1、Designation: E 2097 00 (Reapproved 2006)Standard Guide forDetermining the Impact of Extractables from Non-MetallicMaterials on the Safety of Biotechnology Products1This standard is issued under the fixed designation E 2097; the number immediately following the designation indicates the year oforigin
2、al adoption or, in the case of revision, 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 covers procedures and test methods forprocess compone
3、nt qualification by the end user. The goal is toassess the safety impact of extractables from non-metallicprocess components used in contact with bioprocessing solu-tions. This encompasses the impact of extractables on thesafety of the final product as it passes through the variousstages of the manu
4、facturing process. This guide is not designedfor evaluation of metallic materials, final product container/closures or those components intentionally added to the prod-uct or production streams during the manufacturing process.Testing of solids and extracts is specified in other ASTMstandards. Mater
5、ials must be qualified by specific use.1.2 The values stated in SI units are to be regarded as thestandard.1.3 There is no companion guide available.1.4 Safety/Fire Hazards: Extractions with organic solventswill be infrequent under this guide, but, when used must betreated as potential fire/explosio
6、n hazards.1.5 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 determine the applica-bility of regulatory limitations prior to use.2. Re
7、ferenced Documents2.1 ASTM Standards:2D 4951 Test Method for Determination of Additive Ele-ments in Lubricating Oils by Inductively Coupled PlasmaAtomic Emission SpectrometryF 619 Practice for Extraction of Medical Plastics3. Terminology3.1 See the Dictionary of Engineering Science and Technol-ogy.
8、Review with Subcommittee E48.91 on Terminology. SeeSection A7 on Terminology and Part E on Terminology inASTM Standards in Form and Style for ASTM Standards fordetails.3.2 Definitions:3.2.1 biopharmaceuticalany drug product produced fromliving organisms.3.2.2 biotechnology solutiona solution contain
9、ing or pro-ducing products from living microbial, animal or plant cells orby the enzymes from those cells.3.2.3 biotechnology producta discrete chemical entityproduced by growing single cell organisms with unique geneticinformation.3.2.4 elution cytotoxicitysee USP.3.2.5 emission spectrographic anal
10、ysis (ESA) an analyti-cal technique for determining metals in a sample vaporized ina plasma arc.3.2.6 extractablesresidues from solid process compo-nents not intentionally part of the product process stream.3.2.7 fermentationthe biochemical reaction processwhere microorganisms in a nutrient medium c
11、onvert a feed-stock to a product.3.2.8 inductively coupled plasma (ICP)an analytical tech-nique designed to quantitate chemical elements.3.2.9 materials of constructionhigh molecular weight orsolid materials, used in biopharmaceutical process equipmentwhich contact process solutions and can potentia
12、lly releaseextractable residues.3.2.10 non-volatile residue (NVR)non-volatile materialremaining after evaporating a solvent into which the residuehas been extracted (See USP).3.2.11 oxidizable substances (OS)chemical compoundswhich may be oxidized by potassium permanganate underspecified conditions
13、(See USP).3.2.12 product contact materiala material which physi-cally contacts a solution containing the chemical entity desig-nated the product.1This guide is under the jurisdiction ofASTM Committee E48 on Biotechnologyand is the direct responsibility of Subcommittee E48.03 on Unit Processes andVal
14、idation.Current edition approved Nov. 1, 2006. Published December 2006. Originallyapproved in 2000. Last previous edition approved in 2000 as E 2097 00.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMSta
15、ndards volume information, refer to the standards Document Summary page onthe ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.3.2.13 process materialshigh molecular weight or solidmaterials which contact process solution
16、s potentially releasingextractable residues.3.2.14 purificationthe process by which the desired prod-uct is separated from the production process solution.3.2.15 residue on ignition (ROI)the residue remainingafter ashing a material at high temperature.3.2.16 total organic carbon (TOC)an analytical t
17、echniquefor measuring the carbon associated with organic molecules ina solution.4. Significance and Use4.1 This guide applies to the determination of the safety ofnon-metallic materials used in contact with biotechnologyproduct containing solutions. Process materials leach low levelof residues into
18、water, cell culture media, buffers, and otherproduct containing solutions. This document offers guidanceon determining the safety of these materials (process materials)for use. The goal is to prevent toxic extractables from enteringprocess streams and ultimately contaminating the final productin una
19、cceptable levels.4.2 The purpose of this guide is to describe tests to qualifymaterials with respect to any extractable substances so as toprevent unintentional introduction of a potential source ofobjectionable substances. An extractable material is objection-able if it is toxic, interacts with pro
20、duct constituents, interfereswith required assays, or otherwise affects the process stream soas to adversely affect critical quality parameters, for example,purity, safety, efficacy, identity, strength of the final product orits successful production. All organizations producing pharma-ceutical prod
21、ucts should consider the points in this guide whenqualifying process materials for use in their production pro-cesses.4.3 This guide outlines the application of the processmaterial tests primarily in ASTM or USP. Typical processmaterials include high molecular weight polymers and solidssuch as hoses
22、, filters, filter housings, containers, valve dia-phragms, gaskets, o-rings, chromatography resins, and chro-matographic columns.4.4 The battery of tests described in this guide is intended tocover a wide variety of potential attributes of materials and tocharacterize possible extractables.4.5 The m
23、aterial specification will vary depending on theimpact on the final product and the point in the process that theproduct solution contacts the material. Tighter specificationsshould be considered for extractables for final product purifi-cation process materials than for fermentation media processma
24、terials.5. Reagents5.1 The quality of reagents used for the procedures indi-cated in this guide are specified in the test standards referenced(for example, ASTM and USP).6. Procedure6.1 During research and development to define the manu-facturing process for a desired biotechnology product, selectfu
25、nctional product contact materials predicted to be suitablebased on manufacturer specifications. Choose materials whichhave specifications defined by pharmaceutical compendia tothe extent possible. The goal is to find and use materials thatwill permit an acceptable level of extractables into the pro
26、cesssolution. Materials should be approved by specific process use.A written protocol should be prepared outlining the tests to bedone on each process material qualified. Qualified materialsmust be well defined and documented to assure equivalentreplacements may be obtained. Vendor audits are necess
27、ary forall suppliers of product contact material with significantextractables.6.2 When a high quality, functional material is identified,subject it to the following procedure as part of the validation ofthe process.TABLE 1 Recommended Tests on Non-Soluble, Non-Metallic Process Components Used in Bio
28、technology ManufacturingTest Test Method Fermentation Purification Final ProductSolid ComponentCharacterize by IR Thin film or ATRIR A B CMetals by ESA or ICP Ash, and analyze residue A B CDried ExtractCharacterize by IR KBr pellet A B CMetalsAby AA or ICP Ash, and analyze residue A B CWater Extract
29、 SolutionAppearance Visual A B COxidizable Substances or TOC USP 23 for Purified Water A B CNon-Volatile Residue USP 23 for Plastic Extract A B CElution CytotoxicityAUSP 23 for Plastic Extract A B CUV Scan ABOrganic Solvent ExtractBAppearance Visual A B CNon-Volatile ResidueUV Scan ABA = Specificati
30、on for Fermentation Process MaterialsB = Specification for Purification Process MaterialsC = Specification for Final Product Process Materials (other than container/closure)AIf elution cytotoxicity fails, run United States Pharmacopeia 23: Biological Reactivity Tests, In-Vitro, p. 1697. Failure of t
31、his latter test renders a materialunacceptable for product contact.BIf ApplicableE 2097 00 (2006)26.3 Choose the production function from Table 1. Usealready validated ASTM or USP test methods wherever pos-sible. If the product is to be licensed in a country with othercompendial requirements, those
32、will have to be considered aswell. If test methods are the same but limits are different, usethe more stringent limits.NOTE 1The cumulative effect of the ongoing removal of extractablescan potentially affect the performance of plastics in certain applications.6.4 Perform the tests designated in Tabl
33、e 1. Where extrac-tions are done, follow Practice F 619-79 (1991) . Increase thetime, temperature and concentration of the extraction severalfold beyond production conditions to build in safety factors andinsure worst case. Also it may be appropriate to exacerbateother factors affecting the extracti
34、on capability of the solventsuch as organic concentration and pH. Demonstration ofdepletion of extractable material can be shown by repeatedextraction and testing for non-volatile residue or oxidizablesubstances.6.5 Characterize the product contact process material bythrough the film, pyrolysis, att
35、enuated total reflectance orsolution infrared methods. The infrared scan will become thereference for subsequent lots of the material unless a manu-facturer or other valid scan is available.6.6 Evaluate the product contact process material for heavymetals using Residue on Ignition followed by Emissi
36、on Spec-trographic or Inductively Coupled Plasma methodologies. Inthis case the amount of Residue on Ignition is not importantexcept as it allows you to calculate the concentration of metalsin the solid. If unacceptable levels of heavy metals are found,appropriate extracts should be tested by Atomic
37、 AbsorptionSpectroscopy to determine if the metals are extractable into therelevant process solution.6.7 Distilled Water ExtractFollow Practice F 619-79(1991), Sections 6 through 12. When choosing a set ofextraction conditions, choose a temperature similar to the worstcase use conditions. Extend the
38、 extraction time as appropriateto create safety factors.6.7.1 Oxidizable Substancesresults will normally be sig-nificantly higher than USP Purified Water limits.6.7.2 Total Organic Carbonmeasurements are very sen-sitive and may be used in place of oxidizable substances inorganic free solvents.6.7.3
39、State of the art materials should be significantly belowthe current USP limit for non-volatile residue from plasticcontainers. Extraction solvents must be pure and used ascontrols.6.7.4 The UV/VIS scan of water solutions should show onlyshow end absorption as defined in the USP Monograph forDehydrat
40、ed Alcohol. Significant UV absorbing peaks mayindicate reactive or toxic compounds. These compounds mayneed to be identified if any cytotoxicity is observed.6.7.5 Extract solutions of state of the art materials shouldshow no elution cytotoxicity. If a cytotoxic effect is observed,a toxicologist shou
41、ld be consulted.6.7.6 Organic solvent extracts should be done if product iscontained in same. Record the amount of residue into suchsolvents and look for the residue or a marker in the finalproduct if levels are significant.6.7.7 Further identification of extractables including chro-matography, infr
42、ared, mass spectrometry, or other appropriatemethods should be undertaken if the extractables level is suchthat it would impact final product quality. Identification of awell defined component of the extract allows use of thatmaterial as a marker in the final product for extract residues.6.7.8 Consi
43、deration should be given to endotoxin content ofextracts if applicable. It should be recognized that a number ofmaterials can give false positives in the Limulus AmebocyteLysate assay.6.7.9 Repeat the extraction a second time. Test the extractfor one or more critical parameters (for example, non-vol
44、atileresidue). If the level of the extractable residue is not reduced,additional review is needed to determine the extent of the totalamount of the contaminant that can be extracted.6.7.10 It is appropriate to do stability testing on productcontact materials which undergo various process cycles. Thi
45、smay be accomplished by running a number of process cycles inexcess of that anticipated in production and testing extract forcritical parameters such as non-volatile residue and elutioncytotoxicity.6.7.11 Use the following procedure to qualify a systemcontaining a number of different material.6.7.11
46、.1 Obtain a list of all product contact materials in thesystem. This is necessary to assure replacement with identicalmaterials to those you qualify.6.7.11.2 Determine the outside parameters for the systemuse, for example, maximum temperature, maximum contacttime, hold up volume, most effective extr
47、action medium(typical order of increasing extraction capability is water thencell culture medium then serum solutions). lt should berecognized that cell culture and serum containing media willnot be compatible with standard physicochemical tests such asNon-Volatile Residue, Oxidizable Substances, an
48、d so forth.E 2097 00 (2006)36.7.11.3 Take each parameter and exacerbate it to the extentpractical to create safety factors. For example, if the maximumoperating temperature is 37C and the system will withstandsteam, start with 80C Purified Water and hold or let it rampdown to operating temperature.
49、If a process run is eight hoursextract for at least twice that amount of time. Use the minimumhold up volume of solution to obtain the maximum surface tovolume ratio. Recirculate with Purified Water after taking a 2liter control. Use the tests listed in Table 1 for Water ExtractSolution or Organic Extract solution or Test Regimen A belowfor a process solutionTest Regimen A (Process solution)pH change versus controlUV scan versus controlMetals as above versus controlElution cytotoxicity (USP) versus control where possible7. Test MethodsNon-Volatile Residue, USP
