/
environmental
conditions/comm
on personnel
Application/compendial
requirements
Annual report
2 Same continuous
campus Common
personnel
No other changes
Application/ compendial
Requirements /Notification of
location of new site/ Updated
batch record/ Multipoint
dissolution profile with three
buffer until 80% drug released
Annual report
Changes being
effected
supplement
20
Level Classification Test Filling
3 Different campus
Different personnel
Application/ compendial
Requirements Notification of
location of new site Updated
batch record Multipoint
dissolution profile with three
buffer until 80% drug released
Prior approval
supplement
Annual report
21
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 references ex: excipient handbook
22
23

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SUPAC(Scale Up and Post Approval changes for RA 1st sempptx

  • 1. Scale Up and Post Approval changes (SUPAC) 1 Prepared By : Charmi shah 2308212170009
  • 2. Introduction Purpose of Guidelines Level of changes Requirements for post approval changes Limitations of SUPAC References CONTENTS 2
  • 3. What is SUPAC? 3 Technology transfer of a pharmaceutical product from research to the production floor with simultaneous increase in production outputs is commonly known as scale - up. In simple terms, the process of increasing batch size is termed as scale- up. Conversely, scale- down refers to decrease in batch size in response to reduced market requirements. The scale-up process and the changes made after approval in the composition, manufacturing process, manufacturing equipment, and change of site have become known as Scale-Up and Post approval Changes, or SUPAC. Hence while making such a changes from lab scale to pilot scale or to plant scale, submission of all this data including excipients, their purpose and quantities to FDA is necessary for getting the marketing approval.
  • 4. Purpose of Guidelines 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 post approval period, to change: 1. The components or composition 2. The site of manufacture 3. The scale-up/scale-down of manufacture 4. The manufacturing (process and equipment) of an immediate release oral formulation. 4
  • 5.  A series of documents were issued by US FDA (CDER) to help applicants with post-approval changes. Currently finalized SUPAC guidance are as below :  SUPAC-IR(immediate release) -Nov 1995.  SUPAC-IR Ques and Answers- Feb 1997.  SUPAC –MR(modified release)- Sep 1997.  SUPAC SS(non sterile semisolid)- May 1997. (CDER- Centre for Drug Evaluation and Research) 5
  • 6. SUPAC Guideline: Defines • Minor change • Moderate change • Major change Level of changes • Application/Compendial Test • Invitro Dissolution / Release • In vivo Test documentation • Annual report • Change being effected supplement • Prior approval supplement Fillings 6
  • 7. LEVEL CHANGES Level 1 Those change that are unlikely to have any detectable impact on formulation quality and performance. E.g. Changes in the colour, flavours changes in the excipient express as the percentage (w/w)of total formulation, less than or equal to the following range. Level 2 Changes are those that could have significant impact on the formulation quality and performance. E.g. changes in the technical grade of excipient changes expressed as percent level 2 change. Level 3 Those that are likely to have significant impact on formulation quality and performance. E.g Any qualitative or quantitative excipient changes to a narrow therapeutic drug beyond the range for level 1 all other drug not meeting the dissolution criteria as per level 2. 7
  • 8. Requirements for Post Approval Changes A. Components and composition of drug product B. Change in batch size C. Manufacturing equipment change D. Manufacturing site change 8
  • 9. A)Components and Composition of Drug Product 1. SUPAC-IR: Focus on changes in the amount of excipients in the drug product. 2. SUPAC-MR: Excipient critical or non critical to the drug release. 9
  • 10. (A)Components and composition of drug product In general, mainly focus on change in ingredients in drug products. Change in adding or deleting an excipient are describe in level 3. Adding or deleting of ingredients must be filled as prior approval supplement. The exception to this applied to colors, which can be removed or reduce from formulation and filled in an annual report. Case A: High permeability, High solubility drugs Case B: Low permeability, High solubility drugs. Case C: High permeability, Low solubility drugs 10
  • 11. Component and Composition IR Level Classification Excipients range %w/w of total formulation Test Documentation Filling 1 Deletion/partial deletion of ingredient (colour, flavour, etc) Filler ±5 Starch ±3 Stability application/ Annual compendial requirements report Annual repórt Changes in excipients less than or equal to. Lubricant Ca/Mg. stearate ±0.25 2 Change in technical grade of excipients Filler±10 Stability application/ compendial requirements Depends on solubility, therapeutic range and permeability Case A,B,C Prior approval supplement Changes in excipients greater than level 1 Starch (±)6 Annual repórt 11
  • 12. 12 Level classification Excipients range %w/w of total formulation Test Filling 3 Higher than level 1 and 2 excipient changes - Stability application/ compendial requirements Case B Biostudy / IVIVC Prior approval supplement Annual repórt
  • 13. SUPAC MR: Component and composition 13 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING 1 Deletion or partial deletion of an ingredient up to SUPAC-IR Level 1. Stability Application/compendial requirements. Annual report 2 Change in technical grade of excipients Stability Application/compendial requirements. Prior approval supplement
  • 14. LEVEL CLASSIFICATION TEST DOCUMENTATION FILING 3 Higher than SUPAC- IR Level 1 and Level 2 excipient Stability application/compendia l requirements. Prior approval supplement 14
  • 15. B) Change in batch size Change in batch size from pivotal/pilot scale bio batch to larger or smaller production batches tends to change the operating parameter. Therefore, all the parameters, such as mixing time, speed, etc., are adjusted according to the equipment (large or small) used in the process. Below 100,000 dosage unit are not covered by this guidance. 15
  • 16. Change in batch IR Level Classification Test Filling 1 Change in batch size up to 10 times more of pilot batch Update batch record/ Application/ compendial Requirements/stability Annual report 2 Change in batch size beyond 10 times more of pilot batch No other changes Application/compendial Requirements, stability Updated batch record Multipoint dissolution profile with three buffer until 80% drug released Annual report Changes being effected supplement 16
  • 17. 17 C) Manufacturing Equipment change Any change in manufacturing equipment other than that used in the approved application requires appropriate validation studies to demonstrate that the new equipment is similar to the original equipment. Equipment should be same design and operating principle according to SUPAC IR. Change in V-blender from one manufacturer to another manufacturer would not represent a change in operating principle, and hence be considered to be the same under SUPAC-IR, whereas a change in equipment from one class (V- blender) to a different class (ribbon blender) would be considered a change in design and operating principle and would be considered different under SUPAC-IR.
  • 18. 18 Equipment IR Level Classification Test Filling 1 Alternate equipment of same design and principles Automated Update batch record/ Application/compendial Requirements/stability Annual report 2 Change to equipment of different design and principles Application/compendial Requirements, stability Updated batch record Multipoint dissolution profile with three buffer until 80% drug released Annual report Changes being effected supplement
  • 19. D) Manufacturing site change •The sponsor of an ANDA must include in its application the site of manufacture, where the drug product will be produced, tested, packaged, or labelled. •A change in any of these sites can adversely affect the identity, strength, quality, purity, or potency of the finished product. •Therefore, any site change under SUPAC-IR calls for the new site to be in compliance with good manufacturing practice (cGMP) regulations. 19
  • 20. Manufacturing site changes IR Level Classification Test Filling 1 Site change in single facility No change in SOP/equipment's/ environmental conditions/comm on personnel Application/compendial requirements Annual report 2 Same continuous campus Common personnel No other changes Application/ compendial Requirements /Notification of location of new site/ Updated batch record/ Multipoint dissolution profile with three buffer until 80% drug released Annual report Changes being effected supplement 20
  • 21. Level Classification Test Filling 3 Different campus Different personnel Application/ compendial Requirements Notification of location of new site Updated batch record Multipoint dissolution profile with three buffer until 80% drug released Prior approval supplement Annual report 21
  • 22. 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 references ex: excipient handbook 22
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