1、Designation: F 2210 02Standard Guide forProcessing Cells, Tissues, and Organs for Use in TissueEngineered Medical Products1This standard is issued under the fixed designation F 2210; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision,
2、the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide describes the processing, characterization,production, and quality assurance of cells, tissues
3、, and organsused for Tissue Engineered Medical Products (TEMPs). Itconcerns aspects of processing activities for cells, tissues, andorgans to be further processed. These aspects include: (1) cell,tissue, and organ processing (that is, facility, reagents, andprocedures for receipt, inspection, and st
4、orage; tissue culturecomponents, 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 ofhuman origin regulated by the U.S. Food and Drug Admini
5、s-tration (FDA) under 21 CFR Parts 16 and 1270 (1)2and 21CFR Parts 207, 807, and 1271 (2).1.3 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety and health practic
6、es and determine the applica-bility of regulatory requirements prior to use.2. Terminology2.1 Definitions of Terms Specific to This Standard:2.1.1 allogeneic or allogenic, adjcells, tissues, and organsin which the donor and recipient are genetically differentindividuals of the same species. Synonyms
7、: allograft andhomograft.2.1.2 autologous, adjcells, tissues, and organs in whichthe donor and recipient is the same individual. Synonyms:autogenous, autograft,orautotransfusion,aself-to-self graft.2.1.3 biological product, n“any virus, therapeutic serum,toxin, antitoxin, vaccine, blood, blood compo
8、nent or deriva-tive, allergenic product, or analogous product, or arsphenamineor its derivatives (or any trivalent organic arsenic compound)applicable to the prevention, treatment, or cure of diseases orinjuries of man.” (3) The term “analogous product” is inter-preted to encompass somatic cell and
9、gene therapy (21 CFR600.3 (h). A biological product may be used as a componentof a TEMP. For the purposes of TEMPs, these biologicalproducts may be of any origin (that is, organism), tissue type,developmental stage, and may be living, non-living, andgenetically or otherwise modified.2.1.4 cell cultu
10、re, nthe in vitro growth or maintenance ofcells.2.1.5 cell, n“the smallest structural unit of an organismthat is capable of independent functioning, consisting of one ormore nuclei, cytoplasm, and various organelles, all surroundedby a semipermeable cell membrane.” (4) Cells are highlyvariable and s
11、pecialized in both structure and function, thoughall must at some stage synthesize proteins and nucleic acids,use energy, and reproduce. A cell or cells may be of any origin(that is, organism), tissue type, developmental stage, and maybe living, non-living, and genetically or otherwise modified.Cell
12、s may be used as a component of a TEMP.2.1.6 combination product, n“As defined in 21 CFR 3.2(e), the term “combination product” includes: (1) A productcomprised of two or more regulated components, that is,drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, che
13、mically, or otherwise com-bined or mixed and produced as a single entity; (2) Two ormore separate products packaged together in a single packageor as a unit and comprised of drug and device products, deviceand biological products, or biological and drug products; (3)Adrug, device, or biological prod
14、uct packaged separately thataccording to its investigational plan or proposed labeling isintended for use only with an approved individually specifieddrug, device, or biological product where both are required toachieve the intended use, indication, or effect and where uponapproval of the proposed p
15、roduct, the labeling of the approvedproduct would need to be changed, for example, to reflect achange in intended use, dosage form, strength, route ofadministration, or significant change in dose; or (4) Anyinvestigational drug, device, or biological product packagedseparately that according to its
16、proposed labeling is for useonly with another individually specified investigational drug,device, or biological product where both are required toachieve the intended use, indication, or effect.” Furthermore,“many somatic cell products administered to patients will be1This guide is under the jurisdi
17、ction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.43 on Tissue Engineered Biomaterials.Current edition approved Nov. 10, 2002. Published January 2003.2The boldface numbers in parentheses refer to the list of references at the
18、 end ofthis standard.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United Sbinations of a biological product and a device or of a drug,a biological product, and a device.” (5) The term “combinationproduct” may apply to TEMPs.2.1.7 cross-contamin
19、ation, nthe unintended presence of acell or a material with another cell or material.2.1.8 disinfection, nthe destruction or reduction of patho-genic and other kinds of microorganisms by thermal orchemical means (for example, alcohol, antibiotics, germicides).2.1.9 donor, na living or deceased organ
20、ism who is thesource of cells or tissues, or both, for research or furtherprocessing for transplantation in accordance with establishedmedical criteria and procedures.2.1.10 genetically modified, vtreferring to cells, tissues,and organs of any origin that have an altered or modifiedgenetic content.2
21、.1.11 implantation, nthe procedure of inserting materialssuch as a cell(s), tissue(s), or organ(s) for therapeutic purposes.Synonym: graft or grafting. TEMPs may be applied to arecipient by implantation or grafting.2.1.12 in-process control, nmonitoring and, if necessary,adjustments performed to ens
22、ure that the process conforms toits specification. The control of the environment or equipmentmay be part of in-process control.2.1.13 organ, na differentiated part of an organism thatperforms specific functions. Organs are biologic body parts,that after embryonic and early fetal stages, are compose
23、d of thefour primary tissue types (that is, epithelial/mesothelial/endothelial, connective, muscular, and nervous tissues) thatform a specific structure. For example, the intestine aidsdigestion and, simply put, it is composed of an epithelial lining,loose connective tissue, nervous tissue, and smoo
24、th muscle. Anorgan and its derivatives may be used as a component of aTEMP.2.1.14 processing, vtany activity performed on cells,tissues, and organs other than recovery, such as preparation andpreservation for storage and packaging.2.1.15 processing materials, nany item or material that isnot a compo
25、nent of the TEMP and is in contact with the cells,tissues, and organs during processing.2.1.16 recipient, nthe individual or organism into whommaterials are grafted or implanted.2.1.17 recovery, nthe obtaining of cells or tissues whichmay be used for the production of TEMPs.2.1.18 reprocessing, vtth
26、e reworking of cells, tissues, andorgans of unacceptable quality from a defined stage of process-ing, so that the quality may be rendered acceptable by one ormore additional operations.2.1.19 stem cells, nprogenitor cells capable of self-replication, proliferation, and differentiation.2.1.20 syngene
27、ic, ncells, tissues, and organs in which thedonor has an unreactive genotype with the recipient. Syn-onyms: syngraft, isograft, isogeneic,orisogenic.2.1.21 tissue, na grouping of cells and extracellular ma-trix (that is, soluble and insoluble, fibrous and nonfibrousbiological materials) that collect
28、ively have a specific structureand function. After embryonic and early fetal stages, there arefour primary tissues which may have various forms: (1)epithelium, mesothelium, or endothelium, or combinationthereof; (2) connective tissues (for example, adipose, blood,bone, and cartilage and loose connec
29、tive tissue); (3) muscletissue (that is, smooth, skeletal, cardiac); and (4) nerve tissue.Within a differentiated organ, all four primary tissue types arerepresented. A tissue and its derivatives may be used as acomponent of a TEMP.2.1.22 transplantation, nfor therapeutic purposes, theprocess of imp
30、lanting in one part, cells, tissue(s), or organ(s)taken from another part or from another individual. Transplan-tation in this sense is regulated by the U.S. Food and DrugAdministration (FDA) under 21 CFR Parts 16 and 1270 (1) and21 CFR Parts 207, 807, and 1271 (2).2.1.23 xenogeneic or xenogenic, nc
31、ells, tissues, and or-gans in which the donor and recipient belong to differentspecies. Synonyms: xenogenous, heterogeneic,orheterolo-gous.2.1.24 xenotransplantation, nany procedure that involvesthe transplantation or infusion into a human recipient of either(1) live cells, tissues, or organs from a
32、 nonhuman animalsource or (2) human body fluids, cells, tissues, or organs thathave had ex vivo contact with live nonhuman cells, tissues, ororgans (24).3. Significance and Use3.1 This guide describes the general product developmentcriteria and analyses applicable to processing of cells, tissues,and
33、 organs used for the production of TEMPs. For the purposesof this guide, cells, tissues, and organs may be derived fromany organism at any developmental stage and in any state ofhealth. For example, this guide applies to stem, progenitor,somatic, and germline cells, as well as cells from specific ti
34、ssueand organ types. This guide also applies to cells, tissues, andorgans from healthy, diseased, or injured embryos to adults.3.2 Cells, tissues, and organs may be combined with ascaffold and may contain locally or systemically acting bio-molecules or a drug (medicinal) product. This type of TEMPwo
35、uld be a “combination product.”4. Facility, Reagents, and Procedures4.1 Facility:4.1.1 Receipt, Inspection, and StorageFacility issues in-cluding establishment of clean room classifications, training ofpersonnel, environmental monitoring, sampling plans, andlimits should comply with current good man
36、ufacturing prac-tices (cGMP) (6, 7) and AATB standard for tissue bankingrelated to good tissue practices (cGTP) (8). The FDA hasproposed a new regulation on current good tissue practice(GTP) which, if finalized, would also be applicable, forexample, FDA 21 CFR 1271 (9). All regions should bequalifie
37、d using a rationale and scientifically sound qualificationprogram that includes: (1) information on traceability, (2)assessment of risks for each material, and (3) the specificcharacterization tests. Guidelines for the storage of materialsfor processing can be found in FDA 21CFR 820 (6) as well asin
38、 GMP guidelines for shelf-life (2, 8).4.2 Reagents:4.2.1 Tissue Culture ComponentsAll media and reagentsused for the growth or maintenance of cells, tissues, and organsF2210022should be manufactured under cGMP guidelines or be pur-chased from an organization that meets the guidelines (6).Ideally, al
39、l media and reagents should be of non-animal originor contain no components of animal origin (10) to minimize theopportunity for virus or prion contamination and transmission.At the minimum, one should utilize media and reagents fromorganizations that have applied stringent sourcing controls andhave
40、 validated terminal processes to minimize the risk ofinfection (11) It would be even more ideal, when working withanimal cells, tissues, or derivatives, to obtain these biologicalmaterials from special breeding facilities (for instance, closedpathogen-free herds) and to include control ancestors.4.2
41、.1.1 Basal Culture Media and SupplementsGuidelinesfor sterile drug products produced by aseptic processing arepublished by CBER, 6/87 (12). Additional information con-cerning the use of basal media, supplements, recombinant,animal origin, non-animal origin, enzymes, feeder cells, sub-strates (two or
42、 three dimensional; exogenous versus endog-enous), animal derived, non-animal derived, and other compo-nents of animal origin can be can be found in Brown et al. (10).Validation of aseptic filling for solution drug products ispublished by the PDA, 1980 (13). Quality assurance measuresfor acceptance
43、of all components, including media, serum, andother additives should include records detailing source and lotnumbers.4.3 Procedures:4.3.1 Biological Risk Factors:4.3.1.1 Adventitious AgentsUSFDA and WHO providepoints to be considered regarding adventitious agents(11, 14, 15). Contamination by advent
44、itious agents, includingviruses such as HBV, HCV, or HIV, must be assessed(6, 16, 17). Media components and processing agents shouldbe tested for the presence of pyrogens such as endotoxin.Typically, the Limulus Amebocyte Lysate (LAL) assay orchromogenic assay is used for this measurement (16-18). T
45、heLAL and the chromogenic assays are recommended by theFDA as an end-product test for endotoxin in human biologicsand are listed in the USP (16). The validation of assays forpyrogenicity should follow prescribed protocols recommendedby the FDA and the USP (16-18).4.3.1.2 Bioburden TestingNon-cellula
46、r components usedfor production of TEMPs must be sterilized and qualified assterile, especially prior to the addition of living cells or otherbiological components (19). CFR 210 (6) and EN 12442 (7)indicated that if living cells are to be maintained in the finalproduct, it is necessary to demonstrat
47、e that the cells, tissues,and organs are safe before their incorporation into the productwhether derived from autologous, allogeneic, xenogeneic, orgenetically modified sources. Other comments on this subjectcan be found in referenced documents (11, 15, 20-24).4.3.2 Processing AreaGuidelines for the
48、 processing areamust be followed to demonstrate qualified procedures andequipment which are able to keep contamination below aspecified level (19, 25-27).4.3.2.1 Environmental Monitoring ControlsEnvironmental controls typically include establishing andmaintaining clean room classifications at approp
49、riate baselinelevels through scheduled monitoring (28). cGMP guidelinesshould attempt to meet Class 100 requirements for criticalaseptic processing operations (6, 19). The adequacy of theclean room environment is monitored by close microbiologicalsurveillance of air, water, surfaces, clean room, and personnel.Routine environmental monitoring with established alert levelscan provide early warning on the adequacy of cleaning andsanitization procedures before action levels are exceeded. Inaddition to the environmental monitoring of the productionarea
