ASTM F2210-02
(Guide)Standard Guide for Processing Cells, Tissues, and Organs for Use in Tissue Engineered Medical Products
Standard Guide for Processing Cells, Tissues, and Organs for Use in Tissue Engineered Medical Products
SIGNIFICANCE AND USE
This guide describes the general product development criteria and analyses applicable to processing of cells, tissues, and organs used for the production of TEMPs. For the purposes of this guide, cells, tissues, and organs may be derived from any organism at any developmental stage and in any state of health. For example, this guide applies to stem, progenitor, somatic, and germline cells, as well as cells from specific tissue and organ types. This guide also applies to cells, tissues, and organs from healthy, diseased, or injured embryos to adults.
Cells, tissues, and organs may be combined with a scaffold and may contain locally or systemically acting biomolecules or a drug (medicinal) product. This type of TEMP would be a “combination product.”
SCOPE
1.1 This guide describes the processing, characterization, production, and quality assurance of cells, tissues, and organs used for Tissue Engineered Medical Products (TEMPs). It concerns aspects of processing activities for cells, tissues, and organs to be further processed. These aspects include: (1) cell, tissue, and organ processing (that is, facility, reagents, and procedures for receipt, inspection, and storage; tissue culture components, biological risk factors, and processing area), (2) donors (human and nonhuman) and screening, and (3) cell, tissue, and organ characterization and processing.
1.2 This guide does not apply to any medical products of human origin regulated by the U.S. Food and Drug Administration (FDA) under 21 CFR Parts 16 and 1270 (1) and 21 CFR Parts 207, 807, and 1271 (2).
1.3 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory requirements prior to use.
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Designation:F2210–02
Standard Guide for
Processing Cells, Tissues, and Organs for Use in Tissue
Engineered Medical Products
This standard is issued under the fixed designation F2210; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope preted to encompass somatic cell and gene therapy (21 CFR
600.3 (h)). A biological product may be used as a component
1.1 This guide describes the processing, characterization,
of a TEMP. For the purposes of TEMPs, these biological
production, and quality assurance of cells, tissues, and organs
products may be of any origin (that is, organism), tissue type,
used for Tissue Engineered Medical Products (TEMPs). It
developmental stage, and may be living, non-living, and
concerns aspects of processing activities for cells, tissues, and
genetically or otherwise modified.
organs to be further processed. These aspects include: (1) cell,
2.1.4 cell culture, n—the in vitro growth or maintenance of
tissue, and organ processing (that is, facility, reagents, and
cells.
procedures for receipt, inspection, and storage; tissue culture
2.1.5 cell, n—“the smallest structural unit of an organism
components, biological risk factors, and processing area), (2)
that is capable of independent functioning, consisting of one or
donors (human and nonhuman) and screening, and (3) cell,
more nuclei, cytoplasm, and various organelles, all surrounded
tissue, and organ characterization and processing.
by a semipermeable cell membrane.” (4) Cells are highly
1.2 This guide does not apply to any medical products of
variable and specialized in both structure and function, though
human origin regulated by the U.S. Food and Drug Adminis-
2 all must at some stage synthesize proteins and nucleic acids,
tration (FDA) under 21 CFR Parts 16 and 1270 (1) and 21
use energy, and reproduce.Acell or cells may be of any origin
CFR Parts 207, 807, and 1271 (2).
(that is, organism), tissue type, developmental stage, and may
1.3 This standard does not purport to address all of the
be living, non-living, and genetically or otherwise modified.
safety concerns, if any, associated with its use. It is the
Cells may be used as a component of a TEMP.
responsibility of the user of this standard to establish appro-
2.1.6 combination product, n—“As defined in 21 CFR §
priate safety and health practices and determine the applica-
3.2(e), the term “combination product” includes: (1)Aproduct
bility of regulatory requirements prior to use.
comprised of two or more regulated components, that is,
2. Terminology drug/device, biologic/device, drug/biologic, or drug/device/
biologic, that are physically, chemically, or otherwise com-
2.1 Definitions of Terms Specific to This Standard:
bined or mixed and produced as a single entity; (2) Two or
2.1.1 allogeneic or allogenic, adj—cells,tissues,andorgans
more separate products packaged together in a single package
in which the donor and recipient are genetically different
or as a unit and comprised of drug and device products, device
individuals of the same species. Synonyms: allograft and
and biological products, or biological and drug products; (3)A
homograft.
drug, device, or biological product packaged separately that
2.1.2 autologous, adj—cells, tissues, and organs in which
according to its investigational plan or proposed labeling is
the donor and recipient is the same individual. Synonyms:
intended for use only with an approved individually specified
autogenous, autograft,or autotransfusion,a self-to-self graft.
drug, device, or biological product where both are required to
2.1.3 biological product, n—“any virus, therapeutic serum,
achieve the intended use, indication, or effect and where upon
toxin, antitoxin, vaccine, blood, blood component or deriva-
approval of the proposed product, the labeling of the approved
tive,allergenicproduct,oranalogousproduct,orarsphenamine
product would need to be changed, for example, to reflect a
or its derivatives (or any trivalent organic arsenic compound)
change in intended use, dosage form, strength, route of
applicable to the prevention, treatment, or cure of diseases or
administration, or significant change in dose; or (4) Any
injuries of man.” (3) The term “analogous product” is inter-
investigational drug, device, or biological product packaged
separately that according to its proposed labeling is for use
This guide is under the jurisdiction of ASTM Committee F04 on Medical and
only with another individually specified investigational drug,
Surgical Materials and Devices and is the direct responsibility of Subcommittee
device, or biological product where both are required to
F04.43 on Tissue Engineered Biomaterials.
achieve the intended use, indication, or effect.” Furthermore,
Current edition approved Nov. 10, 2002. Published January 2003. DOI: 10.1520/
F2210-02.
“many somatic cell products administered to patients will be
The boldface numbers in parentheses refer to the list of references at the end of
this standard.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.
F2210–02
combinations of a biological product and a device or of a drug, thereof; (2) connective tissues (for example, adipose, blood,
a biological product, and a device.” (5)The term “combination bone, and cartilage and loose connective tissue); (3) muscle
product” may apply to TEMPs. tissue (that is, smooth, skeletal, cardiac); and (4) nerve tissue.
2.1.7 cross-contamination, n—the unintended presence of a Within a differentiated organ, all four primary tissue types are
represented. A tissue and its derivatives may be used as a
cell or a material with another cell or material.
component of a TEMP.
2.1.8 disinfection, n—the destruction or reduction of patho-
2.1.22 transplantation, n—for therapeutic purposes, the
genic and other kinds of microorganisms by thermal or
process of implanting in one part, cells, tissue(s), or organ(s)
chemicalmeans(forexample,alcohol,antibiotics,germicides).
taken from another part or from another individual. Transplan-
2.1.9 donor, n—a living or deceased organism who is the
tation in this sense is regulated by the U.S. Food and Drug
source of cells or tissues, or both, for research or further
Administration(FDA)under21CFRParts16and1270(1)and
processing for transplantation in accordance with established
21 CFR Parts 207, 807, and 1271 (2).
medical criteria and procedures.
2.1.23 xenogeneic or xenogenic, n—cells, tissues, and or-
2.1.10 genetically modified, vt—referring to cells, tissues,
gans in which the donor and recipient belong to different
and organs of any origin that have an altered or modified
species. Synonyms: xenogenous, heterogeneic,or heterolo-
genetic content.
gous.
2.1.11 implantation, n—the procedure of inserting materials
2.1.24 xenotransplantation, n—any procedure that involves
such as a cell(s), tissue(s), or organ(s) for therapeutic purposes.
the transplantation or infusion into a human recipient of either
Synonym: graft or grafting. TEMPs may be applied to a
(1) live cells, tissues, or organs from a nonhuman animal
recipient by implantation or grafting.
source or (2) human body fluids, cells, tissues, or organs that
2.1.12 in-process control, n—monitoring and, if necessary,
have had ex vivo contact with live nonhuman cells, tissues, or
adjustments performed to ensure that the process conforms to
organs (24).
its specification. The control of the environment or equipment
may be part of in-process control.
3. Significance and Use
2.1.13 organ, n—a differentiated part of an organism that
performs specific functions. Organs are biologic body parts, 3.1 This guide describes the general product development
thatafterembryonicandearlyfetalstages,arecomposedofthe
criteria and analyses applicable to processing of cells, tissues,
four primary tissue types (that is, epithelial/mesothelial/ andorgansusedfortheproductionofTEMPs.Forthepurposes
endothelial, connective, muscular, and nervous tissues) that
of this guide, cells, tissues, and organs may be derived from
form a specific structure. For example, the intestine aids any organism at any developmental stage and in any state of
digestionand,simplyput,itiscomposedofanepitheliallining,
health. For example, this guide applies to stem, progenitor,
looseconnectivetissue,nervoustissue,andsmoothmuscle.An somatic,andgermlinecells,aswellascellsfromspecifictissue
organ and its derivatives may be used as a component of a
and organ types. This guide also applies to cells, tissues, and
TEMP. organs from healthy, diseased, or injured embryos to adults.
2.1.14 processing, vt—any activity performed on cells, 3.2 Cells, tissues, and organs may be combined with a
tissues,andorgansotherthanrecovery,suchaspreparationand scaffold and may contain locally or systemically acting bio-
preservation for storage and packaging. molecules or a drug (medicinal) product. This type of TEMP
would be a “combination product.”
2.1.15 processing materials, n—any item or material that is
not a component of the TEMP and is in contact with the cells,
tissues, and organs during processing. 4. Facility, Reagents, and Procedures
2.1.16 recipient, n—the individual or organism into whom
4.1 Facility:
materials are grafted or implanted.
4.1.1 Receipt, Inspection, and Storage—Facility issues in-
2.1.17 recovery, n—the obtaining of cells or tissues which
cluding establishment of clean room classifications, training of
may be used for the production of TEMPs.
personnel, environmental monitoring, sampling plans, and
2.1.18 reprocessing, vt—the reworking of cells, tissues, and
limits should comply with current good manufacturing prac-
organs of unacceptable quality from a defined stage of process-
tices (cGMP) (6, 7) and AATB standard for tissue banking
ing, so that the quality may be rendered acceptable by one or
related to good tissue practices (cGTP) (8). The FDA has
more additional operations.
proposed a new regulation on current good tissue practice
2.1.19 stem cells, n—progenitor cells capable of self-
(GTP) which, if finalized, would also be applicable, for
replication, proliferation, and differentiation.
example, FDA 21 CFR 1271 (9). All regions should be
2.1.20 syngeneic, n—cells, tissues, and organs in which the qualifiedusingarationaleandscientificallysoundqualification
donor has an unreactive genotype with the recipient. Syn- program that includes: (1) information on traceability, (2)
onyms: syngraft, isograft, isogeneic,or isogenic. assessment of risks for each material, and (3) the specific
characterization tests. Guidelines for the storage of materials
2.1.21 tissue, n—a grouping of cells and extracellular ma-
trix (that is, soluble and insoluble, fibrous and nonfibrous for processing can be found in FDA21CFR 820 (6) as well as
in GMP guidelines for shelf-life (2, 8).
biological materials) that collectively have a specific structure
and function. After embryonic and early fetal stages, there are 4.2 Reagents:
four primary tissues which may have various forms: (1) 4.2.1 Tissue Culture Components—All media and reagents
epithelium, mesothelium, or endothelium, or combination usedforthegrowthormaintenanceofcells,tissues,andorgans
F2210–02
should be manufactured under cGMP guidelines or be pur- should attempt to meet Class 100 requirements for critical
chased from an organization that meets the guidelines (6). aseptic processing operations (6, 19). The adequacy of the
Ideally, all media and reagents should be of non-animal origin clean room environment is monitored by close microbiological
orcontainnocomponentsofanimalorigin(10)tominimizethe surveillance of air, water, surfaces, clean room, and personnel.
opportunity for virus or prion contamination and transmission. Routine environmental monitoring with established alert levels
At the minimum, one should utilize media and reagents from can provide early warning on the adequacy of cleaning and
organizations that have applied stringent sourcing controls and sanitization procedures before action levels are exceeded. In
have validated terminal processes to minimize the risk of addition to the environmental monitoring of the production
infection (11) It would be even more ideal, when working with area, products can be monitored for microbiological control
animal cells, tissues, or derivatives, to obtain these biological during critical manufacturing steps (19, 26, 29, 30).
materials from special breeding facilities (for instance, closed
4.3.2.2 Preventive Maintenance Procedures and Routine
pathogen-free herds) and to include control ancestors.
Calibration—Preventive maintenance procedures and calibra-
4.2.1.1 Basal Culture Media and Supplements—Guidelines tion should be performed on equipment at scheduled intervals.
for sterile drug products produced by aseptic processing are Calibrations, where appropriate, should be against traceable
published by CBER, 6/87 (12). Additional information con- standards, for instance U.S. National Institute of Standards and
cerning the use of basal media, supplements, recombinant, Technology (NIST) standards.
animal origin, non-animal origin, enzymes, feeder cells, sub-
4.4 Donor Screening:
strates (two or three dimensional; exogenous versus endog-
4.4.1 Human Sources—General donor suitability which
enous), animal derived, non-animal derived, and other compo-
covers aspects of testing for diseases (microbial and viral) and
nentsofanimalorigincanbecanbefoundinBrownetal. (10).
general safety can be completed by the manufacturer with
Validation of aseptic filling for solution drug products is
validated tests methods or by CLIAcertified testing laboratory
published by the PDA, 1980 (13). Quality assurance measures
(6). If using autologous donors, screening and testing of donor
for acceptance of all components, including media, serum, and
materials intended for transplantation is recommended and
other additives should include records detailing source and lot
mandatory for allogeneic sources (1). Donor specimens must
numbers.
be tested and found to be negative, using FDA licensed donor
4.3 Procedures:
screening tests in accordance with manufacturer’s instructions,
for HIVtypes I and II, hepatitis B and C, Treponema pallidum,
4.3.1 Biological Risk Factors:
human t-lymphotropic virus types 1 and 2, and cytomegalovi-
4.3.1.1 Adventitious Agents—USFDA and WHO provide
rus in leukocyte rich cells and tissues (6, 21, 31).
points to be considered regarding adventitious agents
4.4.2 Donor Records and Archi
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