FDA/ISPE Scale-Up Post Approval Changes

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Industry Exchange Meetings
Providence, Rhode Island
May 4, 2000

COMPARISON OF SUPAC-IR, MR & SS

Bonnie B. Dunn, Ph.D.
Office of Pharmaceutical Science
Center for Drug Evaluation & Research
Food and Drug Administration

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
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Guidances Define:
• Levels of change
• Recommended CMC tests for each level of change
• In vitro dissolution tests and/or in vivo bioequivalence
tests
• Documentation that should support the change

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 2
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Components and Composition

• Focuses on changes in drug product excipients

• qualitative and quantitative changes are described

• chronology of changes needed

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 3
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Components and Composition - Level I Changes

Examples
• deletion of color or flavor

• excipient change with total additive effect of up to

5%

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 4
 Components and Composition - Level I Changes
Test documentation
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IR SS MR (nrc) MR (rc)

Chem: release release release release

Stab: 1 LT 1st LT 1st LT 1st LT

Dissol: none none none none

In Vivo: none none none none

File: AR (LT stab) AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 5
 Components and Composition - Level 2
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Other Considerations
• therapeutic range

• solubility

• permeability

Examples:
• change in technical grade of excipient
• excipient change with total additive effect of up to 10%

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 6
 Components and Composition - Level 2

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IR SS MR (nrc) MR (rc)
Chem: release release release release

Stab: batch rec exec batch rec exec batch rec exec batch rec
1batch w/ (same) (same) (same)
3 months accel
1 batch LT (same) (same) (same)

Dissol: yes-depends yes-compare yes-compare yes-compare

on P&S

In Vivo: none none none none non-narrow

single dose narrow
File: PA (accel stab) CBE (accel stab) PA (accel stab) PA (accel stab)
AR (LT stab) AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 7
 Components and composition - Level 3
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Other Considerations
• therapeutic range
• solubility
• permeability

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 8
 Components and Composition - Level 3
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Examples
• any Q & Q excipient changes to a narrow Rx drug
• other drugs not meeting the dissolution criteria
• changes in excipient range of low solubility, low permeability
• changes in excipient range of all other drugs
• change in the crystalline form of the DS if the drug is in
suspension
• change in release controlling excipient > 10%
• addition or deletion of release controlling excipient(s)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 9
 Components and Composition - Level 3
Test documentation
IR SS MR (nrc) MR (rc)
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Chem: release release release release

batch rec exec batch rec exec batch rec exec batch rec
Stab SBI: 1 batch w/ same same same

3 months accel

1 LT 1st 3 LT 1st 3 LT 1st 3 LT

Stab NSBI: up to 3 batches w/ same same same

3 mos accel

1 LT 1st LT 1st 3 LT 1st 3 LT

Dissol: same as level 2 not req. extended & delayed extended & delayed

In Vivo: bioeq needed same same same

File: PA (accel stab) PA (accel stab) PA (accel stab) PA (accel stab)

AR (LT stab) AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 10
F D A

Preservative

• In SUPAC-SS only
• When any Q or Q change is made
• Additional testing should be performed

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 11
 For the SUPAC-SS Preservative - Level 1 Change
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“quantitatively < 10% or less change in the amount of the

approved preservative”

Test documentation:

Chem: Application / compendial release requirements

Preservative Effectiveness Test

File: AR

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 12
 For the SUPAC-SS Preservative - Level 2 Change
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“quantitatively > 10% < 20% change in the approved amount

of preservative”

Chem: Application / compendial release requirements

Preservative Effectiveness Test

File: CBE

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 13
 For the SUPAC-SS Preservative - Level 3 Change
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Quantitatively > than 20% change in the approved

amount of preservative (including deletion) or use of a different
preservative.

Chem: Release requirements

Preservative Effectiveness Test
Analytical method for ID
Validation studies
Executed batch records

Stab: 1 batch w/ 3 months accelerated data reported in supplement

1st production batch for long term

File: PA (accel stab)

AR (LT stab)
C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 14
F D A

MANUFACTURING SITE CHANGE

* changes in site location only

* no scale-up
* no manufacturing changes
* cGMPs

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 15
 MANUFACTURING SITE CHANGE
F D A LEVEL 1 CHANGE

“within a single facility where the same equipment, SOPs,

environmental conditions and controls, and personnel
common to both sites are used”

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 16
 Manufacturing Site - Level 1 change
Test documentation
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IR SS MR

Chem: release release release

Dissol: release none release

In Vivo: none none none

File: AR AR AR

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 17
 Manufacturing Site - Level 2 Change
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“within a contiguous campus, or between facilities in

adjacent city blocks, where same equipment, SOPs,
environmental conditions and controls, and personnel
common to both sites are used”

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 18
 Manufacturing Site - Level 2 Change
Test Documentation
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IR SS MR

Chem: release release release

upd batch rec same same
location location location
Stab: 1 LT 1st LT 1batch w/3 months accel
1st LT
Dissol: release none extended and delayed
In Vivo: none none none

File: CBE CBE CBE (accel stab)

AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 19
 Manufacturing Site - Level 3 Change
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A change in manufacturing site to a different campus

where the same equipment, SOPs, environmental
conditions and controls are used.

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 20
 Manufacturing Site - Level 3 Change
Test documentation
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IR SS MR
Chem: release release release
upd batch rec same same
location location location
Stab SBI: 1batch w/3 months acc same same
1 LT 1st 3 LT 1st 3 LT
Stab NSBI: up to 3-3 months acc 3-3 months acc 3-3 months acc
up to 3 LT 3 LT 1st 3 LT
Dissol: on low perm, hi sol comparison extended and delayed
In Vivo: none none single dose bioequivalence

File: CBE (accel stab) CBE (accel stab) PA (accel stab)

AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 21
 BATCH SIZE

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*change to larger or smaller production batch
*< 100,000 unit scale down not covered
*scale up validation needed
*may need inspection

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 22
 Batch Size - Level 1 Change
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A change up to and including a factor of 10 times the

pilot/biobatch where cGMPs, SOPs and controls,
formulation and manufacturing procedures are the same.

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 23
 Batch Size - Level 1 Change
Test documentation
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IR SS MR
Chem: release release release
notification notification notification
updated batch rec updated batch rec exec batch rec

Stab: 1 LT 1st LT 1st LT

Dissol: release none release

In Vivo: none none none

File: AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 24
 Batch Size -Level 2 Change
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Defined as a change in batch size beyond a factor of 10

times the pilot / bio batch where cGMPs, equipment,
SOPs and controls, formulation and manufacturing
procedures are same.

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 25
 Batch Size - Level 2 Change
Test documentation
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IR SS MR
Chem: release release release
notification notification notification
upd bat rec upd bat rec upd bat rec
Stab: 1-3 mos accel 1-3 mos accel 1-3 mos accel
1 LT 1st LT 1st LT
Dissol: lo perm, hi sol comparison extended and delayed
In Vivo: none none none
File: CBE (accel stab) CBE (accel stab) CBE (accel stab)
AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 26
 MANUFACTURING CHANGES

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* changes that may affect equipment
* changes that may affect the manufacturing process

Equipment - Level 1 change

Examples include: A change to automated or mechanical equip. to
move ingredients, a change to alternative equipment of same design
and operating principle, a change to different capacity equipment.
(ISPE Equip addendum)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 27
 Manufacturing - Level 1 Change
F D A Test documentation

IR SS MR
Chem: release release release
notification notification notification
upd bat rec upd bat rec upd bat rec
Stab: 1 Long Term 1 Long term 1 Long Term

Dissol: release none release

In Vivo: none none none

File: AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 28
 Manufacturing - Level 2 Change
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Examples include: Changes in equipment to a different

design or different operating principle or a change in the
type of mixing equipment.

(ISPE Equip addendum)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 29
 Manufacturing - Level 2 Change
Test documentation
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IR SS MR

Chem: release release release

notification notification notification
upd bat rec upd bat rec upd exec bat rec
Stab SBD: 1batch;3 months accel same same
1 LT 1st LT 3 LT
Dissol: yes (Case C) comparison extended and delayed
In Vivo: none none none
File: PA (accel stab) CBE (accel stab) PA (accel stab)
AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 30
 Manufacturing Process - Level 1 Change
Defined as including mixing times and operating speeds within
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application / validation ranges.
Test documentation

IR SS MR
Chem: release release release
notification
upd exec bat rec

Dissol: release none release

In Vivo: none none none

File: AR AR AR

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 31
 PROCESS - LEVEL 2 CHANGE
Including mixing times and operating speeds outside of application / validation
ranges.
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IR SS MR

Chem: release release release

notification notification notification
upd bat rec upd bat upd bat rec

Stab: 1 LT 1-3 mos accel

1st LT

Stab SBD: 1-3 mos accel

1st LT

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 32
 PROCESS - LEVEL 2 CHANGE (cont.)

IR SS MR
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Stab NSBD: 3-3 mos accel

Dissol: yes (Case B) comparison extended and delayed

In Vivo: none none none

File: CBE (accel stab) CBE (accel stab) CBE (accel stab)
AR (LT stab) AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 33
 PROCESS - LEVEL 3 CHANGE
Including a change in the type of manufacturing process, such as wet
granulation to compression of dry powder.
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IR SS MR

Chem: release (No level 3) release

notification notification
upd bat rec upd exec bat rec

Stab: 3-3 mos accel

1st 3 LT
Stab SBD: 1-3 mos accel
1 LT

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 34
 PROCESS - LEVEL 3 CHANGE (cont.)

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IR SS MR

Stab NSBD: up to 3-3 mos accel

up to 3 LT

Dissol: yes (Case B) extended and delayed

In Vivo: study needed single dose

File: PA (accel stab) PA (accel stab)

AR (LT stab) AR (LT stab)

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 35
F D A
WEB SITE ADDRESS

• WWW.FDA.GOV/CDER/GUIDANCE/INDEX.HTM

C e n te r fo r D r u g E v a lu a tio n a n d R e s e a r c h
Bonnie B. Dunn, Ph.D. May 4, 2000, Providence, RI 36