Changes to Approved NDA or NDA

REPORTING CATEGORIES

A major change 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. (Prior Approval Supplement)

A moderate change 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. (Supplement – Changes Being Effected in 30 Days)/ (Supplement – Changes Being Effected)

A minor change 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. (Annual Report)

 

CATEGORYMAJOR (PAS)MODERATE (CBE-30/0 days)MINOR (AR)
DefinitionA 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.

 

A change 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.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.
 

Components and composition

Changes in the qualitative or quantitative formulation, including inactive ingredients, as provided in the approved application, are considered major changes requiring a prior approval supplement, unless exempted by regulation or guidance (§ 314.70(b)(2)(i)).

Manufacturing sites

(Manufacture, packaging, label and test)

 

A move to a different manufacturing site that :

·    Never inspected by FDA for the type of operation

·    Facility does not have a satisfactory cGMP inspection

·    A newly constructed aseptic filling facility

·    A newly constructed facility at a different manufacturing site.

·    A move to a different manufacturing site that is not provided in this guidance

·    A move to primary packaging of not listed as major or modified release OSD

CBE – 0

·    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, for labeling, DS intermediate, ink imprinting of OSD
 

Manufacturing process

 

·    Changes that may affect the controlled (or modified) release, metering or other characteristics

·    Changes that may affect drug product sterility assurance

·    changes in the sterilization methods

·         DP:

ü  Dry to wet granulation

ü  Change in type of drying process

·         DS:

ü  Change in route of synthesis

ü  Change made after final intermediate processing

ü  Change in manufacture of DS

·    Any change in the process, process parameters, and/or equipment

·    For sterile drug products, drug substances, and components,

ü  Changes in dry heat depyrogenation processes for glass container systems

ü  Changes to filtration parameters for aseptic processing

ü  Filtration process changes that provide for a change from single to dual sterilizing filters

ü  Changes from one qualified sterilization chamber to another for in-process or terminal sterilization that result in changes to validated operating parameters

ü  For drug substances, redefinition of an intermediate, excluding the final intermediate, as a starting material

CBE – 0

·    A change in methods or controls of drug substance or products

·    For sterile drug products, elimination of in-process filtration performed as part of the manufacture of a terminally sterilized drug product

·    changes to equipment of the same design and operating principle and/or changes in scale

·    Addition/deletion of an ink code imprint or a change in the ink

·    A change in the order of addition of ingredients

 

 

 

 

 

Specification

 

 

 

 

 

 

·    Relaxing  an acceptance criterion

·    Deleting any part of a specification

·    Establishing a new regulatory analytical procedure

·    A change in regulatory analytical procedure

·    Any change in a regulatory analytical procedure

·    Relaxing an acceptance criterion or deleting a test for RM

·    Relaxing an in-process acceptance criterion

·    Relaxing an acceptance criterion or deleting a test to comply with an official compendium

CBE – 0

·    An addition to a specification that provides increased assurance

·    A change in an analytical procedure used for testing

·    Any change in a specification made to comply with an official compendium

·    the addition or revision of an alternative analytical procedure

·    Tightening of acceptance criteria

·    A change in an analytical procedure used for testing raw materials used in drug substance synthesis

Container Closure System

 

 

 

 

 

·    A change in the primary packaging components for liquids & semisolids

·    Deletion of a secondary packaging component intended to provide additional protection to the drug product

·    A change to a new container closure system

·    A change to a flexible container system (bag) from another container system

·    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.

·    A change to or in a container closure system

·    Changes in the size or shape of a container for a sterile drug substance.

·    A change in the number of units

CBE – 0

·    A change in the size and/or shape of a container for a non-sterile drug product, except for solid dosage forms

·    A change in the labeled amount (e.g., grams, milliliters) of drug product for a non-sterile drug product

·    A change in or addition or deletion of a desiccant.

·    A change in the container closure system for a non-sterile drug product, under approved protocol in the application/published in compendium

·    A change in the size and/or shape of a container for a non-sterile solid dosage form

·    Adding or changing a child-resistant closure, changing from a metal to plastic viceversa.

·    Increasing the wall thickness of the container.

·    A change in or addition of a cap liner.

·    A change in or addition of a seal

·    Changes in the closure or cap.

·    Increasing the wall thickness of the container.

·    A change in or addition of a cap liner/seal/ crimp sealant.


 

Labeling

 

 

·    Changes based on postmarketing study results, including, but not limited to, labeling changes associated with new indications and usage.

·    Change in, or addition of, pharmacoeconomic claims based on clinical studies.

·    Changes to the clinical pharmacology or the clinical study section reflecting new or modified data.

·    Changes based on data from preclinical studies

·    Revision (expansion or contraction) of population based on data.

·    Claims of superiority to another drug product.

·    Change in the labeled storage conditions, unless exempted by regulation or guidance.

 CBE 0

·    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

 

·    Changes in the layout of the package or container label that are consistent with FDA regulations without a change in the content of the labeling.

·    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 a certified translation is included.

·    Labeling changes made to comply with an official compendium.

 

 

 

 

 

 

Miscellaneous changes

 

 

 

 

·    Changes requiring completion of studies in accordance with CFR part 320 to demonstrate equivalence of the drug product.

·    Addition of a stability protocol or comparability protocol.

·    Changes to an approved stability protocol or comparability protocol.

·    An extension of an expiration dating period based on (1) data obtained under a new or revised stability testing protocol or (2) full shelf life data on pilot scale batches.

·    Changes to a drug product under an application because of significant questions regarding the integrity of the data supporting that application.

·    Reduction of an expiration dating period·    An extension of an expiration dating period based on full shelf life data on production batches.

·    Addition/ deletion of time points to the stability protocol beyond the approved expiration dating period.

·    A change from previously approved stability storage conditions to storage conditions recommended in ICH.

·    Replacement of an in-house reference standard according to procedures in an approved application.

·    Tightening of acceptance criteria for existing reference standards.

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