3. The acronym "SUPAC" stands for "Scale-Up and Post-
Approval Changes".
It refers to the FDA-recommended testing and filing
actions to be taken by a pharmaceutical firm when it
changes the manufacturing processes of a drug product
that has been approved via a New Drug Application
(NDA), an Abbreviated New Drug Application (ANDA), or
an Abbreviated Antibiotic Drug Application (AADA).
The Agency has provided its recommendations to
industry in the form of Guidances.
3
4. INTRODUCTION
This guidance provides recommendations to
sponsors of new drug applications (NDA's),
abbreviated new drug applications (ANDA's), and
abbreviated antibiotic applications (AADA's) who
intend, during the postapproval period, to change:
the components or composition;
the site of manufacture;
the scale-up/scale-down of manufacture; and/or
the manufacturing (process and equipment)
4
5. This guidance is the result of
1) a workshop on the scale-up of immediate release
drug products conducted by the American
Association of Pharmaceutical Scientists in
conjunction with the United States Pharmacopoeial
Convention and the Food and Drug Administration
(FDA)
2) Research conducted by the University of Maryland
at Baltimore on the chemistry, manufacturing and
controls of immediate release drug products under
the FDA/University of Maryland Manufacturing
Research Contract;
3) the drug categorization research conducted at the
University of Michigan and the University of Uppsala
on the permeability of drug substances;
5
6. 4)the Scale Up and Post Approval Changes (SUPAC)
Task Force which was established by the Center for
Drug Evaluation and Research (CDER) Chemistry,
Manufacturing and Controls Coordinating Committee
to develop guidance on scale-up and other
postapproval changes
6
7. The guidance defines:
1) levels of change;
2) recommended chemistry, manufacturing, and
controls tests for each level of change;
3) in vitro dissolution tests and/or in vivo
bioequivalence tests for each level of change; and
4)documentation that should support the change.
7
8. 21 CFR 314.70 provides instructions for how changes to
approved manufacturing process should be reported to
the Agency.
Why do the SUPAC Guidances offer an advantage over
the regulations?????
The documents are specific for particular dosage
forms.
To date, two Guidances have been finalized. They are:
8
9. Immediate Release Solid Oral Dosage Forms---Scale-
Up and Post-Approval Changes:
Chemistry, Manufacturing and Controls, In Vitro
Dissolution Testing, and In Vivo Bioequivalence
Documentation (November 1995)
Nonsterile Semisolid Dosage Forms---Scale-Up and
Post-Approval Changes:
Chemistry, Manufacturing and Controls; In Vitro
Dissolution Testing and In Vivo Bioequivalence
Documentation (May 1997)
In addition, SUPAC documents covering other dosage
forms (e.g., extended-release products, transdermals,
parenteral solutions), as well as a related document(s) for
bulk active substances, are at various stages of
development.
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10. SUPAC-IR
FDA issued the first of its SUPAC guidances in nov
1995
This guidance addressed scale-up and PACs for
immediate release oral solid dosage forms
When making equipment changes ,the FDA’s
SUPAC-IR/MR immediate release and modified
release solid oral dosage forms Manufacturing
Equipment Addendum ,released in january 1999 has
to be followed This addendum lists various types
of equipment and categorises them into operating
classes and subclasses 10
11. SUPAC-IR Q&A
In feb 1997,the FDA issued a letter containing the
most frequently asked questions regarding SUPAC
The clarification regarding stand-alone packing site
changes
The second change reffered to post-approval
analytical testing site changes
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12. PAC-ALTS
In april 1998 the FDA issued the PAC-ATLS (post
approval changes-analytical testing laboratory site)
guidance document allowing analytical testing
laboratory site changes for all regulated dosage form
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13. LEVELS OF CHANGES
3 levels of changes:
level 1
level 2
level 3
LLeevveell 11:: This level 1 changes may be filed in an
annual report and have no detectable impact on
formulation quality or performance
13
14. LEVEL 2: They could have significant impact on
formulation quality and performance and thus filed
in a changes being effected(CBE) supplement or
prior approval (PA) supplement
This tests and filing depends on therapeutic range
,solubility, permeability
LEVEL3:This changes are likely to have impact on
Rx quality and performance and are thus filed in PA
supplement
This tests and filing documentation vary ,depending
on therapeutic range,solubility,and permeability of
the pharmaceutical product
14
15. COMPONENTS
&COMPOSITION
This section of the guidance focuses on changes in
excipients in the drug product
Changes in the amount of drug substance are not
addressed by this guidance.
Changes in components or composition that have
the effect of adding a new excipient or deleting an
excipient are defined at Level 3
15
16. LEVEL 1:
Examples:
a. Deletion or partial deletion of an ingredient intended
to affect the color or flavor of the drug product; or
change in the ingredient of the printing ink to
another approved ingredient
b. Changes in excipients, expressed as percentage
(w/w) of total formulation, less than or equal to the
following percent ranges:
16
18. Test Documentation
a. Chemistry Documentation
Application/compendial release requirements and
stability testing.
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.
18
20. LEVEL 2 CHANGES
Examples:
Change in the technical grade of an excipient.
(Example: Avicel PH102 vs. Avicel PH200.)
Changes in 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):
20
23. 23
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.
24. Dissolution Documentation
Case A: High Permeability, High Solubility Drugs
Dissolution of 85% in 15 minutes in 900
mL of 0.1N HCl. If a drug product fails to meet this
criterion, the applicant should perform the tests
described for Case B or C (below).
Case B: Low Permeability, High Solubility Drugs
Multi-point dissolution profile should
be performed in the application/compendial medium
at 15, 30, 45, 60 and 120 minutes or until an
asymptote is reached. The dissolution profile of the
proposed and currently used product formulations
should be similar 24
25. Case C: High Permeability, Low Solubility Drugs
Multi-point dissolution profiles should be
performed in water, 0.1 N HCl, and USP buffer
media at pH 4.5, 6.5, and 7.5 (five separate profiles)
for the proposed and currently accepted
formulations. Adequate sampling should be
performed at 15, 30, 45, 60, and 120 minutes until
either 90% of drug from the drug product is dissolved
or an asymptote is reached. A surfactant may be
used, but only with appropriate justification. The
dissolution profile of the proposed and currently used
product formulations should be similar.
25
26. c. In Vivo Bioequivalence Documentation
None: if the situation does not meet the description in
Case A, Case B or Case C, refer to Level 3 changes.
Filing Documentation
Prior approval supplement (all information including
accelerated stability data); annual report (long-term
stability data).
26
27. LEVEL 3
Examples:
a.Any qualitative and quantitative excipient changes to
a narrow therapeutic drug beyond the ranges noted
in level 1
b. All other drugs not meeting the dissolution criteria
under level 2
c. Changes in the excipient ranges of low solubility,
low permeability drugs beyond Changes in the
excipient ranges of all drugs beyond 2x level 1
27
28. Test documentation
a.Chemistry Documentation
Application/compendial release requirements and
batch records.
Significant body of information available:
One batch with three months accelerated stability
data reported in supplement; one batch on long-term
stability data reported in annual report.
Significant body of information not available:
Up to three batches with three months
accelerated stability data reported insupplement; one
batch on long-term stability data reported in annual
report. 28
29. Dissolution Documentation
Case B dissolution profile as described in Section
III.B.2.b.
In Vivo Bioequivalence Documentation
Full bioequivalence study. The bioequivalence study
may be waived with an acceptable in vivo/in vitro
correlation has been verified
29
30. Filing Documentation
Prior approval supplement (all information including
accelerated stability data); annual report (long-term
stability data).
30
59. 59
Phamaceutical process validation .ROBERT A NASH
pg no:705 to747:”change control and supac”-Nelie
helen waterland
Dupont pharmaceuticals co.,wilmington, Delaware,USA
