Scale Up,

Post Approval Changes (SUPAC)

&
Post Marketing Surveillance
 Introduction
►Approval of ANDA is the start of generic drug product history
►Changes are made frequently to chemistry & mfg controls
after approval throughout the life term of product
►Mfr may bring change in drug formulation, batch size,
process, equipment, mfg site may affects the identity,
strength, quality, purity and potency of finished product

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 Introduction
►Changes to approved ANDA may be done
Revised market forecast- change batch size
Qualification of new API source
Optimization of mfg process
Upgrade of container/ closure
Enhancement of analytical method and specs
►Change made may have varied adverse effects
depending on the type or dosage form or product

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 Introduction
►Eg: Change in container/ closures (solid/parenterals),
conc. of inactives (imm rel/ sust rel) – impacts BE
►Frequent & numerous changes may render the
product substantially different than the one approved
in original ANDA
►Supportive data to be submitted – comparison with
original exhibit batch/ bio batch

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 Background

► Food & Drug Administration Modernization Act (FDAMA) – Nov 21,

1997 for “further defining the statutory requirements for marketing
approved drugs in US”
► Post FDAMA, FDA issued Guidance for Industry: Changes to an
Approved NDA or ANDA – P. Ind to assess & report mfg changes
► FDAMA rewrite of 21 CFR 341.70
► 4 reporting categories
►Prior approval supplement: Major changes, need FDA approval
►Supplement – changes being effected (30 days) – Moderate changes
►Supplement – changes being effected (0 days) – Moderate changes
►Annual report – Minor changes, immediately implemented, filed in next
periodic report

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 SUPAC
► Prior to FDAMA, basis of revision of FD&C Guidance for Industry: Scale up &
post approval changes (SUPAC)
► Provided the clear, definitive language regarding regulatory notification process
and requirements for post approval changes, reduced regulatory burden on
industry
► Classified in to levels, provided requirements for each level
► SUPAC expanded 21 CFR 314.70 and defined in much detail the types of
changes and reporting category required.

In the following areas the change is likely

► Components and composition of the drug product
► Manufacturing site change
► Scale-up of the drug product
► Manufacturing equipment
► Packaging

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 SUPAC
►Describes 3 levels of changes
►Recommends chemistry, manufacturing and controls tests, in
vitro dissolution tests, and bioequivalence tests for each level

Level & Definition

►1 - Changes that are unlikely to have any detectable impact
on formulation quality and performance
►2 - Changes that could have a significant impact on
formulation quality and performance
►3 - Changes that are likely to have a significant impact on
formulation quality and performance

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Current Requirements For Post-approval Changes

►Components/ Composition
►Site changes
►Change in batch size
►Manufacturing
►Specifications
►Packaging

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 Current Requirements For Post-approval Changes
Components/ Composition
► Changes to the qualitative/ quantitative composition of the formulation
are considered major changes
► These changes must be considered carefully before implementation.
Such changes require a “Prior Approval Supplement” unless otherwise
exempted by regulation or guidance documents.
► Current guidance for industry, Changes to an Approved ANDA or NDA,
does not address components/ composition in detail
► SUPAC guidance remains in effect for defining components and
composition changes and the reporting category

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 Current Requirements For Post-approval Changes
Components/ Composition
►Addition or deletion of an ingredient can have an adverse
effect on the dissolution profile of the finished product and on
the in vivo bioequivalence to the RLD
►Addition or deletion of an ingredient must be filed as a Prior
Approval Supplement
►Exceptions – colors (removed/ reduced)
►Some cases – less stringent reporting

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 Current Requirements For Post-approval Changes
Site Changes
► The sponsor of an ANDA - include in its application the site of
manufacture, where the drug product will be produced, tested,
packaged, and/or labeled. A change in any of these sites can adversely
affect the identity, strength, quality, purity, or potency of the finished
product
► Any site change under SUPAC-IR calls for the new site to be in
compliance with good manufacturing practice (cGMP) regulations
► A stand-alone packaging operation site change, utilizing container (s)/
closure (s) in the approved application, may be submitted as a “Change
Being Effected Supplement”
► Facility should also have a current and satisfactory cGMP compliance
profile with FDA

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 Current Requirements For Post-approval Changes
Site Changes

►If the facility has not received a satisfactory cGMP Inspection

within the previous two years for the type of packaging
operation involved, a “Prior Approval Supplement” with the
same commitment for stability is recommended
►Supplement should also contain a commitment to place the
first production batch of the product on long-term stability
studies using the approved protocol in the application and to
submit the resulting data in annual reports
►Same for the analytical testing laboratory

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 Current Requirements For Post-approval Changes
Change in Batch Size
► Change in batch size from pivotal/ pilot scale bio-batch to larger or
smaller production batches tends to change the operating parameters.
Therefore, all the parameters, such as mixing time, speed, etc., are
adjusted according to the equipment (large or small) used in the
process.
► This requires proper validation of the batches before submission of
additional information in the application.
► Any change in the production batch for which the operating parameter
falls within the range established for the ANDA batch and validation
batches will be regarded as a level1change.
► If it falls outside the validation ranges, the change would be permitted
under SUPAC-IR as a level 2 change.
► Regardless, SUPAC-IR does not address scale-down below 100,000
units

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 Current Requirements For Post-approval Changes
Manufacturing
► This includes any change made in equipment and the process used in
manufacturing a drug product
1. EQUIPMENT CHANGE
► Any change in manufacturing equipment other than that used in the
approved application requires appropriate validation studies to
demonstrate that the new equipment is similar to the original equipment.
► Equipment within the same class and subclass would be considered to
have the same design and operating principle under SUPAC-IR.
Eg: Change in diff mfr of V-cone blender – acceptable
► Change from one class of equipment to another would be considered a
change in design and operating principle and would be considered
different under SUPAC-IR.
Eg: V-cone blender to ribbon blender 18
 Current Requirements For Post-approval Changes
Manufacturing
►A guidance for industry, SUPAC-IR/MR: Immediate Release
and Modified Solid Oral Dosage Forms Manufacturing
Equipment Addendum, 1999 (3), explains in detail about
various changes in equipment and the regulatory requirement

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The two different levels of change and regulatory requirements on change

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 Current Requirements For Post-approval Changes
Manufacturing
PROCESS CHANGE
► Change in manufacturing process or technology – may have
adverse effects on the identity, strength, quality, purity, or potency
of a drug product.
► The safety or effectiveness of the product depends on the type of
the manufacturing process and the changes being instituted for the
drug substance or drug product.
► Any fundamental change in the manufacturing process, e.g., dry to
wet granulation or change from one type of drying process to
another (e.g., oven tray, fluid bed) is considered a major change,
whereas change in mixing time, operating speed, etc., within an
approved range is considered a minor change
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The guidance defines 3 levels of in-process changes

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 Current Requirements For Post-approval Changes
Specifications
►Specifications are the standards a drug product must meet to
ensure conformance to predetermined criteria for consistency,
reproducibility, and quality.
►Such changes generally require a “Prior Approval
Supplement” unless the specification is tightening or
otherwise exempted by regulation guidance documents

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 Current Requirements For Post-approval Changes
Specifications
►Prior approval is required on the following major changes in
specification except as provided in the SUPAC-IR guidance
 Relaxing an acceptance criterion
 Deleting any part of a specification
 Changing or establishing a new regulatory analytical procedure that does not
provide the same or increased assurance of the identity, strength, quality, purity,
or potency of the material being tested as the analytical procedure described in the
approved application
►A 30 days Changes Being Effected Supplement needs to be
filed in case of moderate changes in specifications, e.g.,
 Change in regulatory analytical procedures other than editorial or identified as
major
 A change in analytical procedure or deletion of a test for raw materials used in
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drug substance man
 Current Requirements For Post-approval Changes
Specifications
►The following include changes in specifications that are
considered to have minimal potential for an adverse effect on
the identity, strength, quality, purity, or potency of a product as
they may relate to the safety or effectiveness of the product,
and therefore can be submitted in an annual report:
 Change in specification made to comply with an official compendium
 Change in analytical procedure for testing raw material, drug substance or drug
product that provides the same or increased assurance of identity, strength,
purity, or potency of the material being tested as the analytical procedure
described in the approved application
 Tightening of acceptance criteria

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 Current Requirements For Post-approval Changes
Packaging
►A container/closure system for a solid oral dosage form tends
to be low risk and will have little impact on the shelf life of the
finished product. Therefore, under the new guidance for
industry, and the stability guidance, the requirements for
packaging changes have been relaxed significant

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Comparability Protocols
► A comparability protocol is a plan for anticipated future CMC changes.
FDA recently published a draft guidance, “Comparability Protocols
Chemistry, Manufacturing, and Controls Information”, to provide
recommendations on preparing and using comparability protocols for
post-approval changes in the CMC section of an NDA or ANDA.
► According to the guidance, ‘‘A comparability protocol is a well defined,
detailed, written plan for assessing the effect of specific CMC changes
in the identity, strength, quality, purity, and potency of a specific drug
product as these factors relate to the safety and effectiveness of the
product. A comparability protocol describes the changes that are
covered under the protocol and specifies the tests and studies that will
be performed, including analytical procedures that will be used, and
acceptance criteria that will be achieved to demonstrate that specified
CMC changes do not adversely affect the product.’’
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Comparability Protocols

► A comparability protocol may be submitted with an ANDA or NDA

application or as a Prior Approval Supplement (post-approval).
► The benefit of the comparability protocol is that an FDA request for
additional information to support a change is less likely when the change
is covered under an approved protocol.
► Thus, the sponsor could implement a CMC post approval change as
described in the comparability protocol. This would allow the sponsor to
place the product in distribution sooner

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Post Marketing Surveillance
► Once the FDA approves a generic drug product, manufacturers are
responsible for conducting post-marketing surveillance.
► Post-marketing reporting requirements for an approved ANDA are set forth
in the US Federal Code of Regulations, 21 CFR 314.80 (5) and 314.98 .
► The main component of this requirement is the reporting of adverse drug
experiences (ADEs).
► According to 21 CFR 314.80(a), an adverse drug experience is defined as
‘‘any adverse event associated with the use of a drug in humans, whether
or not considered drug related’’
► The definition continues by stating that adverse events include those that
occur in the course of the use of a drug product in professional practice,
occur from drug overdose (accidental or intentional), abuse, or withdrawal,
or involve failure of expected pharmacological action.
► According to the definition, it is irrelevant whether or not an event is
considered drug related.
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Post Marketing Surveillance
► The fact that an adverse event occurred while a person was using a drug
product is reason enough to consider it an ADE.
► It is important to examine who is involved in the process of ADE reporting.
► Generally, there are three members that take part in this process:
► A reporter, a manufacturer, and the FDA. Essentially anyone can report
an ADE.
► The reporter can be a patient, doctor, pharmacist, nurse, or anyone else aware
of such an event. This person can report it to either the manufacturer of the
drug product or directly to the FDA.
► If the manufacturer receives the report first, the manufacturer is responsible for
investigating the ADE and reporting it to the FDA. If the FDA is notified directly
by the reporter, the agency informs the manufacturer so that the ADE can be
investigated.
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Post Marketing Surveillance
► Part of investigating an ADE may include, but is not limited to,
contacting the patient’s physician, the prescriber (if different from the
physician), and the pharmacy that filled the prescription. Other
investigations include performing all required testing of the retain sample
from the lot of the product that was used by the patient .
► Of course, there are many times when the lot number is not known and
therefore, this testing cannot be conducted.
► Once an investigation is complete, the manufacturer is responsible for
submitting the information in a report to the FDA.

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Post Marketing Surveillance
► There is certain information that must be known, though, before a report is
submitted to the FDA.
► Among this information are four elements: an identifiable patient, an
identifiable reporter, a suspect drug/biological product, and an adverse
event or fatal outcome.
► If any of these basic elements remain unknown after being actively sought
by the applicant/ manufacturer, a report on the incident should not be
submitted to the FDA, because reports without this information make
interpretation of their significance difficult, if not impossible.
► In these cases, the applicant/ manufacturer should track the steps taken to
acquire the additional information in their safety files for the product.
► To facilitate the reporting process, FDA created the MedWatch program

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Post Marketing Surveillance
► MedWatch is the FDA Medical Products Reporting Program.
► It was originally designed to emphasize the responsibility of healthcare
providers to identify and report ADEs .
► Through the MedWatch program, healthcare professionals can report
ADEs with the use of FDA Form 3500 (MedWatch Form).
► However, this reporting is done on a voluntary basis. Currently, there are
no regulations that require healthcare professionals to report adverse drug
experiences to the FDA or the manufacturer.
► In contrast, a manufacturer aware of an ADE is required by law to report it
to the FDA (provided the four elements noted earlier are known).
► The FDA/ MedWatch Form 3500A is used for mandatory reporting by
manufacturers.
► At the bottom of the form ‘‘Submission of report does not constitute an
admission that the product caused or contributed to the event.’’
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Post Marketing Surveillance
► After an adverse event is reported to a manufacturer, two classifications
must be made.
► First, the adverse event must be categorized as either serious or non-
serious.
► Second, it must be determined whether the ADE is expected or
unexpected. Again, these terms are defined in 21 CFR 314.80 .
► A serious adverse drug experience is ‘‘any ADE occurring at any dose that
results in any of the following outcomes: death, a life-threatening adverse
drug experience, inpatient hospitalization or prolongation of existing
hospitalization, a persistent or significant disability/incapacity, or a
congenital anomaly/birth defect.’’
► A non-serious ADE is one that does not result in any outcome listed in the
definition of a serious ADE.

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Post Marketing Surveillance
► In regards to the expected and unexpected designation, the labeling of
the product is used to determine the type of ADE.
► If the product labeling lists a particular adverse event, it is considered
expected. If not, it is considered unexpected.
► This classification of ADEs is not always clear.
► Unexpected ADEs also include events that may be symptomatically and
pathophysiologically related to an event listed in the labeling, but differ
from the event because of greater severity or specificity.
► Eg: Marketed pdt label – Visual disturbances; reported that complete
loss of vision. Now this is severe than what is expected, hence classified
as unexpected ADE.
► As discussed earlier, it is not an admission of guilt or even agreement
that the product caused the event.

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Post Marketing Surveillance
► It is important to correctly classify an ADE as either serious or non-serious
and either expected or unexpected.
► The classification of the ADE will determine the type of report that is
submitted to the FDA.
► ADEs that are considered both serious and unexpected must be submitted
to the FDA in an expedited manner and are known as 15-Day Alert
Reports.
► Manufacturers must submit these reports to the FDA as soon as possible,
but in no case later than 15 calendar days of the initial receipt of the
information.
► All other ADEs (those that are serious and expected, non-serious and
expected, or non-serious and unexpected ) should be reported to the FDA
as Periodic Reports.
► Periodic Reports must be submitted at quarterly intervals for three years
from the date of FDA approval of the product, and then annually . 36
Post Marketing Surveillance
► During the investigation and submission of the ADE report to the FDA,
patient privacy should be maintained.
► The manufacturer should not identify patients by name or address in the
reports. Instead, the manufacturer should assign a unique code (e.g.,
patient’s initials or a tracking number) to each report.
► In addition, names of patients, healthcare professionals, hospitals, and
geographical identifiers in adverse drug experience reports are not
releasable to the public under FDA’s public information regulations.
► The ADE reporting system is efficient and straightforward, but its
complex.

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Post Marketing Surveillance
► Main goal of the requirement is to identify new or previously
unrecognized adverse events that are caused by drug products.
► This often results in the addition of safety information to a product’s
labeling, but can also lead to more severe actions like product recalls or
withdrawals.
► In any case, the objective is to expand the information available to the
medical community and the public regarding a product’s adverse event
profile and therefore increase public safety.

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Any queries…….
• SUPAC & PMS

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