1、Designation: F 2383 05Standard Guide forAssessment of Adventitious Agents in Tissue EngineeredMedical Products (TEMPs)1This standard is issued under the fixed designation F 2383; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the
2、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 is intended as a resource for individuals andorganizations involved in the production, delivery, a
3、nd regula-tion of tissue engineered medical products (TEMPs). Thesafety from contamination by potentially infectious adventi-tious agents is important in the development of all TEMPs aswell as their components. This guide addresses how to assesssafety risks associated with adventitious agents and th
4、eirbyproducts. These agents currently include bacteria, fungi,mycoplasma, viruses, endotoxins, transmissible spongiformencephalopathies (TSEs), and parasitic organisms. This guidedoes not address TEMPs with live animal cells, tissues ororgans, or human cells, including stem cells, grown on anyanimal
5、 feeder cells. Also excluded is patient follow-up testing.1.2 This guide does not apply to any medical products ofhuman origin regulated by the U.S. Food and Drug Adminis-tration under 21 CFR Parts 16 and 1270 and 21 CFR Parts 207,807 and 1271. This guide does apply to cellular therapiesregulated un
6、der the PHS (Public Health Service) act.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 practices and to determine theapplicability of regulatory
7、 limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E 1873 Guide for Detection of Nucleic Acid Sequences bythe Polymerase Chain Reaction TechniqueF 2210 Guide for Processing Cells, Tissues, and Organs forUse in Tissue Engineered Medical ProductsF 2211 Classification for Tissue Engin
8、eered Medical Prod-ucts (TEMPs)F 2312 Terminology Relating to Tissue Engineered MedicalProductsF 2386 Guide to Preservation of Tissue Engineered MedicalProducts (TEMPs)2.2 ANSI/AAMI Standard:ST72 Bacterial EndotoxinTest Methodologies, RoutineMonitoring and Alternatives to Batch Testing32.3 Federal R
9、egulations:49 CFR Animals and Animal Products21 CFR 210 Current Good Manufacturing Practice inManufacturing, Processing, Packing, or Holding of Drugs,General21 CFR 211 Current Good Manufacturing Practice forFinished Pharmaceuticals21 CFR 610.12 General Biological Products StandardsSterility21 CFR 61
10、0.13 (b) General Biological ProductsStandardsPurity Test for Pyrogenic Substances21 CFR 820 Quality System Regulation21 CFR 1270 Human Tissue Intended for Transplantation21 CFR 1271 Human Cells, Tissues, and Cellular andTissue-Based Products2.4 MDA Standard:Code of Practice for the Production of Hum
11、an-DerivedTherapeutic Products52.5 U. S. Pharmacopeia Document:United States Pharmacopeia (USP), Edition XXIV (24)63. Terminology3.1 Definitions:3.1.1 adventitious agents, nunintentionally introducedmicrobiological or other infectious contaminant. In the produc-tion of TEMPs, these agents may be uni
12、ntentionally introduced1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.45 on Adventitious Agents Safety.Current edition approved April 1, 2005. Published April 2005.2For referenced ASTM stand
13、ards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor,
14、 New York, NY 10036.4Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401.5Available from Medicines and Healthcare Products Regulatory Agency(MHRA), Hannibal House, Elephant suitablecontrol of the processing environme
15、nt and routine environmen-tal monitoring; operator training; implemented documentationsystems; use of suitable, validated analytical test methods;process design; equipment qualification and process validation;and container-closure system validation. Guide F 2210, GMPs,and GTPs address many of these
16、issues. Process design,equipment qualification, and process validation are discussedin the following sections.6.2 Process Design:6.2.1 Each step in the process should be evaluated forpotential exposure to environmental contamination, includingintroduction of contamination by personnel. Processing ma
17、te-rials, such as water and buffers, should be free from adventi-tious agents. Water quality should be evaluated. Depending onthe intended use, either water for injection (WFI) or sterilepurified water may be appropriate. To ensure further confi-dence in the process, where feasible, inactivation ste
18、ps that aresuitable for adventitious agents should be incorporated into theprocess, and decontamination and cleaning protocols estab-lished for any contact surfaces.6.2.2 When multiple processing steps are used, storageconditions that protect the product intermediates from adven-titious agents must
19、be incorporated into the process scheme.When multiple products are being processed in the sameenvironment, even more stringent environmental controls mayneed to be implemented. The use of disposable equipment maybe advantageous for ensuring microbiological safety of theTEMPs, but that equipment must
20、 be suitably disposed of sothat no other facilities or individuals are put at risk (19).6.3 Equipment Design and QualificationWhere dispos-able equipment is not appropriate, equipment design should beconsidered to prevent contamination by adventitious agents.Dead legs, crevices, and threaded fitting
21、s are likely sites toharbor adventitious agents. Contact surfaces must be accessibleand compatible with decontamination and cleaning agents.Equipment is qualified by performing a design qualification, aninstallation qualification, and an operational qualification.These qualification operations are d
22、efined in an ICH documenton good manufacturing practices for active pharmaceuticalingredients (20).6.4 Use of Suitable, Validated Analytical Test MethodsProcesses cannot be validated without the use of validatedassays. During development, those assays that provide the mostrelevant information should
23、 be established and validated. Insome cases, the data from traditionally used assays for adven-titious agents will not be available in time to release TEMPscontaining viable cells for patient use. Other, more rapid assaysmay have to be validated against the traditional assays. Datafrom in-process te
24、sting are particularly useful for the manu-facture of products containing viable cells since final producttesting results may not all be available prior to product use.Appropriate in-process testing is strongly recommended forsuch products. For further guidance, see Reference (21).6.5 Process Valida
25、tion Issues Relevant to AdventitiousAgent and Contamination Control:6.5.1 In the case of cellular- and tissue-based TEMPs, itmay be necessary to perform many more runs than thetraditional three to five consecutive runs to ensure the processcontrols and outputs are sufficient to minimize the risks fr
26、omadventitious agents and their byproducts. For TEMPs, the useof medium or a product reference standard may be the mostlogical approach to maintaining a validated state. Medium orthe standard can be periodically run through the process toprovide documented evidence that the process provides aproduct
27、 meeting specifications that are related to adventitiousagent control.6.5.2 Information on process validation can be found inseveral documents. FDA has published guides on generalprinciples of process validation and on validation of humantissue products (22,23). The ICH document on active pharma-ceu
28、tical ingredients provides a good framework and definesqualification and validation activities. Two ICH guidelinesprovide information on validation of analytical methods(24,25).6.5.3 Periodic revalidation of the process with the in-housereference standard or media will also provide some confidenceF2
29、383053in the capability of the process to provide TEMPs withminimized risk from adventitious agents. Whenever there arenew reagents, new processes, process changes, new personnel,or other situations, such as an out-of-specification result,process validation should be repeated. If a reference standar
30、d isused, it should be properly stored and its stability validated.6.5.4 The manufacturing process used will depend on theproperties of the components and the requirements for the finalTEMPs. There are a wide range of processes because of thevariability in the sources and properties of different TEM
31、Psand their components. However, in many cases, unit operationswill consist of expansion of cells, removal of excess culturefluid, purification of scaffold, assembly of final product,packaging, and shipping. Each unit operation must be validatedand appropriate validated in-process assays used, where
32、 fea-sible, to minimize risks from adventitious agents. Validatedstorage times and conditions must be used between eachprocess step. The capability of antimicrobial preservatives toinhibit microbial growth should be validated along with thepreservation process. If cryopreservation is used, it is imp
33、ortantto protect the product from microbial contamination in theliquid nitrogen vessel. When feasible, products should betested after thawing (4). The American Association of TissueBanks (AATB) also provides guidance on storage (26).6.5.5 Potential risks from cross-contamination by adventi-tious age
34、nts can be minimized by segregation of differentproducts by time or space or both. Personnel and equipmentshould be dedicated to one product at a time. Closeoutinventories and cleaning validation between products areimportant elements in the prevention of cross-contamination bypotential adventitious
35、 agents.6.5.6 Process validation should be performed for any inac-tivation or removal steps that minimize risks from adventitiousagents and their byproducts. Spiking studies are often per-formed on a model system to demonstrate the effectiveness ofinactivation or removal steps or both. Inactivation
36、or removalof potential adventitious agents in viable tissue or cellularcomponents of the TEMPs may not be possible.6.5.7 Equipment cleaning and decontamination validationcan, in some cases, be accomplished with a combination of thesmall-scale coupon studies (see 6.2.2) and in-process monitor-ing dur
37、ing the conformance batches. Data generated duringvalidation should provide evidence that decontaminationagents do not impair functionality of equipment. Routinemonitoring should be continued after validation is complete.6.6 Container-Closure System ValidationValidation of thecontainer-closure syste
38、m must also be performed. Details canbe found in Refs (27,28). In most cases, TEMPs cannot beterminally sterilized.6.7 PreservationPreservation of TEMPs is addressed inGuide F 2386.7. Final Product7.1 For the design of TEMPs with the lowest possible risksfor disease transmission, it is a prerequisit
39、e that in addition toassessing the safety of the individual components and theprocessing procedures, the final product is also tested.7.2 In many cases, traditional test methods will not besufficiently rapid, and newer technologies will be used torelease the product. In addition to adventitious agen
40、t testing,test methods may include assays for byproducts of adventitiousagents, for example, endotoxin. Stability testing is also ad-dressed by FDA and ICH documents, and part of a stabilityprofile includes a demonstration that it remains uncontami-nated by adventitious agents during its storage per
41、iod (29,30).7.3 In-process sterility testing at critical points duringmanufacturing of viable cellular products is useful when testson the final product will not be available prior to use of theproduct in patients. For example, this might be done routinelyduring extended culture periods and after cr
42、itical points inmanufacturing, such as when cells have undergone activationor other modification. The results of this in-process testingshould meet acceptance criteria as part of required final productspecifications (31). When in process testing is used for productrelease, testing on the final produ
43、ct must also be performed,and a system put in place to report occurrences of sterilityfailure detected after product release.7.4 Representative retention samples, where appropriate,should be maintained under appropriate conditions so that athorough investigation can be performed in the event that an
44、adverse patient reaction is observed. The size of a batch may besmall for many TEMPs, particularly those containing autolo-gous cells, but the TEMPs sponsor should ensure that adequateproduct is archived. Archival time should be established basedon current regulatory expectations and functional life
45、time orbeyond, when feasible.8. Adventitious Agents, Byproducts, and DetectionMethods8.1 In this section, an overview of potential adventitiousagents and testing methods is presented (see Table 1). Fungi,bacteria, mycoplasma, viruses, TSEs, and parasites are in-cluded. Byproducts of some of these ag
46、ents, for example,endotoxin or other pyrogenic material from bacteria, are alsoconsidered. The TEMPs manufacturer should determinewhich, if any, of these agents should be tested for and where inthe process that testing should occur. A risk assessment anddiscussions with relevant regulatory agencies
47、should enable themanufacturer to make appropriate choices. Although the sec-tions below provide examples of some newer test methods, it isimportant to realize that there is rapid progress in this field.8.2 Knowing exactly which tests to perform can requiresignificant expertise. Some tests are better
48、 suited to viablematerials while others are more suitable for nonviable compo-nents of TEMPs. Since scientific progress is rapid in this field,the test methods here are listed for information only. Tradi-tional test methods are not always suited for TEMPs or theircomponents. Traditional test methods
49、 include those for bacteriaand fungi, mycoplasma, endotoxin and other pyrogenic mate-rials, and endogenous and adventitious viruses. Sponsors of aTEMP should discuss their suggested testing plan with theappropriate regulatory agency.8.3 Sterility (Bacteria and Fungi):8.3.1 A vast number of bacterial and fungal species areknown to potentially infect cells and raw materials of humanorigin as well as those derived from animal sources. Thesewould be too numerous to list in this guide, however, theseagents should be shown to be absent from any biotherapeuticF2383054materials. When ma
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