[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]



-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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