Changes to an Approved Application:  
Biological Products:  Human Blood 
and Blood Components Intended for 
Transfusion or for Further 
Manufacture 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-7800, or email ocod@fda.hhs.gov, or 
from the Internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
December 2014 
 
  Contains Nonbinding Recommendations 
Table of Contents 
 
 
I.  INTRODUCTION .............................................................................................................1 
II.  BACKGROUND ................................................................................................................2 
III.  DEFINITIONS ...................................................................................................................3 
IV.  RECOMMENDATIONS ...................................................................................................8 
A.  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)  Reporting Category (PAS) ...............................9 
B.  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)  Reporting Category (CBE30) ..................10 
C.  Changes under 21 CFR 601.12(c)(5) - Changes Requiring Supplement 
Submission Before Distribution of the Product Made Using the Change But 
Such Product May Be Distributed Immediately Upon FDAs Receipt of the 
Supplement  Reporting Category (CBE) ........................................................11 
D.  Changes under 21 CFR 601.12(d) - Changes to be Described in an Annual 
Report (Minor Changes)  Reporting Category (AR) ......................................12 
V.  COMPARABILITY PROTOCOL (CP) UNDER 21 CFR 601.12(E) .........................15 
A.  Description of a Comparability Protocol ...........................................................15 
B.  Applicability of a Comparability Protocol ........................................................16 
C.  Content of a Comparability Protocol Submission ............................................17 
D.  Failure to Meet the Criteria of an Approved Comparability Protocol ...........17 
E.  Additional Considerations of a Comparability Protocol ..................................18 
VI.  LABELING CHANGES UNDER 21 CFR 601.12(F) ...................................................18 
A.  Labeling Changes Requiring FDA Approval Prior to Product Distribution 
(21CFR 601.12(f)(1))  Reporting Category (PAS) ...........................................18 
B.  Labeling Changes Requiring FDA Approval but Product May Be Distributed 
Prior to FDA Approval (21 CFR 601.12(f)(2))  Reporting Category (Special 
Labeling Supplement  Changes Being Effected) .............................................20 
C.  Labeling Changes Requiring Submission in an Annual Report ......................20 
VII.  SUBMISSION OF CHANGES TO FDA .......................................................................20 
VIII.  FAILURE TO COMPLY UNDER 21 CFR 601.12(G) .................................................21 
IX.  REFERENCES .................................................................................................................22 
APPENDIX A:  TYPES OF ESTABLISHMENTS/FACILITIES AND 
MANUFACTURING STEPS PERFORMED .......................................................................... 24 
APPENDIX B:  REPORTING FACILITY CHANGES ......................................................... 25 
APPENDIX C:  REPORTING CHANGES IN FACILITY RELOCATIONS ..................... 28 
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  Contains Nonbinding Recommendations 
APPENDIX D:  REPORTING CHANGES ASSOCIATED WITH BLOOD 
ESTABLISHMENT COMPUTER SOFTWARE (BECS) ..................................................... 29 
APPENDIX E:  REPORTING CHANGES IN APHERESIS OPERATIONS AND 
AUTOMATED BLOOD SEPARATOR DEVICES ................................................................ 31 
APPENDIX F:  REPORTING CHANGES IN SOURCE PLASMA/IMMUNIZATION 
PROGRAMS FOR SOURCE PLASMA DONORS ................................................................ 32 
APPENDIX G:  REPORTING CHANGES IN THE MANUFACTURE OF 
LEUKOCYTES REDUCED BLOOD COMPONENTS ......................................................... 33 
APPENDIX H:  REPORTING CONTRACT CHANGES...................................................... 34 
APPENDIX I:  REPORTING CHANGES IN DONOR HISTORY QUESTIONNAIRES.. 36 
APPENDIX J:  REPORTING CHANGES IN STANDARD OPERATING PROCEURES 
(SOPS) .......................................................................................................................................... 37 
APPENDIX K:  REPORTING CHANGES IN EQUIPMENT .............................................. 40 
APPENDIX L:  REPORTING PRODUCT MANUFACTURING/PROCEDURAL 
CHANGES ................................................................................................................................... 41 
ii 
  Contains Nonbinding Recommendations 
Changes to an Approved Application:  Biological Products:  Human 
Blood and Blood Components Intended for Transfusion or for 
Further Manufacture 
 
 
Guidance for Industry 
 
This guidance represents the Food and Drug Administrations (FDAs or Agencys) current 
thinking on this topic.  It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies 
the requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
 
 
I.  INTRODUCTION 
 
We, FDA, are providing you, manufacturers of licensed Whole Blood and blood components 
intended for transfusion or for further manufacture, including Source Plasma, with 
recommendations intended to assist you in determining which reporting mechanism is 
appropriate for submission of changes to an approved Biologics License Application (BLA) in 
accordance with the requirements under Title 21 of the Code of Federal Regulations (CFR) 
601.12 (21 CFR 601.12), including recommendations in connection with the applicability and 
content of comparability protocols under 21 CFR 601.12(e) and labeling changes under 21 CFR 
601.12(f). 
 
This guidance finalizes the draft guidance of the same title dated June 2013 (78 FR 32668, May 
31, 2013) and supersedes the guidance entitled, Changes to an Approved Application:  
Biological Products:  Human Blood and Blood Components Intended for Transfusion or for 
Further Manufacture dated July 2001 (66 FR 41247, August 7, 2001) (Ref. 1). 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
   
1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
Frequently, a manufacturer of a licensed product determines that it is appropriate to make a 
change in its product, production process, quality controls, equipment, facilities, responsible 
personnel, or labeling.  Section 601.12 (21 CFR 601.12) states the requirements for you to report 
such changes for your licensed biological products to FDA. 
 
Under 21 CFR 601.12, you must report each change in the product, production process, quality 
controls, equipment, facilities, responsible personnel or labeling established in the approved 
license application to FDA in one of the following categories of submissions: 
 
  a supplement which must be approved before distribution of the product made using 
the change; 
  a supplement submitted at least 30 days before distribution of the product made using 
the change; or 
  as a change described in an Annual Report (AR). 
 
The submission category depends on the potential for the change to have an adverse effect on the 
identity, strength, quality, purity, or potency of the product as they may relate to the safety or 
effectiveness of the product (Ref. 2) (referred to in this document as the safety or effectiveness 
of the product).  Before distributing a licensed product made using a change from the approved 
BLA, you are required to assess the effects of the change and demonstrate, through appropriate 
validation and/or other clinical and/or non-clinical laboratory studies, the lack of an adverse 
effect of the change on the safety or effectiveness of the product (21 CFR 601.12(a)(2)). 
 
The three reporting categories into which a change to an approved application may be placed are 
defined in 21 CFR 601.12 and are as follows: 
 
  Major Change.  A change that has a substantial potential to have an adverse effect on the 
safety or effectiveness of the product.  Major changes require the submission of a Prior 
Approval Supplement (PAS) to FDA, which FDA must approve before you distribute the 
product made using the change (21 CFR 601.12(b)). 
 
  Moderate Change.  A change that has a moderate potential to have an adverse effect on 
the safety or effectiveness of the product.  Moderate changes require the submission of a 
Changes Being Effected in 30 Days Supplement (CBE30) to FDA at least 30 days before 
you distribute the product made using the change (21 CFR 601.12(c)).  In certain 
circumstances, FDA may determine that the product made using the change may be 
distributed immediately upon receipt of the Changes Being Effected Supplement (CBE) 
by FDA (21 CFR 601.12(c)(5)). 
 
  Minor Change.  A change that has a minimal potential to have an adverse effect on the 
safety or effectiveness of the product.  Minor changes must be described by the applicant 
in an AR (21 CFR 601.12(d)). 
 
   
2  Contains Nonbinding Recommendations 
If you make a change to an approved BLA, 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 (FD&C Act) (21 U.S.C. 351(a)(2)(B)) and the regulations 
in 21 CFR Parts 210, 211 and Parts 600 through 680.  For example, you must comply with the 
relevant recordkeeping requirements (21 CFR 600.12) and ensure that the relevant records are 
readily available for examination by authorized FDA personnel during an inspection  
(21 CFR 600.22).  The recommendations contained in this guidance reflect current FDA and 
industry experience with reporting changes to an approved BLA, including reporting the 
implementation of new technologies.  Based on our experiences, we have revised 
recommendations that were in the July 2001 Guidance for reporting categories for certain 
changes to an approved application.  In addition, this guidance has been updated to include 
recommendations for reportable changes that were not included in the July 2001 Guidance. 
 
If you have questions concerning which reporting category is appropriate, you may contact FDA 
prior to submitting a supplement.   
 
 
III.  DEFINITIONS 
 
The following terms are defined for the purpose of this document: 
 
Acquisition:  The purchase of a facility previously operated under one United States (U.S.) 
license number by a manufacturer holding a different U.S. license number or by a new applicant.  
This also includes combining facilities operating under different licenses owned by the same 
corporation so that there is only one surviving license number.  Note:  Once the acquisition is 
complete, the acquired facility will no longer be associated with 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 
products at the acquired facility.  If a new applicant has acquired a facility, we will grant a new 
license (Ref. 3).  See Appendix B of this guidance.   
 
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) (42 
U.S.C. 262).  Note:  The applicant assumes responsibility for compliance with the applicable 
product and establishment standards and for quality assurance (QA) oversight of all 
manufacturing steps (Ref. 4). 
 
AR (Annual Report):  A report describing changes in the product, production process, quality 
controls, equipment, facilities, or responsible personnel that have a minimal potential to have an 
adverse effect on the safety or effectiveness of the product (21 CFR 601.12(d)).  Labeling 
changes requiring submission in an AR are described in 21 CFR 601.12(f)(3). 
 
Authorized Official:  A person designated by the applicant to communicate with FDA on behalf 
of the applicant.  Note:  An authorized official can initiate applications or supplements to a 
license application, discuss submissions and product correspondence with FDA representatives,  
   
3  Contains Nonbinding Recommendations 
provide additional information in support of the submissions, and withdraw applications or 
supplements (Ref. 5).  The applicant should immediately notify FDA in writing if there is a 
change in the authorized official.   
 
BLA (Biologics License Application):  An application for a biologics license to manufacture 
and distribute in interstate commerce a product subject to licensure under section 351 of the PHS 
Act, including supportive documentation (Ref. 6). 
 
Blood Product:  A drug which consists of human whole blood, plasma or serum or any product 
derived from human whole blood, plasma or serum (21 CFR 607.3(b)). 
 
Circular of Information:  Required labeling that must be available for distribution with Whole 
Blood or blood components intended for transfusion.  The circular of information must provide 
adequate directions for the use of blood and blood components intended for transfusion, 
including the following information:  a description of the blood product; information on the tests 
performed for communicable disease agents; indications for use; contraindications; side effects 
and hazards; dosage and administration recommendations (21 CFR 606.122) (Ref. 7). 
 
CBE (Changes Being Effected Supplement):  A supplement submission for a change that 
has a moderate potential to have an adverse effect on the safety or effectiveness of the 
product which may be implemented any time after FDA receives the submission describing 
the change.  
 
CBE30 (Changes Being Effected in 30 Days Supplement):  A supplement submission for 
certain changes that have a moderate potential to have an adverse effect on the safety or 
effectiveness of the product which FDA receives at least 30 days before the distribution of the 
product made using the change.   
 
Computer-Assisted Interactive Interview:  The administration of questions to potential donors 
using a computer system without direct oral questioning by donor screening personnel.  The 
software program may make donor eligibility decisions based on the potential donors responses. 
There are non-web-based computer-assisted interactive interview software programs, which can 
be accessed at a firms fixed locations or mobiles and web-based computer-assisted interactive 
interview software programs, which permit potential donors to have remote access to the donor 
history questionnaire via the Internet (Ref. 8).  Note:  This definition does not apply to computer 
programs used to display questions to a blood establishments donor screening personnel who 
administer the questions to the potential donor by direct oral questioning and enter the donors 
responses into the computer. 
 
Contractor:  Any person or entity, other than the applicant, that performs part or all of the 
manufacturing of a licensed product as a service to the applicant under a contract.  Note:  The 
applicant is responsible for determining that a contractor is in compliance with applicable FDA 
requirements (Ref. 9).  All contractors performing a manufacturing step for a licensed product 
must be registered with FDA, unless they are exempt from registration (21 CFR Part 607). 
 
   
4  Contains Nonbinding Recommendations 
Contractual Agreement:  Written legal agreement between a manufacturer and a contractor that 
describes the manufacturing steps performed by the contractor.  Note:  Although the firm does 
not need to include the specific legal contract in the submission, the submission should include a 
description of the services performed by the contractor for each manufacturing step, for example, 
the performance by an outside testing laboratory of routine donor/product testing or confirmatory 
testing, the irradiation of products, the supply of red blood cells for immunization, or the 
provision of storage services.  The agreement should also be available for review during 
inspections. 
 
Core Personnel:  Establishment/facility management, medical personnel and staff responsible 
for quality oversight. 
 
Comparability Protocol (CP):  A PAS describing the specific tests and validation studies and 
acceptable limits to be achieved to demonstrate the lack of adverse effects for specified types of 
manufacturing changes on the safety or effectiveness of the product, which must be approved by 
FDA before distribution of the product (21 CFR 601.12(e)).  
 
Disease-Associated IgG Antibody Donor:  A donor who meets all the required or 
recommended normal Source Plasma donor eligibility criteria and whose plasma contains pre-
existing IgG antibodies as a result of previous exposure to certain diseases or cellular antigens 
(Ref. 10). 
 
Disease-State/High-Risk Donor:  A donor whose plasma contains or lacks a specific property 
(for example, a protein, antibody, inherited trait) as a result of the donors disease.  Note:  This 
donor may not meet all the required or recommended Source Plasma donor eligibility criteria but 
nonetheless may be an acceptable donor under certain circumstances. 
 
eSubmitter:  An electronic submissions program that is currently available for voluntary use by 
sponsors, manufacturers, and importers to submit a variety of submission types for FDA-
regulated products.  eSubmitter is an acceptable mechanism for the submission of BLAs, BLA 
supplements, annual reports and amendments to pending eSubmitter regulatory submissions by 
licensed blood establishments that collect Whole Blood and blood components, including Source 
Plasma (Ref. 11). 
 
Establishment/Facility:  A place of business under one management at one general physical 
location.  The term includes, among others, human blood and plasma donor centers, blood 
banks, transfusion services, other blood product manufacturers and independent laboratories 
that engage in quality control and testing for registered blood product establishments.  Note:  
The facility in which a biological product is manufactured, processed, packed or held must meet 
standards designed to assure that the biological product continues to be safe, pure and potent 
(PHS Act) (42 U.S.C. 262(a)(2)(C)(i)(II)).  The term establishment has the same meaning as 
facility and includes all locations (21 CFR 600.3(w)) (Ref. 12). 
 
   
5  Contains Nonbinding Recommendations 
Types of Facilities: 
 
  Collection Facility:  A facility that collects Whole Blood and/or apheresis products, 
and/or performs plasmapheresis collected by manual or automated methods, but does not 
perform FDA required or recommended blood and plasma donor testing.   Collection 
facilities may also label, store, and distribute blood products. 
 
  Community Blood Bank:  A commercial or non-profit blood collection/processing 
facility, not located in a hospital, that may perform manual and/or automated blood 
collection, prepare components from Whole Blood, perform FDA required or 
recommended blood and plasma donor testing, perform compatibility testing and that 
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, pre-storage pooled Platelets and pre-storage pooled 
Cryoprecipitated AHF. 
 
  Component Preparation Facility:  An intermediate processing facility that prepares 
components from Whole Blood or further processes apheresis components 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 label, store, and 
distribute blood products and/or may prepare irradiated, frozen, deglycerolized and/or 
leukoreduced products, pre-storage pooled Platelets and pre-storage pooled 
Cryoprecipitated AHF. 
 
  Hospital Blood Bank:  A facility located within a hospital or associated with a hospital 
system that routinely performs manual and/or automated blood collection and processes 
Whole Blood into blood components.  A hospital blood bank may also prepare irradiated, 
frozen, deglycerolized and/or leukoreduced products, pre-storage pooled Platelets and 
pre-storage pooled Cryoprecipitated AHF, distribute blood products to other hospitals and 
may perform FDA required or recommended blood and plasma donor testing and 
compatibility testing. 
 
  Plasmapheresis Center:  A facility that collects Source Plasma by manual and/or 
automated methods.  Plasmapheresis centers may also perform FDA required or 
recommended plasma donor testing. 
 
  Product Testing Laboratory:  A facility that performs routine FDA required or 
recommended blood and plasma donor testing. 
 
  Distribution Center:  A facility that stores Whole Blood or blood components under 
specific controlled conditions prior to shipment to the final user, including suppliers of 
source material for further manufacture, such as recovered plasma and Source Plasma or 
Whole Blood, Red Blood Cells, or Platelets for diagnostic use; for example, Source 
Plasma warehouses that intend to redistribute the product to fractionators or recovered 
plasma holding facilities or brokers that intend to redistribute the product to diagnostic  
   
6  Contains Nonbinding Recommendations 
device 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. 
 
Inspection:  A careful, critical, official evaluation conducted by FDA personnel of operations at 
an establishment to assess whether the establishment is in compliance with applicable laws and 
regulations and the standards established in the BLA.   
 
Types of Inspection: 
 
  Pre-License Inspection:  An announced inspection conducted by a team of the Center 
for Biologics Evaluation and Research (CBER) inspectors and/or Office of Regulatory 
Affairs (ORA) investigators.  This comprehensive inspection is conducted as part of the 
review of an application for a U.S. license for a new product by an establishment that has 
not previously manufactured a licensed product. 
 
  Pre-Approval Inspection:  An announced or unannounced inspection conducted by 
inspectors from CBER and/or investigators from ORA, FDA.  This inspection is 
conducted as part of the review of a supplement to an approved BLA.  Note:  Examples 
of supplements that would require a pre-approval inspection include submissions for an 
additional new facility operating under an existing U.S. license, the manufacture of 
irradiated blood products, or implementation of a red blood cell immunization program 
under a Source Plasma 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 blood establishments are in compliance with applicable laws and 
regulations and with commitments made in the approved license application.  Examples 
of post-approval inspections include the annual/biennial inspections and directed 
inspections.  Directed inspections are unannounced for cause inspections conducted by 
ORA investigators who inspect selected operations of an establishment.  Examples of 
directed inspections include a follow-up to a fatality report or consumer complaint. 
 
Manufacture:  The collection, preparation, processing or compatibility testing by chemical, 
physical, biological or other procedures of any blood product which meets the definition of a 
drug, as defined in section 201(g) of the FD&C Act, including manipulation, sampling, testing or 
control procedures applied to the final product or to any part of the process.  The term includes 
packaging, labeling, repackaging or otherwise changing the container, wrapper, or labeling of 
any blood product package in furtherance of the distribution of the blood product from the 
original place of manufacture to the person who makes final delivery or sale to the ultimate 
consumer (21 CFR 607.3(d)).  The term means all steps in propagation or manufacture and 
preparation of products and includes, but is not limited to, filling, testing, labeling, packaging, 
and storage by the manufacturer (21 CFR 600.3(u)). 
 
   
7  Contains Nonbinding Recommendations 
Manufacturer:  Any legal person or entity engaged in the manufacture of a product subject to 
license under the PHS Act.  The term also includes any legal person or entity who 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)). 
 
Manufacturers 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.  The term may also be used to 
describe the instructions in equipment operators manuals and product labels. 
 
Merger:  A union of two or more licensed manufacturers to form a new legal entity (See SOPP 
8403:  Issuance and Reissuance of Licenses for Biological Products) (Ref. 13). 
 
Prior Approval Supplement (PAS):  A supplement submission for a major change that has a 
substantial potential to have an adverse effect on the safety or effectiveness of the product and 
for which distribution of the product made using the change cannot occur before FDA approval 
is obtained (21 CFR 601.12(b)). 
 
Product Correspondence:  Any communication from a manufacturer to FDA, excluding ARs, 
that is not related to a pending supplement or application.  Examples of product correspondence 
include changes in corporate mailing addresses or a change in or addition of, an authorized 
official.  Note:  Product correspondence is not a reporting category under 21 CFR 601.12. 
 
Self-Administered Questionnaire:  Questionnaire in which the donor reads or listens to the 
medical/health history questions and/or high-risk questions and documents his/her answers.  A 
self-administered questionnaire process allows a donor to answer the pre-donation screening 
questions without direct oral questioning by collection personnel (Ref. 8). 
 
Supplement:  Request submitted to the Director, CBER, to approve a change in an approved 
license application (21 CFR 600.3(gg)). 
 
 
IV.  RECOMMENDATIONS 
 
In this guidance document, we provide examples of changes to be submitted in each reporting 
category described in 21 CFR 601.12.  These examples are not intended to be all-inclusive and 
the recommended reporting categories may change as new products and technologies become 
available. 
 
When you implement recommendations contained in a specific guidance document, you should 
report the changes to FDA in accordance with the instructions in that specific guidance 
document. 
 
8  Contains Nonbinding Recommendations 
A.  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)  Reporting Category (PAS) 
 
Under 21 CFR 601.12(b), if you make any change to your product, production process, 
quality controls, equipment, facilities or responsible personnel 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 approval from FDA prior to distribution of the product 
made using the change.  You must submit product manufacturing/procedural changes, 
equipment changes, contractor changes and facility changes in a PAS, as required under  
21 CFR 601.12(b), unless this guidance specifies that the change may be reported in 
another category.  Labeling changes requiring submission in a PAS are described in  
21 CFR 601.12(f)(1). 
 
Under 21 CFR 601.12(b)(3), for a change under this category, you must submit a 
supplement to your approved BLA that includes the following: 
 
  a detailed description of the proposed change; 
  the product(s) 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 products safety or effectiveness; 
  the data derived from such studies; 
  relevant validation protocols and data; and 
  a reference list of relevant Standard Operating Procedures (SOPs).  In some cases, 
we may recommend submission of a complete set of SOPs describing all 
manufacturing impacted by the proposed change. Please refer to the FDA 
guidance to industry entitled, 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 dated May 1999 (May 1999 Guidance) (Ref. 14). 
 
In addition, if the change involves a change in labeling, you must follow the requirements 
in 21 CFR 601.12(f), discussed in section VI of this guidance. 
 
Refer to the following appendices for examples of applicable changes: 
 
  Appendix B:  Reporting Facility Changes 
  Appendix C:  Reporting Changes in Facility Relocations 
  Appendix D:  Reporting Changes Associated with Blood Establishment Computer 
Software (BECS) 
  Appendix E:  Reporting Changes in Apheresis Operations and Automated Blood 
Separator Devices 
 
9  Contains Nonbinding Recommendations 
  Appendix F:  Reporting Changes in Source Plasma/Immunization Programs for 
Source Plasma Donors 
  Appendix G:  Reporting Changes in Manufacture of Leukocytes Reduced Blood 
Components 
  Appendix H:  Reporting Contract Changes 
  Appendix I:  Reporting Changes in Donor History Questionnaires 
  Appendix J:  Reporting Changes in Standard Operating Procedures (SOPS) 
  Appendix K:  Reporting Changes in Equipment  
  Appendix L:  Reporting Product Manufacturing/Procedural Changes 
 
B.  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)  Reporting Category (CBE30) 
 
Under 21 CFR 601.12(c), if you make any change to your product, production process, 
quality controls, equipment, facilities or responsible personnel that has a moderate 
potential to have an adverse effect on the safety or effectiveness of the product, you must 
submit a supplement to FDA at least 30 days prior to distribution of the product made 
using the change.  The information contained in the supplement is the same as for a PAS  
(See 21 CFR 601.12(b)(3)). 
 
You must specify that the changes are being reported in this category by labeling the 
submission:  Supplement - Changes Being Effected in 30 Days (21 CFR 601.12(c)).  
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.   
 
Note:  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 have been reported in the proper category. 
 
We will not notify you when we receive your CBE30 supplement; instead, we 
recommend that you have a mechanism to track the date we received the supplement 
submission; for example, a courier 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 problem(s) 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  
   
10  Contains Nonbinding Recommendations 
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. 
 
Refer to the following appendices for examples of applicable changes: 
 
  Appendix B:  Reporting Facility Changes 
  Appendix C:  Reporting Changes in Facility Relocations 
  Appendix D:  Reporting Changes Associated with Blood Establishment Computer 
Software (BECS) 
  Appendix E:  Reporting Changes in Apheresis Operations and Automated Blood 
Separator Devices 
  Appendix F:  Reporting Changes in Source Plasma/Immunization Programs for 
Source Plasma Donors 
  Appendix G:  Reporting Changes in Manufacture of Leukocytes Reduced Blood 
Components 
  Appendix H:  Reporting  Contract Changes 
  Appendix I:  Reporting Changes in Donor History Questionnaires 
  Appendix J:  Reporting Changes in Standard Operating Procedures (SOPS) 
  Appendix K:  Reporting Changes in Equipment   
  Appendix L:  Reporting Product Manufacturing/Procedural Changes 
 
C.  Changes under 21 CFR 601.12(c)(5) - Changes Requiring Supplement 
Submission Before Distribution of the Product Made Using the Change But 
Such Product May Be Distributed Immediately Upon FDAs Receipt of the 
Supplement  Reporting Category (CBE) 
 
As described in 21 CFR 601.12(c)(5), in certain circumstances, we may determine that, 
based on our experience with a particular type of change, the supplement for such change 
is usually complete and provides the proper information.  Likewise, there may be 
particular assurances that the proposed change has been appropriately submitted, such as 
when the change has been validated in accordance with a previously approved protocol.  
In these circumstances, 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, as mentioned 
in section IV.B. of this guidance.  Labeling changes requiring submission in a CBE are 
described in 21 CFR 601.12(f)(2). 
 
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.    
 
   
11  Contains Nonbinding Recommendations 
Note:  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 
change is 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 problem(s) 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. 
 
Refer to the following appendices for examples of applicable changes: 
 
  Appendix B:  Reporting Facility Changes 
  Appendix C:  Reporting Changes in Facility Relocations 
  Appendix D:  Reporting Changes Associated with Blood Establishment Computer 
Software (BECS) 
  Appendix E:  Reporting Changes in Apheresis Operations and Automated Blood 
Separator Devices 
  Appendix F:  Reporting Changes in Source Plasma/Immunization Programs for 
Source Plasma Donors 
  Appendix G:  Reporting Changes in Manufacture of Leukocytes Reduced Blood 
Components 
  Appendix H:  Reporting Contract Changes  
  Appendix I:  Reporting Changes in Donor History Questionnaires 
  Appendix J:  Reporting Changes in Standard Operating Procedures (SOPS) 
  Appendix K:  Reporting Changes in Equipment 
  Appendix L:  Reporting Product Manufacturing/Procedural Changes 
 
D.  Changes under 21 CFR 601.12(d) - Changes to be Described in an Annual 
Report (Minor Changes)  Reporting Category (AR) 
 
Under 21 CFR 601.12(d), you must document changes to the product, production 
process, quality controls, equipment, facilities or responsible personnel that have minimal 
potential to have an adverse effect on the safety or effectiveness of the product in an AR 
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(s) in your AR.  Labeling changes requiring submission in an AR are 
described in 21 CFR 601.12(f)(3). 
 
12  Contains Nonbinding Recommendations 
Your first anniversary date is based on your first product approval.  You may request an 
alternative date for the purpose of combining ARs for multiple approved applications into 
a single AR submission; such a request must be in writing (21 CFR 601.12(d)(1)).  We 
will notify you if your alternative date is acceptable.  If so, the alternate date will become 
your new anniversary date and the combined report must be submitted within 60 days of 
this date. 
 
You should submit one original AR and two copies to FDA for review.  If there are no 
minor changes to report, you need not submit an AR. 
 
We will review the AR to determine if the changes were reported in the proper category.  
If the AR 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 
AR.  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. 
 
Refer to the following appendices for examples of applicable changes: 
 
  Appendix B:  Reporting Facility Changes 
  Appendix C:  Reporting Changes in Facility Relocations 
  Appendix D:  Reporting Changes Associated with Blood Establishment Computer 
Software (BECS) 
  Appendix E:  Reporting Changes in Apheresis Operations and Automated Blood 
Separator Devices 
  Appendix F:  Reporting Changes in Source Plasma/Immunization Programs for 
Source Plasma Donors 
  Appendix G:  Reporting Changes in Manufacture of Leukocytes Reduced Blood 
Components 
  Appendix H:  Reporting Contract Changes  
  Appendix I:  Reporting Changes in Donor History Questionnaires 
  Appendix J:  Reporting Changes in Standard Operating Procedures (SOPS) 
  Appendix K:  Reporting Changes in Equipment 
  Appendix L:  Reporting Product Manufacturing/Procedural Changes 
 
1.  Information that should not be included in the AR: 
 
a.  Major or moderate changes that have received FDA approval as 
supplements during the reporting period, unless they are included in 
the organizational changes. 
 
b.  Major or moderate changes submitted as supplements and currently 
under our review. 
 
13  Contains Nonbinding Recommendations 
c.  Shipment of inadvertently collected Source Plasma that is repeatedly 
reactive or positive for an infectious disease marker and is to be used 
in the manufacture of vaccines and in vitro diagnostic biological 
products. You must report these shipments in the manner stated in  
21 CFR 610.40(h)(2). 
 
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.  If the development of unexpected antibodies is due to an 
error in immunization practices, you must report this under  
21 CFR 606.171. 
 
e.  Biological product deviation reports, and fatalities as a result of 
complications of blood collection or transfusion.  You must report 
these events as provided under the reporting requirements (21 CFR 
606.170 and 606.171). 
 
f.  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 by 
FDA during inspections, unless FDA has requested it for a specific 
submission, for example, a CP. 
 
g.  Information usually contained in a product correspondence (PC), for 
example, a change in corporate mailing address of the legal entity, a 
change in, or addition of, an authorized official, or a request to change 
an AR date.  
 
Note:  The PC describes changes that may or may not require a review 
and/or approval.  A PC does not normally require a response from FDA.  
The examples listed are not intended to be all-inclusive. 
 
2.  Reporting format for the AR 
 
We recommend that you use the following reporting format or eSubmitter for the 
AR.  However, you may choose to use a different format. In either case, you 
should include the information listed below in your report. 
 
a.  A cover letter summarizing the contents of your AR (for hard copy 
submissions only). 
 
b.  A completed Form FDA 356h, Application to Market a New Drug, 
Biologic, or an Antibiotic Drug for Human Use (Ref. 6).  The form 
should include, reflect or identify: 
 
14  Contains Nonbinding Recommendations 
        i.    Your U.S. license number; and 
ii.  The time period covered in the report. 
 
c.  A description of changes to the organizational systems involved in the 
manufacture of Whole Blood and blood components, including any 
quality assurance activities.  This description may include the 
following information: 
 
i.  If organizational changes have occurred since the last report, 
a current organization chart (optional) with descriptive job 
titles; and 
ii.  A list of the licensed products (optional) you are currently 
approved to distribute in interstate commerce.  
 
d.  A full description of minor changes reported to approved applications.  
This description should include: 
 
i.  The products affected by each change; 
ii.  The facility or facilities where the change was implemented; 
including their registration numbers; 
iii. The date the change became effective; 
iv. The Submission Tracking Number(s) (STNs) for any approved 
CPs used to implement the change; and 
v.  A description of the SOP or process affected by the change. 
 
 
V.  COMPARABILITY PROTOCOL (CP) UNDER 21 CFR 601.12(e)  
 
A.  Description of a Comparability Protocol 
 
The CP described in 21 CFR 601.12(e) and submitted in a PAS, establishes the specific 
tests and validation studies to be done and acceptable limits to be achieved to demonstrate 
the lack of adverse effect for specific types of manufacturing changes on the safety or 
effectiveness of a product.  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 (as approved in the CP).  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 (for example, PAS to CBE30).  The 
reporting category for the changes themselves will be established at the time that the CP 
is approved. 
 
   
15  Contains Nonbinding Recommendations 
B.  Applicability of a Comparability Protocol 
 
1.  You should assess whether the use of a CP is appropriate for the specific 
type of 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: 
 
a.  The product manufactured using the change will meet approved 
product standards; 
b.  The manufacturing process has been validated and all equipment has 
been qualified; and 
c.  Appropriate validated assays are available to evaluate the effect of the 
change on the product. 
 
2.  We have experience with several types of traditional Chemistry, 
Manufacturing and Controls (CMC) protocols that would be appropriate 
for a CP.  The CMC protocols 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: 
 
a.  Acquisition of facilities operating under one manufacturers license by 
another licensee (See Appendix B of this guidance); 
b.  Single change in the manufacture of a product that will be 
implemented in multiple facilities under a single license, for example, 
plateletpheresis; and 
c.  A change that has a long planning stage but a quick implementation 
turn-around time, for example, the relocation of a testing laboratory. 
 
3.  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 or effectiveness of the product.  In such cases, you would need to 
submit a PAS under 21 CFR 601.12(b) to implement the change.  Also, 
changes already reported as CBE or in the AR would have little benefit as 
a CP.  In general, the use of a CP is not appropriate for: 
 
a.  Broad ranging plans, covering any conceivable change in the 
manufacturing process; 
b.  A change with the potential to adversely affect the product; 
c.  A change where pre-specified acceptance criteria are not available to 
determine the effect of the change on the product; 
   
16  Contains Nonbinding Recommendations 
d.  A change resulting in a newly characterized product that is not 
currently licensed; 
e.  The use of a new manufacturing facility for which we would normally 
conduct a pre-license inspection; and 
f.  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 PAS, 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 (include data obtained 
during  validation); 
7.  Description of training plan for the manufacturing change; 
8.  Summary of quality assurance plan for the manufacturing change, 
including quality control testing plan; 
9.  Product statistical sampling plan; and 
10.  Proposed change in reporting category. 
 
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 specified in the approval letter (for 
example, CBE30).  In submitting the change, you should describe the change, refer to the 
STN of 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 testing and validation 
procedures described in section V.C. of this guidance, 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. 
 
D.  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 that require you to deviate from the protocol to 
resolve the problems, deficiencies, or discrepancies.  In such cases, you may elect not to 
17  Contains Nonbinding Recommendations 
make the change and request that the CP be withdrawn, or 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 submission procedure. 
 
E.  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 regulations and current guidance.  If 
modifications are required, you should contact us as soon as possible to discuss the 
proper application procedure.  In some cases, you may need to withdraw the current 
CP and submit the modified CP as a PAS.  
 
 
VI.  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 PAS requiring FDA approval prior to distribution of a product with the 
labeling change (21 CFR 601.12(f)(1)). 
 
2.  As a Labeling Supplement  Changes Being Effected requiring FDA approval but 
permitting distribution of a product bearing such change before FDA approves the 
supplement (21 CFR 601.12(f)(2)). 
 
3.  As a labeling change requiring submission in an AR (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 reporting categories.  This list is not intended to be all-inclusive.   
 
Note: Report changes in the content of the label.  Product labels must be consistent with the 
regulations for Whole Blood and blood components including Source Plasma  
(21 CFR 606.121) and should be consistent with applicable recommendations in FDA 
guidance.  You do not need to report changes in format only. 
 
A.  Labeling Changes Requiring FDA Approval Prior to Product Distribution  
(21 CFR 601.12(f)(1))  Reporting Category (PAS) 
 
1.  Labels containing an additional claim with documentation to support these 
claims. 
 
   
18  Contains Nonbinding Recommendations 
2.  Labels representing a change in the volume of Whole Blood collected, for 
example, 450 mL to 500 mL.  If you do not have an approved SOP that 
states donors must weigh at least 110 lbs, an accompanying SOP should 
be submitted for review. 
 
3.  Labels for products not currently licensed by FDA, when the 
establishment manufactures other licensed products.  This may or may not 
also require concurrent submission and approval of new or revised 
standard operating procedures as described elsewhere in this guidance. 
 
For example: 
 
a.  Labels for Source Plasma intended for further manufacture into 
noninjectable products, if the applicant is already approved to 
manufacture Source Plasma intended for further manufacture into 
injectable products. 
 
b.  Labels for Plasma, Cryoprecipitate Reduced, if the applicant is already 
approved to manufacture Cryoprecipitated AHF and Fresh Frozen 
Plasma (FFP). 
 
c.  Labels for Plasma Frozen within 24 Hours after Phlebotomy, if the 
applicant is already approved to manufacture FFP. 
 
d.  Labels for the inadvertent manual collection of low volume Whole 
Blood or Red Blood Cells, if the applicant is already approved for the 
manufacture of Whole Blood and Red Blood Cells. 
 
e.  Labels for blood and blood components intended for autologous use 
and obtained from a donor who is reactive for evidence of infection 
due to communicable disease agents. 
 
4.  The implementation of a new format for machine-readable labels, for 
example, conversion from ABC Codabar to the International Society of 
Blood Transfusion (ISBT) 128 labels. 
 
5.  Modification of an FDA-accepted Circular of Information where the 
modification impacts licensed blood components.  A copy of the Circular 
of Information must be submitted for review (21 CFR 601.12(f)(1)). 
 
   
19  Contains Nonbinding Recommendations 
B.  Labeling Changes Requiring FDA Approval but Product May Be Distributed 
Prior to FDA Approval (21 CFR 601.12(f)(2))  Reporting Category (Special 
Labeling Supplement  Changes Being Effected) 
 
1.  Print on-demand, black and white ABO/Rh labels. 
 
2.  Change in FDA-approved additive/anticoagulant solutions used in blood 
product collection. 
 
3.  Change in a blood establishments doing business as name that does not 
affect the legal entity name associated with U.S. license number.  Note:  
Your legal entity name must appear on the label (21 CFR 606.121(c)(2)). 
 
4.  Labels reflecting a legal name change or a change in a blood 
establishments street address. 
 
5.  Labels showing the new legal name and U.S. license number when a non-
license holder acquires all facilities from a license holder. 
 
6.  Labels for Source Plasma collected from normal donors with pre-existing 
disease-associated IgG antibodies, red blood cell and/or HLA antibodies 
(Ref. 10). 
 
C.  Labeling Changes Requiring Submission in an Annual Report  
(21 CFR 601.12(f)(3)) 
 
FDA-accepted Circular of Information without modification of the content. 
 
 
VII.  SUBMISSION OF CHANGES TO FDA 
 
You should prominently label each submission with the reporting category under which you are 
reporting your change, for example, Prior Approval Supplement, Supplement - Changes 
Being Effected in 30 Days, Supplement - Changes Being Effected, Special Labeling 
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 if the supplement is being submitted by hard copy or the supplement may be 
submitted by eSubmitter.  For guidance in preparing a supplement, please refer to 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 dated May 1999 (Ref. 14); and 
Guidance for Industry:  Availability of FDAs e Submitter Program for Regulatory Submissions 
from Licensed Blood Establishments dated August 2011 (Ref. 11). 
 
20  Contains Nonbinding Recommendations 
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.  The May 1999 guidance 
describes the specific items that are to be included in a submission (Ref. 14). 
 
You should report changes to your approved establishment, product, or biologics license 
applications to:   
 
U.S. Food and Drug Administration 
Center for Biologicals Evaluation and Research 
Document Control Center 
10903 New Hampshire Avenue 
WO71, G112 
Silver Spring, MD 20992-0002 
 
If you need further guidance, you should call the Division of Blood Components and Devices at 
(240) 402-8360. 
 
 
VIII.  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 (21 CFR 601.12(g)). 
 
21  Contains Nonbinding Recommendations 
IX.  REFERENCES 
 
1.  Guidance for Industry:  Changes to an Approved Application:  Biological Products:  
Human Blood and Blood Components Intended for Transfusion or for Further 
Manufacture, July 2001.   
2.  Final Rule: Changes to an Approved Application (62 FR 39890, July 24, 1997). 
http://www.gpo.gov/fdsys/pkg/FR-1997-07-24/pdf/97-19427.pdf 
3.  Workshop: FDA Regulation and Licensure of Whole Blood and Blood Components, 
Including Source Plasma, September 15 and 16, 2009.  Sponsored by FDA, CBER.  
http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConference
s/ ucm169497.htm 
4.  Final Rule: Elimination of Establishment License Application for Specified Biotechnology 
and Specified Synthetic Biological Products (61 FR 24227, May 14, 1996). 
http://www.gpo.gov/fdsys/pkg/FR-1996-05-14/pdf/96-12144.pdf 
5.  Final Rule: Revision of the Requirements for a Responsible Head for Biological 
Establishments (62 FR 53536, October 15, 1997).          
http://www.gpo.gov/fdsys/pkg/FR-1997-10-15/pdf/97-27298.pdf 
6.  Form FDA 356h, Application to Market a New Drug, Biologic, or an Antibiotic Drug for 
Human Use, November 2012. 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM082348.pdf 
7.  Guidance for Industry:  An Acceptable Circular of Information for the Use of Human 
Blood and Blood Components, Updated April 2014. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm364565.htm 
8.  Guidance for Industry:  Streamlining the Donor Interview Process:  Recommendations for 
Self-Administered Questionnaires, July 2003.  
  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm075086.htm  
9.  Guidance for Industry:  Cooperative Manufacturing Arrangements for Licensed Biologics, 
November 2008. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryI
nformation/Guidances/General/ucm069908.pdf 
10.  Guidance for Industry:  Implementing a Collection Program for Source Plasma Containing 
Disease-Associated and Other Immunoglobulin G (IgG) Antibodies, August 2006. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryI
nformation/Guidances/Blood/ucm079673.pdf 
11.  Guidance for Industry:  Availability of FDAs eSubmitter Program for Regulatory 
Submissions from Licensed Blood Establishments, August 2011.  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm266499.htm 
 
 
22  Contains Nonbinding Recommendations 
12.  Final Rule: Biological Products Regulated Under Section 351 of the Public Health Service 
Act; Implementation of Biologics License; Elimination of Establishment License and 
Product License (64 FR 56441, October 20, 1999). 
http://www.fda.gov/OHRMS/DOCKETS/98fr/102099a.pdf 
13.  SOPP 8403:  Issuance and Reissuance of Licenses for Biological Products, September 21, 
2010. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
ProceduresSOPPs/ucm073468.htm 
14.  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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm077087.htm 
15.  Guidance for Industry:  Implementation of an Acceptable Abbreviated Donor History 
Questionnaire and Accompanying Materials for Use in Screening Frequent Donors of 
Blood and Blood Components, May 2013. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm351107.htm 
16.  Guidance for Industry:  Implementation of Acceptable Full-Length Donor History 
Questionnaire and Accompanying Materials for Use in Screening Donors of Blood and 
Blood Components, October 2006. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm073445.htm  
17.  Guidance for Industry:  Recommendations for Blood Establishment: Training of Back-Up 
Personnel, Assessment of Blood Donor Suitability and Reporting Certain Changes to an 
Approved Application, November 2010.  
  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Blood/ucm235785.htm 
18.  Guidance for Industry:  Recommendations for Management of Donors at Increased Risk for 
Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection, August 2009. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryI
nformation/Guidances/Blood/UCM180844.pdf 
 
   
 
23  Contains Nonbinding Recommendations 
APPENDIX A:  TYPES OF ESTABLISHMENTS/FACILITIES AND MANUFACTURING STEPS PERFORMED 
 
Manufacturing  Collection  Community  Component  Hospital  Plasmapheresis  Product  Distribution 
Steps Performed  Facility  Blood Bank  Preparation  Blood  Center  Testing  Center 
Facility  Bank  Laboratory 
Manual Whole Blood  X  X    X  X      
collection 
Whole Blood    X  X  X  X      
component 
preparation 
Automated  X  X    X       
plateletpheresis 
Automated RBC  X  X    X       
apheresis 
Automated  X  X    X  X     
plasmapheresis 
Manual  X  X    X  X     
plasmapheresis 
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/deglycerolize    X  X  X  X     
Leukocyte reduction    X  X  X       
 does not include 
bedside filtration 
Compatibility testing    X    X       
Pre-storage pooling    X  X  X       
of Platelets and 
Cryoprecipitated 
AHF 
24  Contains Nonbinding Recommendations 
APPENDIX B:  REPORTING FACILITY CHANGES   Reporting Category 
 
 FACILITY  CHANGE PERFORMED  BLA  PAS  CBE30  CBE  AR  PC 
 OPERATION  Note:  BLA is not 
a reporting 
Note:  Product correspondence is not 
category under   
a reporting category under  
21 CFR 601.12 
21 CFR 601.12 
 
 
 
Facility Closures  Partial Closure: Manufacturer permanently            X 
closes some, but not all, of its licensed 
manufacturing facilities. 
Closure of fixed donor sites that perform only          X   
manual Whole Blood collections.  
 Temporary closure of a facility.          X   
Complete Closure:  U.S. license holder            X 
permanently closes all of its manufacturing 
facilities and voluntarily requests revocation of the 
relevant product licenses. 
Facility  U.S. license holder expands its operations to include     X       
Openings  the opening of a new collection facility for Platelets, 
Pheresis Leukocytes 
Reduced under an approved CP. 
U.S. license holder opens a fixed donor site that          X   
performs only manual Whole Blood collections.  
U.S. license holder reopens a facility after temporary         X   
closure provided there are no changes in SOP, major 
equipment, procedures or core center personnel. 
U.S. license holder expands its operations    X         
to include the opening of a Source Plasma 
collection center. 
25  Contains Nonbinding Recommendations 
APPENDIX B:  REPORTING FACILITY CHANGES   Reporting Category 
 
 FACILITY  CHANGE PERFORMED  BLA  PAS  CBE30  CBE  AR  PC 
 OPERATION  Note:  BLA is not 
a reporting 
Note:  Product correspondence is not 
category under   
a reporting category under  
21 CFR 601.12 
21 CFR 601.12 
 
 
 
  U.S. license holder expands operations by adding a    X         
facility where licensed products are manufactured.  
This includes the addition of a contractor to perform 
the manufacturing step(s).  Examples of such 
facility changes include adding: 
 
Facilities where Red Blood Cells, Fresh Frozen 
Plasma, Platelets, and Pheresis products are 
collected using automated blood cell separators, and 
Source Leukocytes are collected using either manual 
or automated collection methods, or where routine 
FDA required or recommended blood and plasma 
testing is performed. 
Self-Contained  Addition or deletion.           X   
Collection Vehicle  
Legal Name  New legal name.            X  
    Deleting Inc. from the legal name.            X 
 
Mergers  Merger of two or more license holders to  X           
form a new legal entity. 
Acquisitions  Non license holder acquires all facilities  X          X  
from a license holder and continues to operate  (buyer)  (seller) 
the acquired facilities using SOPs 
previously approved by FDA. 
  Non license holder acquires some but not all  X          X  
facilities from a license holder.  (buyer)  (seller) 
 
26  Contains Nonbinding Recommendations 
APPENDIX B:  REPORTING FACILITY CHANGES   Reporting Category 
 
 FACILITY  CHANGE PERFORMED  BLA  PAS  CBE30  CBE  AR  PC 
 OPERATION  Note:  BLA is not 
a reporting 
Note:  Product correspondence is not 
category under   
a reporting category under  
21 CFR 601.12 
21 CFR 601.12 
 
 
 
  License holder acquires facilities previously      X       
operating under the sellers U.S. license number 
that will operate under the buyers U.S. license 
number. 
  Combining facilities operating under different      X       
licenses owned by the same corporation into one of 
the existing license number.  
27  Contains Nonbinding Recommendations 
 
APPENDIX C:  REPORTING CHANGES IN FACILITY RELOCATIONS    Reporting Category 
FACILITY OPERATION  PAS  CBE30  AR 
Relocation of a facility where product manufacturing is performed and there are no changes in SOPs or major  X     
equipment but there are major changes in Core Personnel. 
Relocation of a facility where manufacturing is performed that result in a major change in SOPs, major  X     
equipment and Core Personnel. 
Relocation of a facility which in turn requires the manufacture to temporarily close so that new staff can be  X     
hired and trained. 
Relocation of a contractor that results in a change in SOPs and/or equipment.  X     
Relocation of a facility where product manufacturing is performed and there is no change in SOP or    X   
Core Personnel, but there is a change with respect to major equipment. 
Relocation of a product testing laboratory.  X     
Relocation of a facility where product manufacturing is performed and there is no change in SOP, major      X 
equipment or Core Personnel. 
*Relocation of facilities:  Changes in location must be submitted on Form FDA 2830 (Blood Establishment and Product Listing) (21 CFR 607.26) as an 
amendment to registration within 5 days of such change. 
 
 
28 
  Contains Nonbinding Recommendations 
APPENDIX D:  REPORTING CHANGES ASSOCIATED WITH BLOOD ESTABLISHMENT COMPUTER SOFTWARE (BECS) 
 
 
    Reporting Category
 
Type of Change  PAS  CBE30  CBE  AR 
BECS Used With the Donor Interview Process 
  Internal access only: Used only within the company and not remotely accessible by donors for completion of the DHQ. Such systems may be web-based 
(i.e., intranet), wireless, or hard-wired. 
  External access by donors: Remotely accessed by donors via internet for completion of the DHQ.  
 
 A.  Self-Administered Donor History Questionnaires (DHQ) 
1. Implementation of a 510(k) cleared BECS internally accessed for a computer-assisted interactive interview (CASI) software program with a DHQ:  
  
a.  Not previously approved or accepted by FDA in guidance.  X       
b.  Previously approved or accepted by FDA in guidance.    X     
2.  Implementation of a 510(k) cleared BECS externally accessed by donors for a computer-assisted interactive interview (CASI) software program 
with a DHQ: 
a.  Not previously approved or accepted by FDA in guidance.  X       
b.  Previously approved or accepted by FDA in guidance.    X     
B.  Staff-Administered and Documented DHQ 
1.  Implementation of a 510(k) cleared BECS for administering a DHQ  
a.  Not previously approved or accepted by FDA in guidance.  X       
b.  Previously approved or accepted by FDA in guidance.    X     
 
 
29  Contains Nonbinding Recommendations 
APPENDIX D:  REPORTING CHANGES ASSOCIATED WITH BLOOD ESTABLISHMENT COMPUTER SOFTWARE (BECS) 
 
    Reporting Category
 
Type of Change  PAS  CBE30  CBE  AR 
 
Other BECS Applications 
A.  Initial implementation of 510(k) cleared BECS that interfaces with an apheresis    X     
device to permit bi-directional data flow impacting the operation of the 
apheresis device with regard to (not an all-inclusive list) sending eligible 
product combinations, donor information, and initial configuration information 
to the apheresis device and determining component eligibility based on the 
interval, frequency, non-rinse back events and RBC/Plasma loss from a donors 
past donations.  
B.  Implementation of a blood establishment computer system that is interfaced  X       
with an automated blood cell separator device as described in the 510(k) 
clearance for the software. 
C.  Implementation of a blood establishment computer system that maintains data        X 
used by blood establishment personnel to make decisions regarding the 
eligibility of donors and the release of blood and blood components for 
transfusion or for further manufacture.  
 
Note: This does not include the use of a computer-assisted interactive 
interview software program for self-administering of a donor history 
questionnaire. Report the name of the software manufacturer and the name 
and version number of the software.  
1.  Implementation of data entry and retrieval or library database        X 
software systems;  
2.  Initial installation of commercially available or in-house developed        X 
BECS or installation of software upgrades, provided there are no major 
changes in SOPs. Note: This does not apply to BECS installations used 
for self-administered DHQ.  
3.  Implementation of a validated computer crossmatch system.        X 
30  Contains Nonbinding Recommendations 
APPENDIX E:  REPORTING CHANGES IN APHERESIS OPERATIONS AND AUTOMATED BLOOD SEPARATOR DEVICES 
 
 
Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
Change(s) from manufacturing an approved product by automated apheresis to manufacturing  X       
additional products collected at the same facility using the same apheresis instrument, for 
example Platelets Pheresis, single or double units of Red Blood Cells, Source Plasma, or 
Source Leukocytes.  
Manufacture of leukocytes reduced blood components using an automated blood cell separator  X       
new to your establishment and you are not making the change under an approved CP.  
Conversion from manual to automated collection of Platelets, Plasma (including Source Plasma),  X       
Red Blood Cells and Source Leukocytes. 
Change in the manufacturer or model of automated apheresis equipment used in the collection of  X       
Red Blood Cells, Plasma (other than Source Plasma) or Platelets. 
Collection of plasma for transfusion as part of an approved apheresis program provided the    X     
applicant is otherwise approved to manufacture the plasma product.  Note: This does not include 
Source Plasma. 
 
Changes or upgrades in automated apheresis equipment for example: Software changes that may    X     
have a moderate potential to have an adverse effect on the safety or effectiveness of the product. 
Changes or upgrades by the device manufacturer of automated apheresis equipment that does not        X 
affect the safety, purity or potency of the product(s), if the facility is already approved for the 
original procedure. 
Changes or upgrades in automated apheresis equipment that result in a decrease in donation        X 
time. 
 
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 
X 
in storage conditions, change in leukocyte reduction procedure, and collection of an additional or 
different product. 
31  Contains Nonbinding Recommendations 
APPENDIX F:  REPORTING CHANGES IN SOURCE PLASMA/IMMUNIZATION PROGRAMS FOR SOURCE PLASMA 
DONORS 
 
Reporting Category 
Type of Change 
PAS  CBE30  CBE  AR 
Implementation of a new immunization program for Red Blood Cells or vaccines.   X       
Implementation of a vaccine hyperimmunization collection program in which the  X       
licensed vaccine is administered differently from the listed immunization schedule in 
the package insert, such as by dose or route of administration, and is not an 
alternative immunization schedule that has been approved by FDA.  
Collection of Source Plasma from disease-state or high-risk donors.  X       
Implementation of a vaccine hyperimmunization collection program in which the    X     
licensed vaccine administration schedule is consistent with the immunization schedule 
listed in the package insert or where CBER has approved an alternate immunization 
schedule, such as by dose or route of injection.  
Change in the manufacturer of a licensed vaccine previously used in an approved    X     
vaccine hyperimmunization program if the injection protocol of the new package 
insert is different from procedures in the previously approved SOP.  
Collection of Source Plasma from donors with pre-existing disease-associated, Red        X 
Blood Cell and/or HLA antibodies, if previously approved for a Source Plasma 
Collection Program (Ref. 10).  Submit labels for this program under  
21 CFR 601.12(f)(2).  
Changes in manufacturer of a licensed vaccine previously used in an approved        X 
vaccine hyperimmunization program, if the vaccine is administered according to the 
package insert and the package insert is consistent with the currently approved SOP.  
Discontinuation of the manufacture of Source Plasma.         X 
Request for an exception or alternative procedure to 21 CFR 640.62 under   X       
21 CFR 640.120 to implement a physician substitute program.  
Implementation of a hyperimmunization program previously approved by CBER    X     
for licensed vaccines at additional facilities.  
32  Contains Nonbinding Recommendations 
APPENDIX G:  REPORTING CHANGES IN THE MANUFACTURE OF LEUKOCYTES REDUCED BLOOD COMPONENTS 
 
 
Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
Manufacture of leukocytes reduced blood components at a facility other than  X       
the one named under an approved CP. 
Manufacture of leukocytes reduced blood components when you intend to  X       
change your manufacturing process in a manner that presents a substantial 
potential to have an adverse effect on the safety or effectiveness of the 
product. 
 
Manufacture of leukocytes reduced blood components using an automated  X       
blood cell separator new to your establishment and you are not making this 
change under an approved CP. 
 
Change from one type of FDA approved or cleared leukocyte reduction filter        X 
to another type of FDA approved or cleared leukocyte reduction filter. 
Software and hardware upgrades to the leukocyte reduction process for    X     
apheresis collection that may have a moderate potential to have an adverse 
effect on the safety or effectiveness of the product(s). 
 
 
 
33  Contains Nonbinding Recommendations 
APPENDIX H:  REPORTING CONTRACT CHANGES 
 
Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
  X       
Use of an FDA registered contract facility not previously engaged in blood product testing to 
perform routine serologic testing and/or infectious disease screening, and supplemental 
and/or confirmatory testing for blood and blood products.  These contract facilities perform 
the tests of record (tests used to determine donor eligibility/product suitability). 
 
Use of a contract facility that was not previously engaged in performing a manufacturing  X       
step on blood products to perform a manufacturing step. This includes, but is not limited to, 
contract facilities that irradiate blood products or supply Red Blood Cells for immunization. 
 
Expanding operations to include infectious disease test laboratories.  X       
Note:  Refer to Appendix B for reporting facility changes and Appendix C for handling 
changes in facility relocations. 
 
Use of an FDA registered off-site contract storage facility to store an unlicensed product    X     
collected under a pending supplement or for the storage of excess licensed product that 
meets all product release criteria. 
 
Use of an FDA registered contract facility currently engaged in performing manufacturing      X   
steps on blood products, to perform a specific manufacturing step.  
Use of, or change in, a contract testing laboratory that performs reference or quality control        X 
testing or tests that are not required or recommended by FDA.  Note: This does not include 
a change in a contract testing laboratory that performs the infectious disease or ABO/Rh 
tests of record. Such a change must be reported as a CBE.  See sections IV.B. and C. of this 
guidance.  
 
 
   
34  Contains Nonbinding Recommendations 
 
APPENDIX H:  REPORTING CONTRACT CHANGES 
Reporting Category 
 
PAS  CBE30  CBE  AR 
Type of Change 
Changes in infectious disease tests that are required or recommended by FDA at a        X 
previously approved contract testing laboratory. For example: adding an FDA 
required or recommended test to the testing currently performed by the approved 
contract testing laboratory. 
Notification of changes in operations made by an approved contractor, for example,        X 
notification by an approved contract testing laboratory that they have changed the 
contract laboratory they use to perform confirmatory testing. 
Temporary use of a previously approved alternate or back-up contractor to perform a        X 
manufacturing step.  Include the dates the alternate contractor was used. 
Use of, or change in, a contractor to provide personnel responsible for collecting        X 
blood products or performing quality assurance activities. 
 
Change in address of any unlicensed contractor.        X 
 
 
 
 
35  Contains Nonbinding Recommendations 
APPENDIX I:  REPORTING CHANGES IN DONOR HISTORY QUESTIONNAIRES 
 
   
Reporting Category 
Type of Change 
PAS  CBE30  CBE  AR 
Implementation of a donor history questionnaire or associated procedures  X       
that differ from, and are less restrictive than the FDA-accepted donor 
history questionnaire and accompanying materials, manufacturers 
directions or recommendations described in FDA guidance documents. 
Implementation of an abbreviated self-administered donor history        X 
questionnaire using the written form or audio/visual presentation methods 
described in the acceptable aDHQ documents for repeat or frequent 
donors (Ref. 15). 
 Implementation of the acceptable donor history questionnaire and        X 
accompanying materials, if used without modification or if modifications are 
more restrictive (Ref. 16). 
Implementation of the acceptable aDHQ documents using a computer-assisted    X     
interactive interview procedure. 
36  Contains Nonbinding Recommendations 
APPENDIX J:  REPORTING CHANGES IN STANDARD   
OPERATING PROCEURES (SOPS)  Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
Addition or revision of SOP(s) for the following manufacturing categories if  X       
the change is less restrictive than the procedure(s) described in previously 
approved SOP(s) or is not addressed in guidance document(s): 
a.  Donor eligibility, including donor deferral; 
b.  Blood collection and processing, including use of a product for 
preparing the donors arm prior to donation when the product is not 
labeled as a surgical or donor scrub; 
c.  High-risk behavior questions/AIDS information; 
d.  Donor  history  questionnaire  forms  (including  informed 
consent); 
e.  Blood  and  blood  component  manufacturing  for  licensed 
products; and 
f.  Quarantine and disposition of unsuitable products. 
Note:  Report changes in the content of the procedure or form.  Do not 
report formatting or minor changes to SOPs and forms.  You may 
reference previously approved SOPs and forms.  When referencing a 
previously approved SOP or form, please include the FDA application 
or supplement tracking number. 
Implementation of an SOP to contact donors within 24 hours of the time of  X       
collection for obtaining or clarifying a donors response to the donor 
history questionnaire after the donor has left the collection establishment 
(Ref. 17). 
 
Note: This does not include obtaining missing pre-collection vital signs 
and hemoglobin/hematocrit determinations after donation.   
 
Implementation of an SOP for shipping inadvertently collected blood and  X       
blood components that are repeatedly reactive or positive for an infectious 
disease agent and are to be used in the further manufacture of noninjectables 
(21 CFR 610.40(h)(2)(ii)(A)). 
 
37  Contains Nonbinding Recommendations 
APPENDIX J:  REPORTING CHANGES IN STANDARD   
OPERATING PROCEURES (SOPS)  Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
Revision of an SOP for the following categories if the change is more        X 
restrictive than previously recommended or described in published FDA 
guidance documents. 
a.  Donor eligibility, including donor deferral, for example, deferring 
donors who are at risk for Lyme disease; 
b.  Use of a product for the preparation of a donors arm prior to 
donation, when the product is labeled as a surgical or donor scrub; 
c.  High-risk behavior questions/AIDS information; 
d.  Donor history questionnaire forms (including informed consent); 
e.  Blood and blood component manufacturing for licensed products 
only; and 
f.  Quarantine and disposition of unsuitable products. 
Implementation of additional procedures or tests that are not required or        X 
recommended by FDA and which do not conflict with FDA requirements or 
recommendations.  If the test or procedure is included in the informed 
consent form, the form should not contain any exculpatory language or 
claims about the procedure or test. 
 
Discontinuation of procedures no longer required or recommended by FDA.        X 
 
Implementation of another licensed manufacturers FDA approved SOP,        X 
with written permission from the licensed manufacturer. 
 
Revision of SOP for determining donor eligibility to allow individuals who        X 
have had a tattoo or body piercing in the previous 12 months to donate, if the 
tattoo or body piercing was applied by a state regulated entity with sterile 
needles and non-reused ink or single-use equipment. 
Changes in the quality control method if the quality control procedure is        X 
consistent with the manufacturers directions.  This includes the methods 
used to quality control the systems involved in product manufacturing, 
e.g., blood products, equipment, reagents, and supplies. 
 
 
38  Contains Nonbinding Recommendations 
APPENDIX J:  REPORTING CHANGES IN STANDARD   
OPERATING PROCEURES (SOPS)  Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
Implementation of additional infectious disease tests that are required or        X 
recommended by FDA, if directed by the relevant guidance document to 
report implementation in this manner. 
 
 
 
39  Contains Nonbinding Recommendations 
APPENDIX K:  REPORTING CHANGES IN EQUIPMENT 
 
Reporting Category 
Type of Change 
PAS  CBE30  CBE  AR 
Use of a 510(k) cleared automated device for separating Whole Blood    X     
into Red Blood Cells and Plasma. 
Implementation of a computer system that is interfaced with an automated    X     
blood cell separator device as described in the 510(k) clearance for the 
software. 
Change in irradiation equipment used by you or your contractor, for example,        X 
from gamma irradiator to linear accelerator, or to a gamma irradiator by 
another manufacturer or to an x-ray irradiator. 
Changes in infectious disease screening testing methods if the procedures are        X 
consistent with manufacturers directions.  
Changes in equipment that performs total protein and serum/plasma protein        X 
electrophoresis on donor specimens. 
Changes in equipment that performs vital signs testing (for example, pulse,        X 
blood pressure, temperature) and hemoglobin/hematocrit testing on blood 
donors or donor specimens. 
Use of sterile connecting (docking) de vice to manipulate product in a sterile        X 
manner (for example, 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 manufacturers directions. 
 
Changes or upgrades in equipment used for performing product quality        X 
control testing, including White Blood Cell and platelet counts. 
 
Changes or upgrades in equipment used to perform platelet counts on        X 
donor samples. 
 
Implementation of FDA-cleared or approved automated equipment to        X 
perform ABO/Rh testing, syphilis, and infectious disease screening 
testing on donor samples. 
40  Contains Nonbinding Recommendations 
APPENDIX L:  REPORTING PRODUCT MANUFACTURING/PROCEDURAL CHANGES 
 
 
Reporting Category 
Type of Change 
PAS  CBE30  CBE  AR 
Implementation of a new manufacturing process, including, but not limited to:  X       
  Leukocyte reduction of blood components; 
  Irradiation; 
  Freezing/deglycerolizing; 
  Rejuvenating; 
  Washing; 
  Testing for communicable diseases; 
  Pre-storage pooling of Platelets; 
  Pre-storage pooling of Cryoprecipitated AHF; 
  Automated apheresis collections; and 
  Manufacture of Whole Blood derived Platelets. 
 
Request for approval of a Comparability Protocol (CP) (21 CFR 601.12(e)).  X       
 
Request for an exception or alternative procedure under 21 CFR 640.120, for which there  X       
is no published guidance. 
Request for an exception or an alternative procedure under 21 CFR 640.120 for which    X     
published guidance is available and implementation conforms to the guidance, for 
example, implementation of an infrequent plasmapheresis donor collection program 
that is consistent with FDAs guidance for this program. 
 
Implementation of an approved anti-HIV 1/2 test that includes detection of antibodies to        X 
HIV-1 Group O (Ref. 18). 
 Changes in Whole Blood collection sets or leukocyte reduction filters for products        X 
prepared from Whole Blood, if used according to manufacturers instructions. 
 
Statistical Sampling Plans for Validation and/or Quality Control:  X       
  Implementation of new or revised procedures containing a statistical sampling 
plan that has not been previously delineated in FDA guidance. 
 
  Implementation of new or revised procedures containing a statistical sampling  X       
plan that has been delineated in FDA guidance. 
 
 
41  Contains Nonbinding Recommendations 
 
 
APPENDIX L:  REPORTING PRODUCT MANUFACTURING/PROCEDURAL CHANGES  
 
 
Reporting Category 
Type of Change  PAS  CBE30  CBE  AR 
  Revision of previously approved sampling plan procedures in accordance with        X 
recommendations in guidance in the following cases: 
  Change the sample size in a previously approved hypergeometric sampling 
o
plan procedure in accordance with FDA guidance recommendations to 
allow for changes in collections or product manufacturing numbers. 
  Change the sample size in a previously approved binomial or 
o
hypergeometric sampling plan procedure with regard to the number of 
allowable failures; e.g., change from a sample size with 0 failures to a 
sample size with 1 failure or vice versa. 
 
42