SUPAC Guideline
• After a pharmaceutical product is approved, its sponsor
and manufacturer must work to meet ever-changing manufacturing standards, as
well as demand for the drug
• Though the drug product itself is still approved, a
manufacturer must show to FDA that each change it makes to its manufacturing
process (e.g. new production lines, the use of new equipment or new processes)
will have no effect on the safety, efficacy or quality of the approved medicine
• Technology transfer of a pharmaceutical product from
research to the production floor with simultaneous increase in production
outputs is commonly known as scale – up
• Scale-up is an inevitable part of the product life cycle
of every successful drug, and each time it is required, a meticulous process
must be followed to ensure that the end result is identical to the product
formulation as originally devised
SUPAC
guidelines
• In simple terms, the process of increasing batch size is
termed as scale- up
• Conversely, scale- down refers to decrease in batch size
in response to reduced market requirements
• Depending on the magnitude of the proposed changes, FDA
permits sponsors to make them in a variety of different ways
• For minor changes, companies can either make note of those
changes in their Annual Reports or notify FDA at the time a change is made
using the Changes Being Effected (CBE) process
• For most manufacturing changes, however, sponsors must
notify FDA of the change using the Prior Approval Supplement (PAS) (21 CFR
314.70) and await FDA's approval of the change before implementation.
• Determining which change notification process to use—and
knowing which documentation FDA needs to determine if a change is appropriate—can
be difficult
• FDA's latest guidance, SUPAC: Manufacturing Equipment
Addendum, is dedicated to creating a holistic set of recommendations about how
to support proposed manufacturing changes using proper documentation
SUPAC
guidelines- History
• In 1991-92,
two workshops were
held by the
American Association of Pharmaceutical Scientists
(AAPS), the U.S. Food & Drug Administration (FDA) and
the United States Pharmacopeia (UPS) to explore principles for making process
and/or compositional changes in drug products post approval
• These changes ultimately included formulation or
compositional changes, process changes, process scale changes and process site
or campus changes
• The proceedings of these workshops were ultimately published
as a guidance by the FDA titled “Scale-Up and Post-Approval Changes” or SUPAC
• The scale-up process and the changes made after approval in the composition, manufacturing process, manufacturing equipment and change of site have become known as Scale-Up and Post approval Changes, or SUPAC
SUPAC
guidelines
This guidance combines and supersedes the following scale-up
and post-approval changes (SUPAC) guidances for industry:
(1) SUPAC-IR/MR:
Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing
Equipment Addendum, and
(2)SUPAC-SS
Nonsterile Semisolid Dosage Forms - Manufacturing Equipment Addendum. It
removes the lists of manufacturing equipment that were in both guidances and clarifies
the types of processes being referenced
This draft SUPAC addendum should be used in conjunction with
the following SUPAC guidances for industry:
(1) 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,
(2) SUPAC-MR:
Modified Release Solid Oral Dosage Forms Scale-Up and Post-Approval
Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution
Testing and In Vivo Bioequivalence Documentation, and
(3) SUPAC-SS:
Nonsterile Semisolid Dosage Forms, Scale-Up and Post Approval Changes:
Chemistry Manufacturing and Controls; In Vitro Release Testing and In Vivo
Bioequivalence
What You
Should Know about SUPAC?
SUPAC is not
regulation, but only guidance
• It relates only to drug manufacturing and it’s only
available for certain dosage forms: immediate release solid oral dosage forms
including tablets, capsules, and soft gelatin capsules; modified release solid
oral dosage forms including delayed release and extended release; and topical
semi-solid dosage forms including creams, ointments, suspensions, emulsions and
gels
Purpose
This guidance provides recommendations to sponsors of new
drug applications (NDA’s), abbreviated new drug applications (ANDA’s), and
abbreviated antibiotic applications (AADA's)
What does
SUPAC means in drug industry?
SUPAC 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 post
approval period, to change:
1) The components or
composition;
2) The site of
manufacture
3) The
scale-up/scale-down of manufacture; and/or
4) The manufacturing
(process and equipment) of an immediate release oral formulation
What does
the guidance define???
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
4) Documentation that should support the change.
Levels of
Change
• Changes in the size of a batch from pilot scale to small
or large production batches after approval of a new drug application (NDA) or
abbreviated new drug application (ANDA) require submission of additional
information
• All scale-up changes should be properly validated and,
where needed, inspected by appropriate agency personnel
Levels
The FDA divides scale-up into two levels:-
• Level 1 is
defined as a: Change in batch size, up to and including a factor of 10 times
the size of the pilot batch
• Level 2
discusses Changes in batch size beyond a factor of 10 times the size of the
pilot batch. Otherwise, requirements of level 2 are similar to level 1
requirements
Level 1
requirements
1. Chemistry documentation application/compendia release
requirements
2. Notification of change and submission of updated batch
records in annual report
3. One batch on long-term stability reported in annual
report
4. No dissolution or in vivo testing
5. Filing documentation: annual report (long-term stability
commitment)
Level 2
additional requirements
1. Stability testing:
one batch with three months accelerated stability data and one batch on
long-term stability
2. Dissolution
documentation: case B testing
3. Filing
documentation: prior approval supplement; annual report
Dissolution
Testing
|
Case A |
Dissolution of Q = 85% in 15 minutes in 900ml od 0.1N HCL, using the
USP <711> apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM |
|
Case B |
Multi point dissolution profile in the application/compendial medium
at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for
proposed and currently accepted formulation. |
|
Case C |
Multi point dissolution profiles performed in water, 0.1N HCL, and
USP buffer media at ph 4.5, 6.5, and 7.5 (five separate profile) for the
proposed and currently accepted formulation. 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 with appropriate justification. |
SUPAC Level
|
Level |
Classification |
Test Documentation |
Filing |
|
1 |
Quantitatively 10% or less change in the approved amount of
preservative |
- Application/compendial requirement - Preservative effectiveness test at lowest specified preservative
level |
- Annual Repot |
|
2 |
10-20% change in the approved amount of preservative |
- Application/compendial requirement - Preservative effectiveness test at lowest specified preservative
level |
- Changes being effected supplement - Annual eport |
|
3 |
> 20% change in the approved amount of preservative ( including
deletion) or use of different preservative |
- Application/compendial requirement - Executed batch record - For new preservative: analytical method for identification and
assay; validation studies - Preservative effectiveness test |
- Prior approval supplement - Annual report |
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