CVM GFI #83 Chemistry, Manufacturing and Controls Changes to Approved NADA/ANADA

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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 Docke
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://w 	. All written comments should be identified with Docket No. 99D-
651.
lace,
ockville, MD 20855, 240-276-8268. E-mail: dennis.bensley@fda.hhs.gov
1
For questions regarding this guidance document, contact Dennis Bensley, Jr., Center for
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish P
R 	.
inistration, 7519 Standish Place,
da.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
Additional copies of this guidance document may be requested from the Communications Staff,
HFV-12, Center for Veterinary Medicine, Food and Drug Adm
Rockville, MD 20855, and may be viewed on the Internet at
http://www.f
efault.htm.
U.S. Department of Health and Human Services
Center for Veterinary Medicine (CVM)
May 30, 2007
Food and Drug Administration

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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

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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

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GUIDANCE FOR INDUSTRY
Chemistry, Manufacturing and Controls Changes to an Approved
NADA or ANADA
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 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.

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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, CVM’s Division of Manufacturing Technologies,
HFV-140, should be consulted.
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 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

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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.

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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

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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).

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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)).

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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).

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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.

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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

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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).

CONTAINS NON-BINDING RECOMMENDATIONS
14
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).

CONTAINS NON-BINDING RECOMMENDATIONS
15
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:

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16
• 	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.

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17
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).

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18
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

CONTAINS NON-BINDING RECOMMENDATIONS
19
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, F0 , and others).
• 	Changes in scale of manufacturing for terminally sterilized
drug products that increase the bulk solution storage time
by more than 50 percent beyond the validated limits in the
approved application when bioburden limits are unchanged.
e. 	For 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.

CONTAINS NON-BINDING RECOMMENDATIONS
20
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).

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21
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)

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22
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>).

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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,

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24
tial for adverse effect, regardless of direct
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 poten
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.

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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.

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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

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27
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

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28
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

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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.

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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.

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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)

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32
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)
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 TAM 	Type A Medicated Article
GAS 	Medical gas (includes liquid oxygen and other) 	TCM 	Tablets, prompt-release
GSP 	Gas sterilization process 	TCT 	Tablets, delayed-release
HSP 	Dry heat sterilization process TDP 	Transdermal patches
IMN
IMS
Implant Nonsterile
Implant Sterile
TSP 	Fractional (tyndallization) sterilization process
LIQ 	Liquis (includes solutions, suspension, elixirs, and
tinctures)
TTR 	Tablets, extended-release

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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.

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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.

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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)).