1、Designation: F2383 11Standard Guide forAssessment of Adventitious Agents in Tissue EngineeredMedical Products (TEMPs)1This standard is issued under the fixed designation F2383; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the ye
2、ar of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () 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, and
3、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 their
4、byproducts. 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 fe
5、eder 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 under
6、 the PHS (Public Health Service) act.1.3 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the us
7、er of this standard to establish appro-priate safety and health practices and to determine theapplicability of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E1873 Guide for Detection of Nucleic Acid Sequences bythe Polymerase Chain Reaction TechniqueF2210 Guide for P
8、rocessing Cells, Tissues, and Organs forUse in Tissue Engineered Medical ProductsF2211 Classification for Tissue Engineered Medical Prod-ucts (TEMPs)F2312 Terminology Relating to Tissue Engineered MedicalProductsF2386 Guide for Preservation of Tissue Engineered Medi-cal Products (TEMPs)2.2 ANSI/AAMI
9、 Standard:ST72 Bacterial EndotoxinTest Methodologies, RoutineMonitoring and Alternatives to Batch Testing32.3 Federal Regulations:49 CFR Animals and Animal Products21 CFR 210 Current Good Manufacturing Practice inManufacturing, Processing, Packing, or Holding of Drugs,General21 CFR 211 Current Good
10、Manufacturing Practice forFinished Pharmaceuticals21 CFR 610.12 General Biological Products StandardsSterility21 CFR 610.13 (b) General Biological ProductsStandardsPurity Test for Pyrogenic Substances21 CFR 820 Quality System Regulation21 CFR 1270 Human Tissue Intended for Transplantation21 CFR 1271
11、 Human Cells, Tissues, and Cellular andTissue-Based Products2.4 MDA Standard:Code of Practice for the Production of Human-DerivedTherapeutic Products52.5 U. S. Pharmacopeia Document:1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the di
12、rect responsibility of SubcommitteeF04.45 on Adventitious Agents Safety.Current edition approved March 1, 2011. Published March 2011. Originallyapproved in 2005. Last previous edition approved in 2005 as F2383 05. DOI:10.1520/F2383-11.2For referenced ASTM standards, visit the ASTM website, www.astm.
13、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, New York, NY 10036, http:/www.ansi.org
14、.4Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, http:/www.access.gpo.gov.5Available from Medicines and Healthcare Products Regulatory Agency(MHRA), Hannibal House, Elephant suitablecontrol of the processing en
15、vironment 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 F2210, GMPs,and GTPs address many of
16、these 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. Process
17、ing mate-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, inactivati
18、on steps 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
19、 must 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 equipmen
20、t must 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 f
21、ittings 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
22、 are defined 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
23、should 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-proc
24、ess testing 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
25、Validation 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 ri
26、sks fromadventitious 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 toF2383 113provide documented evidence that the process pr
27、ovides aproduct 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 a
28、ctive pharma-ceutical 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
29、some confidencein 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 referenc
30、e standard 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 diff
31、erent TEMPsand 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 us
32、ed, where 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,
33、it is importantto 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-
34、tious agents 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 adv
35、entitious 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. Inac
36、tivation 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 monito
37、r-ing during 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-clos
38、ure system 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 F2386.7. Final Product7.1 For the design of TEMPs with the lowest possible risksfor disease transmission, it is a pr
39、erequisite 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 adventit
40、ious agent 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 st
41、orage period (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 an
42、d after critical 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 f
43、inal product 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 eve
44、nt that anadverse 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 funct
45、ional lifetime 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 o
46、f these agents, 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
47、 agencies 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
48、are better suited to viableF2383 114materials 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. Tradi
49、tional test methods 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 biotherapeuticm
