#253 
 
Current Good Manufacturing Practice 
for Animal Cells, Tissues, and Cell- 
and Tissue-Based Products 
 
Guidance for Industry 
 
Submit comments on this guidance at any time.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with docket number FDA-2021-D-0399. 
 
For further information regarding this document, contact AskCVM@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish 
Place, Rockville, MD 20855, and may be viewed on the Internet at https://www.fda.gov/animal-
veterinary, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or 
http://www.regulations.gov.    
 
 
U.S.  Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
October 2022 Contains Nonbinding Recommendations 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DEFINITIONS .................................................................................................................. 2 
III.  PURPOSE AND SCOPE .................................................................................................. 3 
A.  Category A Establishments ........................................................................................... 4 
B.  Category B Establishments ........................................................................................... 5 
C.  Implementing CGMP .................................................................................................... 5 
IV.  ESTABLISHMENTS OPERATING UNDER A CONTRACT, AGREEMENT, OR 
OTHER ARRANGEMENT ............................................................................................. 6 
V.  ESTABLISHMENT AND MAINTENANCE OF A QUALITY PROGRAM ............ 8 
A.  General .......................................................................................................................... 8 
B.  Functions ....................................................................................................................... 8 
C.  Audits .......................................................................................................................... 11 
D.  Computers ................................................................................................................... 11 
VI.  PERSONNEL .................................................................................................................. 11 
A.  General ........................................................................................................................ 11 
B.  Competent Performance of Functions ........................................................................ 11 
C.  Training ....................................................................................................................... 12 
VII.  PROCEDURES ............................................................................................................... 12 
A.  General ........................................................................................................................ 12 
B.  Review and Approval ................................................................................................. 12 
C.  Availability ................................................................................................................. 12 
D.  Standard Procedures.................................................................................................... 12 
VIII.  FACILITIES ................................................................................................................... 13 
A.  General ........................................................................................................................ 13 
B.  Facility Cleaning and Sanitation ................................................................................. 13 
C.  Operations ................................................................................................................... 13 
D.  Procedures and Records .............................................................................................. 14 
E.  Recovery ..................................................................................................................... 14 
IX.  ENVIRONMENTAL CONTROL AND MONITORING ........................................... 15 
A.  General ........................................................................................................................ 15 
B.  Environmental Control................................................................................................ 15 
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  Contains Nonbinding Recommendations 
C.  Inspections .................................................................................................................. 16 
D.  Environmental Monitoring.......................................................................................... 16 
E.  Temperature and Humidity ......................................................................................... 17 
F.  Records ....................................................................................................................... 17 
G.  Recovery ..................................................................................................................... 17 
X.  EQUIPMENT .................................................................................................................. 18 
A.  General ........................................................................................................................ 18 
B.  Procedures and Schedules ........................................................................................... 18 
C.  Calibrations and Equipment ........................................................................................ 18 
D.  Inspections .................................................................................................................. 19 
E.  Records ....................................................................................................................... 19 
F.  Qualification and Certification ................................................................................... 20 
G.  Recovery ..................................................................................................................... 20 
XI.  SUPPLIES AND REAGENTS ....................................................................................... 21 
A.  General ........................................................................................................................ 21 
B.  Verification ................................................................................................................. 21 
C.  Reagents ...................................................................................................................... 22 
D.  In-House Reagents ...................................................................................................... 22 
E.  Records ....................................................................................................................... 22 
XII.  RECOVERY .................................................................................................................... 23 
A.  General ........................................................................................................................ 23 
B.  Procedures and Records .............................................................................................. 24 
C.  Controlling Contamination ......................................................................................... 24 
D.  Donor Identification .................................................................................................... 25 
E.  Audits .......................................................................................................................... 25 
XIII.  PROCESSING AND PROCESSING CONTROLS .................................................... 25 
A.  General ........................................................................................................................ 25 
B.  Pooling ........................................................................................................................ 26 
C.  In-Process Control and Testing ................................................................................... 27 
D.  Pre-Processing Controls and Testing .......................................................................... 27 
XIV.  PROCESS CHANGES AND PROCESS VALIDATION ........................................... 28 
A.  General ........................................................................................................................ 28 
B.  Approval and Implementation of a Process Change ................................................... 28 
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  Contains Nonbinding Recommendations 
C.  Process Validation ...................................................................................................... 28 
D.  Written Representation ............................................................................................... 28 
E.  Changes ....................................................................................................................... 29 
XV.  LABELING ..................................................................................................................... 29 
A.  General ........................................................................................................................ 29 
B.  Controls ....................................................................................................................... 29 
C.  Verification ................................................................................................................. 30 
D.  Information on the ACTP Finished Product Label and Labeling to Ensure Product 
Quality and Prevent Contamination or Mix Ups ........................................................ 30 
XVI.  STORAGE ....................................................................................................................... 31 
A.  General ........................................................................................................................ 31 
B.  Control of Storage Areas ............................................................................................ 31 
C.  Temperature ................................................................................................................ 32 
D.  Expiration Date ........................................................................................................... 32 
E.  Corrective Actions ...................................................................................................... 33 
F.  Acceptable Temperature Limits .................................................................................. 33 
XVII.  RECEIPT, PREDISTRIBUTION SHIPMENT, AND DISTRIBUTION OF AN 
ACTP ................................................................................................................................ 33 
A.  General ........................................................................................................................ 33 
B.  Receipt ........................................................................................................................ 33 
C.  Predistribution Shipment ............................................................................................ 34 
D.  Availability for Distribution ....................................................................................... 34 
E.  Packaging and Shipping .............................................................................................. 35 
F.  Procedures ................................................................................................................... 35 
G.  Return to Inventory ..................................................................................................... 36 
XVIII. RECORDS ....................................................................................................................... 36 
A.  General ........................................................................................................................ 36 
B.  Records Management System ..................................................................................... 36 
C.  Methods of Retention .................................................................................................. 37 
D.  Length of Retention .................................................................................................... 37 
E.  Contracts and Agreements .......................................................................................... 37 
XIX.  TRACKING..................................................................................................................... 38 
A.  General ........................................................................................................................ 38 
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  Contains Nonbinding Recommendations 
B.  System of ACTP Tracking .......................................................................................... 38 
C.  Distinct Identification Code ........................................................................................ 38 
D.  Tracking from Consignee to Donor ............................................................................ 39 
E.  Tracking from Donor to Consignee or Final Disposition ........................................... 39 
F.  Consignees .................................................................................................................. 39 
XX.  COMPLAINT FILE ....................................................................................................... 39 
A.  General ........................................................................................................................ 40 
B.  Procedures ................................................................................................................... 40 
C.  Complaint file ............................................................................................................. 40 
D.  Review and Evaluation of Complaints ....................................................................... 40 
XXI.  CGMP DEVIATIONS .................................................................................................... 40 
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  Contains Nonbinding Recommendations 
Current Good Manufacturing Practice for Animal Cells, Tissues, 
and Cell- and Tissue-Based Products 
 
Guidance for Industry 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.   It does not establish any rights for any person and is not binding on FDA or the public.   You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
I.  INTRODUCTION 
FDAs Center for Veterinary Medicine (CVM) is issuing this guidance to provide establishments 
that manufacture animal cells, tissues, and cell- and tissue-based products (ACTPs) with 
recommendations for meeting current good manufacturing practice (CGMP) requirements.  All 
new animal drugs, including ACTPs, must be manufactured in accordance with CGMP to ensure 
that such drugs meet the requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
as to safety, and have the identity, strength, quality, and purity characteristics which they purport 
to or are represented to possess.1   
 
There are both statutory and regulatory requirements for CGMP.  The CGMP statutory 
requirements are found in section 501(a)(2)(B) of the FD&C Act.  The CGMP regulatory 
requirements are found in Title 21 of the Code of Federal Regulations, parts 210 and 211 (21 
CFR parts 210 and 211).    
 
FDA recognizes that the manufacture of ACTPs presents unique considerations for complying 
with regulatory CGMP and that these CGMP regulations do not specifically or fully address all 
aspects of the manufacture of ACTPs, including early stages of the ACTP manufacturing 
process.  This document is specific to ACTPs to help establishments that manufacture ACTPs 
meet statutory and applicable regulatory CGMP.  New animal drugs not manufactured in 
conformity with statutory and regulatory CGMP are adulterated under the relevant provisions of 
the FD&C Act. 
 
In this guidance, we address the methods, facilities, and controls used for manufacturing ACTPs, 
including steps in recovery, processing, storage, labeling, packaging, and distribution.  The 
recommendations in this document should be applied to consistently produce quality ACTPs and 
to ensure that ACTPs are not contaminated and do not become contaminated during 
manufacturing.  Generally, when we refer to CGMP in this document, we are referring either to 
statutory CGMP including those ACTP-specific recommendations provided in this document for 
meeting statutory CGMP, or applicable regulatory CGMP, or both. 
 
 
1 See section 501(a)(2)(B) of the FD&C Act [21 U.S.C.  351(a)(2)(B)] 
1  Contains Nonbinding Recommendations 
Each individual manufacturing process may require unique considerations to preserve quality 
and prevent contamination of an ACTP.  For this reason, many of the recommendations provided 
in this guidance are qualified by where appropriate.  A recommendation or other method is 
appropriate if it does not result in contamination of the ACTP, in compromised quality of the 
ACTP, or in the inability to carry out any necessary corrective action(s). 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 Agency guidances means that something is suggested or recommended, but 
not required. 
 
II.  DEFINITIONS 
The following are definitions for terms used in this guidance. 
 
Animal cells, tissues, and cell- and tissue-based products (ACTPs) mean those articles 
containing, consisting of, or derived from cells or tissues that are intended for implantation, 
transplantation, infusion, transfer, or other means of administration to an animal recipient.  In 
this guidance, the term ACTP refers only to those products subject to regulation under the FD&C 
Act.  ACTPs include cell-based products and animal stem cell-based products as defined in 
Guidance for Industry (GFI) #218, Cell-Based Products for Animal Use (July 2015).2   
 
Establishment means a place of business under one management, and at one general physical 
location, that engages in the manufacture of ACTPs.  This could include large and small animal 
facilities or veterinary hospitals where tissues are recovered from animals or other tissue 
recovery facilities, processing facilities, distributors, packaging facilities, contract testing 
laboratories, etc.  The term also includes any individual, partnership, corporation, association, or 
other legal entity engaged in the manufacture of ACTPs, and facilities that engage in contract 
manufacturing services for a manufacturer of ACTPs.  An establishment may be a facility that 
manufactures an ACTP.  Alternately, an establishment might be the corporate headquarters of an 
entity that has facilities in multiple locations that perform the manufacturing steps to produce the 
ACTP. 
 
Facility means the physical location in which manufacturing steps are performed.  
 
In-process control means controls to ensure the identity, strength, quality, and purity of the 
ACTP during the production process. 
 
Manufacturing step means one of the stages involved in a manufacturing process (e.g., 
passaging of cells, filling of vials, etc.). 
 
 
2 https://www.fda.gov/media/88925/download 
2  Contains Nonbinding Recommendations 
Predistribution shipment means the conveyance or shipment of an ACTP within your 
establishment or between establishments before it has met its product release criteria (i.e., it is 
not released for distribution).   
 
Process control means controls put in place to address variability and to ensure product quality.  
Controls can consist of material analysis and equipment monitoring at significant processing 
points. 
 
Processing means any activity performed on an ACTP, other than recovery, donor screening, 
donor testing, storage, labeling, packaging, or distribution.  Processing includes activities such as 
testing for microorganisms, preparation, sterilization, steps to inactivate or remove adventitious 
agents, preservation for storage, and removal from storage. 
 
Quarantine of ACTP means the storage or identification of an ACTP, to prevent improper 
release, in a physically separate area clearly identified for such use or through use of other 
procedures, such as automated designation. 
 
Recovery means obtaining from a donor (live or deceased) cells or tissues that are intended for 
use in implantation, transplantation, infusion, transfer, or other means of administration to an 
animal recipient. 
 
Validation means confirmation by examination and provision of objective evidence that 
particular requirements can consistently be fulfilled (e.g., a process consistently produces an 
ACTP that meets its predetermined specifications). 
 
Validated methods means analytical methods confirmed to be suitable for their intended use 
through parameters such as accuracy, precision, robustness, linearity, range, specificity, limit of 
quantitation, and limit of detection.   
 
Verification means confirmation by examination and provision of objective evidence that 
specific requirements have been fulfilled. 
 
You means the establishment that performs a manufacturing step or the establishment that 
performs a manufacturing step under contract, agreement, or other arrangement for another 
establishment.   
 
III.  PURPOSE AND SCOPE 
This guidance is intended for any establishment that performs a manufacturing step for 
production of an ACTP, including autologous, allogeneic, and xenogeneic ACTPs.  Preserving 
cellular function and integrity, ensuring consistency of the process and product, and preventing 
contamination are critical aspects of manufacturing ACTPs.  The safety, effectiveness, and 
quality of an ACTP are dependent on appropriate control of the manufacturing process.    
 
Establishments performing any part of a manufacturing process or any establishment utilized 
under a contract, agreement, or other arrangement for performing any step in the process must 
comply with applicable statutory and regulatory CGMP.   
3  Contains Nonbinding Recommendations 
We are providing these recommendations to help ensure that establishments are in compliance 
with statutory and regulatory CGMP.  In some cases, regulatory CGMP does not fully or 
specifically address those aspects of ACTP manufacturing necessary to ensure the safety, 
identity, strength, quality, and purity of the product.  For example, regulatory CGMP does not 
address critical items that we consider necessary to meet statutory CGMP such as donor 
eligibility or recovery of ACTPs.    
 
Establishments performing part of a manufacturing process must comply with CGMP that are 
appropriate for the manufacturing steps they perform with the ACTP.  Prior to entering into any 
contract, agreement, or other arrangement with another establishment, the ACTP sponsor should 
ensure that the establishment is following the recommendations for meeting CGMP in this 
document or is otherwise ensuring that the manufacture, processing, packing, or holding of 
ACTPs complies with CGMP. 
 
A.  Category A Establishments 
Establishments that manufacture finished ACTPs, other than Type II finished ACTPs,3 
are Category A establishments.   
 
Statutory and regulatory CGMP are applicable to Category A establishments.  While 
regulatory CGMP and the recommendations in this guidance often address similar 
manufacturing practices, regulatory CGMP does not fully or specifically address all 
aspects of ACTP manufacturing.  The bulleted list below contains aspects of ACTP 
manufacturing addressed in this and a related guidance4 that are not partly or fully 
covered by a corresponding regulatory CGMP and for which an ACTP-specific approach 
is needed to comply with statutory CGMP: 
  Donor eligibility; 
  Recovery (see section XII. Recovery); 
  Prevention of contamination; 
  Parts of manufacturing arrangements under a contract, agreement, or other 
arrangements; 
 
3 Autologous ACTPs are Type II products if they meet all of the following criteria:  
a. The ACTP is minimally manipulated;  
b. The ACTP is for homologous use; 
c. The ACTP is for use in nonfood-producing animals; 
d. The manufacture of the ACTP does not involve the combination of the cells with another article, except for 
water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, 
crystalloids, or the sterilizing, preserving, or storage agent does not raise new safety concerns with respect to 
the product; and  
e. The finished ACTP is not combined with or modified by the addition of any component that is a drug or 
device.  For more information, see GFI #218. 
4 See GFI #254, Donor Eligibility for Animal Cells, Tissues, and Cell- and Tissue-Based Products, (October 2022) 
4  Contains Nonbinding Recommendations 
  Procedures for sharing with other establishments information pertaining to 
possible contamination; 
  Audits; 
  Prohibition on pooling (see section XIII. Processing and Process Controls); 
  Predistribution shipment (see section XVII. Receipt, Predistribution Shipment, 
and Distribution of an ACTP); 
  ACTP availability for distribution only after donor eligibility is established; 
  Packaging and shipping requirements (see section XVII. Receipt, Predistribution 
Shipment, and Distribution of an ACTP); 
  Recordkeeping for 10 years (facility cleaning and sanitation records for 3 years) 
(see section VIII. Facilities); and 
  Tracking (see section XIX. Tracking). 
Category A establishments that follow the recommendations in this document in addition 
to applicable regulatory CGMP will likely be considered compliant with statutory 
CGMP.  Category A establishments may use an alternative approach to the 
recommendations in this document if the approach satisfies applicable statutory and 
regulatory CGMP.  Failure to comply with applicable statutory or regulatory CGMP may 
result in the product being adulterated under the FD&C Act. 
 
B.  Category B Establishments 
The following establishments are considered Category B establishments: 
  Establishments performing steps in the manufacture of an ACTP that do not 
process cells or tissue for the manufacture of the finished ACTP products, other 
than Type II finished products; or 
  Establishments that only manufacture Type II finished products.  
Category B establishments that follow the recommendations in this document will likely 
be considered compliant with statutory CGMP.  Category B establishments may use an 
alternative approach to the recommendations in this document if the approach satisfies 
statutory CGMP and applicable regulations.  Failure to comply with applicable statutory 
CGMP may result in the product being adulterated under the FD&C Act. 
 
C.  Implementing CGMP  
Category A and Category B establishments should implement the recommendations in 
this document at the time the cells or tissues are recovered from the donor, continue 
through the early processing steps and throughout the manufacturing process (where 
appropriate), to ensure product quality and to control contamination.  
 
5  Contains Nonbinding Recommendations 
Category A establishments should follow the regulatory CGMP for finished products as 
specified in 21 CFR parts 210 and 211 as well as the recommendations in this document.  
The regulatory CGMP for finished products should be instituted as the manufacturing 
process progresses (e.g., passaging, harvesting, final formulation, filling, and packaging).  
The following examples are provided to demonstrate when the implementation of 
regulatory CGMP should begin for Category A establishments. 
 
Example 1:  Allogeneic micronized amniotic membrane:  An establishment recovers 
placental membranes, isolates the amniotic tissue, evaluates the tissue for contamination, 
and then ships the tissue to other establishments for further processing.  This is a 
Category B establishment.  Establishments performing further processing, such as 
cryofracture, cell isolation, and packaging are Category A establishments. 
 
Example 2:  Cultured expanded adipose derived mesenchymal stem cells:  An 
establishment recovers adipose tissue from donor horses, washes the tissue with saline, 
cools the tissue, and then ships the tissue to another establishment for further processing.  
This is a Category B establishment.  Establishments performing additional processing, 
such as enzymatic digestion, isolation and culture expansion, cryopreservation, and 
packaging are Category A establishments. 
 
Example 3:  Culture expanded neural stem cells directed to differentiate to a specific 
neural lineage:  An establishment recovers brain tissue from donor dogs, dissects and 
isolates neural tissue, washes and minces the tissue, cools the tissue, and then sends the 
tissue to another establishment for further processing.  This is a category B establishment.  
Establishments performing additional processing, such as cell isolation, cell sorting, 
culture expansion, addition of growth factors, and directed differentiation are Category A 
establishments. 
  
You should contact CVM with questions regarding what constitutes finished product 
manufacturing, and whether your establishment is in Category A or Category B. 
 
IV.  ESTABLISHMENTS OPERATING UNDER A CONTRACT, AGREEMENT, OR 
OTHER ARRANGEMENT 
Before entering into any contract, agreement, or other arrangement with another establishment to 
perform any manufacturing step for you, you should verify that the establishment complies with 
applicable regulatory CGMP in 21 CFR parts 210 and 211.  We recommend that you also verify 
whether the establishment follows the recommended manufacturing practices as discussed in this 
guidance or otherwise ensures the safety, identity, strength, quality, and purity of the resulting 
product as required by section 501(a)(2)(B) of the FD&C Act.  Some ways that you can ensure 
the other establishments compliance with CGMP include the following:  
  Ensure that responsibilities are listed and understood as they relate to CGMP;  
  Review test kit package inserts that are used by a contract test laboratory;  
  Review standard operating procedures (SOPs) applicable to CGMP; 
  Review validation reports;  
6  Contains Nonbinding Recommendations 
  Review certifications, where appropriate;  
  Review previous compliance actions, such as Form FDA 483 and Establishment 
Inspection Reports (EIRs);  
  Perform comparisons of documentation provided by your contractor with source 
documents from the originator of the material;  
  Ensure that the establishment has a quality program that addresses the operations that it 
performs for you; and/or  
  Perform periodic audits of the establishment.  We recommend that such an audit include 
a review of compliance with CGMP that is applicable to the operations the establishment 
performs for you. 
If you become aware that an establishment operating under a contract, agreement, or other 
arrangement for you may no longer be in compliance with applicable CGMP, you should take 
reasonable steps to ensure the establishment is in compliance.  These reasonable steps may 
include reviewing the establishments corrective action plan and verifying that corrective actions 
have been taken under the establishments quality program.  If you determine that the 
establishment remains non-compliant, you should immediately terminate your contract, 
agreement, or other arrangement with the establishment. 
 
Example 1:  You are a processor that receives animal tissue from a recovery establishment under 
contract with you.  You have decided to audit the recovery establishment annually to ensure 
compliance with the recommendations in this document related to recovery, such as donor 
medical history, obtaining specimens for donor disease agent testing, and shipping ACTPs to you 
at appropriate temperatures.  During the audit, you should consider reviewing a representative 
sample of the records that were previously provided by the recovery establishment to confirm 
their accuracy by checking with the source of the information (e.g., the veterinarian, the 
laboratory testing for disease agents, etc.).  You may also want to accompany the recovery team 
on a recovery to review adherence to procedures and to review the quality program activities. 
 
Example 2:  You should ensure that your contract laboratories that perform ACTP donor testing 
are using validated methods.5  Such laboratories are considered establishments that must register 
with FDA because the laboratory performs control activities for a registered drug establishment.6  
These laboratories should have a quality program appropriate for the operations they perform.  
You should consider including in your contract, agreement, or other arrangement with an 
establishment a requirement that the establishment provide you with all Form FDA 483s and 
EIRs that it receives, and copies of its SOPs, and a requirement to be notified of proposed 
changes to any test kit or testing methodology being used.  After your initial assessment to 
ensure that the establishment performing the manufacturing step for you is in compliance, you 
should check periodically to ensure its continued operational compliance. 
 
 
5 We recommend discussing the suitability of the proposed validation methods with CVM early in the review 
process.   
6 See 21 CFR 207.1; 207.17(a) 
7  Contains Nonbinding Recommendations 
Example 3:  You contract out some of your processing steps, such as terminal sterilization and 
microbial testing.  You should ensure that your contractors processing steps have been verified 
or validated to be in compliance with CGMP, and that your contractor has a quality program that 
addresses the SOPs and records. 
 
Example 4:  You determine that an ACTP meets all release criteria and you make the ACTP 
available for distribution; however, you contract out the actual distribution of your product.  
Even though you are not the actual distributor, you should review manufacturing and tracking 
records to determine that the ACTP has been manufactured and tracked in compliance with 
CGMP.  As the establishment that makes the ACTP available for distribution, you should ensure 
that distribution records are kept so that ACTPs can be tracked back to you.  You should also 
review copies of applicable storage SOPs to ensure that your distributed ACTPs are stored per 
your specifications. 
 
V.  ESTABLISHMENT AND MAINTENANCE OF A QUALITY PROGRAM 
A.  General 
A quality program is an establishments comprehensive system for manufacturing and 
tracking ACTPs.  A quality program is designed to prevent, detect, and correct 
deficiencies that may lead to circumstances that increase the risk of introduction of 
contamination or impact product quality. 
 
An establishment that performs any step in the manufacture of ACTPs should establish 
and maintain a quality program that is appropriate for the manufacturing steps performed 
and the specific ACTPs manufactured.  This can be accomplished by defining, 
documenting (in writing or electronically), and implementing procedures, then following, 
reviewing, and as needed, revising procedures on an ongoing basis.  For example, the 
quality program for a recovery establishment could include establishing and maintaining 
procedures to ensure that a donors relevant medical records, including the physical 
assessment, are complete. 
 
B.  Functions 
1.  The quality program should ensure that the establishment complies with procedures 
appropriate to meet CGMP.  The quality program should ensure the review, approval, 
and revision of CGMP procedures. 
2.  The quality program should ensure that the establishment has procedures for 
receiving, investigating, evaluating, and documenting information relating to CGMP, 
including complaints.  You could receive this information before or after distribution 
of the ACTP (e.g., complaints from the consignee or results of tests detecting 
contamination performed by other establishments that recovered ACTPs from a 
shared donor). 
The quality program should ensure that procedures exist to share any information 
pertaining to the possible contamination of the ACTP with the following:  
8  Contains Nonbinding Recommendations 
a.  Other establishments that are known to have recovered ACTPs from the same 
donor; 
b.  Other establishments that are known to have performed manufacturing steps 
with respect to the same ACTP; and 
c.  All entities to whom the affected ACTP was distributed. 
When information regarding contamination of an ACTP is received after the ACTP 
has been made available for distribution, shipped to the consignee, or administered 
(implanted, transplanted, infused or transferred) to the recipient, procedures should 
include provisions for assessing risk and appropriate follow-up, evaluating the effect 
this information has on the ACTP, the notification of all entities to whom the affected 
ACTP was distributed, the quarantine and recall of the ACTP, and/or reporting to 
FDA, as necessary. 
 
Example 1:  An ACTP establishment receives information from another 
establishment that a shared donor horse tested positive for Equine Infectious Anemia.  
The establishment should investigate and evaluate the information received to 
determine if the ACTP from this donor could potentially result in the transmission of 
the relevant disease agent.  Test results indicating contamination means that the donor 
is ineligible to donate.  In this case, the establishments quality program should 
ensure that procedures exist for all of the following: 
  The quarantine of any ACTPs in the establishments inventory from the same 
donor; 
  The notification of all entities to whom the ACTP was distributed.  We 
recommend that this notification include written notification of the facts of the 
case (i.e., the reactive test results, the other establishments additional test 
results, and additional testing that will be or has been performed on archived 
specimens, and the results when known); and  
  The recall of the ACTP, and/or reporting to FDA, as necessary.  We 
recommend that recalls be reported to the FDA District Offices recall 
coordinator.  
In addition, we recommend that establishments instruct all consignees on procedures 
for return of unused ACTPs. 
 
Example 2:  A recovery establishment has contracts with multiple processing 
establishments to recover ACTPs for them.  When the recovery establishment 
receives information from one processing establishment that a recipient of an ACTP 
from a shared donor experienced an adverse drug event, the recovery establishment 
should share this information with the other processing establishments that received 
ACTPs from the same donor.  We recommend that these procedures be defined in 
your contracts, agreements, and other arrangements with other establishments. 
 
9  Contains Nonbinding Recommendations 
3.  The quality program should ensure that appropriate corrective actions relating to 
manufacturing practices are taken and documented and verify that such corrective 
actions are effective and in accordance with CGMP.  The corrective action should not 
adversely affect other operations.  Where appropriate, corrective actions should 
include both short-term action to address the immediate problem and long-term action 
to prevent the problems recurrence. 
You should document (where appropriate) the following: 
a.  Identification of the ACTP affected and a description of its disposition; 
b.  The nature of the problem requiring corrective action;  
c.  A description of the corrective action taken; and 
d.  The date(s) of the corrective action. 
4.  The quality program should ensure that personnel involved in activities related to 
CGMP have proper training, education, and experience to perform those activities, 
and that personnel perform only those activities for which they are qualified and 
authorized. 
Example:  The quality program could ensure that personnel are properly trained and 
educated by establishing training and education criteria for specific positions.  This 
might be accomplished by ensuring that the content of training is relevant for an 
individual performing specific activities related to CGMP and by requiring a certain 
level of education and/or certification, as appropriate.  For example, you may want to 
establish that personnel performing recovery operations on live animals are licensed 
veterinarians. 
 
5.  The quality program should establish and maintain appropriate monitoring systems. 
  Example:  You might develop systems within the facility for environmental control 
(e.g., systems to monitor temperature and humidity), environmental monitoring (e.g., 
viable particulate monitoring in a clean room), and storage (e.g., systems that monitor 
the temperature of ACTP storage units and alarm when out of range). 
6.  The quality program should investigate and document CGMP deviations and trends 
of CGMP deviations related to CGMP and make reports as recommended in this 
document.  Each investigation should include a review and evaluation of the CGMP 
deviation, the efforts made to determine the cause, and the implementation of 
corrective action(s) to address the CGMP deviation and prevent recurrence. 
 
Example:  ACTPs are recovered, but later review of donor records indicate that the 
donor did not meet certain donor criteria stated in your establishments SOPs.  The 
recovered ACTPs are destroyed after processing and before distribution.  This event 
is a deviation from CGMP that should be investigated and documented for ACTPs, 
10  Contains Nonbinding Recommendations 
but as long as no other reporting requirements apply, it is not necessary to report the 
deviation to FDA because the ACTPs were not distributed.7 
 
C.  Audits 
You should periodically perform, for management review, a quality audit of activities 
related to CGMP.  We recommend that a quality audit be conducted at least annually, and 
more frequently, if necessary.  A quality audit is a documented, independent assessment 
and review of the establishments activities related to CGMP.  The audit verifies 
compliance with CGMP by examining and evaluating objective evidence.  An assessment 
and review is considered to be independent when it is performed by an individual who 
does not have direct responsibility for the matter being audited or is external to the 
audited establishment. 
 
It is not FDAs current policy to review or copy your actual quality audit reports during 
routine inspections by FDA.  However, you should have a mechanism to demonstrate to 
the FDA investigator that quality audits are performed. 
 
D.  Computers 
If you rely upon computer software to comply with CGMP, and if the software either is 
custom software or is commercially available software that has been customized or 
programmed (including software programmed to perform a user-defined calculation or 
table), you should validate the software for its intended use.  You should verify the 
performance of all other software for the intended use if you rely upon it to comply with 
CGMP.  You should approve and document these activities and results before 
implementation. 
 
VI.  PERSONNEL 
A.  General 
You should have personnel sufficient to ensure compliance with CGMP and to ensure 
that the ACTP is manufactured in a way that does not compromise product quality or 
increase the risk of contamination. 
 
B.  Competent Performance of Functions 
Personnel should have the necessary education, experience, and training to ensure 
competent performance of their assigned functions.  Personnel should perform only those 
activities for which they are qualified and authorized. 
 
 
7 See 21 CFR 514.80 
11  Contains Nonbinding Recommendations 
C.  Training 
You should train all personnel, and retrain as necessary, to perform their assigned 
responsibilities adequately.  You should establish criteria for each position and 
periodically review the qualifications, training, and professional development of your 
personnel to ensure competency for their assigned functions.  
 
VII.  PROCEDURES 
A.  General 
You should establish and maintain procedures appropriate to meet CGMP for all steps 
that you perform in the manufacture of ACTPs.  You should design these procedures to 
prevent circumstances that compromise product quality or increase the risk of 
contamination. 
 
B.  Review and Approval 
Before implementation, you should have a responsible individual review and approve 
new procedures.  You should also ensure the periodic review and approval of procedures 
and ensure compliance with the recommended procedures with respect to such 
procedures as a function of your quality program. 
 
C.  Availability 
Procedures should be readily available to personnel in the area where operations are 
performed.  However, procedures do not have to be physically maintained in the area of 
operation if such availability is impractical. 
 
Example 1:  Copies (e.g., on paper, or electronic media) of recovery SOPs could travel to 
recovery sites with personnel or could be accessed electronically from a separate 
location, as long as they are easily accessible to all employees performing recovery.   
 
Example 2:  It may not be feasible to physically keep SOPs in clean rooms where 
processing operations occur, because the SOPs could cause contamination of ACTPs.  In 
that case, you could keep the SOPs in an adjacent area outside the clean rooms.  As long 
as a paper and/or electronic copy of the SOPs are physically available, additional 
methods of obtaining information, such as an immediate communication method using 
wired or wireless technologies from personnel with questions to personnel who have 
access to current procedures, could be used to resolve, answer, or clarify questions that 
arise during operations. 
 
D.  Standard Procedures 
If you adopt current standard procedures from another organization, you should verify 
that the procedures meet CGMP and are appropriate for your operations. 
 
12  Contains Nonbinding Recommendations 
VIII.  FACILITIES 
A.  General 
Any facility used in the manufacture of ACTPs should be of suitable size, construction, 
and location to preserve quality and prevent contamination of ACTPs and to ensure 
orderly handling of ACTPs without mix-ups.  You should maintain the facility in a good 
state of repair.  You should provide lighting, ventilation, plumbing, drainage, and access 
to sinks and toilets that are adequate to maintain product quality and prevent the 
introduction of contamination. 
 
All facilities manufacturing or distributing ACTPs must register with FDA and drug list 
their products prior to marketing.8   
 
B.  Facility Cleaning and Sanitation 
You should maintain any facility used in the manufacture of ACTPs in a clean, sanitary, 
and orderly manner to prevent the introduction of contamination.  You also should 
dispose of sewage, trash, and other refuse in a timely, safe, and sanitary manner. 
 
You should have a cleaning program supported by environmental monitoring, where 
appropriate.  You should determine the appropriate frequency, method, and concentration 
of disinfectants to ensure prevention of contamination and cross-contamination in your 
facility. 
 
Example:  You use a broad-spectrum disinfectant that has been demonstrated to 
inactivate bacteria and fungi on surfaces.  You should follow the manufacturers 
instructions for proper dilution and adequate contact time and document that all 
parameters were met. 
 
C.  Operations 
You should divide a facility used in the manufacture of ACTPs into separate or defined 
areas of adequate size for each operation that takes place in the facility, or you should 
establish and maintain other control systems to prevent improper labeling, mix-ups, 
contamination, cross-contamination, and accidental exposure of ACTPs to prevent 
contamination. 
 
It is not necessary that there be a separate designated room for each task performed 
during the manufacture of an ACTP.  You should evaluate the type of area that a task 
would require to prevent contamination or cross-contamination of ACTPs and designate 
an appropriate area for those tasks. 
 
 
8 See 21 CFR part 207; https://www.fda.gov/drugs/electronic-drug-registration-and-listing-system-edrls/electronic-
drug-registration-and-listing-instructions 
13  Contains Nonbinding Recommendations 
Example:  A clean room used for processing ACTPs could have defined areas designated 
for: 
  Initial tissue processing; 
  Cell or tissue culturing; 
  Preparation of media; or  
  Filling of vials.    
It would not be appropriate to utilize a clean room normally used for processing ACTPs 
to perform the following activities: 
  Preparing packaged, recently recovered ACTPs for shipment to another facility; 
  Prepackaging freshly recovered ACTPs for subsequent quarantine; 
  Handling (e.g., centrifugation, serum/plasma separation) of blood specimens to be 
used for relevant disease agent testing; or 
  Decontaminating instruments used for recovery or processing. 
D.  Procedures and Records 
You should establish and maintain procedures for facility cleaning and sanitation for the 
purpose of preventing the introduction of contamination.  These procedures should assign 
responsibility for sanitation and should describe in sufficient detail the cleaning methods 
to be used and the schedule for cleaning the facility.  You should document and maintain 
records of all cleaning and sanitation activities performed to prevent contamination of 
ACTPs.  You should create these records concurrently with cleaning and sanitation 
activities.  We recommend that you retain such records for 3 years after their creation. 
 
E.  Recovery 
The facility-related recommendations apply to recovery of ACTPs.  You should 
determine how to evaluate an area used for recovery to prevent contamination and cross-
contamination, per the general facilities recommendations.  As these recovery facilities 
may not be under your day-to-day control, you should establish and maintain procedures 
to prevent the introduction of contamination that may occur during each recovery. 
 
You should consider the following issues when evaluating an area used for recovery: 
  Facility size, location, and construction for aseptic recovery; 
  Access to recovery site during the recovery procedure/period; 
  State of repair of facility; 
  Lighting and space; 
  Ventilation and airflow; 
  Access to a sink; 
14  Contains Nonbinding Recommendations 
  Cleanliness of working spaces used for recovery operations with verified cleaning 
agents and proper cleaning documentation; and 
  Capability to perform aseptic techniques. 
A description, checklist, and/or other means could be used to document that the recovery 
site meets established, desired parameters each time a recovery is performed.  The site of 
the recovery should be documented.  Before entering into a contract with a recovery 
establishment, you should examine the facilities where recoveries take place. 
 
Example:  A tissue recovery facility may be a barn in which bone marrow or adipose 
tissue is extracted from animals such as horses.  A facility such as this may not have a 
heating and cooling system or specific air filtration.  However, the facility may comply 
with CGMP for facilities by having recovery, handling, and storage procedures in place 
to prevent contamination of the ACTP. 
 
IX.  ENVIRONMENTAL CONTROL AND MONITORING 
A.  General 
Where environmental conditions could reasonably be expected to cause contamination or 
cross-contamination of ACTPs or equipment, or impact the quality of the ACTP, you 
should adequately control environmental conditions. 
 
B.  Environmental Control 
To adequately control environmental conditions, where appropriate, you should provide 
for the following control activities or systems: 
  Temperature and humidity controls; 
  Ventilation and air filtration; 
  Cleaning and disinfecting of rooms and equipment to ensure aseptic processing 
operations; and 
  Maintaining equipment used to control conditions necessary for aseptic 
processing operations. 
We are not recommending clean room classification requirements for particular facilities 
or manufacturing steps; instead, you should determine the appropriate level of control.  
The appropriate level of control may depend on such factors as which manufacturing 
steps are involved, whether they are performed in an open or closed system, whether they 
are performed in a laminar flow hood (LFH) or biological safety cabinet (BSC), and other 
factors as described in FDA GFI, Sterile Drug Products Produced by Aseptic Processing 
 Current Good Manufacturing Practice (September 2004).9  This guidance provides 
useful information for an ACTP establishment that is developing procedures on 
 
9 https://www.fda.gov/media/71026/download 
15  Contains Nonbinding Recommendations 
environmental control and monitoring.  Also, United States Pharmacopoeia Chapter 
<1116> Microbiological Evaluation of Clean Rooms and Other Controlled 
Environments10 contains information on environmental monitoring. 
 
We recommend that you determine the types of microorganisms that could exist in your 
facility and design your cleaning and environmental control and monitoring programs 
accordingly.  You should select the types of disinfectant/cleaning agents to use that are 
effective against microorganisms you have identified. 
 
Example:  Adipose tissue is extracted from a horse in a barn.  The tissue is shipped to a 
processing facility where mesenchymal stem cells (MSCs) are isolated from the tissue.  
Processing (i.e., treatment of the cells with collagenase and extraction of the MSCs) 
should be performed in an LFH or BSC because this equipment provides a controlled 
environment and can be adequately cleaned and monitored. 
 
C.  Inspections 
You should inspect each environmental control system periodically to verify that the 
system, including necessary equipment, is adequate and functioning properly.  You 
should take appropriate corrective action as necessary. 
 
D.  Environmental Monitoring 
You should monitor environmental conditions where environmental conditions could 
reasonably be expected to impact quality of the ACTP, cause contamination or cross-
contamination of ACTPs or equipment, or cause accidental exposure of ACTPs to 
contaminating agents.  Where appropriate, you should provide environmental monitoring 
for microorganisms.  You should design your environmental monitoring system based on 
the type of operations performed in your facility. 
 
You should establish and maintain procedures for environmental control and monitoring.  
We recommend that you define the type and frequency of environmental monitoring to 
be performed, including the monitoring used to verify that cleaning procedures are 
adequate, and that the environmental control systems are capable of maintaining the 
degree of control specified. 
 
You should define alert and action levels for test results and specify potential corrective 
actions when alert and/or action levels are exceeded. 
 
The following types of environmental monitoring should be considered in clean rooms, 
LFHs, and BSCs used for processing: 
  Non-viable particulate air monitoring; 
  Viable particulate air monitoring; 
 
10 http://ftp.uspbpep.com/v29240/usp29nf24s0_c1116.html 
16  Contains Nonbinding Recommendations 
  Clean area positive pressure levels; 
  Surface monitoring (taking into account all different surfaces in the 
manufacturing environment); and 
  Personnel monitoring (e.g., gloves). 
Example:  We recommend that you perform periodic monitoring of non-viable and viable 
particulates, work surfaces, and personnel.  This monitoring should be performed in clean 
rooms using LFHs and BSCs for processing in order to evaluate environmental changes 
that may impact quality of the ACTP or increase the likelihood of contamination or cross-
contamination of ACTPs. 
 
E.  Temperature and Humidity 
Each establishment should determine what temperature ranges and humidity levels could 
reasonably be expected to have an adverse effect on the ACTPs it manufactures.   
 
Example:  If steps in the manufacture of ACTPs have identifiable parameters for 
maintaining a certain temperature and/or humidity, or the performance of the reagents 
used in the manufacturing of ACTPs could be adversely affected by temperature and/or 
humidity over the length of storage of the reagent or product, you should adequately 
control and monitor environmental conditions and provide proper conditions for 
operations. 
 
F.  Records 
You should document and maintain records of environmental control and monitoring 
activities.  In addition, you should retain records concurrently with the performance of 
each step included in the environmental control and monitoring activities. 
 
G. Recovery 
Environmental control and monitoring considerations during recovery operations are 
similar to those of other manufacturing steps.  You should consider the need for 
environmental control and monitoring of facilities used for ACTP recovery.  You should 
establish and maintain procedures to prevent contamination or cross-contamination 
during recovery, or circumstances that otherwise increase the risk contamination with use 
of the ACTP.  While environmental monitoring might not have to be performed at each 
recovery site, you should have controls in place to provide assurance that the recovery 
site does not increase the potential for contamination and cross-contamination of ACTPs.  
You should set specific parameters for recovery site suitability and verify for each 
recovery that these parameters have been met.  A controlled environment with adequate 
temperature and humidity controls and adequate ventilation should be used for recovery.  
We recommend an operating room or similar type of facility. 
 
Recovery establishments should have the following, where appropriate: 
17  Contains Nonbinding Recommendations 
  Air filtration; 
  Temperature and humidity controls; 
  Non-porous surfaces for handling donor specimens; 
  Washable walls; 
  Refrigeration for donor storage; and 
  Appropriately cleaned and sterilized surgical instruments. 
X.  EQUIPMENT 
A.  General 
Equipment used in the manufacture of ACTPs should be of the appropriate design for its 
use and suitably located and installed to facilitate operations, including cleaning and 
maintenance, to control contamination and ensure product quality.  Any automated, 
mechanical, electronic, or other equipment used for inspection, measuring, or testing 
should be capable of producing valid results.  Equipment should be cleaned, sanitized, 
and maintained per established schedules.  The equipments potential to contaminate the 
ACTP should be considered during use.  It is recommended that an installation plan for 
equipment be developed and executed, if applicable, to ensure that the equipment is 
suitably located, installed properly (per the manufacturers specified requirements), and 
operates properly. 
 
B.  Procedures and Schedules 
You should establish and maintain procedures for cleaning, sanitizing, and maintaining 
equipment to prevent malfunctions or contamination of ACTPs. 
 
There are no required schedules for cleaning equipment.  Each establishment should 
determine and justify cleaning procedures to prevent the contamination of ACTPs.  
Manufacturers instructions for cleaning materials and equipment could provide useful 
information for determining appropriate cleaning schedules. 
 
Example:  Apheresis machines or bioreactors using disposable tubing may not require 
cleaning between each ACTP recovery if new sterile tubing is used with each recovery.  
However, if there is a spill, there should be special cleaning procedures in place. 
 
C.  Calibrations and Equipment 
Where appropriate, you should routinely calibrate, per established procedures and 
schedules, all automated, mechanical, electronic, or other equipment used for inspection, 
measuring, and testing.   
 
Example:  An instrument used to monitor the temperature of an ACTP storage unit 
should be regularly calibrated.  
 
18  Contains Nonbinding Recommendations 
To determine an appropriate calibration schedule, you should consult the equipments 
operations manual or contact the manufacturer of the equipment to determine and 
establish appropriate intervals for calibrating each piece of equipment.  You should also 
take into consideration the specific use of the equipment within the manufacturing facility 
to determine if special conditions could warrant more frequent calibration than is 
recommended by the equipment manufacturer.  Calibration accuracy should be traceable 
to accepted/known standards, for example, those from the National Institute of Standards 
and Technology,11 or the manufacturers supplied or recommended standard.  
 
D.  Inspections 
You should routinely inspect equipment for cleanliness, sanitation, and calibration and to 
ensure adherence to applicable equipment maintenance schedules. 
 
E.  Records 
Records of all equipment maintenance, cleaning, sanitizing, calibration, and other 
activities should be documented and maintained.  These records should also be displayed 
on or near each piece of equipment or should be made readily available to the individuals 
responsible for performing these activities and to the personnel using the equipment.  
Records should be maintained of the use of each piece of equipment, including the 
identification of the ACTP manufactured with that equipment.  Records for cleaning and 
maintenance of equipment (including simple instruments that are regularly washed and 
disinfected), tools, and other equipment used or reused in the manufacturing of ACTPs 
should be kept to document that the items were adequately cleaned and maintained to 
prevent contamination. 
 
Example:  For single-use instruments, you should maintain records of the use of that 
equipment, including the identification of each ACTP manufactured with that equipment.  
Maintaining records for the use of single-use instruments would be helpful, for example, 
to the ACTP manufacturer in the event that the single-use devices are recalled because 
the manufacturer discovered that the distributed devices were not sterile. 
 
If it is necessary to implement an alternate method of identifying the current 
maintenance, cleaning, sanitizing, and/or calibration status of each piece of equipment, 
the alternate method should permit the operator to easily check, prior to each use, that the 
equipments maintenance, cleaning, sanitizing, and/or calibration have been properly 
performed. 
 
You may have another establishment perform equipment maintenance, cleaning, 
sanitizing, and/or calibration for you, under a contract, agreement, or other arrangement.  
You may use the other establishments records to demonstrate compliance with the 
recommendations for equipment.  However, you should ensure that the services provided 
are adequate and in compliance with CGMP. 
 
11 http://www.nist.gov/ 
19  Contains Nonbinding Recommendations 
 
See section XVIII. Records for further information about general recordkeeping. 
 
F.  Qualification and Certification 
It is recommended that equipment be qualified and certified to ensure consistent 
operation and the production of desired results.  This is consistent with the 
recommendations outlined in FDAs GFI titled Process Validation:  General Principles 
and Practices (January 2011).12  Routine certification for certain equipment, such as 
LFHs and BSCs, should be performed per the manufacturers specifications. 
 
Example:  Periodic recertification of an LFH could include measuring the air flow and 
velocity, ensuring proper operation of the HEPA filter (e.g., particle testing), and/or 
making sure that the exhaust is properly directed.  An event or activity that warrants 
recertification of the LFH would include, but is not limited to, repair or replacement of 
parts. 
 
G. Recovery 
Recovery equipment should be cleaned to remove dirt, debris, and biological material 
prior to sterilization or high-level disinfection.  Cleaning should involve the use of water 
with detergents or enzymatic products.  Cleaning and disinfection solutions should be 
used per the manufacturers instructions.  Containers used to clean recovery equipment 
should be cleaned and sanitized after each use. 
 
If equipment is cleaned manually, you should have a cleaning procedure in place that 
ensures removal of dirt, debris, and biological material.  Manual cleaning procedures 
should include segregation of instruments from donors at risk of infection with relevant 
disease agents.  If you use an automatic washer, you should ensure that the washer 
operates consistently and is properly cleaned after each use, per established procedures.  
There is no requirement to segregate recovery equipment (e.g., instruments) used for 
different donors prior to cleaning in an automated washer.  It is acceptable to place 
multiple instrument trays into the same automated washers.  If possible, it would be 
preferable to clean instruments used on the same type of tissue together in such loads. 
 
To demonstrate that cleaning and sterilization of recovery instruments performed by a 
contract facility are appropriate, the recovery establishment should:  
  Obtain and approve the procedures, and review the records of cleaning and 
sterilization; 
  Establish and maintain verification procedures for any instruments cleaned and 
sterilized for you by a facility under contract, agreement, or other arrangement; 
and  
 
12 https://www.fda.gov/media/71021/download 
20  Contains Nonbinding Recommendations 
  Have the procedures and records available for review on inspection. 
Establishments that only clean and sterilize recovery equipment (e.g., instruments) under 
contract, agreement, or other arrangement to a registered recovery establishment are not 
required to register, because this function is not considered a manufacturing step.  
However, the sponsor should be able to verify that the recovery instruments are clean and 
sterile at the time of use. 
 
XI.  SUPPLIES AND REAGENTS 
A.  General 
Supplies and reagents include all materials that are used during manufacture, not just 
those coming into direct contact with ACTPs.  Examples of supplies include sterile 
drapes, gauze, cleaning swabs, gloves, alcohol pads, and equipment (e.g., instruments).  
Examples of reagents include cleaning agents, saline, dimethyl sulfoxide, anticoagulants, 
and chemical and antibiotic solutions used in processing. 
 
Control of supplies and reagents is critical to preventing contamination and ensuring the 
quality of your ACTP. 
 
B.  Verification 
You should not use supplies and reagents until they have been verified to meet 
specifications designed to ensure product quality and prevent circumstances that increase 
the risk of contamination.  Verification may be accomplished by the establishment that 
uses the supply or reagent, or by the vendor of the supply or reagent.  Use of a 
contaminated or otherwise defective supply or reagent in the manufacture of an ACTP 
could lead to such problems as the introduction of a relevant disease agent or the failure 
to properly preserve the ACTP. 
 
You should verify that those supplies and reagents used in all steps of the manufacture of 
ACTPs (not only those that come in contact with an ACTP), including recovery, meet 
specifications designed to ensure product quality and prevent circumstances that increase 
the risk of introduction of contamination.  You should store and use supplies and reagents 
per the manufacturers instructions.  We recommend that you keep product information 
data sheets for all supplies and reagents used, update these sheets as products change, and 
keep an archive of previously used products.  Verification that reagents meet 
specifications may be accomplished either by reviewing the Certificate of Analysis 
(COA) or by performing relevant testing.  For supplies, such as sterile drapes or gloves, 
that are not expected to have a COA, we recommend that you obtain information from 
the vendor on the relevant specifications and the manufacturing of the supply.  You 
should maintain records of the verification of each supply or reagent, which may include 
test results and vendor COAs.  If you receive supplies and/or reagents from a vendor or 
another establishment, you should verify that the vendor or other establishment has a 
system in place to certify that the supplies and/or reagents meet established 
specifications.   
21  Contains Nonbinding Recommendations 
 
Example 1:  You could reference specification sheets, COAs, or manufacturers package 
inserts describing the reagent and/or supply to verify suitability. 
 
If you require that specific supplies and reagents be used by recovery establishments, 
then you should verify the supplies and reagents, and should include this information in 
any contract, agreement, or other arrangement with the recovery establishment. 
 
Example 2:  Supplies used to wrap or package the individual ACTPs at recovery should 
be designed to prevent leakage that could cause contamination or cross-contamination 
and should be able to perform in this capacity when subjected to expected storage 
temperatures for that ACTP type. 
 
C.  Reagents 
Reagents used in processing and preserving ACTPs should be sterile, where appropriate. 
 
Example 1:  It may be appropriate to use non-sterile water during processing for an 
ACTP that will be terminally sterilized, if the water meets specifications for use 
determined during process validation.  However, only sterile reagents should be used in 
the processing of an ACTP that is not terminally sterilized.  
 
Reagents of human or animal origin that are used in the manufacture of an ACTP should 
be assessed for their potential to contribute possible contaminating adventitious agents.  
Risk mitigation or testing strategies should be implemented, as appropriate. 
 
Example 2:  Fetal bovine serum utilized in the manufacture of an ACTP may require an 
evaluation of the source animal and collection procedures as it relates to prion 
contamination, in addition to other adventitious agent testing.  As part of the risk 
mitigation strategy to control possible adventitious agents, such as bacteria and viruses, 
filtration and irradiation may be employed.  
 
D.  In-House Reagents 
You should validate and/or verify the processes used for production of in-house reagents.   
 
Example:  In the case of reagents produced for disinfecting recovery processes, the 
recovery establishment should verify that these reagents meet specifications designed to 
prevent circumstances that increase the risk of the introduction of contamination (e.g., 
solutions are sterile (where appropriate), have the proper concentrations, and fall within a 
specific pH range). 
 
E.  Records 
You should maintain the following records pertaining to supplies and reagents: 
22  Contains Nonbinding Recommendations 
  Records of receipt for each supply or reagent, including the type, quantity, 
manufacturer, lot number, date of receipt, and expiration date; 
  Records of verification for each supply or reagent, including test results or, in the 
case of vendor verification, a COA from the vendor; and 
  Records of the supply or reagent lot used in the manufacture of each ACTP. 
You should establish a system under which specific supply and reagent lots can be linked 
to individual ACTPs.  This does not necessarily require an individual record for each 
supply used in preparing every ACTP (e.g., sterile drapes and gloves).  For instance, you 
may track those supplies by recording dates between which certain lot numbers were 
used, rather than individually recording each supply as it is used during the manufacture 
of each ACTP.  Maintaining such records will enable you to determine which supply and 
reagent lots were used at a particular time and which ACTPs were manufactured during 
that same time period.  This would facilitate a recall of ACTPs if the supplies or reagents 
used in their manufacture are later found to increase the risk of introduction of 
contamination. 
 
XII.  RECOVERY 
A.  General 
Recovery means obtaining from a donor, cells or tissues that are intended for 
implantation, transplantation, infusion, transfer, or other means of administration to an 
animal recipient.  You should recover each ACTP in a way that maintains quality of the 
tissue or cells and does not cause contamination or cross-contamination during recovery, 
or otherwise increase the risk of the introduction of contaminating agents with use of the 
ACTP.  
 
Establishments that recover ACTPs must register with FDA because the establishment is 
engaging in the manufacture, preparation, or processing of a drug.13  However, if you are 
a person (e.g., an individual veterinarian, veterinary practice) under contract, agreement, 
or other arrangement with a registered establishment and you are engaged solely in 
recovering cells or tissues (e.g., cord blood, adipose tissue) and sending the recovered 
cells or tissues to the registered establishment, we do not expect you to register or list 
your ACTPs independently.  You should comply with all other applicable CGMP.  When 
operations are conducted at more than one establishment and common ownership and 
control among all the establishments exists, the parent subsidiary or affiliate company 
may submit registration information for all establishments.   
 
 
13 See 21 CFR 207.17(a) 
23  Contains Nonbinding Recommendations 
B.  Procedures and Records 
You should establish and maintain procedures for CGMP related to recovery operations 
where appropriate, such as: 
  Facilities; 
  Environmental control; 
  Equipment; 
  Supplies and reagents; 
  Labeling controls; 
  Storage; and  
  Receipt, predistribution shipment, and distribution of an ACTP. 
Your quality program should address all of these aspects of CGMP.  Maintenance of 
records and a record management system should adhere to the CGMP in section XVIII. 
Records of this document. 
 
C.  Controlling Contamination 
You should evaluate all recovery-related operations to determine how these activities can 
be performed to control contamination and cross-contamination, including the following:  
  Technical procedures used; 
  Personnel involved; 
  Equipment, supplies, and reagents that are used during recovery; and 
  Facilities where recoveries take place (see section VIII. Facilities). 
Specific examples of such activities include: 
  Staff should have the experience, education, and training necessary to perform 
recovery operations; 
  Recovery site suitability parameters should be established and documented, 
including facility cleaning and maintenance, and environmental controls; 
  Recovery should be performed using aseptic technique; 
  Recognized published industry practices appropriate to controlling contamination 
(e.g., zone recovery, isolation draping, and sequencing) should be utilized; 
  ACTPs should not be recovered from an area of the body where there is localized 
infection; 
  Equipment, including instruments used in the manufacture of ACTPs, should be 
of appropriate design for its use.  You should clean, sanitize, and maintain 
equipment per established schedules.  You should document and maintain records 
24  Contains Nonbinding Recommendations 
of all equipment maintenance, cleaning, sanitizing, calibration, and other 
activities performed; and 
  Supplies and reagents used during recovery should be of the appropriate quality 
and standard and records should be maintained. 
Recovery activities and problems related to microbial contamination should be evaluated.  
For example, technical errors should be assessed and pre-processing culture results 
should be tracked and trended. 
 
D.  Donor Identification 
Verifying and documenting the donor identity is the first step in ACTP tracking and is 
critical for preventing contamination with relevant disease agents by ensuring that donor 
eligibility information corresponds to the actual donor of the ACTPs. 
 
Prior to recovering ACTPs from a donor, you should compare the potential donor by a 
permanent identification method with the donors information as indicated on donor 
eligibility documentation.  
 
You should document the methods used to verify the donor identity and should include 
the source of the verification information, the date and time at which the identification 
was made, and the name of the recovery staff member(s) who made the identification.   
 
Example:  Methods of documenting a donor animals identification include 
photographing the donors unique markings or permanent identification tag or tattoo, 
documenting a microchip number, verifying age, sex, weight, markings, and breed of the 
animal. 
 
E.  Audits 
A processor should periodically audit the records provided by the recovery establishment 
by comparing them to other available information related to the donors and could contact 
the responsible person referenced in the donor records.  Before entering into a contract 
with a recovery establishment, a processor should examine the facilities where recoveries 
take place and verify that they are adequate. 
 
XIII.  PROCESSING AND PROCESSING CONTROLS 
A.  General 
You should process each ACTP in a way that maintains quality of the ACTP and does not 
cause contamination or cross-contamination during processing. 
 
Processing is defined as any activity performed on an ACTP, other than recovery, donor 
screening, donor testing, storage, labeling, packaging, or distribution, such as: 
  Testing for microorganisms; 
25  Contains Nonbinding Recommendations 
  Preparation; 
  Sterilization; 
  Steps to inactivate or remove adventitious agents; 
  Preservation for storage; and 
  Removal from storage. 
In the context of this guidance, the set of manufacturing activities that an establishment 
performs on an ACTP taken together would be considered a process. 
 
Example:  In the manufacture of an MSC, a process may consist of activities such as 
treatment of the stromal vascular fraction (SVF) with collagenase, isolation of the MSCs 
from the SVF, growth and passaging, filling into drug product containers, and 
cryopreservation. 
 
Processing also includes obtaining specimens from an ACTP that are subsequently sent 
for microbiological testing (e.g., collection of swab specimens or representative ACTPs 
for destructive cultures), and the actual microbiological testing, including speciation of 
microorganisms that are detected. 
 
When manufacturing an ACTP that cannot be terminally or filter sterilized, aseptic 
technique should be implemented throughout each step of the manufacturing process, 
including recovery and processing of tissue, to prevent contamination and cross-
contamination.  In situations where results of final sterility testing are not available before 
the product is administered, additional controls and testing should be considered.   
 
Example:  Additional sterility tests can be performed at intermediate stages of 
manufacture, such as after the last manipulation of the product prior to harvest in 
combination with other tests that may indicate microbial contamination, such as rapid 
microbial tests, microscopic examination, Gram stain (or other bacterial and fungal stain), 
endotoxin testing, etc.  These tests should be performed and meet acceptance criteria 
prior to product release. 
 
B.  Pooling 
1.  Pooling ACTPs from two or more donors 
Cells or tissue from two or more donors should not be pooled (placed in physical 
contact or mixed in a single receptacle) during manufacturing.  For example, 
commingling MSCs from different donors during processing would be considered 
pooling.  In the event that you determine that pooling of ACTPs from two or more 
donors is necessary to obtain a therapeutic dose, we recommend that you discuss this 
with CVM early in product development.  Pooling does not include the sequential 
administration of ACTPs from different donors to an individual recipient. 
 
2.  Pooling ACTPs recovered at different times from one donor 
26  Contains Nonbinding Recommendations 
In general, we discourage the practice of pooling ACTPs that were recovered from a 
single donor at different points in time during processing or post-thaw because of the 
increased risk that one product could be contaminated and could cross-contaminate 
the other.  However, the practice of pooling ACTPs that were recovered from a single 
donor may be acceptable if the processing otherwise complies with the applicable 
recommendations and the tracking/labeling systems are well-controlled to prevent 
mix-ups. 
 
C.  In-Process Control and Testing 
Your procedures for processing and process controls should ensure that specified 
requirements, for in-process controls are met, and that each in-process ACTP is 
controlled until the required inspection and tests or other verification activities have been 
completed, or until necessary approvals per the quality program are received and 
documented.  Sampling of in-process ACTPs should be representative of the material to 
be evaluated. 
 
You should establish appropriate, objective mechanisms to control and monitor each 
process to ensure that you are processing ACTPs in a way that maintains quality and does 
not cause contamination or cross-contamination during processing.  You could use a 
variety of methods for controlling and monitoring your processes, including statistical 
process-control methods and review of product acceptance criteria and results, as well as 
a meaningful quality audit. 
 
For in-process control and testing you should check the results of testing at various steps 
during processing (e.g., by sampling in-process ACTPs and testing for parameters such as 
viability, cell count, performing a microbiological culture, etc.).  The sample selected for 
testing (e.g., culture) should be representative of the ACTP to be evaluated.  This may not 
be the case if a small portion of a large musculoskeletal ACTP or companion ACTP (i.e., 
ACTPs adjacent to the ACTP that is processed along with the ACTP) is cultured. 
 
D.  Pre-Processing Controls and Testing 
To evaluate each incoming ACTP for the presence of microorganisms or contamination, 
you could utilize practices such as culturing the ACTP prior to processing.  This culture 
is known as the pre-processing culture.  Recovery establishments may perform the 
culture and send the results to the processor.  Alternatively, using pre-established criteria, 
the processor may perform the culture, and based upon the results determine whether to 
reject or accept the ACTP for processing. 
 
For instance, some processors may irradiate the ACTP to reduce the bioburden prior to 
additional processing, depending upon the amount and/or type of microorganisms 
detected. 
 
It may not be possible to culture some ACTPs prior to processing, such as tissues that are 
immediately placed into an antibiotic solution after recovery.  Under these circumstances, 
alternative approaches may be utilized.   
27  Contains Nonbinding Recommendations 
 
Example:  You could use storage or transport solutions that contain a pH indicator where 
a color change could indicate contamination.  Additional testing may also be needed to 
confirm these results. 
 
XIV.  PROCESS CHANGES AND PROCESS VALIDATION 
A.  General 
Any change to a process should be verified or validated to ensure that the change does 
not create an adverse impact elsewhere in the operation and does not affect the quality of 
the ACTP.   
 
Example 1:  If you develop software to store information used to make donor eligibility 
determinations, you should validate the software for this intended use. 
 
Example 2:  If you use a commercial electronic spreadsheet to record donor testing 
results which are used to make a donor eligibility determination, you should verify that 
the unmodified software performs this activity correctly. 
 
B.  Approval and Implementation of a Process Change 
Any change should be approved by a responsible individual with appropriate knowledge 
and background, before implementation.  You should communicate approved changes to 
the appropriate personnel in a timely manner.  This provision does not apply to 
manufacturing steps other than processing. 
 
Changes to verified processes may require either verification or validation.   
 
Example:  A switch from one brand of a solution used in processing to another brand of 
solution would be a process change.  In this situation, the establishment should verify that 
the new solution performs as intended, in a manner that maintains quality, and does not 
introduce contamination. 
 
C.  Process Validation 
Where the results of processing described under section XIII. Processing and Processing 
Controls cannot be fully verified by subsequent inspection and tests, you should validate 
and approve the process per established procedures.  The validation activities and results 
should be documented, including the date and signature of the individual(s) approving the 
validation. 
 
D.  Written Representation 
Any written representation that your processing methods reduce the risk of contamination 
of an ACTP, including but not limited to a representation of sterility or pathogen 
inactivation of an ACTP, should be based on a fully verified or validated process. 
28  Contains Nonbinding Recommendations 
 
E.  Changes 
When changes to a validated process such as described above occur, you should review 
and evaluate the process, and perform revalidation where appropriate.  You should 
document these activities. 
 
XV.  LABELING 
A.  General  
All labeling must be truthful and not misleading.14  You must follow the applicable 
labeling requirements for all animal drugs.15  Labeling information provides important 
information regarding the safety and quality of the ACTP.  It should ensure proper ACTP 
identification and prevent mix-ups. 
 
B.  Controls 
You should establish and maintain procedures to control the labeling of ACTPs. 
 
Your procedures should ensure that each ACTP is labeled in accordance with CGMP, 
including those in the following sections of this guidance and GFI #254, Donor 
Eligibility for ACTPs16: 
  Section XVIII. Records; 
  Section XIX. Tracking;  
  Section XV. Labeling; 
  GFI #254, section VII. Records; 
  GFI #254, section VIII. Quarantine of ACTPs; and 
  GFI #254, section IX. ACTPs From Ineligible Donors. 
Examples of procedures that you could use to prevent labeling errors include the 
following: 
  Identifying dedicated work areas and controlling separation of activities; 
  Enclosing an additional copy of the label in the processing record as evidence of 
the actual label used (or if using electronic systems, you could retain an electronic 
copy); 
  Labeling the ACTPs from one donor at a time; and 
 
14 See sections 502(a) and 201(n) of the FD&C Act [21 U.S.C.  352(a) and 321(n)] 
15 See section 502 of the FD&C Act and 21 CFR part 201; See also footnote 2 on p. 2. 
16 See footnote 4 on p. 4.  
29  Contains Nonbinding Recommendations 
  Confirming that all additional copies of labels or pre-labeled containers issued for 
ACTPs obtained from a specific donor have been reconciled and removed from 
the work area. 
Example:  Two distinct lots of the same culture expanded cell-based product are ready for 
formulation and filling.  However, only one room in the manufacturing facility is 
designed to support aseptic processing and filling operations.  Therefore, processing and 
filling operations are time-staggered to ensure that the products are not intermixed and 
mislabeled.  The first lot of culture expanded cells are processed and filled in the 
biosafety cabinet while labeling for just this lot is prepared.  Sealed and crimped vials are 
then moved to a dedicated work area for controlled labeling.  Processing and filling 
operations of the second lot are now executed while labeling for the second lot is 
prepared.  Sealed and crimped vials of the second lot can be moved to the dedicated work 
area for controlled labeling only once it is verified that all documentation from the first 
lot has been removed. 
 
C.  Verification 
To ensure proper identification of ACTPs at every step of manufacturing, your 
procedures should include verification of label accuracy, legibility, and integrity. 
 
Example:  One way to verify identification of donors and ACTPs at recovery would be to 
have multiple personnel examine the labels.  If a recovery establishment uses hand-
generated labels, one method to verify the accuracy and legibility is to use indelible ink 
and fixative to ensure label integrity. 
 
D.  Information on the ACTP Finished Product Label and Labeling to Ensure 
Product Quality and Prevent Contamination or Mix Ups 
1.  You should label each ACTP made available for distribution clearly and accurately.  
Note that a label can include the affixed container label or an attached tie-tag. 
2.  You should place the following information on the ACTP label: 
  Distinct identification code affixed to the ACTP container; 
  Your labeling procedures should be designed to ensure that consignees 
o
can readily link the product to all required labeling and accompanying 
records, such as instructions for use. 
  Description of the type of ACTP; 
  For ACTPs from eligible donors, a statement that the donor has been 
determined to be eligible and a summary of information used to make the 
donor eligibility determination; and  
30  Contains Nonbinding Recommendations 
  For ACTPs in quarantine and ACTPs from ineligible donors, warnings related 
to donor eligibility.17  For ineligible donors, the reason for ineligibility should 
be stated.  If it is not physically possible to include these warnings on the 
label, the warnings should accompany the ACTP. 
3.  You must include an expiration date on the product label, as appropriate for the 
ACTP.18 
4.  The following information should either appear on the ACTP label or accompany the 
ACTP: 
  Name and address of the establishment that determines that the ACTP meets 
release criteria and makes the ACTP available for distribution; 
  Name and address of the establishment that made the donor eligibility 
determination; 
  The name and address of the establishment that made the donor-
o
eligibility determination should appear in the summary of records that 
accompanies the ACTP.  However, if the establishment that makes the 
donor-eligibility determination is not the same establishment that 
makes the ACTP available for distribution, the labeling or 
accompanying information should contain the name and address of 
both establishments and specify which establishment performed which 
function; and  
  Storage temperature.19 
XVI.  STORAGE 
A.  General 
ACTPs should be stored in an appropriate manner to prevent mix-ups, contamination, and 
cross-contamination, and in a manner that does not compromise the quality of the ACTP.  
 
B.  Control of Storage Areas 
You should control your storage areas and stock rooms to prevent the following: 
  Mix-ups, contamination, and cross-contamination of ACTPs, supplies, and 
reagents; and 
  An ACTP being improperly made available for distribution. 
 
17 See GFI #254, sections VIII. Quarantine of ACTPs and IX. ACTPs From Ineligible Donors 
18 See 21 CFR 201.17.  The format of the expiration date should be appropriate for the product.  See section XVI.D. 
Expiration Date.   
19 See section XVI.C. Temperature 
31  Contains Nonbinding Recommendations 
You should identify and design areas used for storage of ACTPs to facilitate monitoring 
of temperature and locating in-process ACTPs, quarantined ACTPs, and ACTPs that 
have been made available for distribution.  Each storage area should have signs indicating 
the types of supplies, reagents, and ACTPs contained in that area, and should be 
organized to prevent mix-ups, cross-contamination, and improper release of ACTPs. 
 
Before completing the donor-eligibility determination, you should keep an ACTP in 
quarantine and clearly identify it as in quarantine.  The quarantined ACTP should be 
easily distinguishable from ACTPs that are available for release and distribution.  
Quarantine means the storage or identification of an ACTP, to prevent improper release, 
in a physically separate area clearly identified for such use, or through use of other 
procedures, such as automated designation. 
 
C.  Temperature 
You should store ACTPs at an appropriate temperature.  The storage temperature should 
be sufficient to prevent conditions that could increase the risk of contamination of each 
ACTP stored, taking into consideration the types of packaging and preservatives used, 
and the expected duration of storage.  You should establish criteria for storage 
temperature(s) and storage period(s) for specific ACTPs stored in your facility.  These 
criteria may be based on established industry standards issued by professional 
organizations, if applicable. 
 
D.  Expiration Date 
Where appropriate, you should assign an expiration date to each ACTP based on the 
following factors: 
  ACTP type; 
  Processing, including the method of preservation; 
  Storage conditions; and 
  Packaging. 
An expiration date based on the factors listed above would be considered appropriate for 
your ACTP if the absence of a defined expiration date could reasonably be expected to 
negatively impact product quality or result in the product becoming contaminated.  We 
consider it appropriate to assign expiration dates for fresh (i.e., non-cryopreserved) 
ACTPs, and for ACTPs that are thawed or reconstituted prior to administration.  If such 
applicable expiration dates have been established by industry or veterinary practice and 
meet the recommendations of this section, you may be able to use those dates for your 
ACTPs, whether fresh or preserved.  If scientific data do not exist for establishing 
expiration dates, then an expiration date may not be applicable. 
 
Example:  Where appropriate, you should assign expiration dates to final products, both 
fresh and cryopreserved, as needed to ensure that they maintain quality and remain free 
from microbial contamination.  It may not be necessary to assign expiration dates to 
32  Contains Nonbinding Recommendations 
ACTPs that are cryopreserved, because there is a low risk of contamination so long as 
they remain immersed in the liquid phase or retained in the vapor phase of liquid nitrogen 
in containers that maintain their integrity and barrier properties throughout the storage 
period.  Data may be needed to support storage even if an expiry is not specified 
(retesting).  You should assign an expiration time for a cryopreserved product once it is 
thawed to ensure product quality. 
 
E.  Corrective Actions 
You should take and document corrective action whenever proper storage conditions are 
not met.   
 
Example:  In response to an alert from your temperature monitoring system indicating 
temperatures outside acceptable limits, you may need to transfer your ACTPs to an 
alternative storage area.  If the temperature excursion was of sufficient duration to 
increase the risk of contamination or impact quality, you may need to discard or 
otherwise dispose of the affected products.  After taking the appropriate corrective 
action(s), you should document the transfer or other disposition of each affected product. 
 
F.  Acceptable Temperature Limits 
You should establish acceptable temperature limits for storage of ACTPs at each step of 
the manufacturing process to prevent contamination.  You should maintain and record 
storage temperatures for ACTPs.  You should periodically review recorded temperatures 
to ensure that temperatures have been within acceptable limits. 
 
Example:  If you determine that your ACTP can be stored at room temperature, you 
should define the temperature limits (e.g., 20-25 degrees centigrade), and document and 
maintain records of environmental control and monitoring activities.  These records 
should be reviewed periodically to ensure that the temperatures have been within 
acceptable limits. 
 
XVII. RECEIPT, PREDISTRIBUTION SHIPMENT, AND DISTRIBUTION OF AN 
ACTP 
A.  General 
You should evaluate incoming and outgoing ACTPs to confirm the absence of 
contamination and to ensure the ACTP meets the defined release criteria.   
 
B.  Receipt 
You should evaluate each incoming ACTP for the presence and significance of 
microorganisms and inspect for damage, quality, and contamination.  You should 
determine whether to accept, reject, or place in quarantine each incoming ACTP, based 
upon pre-established criteria designed to prevent contamination.  When you receive an 
ACTP, you should visually inspect the shipping carton, packaging, ACTP container, and 
33  Contains Nonbinding Recommendations 
ACTP for damage and contamination.  If there are indications that the quality of the 
product has been compromised or that contamination or cross-contamination of the 
ACTP could have occurred, you should quarantine the ACTP until your investigation is 
complete. 
 
C.  Predistribution Shipment 
Predistribution shipment is the conveyance or shipment of an ACTP within your 
establishment or between establishments before it has met its release criteria (i.e., it is not 
available for distribution).  The sender should determine and document whether the 
ACTP has met pre-established criteria designed to maintain quality and prevent 
contamination before shipping.  The ACTP should be kept in quarantine during 
predistribution shipment and upon receipt. 
 
Example 1:  An ACTP is being shipped from the recovery facility to another facility for 
processing.  The ACTP should be transported in a shipping container that is capable of 
maintaining the desired temperature during transport, and that is capable of withstanding 
physical stress. 
 
Example 2:  Predistribution shipment can also occur within one establishment (e.g., 
transported between buildings or transported between floors in the same building before 
the ACTP is available for distribution).  Transferring ACTPs from one room to the next 
during processing (between steps) within the manufacturing suite is not considered a 
predistribution shipment. 
 
D.  Availability for Distribution 
Available for distribution means that the ACTP has been determined to meet all release 
criteria.  Distribution means any conveyance or shipment (including importation and 
exportation) of an ACTP that has been determined to meet all release criteria, whether or 
not such conveyance or shipment is entirely intrastate.  Before making an ACTP 
available for distribution, you should review manufacturing records (such as records from 
the donor eligibility determination, recovery, processing, and storage) and tracking 
records pertaining to the ACTP, and, on the basis of that record review, verify and 
document that the release criteria have been met.  A responsible individual should 
document and date the determination that the ACTP is available for distribution. 
 
You should not make available for distribution an ACTP that: 
  Is in quarantine; 
  Is contaminated; 
  Is improperly stored or transported; 
  Is from a donor who has been determined to be ineligible or a donor with an 
incomplete donor eligibility determination; or 
  Otherwise does not meet release criteria. 
34  Contains Nonbinding Recommendations 
If you maintain CGMP records in more than one location, you may fax or email records 
for review prior to release for distribution, provided that the records can be adequately 
evaluated (e.g., legible and accurate). 
 
If you deviate from a procedure (e.g., a deviation from an SOP) that is relevant to 
maintaining quality and preventing contamination, you should not make an ACTP 
manufactured under the deviated procedure available for distribution unless a responsible 
individual has determined that the deviation does not decrease the quality of the product 
or increase the risk of introducing contamination through use of the ACTP.  You should 
record and justify any deviation from a procedure at the time of its occurrence. 
 
Example:  You arrive at a recovery site to recover ACTPs from a donor and you discover 
that the cleaning solution that you routinely use to disinfect the work surface is not 
available.  You clean the surface with an alternative cleaning solution and proceed to 
recover ACTPs.  The ACTPs are sent to a processing establishment.  The ACTPs should 
not be made available for distribution until a responsible individual determines that the 
alternate cleaning solution is as effective as the routine cleaning solution and does not 
increase the risk of ACTP contamination. 
 
E.  Packaging and Shipping 
The packaging and shipping containers should be designed and constructed to protect the 
ACTP from contamination and to maintain quality.  For each type of ACTP, you should 
establish appropriate shipping conditions to be maintained during transit.  You could use 
industry standards, if available, or establish for yourself appropriate shipping conditions 
to be maintained during transit.  It is also important to ensure that appropriate shipping 
conditions are maintained throughout distribution.  If you have a contract, agreement, or 
other arrangement with distributors, sub-distributors, and/or sales agents who distribute, 
you should ensure that appropriate shipping conditions will be maintained before entering 
into such contracts, agreements, or other arrangements. 
 
F.  Procedures 
You should establish and maintain procedures, including release criteria, for receipt, 
predistribution shipment, availability for distribution, and packaging and shipping.  For 
example, you could accomplish this with a checklist or a packing list.  Documentation 
should include the following: 
  Identification of the ACTP; 
  Identification of the sender (i.e., the establishment that supplied the ACTP); 
  Activities that you performed on the ACTP (e.g., inspection, acceptance, or 
rejection of the ACTP) and the results of each activity; 
  Date(s) of activity; 
  Quantity of ACTP subject to the activity (e.g., received or distributed); and 
35  Contains Nonbinding Recommendations 
  Disposition of the ACTP (e.g., identity of the consignee to whom the ACTP was 
sent). 
G. Return to Inventory 
You should establish and maintain procedures to determine if an ACTP that is returned to 
your establishment is suitable to be returned to inventory.  If return is not permitted, this 
should be made clear to the consignee.  If return is permitted, you should specify the 
conditions under which the return could be accepted. 
 
XVIII. RECORDS 
A.  General 
Records contain important information, such as donor testing and release criteria, and 
confirm the identity, purity, potency, and safety of ACTPs.  You should maintain records 
concurrently with the performance of each manufacturing step.  Documenting an action 
involves the creation of a record, which is subject to the CGMP in this section.  All 
records should be accurate, indelible, and legible.  The records should identify the 
individual performing the work and the dates of the various entries and should be as 
detailed as necessary to provide a complete history of the work performed and to relate 
the records to the specific ACTP involved.   
 
To help ensure the accuracy of records retained, we recommend that establishments that 
make an ACTP available for distribution obtain records directly from the creator of such 
documents whenever possible (e.g., serology/microbiology results should be obtained 
directly from the testing laboratory).  All records should be in English or, if in another 
language, should be retained and translated to English and accompanied by a statement of 
authenticity by the translator that specifically identifies the translated document so that 
compliance with CGMP can be more easily determined by FDA. 
 
B.  Records Management System 
You should establish and maintain a records management system relating to CGMP.  
Under this system, you should maintain records pertaining to a specific ACTP in such a 
way as to facilitate review of the ACTPs history before making it available for 
distribution and, if necessary, after the ACTPs release, as part of a follow-up evaluation 
or investigation.  You should also maintain and organize records pertinent to the 
manufacture of the ACTP (e.g., labeling and packaging procedures, and equipment logs).  
If you maintain records in more than one location, you should design the records 
management system to ensure prompt identification, location, and retrieval of all records.  
You should organize your records in a useful manner in accordance with this section. 
 
Example:  A recovery establishment under contract with a processor sends ACTPs to the 
processor.  The recovery establishment should send all relevant records, including donor 
records and records relating to recovery site suitability, as described in section XII.B. 
36  Contains Nonbinding Recommendations 
Procedures and Records, to the processor.  The recovery establishment should maintain 
copies of all transferred records and organize them in its records management system. 
 
C.  Methods of Retention 
You may maintain records electronically, as original paper records, or as true copies such 
as photocopies, microfiche, or microfilm.  Equipment that is necessary to make the 
records available and legible, such as computer and reader equipment, should be readily 
available.  You should back up records stored in electronic systems. 
 
Example:  You are a processor that receives paper records of the donors medical history 
from the recovery establishment.  You review the medical history as part of the donor 
eligibility determination.  Later, you scan the paper records and save them as a .pdf file 
on a computer that is backed up.  The electronic records are true copies of the paper 
records.  Therefore, you may destroy the paper records.  However, if instead of scanning, 
you were to re-type (transfer) the information into the computer, you would be creating a 
new record, not making a true copy.  Errors may have been introduced while re-typing 
the information into the new record.  In this scenario, you should keep the original paper 
(hardcopy) records as proof of concurrent recordkeeping. 
 
D.  Length of Retention 
To ensure the identity, purity, potency, and safety of ACTPs, we recommend that records 
be kept for 10 years after their creation, unless stated otherwise in this document.20  You 
should retain the records pertaining to a specific ACTP at least 10 years after the date of 
its administration, or if the date of administration is not known, then at least 10 years 
after the date of the ACTPs distribution, disposition, or expiration, whichever is the 
latest date. 
 
Laboratories that perform relevant disease agent testing of donor specimens and/or 
microbiological testing of ACTPs that do not know the date of administration, 
distribution, disposition, or expiration, should keep donor testing information for 10 years 
after the creation of the record. 
 
E.  Contracts and Agreements 
You should maintain the name and address and a list of the responsibilities of any 
establishment that performs a manufacturing step for you.  You should have this 
information available during inspections conducted by the FDA.  We recommend that 
contracts, agreements, or other arrangements describe the responsibilities of all parties.   
 
 
20 The regulations in 21 CFR 211.180 require that records be kept for at least 1 year after expiration.  However, we 
recognize that expiration of ACTPs varies from hours to an indefinite period of time for some cryopreserved 
ACTPs.  Additionally, some forms of contamination or safety concerns may not be evident until years after the 
product is manufactured.  For these reasons, we recommend a record retention period of at least 10 years. 
37  Contains Nonbinding Recommendations 
Example 1:  A contract, agreement, or other arrangement with an individual or 
establishment who obtains the donors medical records should describe the information 
that you want that individual or establishment to obtain.   
 
Example 2:  When donor eligibility is determined following a review of records obtained 
by another establishment, the contract, agreement, or other arrangement might 
specifically identify what records will be obtained, in what format they will be provided, 
responsibilities for record retention and access, and if the reviewing firm will convey 
donor eligibility conclusions back to the establishment that collected the information. 
 
XIX.  TRACKING 
A.  General 
Each ACTP should be tracked throughout manufacturing, from recovery to final 
disposition, to ensure that the ACTP is free from contamination and to ensure the quality 
of the ACTP.  If you perform any step in the manufacture of an ACTP during which you 
handle the ACTP, you should track the ACTP.  You should perform tracking to facilitate 
the investigation of an actual or suspected incidence of contamination, or impact on 
product quality, and take appropriate and timely corrective action.  If you do not handle 
the ACTP (e.g., the testing laboratory that receives a specimen but does not actually 
handle the ACTP), you would not participate in tracking the ACTP. 
 
B.  System of ACTP Tracking 
You should establish and maintain a tracking system that enables the ACTP to be tracked 
from: 
  The donor to the consignee or final disposition; and  
  The consignee or final disposition to the donor. 
Alternatively, if you perform some, but not all, of the steps in the manufacture of an 
ACTP during which you handle the ACTP, you may participate in a system of ACTP 
tracking established and maintained by another establishment responsible for other steps 
in the manufacture of the same ACTP.  You should verify that the tracking system is 
effective, especially if you participate in a tracking system maintained by another 
establishment. 
 
C.  Distinct Identification Code 
You should ensure that each ACTP that you manufacture is assigned and labeled with a 
distinct identification code that relates the ACTP to the donor and to all records 
pertaining to the ACTP.  You should also ensure that labeling includes information 
needed to facilitate effective tracking from the donor to the recipient and from the 
recipient to the donor.  The distinct identification code should be created specifically for 
tracking purposes. 
 
38  Contains Nonbinding Recommendations 
You may adopt the distinct identification code assigned by another establishment 
engaged in manufacturing or assign a new code.  You should verify and/or validate that 
your tracking system is effective.  The distinct identification code should be able to track 
to the donor but does not necessarily have to be on all records concerning the donor or on 
the package insert.  However, the distinct identification code should be affixed to the 
ACTP container. 
 
D.  Tracking from Consignee to Donor 
As part of your tracking system, you should establish and maintain a method for 
recording the distinct identification code and type of each ACTP distributed to a 
consignee to enable tracking from the consignee to the donor. 
 
E.  Tracking from Donor to Consignee or Final Disposition 
As part of your tracking system, you should establish and maintain a method for 
documenting the disposition of each of your ACTPs, to enable tracking from the donor to 
the consignee or final disposition.  This information should permit the prompt 
identification of the consignee of the ACTP, if any. 
 
F.  Consignees 
As part of the tracking system, you should inform the consignee that the consignee 
should enter the distinct identification code for the ACTP in the recipient animals 
veterinary medical record.  This will help to identify affected recipients in the event you 
become aware of ACTP contamination or a product defect (e.g., contamination with a 
disease agent or improper storage conditions).  Also, you should request that the 
consignee notify you of the distinct identification code for the ACTP if an ACTP is 
associated with any adverse drug experiences or product defects. 
 
Example:  You distribute an ACTP to a veterinary hospital.  As part of your tracking 
system, the ACTP label contains a distinct identification code that relates the ACTP to 
the donor, the donation event, and the records pertaining to that ACTP.  The ACTP label 
also includes a sticker with the distinct identification code and directions for the 
veterinarian to maintain the sticker in the recipient animals veterinary medical record.  
After distribution of the ACTP you become aware that the donor of the ACTP was 
infected with a relevant disease agent at the time of donation.  Using your tracking 
system, you contact the veterinary hospital and inform them of the potential risk of 
infection.  You also provide them with the distinct identification code related to the 
ACTP derived from the infected donor.  Using the sticker placed in the veterinary 
medical records, the veterinary hospital can identify and treat affected recipients and 
report any adverse drug experiences back to you. 
 
XX.  COMPLAINT FILE 
39  Contains Nonbinding Recommendations 
A.  General 
Recording and evaluating complaints is important for monitoring the safety, identity, 
strength, quality, and purity of the ACTP. 
 
B.  Procedures 
You should establish and maintain procedures for the review, evaluation, and 
documentation of complaints, and the investigation of complaints as appropriate. 
 
C.  Complaint file 
You should maintain a record of complaints that you receive in a file designated for 
complaints.  The complaint file should contain sufficient information about each 
complaint for proper review and evaluation of the complaint (including the distinct 
identification code of the ACTP that is the subject of the complaint), and for determining 
whether the complaint is an isolated event or represents a trend.  You should make the 
complaint file available for review and copying upon request from FDA. 
 
D.  Review and Evaluation of Complaints 
You should review and evaluate each complaint and determine whether an investigation 
is necessary.  An investigation may include referring a copy of the complaint to another 
establishment that performed manufacturing steps pertinent to the complaint.  When no 
investigation is made, you should maintain a record that includes the reason no 
investigation was made, and the name of the individual(s) responsible for the decision not 
to investigate.  Complaints related to adverse events or product defects/manufacturing 
defects should be reported to FDA. 
 
XXI.  CGMP DEVIATIONS  
CGMP deviations are deviations from the applicable sections in this guidance or from applicable 
standards or established specifications that relate to preserving quality or preventing 
contamination of the ACTP.  You should report CGMP deviations that may result in adverse 
events or product defects/manufacturing defects to the product sponsor and to other 
establishments that may be impacted by the deviation.  These other establishments may include 
establishments performing downstream processing steps on the same ACTP, establishments 
using tissue from the same donor (e.g., if you discover that the donor did not meet acceptance 
criteria), and establishments and sponsors of other ACTPs that you process that may have been 
impacted by the deviation (e.g., if you discover that an ACTP was contaminated and there is a 
risk of cross contamination to other ACTPs processed in your facility).  If the ACTP is in 
distribution and the CGMP deviation may result in an adverse event, it should be reported to 
FDA within 3 working days. 
 
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