Scale Up and Post Approval

Changes

Shaik. Naseeb Basha, Asst. Prof

Dept. of Pharmaceutics
G. Pulla Reddy College of Pharmacy
Index

! " # $
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 ! (
)
# $

*
Larger Batch size SCALE UP
+, )
 What is SUPAC

- + "
.
/ " + , # 0 $.

/ 0
(
+ 1 - Scale Up and Post
approval Changes or SUPAC.
 Scientific Rationale

) , .

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 / ) 3

A. SUPAC IR # 0 $
B. SUPAC MR # 0 $

C. SUPAC SS # 0
$.
SUPAC GUIDELINES DEFINE
 Levels of change
1 ( ,

4% unlikely +
5% could have
6% likely
Levels of change Cont . . .

Likelihood of impact on formulation quality and performance

Level 1: Those changes that are unlikely to have any detectable impact
on formulation quality and performance. Example Changes in the
color, flavors and 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. Example Changes in the
technical grade of excipient (Avicel PH102 vs. Avicel PH200)
Changes expressed as percent (w/w of total formulation) Level 2
Change
Level 3: Level 3 changes are those that are likely to have significant
impact on formulation quality and performance. Example 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 level 2.
 These guidelines provide recommendations for
post approval changes in
(1) The components or composition,
(2) The site of manufacture,
(3) The scale up of manufacture, and
(4) The manufacturing (process and equipment)
 / 2

0 % '2
.
0 2
0 2
0 %
 SUPAC IR
LEVEL CLASSIFICATION EXCIPIENT RANGES TEST FILING
(%w/w of total DOCUMENTATION DOCUMENTAT
formulation) ION
0Deletion or Filler ±5 stability •Annual
partial deletion Disintegrant application/ report
of an ingredient Starch ±3 compendial
(colour, flavor Other ±1 requirements
or change in Binder
ingredient of ±0.5
the ink) Lubricant
I Changes in Calcium (Ca) or
excipients, Magnesium (Mg)
expressed as % Stearate ±0.25
(w/w) of total Other ±1
formulation, less Glidant
than or equal to Talc ±1
excipient % Other ±0.1
ranges Film Coat ±1
LEVEL CLASSIFICATI EXCIPIENT RANGES TEST DOCUMENTATION FILING
ON (%w/w of total DOCUMEN
formulation) TATION
change in Filler ±10 stability •Prior
technical Disintegrant application/compendial approval
grade of Starch ±6 requirements supplement
excipients Other ±1 Dissolution data depends •Annual
Changes in Binder ±1 on solubility, theraputic report
excipients, Lubricant range and permeability.
expressed as Calcium (Ca) or Case A : High
% (w/w) of Magnesium (Mg) Permeability, High
total Stearate ±0.5 Solubility Drugs
II formulation, Other ±2 Single point Dissolution
greater than Glidant profile .
Level 1 Talc ±2 Case B : Low Permeability,
changes. Other ±0.2 High Solubility Drugs
Film Coat ±2 Multi point dissolution
profile
Case C :High Permeability,
Low Solubility Drugs
Multi point and multi
media dissolution profile
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATION

0Higher than SUPAC stability •Prior approval

IR Level 1 and Level 2 application/compendial supplement
excipient ranges. requirements •Annual report

Case B dissolution profile

(Multi point dissolution
profile in the application
/compendial medium at
III
15, 30, 45, 60, and 120
minutes or until an
asymptote is reached for
the proposed and
currently accepted
formulation.)
Biostudy or IVIVC
 SUPAC – MR Non Release Controlling Excipients
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

0Delition or partial delition of stability •Annual

an ingredient application/compendial report
I
upto SUPAC IR Level 1 requirements
excipient ranges
change in technical grade of stability •Prior
excipients application/compendial approval
upto SUPAC IR Level 2 requirements supplement
excipient ranges 0Multi point dissolution profiles •Annual
(15,30,45,60 & 120 min) report
II
USP buffer media at pH 4.5 7.5
for extended release) Three
different Media (e.g., Water, 0.1N
HCl, and USP buffer media at Ph
4.5 And 6.8 for delayed release)
0Higher than SUPAC IR Level stability •Prior
1 and Level 2 excipient application/compendial approval
III ranges. requirements supplement
Biostudy or IVIVC •Annual
report
 SUPAC – MR Release Controlling Excipients
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMEN
TATION
0≤ 5% w/w change stability •Annual report
based on total application/compendial requirements
I release controlling
excipient content.
0No other changes
change in stability •Prior approval
technical grade of application/compendial requirements supplement
excipients 0Multi point dissolution profiles •Annual report
≤ 10% w/w change (15,30,45,60 & 120 min)
II
based on total USP buffer pH 4.5 7.5 for extended
release controlling release) Three different Media (e.g.,
excipient content. Water, 0.1N HCl, and USP buffer media
at Ph 4.5 And 6.8 for DR release)
0> 10% w/w change stability •Prior approval
based on total application/compendial requirements supplement
III
release controlling Biostudy or IVIVC •Annual report
excipient content.
 SUPAC – SS Components and Composition
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

0Delition or partial delition of an stability •Annual

ingredient application/ compendial report
change in supplier or technical requirements
I
grade of any other excipient
0Upto 5 % change in approved
amount of ingredient.
0Upto >5 % and ≤ 10 % change in stability •Changes
approved amount of ingredient. application/compendial being
Change in particle size requirements effected
distribution of the drug in vitro release test supplement
II
substance, if the drug is in •Annual
Suspension report
change in supplier or technical
grade of any other excipient
change in approved amount of stability •Prior
ingredient. application/compendial approval
III Change in crystalline form of the requirements supplement
drug substance, if the drug is in in vitro release test •Annual
suspension in vivo bioequivalence test. report
 SUPAC – SS Components and Composition Preservative
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

Quantitatively 10% application/compendial •Annual report

or less change in the requirements
I
approved amount of Preservative effectiveness test at
preservative lowest specified preservative level
10% 20 % change in application/compendial •Changes being
the approved requirements effected
II amount of Preservative effectiveness test at supplement
preservative lowest specified preservative level •Annual report

> 20% change in the application/compendial •Prior approval

approved amount of requirements supplement
preservative executed batch records •Annual report
(including deletion) For new preservative: analytical
III
or use of a different method for identification and assay;
preservative. validation studies
Preservative effectiveness test at
lowest specified preservative level
2) Manufacturing Site Changes
1
7 , + ,

, 0
# 7 ( $
.

# $ .
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
DOCUMENTATI
ON

Site change within application/compendial •Annual report

a single facility requirements
No change in SOP,
environmental
I
conditions or
equipments used
Common
personnels
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

Same continuous application/compendial •Annual report

campus requirements •Changes being
Common Notification of Location of new site Effected
personnel Updated batch records Supplement
No other changes
SUPAC – MR
0Multi point dissolution profiles
II
(15,30,45,60 & 120 min)
USP buffer media at pH 4.5 7.5 for
extended release) Three different
Media (e.g., Water, 0.1N HCl, and USP
buffer media at Ph 4.5 And 6.8 for
delayed release)until 80% of Drug
Released.
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
Different campus application/compendial Annual report
Different requirements Prior approval
personnel Notification of Location of new site supplement
Updated batch record

SUPAC –IR
Multi point dissolution profile in the
application/compendial medium
III
SUPAC – MR
0Multi point dissolution profiles
(15,30,45,60 & 120 min)
USP buffer media at pH 4.5 7.5 for
extended release) Three different
Media (e.g., Water, 0.1N HCl, and USP
buffer media at Ph 4.5 And 6.8 for
delayed release) untill 80 % of drug
released.
 3) Batch Size Change (Scale Up)
" + 7
+ + +
- 3
* 8
(
0 + ,
+ " +
+ + + 100000 dosage units /100 kg or 10%
+ - .
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
I Change in batch Updated batch records •Annual
size, up to and application/compendial requirements report
including a stability
factor of 10 times
the size of the
pilot/biobatch
II Changes in batch Updated batch records •Annual
size beyond a application/compendial requirements report
factor of ten Stability Changes
•Changes
times the size of SUPAC –IR being
the pilot or Multi point dissolution profiles Effected
biobatch, SUPAC – MR Supplement
No other changes 0Multi point dissolution profiles in
multiple medias (e.g., USP buffer media
at pH 4.5 7.5 for extended release) three
other media (e.g., Water, 0.1N HCl, and
USP buffer media at Ph 4.5 And 6.8 for
delayed release)
SUPAC SS
In vitro release test Documentation
 4) Manufacturing Changes
%
0 '(
0
 Manufacturing Changes Equipments
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
Alternate equipment of Updated batch records •Annual report
same design and application/compendial
I
principles requirements
Automated equipments stability
Change to equipment of Updated batch records •Annual report
different design and application/compendial •Changes
principle requirements being Effected
Stability Supplement
SUPAC –IR
Multi point dissolution
II profiles in multiple medias
SUPAC – MR
0Multi point dissolution
profiles in multiple medias
SUPAC SS
In vitro release test
Documentation
 Manufacturing Changes Process

LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

I Adjustment of Updated batch records •Annual

equipment application/compendial report
operating requirements
conditions stability
(operating speeds,
mixing times)

Within approved
application ranges
LEVEL CLASSIFICATION TEST DOCUMENTATION FILING

Adjustment of Updated batch records •Annual

equipment application/compendial report
operating requirements •Changes
conditions Stability being
(operating Effected
speeds, mixing SUPAC IR Supplement
times) Multi point dissolution profile

Beyond approved SUPAC MR

II
application 0Multi point dissolution profiles in
ranges multiple medias (e.g., USP buffer media
at pH 4.5 7.5 for extended release)
SUPAC – SS three other media (e.g., Water, 0.1N HCl,
Change in the and USP buffer media at Ph 4.5 And 6.8
process of for delayed release)
combining two
phases SUPAC SS
In vitro release test Documentation
 LEVEL CLASSIFICATION TEST DOCUMENTATION FILING
III Changes in the Updated batch records •Prior
(SUPAC IR type of process application/compendial approval
SUPAC MR) used (e.g. wet requirements supplement
granulation to Stability •Annual
direct Biostudy or IVIVC report
compression
SUPAC IR
Multi point dissolution profile

SUPAC MR
Multi point dissolution profiles in
multiple medias (e.g., USP buffer
media at pH 4.5 7.5 for extended
release) three other media (e.g.,
Water, 0.1N HCl, and USP buffer
media at Ph 4.5 And 6.8 for delayed
release)
Dissolution Profile Comparison Using
Similarity Factor, f2
FDA has placed more emphasis on a dissolution profile
comparison in the area of post approval changes
Among several methods investigated for dissolution
profile comparison, f2 is the simplest.
f2 = 50 + log {[1+ (1/n) ∑t=1 * n (Rt Tt)2] 0.5 *100}
(where Rt and Tt are the cumulative percentage
dissolved at each of the selected n time points of the
reference and test product respectively.
When the two profiles are identical, f2=100. FDA has
set a public standard of f2 value between 50 100 to
indicate similarity between two dissolution profiles.
 SUPAC limitations
%
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