Presented By: Trivedi Darshan (M.

Pharm-II)

A.P.M.C. COLLEGE OF PHARMACEUTICAL EDUCATION & RESEARCH HIMATNAGAR

1 Introduction 2 Component and composition

Level 1 change y Level 2 change y Level 3 change
y

3 Manufacturing site change Level 1 change Level 2 change Level 3 change

4. Batch size changes

Level 1 change Level 2 change

5 . Manufacturing changes Manufacturing equipment changes Manufacturing process changes 6. Reference

The components or compositions Manufacturing (Process and equipment) of an immediate release dosage form

y NDA y ANDA y AADA y changes

The site of manufacture

The scale up/down of manufacture

SUPAC guidance covers y Component and composition change y Manufacturing site change y Batch size change y Manufacturing process and equipment change

y SUPAC IR y SUPAC-SS y SUPAC-MR

SUPAC industry perspective: It is based on interviews with 6 companies in the first half of 1997.  Shorter waiting times for site transfers.  More rapid implementaion of process and equipment changes.

y Production of fewer unmarketable stability batches y Reduced administration costs for documentation of

changes by the regulatory affairs departments. y Estimated saving $51.2 million/year.

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

detectable impact on formulation quality and performance.

Examples
y deletion of color or flavor y excipient change with total additive effect of up to 5%

Nonrelease controlling excipient

Percent excipient (w/w) of total formulation, less than or equal to the following percent ranges
5 3 1 0.5 0.25 1 1 0.1 1

Filler Disintegrants Starch Other Binder Lubricant Ca or Mg Stearates Other Glidant Talc Other Film Coat

SS (Semisolid) Chemistry Application/co same documentation mpendial release requirement* Stability One batch 1 st batch with testing with long term LT stability testing ( 1 LT) None none Dissolution Documentatio n In vivo None none Filling Annual report same documentation (all information including LT)

IR

MR (nrc) same

MR (rc) same

Same as SS

Same as SS

none

none

none same

none same

y Level 2 changes are those that could have a significant

impact on formulation quality and performance.

y Tests and filing documentation for a level 2 change

very depending on three factors:

y y y

therapeutic range solubility permeability

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

Excipient Filler Disintegrant Starch Other Binder Lubricant Calcium or magnesium stearate Other Glidant Talc Other Film Coat

% W/W out of total target dosage for weight 10

6 2 1

0.5 2

2 0.2 2

IR Chemistry documentation Stability documentation Dissolution

SS

MR (nrc)

MR (rc)

In vivo

Release and Release and batch record executed batch record 1 batch with 3 same month accel and 1 batch LT* Yesdepends Yes- Compare on Permeability and solubility@ None none

release and release and executed batch executed batch record record same Same

Yes- compare

Yes- compare

none

Filing documentation

PA (accel stab) AR (LT stab)

CBE (accel Same as IR stab) AR (LT stab)

Non for nonnarrow therapeutic index (T.I.) AND Single dose for narrow T.I. Same as IR

Case A

HP, 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 B

LP, HS

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

Case C

HP, 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.

y Level 3 changes are those that are likely to have a significant impact on

formulation quality and performance.

y y Tests and filing documentation very depending on the following three factors:
y y y

therapeutic range solubility permeability

y
y Examples y
y

y y y
y

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 drug addition or deletion of release controlling excipient(s)
Change in release controlling excipients >10%

IR Chemistry documentation Stability documentation Dissolution In vivo File

SS

MR (nrc) Release and executed batch record Same as SS

MR (rc) Release and executed batch record Same as SS

Release and Release and batch record executed batch record 1 batch with 3 Same and first months accel three batches 1 LT with LT Same as Level Not required 2 Bioequivalence Same needed PA (accel stab) Same AR (LT stab)

Extended delayed* Same Same

and Extended delayed* Same Same

and

A. Manufacturing site Level I changes y Level I changes is defined as changes in manufacturing site
y within a single facility where the same equipment,

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

IR Chemistry documentation Dissolution In vivo File Release Release None AR

SS Same none none AR

MR Same Release None AR

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

manufacturing site
y 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

IR Chemistry documentation

SS

MR Release; Notification of location of new site and updated executed batch record 1 batch w/3 months accel. 1 st LT* Extended and delayed None CBE (accel stab) AR (LT stab)

Same as IR Release; Notification of location of new site and updated batch record 1 LT 1 st LT

Stability testing

Dissolution In vivo File

Release None CBE AR (LT stab)

none none CBE AR (LT stab)

y A change in manufacturing site to a different campus

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

IR Chemistry documentation Stability testing SBI (significant body of 1 batch w/3 months information available) * acel. Upto 3 batch with LT NSBI (significant body Upto 3-3 months accel. of information is not Upto 3 LT* available) * Dissolution In vivo File

SS

MR Release; same

Release; Notification of Release; change and updated same batch record

Same; 1 st three batch Same; 1 st three batch LT LT Three batch with months accel. Three batch with LT 3 Three batch with three months accel. 1 st three production batches with LT Extended and delayed Single bioequivalence PA (accel stab) AR (LT stab) dose

As per low permeability comparison and high solubility None none CBE (accel stab) AR (LT stab) Same as IR

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

y 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.

IR Chemistry documentation Release; Notification of change and updated batch record 1 LT Release none AR (LT stab)

SS Release; Notification of change and updated batch record 1 st LT none none same

MR Release; Notification of change and executed batch record 1 st LT Release None Same

Stability study Dissolution In vivo File

y 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.

IR Chemistry documentation Release; Notification of change and updated batch record 1-3 mos accel 1 LT One batch with 3 months accelerated stability study 1 LT As per low permeability, high solubility None CBE (accel stab) AR (LT stab)

SS Release; Notification of change and updated batch record Same 1 st LT Same 1 st LT

MR Release; Notification of change and updated batch record Same 1 st LT Same Three batch with long term stability study Extended and delayed none same

Stability testing

SBD

Dissolution

comparision

In vivo File

none same

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

y A. Equipment Level 1 change

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.

IR Chemistry Release; Notification of change and updated batch record 1 LT Release None AR (LT stab)

SS Release; Notification of change and updated batch record 1 LT None none same

MR Release; Notification of change and updated batch record 1 LT Release None Same

Stability testing Dissolution In vivo File

y Examples include: Changes in equipment to a different

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

IR Chemistry documentation

SS

MR

Release; Release; Release; Notification of Notification of Notification of change and change and change and updated batch updated batch updated record record executed batch record One batch with 3 Same 1 st LT months accelerated stability study 1 LT Yes (Case C) comparision None PA (accel stab) AR (LT stab) none CBE (accel stab) AR (LT stab) Same Three batch with long term stability study Extended delayed none and

Stability testing SBD

Dissolution In vivo File

PA (accel stab) AR (LT stab)

y A. Manufacturing Process Level 1 Change

This category includes process changes including changes such as mixing times and operating speeds within application/validation

ranges.
IR Chemistry Release documentation SS release MR Release; Notification of change and updated executed batch record Release None AR

Dissolution In vivo File

Release None AR

None none AR

y This category includes process changes including

changes such as mixing times and operating speeds outside of application/validation ranges

IR Chemistry documentation

SS

MR same

Stability testing

Release; Notification Same of change and updated batch record 1 LT

One batch with 3 months accel. 1 st LT

Stability: SBD Stability: NSBD Dissolution File Yes (case B) CBE (accel stab) AR (LT stab)

1-3 mos accel * 1 st LT 3-3 mos accel @ comparision same Extended delayed) same and

y This category includes change in the type of process

used in the manufacture of the product, such as a change from wet granulation to direct compression of dry powder.

IR Chemistry documentation Stability testing

SS

MR Release; notification of change and updated executed batch record Three batch with 3 months accelerated stability study 1 st 3 LT @

Release; Notification of No level 3 change and updated batch record

Stability: SBD

One batch with months accel. 1 LT Upto 3-3 mos accel. Upto 3 LT * Yes (Case B) Study needed PA (accel stab) AR (LT stab)

Stability: NSBD Dissolution In vivo File

Extended and delayed Single dose same

y http://www.fda.gov/cder/guidance.htm