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*  
 
 
Guidance for Industry1 
 
 
Changes to an Approved NDA or ANDA 
 
 
 
 
 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.  
 
 
 
 
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).  
 
* 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  
  Contains Nonbinding Recommendations*  
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-being
effected 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.  
* 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  
  Contains Nonbinding Recommendations*  
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-being
effected-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.  
 
* 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  
  Contains Nonbinding Recommendations*  
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  
* 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  
  Contains Nonbinding Recommendations*  
  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).  
* 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  
  Contains Nonbinding Recommendations*  
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)).  
* 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  
  Contains Nonbinding Recommendations*  
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.  
* 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  
  Contains Nonbinding Recommendations*  
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. 
* 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  
  Contains Nonbinding Recommendations*  
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 modified-
release 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).  
* 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  
  Contains Nonbinding Recommendations*  
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 
* 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  
  Contains Nonbinding Recommendations*  
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).  
* 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  
  Contains Nonbinding Recommendations*  
 
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.  
 
* 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  
  Contains Nonbinding Recommendations*  
 	  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. 
* 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  
  Contains Nonbinding Recommendations*  
 
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.  
* 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  
  Contains Nonbinding Recommendations*  
 	  Changes from one qualified sterilization chamber to another for in-
process or terminal sterilization that result in changes to validated 
operating parameters (time, temperature, F , and others).    
0
 	  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 modified- 
release 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).  
 
* 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  
  Contains Nonbinding Recommendations*  
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 98.0102.0 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).  
* 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  
  Contains Nonbinding Recommendations*  
 
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>).  
* 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  
  Contains Nonbinding Recommendations*  
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.  
 
* 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  
  Contains Nonbinding Recommendations*  
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.  
 
* 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  
  Contains Nonbinding Recommendations*  
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.  
* 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  
  Contains Nonbinding Recommendations*  
 	  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.  
* 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  
  Contains Nonbinding Recommendations*  
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 CDER-
approved 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-being
effected-in-30-days supplement (section IX.C.1) or prior approval supplement (section IX.B.1).  
* 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  
  Contains Nonbinding Recommendations*  
 	  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 CDER-
approved 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 
* 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  
  Contains Nonbinding Recommendations*  
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.  
* 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  
  Contains Nonbinding Recommendations*  
 
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,  
* 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  
  Contains Nonbinding Recommendations*  
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 changes
being-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.  
 
* 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  
  Contains Nonbinding Recommendations*  
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)).  
* 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  
  Contains Nonbinding Recommendations*  
 
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.  
* 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  
  Contains Nonbinding Recommendations*  
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).  
* 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  
  Contains Nonbinding Recommendations*  
 
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.  
* 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  
  Contains Nonbinding Recommendations*  
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 in-
process 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 
* 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  
  Contains Nonbinding Recommendations*  
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  TTR   Tablets, extended-release  
tinctures)  
       
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.)  
* 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  
  Contains Nonbinding Recommendations*  
 
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 immediate-
release 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. 
* 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  
  Contains Nonbinding Recommendations*  
 
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 CDER-
approved 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 CDER-
approved 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. 
* 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  
  Contains Nonbinding Recommendations*  
 
 
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.  
* 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  
  Contains Nonbinding Recommendations*  
 
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)).  
 
* 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