[Federal Register Volume 60, Number 66 (Thursday, April 6, 1995)]
[Notices]
[Pages 17535-17538]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-8382]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 95D-0052]
Changes To Be Reported for Product and Establishment License
Applications; Guidance
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a guidance
document entitled ``Changes to be Reported for Product and
Establishment License Applications; Guidance.'' The guidance document
is intended to provide manufacturers of licensed biological products
guidance on changes in manufacturing procedures and establishments
which may be implemented with and without prior approval by the
Director, Center for Biologics Evaluation and Research (CBER). This
document does not apply to manufacturers of Whole Blood, blood
components, Source Leukocytes, and Source Plasma, and it does not
address labeling changes. By following this guidance document,
manufacturers of licensed biologicals may, in some instances, reduce
their reporting burden and facilitate implementation of certain
changes.
DATES: Written comments may be submitted at any time.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857. Comments should be identified with the docket
number found in brackets in the heading of this document. Two copies of
any comments are to be submitted except that individuals may submit one
copy. A copy of the guidance document and received comments are
available in the Dockets Management Branch between 9 a.m. and 4 p.m.,
Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Stephen M. Ripley, Center for
Biologics Evaluation and Research (HFM-635), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-594-
3074.
SUPPLEMENTARY INFORMATION: Under Sec. 601.12 Changes to be reported (21
CFR 601.12), manufacturers are required to report important proposed
changes in location, equipment, management and responsible personnel,
or in manufacturing methods and labeling, of any product for which a
license is in effect or for which an application for license is
pending, to the Director, CBER. Such reports are to be filed by the
manufacturer not less than 30 days in advance of the time that such
changes are intended to be made except in case of an emergency.
Proposed changes in manufacturing methods and labeling may not become
effective until notification of acceptance is received from the
Director, CBER.
Reporting changes under Sec. 601.12 represents a significant
workload for the industry and the agency. In addition, regulated
industry has expressed concern about delays in implementing changes and
inconsistencies in reporting requirements for product license
applications (PLA's), establishment license applications (ELA's), and
new drug applications (NDA's). To reduce the reporting burden on
manufacturers of biological products and to facilitate the approval
process, FDA is issuing this guidance document, which describes CBER's
current interpretation of Sec. 601.12(a) and (b).
The guidance document is not intended to affect the reporting
requirements currently specified in Sec. 601.12, but to provide
clarifying descriptions of the types of changes that are currently
considered to be ``important'' within the meaning of that section. In
addition, the document clarifies the types of changes which may be
implemented 30 days after submission of a supplement and those which
must await approval of a supplement prior to implementation. Thus, the
guidance document outlines three categories for reporting changes,
based on the importance and nature of the changes. The document lists
examples of changes that would fall into each category.
This document does not apply to changes in manufacturing processes
and facilities associated with the manufacture of Whole Blood, blood
components, Source Leukocytes, or Source Plasma. CBER is currently
evaluating reporting requirements in those areas. In addition, the
guidance document does not address labeling changes. However, in the
Federal Register of August 3, 1994 (59 FR 39570), FDA published a
notice of availability for the revised Office of Establishment
Licensing and Product Surveillance Advertising and Promotional Labeling
Staff (APLS) Procedural Guidance Document. The APLS Procedural Guidance
document details the approach that manufacturers and distributors
should follow in submitting advertising and promotional material for
review by CBER. The APLS Procedural Guidance Document also provides
guidance on CBER's current interpretation of Sec. 601.12 as it applies
to reporting important proposed changes in labeling; specifically,
promotional labeling of biological products for which a license is in
effect or for which an application for a license is pending.
As with other guidance documents, FDA does not intend this document
to be all inclusive. The document is intended to provide information
and does not set forth requirements. Manufacturers may follow the
guidance or may choose to use alternative procedures even though they
are not provided in this document. If a manufacturer chooses to use
alternative procedures, that manufacturer may wish to discuss the
matter further with CBER to prevent expenditure of resources on
activities that FDA may later determine to be unacceptable.
This guidance document is not binding on either FDA or licensed
manufacturers of biological products and does not create or confer any
rights, privileges, or benefits for or on any person.
Interested persons may submit to the Dockets Management Branch
(address above) written comments on the guidance document. Received
comments will be considered to determine if further revision to the
guidance document is necessary.
The text of the guidance document follows: [[Page 17536]]
Food and Drug Administration, Center for Biologics Evaluation and
Research (CBER), Changes to be Reported for Product and Establishment
License Applications; Guidance
I. Introduction and Background
A significant number of supplements to approved biological
product and establishment license applications submitted to CBER
during an average year involve changes which fall under Sec. 601.12
Changes to be reported (21 CFR 601.12).
Under this regulation, important proposed changes in location,
equipment, management and responsible personnel, or in manufacturing
methods and labeling, are required to be reported to CBER not less
than 30 days in advance of the time such changes are intended to be
made (Sec. 601.12(a)). Proposed changes in manufacturing methods and
labeling may not become effective until notification of acceptance
is received from the Director, CBER (Sec. 601.12(b)).
This document is not intended to affect the reporting
requirements in Sec. 601.12, but to provide clarifying descriptions
of those requirements. This guidance does not apply to manufacturers
of Whole Blood, blood components, Source Leukocytes, and Source
Plasma. Guidance on reporting requirements in those areas is
currently under evaluation within CBER. In addition, this document
does not address labeling changes. For guidance on the submission of
advertising and promotional material, see the Office of
Establishment Licensing and Product Surveillance Advertising and
Promotional Labeling Staff (APLS) Procedural Guidance Document
(August 1994).
To facilitate the approval process, CBER performed a review of
the types of changes being reported and assessed the relative impact
of each change on product purity, potency, and safety. Results of
this analysis have provided CBER the rationale for describing three
categories of changes based on potential effect on product safety,
purity, and potency, with each category associated with a different
notification mechanism. In general, the types of changes for which
CBER recommends less stringent reporting represent changes which,
for the most part, have not been associated with demonstrable
effects on product purity, potency, or safety, and/or which are
readily amenable to on-site scrutiny during inspection of the
production facility. In many instances, manufacturers will need to
evaluate changes addressed in the three categories using validated
standard operating procedures (SOP's) or specifications.
Regardless of whether a supplement is required to be filed, the
manufacturer in making such changes must conform to the current good
manufacturing practice (CGMP) requirements of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) and the regulations
in 21 CFR parts 210 and 211. Changes affecting the method of
manufacture require validation under the CGMP regulations. In
addition, manufacturers must comply with the recordkeeping
requirements under the CGMP regulations and ensure that relevant
records are readily available for FDA inspection.
This document identifies and categorizes the types of changes in
manufacturing processes and establishments which may be implemented
with and without prior approval by CBER.
This guidance document is not binding on either FDA or licensed
manufacturers of biological products and does not create or confer
any rights, privileges, or benefits for or on any person. It does,
however, describe CBER's current interpretation of Sec. 601.12.
Where this document reiterates a requirement imposed by statute or
regulation, the force and effect as law of the requirement is not
changed in any way by virtue of its inclusion in this document.
Section A of this document contains general definitions of each
category of change as it pertains to notification or reporting
requirements outlined in Sec. 601.12(a) and (b). This section also
defines a Periodic Report for Category I changes. Section B of this
document provides instruction on sending submissions to CBER.
Section C of this document augments these definitions with selected
examples of modifications appropriately falling under each category.
Section D of this document contains guidance on categorizing
proposed changes which may not be listed in section C. Section E of
this document discusses the kind of information the agency is asking
manufacturers to submit in a Periodic Report.
II. Guidance and Rationale
A. Definitions
General definitions of each category of reporting changes are as
follows:
1. Category I--Change(s) for Which No Supplement Submission is Required
and Which May be Described in a Periodic Report
This category includes modifications to procedures, process
parameters, components, manufacturing methods, reagents, equipment
and facilities which do not rise to the level of the ``important''
changes required to be reported under Sec. 601.12. These are changes
that are designed to tighten control on the production process, or
have not been associated with adverse impact on product safety,
purity or potency. Manufacturers should qualify and, as necessary,
validate such changes before implementing them. These changes should
be shown not to affect the integrity of the product. For this
category, the manufacturer generates and retains all relevant data
defining (and, as necessary, validating) changes which are
implemented. In order to expedite the agency's review of changes,
such data should be readily accessible for FDA-establishment
inspections. The agency recommends that the firm notify CBER in a
Periodic Report (see description below) of the changes and dates of
implementation.
2. Category II--Change(s) Requiring a Supplement Submission and Which
May be Implemented Prior to CBER Approval
This category includes modifications to location, equipment,
management, and personnel that do not change manufacturing methods,
but have the potential to adversely affect product safety, purity,
and potency. For these changes, the manufacturer should submit a
standard supplement, accompanied by all relevant supporting data,
with a request to implement not less than 30 days following the
supplement's receipt by CBER's Document Control Center. Such
supplements should be clearly marked ``Category II Supplement,
Changes to be Implemented'' at the top of the cover letter. CBER
will confirm the submission and its receipt date in the reference
number assignment letter. CBER intends to follow relevant
application review policies in assigning supplement review.
CBER will process Category II changes as establishment or
product license application supplements and will take official
action on such supplements on, before, or after this 30-day period.
If CBER officials do not contact the sponsor via telephone or
written correspondence within 30 days following the documented
receipt date to question or reject the ``Category II'' status, the
manufacturer may implement the change. CBER may communicate with the
firm during this 30 day period for clarification or to advise that
the change is considered to be a Category III supplement (see
description below).
Manufacturers should be aware that Category II changes are
implemented subject to agency approval. The agency may refuse to
approve a supplement for a change that has already been implemented.
In assessing a manufacturer's plans to correct a problem, the agency
intends to consider the manufacturer's reasons for making the change
and the alternatives available to the manufacturer, among other
things. If the circumstances warrant, the agency may require the
change to be immediately discontinued. When circumstances permit, it
is FDA's intent to allow manufacturers to correct a problem with
minimal expense and without unnecessary waste.
3. Category III--Change(s) Which Require CBER Approval Prior to
Implementation
This category includes changes in manufacturing methods and
requires manufactures to submit all relevant supporting
documentation and await CBER's approval prior to implementation. As
with Category II submissions, CBER intends to follow relevant
application review policies in assigning supplement review.
4. Periodic Reports
A Periodic Report is a voluntary written report submitted every
6 months listing and briefly describing Category I changes and
providing the date of implementation of such changes. Reports should
include separate descriptions of EACH change affecting a licensed
product and should identify for each change the specific
establishment location involved. (See section E of this document for
requested information.)
B. Where to Submit Supplements and Periodic Reports
Three copies of all supplements and periodic reports should be
submitted to the Center for Biologics Evaluation and Research (HFM-
99), Food and Drug Administration, 1401 Rockville Pike, suite 200N,
Rockville, MD 20852-1448. [[Page 17537]]
C. Selected Examples
1. Category I
CBER currently considers the following examples to be changes
that will not ordinarily rise to the level of the ``important''
changes required to be reported under Sec. 601.12. These changes
need not be submitted to CBER prior to implementation and may be
submitted in a periodic report as ``Category I changes.'' This
listing provides representative samples of Category I changes and is
not all inclusive.
i. Change in purchasing source of approved final fill components
(stoppers, vials, seals) that meet established specifications. This
does not include change(s) in composition of such components or
suppliers of ancillary chemicals and drug products such as diluents.
ii. Change in harvesting and/or pooling procedures which does
not affect method of manufacture, recovery, storage conditions,
sensitivity of detection of adventitious agents, or production
scale; e.g., collection in smaller quantities to improve process
efficiency.
iii. Changes in cell inoculum; e.g, mode of expansion (attached
versus suspension; bioreactor versus spinner), cell density, staging
of culture. This excludes viral products; e.g., vaccines and in
vitro diagnostic kits.
iv. Change in storage conditions of reference standard or panel
based on stability data generated with an FDA-approved protocol.
v. Extension of dating period for in-house reference standards,
based on real-time data, according to an FDA-approved protocol.
vi. Replacement of inhouse reference standard or reference panel
(or panel member) according to FDA-approved standard operating
procedures (SOP's) and specifications.
vii. Tightening of specifications for reference standard or lot
release analyses.
viii. Establishment of new Working Cell Bank derived from
previously approved Master Cell Bank according to an FDA-approved
SOP.
ix. Narrowing (tightening) of specifications for intermediates
and endproducts to provide greater assurance of product purity and
potency.
x. Use of alternative storage containers for intermediates, with
no change in sterility, depyrogenation status, or composition of
container.
xi. Change in storage conditions of inprocess intermediates
based on data from an FDA-approved stability protocol (labeling not
affected).
xii. Change in bulk pool size for formulation without process
scale-up.
xiii. Batch size changes for ancillary components (specimen
diluents, positive and/or negative controls, substrate buffers,
etc.) where all equipment contact surfaces remain chemically
identical to approved equipment.
xiv. Change in the number of vials per fill with no scale-up or
impact on parameters defined in the environmental assessment.
xv. Change in shipping conditions (e.g., temperature, packaging,
custody) based upon data derived from studies following an FDA-
approved protocol.
xvi. Rework of biologic product which has failed final release
testing using FDA-approved rework protocol. Note: Any lot of product
subject to rework should be so noted on the product release
protocol.
xvii. Change in stability test protocol to include more
stringent parameters; e.g., additional assays, tightened
specifications, etc.
xviii. Replacement of equipment with that of identical design
and operating principle involving no change in process parameters.
xix. The following modifications of areas not used for
production or storage of intermediate or finished product (such as
testing laboratories, materials storage, warehouse, employee break
areas, etc.):
(a) Addition of outside areas that do not adversely affect the
product manufacturing area or utility systems;
(b) Expansion or reorganization of off-site support space that
does not affect the product manufacturing areas;
(c) Modification to or relocation of support space within a
product manufacturing facility that does not affect plant utility
systems and flow patterns, or adversely affect product purity or
environmental conditions (e.g., addition of half partitions or
benches).
xx. The relocation of equipment within appropriate areas of
approved facilities, not increasing risk to product purity or
integrity of testing (e.g., relocation of fermentor in fermentation
suite).
xxi. Upgrade in air quality, material, or personnel flow where
product specifications remain unchanged. Involves no change in
equipment or physical structure of production area.
xxii. Changes in personnel other than the Responsible Head (21
CFR 600.10) or individuals serving in a capacity of alternative or
temporary Responsible Head.
2. Category II
CBER currently considers the following examples to be
``important'' proposed changes in location, equipment, management
and responsible personnel. These changes must be reported pursuant
to Sec. 601.12(a) and meet the definition of a ``Category II
Supplement.'' This listing provides representative samples of
Category II changes and is not all inclusive.
i. Addition of back-up systems for manufacturing processes which
are identical to the primary system and serve as an alternate
resource (not expansion of capacity) within an approved production
area.
ii. Upgrade to production air handling or water systems using
like equipment 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
(Category I).)
iii. Replacement of equipment with that of similar, but not
identical, design and operating principle that does not affect the
process methodology.
iv. Expansion of existing manufacturing support systems (WFI,
heating, ventilation, and air-conditioning (HVAC)); e.g., adding an
additional WFI loop.
v. Relocation of operations within the same production area of
an approved facility with no change in equipment or room
classification.
vi. Modification of an approved manufacturing area which does
not adversely affect safety, purity or potency of product; e.g.,
adding new interior partitions or walls to increase control over the
environment and replacing or adding new surfaces to enhance
cleaning.
vii. Change in Responsible Head (21 CFR 600.10) or individuals
serving in a capacity of alternative or temporary Responsible Head.
3. Category III.
CBER currently considers the following examples to be
``important'' proposed changes in manufacturing methods. These
changes require CBER approval before they may be implemented under
Sec. 601.12(b), and meet the definition of a ``Category III
Supplement.'' This listing provides representative samples of
Category III changes and is not all inclusive.
i. Establishment of new Master Cell Bank.
ii. Change in inhouse reference standard or reference panel
(panel member) resulting in modification of reference
specifications.
iii. Establishment of alternate test method for reference
standards, release panels, product intermediates, or endproduct.
iv. Replacement of existing test method with new procedure or
method; e.g., change from radioimmunoassay (RIA) to enzyme-linked
immunosorbent assay (ELISA).
v. Change in process parameters; e.g., growth cycle,
chromatographic medium, process time and/or temperature, filtration
process.
vi. Change in sequence of processing steps, including addition
of processing step; e.g., viral removal or inactivation.
vii. Change in production scale (up or down) involving changes
in equipment, process parameters, or process methodology.
viii. Change in chemistry or formulation of solutions used
during processing.
ix. Changes in conjugation chemistry or process.
x. Change in composition of the biological product or ancillary
components.
xi. Change in dosage form.
xii. Any change which results in detectable relaxing of product
specifications and modification in potency, sensitivity, or
specificity.
xiii. Change in fill volume (per vial) from an approved
production batch size and/or scale.
xiv. Reprocessing of product without a previously approved
reprocessing protocol.
xv. Change in stability testing program; e.g., substitution of
analytical methods or potency assay, broadening of acceptance
criteria, change in storage temperature, change in test algorithm.
xvi. Extension of dating period for intermediate or endproduct.
xvii. Change in storage conditions for licensed final product or
intermediate based on real-time data from FDA-approved stability
protocol (labeling affected).
xviii. The following changes in manufacturing location that
affect process [[Page 17538]] conditions and thereby have the
potential to affect product safety, purity, or potency:
(a) Use of a previously unapproved manufacturing area or
facility;
(b) Change in air quality, water quality, material, or personnel
flow for licensed product manufacturing areas.
(c) Change from single product manufacturing to multiple product
manufacturing using same equipment and/or personnel.
(d) Renovation to physical structure that alters product,
material, and/or personnel flow.
xix. Addition to or replacement of an FDA-approved manufacturing
step performed under contract to a second facility.
D. Categorization of Proposed Changes
Before implementing a change which is not identified above or
does not clearly fit into one of the defined categories,
manufacturers should discuss the proposed change with CBER. If
guidance is not sought, the change should be reported in the form of
a Category III supplement, subject to CBER approval prior to
implementation.
Requests for information regarding categorization of proposed
changes not included in the above categories may be addressed to the
Director of the appropriate applications Division within the Office
with assigned product, or establishment, responsibility at the
Center for Biologics Evaluation and Research (HFM-99), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD
20852-1448.
E. Information Requested for Category I Periodic Reports
FDA requests that manufacturers submit the following information
for each Category I change in the order shown: (1) Name of the
manufacturer; (2) the establishment license number; (3) the report
dates (time period covered by the report); (4) the product(s)
affected (list each one); (5) the change implemented, including: (a)
A brief description and reason for the change and/or modification,
(b) the establishment location involved, (c) the date the change was
implemented, and (d) a cross-reference to the Approved Validation
Protocol or Standard Operating Procedure, if applicable; and (6) the
signature of the Responsible Head and the date signed.
Dated: March 31, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-8382 Filed 4-5-95; 8:45 am]
BILLING CODE 4160-01-F
