changes to an approved application. (a) Changes to an approved application. The applicant shall notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant shall notify FDA about it in a supplemental application under paragraph (b) or (c) of this section or by inclusion of the information in the annual report to the application under paragraph (d) of this section. Notwithstanding the requirements of paragraphs (b) and (c) of this section, an applicant shall make a change provided for in those paragraphs (for example, the deletion of an ingredient common to many drug products) in accordance with a guideline, notice, or regulation published in the FEDERAL REGISTER that provides for a less burdensome notification of the change (for example, by notification at the time a supplement is submitted or in the next annual report). Except for a supplemental application providing for a change in the labeling, the applicant, other than a foreign applicant, shall include in each supplemental application providing for a change under paragraph (b) or (c) of this section a statement certifying that a field copy of the supplement has been provided to the applicant's home FDA district office.

(b) Supplements requiring FDA approval before the change is made. An applicant shall submit a supplement, and obtain FDA approval of it, before making the changes listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. An applicant may ask FDA to expedite its review of a supplement if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked:

"Supplement-Expedited Review Re

quested."

(1) Drug substance. A change affecting the drug substance to accomplish any of the following:

(i) To relax the limits for a specification;

(ii) To establish a new regulatory analytical method;

(iii) To delete a specification or regulatory analytical method;

(iv) To change the synthesis of the drug substance, including a change in solvents and a change in the route of synthesis.

(v) To use a different facility or establishment to manufacture the drug substance, where: (a) the manufacturing process in the new facility or establishment differs materially from that in the former facility or establishment, or (b) the new facility or establishment has not received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(2) Drug product. A change affecting the drug product to accomplish any of the following:

(i) To add or delete an ingredient, or otherwise to change the composition of the drug product, other than deletion of an ingredient intended only to affect the color of the drug product;

(ii) To relax the limits for a specification;

(iii) To establish a new regulatory analytical method;

(iv) To delete a specification or regulatory analytical method;

(v) To change the method of manufacture of the drug product, including changing or relaxing an in-process control;

(vi) To use a different facility or establishment, including a different contract laboratory or labeler, to manufacture, process, or pack the drug product;

(vii) To change the container and closure system for the drug product (for example, glass to high density polyethylene (HDPE), or HDPE to polyvinyl chloride) or change a specification or regulatory analytical method for the container and closure system;

(viii) To change the size of the container, except for solid dosage forms,

without a change in the container and closure system.

(ix) To extend the expiration date of the drug product based on data obtained under a new or revised stability testing protocol that has not been approved in the application.

(x) To establish a new procedure for reprocessing a batch of the drug product that fails to meet specifications.

(xi) To add a code imprint by printing with ink on a solid oral dosage form drug product.

(xii) To add a code imprint by embossing, debossing, or engraving on a modified release solid oral dosage form drug product.

(3) Labeling. Any change in labeling, except one described in paragraph (c)(2) or (d) of this section.

(c) Supplements for changes that may be made before FDA approval. An applicant shall submit a supplement at the time the applicant makes any kind of change listed below in the conditions in an approved application, unless the change is made to comply with an official compendium. A supplement under this paragraph is required to give a full explanation of the basis for the change, identify the date on which the change is made, and, if the change concerns labeling, include 12 copies of final printed labeling. The applicant promptly revise all promotional labeling and drug advertising to make it consistent with any change in the labeling. The supplement and its mailing cover should be plainly marked: "Special Supplement-Changes Being Effected."

shall

(1) Adds a new specification or test method or changes in the methods, facilities (except a change to a new facility), or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess;

(2) Changes labeling to accomplish any of the following:

(i) To add or strengthen a contraindication, warning, precaution, or adverse reaction;

(ii) To add or strengthen a statement about drug abuse, dependence, or overdosage; or

(iii) To add or strengthen an instruction about dosage and administration

that is intended to increase the safe use of the product.

(iv) To delete false, misleading, or unsupported indications for use or claims for effectiveness.

(3) To use a different facility or establishment to manufacture the drug substance, where: (i) The manufacturing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and (ii) the new facility or establishment has received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.

(d) Changes described in the annual report. An applicant shall not submit a supplement to make any change in the conditions in an approved application, unless otherwise required under paragraph (b) or (c) of this section, but shall describe the change in the next annual report required under §314.81. Some examples of changes that can be described in the annual report are the following:

(1) Any change made to comply with an official compendium.

(2) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form.

(3) An editorial or similar minor change in labeling.

(4) The deletion of an ingredient intended only to affect the color of the drug product.

(5) An extension of the expiration date based upon full shelf-life data obtained from a protocol approved in the application.

(6) A change within the container and closure system for the drug product (for example, a change from one high density polyethylene (HDPE) to another HDPE), except a change in container size for nonsolid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium.

(7) The addition or deletion of an alternate analytical method.

(8) A change in the size of a container for a solid dosage form, without a

179-070 0-98——5

change from one container and closure system to another.

(9) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.

(e) Patent information. The applicant shall comply with the patent information requirements under section 505(c)(2) of the act.

(f) Claimed exclusivity. If an applicant claims exclusivity under §314.108 upon approval of a supplemental application for a change to its previously approved drug product, the applicant shall include with its supplemental application the information required under §314.50(j).

(g) Exception. An applicant proposing to make a change of a type described in paragraphs (a), (b)(1), (b)(2), (c)(1), (c)(3), (d)(1), and (d)(4) through (d)(9) of this section affecting a recombinant DNA-derived protein/polypeptide product or a complex or conjugate of a drug with a monoclonal antibody regulated under the Federal Food, Drug, and Cosmetic Act shall comply with the following:

(1) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes). (i) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

(ii) These changes include, but are not limited to:

(A) Changes in the qualitative or quantitative formulation or other specifications as provided in the approved application or in the regulations;

(B) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;

(C) Changes in the virus or adventitious agent removal or inactivation method(s);

(D) Changes in the source material or cell line;

(E) Establishment of a new master cell bank or seed; and

(F) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation.

(iii) The applicant must obtain approval of the supplement from FDA prior to distribution of the product made using the change. Except for submissions under paragraph (g)(4) of this section, the following shall be contained in the supplement:

(A) A detailed description of the proposed change;

B) The product(s) involved;

(C) The manufacturing site(s) or area(s) affected;

(D) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;

(E) The data derived from such studies;

(F) Relevant validation protocols and data; and

(G) A reference list of relevant standard operating procedures (SOP's).

(2) Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change. (i) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. The supplement shall be labeled "SupplementChanges Being Effected in 30 Days" or, if applicable under paragraph (g)(2)(v) of this section, "Supplement-Changes Being Effected."

(ii) These changes include, but are not limited to:

(A) Change in the site of testing from one facility to another;

(B) An increase or decrease in production scale during finishing steps that involves new or different equipment; and

(C) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters.

(iii) Pending approval of the supplement by FDA, and except as provided in paragraph (g)(2)(v) of this section, distribution of the product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraph (g)(1)(iii)(A) through (g)(1)(iii)(G) of this section shall be contained in the supplement.

(iv) If within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:

(A) The change requires approval prior to distribution of the product in accordance with paragraph (g)(1) of this section; or

(B) Any of the information required under paragraph (g)(2)(iii) of this section is missing; the applicant shall not distribute the product made using the change until FDA determines that compliance with this section is achieved.

(v) In certain circumstances, FDA may determine that, based on experience with a particular type of change, the supplement for such change is usually complete and provides the proper information, and on particular assurances that the proposed change has been appropriately submitted, the product made using the change may be distributed immediately upon receipt of the supplement by FDA. These circumstances may include substantial similarity with a type of change regularly involving a "SupplementChanges Being Effected" supplement, or a situation in which the applicant presents evidence that the proposed change has been validated in accordance with an approved protocol for such change under paragraph (g)(4) of this section.

(3) Changes to be described in an annual report (minor changes). (1) Changes in the product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity,

strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product shall be documented by the applicant in the next annual report in accordance with §314.81(b)(2)(iv).

(ii) These changes include, but are not limited to:

(A) Any change made to comply with an official compendium that is consistent with FDA requirements;

(B) The deletion of an ingredient intended only to affect the color of the product;

(C) An extension of an expiration date based upon full shelf life data obtained from a protocol approved in the application;

(D) A change within the container and closure system for solid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;

(E) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another;

(F) The addition by embossing, debossing, or engraving of a code imprint to a solid dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint; and

(G) The addition or deletion of an alternate analytical method.

(4) An applicant may submit one or more protocols describing the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that

type of change reduces the potential risk of an adverse effect.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0001)

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 58 FR 47959, Sept. 13, 1993; 59 FR 50364, Oct. 3, 1994; 62 FR 39900, July 24, 1997]

§314.71 Procedures for submission of a supplement to an approved application.

(a) Only the applicant may submit a supplement to an application.

(b) All procedures and actions that apply to an application under §314.50 also apply to supplements, except that the information required in the supplement is limited to that needed to support the change. A supplement is required to contain an archival copy and a review copy that include an application form and appropriate technical sections, samples, and labeling; except that a supplement for a change other than a change in labeling is required also to contain a field copy.

(c) All procedures and actions that apply to applications under this part, including actions by applicants and the Food and Drug Administration, also apply to supplements.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0001)

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, 1993]

§ 314.72 Change in ownership of an application.

(a) An applicant may transfer ownership of its application. At the time of transfer the new and former owners are required to submit information to the Food and Drug Administration as follows:

(1) The former owner shall submit a letter or other document that states that all rights to the application have been transferred to the new owner.

(2) The new owner shall submit an application form signed by the new owner and a letter or other document containing the following:

(i) The new owner's commitment to agreements, promises, and conditions made by the former owner and contained in the application;

(ii) The date that the change in ownership is effective; and

(iii) Either a statement that the new owner has a complete copy of the approved application, including supplements and records that are required to be kept under §314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in §20.42 of FDA's public information regulations.

(b) The new owner shall advise FDA about any change in the conditions in the approved application under §314.70, except the new owner may advise FDA in the next annual report about a change in the drug product's label or labeling to change the product's brand or the name of its manufacturer, packer, or distributor.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0001)

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985] §314.80 Postmarketing reporting of adverse drug experiences.

(a) Definitions. The following definitions of terms apply to this section:

Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.

Disability. A substantial disruption of a person's ability to conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred, i.e., it does not include an adverse drug experience that, had it