83 
 
 
Guidance for Industry 
Chemistry, Manufacturing, and Controls Changes to 
an Approved NADA or ANADA 
 
 
Comments and suggestions regarding this guidance should be sent to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, 
Rockville, MD  20852.  Comments may also be submitted electronically on the Internet at 
http://www.regulations.gov.  All written comments should be identified with Docket No.  99D-
1651. 
 
For questions regarding this guidance document, contact Dennis Bensley, Jr., Center for 
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish Place, 
Rockville, MD  20855, 240-276-8268.  E-mail:  dennis.bensley@fda.hhs.gov .    
 
Additional copies of this guidance document may be requested from the Communications Staff, 
HFV-12, Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD  20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
May 30, 2007 
  CONTAINS NON-BINDING RECOMMENDATIONS 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION AND BACKGROUND ..............................................................................................4 
 
II.  REPORTING CATEGORIES .......................................................................................6   
 
III.  GENERAL REQUIREMENTS ......................................................................................7   
 
IV.  ASSESSING THE EFFECT OF MANUFACTURING CHANGES..........................................8  
 
A.  ASSESSMENT OF THE EFFECTS OF THE CHANGE...........................................................8 
1. Conformance to Specifications.....................................................................................................8 
2. Additional Testing...................................................................................................................   9 
B.   EQUIVALENCE.........................................................................................................10 
C.  ADVERSE EFFECT.....................................................................................................10 
 
V.  COMPONENTS AND COMPOSITION...........................................................................11  
 
VI.  MANUFACTURING SITES..........................................................................................11  
 
A.  GENERAL CONSIDERATIONS......................................................................................11 
B.  MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).....................................................13 
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 (MINOR CHANGES AND STABILITY REPORT)......................................15 
 
VII.  MANUFACTURING PROCESS....................................................................................15  
 
A.  GENERAL CONSIDERATIONS......................................................................................15 
B.  MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).....................................................16 
C.  MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED)..............................18 
1. Supplement - Changes Being Effected in 30 Days...........................................................................18 
2. Supplement - Changes Being Effected..........................................................................................19 
D.  MINOR CHANGES (MINOR CHANGES AND STABILITY REPORT)......................................19 
 
VIII.  SPECIFICATIONS.....................................................................................................20  
 
A.  GENERAL CONSIDERATIONS......................................................................................20 
B.  MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).....................................................21 
C.  MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED)..............................22 
1. Supplement - Changes Being Effected in 30 Days...........................................................................22 
2. Supplement - Changes Being Effected..........................................................................................23 
D.  MINOR CHANGES (MINOR CHANGES AND STABILITY REPORT)......................................23 
 
  2 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
IX.  CONTAINER CLOSURE SYSTEM...............................................................................24  
 
A.  GENERAL CONSIDERATIONS.....................................................................................24 
B.  MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT)....................................................24 
C.  MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED)..............................26 
1. Supplement - Changes Being Effected in 30 Days..........................................................................26 
2. Supplement - Changes Being Effected..........................................................................................26 
D.  MINOR CHANGES (MINOR CHANGES AND STABILITY REPORT)......... ............................26 
 
X.  MISCELLANEOUS CHANGES....................................................................................28  
 
A.  MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT).....................................................28 
B.  MODERATE CHANGES (SUPPLEMENT - CHANGES BEING EFFECTED)..............................29 
1. Supplement - Changes Being Effected in 30 Days...........................................................................29 
2. Supplement - Changes Being Effected..........................................................................................29 
C.  MINOR CHANGES (MINOR CHANGES AND STABILITY REPORT).......................................29 
 
XI.  MULTIPLE RELATED CHANGES................................................................................30  
 
ATTACHMENT:  TYPE OF OPERATION AND CGMP INSPECTIONS.......................................31 
GLOSSARY.........................................................................................................................34  
 
 
 
 
 
 
 
 
 
 
 
 
  3 CONTAINS NON-BINDING RECOMMENDATIONS 
 
GUIDANCE FOR INDUSTRY  
 
Chemistry, Manufacturing and Controls Changes to an Approved 
NADA or ANADA 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 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 514.8, it does have binding effect.    If you 
have any questions about the effect of any portion of this guidance, contact the Division of 
Manufacturing Technologies, Office of New Animal Drug Evaluation, Center for Veterinary 
Medicine (HFV-140), Food and Drug Administration, 7500 Standish Place, Rockville, MD 
20855. 
 
 
 
 
I.  INTRODUCTION AND BACKGROUND 
 
This guidance provides recommendations to holders of new animal drug applications (NADAs) 
and abbreviated new animal drug applications (ANADAs) who intend to make post-approval 
chemistry, manufacturing, and controls (CMC) changes in accordance with section 506A of the 
Federal Food, Drug, and Cosmetic Act (the Act) and 21 CFR 514.8.   The guidance covers 
recommended reporting categories for post-approval changes for animal drugs.  
Recommendations are provided for post-approval changes in: (1) components and composition, 
(2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure 
system, as well as (6) miscellaneous changes and (7) multiple related changes. 
 
On November 21, 1997, the President signed the Food and Drug Administration Modernization 
Act of 1997 (the Modernization Act). 1  Section 116 of the Modernization Act amended the Act 
                                                 
1  Public Law 105-115. 
  4 CONTAINS NON-BINDING RECOMMENDATIONS 
 
by adding section 506A, which provides requirements for making and reporting manufacturing 
changes to an approved application and for distributing a drug made with such change.  FDA has 
revised its regulations on supplements and other changes to an approved application (21 CFR 
514.8) 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 as these factors may relate to the safety or effectiveness of the drug.  
An applicant should consider all relevant FDA guidance documents for recommendations on the 
information that should be submitted to support a given change.   
 
FDA 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 21 CFR 514.8(b)(3) 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.  FDA intends to update the previously published 
guidances to make them consistent with this guidance.   
 
If guidance for either recommended filing categories or information that should be submitted to 
support a particular change is not available, CVMs Division of Manufacturing Technologies, 
HFV-140, should be consulted. 
 
FDAs guidance documents, in general, do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 514.8, 
it does have binding effect.  If you have any questions about the effect of any portion of this 
guidance, contact the Division of Manufacturing Technologies, Office of New Animal Drug 
Evaluation, Center for Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 
  5 CONTAINS NON-BINDING RECOMMENDATIONS 
 
Standish Place, Rockville, MD 20855. 
 
II.  REPORTING CATEGORIES 
 
Section 506A of the Act and FDA's regulation at 21 CFR 514.8 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 as these factors may relate to the safety or 
effectiveness of the drug.  A major change requires the submission of a supplement and approval 
by FDA prior to distribution of the drug made using the change.  This type of supplement is 
called, and must be clearly labeled, a Prior Approval Supplement (21 CFR 514.8(b)(2)).  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 the supplement 
would impose an extraordinary hardship on the applicant.  This type of supplement is called, and 
must be clearly labeled, a Prior Approval Supplement-Expedited Review Requested (21 CFR 
514.8(b)(2)(iv)).  Requests for expedited review based on extraordinary hardship should be 
reserved 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 therefore could not 
plan.2 
 
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 a drug as these factors may relate to the safety or 
effectiveness of the drug.  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 made using the change.  This type of supplement is called, and must be clearly 
labeled, a Supplement--Changes Being Effected in 30 Days (21 CFR 514.8(b)(3)).  The drug 
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 (21 CFR 
514.8(b)(3)(v)).  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 (21 CFR 514.8(b)(1)(ii) and (b)(3)(iv)).  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 (21 CFR 
514.8(b)(3)(v)(B)).  FDA may identify certain moderate changes for which distribution can 
occur when FDA receives the supplement.  This type of supplement is called, and must be 
clearly labeled, Supplement--Changes Being Effected (21 CFR 514.8(b)(3)(vi)).  If, after 
review, FDA disapproves a changes being effected in a 30- days supplement or changes-being-
effected supplement, FDA may order the manufacturer to cease distribution of the drugs that 
have been made using the disapproved change (21 CFR 514.8(b)(3)(vii)). 
                                                 
2  CVM intends to issue guidance on requesting expedited reviews of NADAs, ANADAs, supplemental NADAs, 
and supplemental ANADAs. 
 
  6 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
A minor change is a change that has minimal potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of a drug as these factors may relate to the safety or 
effectiveness of the drug.  The applicant must describe minor changes in its next annual report to 
the application and the annual report must be clearly labeled, Minor Changes and Stability 
Report (21 CFR 514.8(b)(4)). 
 
Under 21 CFR 514.8(b)(2)(v), an applicant may 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 must be submitted as a prior approval supplement, if not approved as part 
of the original application (21 CFR 514.8(b)(2)(v)).  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 (21 CFR 514.8(b)(1)(i)). 
 
A supplement or annual report must include a list of all changes contained in the supplement or 
annual report (21 CFR 514.8(b)(1)(v)).  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 
(21 CFR 514.8(b)(1)(v)).  In annual reports, the list should be included in the summary section.  
The supplement or annual report also is required to describe the change fully (21 CFR 
514.8(b)(1)(i)). 
 
An applicant making a change to an approved application under section 506A of the Act also 
must 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, 225, 226, and 514).  
For example, manufacturers must comply with relevant CGMP validation and recordkeeping 
requirements (21 CFR parts 210, 211, 225, 226) and ensure that relevant records are readily 
available for examination by authorized FDA personnel during an inspection.   
 
An applicant must include a statement in each supplement and amendment to a supplement 
certifying that a field copy has been provided to the appropriate FDA district office (21 CFR 
 
  7 CONTAINS NON-BINDING RECOMMENDATIONS 
 
514.8(b)(1)(iv)).3 
 
IV.  ASSESSING THE EFFECT OF MANUFACTURING CHANGES 
 
A.  Assessment of the Effects of the Change 
 
The holder of an approved application under section 512 of the Act must assess the 
effects of the change before distributing a drug made with a manufacturing change (21 
CFR 514.8(b)(1)(ii)).4  For each change, the supplement or annual report must contain 
information determined by FDA to be appropriate and 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 annual report is specified in 21 CFR 514.8(b)(2)(iii), 
(b)(3)(iv), (b)(3)(vi), and (b)(4)(iii). 
 
1.  Conformance to Specifications 
 
An assessment of the effects of a change on the identity, strength, quality, purity, 
and potency of the drug 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.5  A specification is a 
quality standard (i.e., tests, analytical procedures, and acceptance criteria) 
provided in an approved application to confirm the quality of  drugs including, for 
example, drug substances, Type A medicated articles, drug products, 
intermediates, raw materials, reagents, components, in-process materials, 
container closure systems, and other materials used in the production of a drug.  
(21 CFR 514.8(a)(2)(iv)).  Acceptance criteria are numerical limits, ranges, or 
other criteria for the tests described (21 CFR 514.8(a)(2)(iv)). Conformance to a 
specification means that the material, when tested according to the analytical 
procedures listed in the specification, will meet the listed acceptance criteria.  
 
2.  Additional Testing 
                                                 
3  For a change to a product manufactured in a foreign facility, a field copy of the supplement or its 
amendment is not required to be submitted to an FDA district office.  However, FDA recommends that the applicant 
state that the drug made with the change is manufactured only at a foreign site. 
4 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 as these factors may relate to the safety or effectiveness of the drug.  
(21 CFR  514.8(a)(2)(i)).  The term assess or assessment as used in this guidance are not the same as validation. 
Certain validation information, such as sterilization processes, is considered information that is needed to assess the 
effect of the change as specified in 21 CFR 514.8(b)(1)(ii) and should be submitted in an NADA or ANADA. Unless 
otherwise specified by FDA, other validation (e.g., process, equipment) data need not be submitted in the 
application, but must be retained at the facility and be available for review by FDA  (see, e.g., 21 CFR 211.180). 
5 If a specification needs to be revised as a result of the change, this would be considered a multiple change 
(see sections VIII and XI).   
 
  8 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
In addition to confirming that the material affected by manufacturing changes 
continues to meet its specification, the applicant should perform additional 
testing, when appropriate, to assess whether the identity, strength, quality, purity, 
or potency of a drug as these factors may relate to the safety or effectiveness of 
the drug have been or will be affected.  The assessment should include, as 
appropriate, evaluation of any changes in the chemical, physical, microbiological, 
biological, bioavailability, and/or stability profiles.  This additional assessment 
could involve testing of the post-change drug 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, and the effect of the change on the quality of the drug.  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.6 
 
  Evaluation of the hardness or friability of a tablet after certain changes. 
 
  Assessment of the effect of a change on bioequivalence 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 FDA 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, CVM's Division of Manufacturing 
Technologies, HFV-140, should be consulted. 
 
B.  Equivalence 
 
When testing is performed, the applicant should assess the extent to which the 
manufacturing change has affected the identity, strength, quality, purity, and potency of 
the drug product.  Typically, this is accomplished by comparing test results from pre- and 
                                                 
6 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant guidances 
(e.g., VICH GL10(R), Impurities in New Veterinary Drug Substances (Revision), Draft Revised Guidance, (GFI 92) 
(January 6, 2006)). 
 
  9 CONTAINS NON-BINDING RECOMMENDATIONS 
 
post-change material and determining if the test results are equivalent.  Simply stated: Is 
the drug made after the change equivalent to the drug made before the change?  
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 also may 
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.  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, 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.  The applicant's degradation qualification procedures 
may indicate that there are no safety concerns relating to the new degradant.  Even so, the 
applicant should submit this change in a prior approval supplement with appropriate 
information to support the continued safety and effectiveness of the drug.  During the 
review of the prior approval supplement, FDA will assess the impact of any adverse 
effect on the drug as this change may relate to the safety or effectiveness of the drug.   
 
Applicants are encouraged to consult with CVM's Division of Manufacturing 
Technologies, HFV-140, if there are any questions on whether a change in a 
characteristic would be viewed by CVM as adversely affecting the identity, strength, 
quality, purity, or potency of the drug.   
 
V.  COMPONENTS AND COMPOSITION 
 
Changes in the qualitative or quantitative formulation, including inactive ingredients, as 
provided in the approved application are considered major changes and must be submitted in a 
prior approval supplement, unless exempted by regulation or guidance (21 CFR 
514.8(b)(2)(ii)(A)).  The deletion or reduction of an ingredient intended to affect only the color 
of the drug product may be reported in an annual report (21 CFR 514.8(b)(4)(ii)(B)).  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 of the complexity of these 
recommendations, but may be covered in one or more guidance documents describing post-
approval changes (e.g., SUPAC documents).   
 
 
 
  10 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
VI.  MANUFACTURING SITES 
A.  General Considerations 
 
CVM must be notified when a manufacturer changes to a manufacturing site that is 
different from those specified in the approved application (21 CFR 514.8(b)(1)(i)). 
Manufacturing sites can include those used by an applicant to, for example, (1) 
manufacture or process drug products,7 in-process materials, Type A medicated articles, 
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, Type A medicated articles, 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 should 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 subjected to FDA inspection, be submitted as a prior approval supplement if the 
site does not have a satisfactory CGMP inspection8 for the type of operation9 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 as these factors may 
relate to the safety or effectiveness of the drug is considered to be independent of the type 
of drug 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 drugs and operations.  For manufacturing sites used to (1) manufacture or 
process drugs including, for example, drug products, Type A medicated articles, in-
process materials, drug substances, or drug substance intermediates or (2) perform 
                                                 
7 
Manufacturing or processing a drug also includes the preparation (e.g., sterilization, depyrogenation, 
irradiation, washing) 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 CVM 
if there are no other changes (e.g., dimensions, composition, 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). 
8 See Glossary for a definition of satisfactory CGMP inspection. 
9 See Attachment A  for a discussion of the term type of operation. 
 
  11 CONTAINS NON-BINDING RECOMMENDATIONS 
 
primary packaging operations, the potential for adverse effect depends on factors such as 
the type of drug and operation being performed.  Therefore, recommended reporting 
categories may differ depending on the type of drug and operation.   
 
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 CVM. 
 
We recommend that a move to a manufacturing site that involves other changes (e.g., 
process, equipment) should be evaluated as a multiple related change (see section XI) to 
determine the appropriate reporting category.   
 
A change from one drug substance manufacturer to another typically involves more than 
simply a site change.  In the majority of cases, there will be additional differences (e.g., 
route of synthesis, process, solvents, equipment).  Without extensive knowledge of both 
sources (i.e., old and new), an applicant cannot adequately describe the differences 
between the sources, or evaluate the multiple change. Therefore, in the case where the 
applicant does not have the extensive knowledge to provide this information and 
evaluation, the site change should be reported in a prior approval supplement.  When an 
applicant does have the extensive knowledge to describe the differences between the 
sources, it can report the change as appropriate after evaluation as a multiple change.  If 
the change is not reported in a prior approval supplement, the applicant should include a 
statement in the submission that the change involves no changes that should be reported 
in a prior approval supplement. 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
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, 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 
 
  12 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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,10 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.  
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.b).   
 
5.  Transfer of the manufacture of a 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 as these 
factors may relate to the safety or effectiveness of the drug.  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 including, for example, drug product, Type 
                                                 
10 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).  
 
  13 CONTAINS NON-BINDING RECOMMENDATIONS 
 
A medicated article, 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 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 report11 are used, (2) all post-
approval commitments made by the applicant relating to the test 
procedure(s) have been fulfilled (e.g., providing methods 
validation 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 as these 
factors may relate to the safety or effectiveness of the drug.  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. 
 
                                                 
11  For purposes of this guidance document, annual report means a minor changes and stability report 
according to 21 CFR 514.8(b)(4). 
 
 
  14 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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 as these factors may relate to the safety or effectiveness of the drug depends on the 
type of manufacturing process and the changes being instituted for the drug.  In some 
cases, there may be a substantial potential for adverse effect, regardless of direct testing 
of the drug 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). 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
1.  Changes that may affect the controlled (or modified) release, metering, or 
other characteristics (e.g., particle size) of the dose delivered to the 
animal, 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:  
 
 
  15 CONTAINS NON-BINDING RECOMMENDATIONS 
 
  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. 
 
  Changes in materials or pore size rating of filters used in aseptic 
processing. 
 
 
  16 CONTAINS NON-BINDING RECOMMENDATIONS 
 
3.  The following changes for a natural product:12  
 
  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.  Establishment of a new procedure for reprocessing a batch of drug that 
                                                 
12 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 512 of the 
Act.  The specific recommendations for natural products are not applicable to inorganic compounds (e.g., salts, 
minerals). 
 
  17 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
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.6). 
 
  An increase or decrease in production scale during 
finishing steps that involves different equipment. 
 
  Replacement of equipment with that of a 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 
 
  18 CONTAINS NON-BINDING RECOMMENDATIONS 
 
performed. 
 
  Filtration process changes that provide for a change from 
single to dual sterilizing filters in series, or for repeated 
filtration of a bulk. 
 
  Changes from one qualified sterilization chamber to 
another for in-process or terminal sterilization that results 
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 synthetic 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 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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
1.  For drugs, 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.6). 
 
2.  A minor change in an existing code imprint for a dosage form drug 
product.  For example, a change from a numeric to alphanumeric code. 
 
 
  19 CONTAINS NON-BINDING RECOMMENDATIONS 
 
3.  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.   
 
4.  A change in the order of addition of ingredients for solution dosage forms 
or solutions used in unit operations (e.g., granulation solutions). 
 
5.  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. 
 
6.  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 used in manufacturing steps other than 
finishing steps with that of the same design and 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 (21 
CFR 514.8(b)(2)(ii)(A)).  Specifications  are the quality standards (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved application to confirm the 
quality of drugs including, for example, drug substances, Type A medicated articles, drug 
products, intermediates, raw materials, reagents, components, in-process materials, 
container closure systems, and other materials used in the production of a drug.  (21 CFR 
 514.8(a)(2)(iv)).  For the purpose of defining specifications, acceptance criteria are 
numerical limits, ranges, or other criteria for the tests described.  (21 CFR 
 514.8(a)(2)(iv)).  Examples of a test, an analytical procedure, and an acceptance 
criterion are, respectively:  an assay; a specific, fully described high pressure liquid 
chromatography (HPLC) procedure; and a range of 98.0-102.0 percent.  The 
recommendations in this section also apply to specifications associated with sterility 
assurance that are included in NADA and ANADA submissions.13 
 
A regulatory analytical procedure is the procedure in the approved application that is 
                                                 
13 See FDA Guidance for Industry #48, Submission of Documentation for Sterilization Process Validation 
in Applications for Human and Veterinary Drug Products (November 1994). 
 
  20 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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 512(b)(1)(D) of the Act). 
 
The applicant may include in its application alternatives to the approved regulatory 
analytical procedures for testing the drug.  However, for purposes of determining 
compliance with the Act, regulatory analytical procedures are used.   
 
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 procedures used to test 
materials other than the drug. 
 
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 as these factors may relate to the safety or effectiveness of the drug. 
 
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 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) 
 
  21 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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 agents14: (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.  
 
7.  A change in a regulatory analytical method that significantly modifies the 
extraction and purification procedures. 
 
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 as these factors may relate to the safety or effectiveness of the drug. 
 
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 the 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 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 provided for in 
section VIII.B.6.  
                                                 
14 In this context, testing for adventitious agents is not considered to include tests that are found in an official 
compendium (e.g., USP <61>). 
 
  22 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
d.  Relaxing an in-process acceptance criterion associated with 
microbiological monitoring of the production environment, 
materials, and components that are included in NADA and 
ANADA 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 (21 CFR 514.8(b)(3)(ii)(C)). 
 
2.  Supplement-Changes Being Effected  
 
a.  An addition to a specification that provides increased assurance 
that the drug will have the characteristics of identity, strength, 
quality, purity, or potency that it purports or is represented to 
possess.  For example, the addition of a new test and associated 
analytical procedure and acceptance criterion. 
 
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 as these factors may relate to the safety or effectiveness of the drug. 
 
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 (21 CFR 
514.8(b)(4)(ii)(A)). 
 
2.  For a drug, the addition or revision of an alternative analytical procedure 
that provides the same or increased assurance of the identity, strength, 
 
  23 CONTAINS NON-BINDING RECOMMENDATIONS 
 
quality, purity, or potency of the drug 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 as these factors may relate to the safety or effectiveness of the drug when making a 
change to or in the container closure system is generally dependent on the route of 
administration of the drug, 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 testing for conformance with the approved specification.  
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
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 the primary packaging components. 
 
 
  24 CONTAINS NON-BINDING RECOMMENDATIONS 
 
2.  For liquid (e.g., solution, suspension, elixir) and semisolid (e.g., creams, 
ointments) dosage forms in permeable or semi-permeable container 
closure systems, a change in the ink and/or adhesive used on the 
permeable or semi-permeable packaging component.  
 
3.  A change in the primary packaging components for any drug product 
when the primary packaging components control the dose delivered to the 
animal (e.g., the valve or actuator of a metered-dose inhaler or addition of 
a dosing gun). 
 
4.  For sterile drug products, any change that may affect drug product sterility 
assurance such as: 
 
  A change from a glass ampule to a glass vial with an elastomeric 
closure. 
 
  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 (e.g., a carton to protect from light, an 
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. 
 
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.  
 
7.  For a liquid or semisolid dosage form, an increase in the size of a 
container that results in an increase of the labeled amount of drug product. 
 
  25 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
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. 
 
b.  Changes in the size or shape of a container for a sterile drug 
substance. 
 
 
2.  Supplement-Changes Being Effected  
 
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 (21 
CFR 514.8(b)(3)(vi)(B)). 
 
b.  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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
1.  A change within the container closure system for a nonsterile drug 
product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium (21 CFR 514.8(b)(4)(ii)(E)). 
 
2.  A change in the size and/or shape of a container containing the same 
number of dosage units for a nonsterile solid dosage form drug product , 
without a change from one container closure system to another (21 CFR 
514.8(b)(4)(ii)(D)). 
 
3.  The following changes in the container closure system of solid oral dosage 
 
  26 CONTAINS NON-BINDING RECOMMENDATIONS 
 
form drug products as long as the new package provides the same or better 
protective properties (e.g., light, moisture): 
 
  Adding or changing a child-resistant closure, a change from a 
metal to plastic screw cap, or a change from a plastic to metal 
screw cap. 
 
  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). 
 
  An increase in 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 to a new container closure system when the container 
closure system already is approved in the NADA or ANADA for 
other strengths of the drug product. 
 
4.  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:  
 
  Adding or changing a child-resistant closure, a change from a 
metal to plastic screw cap, or a change 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). 
 
5.  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 
 
  27 CONTAINS NON-BINDING RECOMMENDATIONS 
 
the new package provides the same or better protective properties. 
  
6.  The following changes in the container closure system of nonsterile 
semisolid drug products, as long as the new package provides the same or 
better protective properties: 
 
  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. 
 
7.  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.  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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
1.  Changes requiring completion of appropriate clinical studies to 
demonstrate equivalence of the drug to the drug as manufactured without 
the change (21 CFR 514.8(b)(2)(ii)(B)). 
 
2.  Addition of a stability protocol or comparability protocol. 
 
3.  Changes to an approved stability or comparability protocol unless 
otherwise provided for in this guidance (e.g., VIII.C, VIII.D, X.C.2). 
 
4.  An extension of an expiration dating period based upon (1) data obtained 
under a new or revised stability testing protocol that has not been 
approved in the application, (2) full shelf-life data on pilot scale batches 
using an approved protocol, or (3) limited shelf-life data on production 
lots.  
 
5.  Changes to a drug under an application that is subject to a validity 
 
  28 CONTAINS NON-BINDING RECOMMENDATIONS 
 
assessment because of significant questions regarding the integrity of the 
data supporting that application (21 CFR 514.8(b)(2)(ii)(G)). 
 
6.  Change in the labeled storage conditions, except as otherwise provided for 
in this guidance . 
 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
 
1.  Supplement-Changes Being Effected in 30 Days 
 
a.  Reduction of an expiration dating period to provide increased 
assurance of the identity, strength, quality, purity, or potency of the 
drug.  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.  
 
b.  Changes categorized as major changes, other than changes to the 
components and composition, that have been approved by FDA in 
the corresponding human drug product.15 
 
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 as these 
factors may relate to the safety or effectiveness of the drug. 
                                                 
15  This change applies only to those approved animal drug products that have identical composition (i.e., 
formulation), manufacturing processes, and analytical controls to a corresponding approved human drug product.  As 
part of CVM's 30-day assessment to determine the change's eligibility as a change that can be placed into effect 
according to 21 CFR 514.8(b)(3)(iv), the sponsor should also submit, along with the requirements in 21 CFR 
514.8(b)(2)(iii), a copy of FDA's approval letter for the change in the human drug product and a certification that the 
animal and human drug products are identical with the exception of labeling. 
 
 
  29 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
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 
(21 CFR 514.8(b)(4)(ii)(F)).  
 
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 Veterinary International Conference on 
Harmonization (VICH) guidances. 
 
4.  Non-USP reference standards: 
 
  Replacement of an in-house reference standard 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. 
 
5.  Submitting updated stability data generated on commercial or production 
batches under an approved stability protocol or commitment (21 CFR 
514.8(b)(4)(iii)(I)). 
 
 
XI.  MULTIPLE RELATED CHANGES 
 
Multiple related changes involve various combinations of individual changes.  For example, a 
site change also may involve equipment and manufacturing process changes, or a component and 
composition change may necessitate a change in a specification.  For multiple related changes, 
where the recommended reporting categories for the individual changes differ, CVM 
recommends that the submission be in accordance with the most restrictive of the reporting 
categories recommended for the individual changes.  When the multiple related changes all have 
the same recommended reporting category, CVM recommends that the submission be in 
accordance with the reporting category for the individual changes.  
 
 
 
 
 
 
 
 
 
  30 CONTAINS NON-BINDING RECOMMENDATIONS 
 
 
 
ATTACHMENT A: 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 of a type of operation that has 
been discontinued for more than two years at the new manufacturing site, 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" or 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 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 drugs may be produced at a manufacturing site, 
or the manufacturing site may produce only a single class of drug 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 also is 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) 
 
  31 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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 
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 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) 
   
POW  Powders (includes oral and topical) 
CEX  Plant/animal extraction crude drug 
       
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 
   
TAM  Type A Medicated Article 
CTR  Capsules, modified-release 
       
GAS  Medical gas (includes liquid oxygen and other)  TCM  Tablets, prompt-release 
       
GSP  Gas sterilization process  TCT  Tablets, delayed-release 
   
TDP  Transdermal patches 
HSP  Dry heat sterilization process 
       
IMN  Implant Nonsterile  TSP  Fractional (tyndallization) sterilization process 
IMS  Implant Sterile 
LIQ  Liquis (includes solutions, suspension, elixirs, and  TTR  Tablets, extended-release 
tinctures) 
      
 
  32 CONTAINS NON-BINDING RECOMMENDATIONS 
 
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.) 
 
Examples of post-approval 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, prompt-release capsules (CHG) and powders for oral solution (POW).  This 
manufacturing site change should be filed in a prior approval supplement because the new 
manufacturing site does not have a satisfactory CGMP inspection for immediate-release 
tablets. 
 
  An applicant wishes to consolidate product testing to a single analytical laboratory site 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.  Therefore the change to consolidate 
product testing to a single analytical laboratory site with a satisfactory CGMP status may be 
filed in a supplement-changes-being-effected. 
 
 
 
 
 
  33 CONTAINS NON-BINDING RECOMMENDATIONS 
 
GLOSSARY 
 
 
Acceptance Criteria:  Numerical limits, ranges, or other criteria for the tests described (21 CFR 
514.8(a)(2)(iv)). 
 
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 as these factors may relate to the safety 
or effectiveness of the drug (21 CFR 514.8(a)(2)(i)). 
 
Container Closure System:  The sum of packaging components that together contain and 
protect the drug.  This includes primary packaging components and secondary packaging 
components, if the latter are intended to provide additional protection to the drug. 
 
Component:  Any ingredient intended for use in the manufacture of a drug, including those that 
may not appear in such drug. 
 
Drug Product:  A finished dosage form, for example, tablet, capsule, or solution, etc., that 
contains an active ingredient (or drug substance) generally, but not necessarily, in association 
with inactive ingredients (21 CFR 210.3(b)(4)). 
 
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)).  
 
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 Ingredients:  Any intended component of the drug 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 a drug substance, in-process materials are considered those materials that are 
undergoing change (e.g., molecular, physical).  
 
Intermediate:  A material that is produced during the steps of the synthesis of a drug substance 
and undergoes further molecular change before it becomes a drug substance. 
 
  34 CONTAINS NON-BINDING 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. 
 
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 corrective action is left to the firm to take voluntarily and the objectionable conditions will 
not be the subject of further administrative or regulatory actions (Voluntary Action Indicated 
(VAI)).  A manufacturing site may have an unsatisfactory CGMP status for a specific profile 
class or type of operation if, for example, (1) the manufacturing site has not been inspected by 
FDA and found to be in compliance with CGMPs within two years of the last satisfactory FDA 
inspection, (2) an Official Action Indicated (OAI) is designated by FDA for the manufacturing 
site for a different profile class or type of operation, or (3) the manufacturer has not satisfactorily 
addressed the CGMP inspection observations. 
 
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, re-label, or test human drugs, devices, biologics, and animal 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 drug. 
 
Specification:  The quality standard (i.e., tests, analytical procedures, and acceptance criteria) 
provided in an approved application to confirm the quality of drugs, including, for example, drug 
substances, Type A medicated articles, drug products, intermediates, raw materials, reagents, 
components, in-process materials, container closure systems, and other materials used in the 
production of a drug.  (21 CFR 514.8(a)(2)(iv) 
 
Type A Medicated Article:  Product consisting of new animal drug(s) with or without carrier 
(e.g., calcium carbonate, rice hull, corn, gluten) and with or without inactive ingredients.  A 
Type A medicated article is intended solely for use in the manufacture of another Type A 
medicated article or a Type B or C medicated feed (21 CFR 558.3(b)(2)). 
 
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