supac by DG

8/6/2019 supac by DG

1/39


2/39


3/39

4. Batch size changes

Level 1 change

Level 2 change

5 . Manufacturing changes

Manufacturing equipment changes

Manufacturing process changes

6. Reference


4/39

y NDA

y ANDA

y AADA

y changes

The components

or compositions

Manufacturing(Process and

equipment) of an

immediate release

dosage form

The site of

manufacture

The scale up/down of

manufacture


5/39

SUPAC guidance covers

y Component and composition change

y Manufacturing site change

y Batch size changey Manufacturing process and equipment change


6/39

y SUPAC IR

y SUPAC-SS

y SUPAC-MR

SUPAC industry perspective:

It is based on interviews with 6 companies in the firsthalf of1997.

Shorter waiting times for site transfers.More rapid implementaion of process and equipment

changes.


7/39

y Production of fewer unmarketable stability batches

y Reduced administration costs for documentation ofchanges by the regulatory affairs departments.

y Estimated saving $51.2 million/year.


8/39

Level 1 changesy Level 1 changes are those that are unlikely to have any

detectable impact on formulation quality and

performance.

Examplesy deletion of color or flavor

y excipient change with total additive effect of up to 5%


9/39

Nonrelease controlling

excipient

Percent excipient (w/w) of

total formulation, less than

or equal to the followingpercent ranges

Filler 5

Disintegrants

Starch

Other

3

1

Binder 0.5

Lubricant

Ca or Mg Stearates

Other

0.25

1Glidant

Talc

Other

Film Coat

1

0.1

1


10/39

IR SS

(Semisolid)

MR (nrc) MR (rc)

Chemistry

documentation

Application/co

mpendial

release

requirement*

same same same

Stability

testing

One batch

with long term

stability testing

( 1 LT)

1 st batch with

LT

Same as SS Same as SS

Dissolution

Documentation

None none none none

In vivo None none none none

Filling

documentation

Annual report

(all information

including LT)

same same same


11/39

y Level 2 changes are those that could have a significantimpact on formulation quality and performance.

y Tests and filing documentation for a level 2 changevery depending on three factors:

y therapeutic range

y solubility

y permeability

Examples:y change in technical grade of excipient

y excipient change with total additive effect of up to 10%


12/39

Excipient % W/W out of total target dosage for

weight

Filler 10

Disintegrant

Starch 6

Other 2

Binder 1

Lubricant

Calcium or magnesium stearate 0.5

Other 2

Glidant

Talc 2

Other 0.2

Film Coat 2


13/39

IR SS MR (nrc) MR (rc)

Chemistry

documentation

Release and

batch record

Release and

executed batch

record

release and

executed batch

record

release and

executed batch

record

Stabilitydocumentation

1 batch with 3month accel and

1 batch LT*

same same Same

Dissolution Yes- depends

on Permeability

and solubility@

Yes- Compare Yes- compare Yes- compare

In vivo None none none Non for non-

narrowtherapeutic

index (T.I.) AND

Single dose for

narrow T.I.

Filing

documentation

PA (accel stab)

AR (LT stab)

CBE (accel

stab)

AR (LT stab)

Same as IR Same as IR


14/39

Case AHP,

HS

Dissolution of 85 % in 15 min. in 900 ml 0f 0.1 N HCl.

If drug product fails to meet the criteria then go for

the Case B, C

Case BLP,HS

Multi point dissolution profile according thecompendial medium at 15, 30, 45, 60 and 120 min.

Case CHP,

LS

Dissolution profile comparison in water, 0.1 N HCl,

pH 4.5, 6.5 and 7.5. adequate sampling at 15, 30,

45, 60 and 120 minute or until either 90 % of drug

from the drug product is dissolved.


15/39


16/39

IR SS MR (nrc) MR (rc)

Chemistry

documentation

Release and

batch record

Release and

executed batch

record

Release and

executed batch

record

Release and

executed batch

record

Stability

documentation

1 batch with 3

months accel

1 LT

Same and first

three batches

with LT

Same as SS Same as SS

Dissolution Same as Level

2

Not required Extended and

delayed*

Extended and

delayed*

In vivo Bioequivalence

needed

Same Same Same

File PA (accel stab)

AR (LT stab)

Same Same Same


17/39

A. Manufacturing site Level I changes

y Level I changes is defined as changes in manufacturingsite

y within a single facility where the same equipment,SOPs, environmental conditions and controls, andpersonnel common to both sites are used


18/39

IR SS MR

Chemistry

documentation

Release Same Same

Dissolution Release none Release

In vivo None none None

File AR AR AR


19/39

y Level 2 changes may be defined as the changes in themanufacturing site

y within a contiguous campus, or between facilities inadjacent city blocks, where same equipment, SOPs,environmental conditions and controls, and personnelcommon to both sites are used


20/39

IR SS MR

Chemistry

documentation

Release;

Notification of

location of new

site and updated

batch record

Same as IR Release;

Notification of

location of new

site and updated

executed batchrecord

Stability testing 1 LT 1 st LT 1 batch w/3

months accel.

1 st LT*

Dissolution Release none Extended and

delayedIn vivo None none None

File CBE

AR (LT stab)

CBE

AR (LT stab)

CBE (accel stab)

AR (LT stab)


21/39

y A change in manufacturing site to a different campuswhere the same equipment, SOPs, environmentalconditions and controls are used


22/39

IR SS MR

Chemistry

documentation

Release; Notification of

change and updated

batch record

Release;

same

Release;

same

Stability testing

SBI (significant body of

information available) *

1 batch w/3 months

acel.

Upto 3 batch with LT

Same; 1 st three batch

LT

Same;

1 st three batch LT

NSBI (significant body

of information is not

available) *

Upto 3-3 months accel.

Upto 3 LT*

Three batch with 3

months accel.

Three batch with LT

Three batch with three

months accel.

1 st three production

batches with LT

Dissolution As per low permeability

and high solubility

comparison Extended and delayed

In vivo None none Single dose

bioequivalence

File CBE (accel stab)

AR (LT stab)

Same as IR PA (accel stab)

AR (LT stab)


23/39

y change to larger or smaller production batch

y < 100,000 unit scale down not covered

y scale up validation needed

y may need inspection


24/39

y A change up to and including a factor of10 times thepilot/biobatch where cGMPs, SOPs and controls,formulation and manufacturing procedures are the

same.


25/39

IR SS MR

Chemistry

documentation

Release; Notification

of change and

updated batch

record


of change and

updated batch

record


of change and

executed batch

record

Stability study 1 LT 1 st LT 1 st LT

Dissolution Release none Release

In vivo none none None

File AR (LT stab) same Same


26/39

y Defined as a change in batch size beyond a factor of10times the pilot / bio batch where cGMPs, equipment,SOPs and controls, formulation and manufacturing

procedures are same.


27/39


28/39

changes that may affect equipment

changes that may affect the manufacturing process


29/39

y A. Equipment Level 1 change

A change to automated or mechanical equip. to move

ingredients, a change to alternative equipment of samedesign and operating principle, a change to differentcapacity equipment.


30/39

IR SS MR

Chemistry Release; Notification

of change and

updated batch

record


of change and

updated batch

record


of change and

updated batch

record

Stability testing 1 LT 1 LT 1 LT

Dissolution Release None Release


File AR (LT stab) same Same


31/39

y Examples include: Changes in equipment to a differentdesign or different operating principle or a change inthe type of mixing equipment.


32/39

IR SS MR

Chemistry

documentation

Release;

Notification of

change and

updated batch

record

Release;

Notification of

change and

updated batch

record

Release;

Notification of

change and

updated

executed batch

record

Stability testing

SBD One batch with 3

months

accelerated

stability study

1 LT

Same

1 st LT

Same

Three batch with

long term stability

study

Dissolution Yes (Case C) comparision Extended and

delayedIn vivo None none none


AR (LT stab)

CBE (accel stab)

AR (LT stab)

PA (accel stab)

AR (LT stab)


33/39

y A. Manufacturing Process Level 1 ChangeThis category includes process changes including changes such as

mixing times and operating speeds within application/validationranges.

IR SS MR

Chemistry

documentation

Release release Release;

Notification of

change and

updated

executed batch

record

Dissolution Release None Release


File AR AR AR


34/39

y This category includes process changes includingchanges such as mixing times and operating speedsoutside of application/validation ranges


35/39

IR SS MR

Chemistry

documentation


of change and

updated batch

record

Same same

Stability testing 1 LT One batch with 3

months accel.

1 st LT

Stability: SBD 1-3 mos accel *

1 st LT

Stability: NSBD 3-3 mos accel @

Dissolution Yes (case B) comparision Extended and

delayed)File CBE (accel stab)

AR (LT stab)

same same


36/39

y This category includes change in the type of processused in the manufacture of the product, such as achange from wet granulation to direct compression ofdry powder.


37/39

IR SS MR

Chemistry

documentation

Release; Notification of

change and updated

batch record

No level 3 Release; notification of

change and updated

executed batch record

Stability testing Three batch with 3

months accelerated

stability study1 st 3 LT @

Stability: SBD One batch with 3

months accel.

1 LT

Stability: NSBD Upto 3-3 mos accel.

Upto 3 LT *

Dissolution Yes (Case B) Extended and delayed

In vivo Study needed Single dose


AR (LT stab)

same


38/39


39/39

Documents

supac by DG