FDA has published guidance to provide recommendations
to holders of new drug applications (NDAs) and abbreviated new drug
applications (ANDAs) who intend to make post-approval changes.
Reporting Categories:
There are four reporting categories which are
distinguished in the following paragraphs:
A. Major Change:
It
is a
change that has a substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of a drug product as these
factors may relate to the safety or effectiveness of the drug product.
It requires the submission of a supplement and
approval by FDA prior to the distribution of the drug product made using the
change. (Prior Approval Supplement)
B.
Moderate Change (CBE 30):
It is a change that has a moderate potential to
have an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or effectiveness
of the drug product.
It requires the submission of a supplement to
FDA at least 30 days before the distribution of the drug product made using the
change. It is called Supplement - Changes Being Effected in 30 Days (CBE 30)
C.
Moderate Change (CBE 0):
It is a change that has a moderate potential to
have an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or effectiveness
of the drug product.
It requires the submission of a supplement to
FDA at the time of distribution of the drug product made using the change. It
is called Supplement - Changes Being Effected (CBE 0)
If FDA disapproves CBE 30 or CBE 0 Supplement, FDA may order the
manufacturer to cease distribution of drug products made using the disapproved
changes.
D. Minor Change:
It is a change that has minimal potential to
have an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or effectiveness
of the drug product.
The applicant has to describe minor changes in
its next Annual Report.
General Requirements:
Other
than for editorial changes in previously submitted information, an applicant
must notify FDA about each change.
A
supplement or annual report must include a list of all changes contained in the
supplement or annual report.
The
applicant must describe each change fully in the supplement or annual report
Assessing
the Effect of Manufacturing Changes
1. Assessment of the
Effects of the Change:
This assessment is done either by Conformance
to Specifications or Additional Testing
2. Equivalence:
An applicant should usually assess the extent
to which the manufacturing change has affected the SISPQ of the drug product.
3.
Adverse Effect:
Some manufacturing changes have an adverse
effect on the SISPQ of the drug product.
Applicants should consult with the appropriate
CDER chemistry or microbiology review staff if there are any questions on
whether a change in a characteristic would be viewed by CDER as adversely
affecting the SISPQ of the drug product.
Changes
|
Major
|
Moderate
|
Minor
|
Manufacturing
Sites
|
· A move to a different
manufacturing site that has never been inspected by FDA.
· Move to site that does not have a satisfactory CGMP inspection for the type
of operation being moved.
· Transfer of the
manufacture of an aseptically processed sterile drug substance that does not
manufacture similar approved drug products.
· Transfer of the
manufacture of a finished drug product sterilized by terminal processes to a
newly constructed facility at a different manufacturing site
|
·
Change in sites that is not provided in this guidance.
·
A move to a different manufacturing site for the manufacture or processing of the final intermediate.
|
·
A move to a different manufacturing site for secondary
packaging
·
A move to a different manufacturing site for labelling
·
A move to a different manufacturing site for the ink
imprinting of solid oral dosage form drug products.
|
Manufacturing Process
|
· Changes that may
affect the controlled release, metering or other characteristics of the dose
delivered to the patient
· Changes that may
affect drug product sterility assurance
· Changes in the
sterilization method
· Changes in the sterilizer
load configurations that are outside the range of previously validated loads.
· Changes in materials
or pore size rating of filters used in aseptic processing.
|
·
For drug products, any change in the process, process
parameters, and/or equipment except as otherwise provided for in this
guidance
·
Changes in dry heat depyrogenation processes for glass
container systems
·
Changes to filtration parameters for aseptic processing
·
A change in methods or controls that provides increased
assurance about SISPQ of the drug product.
|
· A minor change in an
existing code imprint for a dosage form
· Addition or deletion
of a code imprint by embossing, debossing, or engraving on a solid dosage
form drug product
· A change in the order
of addition of ingredients for solution dosage forms or solutions used in
unit operations
·
|
Specifications
|
· Relaxing an
acceptance criterion
· Deleting any part of
a specification
· Establishing a new
regulatory analytical procedure including designation of an alternative
analytical procedure as a regulatory procedure.
|
· Any change in a regulatory
analytical procedure other than those identified as major changes
· Relaxing an
acceptance criterion or deleting a test for raw materials used in drug
substance manufacturing
· Relaxing an
acceptance criterion or deleting a test to comply with an official compendium
|
· Tightening of
acceptance criteria
· addition or revision
of an alternative analytical procedure that provides the same or increased
assurance about SISPQ of the drug product.
|
Container Closure System
|
· a change from an ink
and/or adhesive used on the permeable or semipermeable packaging component to
an ink or adhesive
· A change in the
primary packaging components, when the primary packaging components control
the dose delivered to the patient
· A change to a
prefilled syringe dosage form from another container system.
· A change from a
single unit dose container to a multiple-dose container system.
|
· Changes in the size
or shape of a container for a sterile drug substance
· A change in the
number of units (e.g., tablets, capsules) or labeled amount (e.g., grams, milliliters)
of a nonsterile drug product in a unit-of-use container
· A change in or
addition or deletion of a desiccant.
|
· A change in the size
and/or shape of a container for a nonsterile solid dosage form
· A change in the
number of units (e.g., tablets, capsules) or labeled amount (e.g., grams) of
nonsterile solid dosage form in a multiple-unit container
|
Labeling
|
· Changes based on
postmarketing study results
· Change in, or
addition of, pharmacoeconomic claims based on clinical studies
· Changes based on data
from preclinical studies.
· Claims of superiority
to another drug product.
|
· Addition of an
adverse event due to information reported to the applicant or Agency
· Addition of a
precaution arising out of a postmarketing study.
· Clarification of the
administration statement to ensure proper administration of the drug product.
|
· Editorial changes,
such as adding a distributor's name.
· Foreign language
versions of the labeling if no change is made to the content of the approved
labeling and the certified translation is included.
· Labeling changes made
to comply with an official compendium.
|
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