|
Guidance for Industry
Changes to an Approved
NDA or ANDA
(PDF
version of this document)
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
April
2004
CMC
Revision
1
Guidance for
Industry
Changes to an Approved
NDA or ANDA
Additional copies
are available from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
April
2004
CMC
Revision
1
TABLE OF CONTENTS
- INTRODUCTION AND BACKGROUND
- REPORTING CATEGORIES
- GENERAL REQUIREMENTS
- ASSESSING THE EFFECT OF
MANUFACTURING CHANGES
- Assessment of the Effects of
the Change
- Conformance to
Specifications
- Additional Testing
- Equivalence
- Adverse Effect
- COMPONENTS AND COMPOSITION
- MANUFACTURING SITES
- General Considerations
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Supplement - Changes Being
Effected in 30 Days
- Supplement - Changes Being
Effected
- Minor Changes (Annual Report)
- MANUFACTURING PROCESS
- General Considerations
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Supplement - Changes Being
Effected in 30 Days
- Supplement - Changes Being
Effected
- Minor Changes (Annual Report)
- SPECIFICATIONS
- General Considerations
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Supplement - Changes Being
Effected in 30 Days
- Supplement - Changes Being
Effected
- Minor Changes (Annual Report)
- CONTAINER CLOSURE SYSTEM
- General Considerations
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Supplement - Changes Being
Effected in 30 Days
- Supplement - Changes Being
Effected
- Minor Changes (Annual Report)
- LABELING
- General Considerations
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Minor Changes (Annual Report)
- MISCELLANEOUS CHANGES
- Major Changes (Prior Approval
Supplement)
- Moderate Changes (Supplement -
Changes Being Effected)
- Supplement - Changes Being
Effected in 30 Days
- Supplement - Changes Being
Effected
- Minor Changes (Annual Report)
- MULTIPLE RELATED CHANGES
ATTACHMENT A: MANUFACTURING SITES
ATTACHMENT B: TYPE OF OPERATION
AND CGMP INSPECTIONS
ATTACHMENT C: CDER-APPROVED DRUG
PRODUCTS
GLOSSARY
Guidance
for Industry1
Changes
to an Approved NDA or ANDA
This guidance
represents the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the
public.** You can use an alternative approach if it satisfies
the requirements of the applicable statutes and regulations. If
you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
** Insofar as this
guidance adjusts reporting categories pursuant to section 506A
of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.70,
it does have binding effect. If you have any questions about
the effect of any portion of this guidance, contact the Office
of Pharmaceutical Science, Center for Drug Evaluation and
Research (HFD-003), Food and Drug Association, 5600 Fishers
Lane, Rockville, MD 20857. |
I. INTRODUCTION AND BACKGROUND
This guidance provides
recommendations to holders of new drug applications (NDAs) and
abbreviated new drug applications (ANDAs) who intend to make
postapproval changes in accordance with section 506A of the Federal
Food, Drug, and Cosmetic Act (the Act) and
§ 314.70
(21 CFR 314.70). The guidance covers recommended reporting
categories for postapproval changes for drugs other than specified
biotechnology and specified synthetic biological products. It
supersedes the guidance of the same title published November 1999.
Recommendations are provided for postapproval changes in (1)
components and composition, (2) manufacturing sites, (3)
manufacturing process, (4) specifications, (5) container closure
system, and (6) labeling, as well as (7) miscellaneous changes and
(8) multiple related changes.
Recommendations on reporting
categories for changes relating to specified biotechnology and
specified synthetic biological products regulated by CDER are found
in the guidance for industry entitled Changes to an Approved
Application for Specified Biotechnology and Specified Synthetic
Biological Products (July 1997).2
On November 21, 1997, the President
signed the Food and Drug Administration Modernization Act of 1997
(the Modernization Act).3
Section 116 of the Modernization Act amended the the Act by adding
section 506A, which provides requirements for making and reporting
manufacturing changes to an approved application and for
distributing a drug product made with such changes. The FDA has
revised its regulations on supplements and other changes to an
approved application (21 CFR 314.70) to conform to section 506A of
the Act.
This guidance does not provide
recommendations on the specific information that should be developed
by an applicant to assess the effect of the change on the identity,
strength (e.g., assay, content uniformity), quality (e.g., physical,
chemical, and biological properties), purity (e.g., impurities and
degradation products), or potency (e.g., biological activity,
bioavailability, bioequivalence) of a drug product as these factors
may relate to the safety or effectiveness of the drug product. An
applicant should consider all relevant CDER guidance documents for
recommendations on the information that should be submitted to
support a given change.4
CDER has published guidances,
including the SUPAC (scale-up and postapproval changes) guidances,
that provide recommendations on reporting categories. To the extent
that the recommendations on reporting categories in
this guidance are found to be inconsistent with guidances published
before this guidance was finalized, the recommended reporting
categories in such previously published guidances are superseded by
this guidance. This guidance does not provide extensive
recommendations on reporting categories for components and
composition changes (see section V). Therefore, recommended
reporting categories for components and composition changes provided
in previously published guidances, such as the SUPAC guidances,
still apply. Section 506A of the Act and §
314.70(c) provide for two types of changes-being-effected
supplements (see section II), while previously there was only one
type. It is important for applicants to use this guidance to
determine which type of changes-being-effected supplement is
recommended. CDER intends to update the previously published
guidances to make them consistent with this guidance.
If guidance for either recommended
reporting categories or information that should be submitted to
support a particular change is not available, the appropriate CDER
chemistry or microbiology review staff can be consulted for advice.
FDA's guidance documents, in
general, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required. Insofar as this guidance adjusts
reporting categories pursuant to section 506A of the Federal Food,
Drug, and Cosmetic Act and 21 CFR 314.70, it does have binding
effect. If you have any questions about the effect of any portion of
this guidance, contact the Office of Pharmaceutical Science, Center
for Drug Evaluation and Research (HFD-003), Food and Drug
Association, 5600 Fishers Lane, Rockville, MD 20857.
II. REPORTING CATEGORIES
Section 506A of the Act and
§ 314.70
provide for four reporting categories that are distinguished in the
following paragraphs.
A major change is a
change that has a substantial potential to have an adverse effect on
the identity, strength, quality, purity, or potency of a drug
product as these factors may relate to the safety or effectiveness
of the drug product. A major change requires the submission of a
supplement and approval by FDA prior to distribution of the drug
product made using the change. This type of supplement is called,
and should be clearly labeled, a Prior Approval Supplement
(§
314.70(b)). An applicant may ask FDA to expedite its review of a
prior approval supplement for public health reasons (e.g., drug
shortage) or if a delay in making the change described in it would
impose an extraordinary hardship on the applicant. This type of
supplement is called, and should be clearly labeled, a Prior
Approval Supplement - Expedited Review Requested (§
314.70(b)(4)).5 FDA is most
likely to grant requests for expedited review based on extraordinary
hardship for manufacturing changes made necessary by catastrophic
events (e.g., fire) or by events that could not be reasonably
foreseen and for which the applicant could not plan.
A moderate change is a
change that has a moderate potential to have an adverse effect on
the identity, strength, quality, purity, or potency of the drug
product as these factors may relate to the safety or effectiveness
of the drug product. There are two types of moderate change. One
type of moderate change requires the submission of a supplement to
FDA at least 30 days before the distribution of the drug product
made using the change. This type of supplement is called, and should
be clearly labeled, a Supplement - Changes Being Effected in
30 Days (§
314.70(c)(3)). The drug product made using a moderate change cannot
be distributed if FDA informs the applicant within 30 days of
receipt of the supplement that a prior approval supplement is
required (§
314.70(c)(5)(i)). For each change, the supplement must contain
information determined by FDA to be appropriate and must include the
information developed by the applicant in assessing the effects of
the change (§
314.70(a)(2) and (c)(4)). If FDA informs the applicant within 30
days of receipt of the supplement that information is missing,
distribution must be delayed until the supplement has been amended
to provide the missing information (§
314.70(c)(5)(ii)).
FDA may identify certain moderate
changes for which distribution can occur when FDA receives the
supplement (§
314.70(c)(6)). This type of supplement is called, and should be
clearly labeled, a Supplement - Changes Being Effected.
If, after review, FDA disapproves a
changes-being-effected-in-30-days supplement or
changes-being-effected supplement, FDA may order the manufacturer to
cease distribution of the drug products made using the disapproved
change (§
314.70(c)(7)).
A minor change is a
change that has minimal potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product
as these factors may relate to the safety or effectiveness of the
drug product. The applicant must describe minor changes in its next
Annual Report (§
314.70(d)).
Under §
314.70(e), an applicant can submit one or more protocols (i.e.,
comparability protocols) describing tests, studies, and acceptance
criteria to be achieved to demonstrate the absence of an adverse
effect from specified types of changes. A comparability protocol can
be used to reduce the reporting category for specified changes. A
proposed comparability protocol that was not approved as part of the
original application must be submitted as a prior approval
supplement
(314.70(e)). On February 25, 2003,
FDA issued a draft guidance on comparability protocols entitled
Comparability protocols - Chemistry, Manufacturing, and Controls
Information.
III.
GENERAL REQUIREMENTS
Other than for editorial changes in
previously submitted information (e.g., correction of spelling or
typographical errors, reformatting of batch records), an applicant
must notify FDA about each change in each condition established in
an approved application beyond the variations already provided for
in the application (§
314.70(a)(1)).
A supplement or annual report must
include a list of all changes contained in the supplement or annual
report. On the list, FDA recommends that the applicant describe each
change in enough detail to allow FDA to quickly determine whether
the appropriate reporting category has been used. For supplements,
this list must be provided in the cover letter (§
314.70(a)(6)). In annual reports, the list should be included in the
summary section (§
314.81(b)(2)(i)). The applicant must describe each change fully in
the supplement or annual report (§
314.70(a)(1)).
An applicant making a change to an
approved application under section 506A of the Act must also conform
to other applicable laws and regulations, including current good
manufacturing practice (CGMP) requirements of the Act (21 U.S.C.
351(a)(2)(B)) and applicable regulations in Title 21 of the Code
of Federal Regulations (e.g., 21 CFR parts 210, 211, 314). For
example, manufacturers must comply with relevant CGMP validation and
recordkeeping requirements and ensure that relevant records are
readily available for examination by authorized FDA personnel during
an inspection.
A changes-being-effected supplement
providing for labeling changes under §
314.70(c)(6)(iii) must include 12 copies of the final printed
labeling (§
314.70(c)(1)). In accordance with
§ 314.70(a)(4),
an applicant also must promptly revise all promotional labeling and
drug advertising to make it consistent with any labeling change
implemented in accordance with §
314.70(b) or (c).
Except for supplements providing
only for a change in labeling, an applicant must include in each
supplement and amendment to a supplement a statement certifying that
a field copy has been provided in accordance with 21 CFR
314.440(a)(4)6 (§
314.70(a)(5)).
IV. ASSESSING THE EFFECT OF
MANUFACTURING CHANGES
A.
Assessment of the Effects
of the Change
The holder of an approved
application under section 505 of the Act must assess the
effects of the change before distributing a drug product made
with a manufacturing change (§
314.70(a)(2)).7 For each
change, the supplement or annual report must contain information
determined by FDA to be appropriate and must include the
information developed by the applicant in assessing the effects
of the change (section 506A(b), (c)(1), (d)(2)(A), and (d)(3)(A)
of the Act). The type of information that must be included in a
supplemental application or an annual report is specified in
§
314.70(b)(3), (c)(4), and (d)(3).
1.
Conformance to
Specifications
An assessment of the effects
of a change on the identity, strength, quality, purity, and
potency of the drug product should include a determination
that the drug substance intermediates, drug substance,
in-process materials, and/or drug product affected by the
change conform to the approved specifications.8
A specification is a quality standard (i.e., tests,
analytical procedures, and acceptance criteria) provided in an
approved application to confirm the quality of drug
substances, drug products, intermediates, raw materials,
reagents, components, in-process materials, container closure
systems, and other materials used in the production of a drug
substance or drug product. Acceptance criteria are
numerical limits, ranges, or other criteria for the tests
described (§
314.3(b)). Conformance to a specification means that the
material, when tested according to the analytical procedures
listed in the specification, will meet the listed acceptance
criteria.
2.
Additional Testing
In addition to confirming that
the material affected by manufacturing changes continues to
meet its specification, we recommend that the applicant
perform additional testing, when appropriate, to assess
whether the identity, strength, quality, purity, or potency of
the drug product as these factors may relate to the safety or
effectiveness of the drug product have been or will be
affected. The assessment should include, as appropriate,
evaluation of any changes in the chemical, physical,
microbiological, biological, bioavailability, and/or stability
profiles. This additional assessment could involve testing of
the postchange drug product itself or, if appropriate, the
material directly affected by the change. The type of
additional testing that an applicant should perform would
depend on the type of manufacturing change, the type of drug
substance and/or drug product, and the effect of the change on
the quality of the drug product. For example:
- Evaluation of changes in the
impurity or degradant profile could first involve profiling using
appropriate chromatographic techniques and then, depending on the
observed changes in the impurity profile, toxicology tests to
qualify a new impurity or degradant or to qualify an impurity that
is above a previously qualified level.9
- Evaluation of the hardness or
friability of a tablet after certain changes.
- Assessment of the effect of a
change on bioequivalence when required under 21 CFR part 320 could
include, for example, multipoint and/or multimedia dissolution
profiling and/or an in vivo bioequivalence study.
- Evaluation of extractables from
new packaging components or moisture permeability of a new container
closure system.
An applicant should refer to
all relevant CDER guidance documents for recommendations on
the information that should be submitted to support a given
change. If guidance for information that should be submitted
to support a particular change is not available, applicants
can consult the appropriate CDER chemistry or microbiology
review staff for advice.
B.
Equivalence
When testing is performed, the
applicant should usually assess the extent to which the
manufacturing change has affected the identity, strength,
quality, purity, and potency of the drug product. Typically this
is accomplished by comparing test results from pre- and
postchange material and determining if the test results are
equivalent. Simply stated: Is the drug product made after the
change equivalent to the drug product made before the change? An
exception to this general approach is that when bioequivalence
is redocumented for certain ANDA postapproval changes, FDA
recommends that the comparator be the reference listed drug.
Equivalence comparisons frequently have a criterion for
comparison with calculation of confidence intervals relative to
a predetermined equivalence interval. For this, as well as for
other reasons, equivalent does not necessarily mean
identical. Equivalence may also relate to maintenance of a
quality characteristic (e.g., stability) rather than a single
performance of a test.
C. Adverse Effect
Some manufacturing changes have
an adverse effect on the identity, strength, quality, purity, or
potency of the drug product. In many cases, the applicant
chooses not to implement these manufacturing changes, but
sometimes the applicant wishes to do so. If an assessment
indicates that a change has adversely affected the identity,
strength, quality, purity, or potency of the drug product,
FDA recommends that the change be submitted in a prior
approval supplement regardless of the recommended reporting
category for the change. For example, a process change
recommended for a changes-being-effected-in-30-days supplement
could cause the formation of a new degradant that requires
qualification and/or identification.10
The applicant's degradation qualification procedures may
indicate that there are no safety concerns relating to the new
degradant. Even so, we recommend that the applicant submit this
change in a prior approval supplement with appropriate
information to support the continued safety and effectiveness of
the drug product. During the review of the prior approval
supplement, the FDA will assess the impact of any adverse effect
on the drug product as this change may relate to the safety or
effectiveness of the drug product.
Applicants are encouraged to
consult with the appropriate CDER chemistry or microbiology
review staff if there are any questions on whether a change in a
characteristic would be viewed by CDER as adversely affecting
the identity, strength, quality, purity, or potency of the drug
product.
V. COMPONENTS AND COMPOSITION
Changes in the qualitative or
quantitative formulation, including inactive ingredients, as
provided in the approved application, are considered major changes
requiring a prior approval supplement, unless exempted by regulation
or guidance (§
314.70(b)(2)(i)). The deletion or reduction of an ingredient
intended to affect only the color of the drug product may be
reported in an annual report (§
314.70(d)(2)(ii)). Guidance on changes in components and composition
that may be submitted in a changes-being-effected supplement or
annual report is not included in this document because of the
complexity of the recommendations, but may be covered in one or more
guidance documents describing postapproval changes (e.g., SUPAC
documents).
VI.
MANUFACTURING SITES11
A.
General Considerations
CDER must be notified when a
manufacturer changes to a manufacturing site that is different
from those specified in the approved application (314.70(a)).
Sites can include those used by an applicant to (1) manufacture
or process drug products,12
in-process materials, drug substances, or drug substance
intermediates, (2) package drug products, (3) label drug
products, and (4) test components, drug product containers,
closures, packaging materials, in-process materials, or drug
products. Sites include those owned by the applicant or contract
sites used by an applicant. Testing sites include those
performing physical, chemical, biological, and microbiological
testing to monitor, accept, or reject materials, as well as
those performing stability testing. Sites used to label drug
products are considered those that perform labeling of the drug
product's primary or secondary packaging components. Sites
performing operations that place identifying information on the
dosage form itself (e.g., ink imprint on a filled capsule) are
considered to be facilities that manufacture or process the drug
product. FDA recommends that the supplement or annual report
identify whether the proposed manufacturing site is an
alternative to or replacement for the site or sites provided for
in the approved application.
FDA recommends that a move to a
different manufacturing site, when it is a type of site
routinely subject to FDA inspection, be submitted as a prior
approval supplement if the site does not have a
satisfactory CGMP inspection13
for the type of operation14
being moved (see sections VI.B.1 and 2).
For labeling, secondary
packaging, and testing site changes, the potential for adverse
effect on the identity, strength, quality, purity, or potency of
a drug product as these factors may relate to the safety or
effectiveness of the drug product is considered to be
independent of the type of drug product dosage form or specific
type of operation being performed. Therefore, the recommended
reporting category for any one of these manufacturing site
changes will be the same for all types of drug products and
operations. For manufacturing sites used to (1) manufacture or
process drug products, in-process materials, drug substances, or
drug substance intermediates or (2) perform primary packaging
operations, the potential for adverse effect depends on factors
such as the type of drug substance or drug product and operation
being performed. Therefore, recommended reporting categories may
differ depending on the type of drug product and operations.
Except for the situations
described in sections VI.B.4, VI.C.1.b, and VI.D.5, construction
activities at a manufacturing site or moving production
operations within a building or between buildings at the same
manufacturing site do not have to be reported to CDER.
We recommend that a move to a
manufacturing site that involves other changes (e.g., process,
equipment) be evaluated as a multiple related change (see
section XII) to determine the appropriate reporting category.
B.
Major Changes (Prior
Approval Supplement)
The following are examples of
changes considered to have a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. A move to a different
manufacturing site, except one used to manufacture or
process a drug substance intermediate, when the new
manufacturing site has never been inspected by FDA for the
type of operation that is being moved or the move results
in a restart at the new manufacturing site of a type of
operation that has been discontinued for more than two
years.
2. A move to a different
manufacturing site, except one used to manufacture or
process a drug substance intermediate, when the new
manufacturing site does not have a satisfactory CGMP
inspection for the type of operation being moved.
3. A move to a different
manufacturing site for (1) the manufacture, processing, or
primary packaging of drug products when the primary
packaging components control the dose delivered to the
patient or the formulation modifies the rate or extent of
availability of the drug, or (2) the manufacture or
processing of in-process materials with modified-release
characteristics. Examples of these types of drug products
include modified-release solid oral dosage forms,15
transdermal systems, liposomal drug products, depot drug
products, oral and nasal metered-dose inhalers (MDIs), dry
powder inhalers (DPIs), and nasal spray pumps.
4. Transfer of the
manufacture of an aseptically processed sterile drug
substance or aseptically processed sterile drug product to
(1) a newly constructed or refurbished aseptic processing
facility or area or (2) an existing aseptic processing
facility or area that does not manufacture similar
(including container types and sizes) approved drug
products. An example would be transferring the manufacture
of a lyophilized drug product to an existing aseptic
process area where no approved lyophilized drug products
are manufactured or where the approved lyophilized drug
products being manufactured have different container types
and/or sizes than the container of the drug product being
transferred. See section VI.C.1.b for recommendations for
other manufacturing site changes relating to aseptically
processed sterile drug substance or aseptically processed
sterile drug product.
5. Transfer of the
manufacture of a finished drug product sterilized by
terminal processes to a newly constructed facility at a
different manufacturing site. Once this change has been
approved, subsequent site changes to the facility for
similar drug product types and processes may be submitted
as a changes-being-effected-in-30-days supplement (see
section VI.C.1.a).
C. Moderate Changes
(Supplement - Changes Being Effected)
The following are examples of
changes considered to have a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product. If the new site
does not have a satisfactory CGMP inspection for the type of
operation being moved (see sections VI.B.1 and 2), then FDA
recommends that the changes listed below (excluding changes
relating to drug substance intermediate manufacturing sites) be
submitted in a prior approval supplement.
a. A move to a different
manufacturing site for the manufacture or processing of
any drug product, in-process material, or drug substance
that is not otherwise provided for in this guidance.
b. For aseptically
processed sterile drug substance or aseptically
processed sterile drug product, a move to an aseptic
processing facility or area at the same or different
manufacturing site except as provided for in section
VI.B.4.
c. A move to a different
manufacturing site for the primary packaging of (1) any
drug product that is not otherwise listed as a major
change and (2) modified-release solid oral dosage form
drug products.
d. A move to a different
manufacturing site for testing if (1) the test
procedures approved in the application or procedures
that have been implemented via an annual report are
used, (2) all postapproval commitments made by the
applicant relating to the test procedures have been
fulfilled (e.g., providing methods validation samples),
and (3) the new testing facility has the capability to
perform the intended testing.
A move to a different
manufacturing site for the manufacture or processing of
the final intermediate.
D. Minor Changes (Annual
Report)
The following are examples of
changes considered to have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product. If the new site
does not have a satisfactory CGMP inspection for the type of
operation being moved, then FDA recommends that the changes
listed below (excluding changes relating to drug substance
intermediate manufacturing sites) be submitted in a prior
approval supplement (see sections VI.B.1 and 2).
1. A move to a different
manufacturing site for secondary packaging.
2. A move to a different
manufacturing site for labeling.
3. A move to a different
manufacturing site for the manufacture or processing of
drug substance intermediates other than the final
intermediate.
4. A change in the
contract sterilization site for packaging components when
the process is not materially different from that provided
for in the approved application
5. A transfer of the
manufacture of a finished product sterilized by terminal
processes to a newly constructed building or existing
building at the same manufacturing site.
6. A move to a different
manufacturing site for the ink imprinting of solid oral
dosage form drug products.
VII. MANUFACTURING PROCESS
A. General Considerations
The potential for adverse
effects on the identity, strength, quality, purity, or potency
of a drug product as these factors may relate to the safety or
effectiveness of the drug product depends on the type of
manufacturing process and the changes being instituted for the
drug substance or drug product. In some cases, there may be a
substantial potential for adverse effect regardless of direct
testing of the drug substance or drug product for conformance
with the approved specification. When there is a substantial
potential for adverse effects, a change must be submitted in a
prior approval supplement (section 506A(c) of the Act).
B. Major Changes (Prior
Approval Supplement)
The following are examples of
changes considered to have a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. Changes that may affect
the controlled (or modified) release, metering or other
characteristics (e.g., particle size) of the dose
delivered to the patient, including the addition or
deletion of a code imprint by embossing, debossing, or
engraving on a modified-release solid oral dosage form.
2. Changes that may affect
drug product sterility assurance including, where
appropriate, process changes for sterile drug substances
and sterile packaging components. These include:
- Changes in the sterilization
method (e.g., gas, dry heat, irradiation). These include changes
from sterile filtered or aseptic processing to terminal
sterilization, or vice versa.
- Addition, deletion, or
substitution of sterilization steps or procedures for handling
sterile materials in an aseptic processing operation.
- Replacing sterilizers that
operate by one set of principles with sterilizers that operate by
another principle (e.g., substituting a gravity displacement steam
process with a process using superheated water spray).
- Addition to an aseptic processing
line of new equipment made of different materials (e.g., stainless
steel versus glass, changes between plastics) that will come in
contact with sterilized bulk solution or sterile drug components, or
deletion of equipment from an aseptic processing line.
- Replacing a Class 100 aseptic
fill area with a barrier system or isolator for aseptic filling.
Once this change has been approved, subsequent process changes for
similar product types in the same barrier system or isolator may be
submitted as a changes-being-effected-in-30-days supplement.
- Replacement or addition of lyophilization equipment of a different size that uses different
operating parameters or lengthens the overall process time.
- Changes from bioburden-based
terminal sterilization to the use of an overkill process, and vice
versa.
- Changes to aseptic processing
methods, including scale, that extend the total processing,
including bulk storage time, by more than 50 percent beyond the
validated limits in the approved application.
- Changes in sterilizer load
configurations that are outside the range of previously validated
loads.
- Changes in materials or pore size
rating of filters used in aseptic processing.
3. The following changes
for a natural product:16
- Changes in the virus or
adventitious agent removal or inactivation methods. This applies to
any material where such procedures are necessary, including drug
substance, drug product, reagents, and excipients.
- For drug substance and drug
product, changes in the source material (e.g., microorganism, plant)
or cell line.
- For drug substance and drug
product, establishment of a new master cell bank or seed.
4. Any fundamental change
in the manufacturing process or technology from that
currently used by the applicant. For example:
a. Drug product
- Dry to wet granulation or vice
versa.
- Change from one type of drying
process to another (e.g., oven tray, fluid bed, microwave).
b. Drug substance
- Filtration to centrifugation or
vice versa.
- Change in the route of synthesis
of a drug substance.
5. The following changes
for drug substance
- Any process change made after the
final intermediate processing step in drug substance manufacture.
- Changes in the synthesis or
manufacture of the drug substance that may affect its impurity
profile and/or the physical, chemical, or biological properties.
6. Addition of an ink code
imprint or change to or in the ink used for an existing
imprint code for a solid oral dosage form drug product
when the ink as changed is not currently used on
CDER-approved drug products.17
7. Establishing a new
procedure for reprocessing a batch of drug substance or
drug product that fails to meet the approved
specification.
C. Moderate Changes
(Supplement - Changes Being Effected)
The following are examples of
changes considered to have a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
a. For drug products,
any change in the process, process parameters, and/or
equipment except as otherwise provided for in this
guidance.
b. For drug substances,
any change in process and/or process parameters except
as otherwise provided for in this guidance.
c. For natural protein
drug substances and natural protein drug products:
- Any change in the process,
process parameters, and/or equipment except as otherwise provided
for in this guidance (e.g., section VII.B.5, VII.D.7).
- An increase or decrease in
production scale during finishing steps that involves different
equipment.
- Replacement of equipment with
equipment of different design that does not affect the process
methodology or process operating parameters.
d. For sterile drug
products, drug substances, and components, as
appropriate:
- Changes in dry heat depyrogenation processes for glass container systems for drug
substances and drug products that are produced by terminal
sterilization processes or aseptic processing.
- Changes to filtration parameters
for aseptic processing (including flow rate, pressure, time, or
volume, but not filter materials or pore size rating) when
additional validation studies for the new parameters should be
performed.
- Filtration process changes that
provide for a change from single to dual sterilizing filters in
series, or for repeated filtration of a bulk.
- Changes from one qualified
sterilization chamber to another for in-process or terminal
sterilization that result in changes to validated operating
parameters (time, temperature, F0, and others).
- Changes in scale of manufacturing
for terminally sterilized drug products that increase the bulk
solution storage time by more than 50 percent beyond the validated
limits in the approved application when bioburden limits are
unchanged.
e. For drug substances,
redefinition of an intermediate, excluding the final
intermediate, as a starting material.
a. A change in methods
or controls that provides increased assurance that the
drug substance or drug product will have the
characteristics of identity, strength, quality, purity,
or potency that it purports or is represented to
possess.
b. For sterile drug
products, elimination of in-process filtration performed
as part of the manufacture of a terminally sterilized
drug product.
D. Minor Changes (Annual
Report)
The following are examples of
changes considered to have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. For drug products,
changes to equipment of the same design and operating
principle and/or changes in scale except as otherwise
provided for in this guidance (e.g., section VII.C.1.c,
VII.D.7).
2. A minor change in an
existing code imprint for a dosage form. For example,
changing from a numeric to alphanumeric code.
3. Addition of an ink code
imprint or a change in the ink used in an existing code
imprint for a solid oral dosage form drug product when the
ink is currently used on CDER-approved drug products.
4. Addition or deletion of
a code imprint by embossing, debossing, or engraving on a
solid dosage form drug product other than a modified-
release dosage form.
5. A change in the order
of addition of ingredients for solution dosage forms or
solutions used in unit operations (e.g., granulation
solutions).
6. Changes in scale of
manufacturing for terminally sterilized drug products that
increase the bulk solution storage time by no more than 50
percent beyond the validated limits in the approved
application when bioburden limits are unchanged.
7. For natural protein
drug products and natural protein drug substances:
- An increase or decrease in
production scale during finishing steps that does not involve an
equipment change.
- Replacement of equipment with
equipment of the same design, operating principle, and capacity with
no change in production scale.
VIII. SPECIFICATIONS
A.
General Considerations
All changes in specifications
from those in the approved application must be submitted in a
prior approval supplement unless otherwise exempted by
regulation or guidance
(§
314.70(b)(2)(i)). Specifications (i.e., tests, analytical
procedures, and acceptance criteria) are the quality standards
provided in an approved application to confirm the quality of
drug substances, drug products, intermediates, raw materials,
reagents, components, in-process materials, container closure
systems, and other materials used in the production of a drug
substance or drug product. For the purpose of defining
specifications, acceptance criteria are numerical limits,
ranges, or other criteria for the tests described. Examples of a
test, an analytical procedure, and an acceptance criterion are,
respectively, an assay, a specific, fully described high
pressure liquid chromatography (HPLC) procedure, and a range of
98.0-102.0 percent. The recommendations in this section also
apply to specifications associated with sterility assurance that
are included in NDA and ANDA submissions.18
A regulatory analytical
procedure is the procedure in the approved application that is
designated for use in evaluating a defined characteristic of the
drug substance or drug product. Section 501(b) of the Act
recognizes the analytical procedures in the U.S. Pharmacopeia/National
Formulary (USP/NF) as the regulatory analytical procedures
for compendial items. Tests and associated acceptance criteria
and regulatory analytical procedures in addition to those
specified in the USP/NF may be required for approving compendial
items (section 505 of the Act).
The applicant may include in its
application alternatives to the approved regulatory
analytical procedures for testing the drug substance and drug
product. However, for purposes of determining compliance with
the Act, regulatory analytical procedures are used.
In sections B through D below,
the use of the term analytical procedure without a
qualifier such as regulatory or alternative refers
to an analytical procedure used to test materials other than the
drug substance or drug product.
B. Major Changes (Prior
Approval Supplement)
The following are examples of
changes in specifications considered to have a substantial
potential to have an adverse effect on the identity, strength,
quality, purity, or potency of a drug product as these factors
may relate to the safety or effectiveness of the drug product.
1. Relaxing an acceptance
criterion except as otherwise provided for in this
guidance (e.g., section VIII.C.1.b, VIII.C.1.e).
2. Deleting any part of a
specification except as otherwise provided for in this
guidance (e.g., section VIII.D.2).
3. Establishing a new
regulatory analytical procedure including designation of
an alternative analytical procedure as a regulatory
procedure.
4. A change in a
regulatory analytical procedure that does not provide the
same or increased assurance of the identity, strength,
quality, purity, or potency of the material being tested
as the regulatory analytical procedure described in the
approved application.
5. A change in an
analytical procedure used for testing components,
packaging components, the final intermediate, in-process
materials after the final intermediate, or starting
materials introduced after the final intermediate that
does not provide the same or increased assurance of the
identity, strength, quality, purity, or potency of the
material being tested as the analytical procedure
described in the approved application except as otherwise
noted. For example, a change from an HPLC procedure that
distinguishes impurities to (1) an HPLC procedure that
does not, (2) another type of analytical procedure (e.g.,
titrimetric) that does not, or (3) an HPLC procedure that
distinguishes impurities but the limit of detection and/or
limit of quantitation is higher.
6. Relating to testing of
raw materials for viruses or adventitious agents:19
(1) relaxing an acceptance criterion, (2) deleting a test,
or (3) a change in the analytical procedure that does not
provide the same or increased assurance of the identity,
strength, quality, purity, or potency of the material
being tested as the analytical procedure described in the
approved application.
C. Moderate Changes
(Supplement - Changes Being Effected)
The following are examples of
changes in specifications considered to have a moderate
potential to have an adverse effect on the identity, strength,
quality, purity, or potency of a drug product as these factors
may relate to the safety or effectiveness of the drug product.
a. Any change in a
regulatory analytical procedure other than those
identified as major changes or editorial changes.
b. Relaxing an
acceptance criterion or deleting a test for raw
materials used in drug substance manufacturing,
in-process materials prior to the final intermediate,
starting materials introduced prior to the final drug
substance intermediate, or drug substance intermediates
(excluding final intermediate) except as provided for in
section VIII.B.6.
c. A change in an
analytical procedure used for testing raw materials used
in drug substance manufacturing, in-process materials
prior to the intermediate, starting materials introduced
prior to the final drug substance intermediate, or drug
substance intermediates (excluding final intermediate)
that does not provide the same or increased assurance of
the identity, strength, quality, purity, or potency of
the material being tested as the analytical procedure
described in the approved application except as provided
for in section VIII.B.6.
d. Relaxing an
in-process acceptance criterion associated with
microbiological monitoring of the production
environment, materials, and components that are included
in NDA and ANDA submissions. For example, increasing the
microbiological alert or action limits for critical
processing environments in an aseptic fill facility or
increasing the acceptance limit for bioburden in bulk
solution intended for filtration and aseptic filling.
e. Relaxing an
acceptance criterion or deleting a test to comply with
an official compendium that is consistent with FDA
statutory and regulatory requirements (§
314.70(c)(2)(iii)).
a. An addition to a
specification that provides increased assurance that the
drug substance or drug product will have the
characteristics of identity, strength, quality, purity,
or potency that it purports or is represented to
possess. For example, adding a new test and associated
analytical procedure and acceptance criterion.
b. A change in an
analytical procedure used for testing components,
packaging components, the final intermediate, in-process
materials after the final intermediate, or starting
materials introduced after the final intermediate that
provides the same or increased assurance of the
identity, strength, quality, purity, or potency of the
material being tested as the analytical procedure
described in the approved application.
D. Minor Changes (Annual
Report)
The following are examples of
changes in specifications considered to have a minimal potential
to have an adverse effect on the identity, strength, quality,
purity, or potency of a drug product as these factors may relate
to the safety or effectiveness of the drug product.
1. Any change in a
specification made to comply with an official compendium,
except the changes described in section VIII.C.1.e, that
is consistent with FDA statutory and regulatory
requirements (§
314.70(d)(2)(i)).
2. For drug substance and
drug product, the addition or revision of an alternative
analytical procedure that provides the same or increased
assurance of the identity, strength, quality, purity, or
potency of the material being tested as the analytical
procedure described in the approved application or
deletion of an alternative analytical procedure.
3. Tightening of
acceptance criteria.
4. A change in an
analytical procedure used for testing raw materials used
in drug substance synthesis, starting materials introduced
prior to the final drug substance intermediate, in-process
materials prior to the final intermediate, or drug
substance intermediates (excluding final intermediate)
that provides the same or increased assurance of the
identity, strength, quality, purity, or potency of the
material being tested as the analytical procedure
described in the approved application.
IX. CONTAINER CLOSURE SYSTEM
A. General Considerations
The potential for adverse effect
on the identity, strength, quality, purity, or potency of a drug
product as these factors may relate to the safety or
effectiveness of the drug product when making a change to or in
the container closure system is generally dependent on the route
of administration of the drug product, performance of the
container closure system, and the likelihood of interaction
between the packaging component and the dosage form. In some
cases there may be a substantial potential for adverse effect,
regardless of direct drug product testing for conformance with
the approved specification.
A change to or in a packaging
component will often result in a new or revised specification
for the packaging component. This situation does not have to be
considered a multiple related change. Only the reporting
category for the packaging change needs to be considered.
B. Major Changes (Prior
Approval Supplement)
The following are examples of
changes considered to have a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. For liquid (e.g.,
solution, suspension, elixir) and semisolid (e.g., creams,
ointments) dosage forms, a change to or in polymeric
materials (e.g., plastic, rubber) of primary packaging
components, when the composition of the component as
changed has never been used in a CDER-approved drug
product of the same dosage form and same route of
administration. For example, a polymeric material that has
been used in a CDER-approved topical ointment would not be
considered CDER-approved for an ophthalmic ointment.
2. For liquid (e.g.,
solution, suspension, elixir) and semisolid (e.g., creams,
ointments) dosage forms in permeable or semipermeable
container closure systems, a change from an ink and/or
adhesive used on the permeable or semipermeable packaging
component to an ink or adhesive that has never been used
in a CDER-approved drug product of the same dosage form
and same route of administration and with
the same type of permeable or semipermeable packaging
component (e.g., low density polyethylene, polyvinyl
chloride).
3. A change in the primary
packaging components for any drug product when the primary
packaging components control20
the dose delivered to the patient (e.g., the valve or
actuator of a metered-dose inhaler).
4. For sterile drug
products, any change that may affect drug product
sterility assurance, such as:21
- A change from a glass ampule to a
glass vial with an elastomeric closure.
- A change to a flexible container
system (bag) from another container system.
- A change to a prefilled syringe
dosage form from another container system.
- A change from a single unit dose
container to a multiple dose container system.
- Changes that add or delete
silicone treatments to container closure systems (such as elastomeric closures or syringe barrels).
- Changes in the size and/or shape
of a container for a sterile drug product.
5. Deletion of a secondary
packaging component intended to provide additional
protection to the drug product (e.g., carton to protect
from light, overwrap to limit transmission of moisture or
gases) or a change in the composition of, or the addition
of, a secondary packaging component that may affect the
impurity profile of the drug product.
6. A change to a new
container closure system if the new container closure
system does not provide the same or better protective
properties than the approved container closure system.
C. Moderate Changes
(Supplement - Changes Being Effected)
The following are examples of
changes considered to have a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. Supplement - Changes Being
Effected in 30 Days
a. A change to or in a
container closure system, except as otherwise provided
for in this guidance, that does not affect the quality
of the drug product.
b. Changes in the size
or shape of a container for a sterile drug substance.
c. A change in the
number of units (e.g., tablets, capsules) or labeled
amount (e.g., grams, milliliters) of a nonsterile drug
product in a unit-of-use container.22
2. Supplement - Changes
Being Effected
a. A change in the size
and/or shape of a container for a nonsterile drug
product, except for solid dosage forms (see section
IX.D.2), without a change from one container closure
system to another (§ 314.70(c)(6)(ii)).
b. A change in the
labeled amount (e.g., grams, milliliters) of drug
product for a nonsterile drug product in a multiple-unit
container,23 except
for solid dosage forms (see section IX.D.3) .
D. Minor Changes (Annual
Report)
The following are examples of
changes considered to have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. A change in the
container closure system for a nonsterile drug product,
based on a showing of equivalency to the approved system
under a protocol approved in the application or published
in an official compendium (§ 314.70(d)(2)(v)).
2. A change in the size
and/or shape of a container for a nonsterile solid dosage
form (§
314.70(d)(2)(iv)).
3. A change in the number
of units (e.g., tablets, capsules) or labeled amount
(e.g., grams) of nonsterile solid dosage form in a
multiple-unit container.
4. The following changes
in the container closure system of solid oral dosage form
drug products as long as the new package provides the same
or better protective properties (e.g., light, moisture)
and any new primary packaging component materials have
been used in and been in contact with CDER-approved solid
oral dosage form drug products:24
-
Adding or changing a child-resistant closure, changing from a metal
to plastic screw cap, or changing from a plastic to metal screw cap.
- Changing from one plastic
container to another of the same type of plastic (e.g., high density
polyethylene (HDPE) container to another HDPE container).
- Changes in packaging materials
used to control odor (e.g., charcoal packets).
- Changes in bottle filler (e.g.,
change in weight of cotton or amount used) without changes in the
type of filler (e.g., cotton to rayon).
- Increasing the wall thickness of
the container.
- A change in or addition of a cap
liner.
- A change in or addition of a seal
(e.g., heat induction seal).
- A change in an antioxidant,
colorant, stabilizer, or mold releasing agent for production of the
container and/or closure to one that is used at similar levels in
the packaging of CDER-approved solid oral dosage form drug products.
- A change to a new container
closure system when the container closure system is already approved
in the NDA or ANDA for other strengths of the drug product.
5. The following changes
in the container closure system of nonsterile liquid drug
products as long as the new package provides the same or
better protective properties and any new primary packaging
component materials have been used in and been in contact
with CDER-approved liquid drug products with the same
route of administration (i.e., the material in contact
with a liquid topical should already have been used with
other CDER-approved liquid topical drug products):
- Adding or changing a
child-resistant closure, changing from a metal to plastic screw cap,
or changing from a plastic to metal screw cap.
- Increasing the wall thickness of
the container.
- A change in or addition of a cap
liner.
- A change in or addition of a seal
(e.g., heat induction seal).
6. A change in the
container closure system of unit dose packaging (e.g.,
blister packs) for nonsterile solid dosage form drug
products as long as the new package provides the same or
better protective properties and any new primary packaging
component materials have been used in and been in contact
with CDER-approved drug products of the same type (e.g.,
solid oral dosage form, rectal suppository).
7. The following changes
in the container closure system of nonsterile semisolid
drug products as long as the new package provides the same
or better protective properties and any new primary
packaging component materials have been used in and been
in contact with CDER-approved semisolid drug products:
- Changes in the closure or cap.
- Increasing the wall thickness of
the container.
- A change in or addition of a cap
liner.
- A change in or addition of a
seal.
- A change in the crimp sealant.
8. A change in the flip
seal cap color as long as the cap color is consistent with
any established color coding system for that class of drug
products.
X. LABELING
A. General Considerations
A drug product labeling change
includes changes in the package insert, package labeling, or
container label. In accordance with §
314.70(a)(4), an applicant must promptly revise all promotional
labeling and drug advertising to make it consistent with any
labeling change implemented in accordance with paragraphs (b) or
(c) of §
314.70. All labeling changes for ANDA drug products must be
consistent with section 505(j) of the Act.
B. Major Changes (Prior
Approval Supplement)
Any proposed change in the
labeling, except changes designated as moderate or minor by
regulation or guidance, must be submitted as a prior approval
supplement (§ 314.70(b)(2)(v)(A)).
If applicable, any change to a Medication Guide required under
21 CFR part 208, except for changes in the information specified
in §
208.20(b)(8)(iii) and (b)(8)(iv), must be submitted in a prior
approval supplement (§
314.70(b)(v)(B)). The following list contains some examples of
changes currently considered by CDER to fall into this reporting
category.
1. Changes based on
postmarketing study results, including, but not limited
to, labeling changes associated with new indications and
usage.
2. Change in, or addition
of, pharmacoeconomic claims based on clinical studies.
3. Changes to the clinical
pharmacology or the clinical study section reflecting new
or modified data.
4. Changes based on data
from preclinical studies.
5. Revision (expansion or
contraction) of population based on data.
6. Claims of superiority
to another drug product.
7. Change in the labeled
storage conditions, unless exempted by regulation or
guidance.
C. Moderate Changes
(Supplement - Changes Being Effected)
Under
§ 314.70(c)(6)(iii), a
changes-being-effected supplement must be submitted for any
labeling change that (1) adds or strengthens a contraindication,
warning, precaution, or adverse reaction, (2) adds or
strengthens a statement about drug abuse, dependence,
psychological effect, or
overdosage, (3) adds or strengthens an instruction about dosage
and administration that is intended to increase the safe use of
the drug product, (4) deletes false, misleading, or unsupported
indications for use or claims for effectiveness, or (5) normally
requires a supplement submission and approval prior to
distribution of the drug product that FDA specifically requests
be submitted under this provision. A changes-being-effected
supplement that provides for a labeling change under
§§
314.70(c)(6)(iii) must include 12 copies of final printed
labeling (§
314.70(c)(1)). The following list includes some examples of
changes currently considered by CDER to fall into this reporting
category.
1. Addition of an adverse
event due to information reported to the applicant or
Agency.
2. Addition of a
precaution arising out of a postmarketing study.
3. Clarification of the
administration statement to ensure proper administration
of the drug product.
D. Minor Changes (Annual
Report)
Labeling with editorial or
similar minor changes or with a change in the information
concerning the description of the drug product or information
about how the drug is supplied that does not involve a change in
the dosage strength or dosage form should be described in an
annual report (§
314.70(d)(2)(ix) and (d)((2)(x)) . The following list includes
some examples currently considered by CDER to fall into this
reporting category.
1. Changes in the layout
of the package or container label that are consistent with
FDA regulations (e.g., 21 CFR part 201) without a change
in the content of the labeling.
2. Editorial changes, such
as adding a distributor's name.
3. Foreign language
versions of the labeling if no change is made to the
content of the approved labeling and a certified
translation is included.
4. Labeling changes made
to comply with an official compendium.
XI. MISCELLANEOUS CHANGES
A. Major Changes (Prior
Approval Supplement)
The following are examples of
changes considered to have a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. Changes requiring
completion of studies in accordance with 21 CFR part 320
to demonstrate equivalence of the drug product to the drug
product as manufactured without the change or to the
reference listed drug
2. Addition of a stability
protocol or comparability protocol.
3. Changes to an approved
stability protocol or comparability protocol unless
otherwise provided for in this guidance (e.g., VIII.C,
VIII.D, XI.C.2).
4. An extension of an
expiration dating period based on (1) data obtained under
a new or revised stability testing protocol that has not
been approved in the application or (2) full shelf life
data on pilot scale batches using an approved protocol.
5. Changes to a drug
product under an application that is subject to a validity
assessment because of significant questions regarding the
integrity of the data supporting that application (§
314.70(b)(2)(viii)).
B. Moderate Changes
(Supplement - Changes Being Effected)
The following are examples of
changes considered to have a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
Reduction of an expiration
dating period to provide increased assurance of the
identity, strength, quality, purity, or potency of the
drug product. Extension of an expiration date that has
previously been reduced under this provision should be
submitted in a changes-being-effected-in-30-days
supplement even if the extension is based on data obtained
under a protocol approved in the application.
No changes have been identified.
C. Minor Changes (Annual
Report)
The following are examples of
changes considered to have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
1. An extension of an
expiration dating period based on full shelf life data on
production batches obtained under a protocol approved in
the application (§
314.70(d)(2)(vi)).
2. Addition of time points
to the stability protocol or deletion of time points
beyond the approved expiration dating period.
3. A change from
previously approved stability storage conditions to
storage conditions recommended in International Conference
on Harmonisation (ICH) guidances.
4. Non-USP reference
standards:
- Replacement of an in-house
reference standard or reference panel (or panel member) according to
procedures in an approved application.
- Tightening of acceptance criteria
for existing reference standards to provide greater assurance of
drug product purity and potency.
XII. MULTIPLE RELATED CHANGES
Multiple related changes involve
various combinations of individual changes. For example, a site
change may also involve equipment and manufacturing process changes
or a components and composition change may necessitate a change in a
specification. For multiple related changes where the recommended
reporting categories for the individual changes differ, CDER
recommends that the submission be in accordance with the most
restrictive of the categories recommended for the individual
changes. When the multiple related changes all have the same
recommended reporting category, CDER recommends that the submission
be in accordance with the reporting category for the individual
changes.
ATTACHMENT A:
MANUFACTURING SITES
All owners or operators of all drug
establishments (not exempt by regulation) that engage in the
manufacture, preparation, propagation, compounding, or processing of
a drug or drugs are required to register with the FDA (21 CFR
207.20). An establishment means a place of business under one
management at one general physical location (§
207.3(a)(7)). A general physical location is reasonably
construed to include separate buildings within the same city
if the activities in the buildings are closely related to
the same business enterprise, are under the supervision of the same
local management, and are all inspected at the same time (ORA Field
Management Directive No. 132).
For the purposes of determining the
reporting category for moves between buildings, the terms same
manufacturing site and different manufacturing site mean:
Domestic Establishments
Same manufacturing site:
- The new and old buildings are
included under the same drug establishment registration number25
and
- The same FDA district office is
responsible for inspecting the operations in both the new and old
buildings.
Different manufacturing site:
- The new and old buildings have
different drug establishment registration numbers
or
- Different FDA district offices
are responsible for inspecting operations in the new and old
buildings.
For domestic establishments, the
terms same manufacturing site and different
manufacturing site supersede the terms contiguous campus,
same campus, and different campus as used in the SUPAC
guidances.
Foreign Establishments
Foreign establishments are not
currently required to register with the FDA. On May 14, 1999, FDA
published a proposed rule to require registration of foreign
establishments (64 FR 26330). Until registration of foreign
establishments is required, same and different manufacturing sites
mean:
Same manufacturing site:
- A contiguous or unbroken site or
a set of buildings in adjacent city blocks.
Different manufacturing site:
- The new and old buildings
are not on a contiguous site or not in adjacent city blocks.
ATTACHMENT B: TYPE
OF OPERATION AND CGMP INSPECTIONS
Section VI states that a change to a
different manufacturing site should be submitted in a prior approval
supplement when (1) the new manufacturing site has never been
inspected by FDA for the type of operation being moved, (2) the move
results in a restart at the new manufacturing site of a type of
operation that has been discontinued for more than two years, or (3)
the new
manufacturing site does not have a
satisfactory current good manufacturing practice (CGMP) inspection
for the type of operation being moved.
A profile class system is
used by FDA to assist in (1) managing the CGMP inspection process,
(2) evaluating the findings and the compliance follow-up needed, and
(3) communicating the results of inspections. A profile class can
relate to the manufacture of a particular dosage form (e.g., large
volume parenterals, oral liquids), type of drug substance (e.g.,
sterile bulk by chemical synthesis), or specific function performed
at a site (e.g., control testing laboratory). There are profile
class codes for major categories of drug substance processes, dosage
forms, and manufacturing functions (see table below). However, the
system is not comprehensive for all operations performed in the
pharmaceutical industry (see not elsewhere classified (NEC) profile
class code).
The term type of operation
refers to the specialized or even unique conditions and practices
that are employed to manufacture a class or category of drug
substance or drug product or to perform a limited segment of the
manufacturing process. These conditions and practices exist and are
performed within the framework of CGMPs, along with general
conditions and practices that contribute to the manufacture of all
drug products at a given manufacturing site. The conditions and
practices, both general and specific, are inspected to evaluate the
CGMP acceptability of a manufacturing site. A wide variety of
classes or categories of drug substances and drug products may be
produced at a manufacturing site, or the manufacturing site may only
produce a single class of drug substance and/or drug product or
perform a limited segment of a manufacturing process. Each type of
operation is represented by a profile class code.
Generally, a satisfactory CGMP
status for a profile class code is used to communicate a
satisfactory CGMP clearance for all of the products and for all of
the operations included within the category that code represents.
Thus the profile class code for a particular dosage form or type of
drug substance is used to communicate the CGMP status for all
aspects of manufacturing, processing, packing, or holding that are
performed at the specific manufacturing site relating to that
particular dosage form or type of drug substance, including
packaging and labeling operations, testing, and quality control. The
profile class code for a particular dosage form or type of drug
substance is also used to communicate the CGMP status for
manufacturing sites that produce in-process material (e.g.,
controlled-release beads), package drug products, or label drug
products, even if these are stand-alone (e.g., contractor)
operations.
A few profile class codes that
describe certain types of operations (see items in boldface in
table) are provided to report the CGMP status for contractor firms
whose only function in the manufacturing process is to perform this
operation. If one of these operations (e.g., steam sterilization
process) is performed at the manufacturing site involved in
producing the drug product/drug substance, the CGMP status for that
operation is reported as part of the profile class code for the
particular dosage form or type of drug substance. For example, a
manufacturing site producing a terminally sterilized small volume
parenteral drug product would be reported with the profile class
code for the dosage form (SVT), not by the profile code for the
sterilization process (SSP).
Certain inspections may be required
by program priorities even if the rating for a profile class code
indicates an acceptable CGMP status. The current profile
codes/classes for human drugs are:
ADM |
Aerosol dispensed medication |
NEC |
Not
elsewhere classified (when using this class, specific drug
products are noted) |
CBI |
Biotechnology crude drug |
OIN |
Ointment, nonsterile (includes cream, jelly, paste) |
CEX |
Plant/animal extraction crude drug |
POW |
Powders (includes oral and topical) |
CFS |
Sterile bulk by fermentation crude drug |
RAD |
Radiopharmaceutical |
CFN |
Nonsterile bulk by fermentation crude drug |
RSP |
Radiation sterilization process |
CHG |
Capsule, prompt release |
SNI |
Sterile noninjectable |
CRU |
Crude
bulk drugs-nonsynthesized |
SOP |
Soap |
CSG |
Capsules, soft gelatin |
SSP |
Steam sterilization process |
CSN |
Nonsterile bulk by chemical synthesis |
SUP |
Suppositories |
CSP |
Chemical sterilization process |
SVL |
Small
volume parenterals (lyophilized) |
CSS |
Sterile bulk by chemical synthesis |
SVS |
Sterile-filled small volume parenterals |
CTL |
Control testing laboratories |
SVT |
Terminally sterilized small volume parenteral |
CTR |
Capsules, modified-release |
TCM |
Tablets, prompt-release |
GAS |
Medical gas (includes liquid oxygen and other) |
TCT |
Tablets, delayed-release |
GSP |
Gas
sterilization process |
TDP |
Transdermal patches |
HSP |
Dry
heat sterilization process |
TSP |
Fractional (tyndallization) sterilization process |
LIQ |
Liquid
(includes solutions, suspension, elixirs, and tinctures) |
TTR |
Tablets, extended-release |
LVP |
Large
volume parenterals |
WSP |
Water sterilization process |
CGMP inspectional status, based on
the profile class, is available through FDA's Freedom of Information
(FOI) Office. (See Glossary under Satisfactory Current Good
Manufacturing Practice (CGMP) Inspection for more information
regarding FOI requests.)
Examples of postapproval
manufacturing site changes and recommended reporting categories:
- An applicant wants to move the
manufacture of an immediate-release tablet (TCM) to a different
manufacturing site that currently manufactures, and has
satisfactory CGMP status for, capsules (CHG) and powders for oral
solution (POW). This manufacturing site change should be submitted
in a prior approval supplement because the new manufacturing site
does not have a satisfactory CGMP inspection for immediate-release
tablets.
- An applicant wants to contract
out packaging operations for immediate-release tablets (TCM) and
capsules (CHG) and modified-release capsules (CTR). The potential
contract packager has a satisfactory CGMP status for
immediate-release and modified-release capsules but has never
packaged immediate-release tablets. The packaging site change for
the immediate-release tablet drug products should be submitted in
a prior approval supplement. The packaging site change for the
capsule drug products should be submitted as recommended in
section VI of this guidance for packaging sites with a
satisfactory CGMP inspection.
- An applicant wishes to
consolidate product testing to a single analytical laboratory at a
manufacturing site. This manufacturing site produces various solid
oral dosage form drug products, has an operational analytical
laboratory currently at the site, and satisfactory CGMP
inspections for the manufacturing occurring at the facility. Some
of the drug products that will be tested at the analytical
laboratory when the consolidation occurs are not solid oral dosage
form products. Unlike most other production operations, testing
laboratories (and other operations in boldface in the table) are
not inspected on a dosage form/type of drug substance specific
basis. The satisfactory CGMP inspection of the analytical
laboratory, which was performed as part of the CGMP inspection for
manufacture of the solid oral dosage form drug products, is
considered to apply to all dosage forms, including those not
actually produced at the site. The consolidation can be submitted
in a changes-being-effected-in-30-days supplement if the change is
consistent with the recommendations in section VI.C.1.d.
ATTACHMENT C:
CDER-APPROVED DRUG PRODUCTS
In several places throughout the
guidance, different reporting categories are proposed for changes to
or the addition of certain components based on whether the
component/material has been used in and has been in contact with
CDER-approved drug products. Different reporting categories are
recommended once CDER has reviewed certain components/materials in
association with a drug product approval because similar subsequent
changes then have a reduced potential to have an adverse effect on
the identity, strength, quality, purity, or potency of a drug
product as these factors may relate to the safety or effectiveness
of the drug product. For example, certain changes in the container
closure systems of solid oral dosage form drug products may be
included in an annual report as long as the new package provides the
same or better protective properties and any new primary packaging
component materials have been used in and been in contact with
CDER-approved solid oral dosage form drug products (see section
IX.D.4). If the new primary packaging component material has not
been used in or has not been in contact with CDER-approved solid
oral dosage form drug products, then submission of the change in an
annual report is not recommended.
CDER-approved drug products are
considered those drug products subject to an approved NDA or ANDA.
Some information on which components/materials are used in
CDER-approved products is available from the Agency (e.g., FDA,
CDER, Inactive Ingredient Guide, 1996, Division of Drug
Information Resources). When information is not available, an
applicant should use reliable sources of information to determine
that the component or material has been used in and has been in
contact with a CDER-approved drug product of the same dosage form
and route of administration, as appropriate. The applicant should
identify in the supplement or annual report the basis for the
conclusion that the component or material is used in a CDER-approved
drug product.
If an applicant cannot confirm that
a component or material has been used in and has been in contact
with a CDER-approved drug product of the same dosage form and route
of administration, the applicant has the option of submitting the
change for a single NDA or ANDA using the higher recommended
reporting category and, after approval, submitting similar changes
for other NDAs and ANDAs using the lower recommended reporting
category.
GLOSSARY
Acceptance Criteria:
Numerical limits, ranges, or other criteria for the tests described
(21 CFR 314.3(b)).
Active Ingredient/Drug Substance:
Any component that is intended to furnish pharmacological activity
or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of a disease, or to affect the structure or
any function of the human body, but does not include intermediates
used in the synthesis of such ingredient. The term includes those
components that may undergo chemical change in the manufacture of
the drug product and are present in the drug product in a modified
form intended to furnish the specified activity or effect (21 CFR
210.3(b)(7) and 314.3(b)).
Assess the Effects of the Change:
To evaluate the effects of a manufacturing change on the identity,
strength, quality, purity, and potency of a drug product as these
factors may relate to the safety or effectiveness of the drug
product (21 CFR 314.3(b)).
Container Closure System: The
sum of packaging components that together contain and protect the
dosage form. This includes primary packaging components and
secondary packaging components if the latter are intended to provide
additional protection to the drug product.
Component: Any ingredient
intended for use in the manufacture of a drug product, including
those that may not appear in such drug product (21 CFR 210.3(b)(3)).
Drug Product: A finished
dosage form, for example, tablet, capsule, or solution, that
contains an active ingredient generally, but not necessarily, in
association with inactive ingredients (21 CFR 210.3(b)(4)).
Final Intermediate: The last
compound synthesized before the reaction that produces the drug
substance. The final step forming the drug substance involves
covalent bond formation or breakage3B ionic bond formation (i.e.,
making the salt of a compound) does not qualify. Consequently, when
the drug substance is a salt, the precursors to the organic acid or
base, rather than the acid or base itself, should be considered the
final intermediate.
Inactive Ingredient:
Any intended component of the drug product other than an active
ingredient.
In-process Material: Any
material fabricated, compounded, blended, or derived by chemical
reaction that is produced for, and used in, the preparation of the
drug product (21 CFR 210.3(b)(9)). For drug substance, in-process
materials are considered those materials that are undergoing change
(e.g., molecular, physical).
Intermediate: A material that
is produced during steps of the synthesis of a drug substance and
undergoes further molecular change before it becomes a drug
substance.
Package: The container
closure system and labeling, associated components (e.g., dosing
cups, droppers, spoons), and external packaging (e.g., cartons,
shrink wrap).
Packaging Component: Any
single part of a container closure system.
Primary Packaging Component:
A packaging component that is or may be in direct contact with the
dosage form.
Reference Listed Drug: The
listed drug identified by FDA as the drug product on which an
applicant relies in seeking approval of its abbreviated application
(21 CFR 314.3(b)).
Satisfactory Current Good
Manufacturing Practice (CGMP) Inspection: A satisfactory CGMP
inspection is an FDA inspection during which (1) no objectionable
conditions or practices were found (No Action Indicated (NAI)) or
(2) objectionable conditions were found, but voluntary corrective
action is left to the firm and the objectionable conditions will not
be the subject of further administrative or regulatory actions
(Voluntary Action Indicated (VAI)).
Information about the CGMP status of
a firm may be obtained by requesting a copy of the Quality Assurance
Profile (QAP) from the FDA's Freedom of Information (FOI) Office.
The QAP contains information on the CGMP compliance status of firms
that manufacture, package, assemble, repack, relabel, or test human
drugs, devices, biologics, and veterinary drugs. All FOI requests
must be in writing (21 CFR 20.40(a)) and should be prepared
following the instructions found in the reference entitled A
Handbook for Requesting Information and Records from FDA. An
electronic version of this reference is available on the Internet at
http://www.fda.gov/opacom/backgrounders/foiahand.html
Secondary Packaging Component:
A packaging component that is not and will not be in direct contact
with the dosage form.
Specification: The quality
standard (i.e., tests, analytical procedures, and acceptance
criteria) provided in an approved application to confirm the quality
of drug substances, drug products, intermediates, raw materials,
reagents, components, in-process materials, container closure
systems, and other materials used in the production of a drug
substance or drug product (21 CFR 314.3(b)).
1 This guidance has been prepared
under the direction of the Chemistry, Manufacturing and Controls
Coordinating Committee in the Center for Drug Evaluation and
Research (CDER) at the Food and Drug Administration (FDA).
Paperwork Reduction Act Public
Burden Statement: This guidance contains information collection
provisions that are subject to review by the Office of Management
and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44
U.S.C. 3501-3520). The collection(s) of information in this guidance
were approved under OMB Control No. 0910-0538 (until August 31,
2005).
2 FDA is currently revising the 1997
guidance and intends to issue it in draft for public comment.
3 Public Law 105-115.
4 A list of CDER guidances is
available on the Internet at
http://www.fda.gov/cder/guidance/index.htm
5 Internal Agency policies and
procedures relating to processing requests for expedited review of
supplements to approved ANDAs and NDAs are documented in CDER's
Manual of Policies and Procedures (MAPP) at 5240.1 and 5310.3,
respectively. MAPPs can be located on the Internet at
http://www.fda.gov/cder/mapp.htm
6 Mailing information for field
copies is provided in 21 CFR 314.440(a)(4). FDA recommends that the
applicant's home FDA district office referred to in the
regulations be the district office where the applicant's
headquarters is located.
7 Assess the effects of the
change means to evaluate the effects of a manufacturing change
on the identity, strength, quality, purity, and potency of a drug
product as these factors relate to the safety or effectiveness of
the drug product. The terms assess or assessment as
used in this guidance are not the same as validation. Certain
validation information, such as for sterilization processes, is
considered information that is needed to assess the effect of the
change as specified in §
314.70(a)(2) and should be submitted in an NDA or ANDA. Unless
otherwise specified by FDA, validation (e.g., process, equipment)
data need not be submitted in the application, but should be
retained at the facility and be available for review by FDA at the
Agency's discretion under CGMPs.
8 If a specification needs to be
revised as a result of the change, this would be considered a
multiple change (see sections VIII and XII).
9 Recommendations on identifying,
qualifying, and reporting impurities can be found in relevant
guidances (e.g., ICH Q3B Impurities in New Drug Products
(November 1996)).
10 Recommendations on identifying,
qualifying, and reporting impurities can be found in relevant
guidances.
11 See Attachment A for a discussion
of the definition of same manufacturing site and different
manufacturing site.
12 Manufacturing or processing drug
product would also include the preparation (e.g., sterilization,
depyrogenation, irradiation, washing) by the applicant or
applicant's contractor of container closure systems or packaging
components. Changes in the site used to fabricate packaging
components (e.g., bottles) or manufacture packaging materials (e.g.,
resins) need not be reported to CDER if there are no other changes
(e.g., dimensions, compositions, processing aids). If other changes
occur, the reporting category should be based on the recommended
reporting categories for these changes (i.e., the manufacturing site
change does not need to be considered when determining the
appropriate reporting category).
13 See Glossary for a definition of
satisfactory CGMP inspection.
14 See Attachment B for a discussion
of the term type of operation.
15 Certain operations relating to
the manufacture, processing, or primary packaging of
modified-release solid oral dosage form drug products need not be
reported in a prior approval supplement (see sections VI.C.1.c and
VI.D.6).
16 For the purposes of this
guidance, natural product refers to materials (e.g., drug
substance, excipients) that are derived from plants, animals, or
microorganisms, and that are subject to approval under section 505
of the Act. The specific recommendations for natural products are
not applicable to inorganic compounds (e.g., salts, minerals).
17 See Attachment C for a discussion
of CDER-approved drug products.
18 See FDA guidance for industry on
the Submission of Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products
(November 1994).
19 In this context, testing for
adventitious agents is not considered to include tests that are
found in an official compendium (e.g., USP <61>).
20 A container closure system that
is considered to control the dose delivered to the patient is a
container closure system where the system itself, rather than a
person, regulates the amount of drug product ultimately delivered to
a patient. A container closure system where a person controls the
amount of drug product administered or that allows verification that
the appropriate amount has been administered (e.g., number of
tablets, milliliters of liquid) is not considered a container
closure system that controls the dose delivered to the patient.
21 Some of these identified changes,
depending on the circumstances, may have to be submitted as original
NDAs or ANDAs instead of as supplements. Applicants can consult the
appropriate CDER chemistry division/office if there are questions.
22 A unit-of-use container is one
that contains a specific quantity of a drug product and is intended
to be dispensed to the patient without further modification except
for the addition of appropriate labeling.
23 A multiple-unit container is a
container that permits withdrawal of successive portions of the
contents without changing the strength, quality, or purity of the
remaining portion. This type of container is not distributed
directly to patients but is used by health care practitioners who
dispense the drug product in smaller amounts to a patient in
accordance with a physician's instructions.
24 For sections IX.D.4 to IX.D.7,
changes in the container closure system that result in drug product
contact with a component material that has never been used in any
CDER-approved drug product of the same type should be submitted as a
changes-being-effected-in-30-days supplement (section IX.C.1) or
prior approval supplement (section IX.B.1).
25 The registration number is the
number assigned to the establishment as part of the registration
process (e.g., ORA Field Management Directive No. 92).
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