Guidance for Industry

Changes to an Approved 

NDA or ANDA

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

April 2004

CMC

Revision 1
Guidance for Industry

Changes to an Approved 

NDA or ANDA

Additional copies are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

April 2004

CMC

Revision 1
TABLE OF CONTENTS

I. INTRODUCTION AND BACKGROUND...............................................................................................................1

II. REPORTING CATEGORIES....................................................................................................................................3

III. GENERAL REQUIREMENTS .................................................................................................................................4

IV. ASSESSING THE EFFECT OF MANUFACTURING CHANGES ........................................................................5

A. ASSESSMENT OF THE EFFECTS OF THE CHANGE...........................................................................................................5

1. Conformance to Specifications...........................................................................................................................5

2. Additional Testing...............................................................................................................................................6

B. EQUIVALENCE............................................................................................................................................................6

C. ADVERSE EFFECT .......................................................................................................................................................7

V. COMPONENTS AND COMPOSITION ..................................................................................................................7

VI. MANUFACTURING SITES ......................................................................................................................................8

A. GENERAL CONSIDERATIONS.......................................................................................................................................8

B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT)...................................................................................................9

C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................10

1. Supplement - Changes Being Effected in 30 Days............................................................................................10

2. Supplement - Changes Being Effected..............................................................................................................11

D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................11

VII. MANUFACTURING PROCESS........................................................................................................................11

A. GENERAL CONSIDERATIONS.....................................................................................................................................11

B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................12

C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................14

1. Supplement - Changes Being Effected in 30 Days............................................................................................14

2. Supplement - Changes Being Effected..............................................................................................................15

D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................15

VIII. SPECIFICATIONS ..............................................................................................................................................16

A. GENERAL CONSIDERATIONS.....................................................................................................................................16

B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................17

C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................18

1. Supplement - Changes Being Effected in 30 Days............................................................................................18

2. Supplement - Changes Being Effected..............................................................................................................18

D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................19

IX. CONTAINER CLOSURE SYSTEM .......................................................................................................................19

A. GENERAL CONSIDERATIONS.....................................................................................................................................19

B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................20

C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................21

2. Supplement - Changes Being Effected..............................................................................................................21

D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................22

X. LABELING................................................................................................................................................................24

A. GENERAL CONSIDERATIONS.....................................................................................................................................24

B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................24

C. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED) ........................................................................25
D. MINOR CHANGES (ANNUAL REPORT).......................................................................................................................26

XI. MISCELLANEOUS CHANGES..............................................................................................................................26

A. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).................................................................................................26

B. MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED).........................................................................27

1. Supplement - Changes Being Effected in 30 Days............................................................................................27

2. Supplement - Changes Being Effected..............................................................................................................27

C. MINOR CHANGES (ANNUAL REPORT)......................................................................................................................27

XII. MULTIPLE RELATED CHANGES...................................................................................................................28

ATTACHMENT A: MANUFACTURING SITES...........................................................................................................29

ATTACHMENT B: TYPE OF OPERATION AND CGMP INSPECTIONS................................................................31

ATTACHMENT C: CDER-APPROVED DRUG PRODUCTS......................................................................................34

GLOSSARY.........................................................................................................................................................................35
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

1

Guidance for Industry1

Changes to an Approved NDA or ANDA 

I. INTRODUCTION AND BACKGROUND

This guidance provides recommendations to holders of new drug applications (NDAs) and

abbreviated new drug applications (ANDAs) who intend to make postapproval changes in 

accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and 

§ 314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for 

postapproval changes for drugs other than specified biotechnology and specified synthetic 

biological products. It supersedes the guidance of the same title published November 1999. 

Recommendations are provided for postapproval changes in (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. 

Recommendations on reporting categories for changes relating to specified biotechnology and 

specified synthetic biological products regulated by CDER are found in the guidance for industry 

 

1

 This guidance has been prepared under the direction of the Chemistry, Manufacturing and Controls Coordinating Committee in 

the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). 

Paperwork Reduction Act Public Burden Statement: This guidance contains information collection provisions that are subject 

to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 

3501-3520). The collection(s) of information in this guidance were approved under OMB Control No. 0910-0538 (until August 

31, 2005). 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this 

topic. It does not create or confer any rights for or on any person and does not operate to 

bind FDA or the public.** You can use an alternative approach if it satisfies the 

requirements of the applicable statutes and regulations. If you want to discuss an alternative 

approach, contact the FDA staff responsible for implementing this guidance. If you cannot 

identify the appropriate FDA staff, call the appropriate number listed on the title page of this 

guidance.

** Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and 

Cosmetic Act and 21 CFR 314.70, it does have binding effect. If you have any questions about the effect of any portion 

of this guidance, contact the Office of Pharmaceutical Science, Center for Drug Evaluation and Research (HFD-003), 

Food and Drug Association, 5600 Fishers Lane, Rockville, MD 20857.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

2

entitled Changes to an Approved Application for Specified Biotechnology and Specified 

Synthetic Biological Products (July 1997).2

On November 21, 1997, the President signed the Food and Drug Administration Modernization 

Act of 1997 (the Modernization Act).3 Section 116 of the Modernization Act amended the the Act 

by adding section 506A, which provides requirements for making and reporting manufacturing 

changes to an approved application and for distributing a drug product made with such changes. 

The FDA has revised its regulations on supplements and other changes to an approved application 

(21 CFR 314.70) to conform to section 506A of the Act. 

This guidance does not provide recommendations on the specific information that should be 

developed by an applicant to assess the effect of the change on the identity, strength (e.g., assay, 

content uniformity), quality (e.g., physical, chemical, and biological properties), purity (e.g., 

impurities and degradation products), or potency (e.g., biological activity, bioavailability, 

bioequivalence) of a drug product as these factors may relate to the safety or effectiveness of the 

drug product. An applicant should consider all relevant CDER guidance documents for 

recommendations on the information that should be submitted to support a given change.4

CDER has published guidances, including the SUPAC (scale-up and postapproval changes) 

guidances, that provide recommendations on reporting categories. To the extent that the 

recommendations on reporting categories in this guidance are found to be inconsistent with 

guidances published before this guidance was finalized, the recommended reporting categories in 

such previously published guidances are superseded by this guidance. This guidance does not 

provide extensive recommendations on reporting categories for components and composition 

changes (see section V). Therefore, recommended reporting categories for components and 

composition changes provided in previously published guidances, such as the SUPAC guidances, 

still apply. Section 506A of the Act and § 314.70(c) provide for two types of changes-beingeffected supplements (see section II), while previously there was only one type. It is important for 

applicants to use this guidance to determine which type of changes-being-effected supplement is 

recommended. CDER intends to update the previously published guidances to make them 

consistent with this guidance.

If guidance for either recommended reporting categories or information that should be submitted to 

support a particular change is not available, the appropriate CDER chemistry or microbiology 

review staff can be consulted for advice. 

FDA's guidance documents, in general, do not establish legally enforceable responsibilities. 

Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as 

recommendations, unless specific regulatory or statutory requirements are cited. The use of the 

word should in Agency guidances means that something is suggested or recommended, but not 

required. Insofar as this guidance adjusts reporting categories pursuant to section 506A of the 

Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70, it does have binding effect. If you 

 

2

 FDA is currently revising the 1997 guidance and intends to issue it in draft for public comment.

3

 Public Law 105-115.

4

 A list of CDER guidances is available on the Internet at http://www.fda.gov/cder/guidance/index.htm.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

3

have any questions about the effect of any portion of this guidance, contact the Office of 

Pharmaceutical Science, Center for Drug Evaluation and Research (HFD-003), Food and Drug 

Association, 5600 Fishers Lane, Rockville, MD 20857.

II. REPORTING CATEGORIES

Section 506A of the Act and § 314.70 provide for four reporting categories that are distinguished 

in the following paragraphs. 

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, a Prior Approval Supplement (§

314.70(b)). An applicant may ask FDA to expedite its review of a prior approval supplement for 

public health reasons (e.g., drug shortage) or if a delay in making the change described in it would 

impose an extraordinary hardship on the applicant. This type of supplement is called, and should 

be clearly labeled, a Prior Approval Supplement - Expedited Review Requested (§

314.70(b)(4)).5 FDA is most likely to grant requests for expedited review based on extraordinary 

hardship for manufacturing changes made necessary by catastrophic events (e.g., fire) or by events 

that could not be reasonably foreseen and for which the applicant could not plan.

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. There are two types of moderate change. One type of 

moderate change requires the submission of a supplement to FDA at least 30 days before the 

distribution of the 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 (§ 314.70(c)(3)). 

The drug product made using a moderate change cannot be distributed if FDA informs the 

applicant within 30 days of receipt of the supplement that a prior approval supplement is required 

(§ 314.70(c)(5)(i)). For each change, the supplement must contain information determined by 

FDA to be appropriate and must include the information developed by the applicant in assessing 

the effects of the change (§ 314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30 days 

of receipt of the supplement that information is missing, distribution must be delayed until the 

supplement has been amended to provide the missing information (§ 314.70(c)(5)(ii)). 

FDA may identify certain moderate changes for which distribution can occur when FDA receives 

the supplement (§ 314.70(c)(6)). This type of supplement is called, and should be clearly labeled, 

a Supplement - Changes Being Effected. If, after review, FDA disapproves a changes-beingeffected-in-30-days supplement or changes-being-effected supplement, FDA may order the 

 

5

Internal Agency policies and procedures relating to processing requests for expedited review of supplements to approved 

ANDAs and NDAs are documented in CDER's Manual of Policies and Procedures (MAPP) at 5240.1 and 5310.3, 

respectively. MAPPs can be located on the Internet at http://www.fda.gov/cder/mapp.htm.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

4

manufacturer to cease distribution of the drug products made using the disapproved change (§

314.70(c)(7)).

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. The applicant must describe minor changes in its next Annual 

Report (§ 314.70(d)).

Under § 314.70(e), an applicant can submit one or more protocols (i.e., comparability protocols) 

describing tests, studies, and acceptance criteria to be achieved to demonstrate the absence of an 

adverse effect from specified types of changes. A comparability protocol can be used to reduce 

the reporting category for specified changes. A proposed comparability protocol that was not 

approved as part of the original application must be submitted as a prior approval supplement 

(314.70(e)). On February 25, 2003, FDA issued a draft guidance on comparability protocols 

entitled Comparability protocols - Chemistry, Manufacturing, and Controls Information. 

III. GENERAL REQUIREMENTS

Other than for editorial changes in previously submitted information (e.g., correction of spelling or 

typographical errors, reformatting of batch records), an applicant must notify FDA about each 

change in each condition established in an approved application beyond the variations already

provided for in the application (§ 314.70(a)(1)).

A supplement or annual report must include a list of all changes contained in the supplement or 

annual report. On the list, FDA recommends that the applicant describe each change in enough 

detail to allow FDA to quickly determine whether the appropriate reporting category has been 

used. For supplements, this list must be provided in the cover letter (§ 314.70(a)(6)). In annual 

reports, the list should be included in the summary section (§ 314.81(b)(2)(i)). The applicant must 

describe each change fully in the supplement or annual report (§ 314.70(a)(1)).

An applicant making a change to an approved application under section 506A of the Act must also 

conform to other applicable laws and regulations, including current good manufacturing practice 

(CGMP) requirements of the Act (21 U.S.C. 351(a)(2)(B)) and applicable regulations in Title 21 

of the Code of Federal Regulations (e.g., 21 CFR parts 210, 211, 314). For example, 

manufacturers must comply with relevant CGMP validation and recordkeeping requirements and 

ensure that relevant records are readily available for examination by authorized FDA personnel 

during an inspection. 

A changes-being-effected supplement providing for labeling changes under § 314.70(c)(6)(iii) 

must include 12 copies of the final printed labeling (§ 314.70(c)(1)). In accordance with 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

5

§ 314.70(a)(4), an applicant also must promptly revise all promotional labeling and drug 

advertising to make it consistent with any labeling change implemented in accordance with §

314.70(b) or (c). 

Except for supplements providing only for a change in labeling, an applicant must include in each 

supplement and amendment to a supplement a statement certifying that a field copy has been 

provided in accordance with 21 CFR 314.440(a)(4)6 (§ 314.70(a)(5)).

IV. ASSESSING THE EFFECT OF MANUFACTURING CHANGES

A. Assessment of the Effects of the Change

The holder of an approved application under section 505 of the Act must assess the 

effects of the change before distributing a drug product made with a manufacturing 

change (§ 314.70(a)(2)).7 For each change, the supplement or annual report must contain 

information determined by FDA to be appropriate and must include the information 

developed by the applicant in assessing the effects of the change (section 506A(b), (c)(1), 

(d)(2)(A), and (d)(3)(A) of the Act). The type of information that must be included in a 

supplemental application or an annual report is specified in § 314.70(b)(3), (c)(4), and 

(d)(3).

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.8 A specification is a quality 

standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an 

approved application to confirm the quality of drug substances, drug products, 

intermediates, raw materials, reagents, components, in-process materials, container 

closure systems, and other materials used in the production of a drug substance or 

drug product. Acceptance criteria are numerical limits, ranges, or other criteria 

for the tests described (§ 314.3(b)). Conformance to a specification means that the 

 

6

 Mailing information for field copies is provided in 21 CFR 314.440(a)(4). FDA recommends that the applicant's home FDA 

district office referred to in the regulations be the district office where the applicant's headquarters is located.

7 Assess the effects of the change means to evaluate the effects of a manufacturing change on the identity, strength, quality, 

purity, and potency of a drug product as these factors relate to the safety or effectiveness of the drug product. The terms assess

or assessment as used in this guidance are not the same as validation. Certain validation information, such as for sterilization 

processes, is considered information that is needed to assess the effect of the change as specified in § 314.70(a)(2) and should be 

submitted in an NDA or ANDA. Unless otherwise specified by FDA, validation (e.g., process, equipment) data need not be 

submitted in the application, but should be retained at the facility and be available for review by FDA at the Agency's discretion 

under CGMPs. 

8

 If a specification needs to be revised as a result of the change, this would be considered a multiple change (see sections VIII and 

XII). 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

6

material, when tested according to the analytical procedures listed in the 

specification, will meet the listed acceptance criteria. 

2. Additional Testing

In addition to confirming that the material affected by manufacturing changes 

continues to meet its specification, we recommend that the applicant 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 postchange 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 changes in the impurity or degradant profile could first 

involve profiling using appropriate chromatographic techniques and then, 

depending on the observed changes in the impurity profile, toxicology tests 

to qualify a new impurity or degradant or to qualify an impurity that is 

above a previously qualified level.9 

• Evaluation of the hardness or friability of a tablet after certain changes.

• Assessment of the effect of a change on bioequivalence when required 

under 21 CFR part 320 could include, for example, multipoint and/or 

multimedia dissolution profiling and/or an in vivo bioequivalence study.

• Evaluation of extractables from new packaging components or moisture 

permeability of a new container closure system.

An applicant should refer to all relevant CDER guidance documents for 

recommendations on the information that should be submitted to support a given 

change. If guidance for information that should be submitted to support a particular 

change is not available, applicants can consult the appropriate CDER chemistry or 

microbiology review staff for advice.

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 

 

9

 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant guidances (e.g., ICH Q3B 

Impurities in New Drug Products (November 1996)).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

7

drug product. Typically this is accomplished by comparing test results from pre- and 

postchange material and determining if the test results are equivalent. Simply stated: Is the 

drug product made after the change equivalent to the drug product made before the change? 

 An exception to this general approach is that when bioequivalence is redocumented for 

certain ANDA postapproval changes, FDA recommends that the comparator be the 

reference listed drug. Equivalence comparisons frequently have a criterion for comparison 

with calculation of confidence intervals relative to a predetermined equivalence interval. 

For this, as well as for other reasons, equivalent does not necessarily mean identical. 

Equivalence may also relate to maintenance of a quality characteristic (e.g., stability) 

rather than a single performance of a test. 

C. Adverse Effect

Some manufacturing changes have an adverse effect on the identity, strength, quality, purity, 

or potency of the drug product. In many cases, the applicant chooses not to implement 

these manufacturing changes, but sometimes the applicant wishes to do so. 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. For example, a process change recommended for a changes-being-effected-in-30-

days supplement could cause the formation of a new degradant that requires qualification 

and/or identification.10 The applicant's degradation qualification procedures may indicate 

that there are no safety concerns relating to the new degradant. Even so, we recommend 

that the applicant submit this change in a prior approval supplement with appropriate 

information to support the continued safety and effectiveness of the drug product. During 

the review of the prior approval supplement, the FDA will assess the impact of any 

adverse effect on the drug product as this change may relate to the safety or effectiveness of 

the drug product. 

Applicants are encouraged to consult with the appropriate CDER chemistry or 

microbiology review staff if there are any questions on whether a change in a characteristic 

would be viewed by CDER as adversely affecting the identity, strength, quality, purity, or 

potency of the drug product. 

V. 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)). The deletion or reduction of an 

ingredient intended to affect only the color of the drug product may be reported in an annual report 

(§ 314.70(d)(2)(ii)). Guidance on changes in components and composition that may be submitted 

in a changes-being-effected supplement or annual report is not included in this document because 

 

10 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant guidances.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

8

of the complexity of the recommendations, but may be covered in one or more guidance documents 

describing postapproval changes (e.g., SUPAC documents).

VI. MANUFACTURING SITES11

A. General Considerations

CDER must be notified when a manufacturer changes to a manufacturing site that is 

different from those specified in the approved application (314.70(a)). Sites can include 

those used by an applicant to (1) manufacture or process drug products,12 in-process 

materials, drug substances, or drug substance intermediates, (2) package drug products, (3) 

label drug products, and (4) test components, drug product containers, closures, packaging 

materials, in-process materials, or drug products. Sites include those owned by the 

applicant or contract sites used by an applicant. Testing sites include those performing 

physical, chemical, biological, and microbiological testing to monitor, accept, or reject 

materials, as well as those performing stability testing. Sites used to label drug products 

are considered those that perform labeling of the drug product's primary or secondary 

packaging components. Sites performing operations that place identifying information on 

the dosage form itself (e.g., ink imprint on a filled capsule) are considered to be facilities 

that manufacture or process the drug product. FDA recommends that the supplement or 

annual report identify whether the proposed manufacturing site is an alternative to or 

replacement for the site or sites provided for in the approved application. 

FDA recommends that a move to a different manufacturing site, when it is a type of site 

routinely subject to FDA inspection, be submitted as a prior approval supplement if the site 

does not have a satisfactory CGMP inspection13 for the type of operation14 being moved 

(see sections VI.B.1 and 2).

For labeling, secondary packaging, and testing site changes, the potential for 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 is considered to be independent of 

the type of drug product dosage form or specific type of operation being performed. 

Therefore, the recommended reporting category for any one of these manufacturing site 

changes will be the same for all types of drug products and operations. For manufacturing 

sites used to (1) manufacture or process drug products, in-process materials, drug 

substances, or drug substance intermediates or (2) perform primary packaging operations, 

 

11 See Attachment A for a discussion of the definition of same manufacturing site and different manufacturing site.

12 Manufacturing or processing drug product would also include the preparation (e.g., sterilization, depyrogenation, irradiation, 

washing) by the applicant or applicant's contractor of container closure systems or packaging components. Changes in the site 

used to fabricate packaging components (e.g., bottles) or manufacture packaging materials (e.g., resins) need not be reported to 

CDER if there are no other changes (e.g., dimensions, compositions, processing aids). If other changes occur, the reporting 

category should be based on the recommended reporting categories for these changes (i.e., the manufacturing site change does 

not need to be considered when determining the appropriate reporting category).

13 See Glossary for a definition of satisfactory CGMP inspection.

14 See Attachment B for a discussion of the term type of operation.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

9

the potential for adverse effect depends on factors such as the type of drug substance or 

drug product and operation being performed. Therefore, recommended reporting 

categories may differ depending on the type of drug product and operations. 

Except for the situations described in sections VI.B.4, VI.C.1.b, and VI.D.5, construction 

activities at a manufacturing site or moving production operations within a building or 

between buildings at the same manufacturing site do not have to be reported to CDER. 

We recommend that a move to a manufacturing site that involves other changes (e.g., 

process, equipment) be evaluated as a multiple related change (see section XII) to 

determine the appropriate reporting category. 

B. Major Changes (Prior Approval Supplement)

The following are examples of changes considered to have 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.

1. 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.

2. A move to a different manufacturing site, except one used to manufacture or 

process a drug substance intermediate, when the new manufacturing site 

does not have a satisfactory CGMP inspection for the type of operation 

being moved.

3. A move to a different manufacturing site for (1) the manufacture, 

processing, or primary packaging of drug products when the primary 

packaging components control the dose delivered to the patient or the 

formulation modifies the rate or extent of availability of the drug, or (2) the 

manufacture or processing of in-process materials with modified-release 

characteristics. Examples of these types of drug products include modifiedrelease solid oral dosage forms,15 transdermal systems, liposomal drug 

products, depot drug products, oral and nasal metered-dose inhalers 

(MDIs), dry powder inhalers (DPIs), and nasal spray pumps.

4. Transfer of the manufacture of an aseptically processed sterile drug 

substance or aseptically processed sterile drug product to (1) a newly 

constructed or refurbished aseptic processing facility or area or (2) an 

existing aseptic processing facility or area that does not manufacture similar 

(including container types and sizes) approved drug products. An example 

 

15 Certain operations relating to the manufacture, processing, or primary packaging of modified-release solid oral dosage form 

drug products need not be reported in a prior approval supplement (see sections VI.C.1.c and VI.D.6). 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

10

would be transferring the manufacture of a lyophilized drug product to an 

existing aseptic process area where no approved lyophilized drug products 

are manufactured or where the approved lyophilized drug products being 

manufactured have different container types and/or sizes than the container 

of the drug product being transferred. See section VI.C.1.b for 

recommendations for other manufacturing site changes relating to 

aseptically processed sterile drug substance or aseptically processed sterile 

drug product. 

5. Transfer of the manufacture of a finished drug product sterilized by terminal 

processes to a newly constructed facility at a different manufacturing site. 

Once this change has been approved, subsequent site changes to the facility 

for similar drug product types and processes may be submitted as a 

changes-being-effected-in-30-days supplement (see section VI.C.1.a).

C. Moderate Changes (Supplement - Changes Being Effected)

The following are examples of changes considered to have a moderate 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. If the new site does 

not have a satisfactory CGMP inspection for the type of operation being moved (see 

sections VI.B.1 and 2), then FDA recommends that the changes listed below (excluding 

changes relating to drug substance intermediate manufacturing sites) be submitted in a prior 

approval supplement.

1. Supplement - Changes Being Effected in 30 Days

a. A move to a different manufacturing site for the manufacture or 

processing of any drug product, in-process material, or drug 

substance that is not otherwise provided for in this guidance.

b. For aseptically processed sterile drug substance or aseptically 

processed sterile drug product, a move to an aseptic processing 

facility or area at the same or different manufacturing site except as 

provided for in section VI.B.4.

c. 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. 

d. A move to a different manufacturing site for testing if (1) the test 

procedures approved in the application or procedures that have 

been implemented via an annual report are used, (2) all 

postapproval commitments made by the applicant relating to the test 

procedures have been fulfilled (e.g., providing methods validation 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

11

samples), and (3) the new testing facility has the capability to 

perform the intended testing.

2. Supplement - Changes Being Effected 

A move to a different manufacturing site for the manufacture or processing 

of the final intermediate. 

D. Minor Changes (Annual Report)

The following are examples of changes considered to have a minimal 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. If the new site does 

not have a satisfactory CGMP inspection for the type of operation being moved, then FDA 

recommends that the changes listed below (excluding changes relating to drug substance 

intermediate manufacturing sites) be submitted in a prior approval supplement (see 

sections VI.B.1 and 2).

1. A move to a different manufacturing site for secondary packaging. 

2. A move to a different manufacturing site for labeling.

3. A move to a different manufacturing site for the manufacture or processing 

of drug substance intermediates other than the final intermediate.

4. A change in the contract sterilization site for packaging components when 

the process is not materially different from that provided for in the 

approved application

5. A transfer of the manufacture of a finished product sterilized by terminal 

processes to a newly constructed building or existing building at the same 

manufacturing site.

6. A move to a different manufacturing site for the ink imprinting of solid oral 

dosage form drug products.

VII. MANUFACTURING PROCESS

A. General Considerations

The potential for adverse effects 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 

depends on the type of manufacturing process and the changes being instituted for the drug 

substance or drug product. In some cases, there may be a substantial potential for adverse 

effect regardless of direct testing of the drug substance or drug product for conformance 

with the approved specification. When there is a substantial potential for adverse effects, 

a change must be submitted in a prior approval supplement (section 506A(c) of the Act). 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

12

B. Major Changes (Prior Approval Supplement)

The following are examples of changes considered to have 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.

1. 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. 

2. Changes that may affect drug product sterility assurance including, where 

appropriate, process changes for sterile drug substances and sterile 

packaging components. These include: 

• Changes in the sterilization method (e.g., gas, dry heat, irradiation). These 

include changes from sterile filtered or aseptic processing to terminal 

sterilization, or vice versa. 

• Addition, deletion, or substitution of sterilization steps or procedures for 

handling sterile materials in an aseptic processing operation.

• Replacing sterilizers that operate by one set of principles with sterilizers 

that operate by another principle (e.g., substituting a gravity displacement 

steam process with a process using superheated water spray).

• Addition to an aseptic processing line of new equipment made of different 

materials (e.g., stainless steel versus glass, changes between plastics) that 

will come in contact with sterilized bulk solution or sterile drug 

components, or deletion of equipment from an aseptic processing line. 

• Replacing a Class 100 aseptic fill area with a barrier system or isolator for 

aseptic filling. Once this change has been approved, subsequent process 

changes for similar product types in the same barrier system or isolator may 

be submitted as a changes-being-effected-in-30-days supplement.

• Replacement or addition of lyophilization equipment of a different size that 

uses different operating parameters or lengthens the overall process time.

• Changes from bioburden-based terminal sterilization to the use of an 

overkill process, and vice versa. 

• Changes to aseptic processing methods, including scale, that extend the total 

processing, including bulk storage time, by more than 50 percent beyond the 

validated limits in the approved application.

• Changes in sterilizer load configurations that are outside the range of 

previously validated loads.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

13

• Changes in materials or pore size rating of filters used in aseptic 

processing.

3. The following changes for a natural product:16

• Changes in the virus or adventitious agent removal or inactivation methods. 

 This applies to any material where such procedures are necessary, 

including drug substance, drug product, reagents, and excipients.

• For drug substance and drug product, changes in the source material (e.g., 

microorganism, plant) or cell line.

• For drug substance and drug product, establishment of a new master cell 

bank or seed.

 4. Any fundamental change in the manufacturing process or technology from 

that currently used by the applicant. For example:

a. Drug product

• Dry to wet granulation or vice versa.

• Change from one type of drying process to another (e.g., oven tray, 

fluid bed, microwave).

b. Drug substance

• Filtration to centrifugation or vice versa.

• Change in the route of synthesis of a drug substance.

5. The following changes for drug substance

• Any process change made after the final intermediate processing step in 

drug substance manufacture.

• Changes in the synthesis or manufacture of the drug substance that may 

affect its impurity profile and/or the physical, chemical, or biological 

properties.

6. Addition of an ink code imprint or change to or in the ink used for an 

existing imprint code for a solid oral dosage form drug product when the 

ink as changed is not currently used on CDER-approved drug products.

17

 

16 For the purposes of this guidance, natural product refers to materials (e.g., drug substance, excipients) that are derived from 

plants, animals, or microorganisms, and that are subject to approval under section 505 of the Act. The specific recommendations 

for natural products are not applicable to inorganic compounds (e.g., salts, minerals).

17 See Attachment C for a discussion of CDER-approved drug products.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

14

7. Establishing a new procedure for reprocessing a batch of drug substance or 

drug product that fails to meet the approved specification. 

C. Moderate Changes (Supplement - Changes Being Effected)

The following are examples of changes considered to have a moderate 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.

1. Supplement - Changes Being Effected in 30 Days

a. For drug products, any change in the process, process parameters, 

and/or equipment except as otherwise provided for in this guidance.

b. For drug substances, any change in process and/or process 

parameters except as otherwise provided for in this guidance.

c. For natural protein drug substances and natural protein drug 

products:

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

except as otherwise provided for in this guidance (e.g., section 

VII.B.5, VII.D.7).

• An increase or decrease in production scale during finishing steps 

that involves different equipment.

• Replacement of equipment with equipment of different design that 

does not affect the process methodology or process operating 

parameters.

d. For sterile drug products, drug substances, and components, as 

appropriate:

• Changes in dry heat depyrogenation processes for glass container 

systems for drug substances and drug products that are produced by 

terminal sterilization processes or aseptic processing.

• Changes to filtration parameters for aseptic processing (including 

flow rate, pressure, time, or volume, but not filter materials or pore 

size rating) when additional validation studies for the new 

parameters should be performed.

• Filtration process changes that provide for a change from single to 

dual sterilizing filters in series, or for repeated filtration of a bulk.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

15

• Changes from one qualified sterilization chamber to another for inprocess or terminal sterilization that result in changes to validated 

operating parameters (time, temperature, F0, and others). 

• Changes in scale of manufacturing for terminally sterilized drug 

products that increase the bulk solution storage time by more than 50 

percent beyond the validated limits in the approved application 

when bioburden limits are unchanged.

e. For drug substances, redefinition of an intermediate, excluding the 

final intermediate, as a starting material.

2. Supplement - Changes Being Effected 

a. 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. 

b. For sterile drug products, elimination of in-process filtration 

performed as part of the manufacture of a terminally sterilized drug 

product.

D. Minor Changes (Annual Report)

The following are examples of changes considered to have a minimal 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.

1. For drug products, changes to equipment of the same design and operating 

principle and/or changes in scale except as otherwise provided for in this 

guidance (e.g., section VII.C.1.c, VII.D.7). 

2. A minor change in an existing code imprint for a dosage form. For 

example, changing from a numeric to alphanumeric code.

3. Addition of an ink code imprint or a change in the ink used in an existing 

code imprint for a solid oral dosage form drug product when the ink is 

currently used on CDER-approved drug products.

4. Addition or deletion of a code imprint by embossing, debossing, or 

engraving on a solid dosage form drug product other than a modifiedrelease dosage form. 

5. A change in the order of addition of ingredients for solution dosage forms 

or solutions used in unit operations (e.g., granulation solutions).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

16

6. Changes in scale of manufacturing for terminally sterilized drug products 

that increase the bulk solution storage time by no more than 50 percent 

beyond the validated limits in the approved application when bioburden 

limits are unchanged.

7. For natural protein drug products and natural protein drug substances:

• An increase or decrease in production scale during finishing steps that does 

not involve an equipment change.

• Replacement of equipment with equipment of the same design, operating 

principle, and capacity with no change in production scale. 

VIII. SPECIFICATIONS

A. General Considerations

All changes in specifications from those in the approved application must be submitted in a 

prior approval supplement unless otherwise exempted by regulation or guidance 

(§ 314.70(b)(2)(i)). Specifications (i.e., tests, analytical procedures, and acceptance 

criteria) are the quality standards provided in an approved application to confirm the 

quality of drug substances, drug products, intermediates, raw materials, reagents, 

components, in-process materials, container closure systems, and other materials used in 

the production of a drug substance or drug product. For the purpose of defining 

specifications, acceptance criteria are numerical limits, ranges, or other criteria for the 

tests described. Examples of a test, an analytical procedure, and an acceptance criterion 

are, respectively, an assay, a specific, fully described high pressure liquid chromatography 

(HPLC) procedure, and a range of 98.0–102.0 percent. The recommendations in this 

section also apply to specifications associated with sterility assurance that are included in 

NDA and ANDA submissions.18

A regulatory analytical procedure is the procedure in the approved application that is 

designated for use in evaluating a defined characteristic of the drug substance or drug 

product. Section 501(b) of the Act recognizes the analytical procedures in the U.S. 

Pharmacopeia/National Formulary (USP/NF) as the regulatory analytical procedures for 

compendial items. Tests and associated acceptance criteria and regulatory analytical 

procedures in addition to those specified in the USP/NF may be required for approving 

compendial items (section 505 of the Act).

The applicant may include in its application alternatives to the approved regulatory 

analytical procedures for testing the drug substance and drug product. However, for 

purposes of determining compliance with the Act, regulatory analytical procedures are 

used. 

 

18 See FDA guidance for industry on the Submission of Documentation for Sterilization Process Validation in Applications 

for Human and Veterinary Drug Products (November 1994).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

17

In sections B through D below, the use of the term analytical procedure without a qualifier 

such as regulatory or alternative refers to an analytical procedure used to test materials 

other than the drug substance or drug product.

B. Major Changes (Prior Approval Supplement)

The following are examples of changes in specifications considered to have 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.

1. Relaxing an acceptance criterion except as otherwise provided for in this 

guidance (e.g., section VIII.C.1.b, VIII.C.1.e).

2. Deleting any part of a specification except as otherwise provided for in this 

guidance (e.g., section VIII.D.2).

3. Establishing a new regulatory analytical procedure including designation of 

an alternative analytical procedure as a regulatory procedure. 

4. A change in a regulatory analytical procedure that does not provide the 

same or increased assurance of the identity, strength, quality, purity, or 

potency of the material being tested as the regulatory analytical procedure 

described in the approved application.

5. A change in an analytical procedure used for testing components, packaging 

components, the final intermediate, in-process materials after the final 

intermediate, or starting materials introduced after the final intermediate 

that does not provide the same or increased assurance of the identity, 

strength, quality, purity, or potency of the material being tested as the 

analytical procedure described in the approved application except as 

otherwise noted. For example, a change from an HPLC procedure that 

distinguishes impurities to (1) an HPLC procedure that does not, (2) another 

type of analytical procedure (e.g., titrimetric) that does not, or (3) an HPLC 

procedure that distinguishes impurities but the limit of detection and/or limit 

of quantitation is higher.

6. Relating to testing of raw materials for viruses or adventitious agents:19 

(1) relaxing an acceptance criterion, (2) deleting a test, or (3) a change in 

the analytical procedure that does not provide the same or increased 

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

being tested as the analytical procedure described in the approved 

application. 

 

19 In this context, testing for adventitious agents is not considered to include tests that are found in an official compendium (e.g., 

USP <61>).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

18

C. Moderate Changes (Supplement - Changes Being Effected)

The following are examples of changes in specifications considered to have a moderate 

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.

1. Supplement - Changes Being Effected in 30 Days

a. Any change in a regulatory analytical procedure other than those 

identified as major changes or editorial changes.

b. Relaxing an acceptance criterion or deleting a test for raw materials 

used in drug substance manufacturing, in-process materials prior to

the final intermediate, starting materials introduced prior to the final 

drug substance intermediate, or drug substance intermediates 

(excluding final intermediate) except as provided for in section 

VIII.B.6.

c. A change in an analytical procedure used for testing raw materials 

used in drug substance manufacturing, in-process materials prior to 

the intermediate, starting materials introduced prior to the final drug 

substance intermediate, or drug substance intermediates (excluding 

final intermediate) that does not provide the same or increased 

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

material being tested as the analytical procedure described in the 

approved application except as provided for in section VIII.B.6. 

d. Relaxing an in-process acceptance criterion associated with 

microbiological monitoring of the production environment, 

materials, and components that are included in NDA and ANDA 

submissions. For example, increasing the microbiological alert or 

action limits for critical processing environments in an aseptic fill 

facility or increasing the acceptance limit for bioburden in bulk 

solution intended for filtration and aseptic filling.

e. Relaxing an acceptance criterion or deleting a test to comply with an 

official compendium that is consistent with FDA statutory and 

regulatory requirements (§ 314.70(c)(2)(iii)).

2. Supplement - Changes Being Effected 

a. 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.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

19

b. A change in an analytical procedure used for testing components, 

packaging components, the final intermediate, in-process materials 

after the final intermediate, or starting materials introduced after the 

final intermediate that provides the same or increased assurance of 

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

tested as the analytical procedure described in the approved 

application. 

D. Minor Changes (Annual Report)

The following are examples of changes in specifications considered to have a minimal 

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.

1. Any change in a specification made to comply with an official compendium, 

except the changes described in section VIII.C.1.e, that is consistent with 

FDA statutory and regulatory requirements (§ 314.70(d)(2)(i)). 

2. For drug substance and drug product, the addition or revision of an 

alternative analytical procedure that provides the same or increased 

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

being tested as the analytical procedure described in the approved 

application or deletion of an alternative analytical procedure. 

3. Tightening of acceptance criteria.

4. A change in an analytical procedure used for testing raw materials used in 

drug substance synthesis, starting materials introduced prior to the final 

drug substance intermediate, in-process materials prior to the final 

intermediate, or drug substance intermediates (excluding final intermediate) 

that provides the same or increased assurance of the identity, strength, 

quality, purity, or potency of the material being tested as the analytical 

procedure described in the approved application. 

IX. CONTAINER CLOSURE SYSTEM

A. General Considerations

The potential for 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 

when making a change to or in the container closure system is generally dependent on the 

route of administration of the drug product, performance of the container closure system, 

and the likelihood of interaction between the packaging component and the dosage form. In 

some cases there may be a substantial potential for adverse effect, regardless of direct drug 

product testing for conformance with the approved specification.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

20

A change to or in a packaging component will often result in a new or revised specification 

for the packaging component. This situation does not have to be considered a multiple 

related change. Only the reporting category for the packaging change needs to be 

considered.

B. Major Changes (Prior Approval Supplement)

The following are examples of changes considered to have 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.

1. For liquid (e.g., solution, suspension, elixir) and semisolid (e.g., creams, 

ointments) dosage forms, a change to or in polymeric materials (e.g., 

plastic, rubber) of primary packaging components, when the composition of 

the component as changed has never been used in a CDER-approved drug 

product of the same dosage form and same route of administration. For 

example, a polymeric material that has been used in a CDER-approved 

topical ointment would not be considered CDER-approved for an 

ophthalmic ointment. 

2. For liquid (e.g., solution, suspension, elixir) and semisolid (e.g., creams, 

ointments) dosage forms in permeable or semipermeable container closure 

systems, a change from an ink and/or adhesive used on the permeable or 

semipermeable packaging component to an ink or adhesive that has never 

been used in a CDER-approved drug product of the same dosage form and 

same route of administration and with the same type of permeable or 

semipermeable packaging component (e.g., low density polyethylene, 

polyvinyl chloride). 

3. A change in the primary packaging components for any drug product when 

the primary packaging components control20 the dose delivered to the 

patient (e.g., the valve or actuator of a metered-dose inhaler).

4. For sterile drug products, any change that may affect drug product sterility 

assurance, such as:21

• A change from a glass ampule to a glass vial with an elastomeric closure.

 

20A container closure system that is considered to control the dose delivered to the patient is a container closure system where the 

system itself, rather than a person, regulates the amount of drug product ultimately delivered to a patient. A container closure 

system where a person controls the amount of drug product administered or that allows verification that the appropriate amount 

has been administered (e.g., number of tablets, milliliters of liquid) is not considered a container closure system that controls the 

dose delivered to the patient.

21 Some of these identified changes, depending on the circumstances, may have to be submitted as original NDAs or ANDAs 

instead of as supplements. Applicants can consult the appropriate CDER chemistry division/office if there are questions. 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

21

• 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.

• Changes that add or delete silicone treatments to container closure systems 

(such as elastomeric closures or syringe barrels).

• Changes in the size and/or shape of a container for a sterile drug product.

5. Deletion of a secondary packaging component intended to provide 

additional protection to the drug product (e.g., carton to protect from light, 

overwrap to limit transmission of moisture or gases) or a change in the 

composition of, or the addition of, a secondary packaging component that 

may affect the impurity profile of the drug product.

6. A change to a new container closure system if the new container closure 

system does not provide the same or better protective properties than the 

approved container closure system. 

C. Moderate Changes (Supplement - Changes Being Effected)

The following are examples of changes considered to have a moderate 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.

1. Supplement - Changes Being Effected in 30 Days

a. A change to or in a container closure system, except as otherwise 

provided for in this guidance, that does not affect the quality of the 

drug product.

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

substance.

c. A change in the number of units (e.g., tablets, capsules) or labeled 

amount (e.g., grams, milliliters) of a nonsterile drug product in a 

unit-of-use container.22

2. Supplement - Changes Being Effected 

 

22A unit-of-use container is one that contains a specific quantity of a drug product and is intended to be dispensed to the patient 

without further modification except for the addition of appropriate labeling.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

22

a. A change in the size and/or shape of a container for a nonsterile 

drug product, except for solid dosage forms (see section IX.D.2), 

without a change from one container closure system to another 

(§ 314.70(c)(6)(ii)).

b. A change in the labeled amount (e.g., grams, milliliters) of drug 

product for a nonsterile drug product in a multiple-unit container,23

except for solid dosage forms (see section IX.D.3) .

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

D. Minor Changes (Annual Report)

The following are examples of changes considered to have a minimal 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.

1. A change in the container closure system for a nonsterile drug product, 

based on a showing of equivalency to the approved system under a protocol 

approved in the application or published in an official compendium 

(§ 314.70(d)(2)(v)).

2. A change in the size and/or shape of a container for a nonsterile solid 

dosage form (§ 314.70(d)(2)(iv)).

3. A change in the number of units (e.g., tablets, capsules) or labeled amount 

(e.g., grams) of nonsterile solid dosage form in a multiple-unit container.

4. The following changes in the container closure system of solid oral dosage 

form drug products as long as the new package provides the same or better 

protective properties (e.g., light, moisture) and any new primary packaging 

component materials have been used in and been in contact with CDERapproved solid oral dosage form drug products:24

• Adding or changing a child-resistant closure, changing from a metal to 

plastic screw cap, or changing from a plastic to metal screw cap.

 

23A multiple-unit container is a container that permits withdrawal of successive portions of the contents without changing the 

strength, quality, or purity of the remaining portion. This type of container is not distributed directly to patients but is used by 

health care practitioners who dispense the drug product in smaller amounts to a patient in accordance with a physician's 

instructions.

24 For sections IX.D.4 to IX.D.7, changes in the container closure system that result in drug product contact with a component 

material that has never been used in any CDER-approved drug product of the same type should be submitted as a changes-beingeffected-in-30-days supplement (section IX.C.1) or prior approval supplement (section IX.B.1).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

23

• Changing from one plastic container to another of the same type of plastic 

(e.g., high density polyethylene (HDPE) container to another HDPE 

container).

• Changes in packaging materials used to control odor (e.g., charcoal 

packets).

• Changes in bottle filler (e.g., change in weight of cotton or amount used) 

without changes in the type of filler (e.g., cotton to rayon).

• Increasing the wall thickness of the container.

• A change in or addition of a cap liner.

• A change in or addition of a seal (e.g., heat induction seal).

• A change in an antioxidant, colorant, stabilizer, or mold releasing agent for 

production of the container and/or closure to one that is used at similar 

levels in the packaging of CDER-approved solid oral dosage form drug 

products.

• A change to a new container closure system when the container closure 

system is already approved in the NDA or ANDA for other strengths of the 

drug product.

5. The following changes in the container closure system of nonsterile liquid 

drug products as long as the new package provides the same or better 

protective properties and any new primary packaging component materials 

have been used in and been in contact with CDER-approved liquid drug 

products with the same route of administration (i.e., the material in contact 

with a liquid topical should already have been used with other CDERapproved liquid topical drug products): 

• Adding or changing a child-resistant closure, changing from a metal to 

plastic screw cap, or changing from a plastic to metal screw cap.

• Increasing the wall thickness of the container.

• A change in or addition of a cap liner.

• A change in or addition of a seal (e.g., heat induction seal).

6. A change in the container closure system of unit dose packaging (e.g., 

blister packs) for nonsterile solid dosage form drug products as long as the 

new package provides the same or better protective properties and any new 

primary packaging component materials have been used in and been in 

contact with CDER-approved drug products of the same type (e.g., solid 

oral dosage form, rectal suppository).

7. The following changes in the container closure system of nonsterile 

semisolid drug products as long as the new package provides the same or 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

24

better protective properties and any new primary packaging component 

materials have been used in and been in contact with CDER-approved 

semisolid drug products:

• Changes in the closure or cap.

• Increasing the wall thickness of the container.

• A change in or addition of a cap liner.

• A change in or addition of a seal. 

• A change in the crimp sealant.

8. A change in the flip seal cap color as long as the cap color is consistent 

with any established color coding system for that class of drug products.

X. LABELING

A. General Considerations

A drug product labeling change includes changes in the package insert, package labeling, 

or container label. In accordance with § 314.70(a)(4), an applicant must promptly revise 

all promotional labeling and drug advertising to make it consistent with any labeling 

change implemented in accordance with paragraphs (b) or (c) of § 314.70. All labeling 

changes for ANDA drug products must be consistent with section 505(j) of the Act.

B. Major Changes (Prior Approval Supplement)

Any proposed change in the labeling, except changes designated as moderate or minor by 

regulation or guidance, must be submitted as a prior approval supplement 

(§ 314.70(b)(2)(v)(A)). If applicable, any change to a Medication Guide required under 

21 CFR part 208, except for changes in the information specified in § 208.20(b)(8)(iii) and 

(b)(8)(iv), must be submitted in a prior approval supplement (§ 314.70(b)(v)(B)). The 

following list contains some examples of changes currently considered by CDER 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.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

25

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

6. Claims of superiority to another drug product. 

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

guidance.

C. Moderate Changes (Supplement - Changes Being Effected)

Under § 314.70(c)(6)(iii), a changes-being-effected supplement must be submitted for any 

labeling change that (1) adds or strengthens a contraindication, warning, precaution, or 

adverse reaction, (2) adds or strengthens a statement about drug abuse, dependence, 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

26

psychological effect, or overdosage, (3) adds or strengthens an instruction about dosage 

and administration that is intended to increase the safe use of the drug product, (4) deletes 

false, misleading, or unsupported indications for use or claims for effectiveness, or 

(5) normally requires a supplement submission and approval prior to distribution of the 

drug product that FDA specifically requests be submitted under this provision. A changesbeing-effected supplement that provides for a labeling change under §§ 314.70(c)(6)(iii) 

must include 12 copies of final printed labeling (§ 314.70(c)(1)). The following list 

includes some examples of changes currently considered by CDER 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 postmarketing study.

3. Clarification of the administration statement to ensure proper administration 

of the drug product. 

D. Minor Changes (Annual Report)

Labeling with editorial or similar minor changes or with a change in the information 

concerning the description of the drug product or information about how the drug is 

supplied that does not involve a change in the dosage strength or dosage form should be 

described in an annual report (§ 314.70(d)(2)(ix) and (d)((2)(x)) . The following list 

includes some examples currently considered by CDER to fall into this reporting category.

1. Changes in the layout of the package or container label that are consistent 

with FDA regulations (e.g., 21 CFR part 201) without a change in the 

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. 

4. Labeling changes made to comply with an official compendium.

XI. MISCELLANEOUS CHANGES

A. Major Changes (Prior Approval Supplement)

The following are examples of changes considered to have 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.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

27

1. Changes requiring completion of studies in accordance with 21 CFR part 

320 to demonstrate equivalence of the drug product to the drug product as 

manufactured without the change or to the reference listed drug 

(§ 314.70(b)(2)(ii)).

2. Addition of a stability protocol or comparability protocol.

3. Changes to an approved stability protocol or comparability protocol unless 

otherwise provided for in this guidance (e.g., VIII.C, VIII.D, XI.C.2).

4. An extension of an expiration dating period based on (1) data obtained 

under a new or revised stability testing protocol that has not been approved 

in the application or (2) full shelf life data on pilot scale batches using an 

approved protocol. 

5. Changes to a drug product under an application that is subject to a validity 

assessment because of significant questions regarding the integrity of the 

data supporting that application (§ 314.70(b)(2)(viii)).

B. Moderate Changes (Supplement - Changes Being Effected)

The following are examples of changes considered to have a moderate 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.

1. 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. 

2. Supplement - Changes Being Effected 

No changes have been identified.

C. Minor Changes (Annual Report)

The following are examples of changes considered to have a minimal 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.

1. An extension of an expiration dating period based on full shelf life data on 

production batches obtained under a protocol approved in the application 

(§ 314.70(d)(2)(vi)). 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

28

2. Addition of time points to the stability protocol or deletion of time points 

beyond the approved expiration dating period.

3. A change from previously approved stability storage conditions to storage 

conditions recommended in International Conference on Harmonisation 

(ICH) guidances.

4. Non-USP reference standards:

• Replacement of an in-house reference standard or reference panel (or panel 

member) according to procedures in an approved application.

• Tightening of acceptance criteria for existing reference standards to provide 

greater assurance of drug product purity and potency.

XII. MULTIPLE RELATED CHANGES

Multiple related changes involve various combinations of individual changes. For example, a site 

change may also involve equipment and manufacturing process changes or a components and 

composition change may necessitate a change in a specification. 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. 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

29

ATTACHMENT A: MANUFACTURING SITES

All owners or operators of all drug establishments (not exempt by regulation) that engage in the 

manufacture, preparation, propagation, compounding, or processing of a drug or drugs are required 

to register with the FDA (21 CFR 207.20). An establishment means a place of business under one 

management at one general physical location (§ 207.3(a)(7)). A general physical location is 

reasonably construed to include separate buildings within the same city if the activities in the 

buildings are closely related to the same business enterprise, are under the supervision of the same 

local management, and are all inspected at the same time (ORA Field Management Directive No. 

132).

For the purposes of determining the reporting category for moves between buildings, the terms 

same manufacturing site and different manufacturing site mean:

Domestic Establishments

Same manufacturing site:

• The new and old buildings are included under the same drug establishment 

registration number25

and

• The same FDA district office is responsible for inspecting the operations in both 

the new and old buildings.

Different manufacturing site:

• The new and old buildings have different drug establishment registration numbers

or

• Different FDA district offices are responsible for inspecting operations in the new 

and old buildings.

For domestic establishments, the terms same manufacturing site and different manufacturing site

supersede the terms contiguous campus, same campus, and different campus as used in the 

SUPAC guidances.

Foreign Establishments

 

25 The registration number is the number assigned to the establishment as part of the registration process (e.g., ORA Field 

Management Directive No. 92).
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

30

Foreign establishments are not currently required to register with the FDA. On May 14, 1999, 

FDA published a proposed rule to require registration of foreign establishments (64 FR 26330). 

Until registration of foreign establishments is required, same and different manufacturing sites 

mean:

Same manufacturing site:

• A contiguous or unbroken site or a set of buildings in adjacent city blocks.

Different manufacturing site:

• The new and old buildings are not on a contiguous site or not in adjacent city 

blocks.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

31

ATTACHMENT B: TYPE OF OPERATION AND CGMP INSPECTIONS

Section VI states that a change to a different manufacturing site should be submitted in a prior 

approval supplement when (1) the new manufacturing site has never been inspected by FDA for 

the type of operation being moved, (2) 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, or (3) the new 

manufacturing site does not have a satisfactory current good manufacturing practice (CGMP) 

inspection for the type of operation being moved.

A profile class system is used by FDA to assist in (1) managing the CGMP inspection process, (2) 

evaluating the findings and the compliance follow-up needed, and (3) communicating the results of 

inspections. A profile class can relate to the manufacture of a particular dosage form (e.g., large 

volume parenterals, oral liquids), type of drug substance (e.g., sterile bulk by chemical synthesis), 

or specific function performed at a site (e.g., control testing laboratory). There are profile class 

codes for major categories of drug substance processes, dosage forms, and manufacturing functions 

(see table below). However, the system is not comprehensive for all operations performed in the 

pharmaceutical industry (see not elsewhere classified (NEC) profile class code).

The term type of operation refers to the specialized or even unique conditions and practices that 

are employed to manufacture a class or category of drug substance or drug product or to perform a 

limited segment of the manufacturing process. These conditions and practices exist and are 

performed within the framework of CGMPs, along with general conditions and practices that 

contribute to the manufacture of all drug products at a given manufacturing site. The conditions 

and practices, both general and specific, are inspected to evaluate the CGMP acceptability of a

manufacturing site. A wide variety of classes or categories of drug substances and drug products 

may be produced at a manufacturing site, or the manufacturing site may only produce a single class 

of drug substance and/or drug product or perform a limited segment of a manufacturing process. 

Each type of operation is represented by a profile class code.

Generally, a satisfactory CGMP status for a profile class code is used to communicate a 

satisfactory CGMP clearance for all of the products and for all of the operations included within 

the category that code represents. Thus the profile class code for a particular dosage form or type 

of drug substance is used to communicate the CGMP status for all aspects of manufacturing, 

processing, packing, or holding that are performed at the specific manufacturing site relating to that 

particular dosage form or type of drug substance, including packaging and labeling operations, 

testing, and quality control. The profile class code for a particular dosage form or type of drug 

substance is also used to communicate the CGMP status for manufacturing sites that produce inprocess material (e.g., controlled-release beads), package drug products, or label drug products, 

even if these are stand-alone (e.g., contractor) operations.

A few profile class codes that describe certain types of operations (see items in boldface in table) 

are provided to report the CGMP status for contractor firms whose only function in the 

manufacturing process is to perform this operation. If one of these operations (e.g., steam 

sterilization process) is performed at the manufacturing site involved in producing the drug 

product/drug substance, the CGMP status for that operation is reported as part of the profile class 

code for the particular dosage form or type of drug substance. For example, a manufacturing site 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

32

producing a terminally sterilized small volume parenteral drug product would be reported with the 

profile class code for the dosage form (SVT), not by the profile code for the sterilization process 

(SSP). 

Certain inspections may be required by program priorities even if the rating for a profile class 

code indicates an acceptable CGMP status. The current profile codes/classes for human drugs 

are:

ADM Aerosol dispensed medication NEC Not elsewhere classified (when using this class, specific 

drug products are noted) 

CBI Biotechnology crude drug OIN Ointment, nonsterile (includes cream, jelly, paste)

CEX Plant/animal extraction crude drug POW Powders (includes oral and topical)

CFS Sterile bulk by fermentation crude drug RAD Radiopharmaceutical

CFN Nonsterile bulk by fermentation crude drug RSP Radiation sterilization process

CHG Capsule, prompt release SNI Sterile noninjectable

CRU Crude bulk drugs-nonsynthesized SOP Soap

CSG Capsules, soft gelatin SSP Steam sterilization process

CSN Nonsterile bulk by chemical synthesis SUP Suppositories

CSP Chemical sterilization process SVL Small volume parenterals (lyophilized)

CSS Sterile bulk by chemical synthesis SVS Sterile-filled small volume parenterals

CTL Control testing laboratories SVT Terminally sterilized small volume parenteral

CTR Capsules, modified-release TCM Tablets, prompt-release

GAS Medical gas (includes liquid oxygen and other) TCT Tablets, delayed-release

GSP Gas sterilization process TDP Transdermal patches

HSP Dry heat sterilization process TSP Fractional (tyndallization) sterilization process

LIQ Liquid (includes solutions, suspension, elixirs, and 

tinctures)

TTR Tablets, extended-release

LVP Large volume parenterals WSP Water sterilization process

CGMP inspectional status, based on the profile class, is available through FDA's Freedom of 

Information (FOI) Office. (See Glossary under Satisfactory Current Good Manufacturing Practice 

(CGMP) Inspection for more information regarding FOI requests.)
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

33

Examples of postapproval manufacturing site changes and recommended reporting categories:

• An applicant wants to move the manufacture of an immediate-release tablet (TCM) to a 

different manufacturing site that currently manufactures, and has satisfactory CGMP status for, 

capsules (CHG) and powders for oral solution (POW). This manufacturing site change should 

be submitted in a prior approval supplement because the new manufacturing site does not have 

a satisfactory CGMP inspection for immediate-release tablets.

• An applicant wants to contract out packaging operations for immediate-release tablets (TCM) 

and capsules (CHG) and modified-release capsules (CTR). The potential contract packager 

has a satisfactory CGMP status for immediate-release and modified-release capsules but has 

never packaged immediate-release tablets. The packaging site change for the immediaterelease tablet drug products should be submitted in a prior approval supplement. The 

packaging site change for the capsule drug products should be submitted as recommended in 

section VI of this guidance for packaging sites with a satisfactory CGMP inspection.

• An applicant wishes to consolidate product testing to a single analytical laboratory at a 

manufacturing site. This manufacturing site produces various solid oral dosage form drug 

products, has an operational analytical laboratory currently at the site, and satisfactory CGMP 

inspections for the manufacturing occurring at the facility. Some of the drug products that will 

be tested at the analytical laboratory when the consolidation occurs are not solid oral dosage 

form products. Unlike most other production operations, testing laboratories (and other 

operations in boldface in the table) are not inspected on a dosage form/type of drug substance 

specific basis. The satisfactory CGMP inspection of the analytical laboratory, which was 

performed as part of the CGMP inspection for manufacture of the solid oral dosage form drug 

products, is considered to apply to all dosage forms, including those not actually produced at 

the site. The consolidation can be submitted in a changes-being-effected-in-30-days 

supplement if the change is consistent with the recommendations in section VI.C.1.d.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

34

ATTACHMENT C: CDER-APPROVED DRUG PRODUCTS

In several places throughout the guidance, different reporting categories are proposed for changes 

to or the addition of certain components based on whether the component/material has been used in 

and has been in contact with CDER-approved drug products. Different reporting categories are 

recommended once CDER has reviewed certain components/materials in association with a drug 

product approval because similar subsequent changes then have a reduced 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. For example, certain changes in the 

container closure systems of solid oral dosage form drug products may be included in an annual 

report as long as the new package provides the same or better protective properties and any new 

primary packaging component materials have been used in and been in contact with CDERapproved solid oral dosage form drug products (see section IX.D.4). If the new primary 

packaging component material has not been used in or has not been in contact with CDERapproved solid oral dosage form drug products, then submission of the change in an annual report 

is not recommended. 

CDER-approved drug products are considered those drug products subject to an approved NDA 

or ANDA. Some information on which components/materials are used in CDER-approved 

products is available from the Agency (e.g., FDA, CDER, Inactive Ingredient Guide, 1996, 

Division of Drug Information Resources). When information is not available, an applicant should 

use reliable sources of information to determine that the component or material has been used in 

and has been in contact with a CDER-approved drug product of the same dosage form and route of 

administration, as appropriate. The applicant should identify in the supplement or annual report 

the basis for the conclusion that the component or material is used in a CDER-approved drug 

product.

If an applicant cannot confirm that a component or material has been used in and has been in 

contact with a CDER-approved drug product of the same dosage form and route of administration, 

the applicant has the option of submitting the change for a single NDA or ANDA using the higher 

recommended reporting category and, after approval, submitting similar changes for other NDAs 

and ANDAs using the lower recommended reporting category. 
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

35

GLOSSARY

Acceptance Criteria: Numerical limits, ranges, or other criteria for the tests described (21 CFR 

314.3(b)).

Active Ingredient/Drug Substance: Any component that is intended to furnish pharmacological 

activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a 

disease, or to affect the structure or any function of the human body, but does not include 

intermediates used in the synthesis of such ingredient. The term includes those components that 

may undergo chemical change in the manufacture of the drug product and are present in the drug 

product in a modified form intended to furnish the specified activity or effect (21 CFR 210.3(b)(7) 

and 314.3(b)).

Assess the Effects of the Change: To evaluate the effects of a manufacturing change on the 

identity, strength, quality, purity, and potency of a drug product as these factors may relate to the 

safety or effectiveness of the drug product (21 CFR 314.3(b)).

Container Closure System: The sum of packaging components that together contain and protect 

the dosage form. This includes primary packaging components and secondary packaging 

components if the latter are intended to provide additional protection to the drug product.

Component: Any ingredient intended for use in the manufacture of a drug product, including those 

that may not appear in such drug product (21 CFR 210.3(b)(3)).

Drug Product: A finished dosage form, for example, tablet, capsule, or solution, that contains an 

active ingredient generally, but not necessarily, in association with inactive ingredients (21 CFR 

210.3(b)(4)).

Final Intermediate: The last compound synthesized before the reaction that produces the drug 

substance. The final step forming the drug substance involves covalent bond formation or 

breakage; ionic bond formation (i.e., making the salt of a compound) does not qualify. 

Consequently, when the drug substance is a salt, the precursors to the organic acid or base, rather 

than the acid or base itself, should be considered the final intermediate.

Inactive Ingredient: Any intended component of the drug product other than an active ingredient.

In-process Material: Any material fabricated, compounded, blended, or derived by chemical 

reaction that is produced for, and used in, the preparation of the drug product (21 CFR 

210.3(b)(9)). For drug substance, in-process materials are considered those materials that are 

undergoing change (e.g., molecular, physical). 

Intermediate: A material that is produced during steps of the synthesis of a drug substance and 

undergoes further molecular change before it becomes a drug substance.
Contains Nonbinding Recommendations*

* Insofar as this guidance adjusts reporting categories pursuant to section 506A of the Federal Food, Drug, and Cosmetic Act 

and 21 CFR 314.70, it does have binding effect.

36

Package: The container closure system and labeling, associated components (e.g., dosing cups, 

droppers, spoons), and external packaging (e.g., cartons, shrink wrap).

Packaging Component: Any single part of a container closure system.

Primary Packaging Component: A packaging component that is or may be in direct contact with 

the dosage form.

Reference Listed Drug: The listed drug identified by FDA as the drug product on which an 

applicant relies in seeking approval of its abbreviated application (21 CFR 314.3(b)).

Satisfactory Current Good Manufacturing Practice (CGMP) Inspection: A satisfactory 

CGMP inspection is an FDA inspection during which (1) no objectionable conditions or practices 

were found (No Action Indicated (NAI)) or (2) objectionable conditions were found, but voluntary 

corrective action is left to the firm and the objectionable conditions will not be the subject of 

further administrative or regulatory actions (Voluntary Action Indicated (VAI)).

Information about the CGMP status of a firm may be obtained by requesting a copy of the Quality 

Assurance Profile (QAP) from the FDA's Freedom of Information (FOI) Office. The QAP 

contains information on the CGMP compliance status of firms that manufacture, package, assemble, 

repack, relabel, or test human drugs, devices, biologics, and veterinary drugs. All FOI requests 

must be in writing (21 CFR 20.40(a)) and should be prepared following the instructions found in 

the reference entitled A Handbook for Requesting Information and Records from FDA. An 

electronic version of this reference is available on the Internet at 

http://www.fda.gov/opacom/backgrounders/foiahand.html.

Secondary Packaging Component: A packaging component that is not and will not be in direct 

contact with the dosage form.

Specification: The quality standard (i.e., tests, analytical procedures, and acceptance criteria) 

provided in an approved application to confirm the quality of drug substances, drug products, 

intermediates, raw materials, reagents, components, in-process materials, container closure 

systems, and other materials used in the production of a drug substance or drug product (21 CFR 

314.3(b)).