SUPAC Guidelines

Scale-Up and Post-approval Changes

Immediate Release Solid Oral Dosage Forms
(Guidance for Industry)
Center for Drug Evaluation and Research (CDER),
USFDA

Department of Pharmaceutics
Bombay College of Pharmacy,
 Purpose Statement

At the end of the lecture the students should be able

to –
Understand the SUPAC guidelines(Scale-Up and
Post-approval Changes -
Immediate Release guidelines) for Solid Oral
Dosage Forms.
 CO and Competencies

Competencies
BP702T-1 : Underline the SUPAC guidelines.

Course Outcome:
BP702 T-CO2 : Describe pilot plant setup and scale up
operations
 Learning Objective

Sr. Learning objectives Domain Leve Criteri CO PO

No l a
1 Understand the PURPOSE Cognitive Must All BP702 T- PO-1,
OF GUIDANCE know CO2 PO-2
2 Understand the types of Cognitive Must All PO-3,
Scale up and post- know
PO-4,
approval changes and
able to describe it PO-6,
3 Describe the Level 1, 2 Cognitive Must All PO-7,
and 3 changes with the know PO-11
documentation required
 PURPOSE OF GUIDANCE

This guidance provides recommendations to sponsors of

• New drug applications (NDA's)
• Abbreviated new drug applications (ANDA's), and
• Abbreviated antibiotic drug applications (AADA's)

who intend, during the postapproval period, to change:

1) Components or composition
2) Site of manufacture
3) Scale-up/scale-down of manufacture and/or
4) Manufacturing (equipment and process) of an immediate
release oral formulation.
 Definitions
Batch
A specific quantity of a drug or other material produced
according to a single manufacturing order during the same
cycle of manufacture and intended to have uniform character
and quality, within specified limits.

Contiguous Campus
Continuous or unbroken site or a set of buildings in adjacent
city blocks
Drug Product
A drug product is a finished dosage form that contains a
drug substance, generally, but not necessarily, in
association with one or more other ingredients .

A solid oral dosage form includes tablets, chewable

tablets, capsules, and soft gelatin capsules.
Drug Substance
An active ingredient that is intended to furnish
pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of a
disease, or to affect the structure of any function of the
human body, but does not include intermediates used in the
synthesis of such ingredient.

Equipment
Automated or non-automated, mechanical or non-mechanical
equipment used to produce the drug product, including
equipment used to package the drug product.
Formulation
A listing of the ingredients and composition of the dosage
form.

Justification
Reports containing scientific data and expert professional
judgment to substantiate decisions.
Components CHANGES IN BATCH
Site changes SIZE
and
composition Level 1
(SCALE-UP/SCALE-
change DOWN)
Level 1
s Level 1
change change
s Level 2
change s
Level 2 s Level 2
change change
Level 3 s
s change
Level 3 s
change
s
Manufacturing

Equipment Process
Level
Level 1
1 changes
chang
Level 2
es 2
Level changes
changes Level 3
changes
Components and
composition
Level 1
chang
es
Level 2
chang
es
Level 3
chang
es
 COMPONENTS AND COMPOSITION

• This section focuses on changes in excipients or level of

excipients in the drug product.
• Changes in the amount of drug substance are not
addressed by this guidance.
• There are three levels of changes.
 Level 1 Changes

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

detectable impact on formulation quality and performance.

• Examples
a.Deletion or partial deletion of coloring agent or flavoring agent of
the drug product
b.Change in the ingredient of the printing ink to another approved
ingredient
c.Changes in quantity of excipients, expressed as percentage
(w/w) of total formulation, less than or equal to the following
percent ranges
 EXCIPIEN PERCENT EXCIPIENT (w/w) OUT OF
T TOTAL TARGET DOSAGE FORM WEIGHT
Filler ±5
Disintegra Starch ±3
nt Other ±1
Binder ±0.5
Lubricant Calcium (Ca) or Magnesium (Mg) Stearate
±0.25
Other ±1
Glidant Talc ±1
Other ±0.1
Film Coat ±1
• The total additive effect of all excipient changes should not
be more than 5%.

• (Example: In a product consisting of active ingredient A,

lactose, microcrystalline cellulose and magnesium stearate,
the lactose and microcrystalline cellulose should not vary by
more than an absolute total of 5% (e.g. lactose increases
2.5% and microcrystalline cellulose decreases by 2.5%)
relative to the target dosage form weight if it is to stay within
the Level 1 range).
 Documentation required

1. Test Documentation
a. Chemistry Documentation
• Application/compendial release requirements
• Stability testing: one batch on long-term stability data
reported in annual report.
b. Dissolution Documentation - None beyond
application/compendial requirements.
c. In Vivo Bioequivalence Documentation - None.

2. Filing Documentation Annual report (all information including

long-term stability data)
 Level 2 Changes

• Level 2 changes are those that could have a significant

impact on formulation quality and performance.

• Tests and filing documentation for a Level 2 change vary

depending on three factors: therapeutic range, solubility,
and permeability.

• Therapeutic range is defined as either narrow or non-

narrow.

• A list of narrow therapeutic range drugs is provided in

Appendix A.

• Drug solubility and drug permeability are defined as

 Extracted
from SUPAC
Guideline for
Immediate
Release Solid
Oral Dosage
Forms
• Solubility considered here is the lowest solubility in
milligram/milliliter (mg/mL), of the largest dosage strength,
determined in the physiological pH range (pH 1 to 8) and
temperature (37 + 0.5 C).

• And another factor considered is volume of media required to

solubilize all dose in largest dosage strength.

• High solubility drugs are those with a dose/solubility

volume of less than or equal to 250 mL.

• Example: Compound A has as its lowest solubility at pH 7, 37

± 0.5 C which is 1.0 mg/ml, and is available in 100 mg, 200
mg and 400 mg strengths. This drug would be considered a
low solubility drug as its dose/solubility volume is greater
than 250 mL (400 mg/1.0 mg/mL=400 mL).
• Permeability is defined as the effective human jejunal wall
permeability of a drug and includes an apparent resistance to
mass transport to the intestinal membrane.
• High permeability drugs are generally those with an extent of
absorption greater than 90% in the absence of documented
instability in the gastrointestinal tract,
or
those whose permeability attributes have been determined
experimentally.
Examples:

a. Change in the technical grade of an excipient (Example: Avicel

PH102 vs. Avicel PH200)
b. Changes in quantity of excipients, expressed as percent (w/w)
of total formulation, greater than those listed above for a
Level 1 change but less than or equal to the following percent
ranges (which represent a two fold increase over Level 1
changes)
 EXCIPIEN Percent Change Percent Change
T Level 1 Level 2
Filler ±5 ±10
Disintegra Starch ±3 ±6
nt Other ±1 ±2
Binder ±0.5 ±1
Lubricant Calcium or
Magnesium Stearate ±0.5
±0.25 ±2
Other ±1
Glidant Talc ±1 ±2
Other ±0.1 ±0.2
Film Coat ±1 ±2
 Documentation required

1. Test Documentation
a. Chemistry Documentation
• Application/compendial release requirements and
batch records.
• Stability testing: 1 batch with 3 months accelerated
stability data in supplement and 1 batch on long-term
stability.
a. Dissolution
Case Documentation
A: High Permeability, Dissolution of 85% in 15 minutes in 900 mL of
High Solubility Drugs 0.1N HCl.
Case B: Low Permeability, Multi-point dissolution in compendial medium at
High Solubility Drugs 15, 30, 45, 60 and 120 minutes or until an
asymptote is reached
Case C: High Permeability, Multi-point dissolution in multiple medias (water,
Low Solubility Drugs 0.1 N HCl, and USP buffer media at pH 4.5, 6.5,
and 7.5)
 c. In Vivo Bioequivalence Documentation - None

2. Filing Documentation
• Prior approval supplement (all information including
accelerated stability data)
• annual report (long-term stability data)
 Level 3 Changes
• Level 3 changes are those that are likely to have a
significant impact on formulation quality and performance.

• Tests and filing documentation vary depending on the following

three factors: therapeutic range, solubility, and permeability.

• Examples:
a. Any qualitative and quantitative excipient changes to a
narrow therapeutic drug beyond the ranges noted in Section
of level 2 change.
b. All other drugs not meeting the dissolution criteria under
Section of level 2 change.
c. Changes in the excipient ranges of low solubility, low
permeability drugs beyond those listed in Section of level 2
change.
d. Changes in the excipient ranges of all drugs beyond those
 Documentation required
1. Test Documentation
a.Chemistry Documentation
• Application/compendial release requirements and batch
records.
• Significant body of information available: One batch – 3 months
accelerated stability data and one batch on long-term stability
data.
• Significant body of information not available: Up to three
batches - 3 months accelerated stability data and one batch on
long-term stability data.

b. Dissolution Documentation
• Case B dissolution profile as described for level 2 changes.

c.In Vivo Bioequivalence Documentation

• Full bioequivalence study.
• But it may be waived with an acceptable in vivo/in vitro
2. Filing Documentation
• Prior approval supplement (all information including
accelerated stability data)
• Annual report (long-term stability data).
 Summary:

• Purpose of guidance
• Types of scale-up and post-approval changes
• Level 1, 2 and 3 changes in component and
composition of the formulation
• Required documentation
Reference:

• SUPAC Guidelines (Scale-Up and Post-approval Changes -

Immediate Release Solid Oral Dosage Forms), Guidance for
Industry, Center for Drug Evaluation and Research (CDER),
USFDA
• Text book of FDA Regulatory Affairs A Guide for Prescription
Drugs, Medical Devices, and Biologics’ Second Edition.
• Regulatory Affairs brought by learning plus, inc. available
at http.//www.cgmp.com/ra.html
Questions

• Describe Level 1 and 2 batch size changes and Level 1 and 2

equipment changes in Immediate release solid oral dosage
forms with test and filing documentation.
• Describe Level 1,2 and 3 site changes in Immediate release
solid oral dosage forms with test and filing documentation.
• Define dissolution testing. Describe Case A, Case B and Case
C dissolution testing as per SUPAC.
• Describe Level 1 changes in components and composition in
Immediate release solid oral dosage forms with examples,
test and filing documentation.
• Describe Level 1 and Level 2 site changes in Immediate
release solid oral dosage forms with test and filing
documentation.
Thank
you.