Guidance for Industry

Changes to an Approved Application

for Specified Biotechnology and

Specified Synthetic Biological Products

U.S. Department of Public Health

Food and Drug Administration

Center for Biologics Evaluation and Research

Center for Drug Evaluation and Research

July 1997

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TABLE OF CONTENTS

Note: page numbering may vary for documents distributed electronically

I. INTRODUCTION 1

II. CHANGES UNDER §§601.12(b) and 314.70(g)(1) 3

Changes requiring supplement submission and approval prior to

distribution of the product made using the change (major changes).

III. CHANGES UNDER §§601.12(c) and 314.70(g)(2) 4

Changes requiring supplement submission at least 30 days

prior to distribution of the product made using the change.

IV. CHANGES UNDER §§601.12(d) and 314.70(g)(3) 5

Changes to be described in an annual report (minor changes).

V. COMPARABILITY PROTOCOLS UNDER §§601.12(e) 6

and 314.70(g)(4)

VI. CHANGES UNDER §601.12(f) 7

Labeling changes.

A. Changes under §601.12(f)(1) - Labeling changes requiring 7

supplement submission - FDA approval must be obtained

before distribution of the product with the labeling change.

B. Changes under §601.12(f)(2) - Labeling changes requiring 7

supplement submission - product with a labeling change

may be distributed before FDA approval.

C. Changes under §601.12(f)(3) - Labeling changes requiring 8

submission in an annual report.

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Guidance for Industry1:

Changes to an Approved Application for Specified Biotechnology and

Specified Synthetic Biological Products

I. INTRODUCTION

Sections 314.70 and 601.12 of Title 21 of the Code of Federal Regulations (21 CFR 314.70 and

601.12) prescribe the requirements for the reporting to FDA of changes to the approved applications

for licensed biological products and approved drug products.

Under §§ 601.12 and 314.70(g), a change to a product, production process, quality controls,

equipment, or facilities is required to be reported to FDA in: 1) a supplement requiring approval prior to

distribution; 2) a supplement at least 30 days prior to distribution of the product made using the change;

or 3) in an annual report, depending on its 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.

Before distributing a product made using a change, the regulations require applicants to demonstrate,

through appropriate validation and/or other clinical or non-clinical laboratory studies, the lack of adverse

effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate

to its safety or effectiveness.

The three reporting categories for changes to an approved application are defined in § 601.12 and §

314.70(g): 1) those changes that have 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, which require submission of a supplement and approval by FDA prior to distribution of the

product made using the change; 2) changes that have a moderate potential to have an adverse effect on

the identity, strength, quality, purity, or potency of the

1 This guidance document represents FDA’s current thinking on changes to an approved application for

specified biotechnology and specified synthetic biological products listed in 21 CFR 601.2(c),

recombinant DNA-derived protein/polypeptide products approved under the Federal Food, Drug, and

Cosmetic Act (FDCA) and complexes or conjugates of a drug with a monoclonal antibody approved

under the FDCA. It does not create or confer any rights for or on any person and does not operate to

bind FDA or the public. An alternative approach may be used if such approach satisfies the

requirements of the applicable statute, regulations, or both. Written requests for single copies of this

document may be submitted to the Office of Communication, Training and Manufacturers Assistance

(HFM-40), Center for Biologics Evaluation and Research, Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852-1448. The document may also be obtained by mail by calling

the CBER Voice Information System at 1-800-835-4709 or 301-827-1800, or by fax by calling the

FAX Information System at 1-888-CBER-FAX or 301-827-3844. Persons with access to the

INTERNET may obtain the document using the World Wide Web (WWW) or bounce-back e-mail.

For WWW access, connect to CBER at “http://www.fda.gov/cber.” To receive the document by

bounce-back e-mail, send a message to “character@a1.cber.fda.gov.”
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 product as they may relate to the safety or effectiveness of the product, which require submission of a

supplement to FDA at least 30 days prior to distribution of the product made using the change; and 3)

changes 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, which are to

be described by the applicant in an annual report. Section 314.70(g) applies only to recombinant

DNA-derived protein/polypeptide products approved under the Federal Food, Drug, and Cosmetic

Act (FDCA) and complexes or conjugates of a drug with a monoclonal antibody approved under the

FDCA.

For licensed biologics subject to § 601.12, changes to a product package label, container label, and

package insert require either: (1) submission of a supplement with FDA approval needed prior to

product distribution; (2) submission of a supplement with product distribution allowed at the time of

submission of the supplement; or (3) submission of the final printed label in an annual report. These

requirements are now harmonized fully for drugs and biologics.

Under § 601.12(f)(4), changes to advertising and promotional labeling for licensed biological products

must be made in accordance with the provisions of 21 CFR 314.81(b)(3)(i), which requires the

submission to FDA of specimens of mailing pieces and any other labeling or advertising devised for

promotion of a drug product at the time of initial dissemination of the labeling, and at the time of initial

publication of the advertisement for a prescription drug product. Mailing pieces and labeling that are

designed to contain samples of a drug product are required to be complete, except the sample of the

drug product may be omitted from the container. Each submission to the Center for Biologics

Evaluation and Research (CBER) should be accompanied by a completed transmittal Form FDA-2567,

or, when it is made available, the revised Form FDA-2253.

This guidance applies only to specified biotechnology and specified synthetic biological products,

including recombinant DNA-derived protein/polypeptide products approved under the FDCA and

complexes or conjugates of a drug with a monoclonal antibody approved under the FDCA, or

biological products licensed under the Public Health Service (PHS) Act and outlined in

21 CFR 601.2(c). The section on labeling applies only to licensed biological products. This guidance is

intended to assist manufacturers in determining which reporting mechanism is appropriate for a change

to an approved application for such products.

In addition to the requirements in 21 CFR 601.12 and 314.70(g), an applicant making a change to an

approved application must conform to other applicable law and regulations, including the current good

manufacturing practice (CGMP) requirements of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 351(a)(2)(B)) and applicable regulations in 21 CFR parts 210, 211, 600 through 680, and 820.

For example, manufacturers must comply with record-keeping requirements and ensure that relevant

records are readily available for examination by authorized FDA personnel during an inspection.

Under each subsection of the guidance, FDA describes a category of changes to be reported under §§

601.12 and 314.70(g). FDA also provides a listing of various changes that FDA currently believes fall

under each category.
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II. CHANGES UNDER §§ 601.12(b) AND 314.70(g)(1) - Changes requiring supplement

submission and approval prior to distribution of the product made using the change

(major changes).

Under §§601.12(b) and 314.70(g)(1), changes to a product, production process, quality controls,

equipment, or facilities that have a substantial potential to have an adverse effect on the identity,

strength, quality, purity, or potency of the product as they may relate to its safety or effectiveness

require submission of a supplement and approval by FDA before a product made using the change is

distributed. For a change under this category, an applicant is required to submit a supplement to the

license application that includes a detailed description of the proposed change; the products involved;

the manufacturing site(s) or area(s) affected; a description of the methods used and studies performed to

evaluate the effect of the change on the product's identity, strength, quality, purity, or potency as they

may relate to its safety or effectiveness; the data derived from those studies; relevant validation

protocols and data; and a reference list of relevant standard operating procedures (SOPs). The

applicant must obtain approval of the supplement by FDA prior to distribution of the product made

using the change.

In FDA's experience, the following changes to a product, production process, quality controls,

equipment, or facilities have caused detrimental effects on the identity, strength, quality, purity, or

potency of products as they relate to the products’ safety or effectiveness even where applicants

performed validation or other studies. FDA believes that these changes have a substantial potential to

have an adverse effect on a product’s identity, strength, quality, purity, or potency as they may relate to

its safety or effectiveness and that the agency's continued premarket review and approval of such

changes is currently necessary to protect the public from products whose identity, strength, quality,

purity, potency, safety, or effectiveness may be compromised.

1. Process changes including, but not limited to,

• extension of culture growth time leading to significant increase in number of cell

doublings beyond validated parameters;

• new or revised recovery procedures;

• new or revised purification process, including a change in a column;

• a change in the chemistry or formulation of solutions used in processing;

• a change in the sequence of processing steps or addition, deletion, or substitution of a

process step; or

• reprocessing of a product without a previously approved reprocessing protocol.

2. Any change in manufacturing processes or analytical methods that

• results in change(s) of specification limits or modification(s) in potency, sensitivity,

specificity, or purity;

• establishes a new analytical method;

• deletes a specification or an analytical method;

• eliminates tests from the stability protocol; or

• alters the acceptance criteria of the stability protocol.
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3. Scale-up requiring a larger fermentor, bioreactor, and/or purification equipment (applies to

production up to the final purified bulk).

4. Change in the composition or dosage form of the product or ancillary components (e.g., new or

different excipients, carriers, or buffers).

5. New lot of, new source for, or different, in-house reference standard or reference panel (panel

member) resulting in modification of reference specifications or an alternative test method.

6. Extension of the expiration dating period and/or a change in storage temperature,

container/closure composition, or other conditions, other than changes based on real time data

in accordance with a stability protocol in the approved application.

7. Change of the site(s) at which manufacturing, other than testing, is performed, addition of a new

location, or contracting of a manufacturing step in the approved application, to be performed at

a separate facility.

8. Conversion of production and related area(s) from single to multiple product manufacturing

area(s). (Addition of products to a multiple product manufacturing area could be submitted as a

“Supplement - Changes Being Effected in 30 Days” if there are no changes to the approved

and validated cleaning and changeover procedures and no additional containment requirements).

9. Changes in the location (room, building, etc.) of steps in the production process which could

affect contamination or cross contamination precautions.

III CHANGES UNDER §§ 601.12(c) AND 314.70(g)(2) - Changes requiring supplement

submission at least 30 days prior to distribution of the product made using the change.

Under §§ 601.12(c) and 314.70(g)(2), changes to a product, production process, quality controls,

equipment, or facilities that have a moderate potential to have an adverse effect on a product’s identity,

strength, quality, purity, or potency as they may relate to its safety or effectiveness require submission

of a supplement to FDA at least 30 days prior to distribution of the product made using the change.

The requirements for the contents of these supplements are the same as for those requiring approval

prior to distribution.

 

Some examples of changes to the product, production process, quality controls, equipment, and

facilities that FDA currently considers to have moderate potential to have an adverse effect on a

product’s identity, strength, quality, purity, or potency as they may relate to its safety or effectiveness

are set forth in the following list which FDA has developed based on experience gained in reviewing

submissions received in the past.

1. Addition of duplicated process chain or unit process, such as a fermentation process or

duplicated purification columns, with no change in process parameters.

2. Addition or reduction in number of pieces of equipment (e.g., centrifuges, filtration devices,

blending vessels, columns, etc.) to achieve a change in purification scale not associated with a

process change.

3. Manufacture of an additional product in a previously approved multiple product manufacturing

area using the same equipment and/or personnel, if there have been no changes to the approved
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and validated cleaning and changeover procedures and there are no additional containment

requirements.

4. Change in the site of testing from one facility to another (e.g., from a contract lab to the

applicant; from an existing contract lab to a new contract lab; from the applicant to a

new contract lab).

5. Change in the structure of a legal entity that would require issuance of a new license(s), or

change in name of the legal entity or location that would require reissuance of the

license(s)(applies only to licensed biological products).

As described in §§ 314.70(g)(2)(v) and 601.12(c)(5), 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. Likewise, there may be particular assurances that the

proposed change has been appropriately submitted, such as when the change has been validated in

accordance with a previously approved protocol. In these circumstances, FDA may determine that the

product made using the change may be distributed at the time of receipt of the supplement by FDA.

The following are changes that in FDA's experience have been submitted properly with the appropriate

information, and could be implemented under §§ 314.70(g)(2)(v) and 601.12(c)(5) at the time of

receipt of the supplement by FDA without a previously approved comparability protocol.

1. Addition of release tests and/or specifications or tightening of specifications for

intermediates.

2. Minor changes in fermentation batch size using the same equipment and resulting in no change in

specifications of the bulk or final product.

In addition, applicants that use the protocol described in §§ 314.70(g)(4) and 601.12(e)to validate a

proposed change may request that a change usually subject to supplement submission and approval

prior to distribution be reported as a change subject to supplement submission at least 30 days prior to

distribution of the product made using the change, or as a "Changes Being Effected" supplement

submission, in which event the product made using the change may be distributed immediately upon

receipt of the supplement by FDA.

IV. CHANGES UNDER §§ 601.12(d) AND 314.70(g)(3) - Changes to be described in an

annual report (minor changes).

Under §§ 601.12(d) and 314.70(g)(3), changes to the product, production process, quality controls,

equipment, or facilities that have minimal potential to have an adverse effect on a product’s identity,

strength, quality, purity, or potency as they may relate to its safety or effectiveness are required to be

documented in an annual report submitted each year within 60 days of the anniversary date of approval

of the application for a biological product and in the next annual report required under §-

314.81(b)(2)(iv)(b) for drug products approved under the FDCA. For changes under this category,

the applicant is required to submit in the annual report a list of all products involved; and a full

description of the manufacturing and controls changes including: the manufacturing site(s) or area(s)
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involved, the date each change was made, a cross-reference to relevant validation protocol(s) and/or

SOPs, and relevant data from studies and tests 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.

Some examples of changes that FDA currently considers to have minimal potential to have an adverse

effect on a product’s identity, strength, quality, purity, or potency as they may relate to its safety or

effectiveness are listed below. The list is not all-inclusive but contains items that, in FDA's experience

reviewing supplements, have caused few instances in which an adverse effect on the product’s identity,

strength, quality, purity, or potency as they may relate to its safety or effectiveness has been observed.

1. Increase in aseptic manufacturing scale for finished product without change in equipment, e.g.,

increased number of vials filled.

2. Modifications in analytical procedures with no change in the basic test methodology or existing

release specifications provided the change is supported by validation data.

3. Change in harvesting and/or pooling procedures which does not affect the method of

manufacture, recovery, storage conditions, sensitivity of detection of adventitious agents, or

production scale.

4. Replacement of an in-house reference standard or reference panel (or panel member) according

to SOPs and specifications in an approved application.

5. Tightening of specifications for existing reference standards to provide greater assurance of

product purity and potency.

6. Establishment of an alternate test method for reference standards, release panels, or product

intermediates, except for release testing of intermediates licensed for further manufacture.

7. Establishment of a new Working Cell Bank derived from a previously approved Master

Cell Bank according to an SOP on file in the approved license application.

8. Change in the storage conditions of in-process intermediates, which does not affect labeling,

based on data from a stability protocol in an approved application.

9. Change in shipping conditions (e.g., temperature, packaging, or custody) based on data derived

from studies following a protocol in the approved application.

10. A change in the stability test protocol to include more stringent parameters (e.g., additional

assays or tightened specifications).

11. Addition of time points to the stability protocol.

12. Change in the simple floor plan that does not affect production process or contamination

precautions.

13. Trend analyses of release specification testing results for bulk drug substances and drug

products obtained since the last annual report.

V. COMPARABILITY PROTOCOLS UNDER §§ 601.12(e) AND 314.70(g)(4)

The comparability protocol described in §§ 601.12(e) and 314.70(g)(4) is a supplement that establishes

the tests to be done and acceptable limits to be achieved to demonstrate the lack of adverse effect for
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specified types of manufacturing changes on the safety and effectiveness of a product. A new

comparability protocol, or a change to an existing one, requires approval prior to implementation

because it may result in decreased reporting requirements for the changes covered. In general, a

decrease in reporting requirement will be one reporting tier, e.g., from supplement with distribution of

product in 30 days to annual report, or from prior approval supplement to supplement with distribution

of product in 30 days. In some cases the decrease may be greater. The reporting category will be

established at the time that the comparability protocol is approved. FDA intends to issue further

guidance on the use of such protocols in the near future.

VI. CHANGES UNDER § 601.12(f) - Labeling changes.

This section applies only to licensed biological products. Under § 601.12(f), changes to labeling are

required to be submitted to CBER in one of the following ways: (1) As a supplement requiring FDA

approval prior to distribution of a product with the labeling change; (2) as a supplement requiring FDA

approval but permitting distribution of a product bearing such change prior to FDA approval; or (3) in

an annual report. Some examples of changes to labeling that CBER currently considers to be

appropriate for submission in each of these three categories are listed below. These lists are not

intended to be comprehensive. Pursuant to § 601.12(f)(4), promotional labeling and advertising must

be submitted to CBER at the time of initial dissemination or publication.

A. Changes under §601.12(f)(1) - Labeling changes requiring supplement

submission - FDA approval must be obtained before distribution of a product

with the labeling change.

Under § 601.12(f)(1), any proposed change in the package insert, package label, or container

label, except those described in § 601.12(f)(2) and (3), is required to be submitted as a

supplement and receive FDA approval prior to distribution of a product with the label change.

In such a supplement, the applicant is required to present clearly the proposed change in the

label and the information necessary to support the proposed change. The following list contains

some examples of changes that are currently considered by CBER to fall into this reporting

category.

1. Changes based on postmarketing study results, including, but not limited to, labeling

changes associated with new indications and usage.

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

3. Changes to the clinical pharmacology or the clinical study section reflecting new or

modified data.

4. Changes based on data from preclinical studies.

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

6. Claims of superiority to another product.
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B. Changes under § 601.12(f)(2) - Labeling changes requiring supplement

submission - product with a labeling change that may be distributed before FDA

approval.

Under § 601.12(f)(2), a supplement is required to be submitted for any change to a package

insert, package label, or container label that adds or strengthens a contraindication, warning,

precaution, or adverse reaction; adds or strengthens a statement about abuse, dependence,

psychological effect, or overdosage; adds or strengthens an instruction about dosage and

administration that is intended to increase the safety of the use of the product; or deletes false,

misleading, or unsupported indications for use or claims for effectiveness. The applicant may

distribute product with a label bearing such a change at the time the supplement is submitted,

although the supplement is still subject to approval by FDA. The following list includes some

examples of changes that are currently considered by FDA to fall into this reporting category.

1. Addition of an adverse event due to information reported to the applicant or Agency.

2. Addition of a precaution arising out of a post-marketing study.

3. Clarification of the administration statement to ensure proper administration of the

product.

C. Changes under § 601.12(f)(3) - Labeling changes requiring submission in an

annual report.

Under § 601.12(f)(3), a package insert, package label, or container label with editorial or

similar minor changes or with a change in the information on how the drug is supplied that does

not involve a change in the dosage strength or dosage form is required to be described in an

annual report. Some examples that are currently considered by FDA to fall into this reporting

category include:

1. Changes in the layout of the package or container label without a change in content of

the labeling.

2. Editorial changes such as adding a distributor’s name.

3. Foreign language versions of the labeling, if no change is made to the content of the

approved labeling and a certified translation is included.