- INTRODUCTION
Sections 314.70 and 601.12 of Title 21 of the Code of
Federal Regulations (21 CFR 314.70 and 601.12) prescribe the
requirements for the reporting to FDA of changes to the
approved applications for licensed biological products and
approved drug products.
Under §§ 601.12 and 314.70(g), a change to a product,
production process, quality controls, equipment, or
facilities is required to be reported to FDA in: 1) a
supplement requiring approval prior to distribution; 2) a
supplement at least 30 days prior to distribution of the
product made using the change; or 3) in an annual report,
depending on its potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the
product as they may relate to the safety or effectiveness of
the product. Before distributing a product made using a
change, the regulations require applicants to demonstrate,
through appropriate validation and/or other clinical or non-clinical
laboratory studies, the lack of adverse effect of
the change on the identity, strength, quality, purity, or
potency of the product as they may relate to its safety or
effectiveness.
The three reporting categories for changes to an approved
application are defined in § 601.12 and § 314.70(g): 1)
those changes that have a substantial potential to have an
adverse effect on the identity, strength, quality, purity,
or potency of the product as they may relate to the safety
or effectiveness of the product, which require submission of
a supplement and approval by FDA prior to distribution of
the product made using the change; 2) changes that have a
moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the
product as they may relate to the safety or effectiveness
of the product, which require submission of a supplement to
FDA at least 30 days prior to distribution of the product
made using the change; and 3) changes that have a minimal
potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product,
which are to be described by the applicant in an annual
report. Section 314.70(g) applies only to recombinant DNA-derived
protein/polypeptide products approved under the
Federal Food, Drug, and Cosmetic Act (FDCA) and complexes or
conjugates of a drug with a monoclonal antibody approved
under the FDCA.
For licensed biologics subject to § 601.12, changes to a
product package label, container label, and package insert
require either: (1) submission of a supplement with FDA
approval needed prior to product distribution; (2)
submission of a supplement with product distribution allowed
at the time of submission of the supplement; or (3)
submission of the final printed label in an annual report.
These requirements are now harmonized fully for drugs and
biologics.
Under § 601.12(f)(4), changes to advertising and promotional
labeling for licensed biological products must be made in
accordance with the provisions of 21 CFR 314.81(b)(3)(i),
which requires the submission to FDA of specimens of mailing
pieces and any other labeling or advertising devised for
promotion of a drug product at the time of initial
dissemination of the labeling, and at the time of initial
publication of the advertisement for a prescription drug
product. Mailing pieces and labeling that are designed to
contain samples of a drug product are required to be
complete, except the sample of the drug product may be
omitted from the container. Each submission to the Center
for Biologics Evaluation and Research (CBER) should be
accompanied by a completed transmittal Form FDA-2567, or,
when it is made available, the revised Form FDA-2253.
This guidance applies only to specified biotechnology and
specified synthetic biological products, including
recombinant DNA-derived protein/polypeptide products
approved under the FDCA and complexes or conjugates of a
drug with a monoclonal antibody approved under the FDCA, or
biological products licensed under the Public Health Service
(PHS) Act and outlined in 21 CFR 601.2(c). The section on
labeling applies only to licensed biological products. This
guidance is intended to assist manufacturers in determining
which reporting mechanism is appropriate for a change to an
approved application for such products.
In addition to the requirements in 21 CFR 601.12 and
314.70(g), an applicant making a change to an approved
application must conform to other applicable law and
regulations, including the current good manufacturing
practice (CGMP) requirements of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 351(a)(2)(B)) and applicable
regulations in 21 CFR parts 210, 211, 600 through 680, and
820. For example, manufacturers must comply with record-keeping
requirements and ensure that relevant records are
readily available for examination by authorized FDA
personnel during an inspection.
Under each subsection of the guidance, FDA describes a
category of changes to be reported under 601.12 and
314.70(g). FDA also provides a listing of various changes
that FDA currently believes fall under each category.
Table of Contents
- CHANGES UNDER §§ 601.12(b) AND 314.70(g)(1) - Changes
requiring supplement submission and approval prior to
distribution of the product made using the change
(major changes).
Under §§ 601.12(b) and 314.70(g)(1), changes to a product,
production process, quality controls, equipment, or
facilities that have a substantial potential to have an
adverse effect on the identity, strength, quality, purity,
or potency of the product as they may relate to its safety
or effectiveness require submission of a supplement and
approval by FDA before a product made using the change is
distributed. For a change under this category, an applicant
is required to submit a supplement to the license
application that includes a detailed description of the
proposed change; the products involved; the manufacturing
site(s) or area(s) affected; a description of the methods
used and studies performed to evaluate the effect of the
change on the product's identity, strength, quality, purity,
or potency as they may relate to its safety or
effectiveness; the data derived from those studies; relevant
validation protocols and data; and a reference list of
relevant standard operating procedures (SOPs). The
applicant must obtain approval of the supplement by FDA
prior to distribution of the product made using the change.
In FDA's experience, the following changes to a product,
production process, quality controls, equipment, or
facilities have caused detrimental effects on the identity,
strength, quality, purity, or potency of products as they
relate to the products' safety or effectiveness even where
applicants performed validation or other studies. FDA
believes that these changes have a substantial potential to
have an adverse effect on a product's identity, strength,
quality, purity, or potency as they may relate to its safety
or effectiveness and that the agency's continued premarket
review and approval of such changes is currently necessary
to protect the public from products whose identity,
strength, quality, purity, potency, safety, or effectiveness
may be compromised.
- Process changes including, but not limited to,
- extension of culture growth time leading to
significant increase in number of cell doublings
beyond validated parameters;
- new or revised recovery procedures;
- new or revised purification process, including a
change in a column;
- a change in the chemistry or formulation of
solutions used in processing;
- a change in the sequence of processing steps or
addition, deletion, or substitution of a process
step; or
- reprocessing of a product without a previously
approved reprocessing protocol.
- Any change in manufacturing processes or analytical
methods that
- results in change(s) of specification limits or
modification(s) in potency, sensitivity,
specificity, or purity;
- establishes a new analytical method;
- deletes a specification or an analytical method;
- eliminates tests from the stability protocol; or
- alters the acceptance criteria of the stability
protocol.
- Scale-up requiring a larger fermentor, bioreactor,
and/or purification equipment (applies to production up
to the final purified bulk).
- Change in the composition or dosage form of the product
or ancillary components (e.g., new or different
excipients, carriers, or buffers).
- New lot of, new source for, or different, in-house
reference standard or reference panel (panel member)
resulting in modification of reference specifications
or an alternative test method.
- Extension of the expiration dating period and/or a
change in storage temperature, container/closure
composition, or other conditions, other than changes
based on real time data in accordance with a stability
protocol in the approved application.
- Change of the site(s) at which manufacturing, other
than testing, is performed, addition of a new location,
or contracting of a manufacturing step in the approved
application, to be performed at a separate facility.
- Conversion of production and related area(s) from
single to multiple product manufacturing area(s).
(Addition of products to a multiple product
manufacturing area could be submitted as a "Supplement-
Changes Being Effected in 30 Days" if there are no
changes to the approved and validated cleaning and
changeover procedures and no additional containment
requirements).
- Changes in the location (room, building, etc.) of steps
in the production process which could affect
contamination or cross contamination precautions.
Table of Contents
- CHANGES UNDER §§ 601.12(c) AND 314.70(g)(2) - Changes
requiring supplement submission at least 30 days prior
to distribution of the product made using the change.
Under §§ 601.12(c) and 314.70(g)(2), changes to a product,
production process, quality controls, equipment, or
facilities that have a moderate potential to have an
adverse effect on a product's identity, strength, quality,
purity, or potency as they may relate to its safety or
effectiveness require submission of a supplement to FDA at
least 30 days prior to distribution of the product made
using the change. The requirements for the contents of
these supplements are the same as for those requiring
approval prior to distribution.
Some examples of changes to the product, production process,
quality controls, equipment, and facilities that FDA
currently considers to have moderate potential to have an
adverse effect on a product's identity, strength, quality,
purity, or potency as they may relate to its safety or
effectiveness are set forth in the following list which FDA
has developed based on experience gained in reviewing
submissions received in the past.
- Addition of duplicated process chain or unit
process, such as a fermentation process or
duplicated purification columns, with no change in
process parameters.
- Addition or reduction in number of pieces of equipment
(e.g., centrifuges, filtration devices, blending
vessels, columns, etc.) to achieve a change in
purification scale not associated with a process
change.
- Manufacture of an additional product in a previously
approved multiple product manufacturing area using the
same equipment and/or personnel, if there have been no
changes to the approved and validated cleaning and
changeover procedures and there are no additional
containment requirements.
- Change in the site of testing from one facility to
another (e.g., from a contract lab to the
applicant; from an existing contract lab to a new
contract lab; from the applicant to a new contract
lab).
- Change in the structure of a legal entity that would
require issuance of a new license(s), or change in name
of the legal entity or location that would require
reissuance of the license(s)(applies only to licensed
biological products).
As described in §§ 314.70(g)(2)(v) and 601.12(c)(5), in
certain circumstances FDA may determine that, based on
experience with a particular type of change, the supplement
for such change is usually complete and provides the proper
information. Likewise, there may be particular assurances
that the proposed change has been appropriately submitted,
such as when the change has been validated in accordance
with a previously approved protocol. In these
circumstances, FDA may determine that the product made using
the change may be distributed at the time of receipt of the
supplement by FDA. The following are changes that in FDA's
experience have been submitted properly with the appropriate
information, and could be implemented under
§§ 314.70(g)(2)(v) and 601.12(c)(5) at the time of receipt of
the supplement by FDA without a previously approved
comparability protocol.
- Addition of release tests and/or specifications or
tightening of specifications for intermediates.
- Minor changes in fermentation batch size using the same
equipment and resulting in no change in specifications
of the bulk or final product.
In addition, applicants that use the protocol described in
§§ 314.70(g)(4) and 601.12(e)to validate a proposed change
may request that a change usually subject to supplement
submission and approval prior to distribution be reported as
a change subject to supplement submission at least 30 days
prior to distribution of the product made using the change,
or as a "Changes Being Effected" supplement submission, in
which event the product made using the change may be
distributed immediately upon receipt of the supplement by
FDA.
Table of Contents
- CHANGES UNDER §§ 601.12(d) AND 314.70(g)(3) - Changes
to be described in an annual report (minor changes).
Under §§ 601.12(d) and 314.70(g)(3), changes to the product,
production process, quality controls, equipment, or
facilities that have minimal potential to have an adverse
effect on a product's identity, strength, quality, purity,
or potency as they may relate to its safety or effectiveness
are required to be documented in an annual report submitted
each year within 60 days of the anniversary date of approval
of the application for a biological product and in the next
annual report required under § 314.81(b)(2)(iv)(b) for drug
products approved under the FDCA. For changes under this
category, the applicant is required to submit in the annual
report a list of all products involved; and a full
description of the manufacturing and controls changes
including: the manufacturing site(s) or area(s) involved,
the date each change was made, a cross-reference to relevant
validation protocol(s) and/or SOPs, and relevant data from
studies and tests performed to evaluate the effect of the
change on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or
effectiveness of the product.
Some examples of changes that FDA currently considers to
have minimal potential to have an adverse effect on a
product's identity, strength, quality, purity, or potency as
they may relate to its safety or effectiveness are listed
below. The list is not all-inclusive but contains items
that, in FDA's experience reviewing supplements, have caused
few instances in which an adverse effect on the product's
identity, strength, quality, purity, or potency as they may
relate to its safety or effectiveness has been observed.
- Increase in aseptic manufacturing scale for finished
product without change in equipment, e.g., increased
number of vials filled.
- Modifications in analytical procedures with no change
in the basic test methodology or existing release
specifications provided the change is supported by
validation data.
- Change in harvesting and/or pooling procedures which
does not affect the method of manufacture, recovery,
storage conditions, sensitivity of detection of
adventitious agents, or production scale.
- Replacement of an in-house reference standard or
reference panel (or panel member) according to SOPs and
specifications in an approved application.
- Tightening of specifications for existing reference
standards to provide greater assurance of product
purity and potency.
- Establishment of an alternate test method for reference
standards, release panels, or product intermediates,
except for release testing of intermediates licensed
for further manufacture.
- Establishment of a new Working Cell Bank derived
from a previously approved Master Cell Bank
according to an SOP on file in the approved
license application.
- Change in the storage conditions of in-process
intermediates, which does not affect labeling, based on
data from a stability protocol in an approved
application.
- Change in shipping conditions (e.g., temperature,
packaging, or custody) based on data derived from
studies following a protocol in the approved
application.
- A change in the stability test protocol to include more
stringent parameters (e.g., additional assays or
tightened specifications).
- Addition of time points to the stability protocol.
- Change in the simple floor plan that does not affect
production process or contamination precautions.
- Trend analyses of release specification testing results
for bulk drug substances and drug products obtained
since the last annual report.
Table of Contents
- COMPARABILITY PROTOCOLS UNDER §§ 601.12(e) AND 314.70(g)(4)
The comparability protocol described in §§ 601.12(e) and
314.70(g)(4) is a supplement that establishes the tests to
be done and acceptable limits to be achieved to demonstrate
the lack of adverse effect for specified types of
manufacturing changes on the safety and effectiveness of a
product. A new comparability protocol, or a change to an
existing one, requires approval prior to implementation
because it may result in decreased reporting requirements
for the changes covered. In general, a decrease in
reporting requirement will be one reporting tier, e.g., from
supplement with distribution of product in 30 days to annual
report, or from prior approval supplement to supplement with
distribution of product in 30 days. In some cases the decrease may
be greater. The reporting category will be
established at the time that the comparability protocol is
approved. FDA intends to issue further guidance on the use
of such protocols in the near future.
Table of Contents
- CHANGES UNDER § 601.12(f) - Labeling changes.
This section applies only to licensed biological products.
Under § 601.12(f), changes to labeling are required to be
submitted to CBER in one of the following ways: (1) As a
supplement requiring FDA approval prior to distribution of a
product with the labeling change; (2) as a supplement
requiring FDA approval but permitting distribution of a
product bearing such change prior to FDA approval; or (3) in
an annual report. Some examples of changes to labeling that
CBER currently considers to be appropriate for submission in
each of these three categories are listed below. These
lists are not intended to be comprehensive. Pursuant to
§ 601.12(f)(4), promotional labeling and advertising must be
submitted to CBER at the time of initial dissemination or
publication.
- Changes under § 601.12(f)(1) - Labeling changes
requiring supplement submission - FDA approval
must be obtained before distribution of a product
with the labeling change.
Under § 601.12(f)(1), any proposed change in the
package insert, package label, or container label,
except those described in 601.12(f)(2) and (3), is
required to be submitted as a supplement and receive
FDA approval prior to distribution of a product with
the label change. In such a supplement, the applicant
is required to present clearly the proposed change in
the label and the information necessary to support the
proposed change. The following list contains some
examples of changes that are currently considered by
CBER to fall into this reporting category.
- Changes based on postmarketing study results,
including, but not limited to, labeling changes
associated with new indications and usage.
- Change in, or addition of, pharmacoeconomic claims
based on clinical studies.
- Changes to the clinical pharmacology or the
clinical study section reflecting new or modified
data.
- Changes based on data from preclinical studies.
- Revision (expansion or contraction) of population
based on data.
- Claims of superiority to another product.
- Changes under § 601.12(f)(2) - Labeling changes
requiring supplement submission - product with a
labeling change that may be distributed before FDA
approval
Under § 601.12(f)(2), a supplement is required to be
submitted for any change to a package insert, package
label, or container label that adds or strengthens a
contraindication, warning, precaution, or adverse
reaction; adds or strengthens a statement about abuse,
dependence, psychological effect, or overdosage; adds
or strengthens an instruction about dosage and
administration that is intended to increase the safety
of the use of the product; or deletes false,
misleading, or unsupported indications for use or
claims for effectiveness. The applicant may distribute
product with a label bearing such a change at the time
the supplement is submitted, although the supplement is
still subject to approval by FDA. The following list
includes some examples of changes that are currently
considered by FDA to fall into this reporting category.
- Addition of an adverse event due to information
reported to the applicant or Agency.
- Addition of a precaution arising out of a post-marketing
study.
- Clarification of the administration statement to
ensure proper administration of the product.
- Changes under § 601.12(f)(3) - Labeling changes
requiring submission in an annual report.
Under § 601.12(f)(3), a package insert, package label,
or container label with editorial or similar minor
changes or with a change in the information on how the
drug is supplied that does not involve a change in the
dosage strength or dosage form is required to be
described in an annual report. Some examples that are
currently considered by FDA to fall into this reporting
category include:
- Changes in the layout of the package or container
label without a change in content of the labeling.
- Editorial changes such as adding a distributor's
name.
- Foreign language versions of the labeling, if no
change is made to the content of the approved
labeling and a certified translation is included.
