1、Designation: E2097 00 (Reapproved 2014)Standard Guide forDetermining the Impact of Extractables from Non-MetallicMaterials on the Safety of Biotechnology Products1This standard is issued under the fixed designation E2097; the number immediately following the designation indicates the year oforiginal
2、 adoption or, in the case of revision, the year 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 covers procedures and test methods forprocess component
3、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 manufac
4、turing 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. Material
5、s must be qualified by specific use.1.2 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.3 There is no companion guide available.1.4 Safety/Fire Hazards: Extractions with organic solventswill be infrequent under this guide, but
6、, when used must betreated as potential fire/explosion 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 applic
7、a-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D4951 Test Method for Determination of Additive Elementsin Lubricating Oils by Inductively Coupled PlasmaAtomic Emission SpectrometryF619 Practice for Extraction of Medical Plastics3. Terminology3.1 See the Di
8、ctionary of Engineering Science and Technol-ogy. 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 organis
9、ms.3.2.2 biotechnology solutiona solution containing 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 cytot
10、oxicitysee USP.3.2.5 emission spectrographic analysis (ESA) an analyti-cal technique for determining metals in a sample vaporized ina plasma arc.3.2.6 extractablesresidues from solid process componentsnot intentionally part of the product process stream.3.2.7 fermentationthe biochemical reaction pro
11、cess wheremicroorganisms in a nutrient medium convert a feedstock to aproduct.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 equipmentwhi
12、ch contact process solutions and can potentially 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 pota
13、ssium permanganate underspecified conditions (see USP).1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products and is the direct responsibility of Subcommittee E55.04on General Biopharmaceutical Standards.Current edition approved Dec. 1, 2014. Published J
14、anuary 2015. Originallyapproved in 2000. Last previous edition approved in 2006 as E2097 00 (2006).DOI: 10.1520/E2097-00R14.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, r
15、efer to the standards Document Summary page onthe ASTM website.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States13.2.12 product contact materiala material which physi-cally contacts a solution containing the chemical entity desig-nated
16、the product.3.2.13 process materialshigh molecular weight or solidmaterials which contact process solutions 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 res
17、idue remainingafter ashing a material at high temperature.3.2.16 total organic carbon (TOC)an analytical techniquefor 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
18、contact with biotechnologyproduct containing solutions. Process materials leach low levelof residues into 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 pr
19、event toxic extractables from enteringprocess streams and ultimately contaminating the final productin unacceptable 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 sourc
20、e ofobjectionable substances. An extractable material is objection-able if it is toxic, interacts with product constituents, interfereswith required assays, or otherwise affects the process stream soas to adversely affect critical quality parameters, for example,purity, safety, efficacy, identity, s
21、trength of the final product orits successful production. All organizations producing pharma-ceutical products 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 primari
22、ly in ASTM or USP. Typical processmaterials include high molecular weight polymers and solidssuch as hoses, filters, filter housings, containers, valvediaphragms, gaskets, o-rings, chromatography resins, and chro-matographic columns.4.4 The battery of tests described in this guide is intended tocove
23、r a wide variety of potential attributes of materials and tocharacterize possible extractables.4.5 The material 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
24、for extractables for final product purifi-cation process materials than for fermentation media processmaterials.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 res
25、earch and development to define the manu-facturing process for a desired biotechnology product, selectfunctional product contact materials predicted to be suitablebased on manufacturer specifications. Choose materials whichhave specifications defined by pharmaceutical compendia tothe extent possible
26、. The goal is to find and use materials thatwill permit an acceptable level of extractables into the processsolution. 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 b
27、e well defined and documented to assure equivalentreplacements may be obtained. Vendor audits are necessary 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 valida
28、tion ofthe process.6.3 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 will have to be considered aswell. If test methods are the same but limits are
29、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 Table 1. Where extrac-tions are done, follow Practice F619 79 (1991). Increase thet
30、ime, 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 extraction capability of the solventsuch as organic concentration and pH. Demonstration o
31、fdepletion 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, attenuated total reflectance orsolution infrared methods. The infrared scan will bec
32、ome 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 Emission Spec-trographic or Inductively Coupled Plasma methodologies. Inthis case the a
33、mount 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 AbsorptionSpectroscopy to determine if the metals are extractable into thereleva
34、nt process solution.6.7 Distilled Water ExtractFollow Practice F619 79(1991), Sections 6 through 12. When choosing a set ofextraction conditions, choose a temperature similar to the worstcase use conditions. Extend the extraction time as appropriateto create safety factors.E2097 00 (2014)26.7.1 Oxid
35、izable 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 State of the art materials should be significantly belowthe curren
36、t 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 forDehydrated Alcohol. Significant UV absorbing peaks mayindicate reactive or
37、 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 should be consulted.6.7.6 Organic solvent extracts should be done if p
38、roduct 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 includingchromatography, infrared, mass spectrometry, or other appro-priate methods should be und
39、ertaken if the extractables level issuch that it would impact final product quality. Identification ofa well defined component of the extract allows use of thatmaterial as a marker in the final product for extract residues.6.7.8 Consideration should be given to endotoxin content ofextracts if applic
40、able. 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-volatileresidue). If the level of the extractable residue is not redu
41、ced,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. Thismay be accomplished by running a number of process cycles inexces
42、s 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.6.7.11.1 Obtain a list of all product contact materials in thesystem. Th
43、is 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 extraction medium(typical order of increasing extraction capability is
44、 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, and so forth.6.7.11.3 Take each parameter and exacerbate it to the e
45、xtentpractical 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. If a process run is eight hoursextract for at least twice that amount of time. Use
46、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 (Proces
47、s solution)pH change versus controlUV scan versus controlMetals as above versus controlElution cytotoxicity (USP) versus control where possibleTABLE 1 Recommended Tests on Non-Soluble, Non-Metallic Process Components Used in Biotechnology ManufacturingTest Test Method Fermentation Purification Final
48、 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 SolutionAppearance Visual A B COxidizable Substances or TOC USP 23 for
49、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 = Specification 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 this latter test renders a material u
