Changes To Be Reported for Product and Establishment License Applications; Guidance

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