Guidance for Industry

Changes to an Approved Application:

Biological Products: Human Blood and

Blood Components Intended for

Transfusion or for Further

Manufacture

Additional copies are available from:

Office of Communication, Training and Manufacturers Assistance (HFM-40)

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 2001
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TABLE OF CONTENTS

I. INTRODUCTION ..................................................................................................... 1

II. DEFINITIONS....................................................................................................... 3

III. 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). [PAS] ..................................................................................................... 8

IV. CHANGES UNDER 21 CFR 601.12(c) - Changes requiring supplement

submission at least 30 days prior to distribution of the product made using the change

(moderate changes). [CBE30] ........................................................................................ 11

V. CHANGES UNDER 21 CFR 601.12(c)(5) - Changes requiring supplement

submission prior to distribution of the product made using the change (30 days is

waived). [CBE] ................................................................................................................ 14

VI. CHANGES UNDER 21 CFR 601.12(d) - Changes to be described in an annual

report (minor changes). [AR].......................................................................................... 15

VII. COMPARABILITY PROTOCOL UNDER 21 CFR 601.12(e)........................ 20

VIII. LABELING CHANGES UNDER 21 CFR 601.12(f)......................................... 23

IX. FAILURE TO COMPLY UNDER 21 CFR 601.12(g)....................................... 24

X. REFERENCES ........................................................................................................ 25

APPENDIX A: Sample of a Blood Bank Annual Report.............................................. 27

APPENDIX B: Sample of a Source Plasma Facility Annual Report............................ 28

APPENDIX C: Sample of a Blood Establishment with Multiple Facilities Annual

Report............................................................................................................................... 29

APPENDIX D: Table: Types of Facilities as Determined by the Manufacturing Steps

They Perform.................................................................................................................... 30
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GUIDANCE FOR INDUSTRY

Changes to an Approved Application: Biological Products:

Human Blood and Blood Components Intended for Transfusion

or for Further Manufacture

This guidance document represents FDA’s current thinking on changes to an approved

application for all licensed human blood and blood components intended for transfusion or for

further manufacture. 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 and regulations.

INTRODUCTION

Frequently, a licensed biological product manufacturer determines that it is appropriate to make

a change in the product, labeling, production process, quality controls, equipment, or facilities as

documented in its approved license application(s). Section 601.12 of Title 21, Code of Federal

Regulations (21 CFR 601.12) prescribes the requirements for you, the licensed biological

product manufacturer, to report such changes for your licensed biological products to the Food

and Drug Administration (FDA). This regulation only applies to the manufacture and

distribution of licensed products. It does not apply to unlicensed products manufactured at

unlicensed, registered-only facilities.

Under 21 CFR 601.12, you must report a change in the approved product, labeling, production

process, quality controls, equipment, or facilities to FDA. You may report the change in: 1) a

supplement requiring approval prior to distribution; 2) a supplement submitted 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” (Ref. 1)

(referred to as “the safety or effectiveness of the product”). Before distributing a licensed

product manufactured using a change, you are required to demonstrate, through appropriate

validation and/or clinical or non-clinical laboratory studies, the lack of adverse effect of the

change on the safety or effectiveness of the product.

The three reporting categories for changes to an approved application are defined in 21 CFR

601.12:
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1) Changes that have a substantial potential to have an adverse effect on the safety or

effectiveness of the product, that require submission of a supplement and approval

by FDA prior to distribution of the product made using the change (major changes);

2) Changes that have a moderate potential to have an adverse effect on the safety or

effectiveness of the product, that require submission of a supplement to FDA at

least 30 days prior to distribution of the product made using the change or, for some

changes, the 30 days may be waived (moderate changes); and

3) Changes that have minimal potential to have an adverse effect on the safety or

effectiveness of the product, that are to be described by the applicant in an annual

report (minor changes).

We, the Center for Biologics Evaluation and Research (CBER), have developed this guidance

in response to public comments on the July 1997, Guidance for Industry - Changes to an

Approved Application: Biological Products (Ref. 2), and on the CBER Biologics Workshop on

December 2, 1997, discussing the Biologics License Application (BLA) and the reporting

requirements for changes to an approved application for manufacturers of licensed Whole

Blood and Blood Components intended for transfusion and for further manufacture (Ref. 3).

This guidance applies to the manufacture of all licensed Whole Blood and blood components,

Source Plasma, and Source Leukocytes intended for transfusion and for further manufacture

into both injectable and non-injectable products. It is intended to assist you in determining

which reporting mechanism is appropriate for a change to an approved license application. It

replaces the recommendations in the Guidance for Industry: Changes to an Approved

Application: Biological Products, July 1997, for the above mentioned products. This guidance

also revises and finalizes the draft guidance entitled “Guidance for Industry: Changes to an

Approved Application: Biological Products: Human Blood and Blood Components Intended for

Transfusion or for Further Manufacture,” that was announced in the Federal Register of January

3, 2000 (65 FR 134).

If you make a change to an approved license application, you must also conform to other

applicable laws 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

regulations in 21 CFR parts 210, 211, and 600 through 680. For example, you must comply

with recordkeeping requirements and ensure that relevant records are readily available for

examination by authorized FDA personnel during an inspection.

Under each section of the guidance document, we provide categories of changes to be reported

under 21 CFR 601.12. The guidance also provides lists of changes that we currently believe

you may report under each category. The lists are not intended to be all-inclusive. We have

moved some of the changes listed in a specific reporting category in the July 1997 guidance on

reporting changes to an approved application for biological products to other reporting

categories in this guidance. In this guidance, we describe the format for the annual report and
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explain the comparability protocol. We have included a separate section on labeling, describing

the labeling changes that you would submit as supplements requiring prior approval supplements

submitted at the time the change is made, or to be included in the annual report. If you need

further guidance, you should call the Division of Blood Applications at (301) – 827-3543.

Because we have replaced the individual establishment and product licenses with a single

biologics license (Ref. 4), you may combine or bundle multiple changes into one submission.

For example, you may report a change in the manufacture of one or more products at one or

more manufacturing locations. For clarity, we request that bundling be limited to related

changes. If the review of all items in a bundled submission cannot be completed at the same

time, we will separate the items still under review from the items for which the review is

complete and final action (e.g., approval) can go forward. We have published additional

guidance describing the specific items that are to be included in a submission (Ref. 5).

You should prominently label each submission with the reporting category under which you are

reporting your change, e.g., “Prior Approval Supplement”, “Supplement - Changes Being

Effected in 30 Days”, “Supplement - Changes Being Effected” or “Annual Report.” You

should include a Form FDA 356h “Application to Market a New Drug, Biologic, or an

Antibiotic Drug for Human Use” with each submission (Ref. 6). We encourage you to use a

cover letter to introduce and summarize the supplement. For guidance in preparing a

supplement, you may refer to the Guidance for Industry – For the Submission of Chemistry,

Manufacturing and Controls and Establishment Description Information for Human Blood and

Blood Components Intended for Transfusion or for Further Manufacture and For the

Completion of the Form FDA 356h “Application to Market a New Drug, Biologic, or an

Antibiotic Drug for Human Use” (Ref. 5).

You should report changes to your approved establishment, product or biologics license

applications to the Director, Center for Biologics Evaluation and Research, Office of Blood

Research and Review, Division of Blood Applications, HFM-370, c/o Document Control

Center (HFM-99), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448.

II. DEFINITIONS

Acquisition - the purchase of a facility previously operated by an applicant under one U.S.

license number by an applicant holding a different U.S. license number or by a new applicant.

The acquired facility will no longer be connected to the original U.S. license number. We will

either revoke or modify the original license to delete the facility. The license application for the

legal entity acquiring the facility will be supplemented to include the manufacture of product at

the acquired facility. If a new applicant has acquired a facility, we will grant a new license. We

previously referred to acquisitions as ‘rollovers’ (Ref. 7).
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Applicant - any person or legal entity that has submitted an application to manufacture a

product subject to licensure under section 351 of the Public Health Service Act (PHS Act).

The applicant assumes responsibility for compliance with the applicable product and

establishment standards and for Quality Assurance (QA) oversight of all manufacturing steps

(Ref. 8). Also see manufacturer.

Application - request submitted by the applicant for a biologics license, including supportive

documentation, in order to manufacture and distribute in interstate commerce, a product subject

to licensure under section 351 of the PHS Act.

AR - Annual Report [21 CFR 601.12(d)].

Authorized Official - person(s) designated by the applicant to communicate with the FDA on

behalf of the applicant. Authorized officials can initiate applications or supplements to a license

application, discuss submissions with our representatives, provide additional information in

support of the submissions, and withdraw applications or supplements (Ref. 9). The applicant

or manufacturer should immediately notify us in writing if there is a change in the authorized

official(s). We will acknowledge receipt of the notification.

Circular of Information - instruction circular that provides adequate directions for the use of

blood products intended for transfusion. The circular contains descriptions of the blood

products, information on the tests performed on the components, indications for use,

contraindications, cautions and administration recommendations [21 CFR 606.122].

CBE – Changes being effected (30 days waived) [21 CFR 601.12(c)(5)].

CBE30 – Changes being effected in 30 days [21 CFR 601.12(c)].

Contractor - any person or entity, other than the applicant, that performs part or all of the

manufacturing of the licensed product as a service to the applicant. The applicant assumes

responsibility for the contractor’s compliance with the applicable product and establishment

standards. Both the applicant and the contractor are legally responsible for the work performed

by the contractor (Ref. 10). All contractors performing a manufacturing step of a licensed

product must be registered with FDA, unless they are exempt from registration [21 CFR part

607].

Contractual Agreement – agreement between a manufacturer and a contractor, that describes

the manufacturing steps performed by the contractor. Although you do not need to include the

specific legal contract in your submission, you should include a description of the services

requested from all contractors performing a manufacturing step for you (e.g., outside testing

laboratories performing routine donor/product testing and confirmatory testing, irradiation

facilities, suppliers of red blood cells for immunization, and storage facilities). This should also

be available for review during inspection.
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CP – Comparability Protocol [21 CFR 601.12(e)].

Disease-Associated Antibody Donors - donors who meet all the required/recommended

normal Source Plasma donor suitability criteria, except that their plasma contains pre-existing

IgG antibodies as a result of previous exposure to certain diseases or cellular antigens (Ref. 11).

Disease-State/High-Risk Donors - donors whose plasma contains or lacks a specific

property (e.g., protein, antibody, inherited trait) as a result of their disease. These donors may

not meet all the required or recommended normal Source Plasma donor suitability criteria.

Establishment/Facility - includes any and all establishments used by the manufacturer for

collection, processing, product testing, compatibility testing, storage, or distribution of licensed

Whole Blood and blood components. Any facility in which a manufacturing step is performed

must meet the specifications and procedures established in the biologics license application

designed to insure the continued safety, purity and potency of the biological product [21 CFR

600.3(w)]. Establishment and facility have the same meaning (Ref. 4). For the purposes of this

document, the facilities are separated into three categories determined by the manufacturing

steps they perform: Major Facilities, Auxiliary Facilities and Transfusion Services (see Appendix

D).

Major Facilities:

• Collection Facility – facility that collects Whole Blood and/or apheresis products,

and/or performs infrequent plasmapheresis, but that does not perform FDA

required or recommended blood and plasma donor testing or prepare components

from Whole Blood. Collection facilities may also label, store, and distribute blood

products.

• Community Blood Bank - commercial or non-profit blood collection/processing

facility, not part of a hospital system, that may perform manual and/or automated

blood collection, prepare components from Whole Blood, perform FDA required

or recommended blood and plasma donor testing (including compatibility testing),

and routinely labels, stores, and distributes blood and/or blood products to one or

more hospitals. Community blood banks may also prepare irradiated, frozen,

deglycerolized and/or leukoreduced products.

• Component Preparation Facility - intermediate processing facility that prepares

components from Whole Blood collected at a mobile or fixed collection site but

does not perform FDA required or recommended blood and plasma donor testing.

Component preparation facilities may also perform automated collection of blood

products, and/or label, store, and distribute blood products and/or may prepare

irradiated, frozen, deglycerolized and/or leukoreduced products.
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• Hospital Blood Bank - facility located within a hospital that routinely performs

manual and/or automated blood collection and processes Whole Blood into

components. A hospital blood bank may also prepare irradiated, frozen,

deglycerolized and/or leukoreduced products, distribute blood products to other

hospitals and may perform FDA required or recommended blood and plasma

donor testing and compatibility testing.

• Plasmapheresis Center - facility licensed by CBER that collects Source Plasma

by manual and/or automated methods for commercial distribution. Plasmapheresis

centers may also perform FDA required or recommended blood and plasma donor

testing.

• Product Testing Laboratory – facility that performs routine FDA required or

recommended blood and plasma donor testing.

Auxiliary Facilities:

• Distribution Center - facility that stores blood or blood products under specific

controlled conditions prior to shipment to the final user, including suppliers of source

material for further manufacture, such as Recovered Plasma, Source Plasma, Whole

Blood, Red Blood Cells, or Platelets for diagnostic product use; for example,

Whole Blood facilities that intend to redistribute the product to transfusion centers,

Source Plasma warehouses that intend to redistribute the product to fractionators or

Recovered Plasma holding facilities or brokers intending to redistribute the product

to diagnostic product manufacturers or fractionators. This term does not include

transfusion services that occasionally ship excess products as a means to manage

the blood supply in a specific region or during a rare emergency because their

products are not being stored with the intent to distribute.

• Donor Center - facility that only performs manual collection of Whole Blood and

does not collect blood product by automated methods, prepare blood components

or perform routine FDA required or recommended blood and plasma donor testing.

Transfusion Services:

• Transfusion Service – facility that performs compatibility testing for blood and

blood components, but does not routinely collect blood, process Whole Blood into

components (except Red Blood Cells and Recovered Plasma) and does not

perform FDA required or recommended blood and plasma donor testing.

Fractionated Blood Derivatives - sterile solutions of a specific protein(s) derived from human

blood, e.g., albumin, plasma protein fraction and immune globulin.
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Inspection – an on-site evaluation conducted by FDA personnel of operations at a regulated

establishment to assess whether it is in compliance with applicable laws and regulations and in

conformance with the establishment’s approved applications or the establishment’s application

for a U.S. license. FDA inspections may be conducted for several purposes.

• Pre-Approval Inspection – an announced or unannounced inspection conducted

by CBER personnel and/or investigators from the Office of Regulatory Affairs

(ORA). This inspection is conducted as part of the review of a supplement to an

approved biologics license application. Examples of supplements that would

require pre-approval inspections include submissions for irradiated blood products,

or implementation of a red blood cell immunization program under a Source Plasma

license.

• Pre-License Inspection – an announced inspection conducted by a team of

CBER and ORA personnel. This comprehensive inspection is conducted as part of

the review of an application for a U.S. license, or a supplement to an approved

biologics license application for a new facility or product. Examples of applications

and supplements that would require pre-license inspections include a new blood

establishment, or an additional major facility operating under an existing U.S.

license.

• Post-Approval Inspection – a periodic unannounced inspection conducted by

ORA investigators. This inspection is a surveillance activity, conducted to assess

whether the operations of licensed and unlicensed blood establishments are in

compliance with applicable laws and regulations and with commitments made in the

approved license application (for licensed establishments). Examples of postapproval inspections include the annual/biennial inspections and directed

inspections. Directed inspections are unannounced “for cause” inspections

conducted by ORA investigators who audit selected operations of an establishment.

Examples of directed inspections include a follow-up to a fatality investigation or

consumer complaint.

Manufacturer - any person or legal entity engaged in the manufacture of a product subject to

licensure under the PHS Act. Manufacturer also includes any person or legal entity that is an

applicant for a license where the applicant assumes responsibility for compliance with the

applicable product and establishment standards [21 CFR 600.3(t)].

Manufacturer’s Instructions – instructions for use of equipment, test kits, reagents, supplies,

etc., used in the manufacture of Whole Blood and blood components that are prepared by the

manufacturer of the equipment, test kits, reagents, supplies, etc. Manufacturer’s instructions

may be described in the equipment operator’s manuals and reagents or supplies package

inserts.
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Manufacturing - all steps involved in the preparation of a product intended for transfusion or

for further manufacture into injectable or non-injectable products. Manufacturing includes

determining donor suitability, the informed consent and collection procedure, component

preparation, product/donor testing (including quality control), labeling, storage of the product,

compatibility testing, and the quarantine and destruction of unsuitable blood products [21 CFR

600.3(u) and 21 CFR 607.3(d)]. The steps may be performed by the manufacturer holding the

biologics license or by a contractor who performs one or more of the manufacturing steps.

Merger - union of two or more licensed manufacturers to form a new legal entity. FDA will

issue a new U.S. license number to the new entity.

PAS – Prior approval supplement [21 CFR 601.12(b)].

Source Material - blood component derived from human blood that is collected by either

manual or automated apheresis techniques and is intended for further manufacturing into

injectable or non-injectable products.

Supplement - written request submitted to the Director, Center for Biologics Evaluation and

Research, to approve a change in an approved license application [21 CFR 600.3(gg)].

Transfusion Blood Components - blood components (Whole Blood, Red Blood Cells,

Platelets, Plasma, Cryoprecipitate, or Granulocytes) derived from human blood collected by

either manual whole blood collection or automated apheresis techniques and intended to be

transfused to human recipients.

III. 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). [PAS]

Under 21 CFR 601.12(b), if you make any change to your product, production process, quality

controls, facilities, or equipment, that has a substantial potential to have an adverse effect on the

safety or effectiveness of the product, you must submit a supplement and receive our approval

before distributing the product made using the change. For a change under this category, you

must submit a supplement to your approved license application that includes the following:

• 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 safety or effectiveness;

• the data derived from those studies;

• relevant validation protocols and data;
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• appropriate labels; and

• relevant standard operating procedure(s) (SOP) or a list referencing previously

approved relevant SOP.

You should submit any change in a facility or manufacturing process in the prior approval

category unless specified in this guidance that it may be reported in another category.

We consider the following types of changes to be major changes, for which submission and

approval of a supplement prior to distribution of product made using the change must occur:

A. Product Manufacturing/Procedural Changes

1. Implementation of a new manufacturing process, to include but not be limited to:

a. Leukocyte reduction;

b. Irradiation;

c. Freezing/deglycerolizing;

d. Rejuvenating; and

e. Washing.

2. Addition or revision of SOP for the following categories if the change is less

restrictive than previously approved or is not addressed in published FDA

guidance documents* (Ref. 7):

a. Donor suitability, including donor deferral;

b. Blood collection, including arm preparation;

c. High risk behavior questions, including AIDS information;

d. Donor history forms, including informed consent;

e. Product manufacturing for licensed products; and

f. Quarantine and disposition of unsuitable product.

*NOTES:

• Report changes in the content of the procedure or form. You do not

need to report changes in format only and minor editorial changes to

SOP and forms.

• You may reference previously approved SOP and forms. You

should include the FDA application or supplement tracking number

when referencing a previously approved SOP or form.

• You should submit to us for review SOP revisions in the above

areas prepared in response to post-approval inspectional

observations

3. Implementation of procedures and/or donor history forms that differ from and

are less restrictive than the FDA-approved AABB Uniform Donor History

Questionnaire, manufacturer’s directions or recommendations described in

FDA guidance documents. This includes a change in quality control

procedures. If the modifications are more restrictive or if the procedure is

performed following the manufacturer’s directions, you may report the change in
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the annual report. You may report the addition of procedures or tests that are

not required or recommended by FDA in the annual report.

4. Use of an abbreviated donor history questionnaire for repeat or frequent

donors.

5. Implementation of a computer-assisted donor history questionnaire where the

computer system can be accessed from remote locations, is able to make

decisions about donor suitability or is interfaced with other computer systems,

either at the same collection center or at other facilities.

6. Change from manufacturing a sole product by automated apheresis to

manufacturing additional products as by-products. Exception: Collection of

plasma as a by-product to an approved plateletpheresis program should be

reported as a CBE30 (see section IV.A.2.).

7. Request to manufacture additional products; e.g., Platelets Pheresis, Source

Plasma or Source Leukocytes.

8. Addition of an immunization program for red blood cells or unlicensed vaccines.

9. Implementation of a physician substitute program in a Source Plasma facility

(Ref. 12).

10. Collection of Source Plasma from disease-state or high-risk donors.

11. Request for approval of a comparability protocol.

12. Request for approval of an alternative procedure under 21 CFR 640.120 for

which there is no published guidance.

B. Equipment Changes

1. Conversion from manual to automated collection of blood components; e.g.,

Platelets, Plasma (both Fresh Frozen and Source), Red Blood Cells, Source

Leukocytes.

2. Changes or upgrades in automated apheresis equipment that affect the purity,

potency or quality of the product(s). These changes include but are not limited

to: increase in product yield; change in storage conditions; change in

anticoagulant; leukocyte reduction; collection of an additional or different

product, for example, a change from COBE LRS Version 5.1 to Turbo Version

7.

3. Change in manufacturer of automated apheresis equipment used in the collection

of Red Blood Cells or Platelets, e.g., change from Haemonetics MCS to Cobe

Trima.

C. Contractor Changes

1. Use of, or change to, a new facility or any facility not previously engaged in

blood product testing as a contract testing laboratory to perform the routine

serologic and infectious disease screening testing, and supplemental and/or
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confirmatory testing for blood and blood products. These laboratories perform

the tests of record (tests used to determine donor/product suitability).

2. Use of, or change in, a contractor that was not previously engaged in

performing a manufacturing step on blood products, to perform the

manufacturing step. This includes, but is not limited to, contractors who

irradiate blood products or supply red blood cells for immunization.

D. Facility Changes

1. Expanding operations by adding a major facility where licensed products are

manufactured. This includes the addition of a contractor to perform the

manufacturing step.

a. Major facilities where Red Blood Cells, Fresh Frozen Plasma, Platelets,

and Platelets, Pheresis are collected using automated collection systems,

Source Plasma and Source Leukocytes are collected using either

manual or automated collection methods, or routine FDA required or

recommended blood and plasma testing is performed.

b. Acquisition of major facilities previously operating under another

U.S. license number that will now manufacture product under the U.S.

license number of the legal entity acquiring the facility.

2. Relocation of a major facility where product manufacturing is performed that

results in a change in core center personnel, and/or a change in SOP or

equipment. You should also report the relocation of any contractor that results

in a change in personnel and/or a change in SOP or equipment.

IV. CHANGES UNDER 21 CFR 601.12(c) - Changes requiring supplement

submission at least 30 days prior to distribution of the product made using the

change (moderate changes). [CBE30]

Under 21 CFR 601.12(c), if you make any change in your product, production process, quality

controls, equipment, or facilities that has a moderate potential to have an adverse effect on the

safety or effectiveness of the product, you must submit a supplement to us at least 30 days prior

to distribution of a licensed product made using the change. The requirements for the content of

these supplements are the same as for PAS.

You must specify that the changes are being reported in this category by labeling the submission:

“Supplement - Changes Being Effected in 30 Days.” Within 30 days of the date we receive the

submission, we will determine if the change or changes have been reported in the proper

category and will notify you if they have not. If we have not notified you otherwise within 30

days after we receive the supplement, you may distribute your product under licensure, using the

change described in your supplement. You do not have to wait for our written approval before

distributing a product made using a change reported in this category. If we do not notify you, it
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does not mean that we have approved the changes reported in your supplement, merely that

you have reported the changes in the proper category. Our review of your submission will

proceed after we have determined that the changes are reported in the proper category.

We will not notify you when we receive your CBE30 supplements; instead, we recommend that

you have a mechanism to track the date we received the submission; e.g., a mail service that will

return confirmation of the receipt date.

If we determine that the information submitted in your supplement fails to demonstrate the

continued safety or effectiveness of the product made using the change, we will try to resolve

the problems with you. In assessing your plans to correct the problem, we will consider your

reasons for making the change and the available alternatives to the change. If we find that your

product in distribution poses a danger to public health, or if we determine that there are

unresolved issues, we may require that you cease distribution of the product made using the

change or that you remove the product from distribution pending resolution of the issues related

to the change.

We consider the following types of changes to be moderate changes, for which submission of a

supplement at least 30 days prior to the distribution of the product made using the change

should occur:

A. Product Manufacturing/Procedural Changes

1. Addition of the collection of plasma as a by-product in an approved

plateletpheresis program, provided the applicant is otherwise approved to

manufacture the plasma product.

2. Request to manufacture the following products:

a. Plasma Cryoprecipitate-Reduced, provided the applicant is approved

to manufacture Cryoprecipitated AHF and Fresh Frozen Plasma.

b. Fresh Frozen Plasma Donor Retested, provided the applicant is

approved to manufacture Fresh Frozen Plasma.

3. Implementation of an immunization program for licensed vaccines where the

program is consistent with the vaccine insert instructions.

4. Implementation of a self-administered donor history questionnaire where the

information is presented to the donor on a printed form that the donor must read

or that is presented using audio/visual tools.

5. Implementation of a computer-assisted donor history questionnaire where the

computer system operates as a stand-alone system, does not make decisions

about donor suitability, and is not interfaced with other computer systems, either

at the same collection center or at other facilities.

6. Request for an alternative procedure under 21 CFR 640.120 for which

published guidance is available and implementation conforms with the guidance,
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e.g., implementation of an infrequent plasmapheresis donor collection program

that is consistent with FDA’s guidance for this program.

7. Implementation of recommendations described in FDA guidance documents, if

followed without modifications and directed to be reported in this manner by the

guidance document.

B. Equipment Changes

1. Change in manufacturer of automated plasma apheresis equipment, e.g., change

from Haemonetics PCS to Fenwal Autopheresis C.

C. Contractor Changes

1. Use of, or change to, an FDA registered contract testing laboratory, currently

engaged in blood product testing, to perform the routine serologic and infectious

disease screening testing, and supplemental and/or confirmatory testing for

blood and blood products. These laboratories perform the tests of record

(tests used to determine donor/product suitability).

2. Use of, or change to, an FDA registered contractor, currently engaged in

performing manufacturing steps on blood products, to perform a specific

manufacturing step, e.g., irradiation of blood products.

3. Use of an off-site contract storage facility to store unlicensed product collected

under a pending license application or for the storage of excess licensed product

that meets all product release criteria. The storage facility may also distribute

licensed product to the final user.

D. Facility Changes

1. Change in legal name of the applicant. This will cause the issuance of a new

license number.

2. Relocation of a major facility where product manufacturing is performed and

there is no change in SOP, equipment, and core center personnel, especially

center management and medical personnel. Report relocations of facilities that

result in a change in core center personnel as a prior approval supplement.

a. Include relocation of all contractors where there is no change in SOP,

equipment, and core personnel.

b. Do not include move of auxiliary facilities. You must report this

submitting a revised Form FDA 2830 at the time of the move and by

updating your organizational report in the annual report.
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V. CHANGES UNDER 21 CFR 601.12(c)(5) - Changes requiring supplement

submission prior to distribution of the product made using the change (30 days

is waived). [CBE]

As described in 21 CFR 601.12(c)(5), we may determine that, based on our experience with a

particular type of change, that 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, we may determine that the

product made using the change may be distributed under licensure at the time we receive your

supplement. We recommend that you have a mechanism to track the date we received your

CBE submission.

You should specify that the changes are being reported in this category by labeling the

submission: “Supplement - Changes Being Effected.” We will determine if the change has been

reported in the proper category and will notify you if it has not. You do not have to wait for our

written approval before distributing a product made using a change in this category. If we do

not notify you, it does not mean that we have approved the changes reported in your

supplement, merely that you have reported the changes in the proper category. Our review of

your submission will proceed after we have determined that the changes are reported in the

proper category.

If we determine that the information submitted in your supplement fails to demonstrate the

continued safety or effectiveness of the product made using the change, we will try to resolve

the problems with you. In assessing your plans to correct the problem, we will consider your

reasons for making the change and the available alternative to the change. If we find that your

product in distribution poses a danger to public health, or if we determine that there are

unresolved issues, we may require that you cease distribution of the product made using the

change or that you remove the product from distribution pending resolution of the issues related

to the change.

Under 21 CFR 601.12(c)(5) and based on our experience, we consider the following types of

changes to be moderate changes that could be implemented, without a previously approved

comparability protocol (see section VII), at the time we receive your supplement:
15

A. Product Manufacturing/Procedural Changes

1. Implementation of another manufacturer’s previously approved SOP, with

written permission from the manufacturer.

2. Implementation of recommendations described in final FDA guidance

documents, if followed without modifications and directed to be reported in this

manner by the guidance document.

B. Facility Changes

1. Voluntary revocation or permanent closure of a major facility. You may report

closure of auxiliary facilities in the annual report.

2. Temporary move or closure and reopening of a major facility provided there are

no changes in SOP, equipment, and core center personnel. You should indicate

the estimated time for the change and describe the plans for restarting

operations at the original site in your submission.

VI. CHANGES UNDER 21 CFR 601.12(d) - Changes to be described in an annual

report (minor changes). [AR]

Under 21 CFR 601.12(d), you must document changes to the product, production process,

quality controls, equipment, or facilities, that have minimal potential to have an adverse effect on

the safety or effectiveness of the product in an annual report submitted within 60 days of the

anniversary date of approval of your first product application in each year you have changes to

report in this category. You must include a list of all licensed 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, and a cross-reference to relevant validation

protocol(s) and/or approved SOP in your annual report.

On October 20, 1997, we sent a letter to all licensed blood and plasma establishments notifying

them of the date of their first product application approval. The month and day of this date

represents your annual report date. Minor changes to any and all licensed products must be

reported in the annual report within 60 days of this date. You may request an alternate date,

but you must make your request to us in writing. We will notify you if this date is acceptable.

Once approved, this alternate date will become your new annual report date.

Annual reports should contain information about minor changes to any and all licensed products

implemented since the prior annual report. Submit one original annual report and two copies to

us for review. If there are no minor changes, you need not submit an annual report.
16

We will review the annual report to determine if the changes were reported in the proper

category. If the annual report contains changes that should have been reported as supplements,

we will notify you in writing and by telephone of those changes that should be submitted as

supplements. In such cases, we will try to resolve problems with you concerning your annual

report. If we find that your product in distribution poses a danger to public health, or if we

determine that there are unresolved issues, we may require that you cease distribution of the

product made using the change or that you remove the product from distribution pending

resolution of the issues related to the change.

We consider the following types of changes to be minor changes, to be reported in an annual

report:

A. Product Manufacturing/Procedural Changes

1. Revision of SOP for the following categories if the change is more restrictive

than previously approved or is not described in published FDA guidance

documents, e.g. deferring donors who are at risk for Lyme disease:

a. Donor suitability, including donor deferral

b. Blood collection, including arm preparation (if changing to an approved

method and following manufacturer’s instructions)

c. High risk behavior questions, including AIDS information

d. Donor history forms, including informed consent

e. Product manufacturing for licensed products

f. Quarantine and disposition of unsuitable product

2. Implementation of a program to collect Source Plasma from normal donors with

pre-existing disease-associated, red blood cell and/or HLA antibodies in

Source Plasma (Ref. 11).

3. Implementation of a FDA-approved AABB Uniform Donor History

Questionnaire, if used without modifications or if modifications are more

restrictive.

4. Implementation of recommendations described in final FDA guidance

documents, if followed without modifications and directed to be reported in this

manner by the guidance document.

5. Change in the quality control method if the procedure is consistent with the

manufacturer’s directions. This includes the methods used to quality control the

systems involved in product manufacturing, e.g., blood products, equipment,

reagents, supplies.

6. Implementation of additional procedures or tests which are not required or

recommended by FDA. (If the test or procedure is included in the informed

consent, the form should not contain any exculpatory language or claims about

the procedure or test.)

7. Change in collection sets or leukocyte reduction filters for products prepared

from Whole Blood, if used according to manufacturer’s instructions.
17

B. Equipment Changes

1. Changes or upgrades by the device manufacturer of automated apheresis

equipment that does not affect the purity, potency or quality of the product(s), if

the facility is already approved for the original procedure, e.g., upgrade in

plasmapheresis equipment from Haemonetics PCS to Haemonetics PCS2 or

upgrade to Haemonetics PCS2 Version G to display red blood cell loss.

2. Change in irradiation equipment used by you or your contractor, e.g., from

gamma irradiator to linear accelerator or to a different gamma irradiator

manufacturer.

3. Implementation of a blood establishment computer system that maintains data

used by blood establishment personnel to make decisions regarding the

suitability of donors and the release of blood and blood components for

transfusion or for further manufacture. Do not include the use of a computerassisted donor history questionnaire. Report the name of the software

manufacturer, name and version number of the software. You should include

the following in the annual report:

a. Installation of both commercially developed software and software

developed and used in-house.

b. Implementation of data entry and retrieval or library database systems.

c. Change in blood establishment computer software manufacturers or

software versions, provided there are no major changes in the

processes performed by the computer (e.g., adding an electronic

crossmatch function) or no modifications made by the user that changes

the intended functionality of the new system.

d. Implementation of a computer/electronic crossmatch.

4. Implementation of automated equipment to perform ABO/Rh, syphilis and

infectious disease screening testing on donor blood samples.

5. Change in infectious disease screening testing methodology if the procedure is

consistent with manufacturer’s directions.

6. Change in equipment that performs total protein and serum/plasma protein

electrophoresis on donor specimens.

7. Change in equipment that performs vital sign testing (e.g., pulse, blood pressure,

temperature) and hemoglobin/hematocrit testing on blood donors or donor

specimens.

8. Use of sterile connecting (docking) device to manipulate product in a sterile

manner (e.g., take samples; attach transfer bag, needle, saline, anticoagulant or

other processing solutions; prepare aliquots; pool products) if approved to

manufacture the product and use of the device is consistent with manufacturer’s

directions.

9. Changes or upgrades in automated apheresis equipment that results in a

decrease in donation time.
18

C. Contractor Changes

1. Use of, or change in, a contract testing laboratory that performs reference or

quality control testing or tests that are not required or recommended by FDA.

This does not include a change in a contract testing laboratory that performs the

infectious disease tests of record. Such a change must be reported as a PAS or

CBE30. (See sections III. C. 1. and IV. C. 1.)

2. Temporary use of a previously approved alternate or back-up contractor to

perform a manufacturing step. Include the dates the alternate contractor was

used. A permanent change in a contractor should be reported as a PAS or

CBE30. (See sections III. C. 1. and IV. C. 1.)

3. Use of, or change in, a contractor to provide personnel responsible for

collecting blood products or performing quality assurance activities.

D. Facility Changes

1. Addition or deletion of a self contained motorized vehicle used for blood and

blood product collection.

2. Change in “doing business as” name that does not affect the legal entity name

on the license.

3. Openings, moves and closures of auxiliary facilities operating under a U.S.

license. You must send in a facility registration form (Form FDA 2830) within

five days of an opening, move or closure of the center [21 CFR 607.21 and

607.26].

The following information should not be included in the annual report:

• Major or moderate changes that have received FDA approval as supplements

during the reporting period, unless they are included in the organizational changes.

• Major or moderate changes submitted as supplements and currently under our

review.

• Shipment of source blood, plasma or serum that is repeatedly reactive for an

infectious disease marker and is to be used in the manufacture of vaccines and

licensed or unlicensed in-vitro diagnostic biological products. You must still report

these shipments in the manner stated in 21 CFR 610.40(d).

• Notification of the development of unexpected antibodies in donors participating in

red blood cell immunization programs. You should keep this information available

so that it may be reviewed during FDA inspections (Ref. 7). If the development of

unexpected antibodies is due to an error in immunization practices, you must report

this under 21 CFR 600.14.
19

• Biological product deviation (error and accident) or incident reports, fatalities and

recalls. You must still notify CBER, Office of Compliance and Biologics Quality, of

these events using the current reporting requirements [21 CFR 606.170].

• Validation data compiled during the installation and qualification of new or upgraded

equipment, computer systems or software. You should keep this information

available so that it may be reviewed during FDA inspections.

• You should report the following corporate changes to us at the time they occur:

• Change in corporate mailing address of the legal entity.

• Change in, or addition of, an authorized official.

Reporting Format for the Annual Report

We recommend that you use the following reporting format for the annual report. However,

you may choose to use a different format. In either case, we request that you include the

information listed below in your report. See appendices for examples of annual reports.

• We ask that you submit a cover letter describing the contents of your annual report.

• Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use

(FDA Form 356h) (Ref. 5).

1. Include U.S. license number of the manufacturer.

2. Identify the time period covered in the report.

• Description of the current organizational systems involved in the manufacture of

Whole Blood and blood components, to include any quality assurance activities.

1. If organizational changes have occurred since the last report, submit a

current organization chart with descriptive job titles.

2. List the licensed products you are currently approved to distribute in

interstate commerce.

• Full description of minor changes reported to approved applications, as described

in section VI.

1. List products affected by each change.

2. List the address of the facility or facilities where the change was

implemented. Include the registration number of the facility.

3. Include the date the change became effective.

4. Reference any approved CPs used to implement the change.

5. Describe the SOP or process affected by the change.
20

VII. COMPARABILITY PROTOCOL UNDER 21 CFR 601.12(e)

A. Description of a Comparability Protocol (CP)

The CP described in 21 CFR 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

specific manufacturing changes on the safety or effectiveness of the product. A CP is a

highly specific, well-defined plan for the future implementation of a Chemistry,

Manufacturing and Controls (CMC) change. The purpose of a CP is to allow for a

more expedient distribution of product by permitting you to submit a protocol for a

change, which if approved, may justify a reduced reporting category for the particular

change at the time the change is implemented. A new CP, or a change to an existing

one, requires approval prior to implementation because it may result in a decreased

reporting category for the changes covered in the CP (e.g., PAS to CBE30). The

reporting category will be established at the time that the CP is approved.

You may wish to receive our input on your implementation plans prior to commencing

your activities. For example, you could submit your validation plan as a CP for our

review in advance of implementing any change. This may allow you to make future

changes more expeditiously.

B. Applicability of a Comparability Protocol

You should assess if the use of a CP is appropriate for the specified manufacturing

change. Generally, the change should be a discrete, specific manufacturing change in a

facility, equipment, or process. There should be sufficient manufacturing experience and

acceptance criteria available to demonstrate that the change does not have an adverse

effect on the safety or effectiveness of the product. A CP should only be considered if:

1. The product manufactured using the change will meet approved product

standards.

2. The manufacturing process has been validated and all equipment qualified.

3. Appropriate validated assays are available to evaluate the effect of the change

on the product.

We have experience with several types of traditional CMC protocols that would be

appropriate for a CP. These include a change with a long planning or development

cycle but a short implementation window or a change that will be repeated several times

by the applicant in a similar, but not identical way. Examples of changes for which a CP

might be useful are:

1. Acquisition of facilities operating under one manufacturer’s license by another
21

licensee.

2. Single change in the manufacture of a product that will be implemented in

multiple facilities under a single license, e.g., plateletpheresis.

3. Change to use a cleared apheresis device for the collection of products

approved for this device, e.g., use of Fenwal Amicus to also collect Platelets,

Pheresis; Platelets, Pheresis, Leukocytes Reduced; and Fresh Frozen Plasma,

concurrently with plateletpheresis.

The use of a CP is not appropriate for all manufacturing changes. Certain changes may

be too critical, complex, or of such a magnitude that a CP cannot be designed to

adequately evaluate the effect of the change on the safety and effectiveness of the

product. In such cases, you would need a PAS to implement the change. Also,

changes already reported as CBE or in the annual report would have little benefit as a

CP. In general, the use of a CP is not appropriate for:

1. Broad ranging plans, covering any conceivable change in the manufacturing

process.

2. A change with the potential to adversely affect the product.

3. A change where pre-specified acceptance criteria are not available to determine

the effect of the change on the product.

4. A change resulting in a newly characterized product that is not currently

licensed.

5. The use of a new manufacturing facility for which we would normally conduct a

pre-license inspection.

6. A change in a facility, equipment or process for which we would normally

conduct a pre-approval inspection.

C. Content of a Comparability Protocol Submission

In addition to the information usually submitted in a prior approval supplement, you

should include some or all of the following in a CP:

1. Description of the planned manufacturing change;

2. Implementation plan;

3. Specific tests and validation protocols (include the rationale for selecting the

specific tests and protocols);

4. Criteria for acceptance of product prepared under changed conditions;

5. Description of actions taken if the acceptable results are not achieved;

6. Supportive data obtained from selected testing;

7. Training program;

8. Quality assurance program, including quality control testing plan;

9. Product submission sampling plan; and

10. Proposed change in reporting category.
22

D. Submission of a Comparability Protocol and Reporting of the

Manufacturing Change(s) Implemented Using an Approved Comparability

Protocol

You should submit the CP as a PAS and describe how you will implement a

manufacturing change. You should submit the actual change implemented using the

approved CP in the reporting category that we had specified in the approval letter (e.g.,

CBE30). In the second submission, you should describe the change, refer to the

approved CP, and include all the data committed to be collected under the CP.

The CP may contain supportive data and a request to distribute product made with the

specified manufacturing change or may only contain the implementation procedures

described in VII.C. with a request to review and approve the CP before the supportive

data are generated. If the CP is accompanied by supporting data and is approved, the

product made using the change described in the CP can be distributed. If the CP is

approved prior to the generation of data supporting the change, the supportive data

should be submitted in the reduced reporting category we specified in the approval

letter.

E. Failure to Meet the Criteria of an Approved Comparability Protocol

During the implementation of changes using an approved CP, you may discover

instances with unpredicted or unwanted outcomes and you must deviate from the

protocol to resolve the problems, deficiencies, or discrepancies. In such cases, you

may elect not to make the change, request that the CP be withdrawn, and report the

change as a PAS instead of the reporting category we specified when the CP was

approved. You should contact us as soon as possible to discuss the proper application

procedure.

F. Additional Considerations of a Comparability Protocol

Technical innovations may change the procedures and parameters specified in an

approved CP and may render the CP obsolete. If you are using an approved CP, you

should routinely review the procedures and specifications in the CP to assure that they

remain current and consistent with the applicable application and current guidance. If

modifications are required, you should withdraw the current CP and submit the modified

CP as a PAS.
23

VIII. LABELING CHANGES UNDER 21 CFR 601.12(f)

Under 21 CFR 601.12(f), you must report changes to labeling in one of the following ways:

1) As a supplement requiring FDA approval prior to distribution of a product with the

labeling change [21 CFR 601.12(f)(1)];

2) as a supplement requiring FDA approval but permitting distribution of a product bearing

such change prior to FDA approval [21 CFR 601.12(f)(2)]; or

3) in an annual report [21 CFR 601.12(f)(3)].

We have listed below examples of changes to labeling (product labels, circular of information,

package inserts) that we currently consider to be appropriate for submission in each of the

categories.* This list is not intended to be all-inclusive. A completed Form FDA 2567

“Transmittal of Labels and Circulars Form” should accompany each submission.

*NOTE: Report changes in the content of the label. Product labels must be consistent

with requirements stated in 21 CFR 606.121 for Whole Blood and blood components

and in 21 CFR 640.70 for Source Plasma and should be consistent with

recommendations in published guidance. You do not need to report changes in format

only.

A. Labeling changes requiring approval prior to product distribution [21 CFR

601.12(f)(1)]: Where applicable, circular of information must also be

submitted as part of the labeling submission. (NOTE: A current circular of

information does not have to be submitted if it is already in your file at

FDA.)

1. Labels submitted as part of a pending application or Prior Approval

Supplement.

2. Labeling which contains an additional claim. You may need to provide

documentation to support these claims.

3. Labels representing a change in the volume of Whole Blood collected, e.g., 450

mL. to 500 mL., with an approved SOP stating donor must weigh at least 110

lbs.

4. If you are already approved to manufacture Source Plasma for injectable

products and now want to include the manufacture of Source Plasma for noninjectable products, you should submit your non-injectable product label(s) in

this category.

5. If you are already approved to manufacture Source Plasma for non-injectable

products and now want to include the manufacture of Source Plasma for

injectable products, you should submit your injectable product label(s) in this

category.

6. Green base labels for units intended for autologous use only and labels printed

using black ink for all text (exemptions to 21 CFR 606.121 approved as 21

CFR 640.120 variance).
24

7. Conversion from Codabar to ISBT128 labels.

B. Labeling changes requiring FDA approval but product may be distributed

prior to FDA approval [21 CFR 601.12(f)(2)]:

1. Labels submitted as part of a Changes Being Effected (CBE30 or CBE)

supplement.

2. Labels consistent with an FDA-approved uniform Codabar labeling guideline.

3. Print on-demand, black and white ABO/Rh labels.

4. Labels representing a change in FDA-approved additive/anticoagulant solutions

used in blood product collection.

C. Labeling changes requiring submission in an annual report [21 CFR

601.12(f)(3)]:

1. Labels for Source Plasma collected from normal donors with pre-existing

disease-associated, red blood cell and/or HLA antibodies.

2. Labels representing a change in “doing business as” name that does not affect

the legal entity name on the license. Your legal entity name should appear on

the label.

IX. FAILURE TO COMPLY UNDER 21 CFR 601.12(g)

In addition to other remedies available in the law and regulations, if you repeatedly fail to

comply with 21 CFR 601.12, we may require that you submit a supplement for any proposed

change and obtain our approval of the supplement prior to distribution of the product made

using the change.
25

X. REFERENCES

1. Federal Register, 7/24/97 (62 FR 39890), Final Rule: Changes to an Approved

Application. (http://www.fda.gov/cber/rules/chng072497.htm)

2. Federal Register, 7/24/97 (62 FR 39904), Guidance for Industry: Changes to an

Approved Application: Biological Products, July 1997.

(http://www.fda.gov/cber/gdlns/chbiol.txt) (or substitute pdf for txt in the URL)

3. Federal Register, 10/29/97 (62 FR 56193), Workshop on the Biologics License

Application (BLA) for Blood Products and Reporting Changes to an Approved

Application, December 2, 1997. Sponsored by FDA, CBER.

4. Federal Register, 10/20/99 (64 FR 56441), Final Rule: Biological Products

Regulated Under Section 351 of the Public Health Service Act; Implementation of

Biological License; Elimination of Establishment License and Product License.

(http://www.fda.gov/cber/rules/elapla.txt) (or substitute pdf for txt in the URL)

5. Federal Register, 5/10/99 (64 FR 25049), Guidance for Industry: For the

Submission of Chemistry, Manufacturing and Controls and Establishment

Description Information for Human Blood and Blood Components Intended for

Transfusion or for Further Manufacture and For the Completion of the Form FDA

356h “Application to Market a New Drug, Biologic, or an Antibiotic Drug for

Human Use,” May 1999. (http://www.fda.gov/cber/gdlns/cmcblood.txt) (or

substitute pdf for txt in the URL)

6. Revised Form FDA 356h, Application to Market a New Drug, Biologic, or an

Antibiotic Drug for Human Use.

(http://www.fda.gov/opacom/morechoices/fdaforms/cber.html)

7. Workshop for Licensing Blood Establishments, January 30 & 31, 1995.

Sponsored by FDA, CBER.

8. Federal Register, 5/14/96 (61 FR 24227), Final Rule: Elimination of Establishment

License Application for Specified Biotechnology and Specified Synthetic Biological

Products. (http://www.fda.gov/cber/rules/ela051496.pdf)

9. Federal Register, 10/15/97 (62 FR 53536), Final Rule: Revision of the

Requirements for a Responsible Head for Biological Establishments.

(http://www.fda.gov/cber/genadmin/resphead.htm)

10. Federal Register, 11/25/92 (57 FR 55544), Notice: FDA’s Policy Statement

Concerning Cooperative Manufacturing Arrangements for Licensed Biologics.
26

11. Draft Reviewer’s Guide: “Disease Associated Antibody Collection Program,”

October 1, 1995. (by fax at 888-CBER-FAX)

12. Memorandum to All Licensed Manufacturers of Source Plasma: “Physician

Substitutes,” August 15, 1988. (http://www.fda.gov/cber/bldmem/081588.txt) (or

substitute pdf for txt in the URL)
27

APPENDIX A: Sample of a Blood Bank Annual Report

Annual Report for Community or Hospital Blood Bank

 123 Sunshine Drive

Any town, USA xxxxx

U.S. License Number xxxx

Registration # xxxxxxx

Reporting period: January 1, 1998 to December 31, 1998

XYZ Blood Establishment is currently licensed to manufacture:

Whole Blood; Red Blood Cells; Platelets; Platelets, Pheresis; Fresh Frozen Plasma;

Red Blood Cells, Irradiated; Platelets, Leukocytes Reduced; Source Plasma

See attached organizational chart, including a list of all facilities and contractors.

Equipment changes:

March 1, 1998

Removal of all Fenwal CS3000 and using Cobe Spectra exclusively for Platelets,

Pheresis.

August 1, 1998

Implement use of computerized donor information system. LAN at all transfusion

centers, Mainframe at Reg. No. xxxxxxx

Facility changes:

June 13, 1998

Closed Whole Blood Donor Center at 321 Sunshine Dr., Anytown, USA (Reg. No.

xxxxxxx).

Procedure changes:

September 10,1998

Implemented Anti-HTLV-II testing in accordance with FDA guidance document

(8/97). At the same time changed from Abbott HTLV-I EIA assay to Abbott HTLVI/II EIA assay.

Contractual changes:

None
28

APPENDIX B: Sample of a Source Plasma Facility Annual Report

Annual report for Source Plasma Center

U.S. License Number xxxx

Reporting period: July 1, 1998 to June 30, 1999

XYZ Blood Establishment is currently approved to manufacture Source Plasma for further

manufacture into injectable and non-injectable products collected from the following donors:

• Normal, non-immunized

• Pre-existing disease associated antibodies (CMV, RSV, HAV, VSV)

• Immunized with red blood cells for the Rho (D) antigen

Minor changes:

Description of Change - Installed our 510k approved computerized donor information system

in 3 of our facilities. We are using the same SOP and there have been no user modifications of

the software. Staff training is on file at the facility.

Facilities using change - 123 Road, City1, State, Reg. No. xxxxxx1; 456 Street, City2,

State, Reg. No.xxxxxx2; 789 Avenue, City3, State, Reg. No. xxxxxx3.

Implementation Date - Reg. No. xxxxxx1 - July 4, 1998; Reg. No. xxxxxx2 - September 7,

1998; Reg. No. xxxxxx3 - February 14, 1999

Description of Change - Started collecting plasma from donors with pre-existing diseaseassociated antibodies to CMV, RSV, HAV and VSV.

Facilities using change - All

Implementation Date - August 31, 1998

Comments - SOP xx: Disease Associated Antibody Collection Program. We are using labels

approved under label review number 19980810001.

Description of Change - Upgraded all of our Haemonetics PCS automated plasmapheresis

machines to Haemonetics PCS-2. Documentation of staff training is on file at the centers.

Facilities using change - All

Implementation Date - December 10, 1998

See attached organizational chart.

See attached list of major facilities including contractors.
29

APPENDIX C: Sample of a Blood Establishment with Multiple Facilities Annual

Report

Annual Report for Blood Establishment with major and auxiliary facilities.

U.S. License Number xxxx

Reporting period: January 1, 1998 to December 31, 1998

XYZ Blood Establishment is currently licensed to manufacture:

Source Plasma, Whole Blood

Major Facilities:123 Sunshine Drive 456 Snowstorm Street

Any town, USA xxxxx Any town, USA xxxxx

Registration # xxxxxxx Registration # xxxxxx1

Auxiliary Facilities: 321 Sunshine Drive

Anytown, USA

Registration #. xxxxxxx

See attached organizational chart.

Description of Change Facilities using change Implementation Date Comments

Change in SOP

• Revised SOP for training

• Additional procedures for QC

of electronic donor weight

scale

• Addition of procedures for

handling audits and inspections

All

January 3, 1998

March 7, 1998

April 13, 1998

Implement use of computerized

donor information system

LAN at all centers,

Mainframe at Reg. No.

xxxxxx1

August 1, 1998

Implemented Anti-HTLV-II in

accordance with FDA guidance

document (8/97)

All September 10, 1998 All cellular

products

Change in facilities and locations:

June 13, 1998 – Opened new Whole Blood donor center at 321 Sunshine Drive,

Anytown, USA (Reg. No. xxxxxxx, if available) for the manual

collection of Whole Blood only.

Change in major equipment: None

Change in donor suitability criteria: None, other than those already reported

Change in contractors: None
30

APPENDIX D: Table: Types of Facilities as Determined by the Manufacturing Steps They Perform

Facilities Major Facilities

(Major Facilities may perform some or all of the manufacturing steps listed below.)

Auxiliary Facilities

(Auxiliary facilities may

perform some or all of

the steps listed below.)

Transfusion

Services

Manufacturing Steps

Collection

Facility

Community

Blood Bank

Component

Preparation

Facility

Hospital

Blood Bank

Plasmapheresis

Center

Product Testing

Laboratory

Distribution

Center

Donor

Center

Transfusion

Service

Manual WB1 collection X X X X

WB1 component preparation X X X

Auto.1 Plateletpheresis X X X X X

3

Automated RBC apheresis X X X X

Automated Plasmapheresis X X X X X X

4

Manual Plasmapheresis X X X X X

Product testing X X X X

Labeling X X X X X

Storage X X X X X X

Distribution X X X X X X

Irradiation X X X

Freeze/Deglycerolization X X X

Leukocyte reduction2 X X X

Compatibility testing X X X

1. WB = Whole Blood; Auto = Automated

2. Leukocyte reduction – does not include bedside filtration

3. If the applicant wishes to distribute platelets made at these centers under licensure, a PAS for the manufacture of Platelets Pheresis should be

submitted.

4. Only applies to an infrequent plasmapheresis donor collection program.