Changes-approved NDA or ANDA
After the approval of NDA or ANDA, the applicant may make post approval changes, provided the changes are reported to the FDA under the appropriate categories.
Section 506 A of the Federal Food, Drugs and Cosmetics act and 21 CFR 314.70 provide for 4 reporting categories of the post approval changes which are listed below-
1. Major Change
2. Moderate Change- It is categorized into 2 types-
(a) The change requiring the submission of Supplement – Changes Being Effected in 30 Days
(b) The change requiring the submission of Supplement – Changes Being Effected
3. Minor Change
3. Minor Change
1. Major Change-
- 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.
- A major change requires the submission of a supplement and approval by FDA prior to distribution of the drug product made using the change. This type of supplement is called and should be clearly labeled as Prior approval supplement.
- An applicant may ask FDA to expedite its review of a prior approval supplement for public health reasons like drug shortage or in case if there is a delay would impose an extraordinary hardship on the applicant.
2. Moderate Change- 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.
The moderate change is categorized into 2 types based on the type of supplement being filed –
a) Supplement – Changes Being Effected in 30 Days
- This type of change requires submission of supplement to FDA at least 30 days before the distribution of drug product made using the change.
- This type of supplement is called, and should be clearly labeled, a Supplement – Changes being effected in 30 Days.
- The drug product made using moderate changes cannot be distributed if the FDA informs the applicant to file a prior approval supplement for the changes made or if FDA informs that the information is missing or if FDA disapproves the changes being affected in 30 days.
b) Supplement – Changes Being Effected
- This type of supplement contains changes for which distribution can occur when FDA receives the supplement.
- FDA may order the manufacturer to cease distribution of the drug products made using the disapproved change, If, after review, FDA disapproves a changes-being effected.
3. Minor change -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.
Assessing the effect of manufacturing changes
A. Assessment of the effects of the change-The applicant must assess the effects of the change before distributing a drug product made with a manufacturing change. Assessment should be made on the following-
1. Conformance to specifications- An assessment of the effects of a change on the identity, strength, quality, purity, and potency of the drug product should include a determination that the drug substance intermediates, drug substance, in-process materials, and/or drug product affected by the change conform to the approved specifications.
2. Additional Testing-
- Apart from checking for conformance to specifications, the applicant should perform additional testing, when appropriate, to assess whether 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 have been or will be affected.
- The assessment should include, as appropriate, evaluation of any changes in the chemical, physical, microbiological, biological, bioavailability, and/or stability profiles.
- This additional assessment could involve testing of the post change drug product itself or, if appropriate, the material directly affected by the change.
- The type of additional testing that an applicant should perform would depend on the type of manufacturing change, the type of drug substance and/or drug product, and the effect of the change on the quality of the drug product.
For Example- Evaluation of the hardness or friability of a tablet after certain changes.
B. Equivalence- When testing is performed, the applicant should usually assess the extent to which the manufacturing change has affected the identity, strength, quality, purity, and potency of the drug product. Typically this is accomplished by comparing test results from pre- and post change material and determining if the test results are equivalent.
C. Adverse Effects- Some manufacturing changes have an adverse effect on the identity, strength, quality, purity, or potency of the drug product, which in most cases are not implemented by applicant. If an assessment indicates that a change has adversely affected the identity, strength, quality, purity, or potency of the drug product, FDA recommends that the change be submitted in a prior approval supplement regardless of the recommended reporting category for the change.
The reporting categories for the post approval changes are provided with respect to the following-
(1) Components and composition
(2) Manufacturing sites
(3) Manufacturing process
(4) Specifications
(5) Container closure system
(6) Labeling
(7) Miscellaneous changes
(8) Multiple related changes
(1) 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.
- The deletion or reduction of an ingredient intended to affect only the color of the drug product may be reported in an annual report.
(2) Manufacturing sites
Example under reporting category of major change (Prior approval supplement)-
A move to a different manufacturing site, except one used to manufacture or process a drug substance intermediate, when the new manufacturing site has never been inspected by FDA for the type of operation that is being moved or the move results in a restart at the new manufacturing site of a type of operation that has been discontinued for more than two years.
Example under reporting category of moderate change (supplement changes being effected in 30 days)-
A move to a different manufacturing site for the primary packaging of (1) any drug product that is not otherwise listed as a major change and (2) modified-release solid oral dosage form drug products.
A move to a different manufacturing site for the primary packaging of (1) any drug product that is not otherwise listed as a major change and (2) modified-release solid oral dosage form drug products.
Example under reporting category of moderate change (supplement changes being effected)-
Move to a different manufacturing site for the manufacture or processing of the final intermediate.
Example under reporting category Minor Changes (Annual Report)
A move to a different manufacturing site for secondary packaging.
(3) Manufacturing process
Example under reporting category of major change (Prior approval supplement)-
Changes that may affect the controlled (or modified) release, metering or other characteristics (e.g., particle size) of the dose delivered to the patient, including the addition or deletion of a code imprint by embossing, debossing, or engraving on a modified-release solid oral dosage form.
Example under reporting category of moderate change (supplement changes being effected in 30 days)-
For Drug substance, redefinition of an intermediate, excluding the final material, as the starting material.
For Drug substance, redefinition of an intermediate, excluding the final material, as the starting material.
Example under reporting category of moderate change (supplement changes being effected)-
A change in methods or controls that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess.
Example under reporting category of minor Changes (Annual Report)
A minor change in an existing code imprint for a dosage form. For example, changing from a numeric to alphanumeric code.
(4) Specifications
Example under reporting category of major change (Prior approval supplement)-
Establishing a new regulatory analytical procedure including designation of an alternative analytical procedure as a regulatory procedure.
Example under reporting category of moderate change (supplement changes being effected in 30 days)-
Relaxing an acceptance criterion or deleting a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements
Example under reporting category of moderate change (supplement changes being effected)-
An addition to a specification that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess. For example, adding a new test and associated analytical procedure and acceptance criterion
.
Example under reporting category of minor Changes (Annual Report)
Tightening of acceptance criteria.
(5) Container closure system
Example under reporting category of major change (Prior approval supplement)-
A change in the primary packaging components for any drug product when the primary packaging components control the dose delivered to the patient (e.g., the valve or actuator of a metered-dose inhaler).
Example under reporting category of moderate change (supplement changes being effected in 30 days)-
Changes in the size or shape of a container for a sterile drug substance.
Changes in the size or shape of a container for a sterile drug substance.
Example under reporting category of moderate change (supplement changes being effected)-
A change in or addition or deletion of a desiccant.
Example under reporting category of minor Changes (Annual Report)
A change in the size and/or shape of a container for a nonsterile solid dosage form
(6) Labeling
Example under reporting category of major change (Prior approval supplement)-
Changes based on postmarketing study results, including, but not limited to, labeling changes associated with new indications and usage.
Example under reporting category of moderate change (supplement changes being effected)-
Addition of an adverse event due to information reported to the applicant or Agency.
Example under reporting category of minor Changes (Annual Report)
Labeling changes made to comply with an official compendium.
(7) Miscellaneous changes
Example under reporting category of major change (Prior approval supplement)-
Addition of a stability protocol or comparability protocol
Example under reporting category of moderate change (supplement changes being effected in 30 days)-
Reduction of an expiration dating period to provide increased assurance of the identity, strength,quality, purity, or potency of the drug product. Extension of an expiration date that has previously been reduced under this provision should be submitted in a changes-being-effected-in-30-days supplement even if the extension is based on data obtained under a protocol approved in the application.
Example under reporting category of moderate change (supplement changes being effected)- No changes have been identified.
Example under reporting category of minor Changes (Annual Report)
An extension of an expiration dating period based on full shelf life data on production batches obtained under a protocol approved in the application
(8) Multiple related changes
For multiple related changes where the recommended reporting categories for the individual changes differ, CDER recommends that the submission be in accordance with the most restrictive of the categories recommended for the individual changes. When the multiple related changes all have the same recommended reporting category, CDER recommends that the submission be in accordance with the reporting category for the individual changes.
Note- View the guidance-Changes to an approved NDA or ANDA for categorization of all the possible changes.
Note- View the guidance-Changes to an approved NDA or ANDA for categorization of all the possible changes.
Reference-
Further reading-
Changes to an approved NDA or ANDA Questions and Answers
Changes to an approved NDA or ANDA Questions and Answers
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