Guidance for Industry
Changes to an Approved Application: Biological Products
[PDF version of this document]
Additional copies of this guidance document are available from:
Office of Communication, Training and Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research (CBER)
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 1-800-835-4709 or 301-827-1800
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
July 1997
TABLE OF CONTENTS
- INTRODUCTION
- CHANGES UNDER 21 CFR 601.12(b)
Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes)
- CHANGES UNDER 601.12(c)
Changes requiring supplement submission at least 30 days
prior to distribution of the product made using the change.
- CHANGES UNDER 601.12(d)
Changes to be described in an annual report (minor changes).
- COMPARABILITY PROTOCOLS UNDER 601.12(e)
- CHANGES UNDER 601.12(f)
Labeling changes.
- Changes under 601.12(f)(1) - Labeling changes requiring
supplement submission - FDA approval must be obtained
before distribution of the product with the labeling change.
- Changes under 601.12(f)(2) - Labeling changes requiring
supplement submission - product with a labeling change
may be distributed before FDA approval.
- Changes under 601.12(f)(3) - Labeling changes requiring
submission in an annual report.
GUIDANCE FOR INDUSTRY
Changes to an Approved Application: Biological Products
This guidance document represents FDA's current thinking on changes to an approved application for all licensed biological products, except the specified biotechnology and specified synthetic biological products listed in 601.2(c). It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. |
- INTRODUCTION
Frequently, a licensed applicant determines that it is appropriate to make a change in the product, labeling,
production process, quality controls, equipment, facilities, or responsible personnel established in the approved license application(s). Section 601.12 of Title 21 of the Code of Federal Regulations (21 CFR 601.12) prescribes the requirements for reporting such changes for licensed biological products to FDA.
Under 601.12, a change to a product, production process, quality controls, equipment, facilities, or responsible
personnel 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) an annual report,
depending on its potential to have an adverse effect on the identity, strength, quality, purity, or potency of the
biological product as they may relate to the safety or effectiveness of the product. Before distributing a product
made using a change, applicants are required 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 as they may relate to the safety or effectiveness of the product.
The three reporting categories for changes to an approved application are defined in 601.12: 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 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.
Under 601.12(f), 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.
Under 601.12(f)(4), changes to advertising and promotional labeling 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 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 to all licensed biological products, including Whole Blood, blood components, Source Plasma, and Source Leukocytes, but not including the specified biotechnology and specified synthetic biological products
listed in 21 CFR 601.2(c) (see Guidance to Industry - Changes To An Approved Application For Specified
Biotechnology And Specified Synthetic Biological Products), and to all licensed establishments, including contract
locations. This guidance is intended to assist manufacturers in determining which reporting mechanism is appropriate for a change to an approved license application.
In addition to the requirements in 21 CFR 601.12, an applicant making a change to an approved license 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 this guidance, FDA describes a
category of changes to be reported under 601.12. FDA also
provides a listing of various changes that FDA currently
believes fall under each category. Additional changes
applicable only to Whole Blood, blood components, Source
Plasma, and Source Leukocytes are listed separately. A
separate section on labeling describes those labeling
changes to be submitted as supplements requiring prior
approval, supplements submitted at the time the change is
made, and submission in an annual report.
Table of Contents
- CHANGES UNDER 601.12(b) - Changes requiring supplement
submission and approval prior to distribution of the
product made using the change (major changes).
Under 601.12(b), changes to a product, production process,
quality controls, equipment, facilities, or responsible
personnel 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 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 approved 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, and potency of the product 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). As noted, 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, facilities,
or responsible personnel have caused detrimental effects on
the identity, strength, quality, purity, or potency of
products as they related to the safety or effectiveness of
the product even where applicants performed validation or
other studies. FDA believes that these changes would
generally 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.
Biological Products Including Whole Blood, Blood Components,
Source Plasma, and Source Leukocytes:
- 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
biological 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 license
application.
- Installation of a new Water For Injection (WFI)
system; or modifications to an existing WFI system
that would have a significant potential to stress
or challenge the system, such as
- lengthy or complicated distribution system
extensions to service new or remote production
areas;
- use of components of lesser quality or function;
- expansions of ambient temperature water
distribution loops; or
- conversion from hot loop to ambient loop.
- Change of the site(s) at which manufacturing,
other than testing, is performed; addition of a
new location (including donor centers
manufacturing platelets and/or performing
automated pheresis procedures); or contracting of
a manufacturing step in the approved license, 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.
- Major construction, or changes in location,
involving or affecting environmentally controlled
manufacturing or related support areas, such as:
- new buildings;
- new production areas or rooms in existing
buildings;
- aseptic processing areas;
- modifications to support systems with significant
potential to affect air, water, or steam quality;
- installation of a new HVAC system involving or
affecting environmentally controlled manufacturing
or related support areas; or
- modifications to an existing HVAC system that
supplies aseptic processing areas.
Whole Blood, Blood Components, Source Plasma, and Source
Leukocytes:
- Change in SOPs in the following categories:
- donor suitability, including donor deferral;
- blood collection, including arm preparation;
- high risk behavior questions/AIDS information;
- donor history forms, including informed
consent;
- product manufacturing; or
- quarantine and disposition of unsuitable product.
- Process changes; e.g., leukoreduction; irradiation;
freezing/deglycerolizing/rejuvenating; manual to
automated collection of Source Plasma, Fresh
Frozen Plasma, or platelets; immunization
programs; disease-state (as opposed to disease-associated)
or high risk donor collections.
Table of Contents
- CHANGES UNDER 601.12(c) - Changes requiring supplement
submission at least 30 days prior to distribution of
the product made using the change.
Under 601.12(c), changes to a product, production process,
quality controls, equipment, facilities, or responsible
personnel 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 require submission of a
supplement to FDA at least 30 days prior to distribution of
a product made using the change. The requirements for the
content 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, facilities, and responsible
personnel that FDA currently considers to have 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 are
set forth in the following list, which FDA has developed
based on experience gained in reviewing submissions received
in the past.
Biological Products Including Whole Blood, Blood Components,
Source Plasma, and Source Leukocytes:
- Automation of one or more process steps without a
change in process methodology.
- 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.
- Change in the fill volume (per vial) from an
approved production batch size and/or scale
(excludes going from single dose to multidose vial
or change in product concentration, both of which
should be submitted as a supplement requiring
prior approval).
- Changes in responsible individuals specified in
the approved application, including manufacturers'
representatives, responsible experts, and other
individuals designated to communicate with CBER.
- Modification of an approved manufacturing facility
or room(s) that is not likely to have an adverse
effect on safety, sterility assurance, purity, or
potency of product; e.g., adding new interior
partitions or walls to increase control over the
environment.
- 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 license
holder; from an existing contract lab to a new
contract lab; from the license holder to a new
contract lab).
- Change in the structure of a legal entity that
would require issuance of new license(s), or
change in name of the legal entity or location
that would require reissuance of license(s).
- Computer process control for steps to replace manual
process control.
- Downgrade of room or area environmental quality
classification except for aseptic processing areas.
- Installation of a new, or modification to an existing,
Purified Water system, not including pretreatment
systems for WFI.
Whole Blood, Blood Components, Source Plasma, and Source
Leukocytes:
- Change in automated collection equipment used in
plasmapheresis.
- Change in mailing address, move of a donor center
at which blood components are prepared, move of an
establishment, or temporary or permanent closure
of a facility.
- Off-site storage, in a location listed in the
establishment license application, of product for
which a supplement is pending.
- Alternate procedure request (under 640.120) where
there are published FDA recommendations/criteria.
- Infrequent donor collection variance at blood
establishment.
As described in 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 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.
- Modifications to an existing HVAC system involving
or affecting environmentally controlled
manufacturing or related support areas, but not
aseptic processing areas, with no change in air
quality.
In addition, applicants that use the protocol described in
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) - Changes to be described in
an annual report (minor changes).
Under 601.12(d), changes to the product, production
process, quality controls, equipment, facilities, or
responsible personnel that have 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 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 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 the
identity, strength, quality, purity, or potency of the
product as they may relate to the safety or effectiveness of
the product 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.
Biological Products Including Whole Blood, Blood Components,
Source Plasma, and Source Leukocytes:
- Addition of equipment for manufacturing processes
which is identical to the primary system and
serves as an alternate resource within an approved
production room or area.
- Upgrade or minor corrective change to production
air handling, water, or steam supply systems using
equipment of same or similar materials of
construction, design and operating parameters, and
not affecting established specifications; e.g.,
removal of dead legs in water for injection (WFI)
system. (Does not include replacement of parts or
routine repair and maintenance which would not be
changes to an approved application and would not
need to be reported).
- Relocation of analytical testing laboratories
between areas specified in the license.
- Room upgrades, such as installation of improved
finishes on floors/walls.
- Installation of non-process-related equipment or
rooms to improve the facility, such as warehousing
refrigerators or freezers.
- 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 license
application.
- Tightening of specifications for existing
reference standards to provide greater assurance
of product purity, identity, 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 based on data from a stability
protocol in an approved license application, which
does not affect labeling, except for changes in
storage conditions which are specified by
regulation (see 21 CFR Part 640).
- Change in shipping conditions (e.g., temperature,
packaging, or custody) based on data derived from
studies following a protocol in the approved
license application (except for changes in
shipping conditions that are required by
regulation to be submitted as a supplement, see 21
CFR 600.15(b)).
- 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.
- Replacement of equipment with that of identical
design and operating principle involving no change
in process parameters.
- Upgrade in air quality, material, or personnel
flow where product specifications remain
unchanged. Involves no change in equipment or
physical structure of production rooms.
- Relocation of equipment within an approved operating
room, rearrangement of the operating area or rooms
where production is performed or relocation of
equipment to another approved area to improve
product/personnel/raw material flow and improve
segregation of materials with no change in room air
classification.
- Modifications to the pretreatment stages of a WFI
system, including Purified Water systems used solely
for pretreatment in WFI production.
- 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.
Whole Blood, Blood Components, Source Plasma, and Source
Leukocytes:
- Organizational and facilities changes which have
occurred since the last report.
- A listing of all facilities, including self-contained
collection vehicles.
- Current Organizational chart, including
descriptive job titles and names. The chart
should be sufficiently detailed to clearly
demonstrate areas of responsibility of managerial
staff.
- List of contractual agreements in effect since the
last annual report. This should contain the name
of the contractor, the contractor's FDA license
and/or registration number, and a description of
the service or product provided. Include
contractual agreements for those involved in the
manufacturing process; for example, testing
laboratories, contract apheresis services,
contract donor collection services, suppliers of
red blood cells for immunization, emergency
treatment services, and short supply vendors. Contracts
for blood bags, apheresis soft goods, or reagents
should not be reported.
- Change in "doing business as" name that does not
affect licensed establishment name.
- Change in computer system in conformance with FDA
guidance.
- Implementation of an FDA-approved uniform
procedure (e.g., uniform donor history form or
Circular of Information); implementation of FDA
recommendations contained in memoranda to blood
establishments.
- Unexpected antibodies produced in immunization
programs.
- Addition of a new fixed blood collection site at
which only donor suitability and Whole Blood
collection are performed and for which the site is
identified as an auxiliary facility to the
licensed establishment on Form FDA 2830.
Table of Contents
- COMPARABILITY PROTOCOLS UNDER 601.12(e)
The comparability protocol described in 601.12(e) 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 an 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.
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 the
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 distributing 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 FDA 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.
- Change in container labels for licensed blood.
- Changes under 601.12(f)(2) - Labeling changes
requiring supplement submission - product with a
labeling change 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 applicant or FDA.
- 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.
Table of Contents
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