The document discusses guidelines for supplemental new drug applications (sNDAs) according to the US FDA. It outlines three categories of variations - major, moderate, and minor - based on their potential impact. Major changes require prior approval and could impact safety or efficacy. Moderate changes require submission 30 days before distribution or upon FDA receipt. Minor changes only require description in the annual report. The document provides examples of changes in manufacturing sites, processes, specifications, container closure systems, and labeling that would fall under each category. Close monitoring and reporting of any post-approval changes is recommended to ensure the quality, safety and efficacy of pre-qualified products are not adversely affected.

1. SUPPLIMENT NEW DRUG APPLICATION
(SNDA)
Variations to a prequalified product
By sakshi dahiya
mpharm 1st year

2.  Supplement A supplement is an application to
allow a company to make changes in a product
that already has an approved new drug
application (NDA). CDER must approve all
important NDA changes (in packaging or
ingredients, for instance) to ensure the conditions
originally set for the product are still met.
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3.  Supplement Number A supplement number is
associated with an existing FDA New Drug
Application (NDA) number. Companies are
allowed to make changes to drugs or their labels
after they have been approved. To change a
label, market a new dosage or strength of a
drug, or change the way it manufactures a
drug, a company must submit a supplemental
new drug application (sNDA). Each sNDA is
assigned a number which is usually, but not
always, sequential, starting with 001.
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4.  Supplement Type Companies are allowed to
make changes to drugs or their labels after they
have been approved. To change a label, market a
new dosage or strength of a drug, or change the
way it manufactures a drug, a company must
submit a supplemental new drug application
(sNDA). The supplement type refers to the kind
of change that was approved by FDA. This
includes changes in manufacturing, patient
population, and formulation.
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5.  Why change is required:
 May wish to alter / improve the product
or to introduce additional safeguard
 To meet the market requirements--
scale up, add manufactuing site.
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6. Post approval changes include:
 (1) components and composition, (2)
 manufacturing sites, (3) manufacturing
process, (4) specifications, (5) container
closure system,
 and (6) labeling, as well as (7)
miscellaneous changes and (8) multiple
related changes.
 An applicant should consider all relevant
CDER guidance documents &submit all
necessary information to support a given
change.
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7. CONDITION
Changes may have potential impact on the
quality, safety or efficacy of products.
Any change to prequalified products are
subject to approval by FDA &CDER.
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8. GUIDANCE ON VARIATION AS PER US FDA
 Three categories of variations according to
their potential impact on pharmaceutical
quality
 Major changes: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.
 These are labelled as Prior Approval
Supplement. 8

9.  Moderate changes: moderate potential to
have an adverse effect.
 2 types
 1 requires the submission of a supplement
to FDA at least 30 days before the
distribution of drug product.labelled as
 Supplement - Changes Being Effected
in 30 Days.
 2 for which distribution can occur when
FDA receives the supplement.labelled as
 Supplement - Changes Being Effected.
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10.  IfFDA disapproves may cease
distribution.
 FDA say prior approval suppliment is
required.
 Information is missing: distribution is
delayed untill amendment is made.
 Minor changes:has minimal potential to
have an adverse effect.The applicant must
describe minor changes in its next
Annual Report
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11. GUIDANCE ON VARIATION TO A
PREQUALIFIED PRODUCT
To facilitate classification of various types of
changes, the variation guide is composed of 4
Appendixes
- Appendix I: lists minor changes, including
notification (N).
- Appendix II: definition and examples of
major changes
- Appendix III: changes that make a new
application /extension application necessary
- Appendix IV: stability requirements for
variations and changes to Pre-qualified FPPs 11

12. APPENDIX I – MINOR CHANGES
 Only few types of variation
predominantly occur
Change in batch size of FPP
 Additional new API source
 Extension shelf life of FPP
 Addition of FPP manufacturing site
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13. APPENDIX II – MAJOR CHANGES
 Major changes
Exceed the scope of minor changes—doesn't
fulfil the conditions
 Do not yet reach the scope of Appendix
III—new application necessary
 Examples:
 Change in the manufacturing process
of the API
 Change in the composition of the FPP
 Change to the immediate primary
packaging of the FPP
 Applicant's responsibility to provide the
relevant documentation to prove that the 13
intended change will not affect the quality of
the prequalified product negatively

14. APPENDIX III – CHANGES MAKING A NEW
APPLICATION /EXTENSION APPLICATION
NECESSARY
 Changes to the API
Change of the API to a different API, e.g.
different salt/ester/derivative, different isomer
 Changes to the pharmaceutical form/
dosage form
Change from an immediate-release product to a
modified release dosage form or vice versa
Change from a liquid to a powder for
reconstitution, or vice versa
 Change or addition of a new route of
administration.
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15. APPENDIX IV - STABILITY REQUIREMENTS
FOR VARIATIONS TO PRE-QUALIFIED FPPS
Responsibility of the pre-qualified supplier
to investigate whether or not the intended
change will have an impact on the quality
characteristics of APIs and /or FPPs and
consequently on their stability.
 Base on the knowledge and experience
acquired on APIs and FPPs (Stress testing,
supportive data, accelerated and long-
term testing)
 At the time of submission, 3 or 6 months
stability data should be provided
according to the nature of the change,
stability of the API, dosage form of the 15
FPP,etc

16. CHANGES IN MANUFACTURING SITE:-
 Major changes eg:-
 Move to new site never inspected by FDA
or cGMP.
 Transfer of aseptically processed sterile
drug substance eg lyophilized drug.
 Finished drug product sterilized by
terminal process.
 Manufacture of primery package when it
control doge delivered eg aerosols
 Moderate changes eg:-
 Manufacture of drug product that is not. 16

17.  otherwise provided for in this guidence.
 Minor changes eg:-
for secondary packaging
 For labelling.
 Manufacture of drug substance
intermediate other then the final
intermediate.
 Ink imprinting of solid oral dogage form
drug product.
 Sterilization site for packaging component
when process is same.
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18. CHANGES IN MANUFACTURING PROCESS
 Major changes eg:-
 When it effect release of drug eg modified
release or controlled release.
 Change in sterility method.
 Addition or deletion of sterilization
procedure.
 Replacing sterilizer with other of different
principle.
 Addition of new equipment.
 Replace Class 100 aseptic fill area with
barrier system.
 Change to aseptic process methed beyond
50%. 18

19.  Replacing lyophilization equipment of
different size.
 Change in sterilizer load limit from pre
validated load limit.
 Change in pore size of filter.
 For natural product:-change in source
material eg microbe,cell,plant.
 Change in process:-
 from dry to wet granulation.
 One type of drying to another.
 Change in route of synthesis of drug
substance.
 Synthesis of drug substance that may effect
impurity.
 Addition of ink cod imprint not currently
used in CDER. 19

20.  Moderate changes:-
 In drug substance or product except as
otherwise provided for in this guidance.
 Change in filteration parameters flow
rate, pressure, time.
 change from single to dual sterilizing
filters.
 increase the bulk solution storage time by
more than 50%
 Supplement - Changes Being Effected.
 A change in methods that provides
increased assurance that the drug
substance will have the characteristics of 20
identity, strength, quality, purity.

21.  Minor changes:-
 changes to equipment of the same design
 minor change in an existing code imprint
 Addition or change in ink imprint when
the ink is currently used on CDER-
approved drug product.
 change in the order of addition of
ingredients.
 increase the bulk solution storage time by
no more than 50 percent.
 For natural increase or decrease in
production.
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 Replacement with equipment of the same
design.

22.  Specifications (i.e., tests, analytical
procedures, and acceptance criteria) are
the quality standards.
 acceptance criteria are numerical
limits, ranges, or other criteria for the
tests described.
 regulatory analytical procedure i.e
specified in USP/NF.
 CONTAINER CLOSURE SYSTEM
 Major Changes:-
 Change from ampule to vial.
 Change that may effect drug product
sterility assurance. 22
 From single dose to multiple dose.

23.  change to a flexible container system.
 change to a prefilled syringe dosage.
 Change in size of sterile container.
 Deletion of 2ndary package when it
provide light,moisture protection.
 Addition of secondary package when it
may effect impurity.
 Moderate changes:-
 Change in container size no of units in
unit dosage form.
 Change in label amount.
 Addiion deletion of desiccant.
 Minor changes:-
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 Change from metal to plastic.

24.  Change in child resistant pack.
 Increasing the wall thickness.
 change in or addition of a cap liner.
 Change in antioxidant,colorant,stabilizer.
 Change to new container already in NDA.
 A change in or addition of a seal.
 LABELING:-
 Major Changes:-
 Changes based on data from preclinical
studies.
 Changes to the clinical pharmacology.
 Claims of superiority to another drug 24
product.

25.  Changes based on postmarketing study
results with new indication use.
 Revision of population based on data.
 Change in the labeled storage conditions.
 Moderate Changes:-
 Addition of an adverse event.
 Addition of a
precaution,warning,contraindication
arising out of a postmarketing study,
 adds about drug abuse,
dependence,psycological effect.
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26.  Minor Changes:-
 Editorial changes eg distributer name
add.
 Foreign language versions of the labeling.
 Changes in the layout of the package
label.
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27. CONCLUSION
 Any change to the content of the pre-qualified
dossier should be reported
 The change should not adversely affect the
quality, safety and efficacy of the pre-qualified
product
 Position correctly the variation and submit
necessary data
 Contact prequalification for assistance in
classifying an unforeseen change pre-submission.
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28. Thank You
THANK YOU
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