REVIEW ARTICLE

Extractable Substances from Plastic Materials Used in Solution Contact Applications: An Updated Review
DENNIS JENKE* Technology Resources, Baxter Healthcare Corporation, Round Lake, IL ABSTRACT: This is an updated review related to the identication and/or accumulation of organic and inorganic extractable substances from di(2-ethylhexyl) phthalate (DEHP)-plasticized polyvinyl chloride (PVC), polyolen, and various other plastic materials. The review considers the identication of such extractables, their reported levels in material extracts, and the strategic issues associated with investigations of extractables/leachables.

Introduction Plastic materials are widely used in medical items, such as solution containers, transfusion sets, transfer tubing, and devices. The physiochemical nature of these materials provides medical products with their necessary, desirable performance characteristics. While an important performance characteristic of plastics used in medical applications is chemical inertness, interactions between a plastic material and the pharmaceutical product it contacts are well documented. One such interaction is leaching, the release of plastic material components to the product, where both the identities of the leached substances and their accumulation levels may affect the materials ultimate compatibility with the product. The assessment of the impact of the accumulation of leached substances in pharmaceutical products contacted by a plastic material during their manufacture, storage, or use is a multi-faceted undertaking that includes the identication of the leached substances, the measurement of the actual or probable accumulation levels of the identied substances, and an assessment of the impact of these substances under conditions of clinical use. The identication phase of such an undertaking is greatly facilitated by prior knowledge of the materials composition and processing history (thereby establishing the materials extractables prole) and by review of the available chemical literature, as the alternative is a comprehensive (and at times expensive) process of utilizing sensitive and

information-rich scouting analytical methods whose dual purposes are to reveal the leachables and then provide relevant information (e.g., formula and structure) that leads to their identication. Similarly, establishing the levels to which leachables accumulate in a contacted pharmaceutical product can be greatly facilitated by any relevant published information. In the absence of such information, the analytical investigation is considerably more complicated and the analytical team is faced with the unenviable challenge of nding an unknown number of unspecied compounds that may accumulate in the product at levels much lower than its other constituents, including both intentional additives and product-related contaminants such as ingredient impurities and degradation products. A previous article compiled and summarized extractables and leachables information available at its time of publication (1). This review seeks to augment that compilation with additional information, drawing from the knowledge base established by both pharmaceutical and food science investigators. Summaries of the relevant literature are contained in a series of tables and are discussed briey. Additionally, recent articles related to the strategic aspects of performing leachables/extractables assessments are considered. Discussion Organic Extractables from Polyolen Materials An ongoing development in the pharmaceutical industry is the utilization of polyolen-based and other nonpolyvinyl chloride (PVC) materials in container and/or device applications. The European Pharamcopeia provides the following denition of polyolen (2): 191

*Author to whom correspondence should be addressed: Round Lake, IL

Vol. 60, No. 3, MayJune 2006

192 TABLE I Organic Extractables Associated with Polyethylene (PE) Materials Extraction Medium 95% ethanol (1) Organic solvents Various organic solvents Ethanol Water Extraction Conditions 4 h at 70C Unspecied 24 h at 60C Various conditions 72 h at ambient Analytical Method Headspace GC/MS GC/MS, LC/MS, LC/DAD GC/MS, Headspace GC/MS GC/FID GC/MS, HPLC Compound Identication 1,3-di-tert-butyl benzene, 2,4-di-tert-butyl phenol Di-t-butyl phenol, oxidation products of antioxidants Unspecied oligomers Ref. 15 16 17 19 27 PDA Journal of Pharmaceutical Science and Technology Irganox 1076 (2) 2-(2-butoxyethoxy)-ethyl acetate, diisobutyl phthalate, dibutyl phthalate, ethyl-4ethoxybenzoate, isophorone, 2,4-di-tert-butyl phenol, 2,6-di-tertbutylbenzoquinone, ethlybenzoate, 4-methylbenzaldehyde, benzophenone, diisobutyladipate, mesitylaldehyde, tert-butyl-phenylether, caprolactam, 1hydroxycyclohexyl-phenone, cyclohexanone-2-cyclohexylidene, 7,9,-di-tertbutyl-1-oxasoiro[4.5] deca-6,9-diene-2,8-dione, triphenyl phosphate, nonanal, 2,2,4,6,6-pentamethyl-heptane Thermal (1) Headspace GC/MS Decene, dodecene, 1,3-di-tert-butylbenzene, 2,4-di-tert-butyl phenol Notes: (1) Irradiated material studied. (2) The migration of this additive was found to t Fick diffusion equations with D c 1.1 10 12 m2 sec 1 and 113 kJ/mole. 58 Ea

TABLE II Organic Extractables Associated Polypropylene (PP) Materials Extraction Medium Acetonitrile Extraction Conditions 10 min at ambient temperature 24 h at 60C Analytical Method LC-TOF-MS Compound Identication Didodecyl 3,3 -thiodipropionate and sulphone and sulfoxide oxidations products thereof 1,3-di-tert-butyl benzene, 2,4-di-tert-butyl phenol, stearic acid, oxidation product of Irgafos 168 Antioxidants, myristic acid, palmitic acid, stearic acid, eicosanoic acid, polyethylene glycol, lauryl hydrogen sulphate, benzopyrene 2,4-di-tert-butyl phenol Studied the effect of high pressure processing (HPP) on the migration of Irganox 1076; concluded that the HPP did not change the migration properties. Ref. 6

Various organic solvent (1) Not specied

Not specied

GC/MS, Headspace GC/MS LC/MS

17

25

Water Ethanol/water (1095%)

Boiling for up to 2 weeks 20 days at 40 and 60C

GC/MS, LC HPLC

26 59

Note: (1) Irradiated material studied.

Polyolenes are obtained from the polymerization of ethylene or propylene or by copolymerization of these substances with not more than 25% of higher homologues (C4 to C10) or of carboxylic acids or of esters. Certain materials may be mixtures of polyolens and polyolens may contain a certain number of additives in order to optimize their chemical, physical and mechanical properties in order to adapt them for their intended use. All of these additives are chosen from an appended list which species for each product the maximum allowable content. Polyolens may contain at most 3 antioxidants, one of several lubricants or antiblocking agents as well as titanium dioxide as an opacifying agent when the material must provide protection from light. Polyolens nd use in the pharmaceutical industry in solution-contact applications such as containers and other packaging materials, transport devices (e.g., tubing, administration sets), component housings, syringes, etc. While such materials are routinely publicized as low in extractables, it is an oversimplication to presume that a pharmaceutical products purity will not be affected by contact with polyolen materials. Although such materials may not contain the large amounts of additives, on a weight-to-weight Vol. 60, No. 3, MayJune 2006

basis, that is typical of other exible storage and transport materials (e.g., plasticized PVC), polyolens are not unilaterally free from migrating additives and are not immune to the leaching action of a pharmaceutical preparation. The extractables/leachables information for polyolens is summarized in two tables, differentiated in terms of whether the material is polyethylene- or polypropylene-based. The information provided in Tables I and II includes an indication of the manner in which the plastic material was handled (both preextraction and during extraction) and the analytical methodology used for identication. Organic Extractables from Miscellaneous Plastic Materials As plastic and related materials have been extensively utilized in the food industry as packaging materials, there is a wide-ranging database considering the leaching of material components into foods and food-simulating solvents. To the extent that this information provides the identication of likely extractables, this information base is pertinent to pharmaceutical applications. This is fortunate because publications considering extractables accumulation in pharmaceutical applications are not commonly available for the less frequently utilized materials. However, as the condi193

194 Analytical Method Compound Identication Ref. 10 11 13 GC/MS, LC/ MS GC/MS, LC/ MS LC/MS/UV 2-mercaptobenzothiazole, tetrakis [methylene(3,5-ditertbutyl-4-hydroxy-hydrocinnamate)]methane, tetramethylthiuramsulde 4-(1,1-dimethylpropyl) phenol, sulfur, 2,6-di-tert-butyl-[1,4]-benzoquinone, 2-bromo-4-(1,1-dimethylpropyl)-phenol, furan-2-yl-(5-hydroxymethyl-furan-2-yl)-methanol BHT GC/MS Headspace GC/MS GC/MS Dimethylamine, acrylonitrile monomer, carbon disulphide, diethylamine Benzyl alcohol, 2,2 -methylene-bis-(4-methyl-6-tert-butyl) phenol 3 25 28 30 (1)

TABLE III Organic Extractables Associated with Elastomeric Materials

Extraction Medium

Extraction Conditions

Methylene chloride Acetonitrile

24-h reux

Tetra- through nona-decane, phytane, henicosane, docosane, tricosane, tetratricontane, hexatricontane, 2,6,10-trimethylpentadecane, 2,6,10,14-tetramethyl-pentadecane, cyclododecane, cyclohexadecane, cycloicosane, 1-hexadecene, 1-octadacene, 1-nonadecene, 1-docosene, 2,6-diisopropylnapththalene, alphacubebene, squalene, lauric acid, 9-hexadecenoic acid, palmitic acid, linoleic acid, elaidic acid, oleic acid, 1-pentadecanol, icosan-1-ol, 2-phenylphenol, 2,6-di-tert-butyl-p-cresol, 2,2-methylenebis(4-methyl-6-tertbutylphenol), campesterol, stigmasterol, sitosterol, Vitamin E, lupeol, alpha amyrin, 2-pentylnonenal, hexadecyloxirane, hexahydrofarnesyl acetone, steryl mercaptan, dibutylphthalate, diisohexylphthalate, stearyl chloride, heptadecylacetate, octadecylacetate, n-butyl palmeate, dibenzylamine, tetradecanamide, hexadecanamide, oleimide, stearamide, erucamide Water, diethyl Various GC/MS, LC/ Natural rubber: mercaptobenzothiazole, benzothiazole, n-cyclohexyl formamide, chlorinated benzothiazole, ether, conditions MS benzothiazolone, cyclohexamine, cyclohexanone, isocyanato cyclohexane, 2-(methythio)-benzothiazole, thermal 2(3H)-benzothiazolone, 2-benzothiazoleamine. Nitrile rubber: hydroxy methyl pentanone, dihydrofuranone, dihydromethylfuranone, dihydrodimethylfuranone, dihydroethylfuranone, methyl pentanal, pyrene, acrylonitrile, mercaptobenzothiazole, benzothiazole. EDPM: isothiocyanato-ethane, dicyclopentadiene, N-formylpiperidine, tetramethylthiourea, benzothiazole, 2-(methylthio)-benzothiazole, N-ethyl-2-benzothiazolamine, N-(2-hydroxyethyl)-dodecanamide, pyrene, di-(2-ethylhexyl)phthalate, 4-ethyl-2-propyl-thiazole, hydroxy methyl pentanone, dihydrofuranone, dihydroxymethylfuranone, dihydrodimethylfuranone, dihydroetrhylfuranone, methyl pentanal. Fluoropolymer: triphenyl phosphine oxide Note: (1) Six elastomeric materials were examined in this study and the composition of these samples is included in the manuscript.

Unspecied drug product Oils, solvents, water Thermal desorption Acetone

18 g per 33 mL, reux for 8 h Lyophilization conditions

Various conditions 150C for 10 min 30 min ultrasound

PDA Journal of Pharmaceutical Science and Technology

TABLE IV Organic Extractables Associated with Miscellaneous Plastic Materials Extraction Conditions Compound Identication 2,6,-bis(tert-butyl)-4-methyl phenol, di-n-butyl phthalate, di-(2-ethylhexyl) phthalate, 2,4,6-tris-(tertbutyl) phenol Various conditions GC/MS Analytical Method Ref. 3

Material

Extraction Medium

Polystyrene

Vol. 60, No. 3, MayJune 2006 40C for 21 days GC/MS 21 100C for 2 h High temperature, short duration 1030 mg dissolved in 10 mL GC/MS GC/MS LC 26 60 Platinum octaethyl porphine ketone, platinum tetrakis-(pentauorophenyl)porphin, tris(4,7-diphenyl-1,10-phenantroline) ruthenium (II) perchlorate (2) 2-hydroxy-4-(n-octyl) benzophenone (Cimmasorb 81), 2,5-bis(5-tert-butyl2-benzoxazoyl) thiophene (Uvitex OB) Styrene monomer, dimer, trimer Unspecied conditions Various conditions Tripropylene glycol diacrylate, trimethylol propane triacrylate, 1,6 hexane diol diacrylate, dipropylene glycol diacrylate, pentaerythritol triacrylate, N-vinylpyrrolidone, octyl decyl acrylate, butanediol monoacrylate, ethoxylated trimethylol propane triacrylate, ethoxylated 1,6 hexane diol triacrylate, glyceryl propoxylated triacrylate, propoxylated neopentyl glycol diacrylate, di-trimethylol propane tetraacrylate, 1hydroxycyclohexyl-1-phenyl methanone, 2,2-dimethoxy-2phenylacetophonone, 2-methyl-1-(4-methyl thio) phenyl-2-(4morpholinyl)-1 propanone, isopropylthioxanthene-9-one, N,N,N ,N tetraethyl-4,4 -diamino benzophenone, ethyl-4-dimethylamino benzoate, 4-benzoyl-4-methyldiphenyl sulde, di-phenyl ketone, 2,4,6trimethylbenzoyl-diphenyl phosphine oxide, ethyl-2,4,6trimethylbenzoylphenyl phosphinate, octyl dimethyl para amino benzoic acid, 2-benzyl-2-(dimethylamino)-1-[4-(moropholinyl) phenyl)]-1butanone 2-(2-butoxyethoxy) ethyl acetate, 2-(2-butoxyethoxy) ethanol 5 13 LC/ELS with supporting MS LC/MS, LC/ CLND, GC/ MS 2,4-toluene diamine (TDA), 2,6-toluene diamine, 4,4 -methylene dianiline, toluene diisocyanate (TDI), TDA/TDI oligomers 20

Polystyrene, polysulfone

Polystyrene

Oils, solvents, water Food simulating solvents Olive oil

Polystyrene

UV/EB curable printing formulations

Water, ethanol, n-heptane Methylene chloride

Platinum cured silicone tubing

Polyurethane (toluene disisocynate based)

Unspecied drug product 0.1% acetic acid, water

195

196 Extraction Conditions Compound Identication Propylene glycol, oligomers of hydroxypropyl acetate (HPA) cross-linker (mixed acrylate esters) 24-h ll at ambient temperature 40 or 60C for 60 min Headspace GC/MS NMR Analytical Method Ref. 18 22 37C; 1 day for ethanol, 7 days for LR GC/MS 23 Up to 7 days ambient temperature Not provided LC, GC/MS 14 GC/MS, NMR 4-phenylcyclohexene (3), (E,E)-hepta-2,4-dienal, 4,5-epoxydec-2-enal, hexanal, oct-1-en-3-one, (E)-oct-2-enal, (E)-non-2-enal, octa-3,5-dien-2one, (E,E)-nona-2,4-dienal, (E,E)-deca-2,4-dienal, 4,5-epoxydec-2-enal, 2,5-dimethyl-4-hydroxy-2H-furan-3-one, 3-hydroxy-4,5-dimethyl-5Hfuran-2-one (4) Monomers: 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, ethyleneglycol di-methacrylate, triethyleneglycol dimethacrylate, tetraethyleneglycol dimethacrylate, trimethylolpropane trimethacrylate. Initiators: 1,7,7-trimethyl-bicyclo[2.2.1] heptane-2,3-dione, benzoic acid, 4-(dimethylamino)-, ethylester Reaction products: 2 (3)-endo-hydroxyepicamphor, s-phenyl benzenethiosulfonate, butylphenyl sulfone, benzene iodide. Stabilizers: butylated hydroxytoluene; 4-methoxyphenol; 2-hydroxy-4methoxybenzophenone, triphenyl antimony Others: diethylene glycol, benzene iodide, -ethycaproic acid, n-caprylic acid, 2-ethoxyethyl acrylate, camphoroquinone, decanoic acid, 2,6-ditert-butyl-p-benzoquinone, ethylmalanoic acid dibutyl ester, butylphenyl sulfone, 3,5-di-t-butyl-4-hydroxybenzyl alcohol, isopropyl myristate, 2-(hydroxy-5-methylphenyl) benzotriazole, 7-phenyl-7Htriazolo[e]benzofurazan di-butyl phthalate, butyl phthalyl butyl glycolate, methyl methacrylate, 2-hydroxyethyl methacrylate, 1,3-butanediol dimethacrylate, N,Ndimethyl-p-toluidine, N,N-di(2-hydroxyethyl)-p-toluidine, abietic acid 2-chloromethyl-3-methoxy-1-phenyl-1-propanol 24

TABLE IV (continued)

Material

Extraction Medium

Polyvinylidene uoride (PVDF) (1) Printed paper packaging

Numerous media

Thermal desorption

Methacrylates

Ethanol or Lactated Ringers (LR)

PolyEthanol methylmethacrylate

PDA Journal of Pharmaceutical Science and Technology

Styrenedivinylbenzene copolymer

Solvent extraction

TABLE IV (continued) Extraction Conditions Compound Identication (a) 100C for 30 min, (b) 175C for 30 min GC/MS, LC Analytical Method Ref. 27

Material

Extraction Medium

Vol. 60, No. 3, MayJune 2006 Unspecied GC/MS, LC/ MS, LC/ DAD GC/MS Caprolactam, 1,8-diaza-cyclotetradecane-2,9-dione, 1,8-diazacyclotetradecane-2,7-dione, 2-cyclopentylidene-cyclopentanone, 7,9-di-tbutyl-1-oxaspiro [4.5] deca-6,9-diene-2,8-dione, 1,8,15-triazacycloheneicosane-2,9,16-trione, bisphenol A, 3-ethenyl pyridine, 5ethyl-2-methyl-pyridine, z-9-octadecanamide, 3-pyridinecarboxylic acid, 5-ethylenyl-methyl ester, 2,4-di-t-butylphenol, diphenylamine, aniline, 4,4-methylene-dianiline, 5-cyanopentanamide, 2,2-dimethly-1,3propanediol, n-methylbenzeneamide, 1,6-hexanediol, nonylphenol isomers, n-butylbenzene sulphonamide, 2,2,4-trimethyl-1,2-dihydroquinoline monomer n-butanal, MEK, acetic acid, n-pentanal, methylcyclopentane-1-one 16 32 Unspecied DL-camphorquinone, 2,2-dimethylaminobenzoic acid ethyl ester, drometrizole, 1,7,7-trimethylbicyclo[2,2,1]heptane, 2,2-dimethoxy-1,2diphenylethanone, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate Acetaldehyde, butane, ethyl alcohol, MEK, acetic acid, propionic acid, butanoic acid, pentanoic acid, 2-butanol 2,6-di-t-butyl-p-cresol (BHT), 1,2-benzene dicarboxylic acid bis(2-methyl ethyl) ester, 10-methyl-11-aminoundecanoic methyl ester, nonadecanoic methyl ester, 1,2-benzene dicarboxylic acid diisooctyl ester 16 Ambient temperature rinse GC/MS, LC/ MS, LC/ DAD GC/MS, IR 31 70C for 3 days GC/MS, LC/ MS Acetic acid, formic acid, caprolactam, erucamide, p-toluenesulfonamide, hexanoic acid, octanoic acid, decomposition products of hindered phenol antioxidants including 3-(3 ,5 -di-t-butyl-4 -hydroxyphenyl) propanoic acid, 3-(3 ,5 -di-t-butyl-1 -hydroxy-4 -oxacyclohexa-2 ,5 dienyl) propanoic acid, 7,9-di-t-butyl-1-oxaspiro[4.5] deca-6,9-diene2,8-dione, cyclic compounds from the adhesive including 1,4dioxacyclo-tetradecane-5,14-dione, 1,8-dioxacyclo-tetradecane-2,7dione, 3,3-dimethyl-1,5-dioxacyclo-pentadecane-6,15-dione, 3,3dimethyl-1,5-dioxacycloundecane-6,11-dione 33 35

Polyamide

Water (a) or oil (b)

Polyamide (10)

Organic solvents

Dental lling materials

EVOH (10)

Organic solvents

Cuprophan hollow ber dialyzer, polyacrylnitrile parallel plate dialyzer Multi-layer polyolen laminate (8)

Water

Various buffer media

197

198 Extraction Conditions Compound Identication 2,4-di-tert-butyl phenol, 2,4-bis(1,1-dimethylethyl) phenol, 1,3-bis(1,1dimethylethyl) benzene, acetaldehyde, acetone, 2-methyl-2-propanol, isopropanol, acetic acid 55C for 1 week GC/MS, LC/ MS Analytical Method Ref. 36 70C for 1 day LC/MS Cyclic oligomers of caprolactam through n of such oligomers 9, also hydrolysis products 37 70C for 120 min GC/MS, LC 27 GC/MS Diisooctyladipate, 2-(2-butoxyethoxy)ethanol, BADGE, hexanedioic acid, dioctyl ester, dehydroabietic acid, methyl ester, 6-caprolactam, n-ethyltoluenesulphonamide (5), BHT, 2-methyl-aniline, 2,4-dimethyl-aniline, 2-methoxy-aniline, 4,4 -methylene-dianiline Di-ethyl phthalate, di-propyl phthalate, di-iso-butyl phthalate, di-butyl phthalate, benzyl butyl phthalate, di-cyclohexyl phthalate, di-(2ethylhexyl) phthalate, di-octyl phthalate Formaldehyde, acetaldehyde, 1,3-diaxolane, 2-methyl-1,3-dioxalone 29 Ultrasonication for 30 min at ambient temperature 24 h at 60C 27 Unspecied GC/MS, headspace GC/MS GC/MS, LC/ MS, LC/ DAD LC/MS GC/MS LC/ECD Ethyl acetate, formic acid, acetic acid, 2-methyl-1,3-dioxolane, monohydroxyethylterephthalic acid, cyclic trimer of terephthalic acid, acetaldehyde Bisphenol A (11) Bisphenol A (12) Bisphenol A (13), Bisphenol-o-quinone 16

TABLE IV (continued)

Material

Extraction Medium

Multi-layer polyolen lm

Multi-layer polyolen lm (9)

Plastic laminates

Aqueous, pH 3 to 10; ethanol/ water (40/ 60) Ethanol/ water (40/ 60) Water or olive oil

Various food contact materials (6, 7)

Hexane, acetone, water

PET (10)

Organic solvents

PETG (10)

Organic solvents

PDA Journal of Pharmaceutical Science and Technology

Water 50 days at 2037C 4 Water 30 h at 95C 9 37C for up to 10 12 Buffers, days amino acids, albumin Notes: (1) Used as a lter membrane. (2) Oxygen sensors encorporated into the polymer matrix. (3) A byproduct of the polymerization process between styrene and butadiene. (4) Many of these substances produced by the oxidation of the printing ink resins. (5) M, p, o isomers. (6) Materials studied included polyethylene, polystyrene, cellophane, PVC. (7) Of 25 materials studied only one was phthalate-free. The predominant phthalate detected was DEHP. (8) LDPE contact layer, ethyl-vinyl alcohol and polyurethane tie layer. Material was gamma irradiated. (9) Layers include copolyester ether, polyethylene, ethylene vinyl alcohol and ethylene alpha olen. Material was gamma irradiated. (10) Material was gamma irradiated. (11) Extraction of 110 16 mm tube with 10 mL of water produced bisphenol levels of 5 ng/mL at 20C and 40 ng/mL at 37C. (12) Maximum level observed was 79 g/L. (13) Levels increased at basic pH and in the presence of amino acids; oxidized to form quinone in the presence of amino acids.

Polycarbonate Polycarbonate Polycarbonate

TABLE V Inorganic Extractables Associated with Miscellaneous Plastic Materials Material LDPE raw material Sample Processing Cl, 1 Extracted Entities (concentrations in mg/kg) Ref. 38

N/A, neutron activation analysis of intact materials (1) HDPE raw material N/A, neutron activation analysis of intact materials (1) PP raw material N/A, neutron activation analysis of intact materials (1) PET raw materials N/A, neutron activation analysis of intact materials (1) PS raw material N/A, neutron activation analysis of intact materials (1) PET bottle N/A, neutron activation analysis of intact materials (1) White polystyrene N/A, neutron activation analysis of intact materials (1) PET Extraction with food simulating solvents, 10 days at 40C LDPE Extraction with food simulating solvents, 10 days at 40C Laminated plastic Microwave-assisted acid (LDPE/Al/PET/LDPE) digestion Laminated plastic (PP Microwave-assisted acid layers) digestion PET bottles (4) Analyzed commercial soft drinks stored in the bottles

Na, 0.27; Al, 1.5; Si, 180; Cl, 0.5; Ca, 0.5; Ti, 0.3; Cr, 1.9; K, 0.5 Na, 2.1; Mg, 0.5; Al, 28; Cl, 31; Ti, 33

38

38

Na, 10; Mn, 0.1; Co, 35; Br, 0.5; Sb, 140; Nd, 1.3 Cl, 3.4; Zn, 81

38

38

Na, 0.8; Mg, 50; Al, 0.4; Cl, 1.4; Co, 17; Sb, 117 Na, 11; Mg, 0.5; Al, 44; Cl, 2.9; K, 1.8; Ti, 2800; Zn, 35; Sb, 0.1 Sb 0.001 (2)

38

38

39 39 40 40 41

Co, Cr, Zn, Sb migration tracked but not measurable Cr, 0.3; Sb, 1.8; Pb, 1.1 (3) Cr, 0.3; Pb, 1.1 Al, 170; Si, 350; P, 520; S, 26; Cl, 28; K, 48; Ca, 103; Ti, 2.4; Cr, 3.6; Mn, 24; Fe, 41; Co, 27; Ni, 1.2; Cu, 2.2; Zn, 4.6; As, 2.1; Sb, 67; Ba, 13; Pb, 4.6 Zn, 0.0120.25; Fe, 0.040.11 (5) LDPE: Mg, 0.34; Al, 0.004. HDPE: Al, 0.06; Cr, 0.39; Zr, 0.4. PP: Mg, 0.45; Al, 0.1; Cr, 0.5 PS: Mg, 6.9; Al, 3.9; Co, 0.02; Cu, 0.6; Zn, 7. PET: Mg, 13; Al, 200; Co, 0.01; Ge, 0.1; Sb, 0.01. PMMA: Mg, 9; Zn, 0.8. ABS: Mg, 11; Co, 0.01; Cu, 0.2; Zn, 1; Sb, 0.01.

Paper and board Various materials (6)

Contact with solid foods, 2 hours to 90 days. Digestion or extraction with food simulating solvents (3% acetic acid, 15% ethanol, olive oil), 10 days at 40C or 2 hours at 100C (6)

42 43

Vol. 60, No. 3, MayJune 2006

199

TABLE V (continued) Material Sample Processing Extracted Entities (concentrations in mg/kg) Stoppers: Al, 34 g/L; Cd, 4 g/L; Pb, 3 g/L Glass: Al, 3500 g/L; Cd, 175 g/L Ref. 44

Glass: Al, 70 g/L in water, up to 4500 g/L 45 in sodium hydroxide. Rubber: Al, 50 g/L in water, up to 5000 g/L in EDTA. Notes: (1) The NAA analysis included 64 elements with detection limits typically less than 1 mg/kg. (2) The extracted material contained 200 mg/kg Sb. (3) Mg, K, Ca, Mn, Cu, Al and Ba were also detected in the digests but not quantitated. (4) Mean results for bottles from various vendors and for various soft drinks. (5) Analysis method used was capable of detecting 60 elements. The paper and board material examined contained high levels of many elements, including Cr (0.9 15 mg/kg) and Ba (3.37.5 mg/kg). (6) Materials investigated included LDPE, HDPE, PP, PS, PET, PMMA and others. Analysis included 69 elements, only those detected are reported. In most cases, there was no detectable migration of the elements into the simulating solvents. The highest level of the element found in several tested materials are reported herein. (7) Analysis included Al, Cd, Pb. The highest numbers are reported herein.

Glass bottles with rubber Extraction of the glass and stoppers stoppers with Large Volume Parenteral (LVP) solutions (7) Glass ampoules and Extraction with solutions bottles and rubber containing various chemicals, stoppers 121C for 30 min

tions of contact and the solvating nature of foods and pharmaceuticals may be vastly different, data reecting the specic accumulation levels of extractables in foods and food simulants may or may not be directly relevant to pharmaceutical applications. The extractables/leachables information is summarized in Tables III and IV, differentiated in terms of material type. The information provided in these tables includes an indication of the manner in which the material was handled (both pre-extraction and during extraction) and the analytical methodology used for identication. Extractable Metals and Trace Elements from Various Plastic Packaging Materials While packaging material-derived organic contaminants have received considerable attention in the chemical literature, extracted metals and/or trace elements may also have a noteworthy impact on the purity of pharmaceutical products as a result of their direct or indirect contact with plastics. Experimental studies have demonstrated the ability of heavy metals, including manganese, lead, cadmium, chromium, copper, zinc, and aluminum, to exert both an acute and chronic inuence on health. Information related to the presence of metals in packaging materials and/or the 200

leaching of metals from packaging materials in pharmaceutical and food applications is summarized in Table V. The extracted metals are identied and accumulation levels are provided when they are available from the cited primary reference. The information provided in Table V includes an indication of the manner in which the plastic material was handled (both pre-extraction and during extraction) and the analytical methodology used for identication. Leachables from Plasticized PVC PVC is one of the most widely used plastics in medical applications. While pure PVC is a hard and brittle material; when plasticized with esters of phthalic, citric, maleic, sebacic, adipic, and other acids it becomes soft and exible. Medical-grade, exible PVC most often contains di(2-ethylhexyl) phthalate (DEHP) as the primary plasticizer and as well as secondary additives. Many investigations have been published regarding the migration of these additives and other material-related compounds from PVC-containing products into intravenous solutions, primarily in static applications (1). Recent information related to DEHP leaching under dynamic, or ow, conditions (e.g., with tubing, devices, or sets) is considered in this paper (Table VI). PDA Journal of Pharmaceutical Science and Technology

TABLE VI Dynamic Extraction of DEHP from Plasticized PVC Materials Conditions of Contact 46 Findings Reference

Application

Tubing

Leachability of DEHP depends on the lipid content and ow rate. Estimated exposure was 0.8 to 2 mg of DEHP per day. DEHP levels up to 1800 ng/ mL observed in the tubing efuent. Estimated that 27 mg of DEHP was leached during simulated 24-h infusion ( volume of 500 mL). Leaching due to vehicle, not drug. Level of leached DEHP was 74107 g/mL for pure PVC. Lines made from other materials had lesser DEHP leaching.

47

Vol. 60, No. 3, MayJune 2006 48 49 Concentration of DEHP in solution reaches a plateau of 1 g/mL after 10 min of contact. Authors propose a three process mechanism for DEHP leaching. Authors cite direct correlation of DEHP leached and oil concentration. Cumulative DEHP released after 4 h was greatest in oil in water and least in oil in sugar solution due to interactions between oil and sugar molecules. The maximum amount of DEHP leached was 776 g. 50 51 Release levels included BHT, 100 ng/L; DEHP, 16 ng/L; 2-ethylhexanol and p-nonyl phenol, 7 ng/L. Authors report compounds volatilized from tubing at 250C. Volatile compounds found included BHT, di-ethyl phthalate, DEHP, 2-ethylhexanol, benzoic acid, ionol, cumyl alcohol, 7methyl tridecane, and many others at lower levels. Amount of DEHP leached depended on ow rate, tubing length, and etopside concentration. Concentration of DEHP leached from 80-cm tube after 250 mL of 0.4 mg/mL solution was 2.53.5 g/mL. Leaching of DEHP up to 540 g/mL reported. Authors report that the rate of extraction is dependent on the time and temperature of contact. 52 53 54 Leaching of DEHP increased with increasing level of solubilizing agent but decreased with increasing ow rate. The authors determined the leaching was due to the solubilizing agent and not the drug substance. Adipic acid, 1,4-butane diol, and polyadipate oligomers were reported as the dominant migrating entities. 57

Infusion of lipid-containing TPN solutions. Studied the effect of ow rate and lipid content. Infusion sets Infusion of Taxol admixture containing Cremophor EL and dehydrated alcohol. Perfusion lines Infusion of Lipid Emulsions, tested lines of 1.5 m length, 1 mL/hr for 24 h Enteral feeding Enteral nutrition solution, (Ensure tube Liquid), ow of 70 mL/h at 37C. 100-cm long tube, 0.1-cm diameter Intraveneous (IV) Extracted at 60 mL/hr with administration set polyoxyethylated hydrogenated castor oil (0.03 to 10 mg/mL) in water for injection, physiological saline or sugar (TZ) solutions. Medical tubing 14.1 cm tube (internal diameter 3.94 mm), air ow rate of 5 mL/min, volatiles trapped on Tenax absorbant.

IV extension tubing

IV infusion tubing

Administration set

Feeding tubes (plasticized with polyadipate)

Eptopside injection in 0.9% saline. Tubing lengths: 20, 50, 80 cm. Flow rates: 30, 60, 90 mL/h. Total infusion volume: 250 mL. 24 hour infusion at 27 to 33C, extracting solution 20% lipid emulsion, 2.25-m tubes, 1 mL/h for 24 h. Used polyoxyethylated caster oil as the solubilizing agent under conditions of continuous infusion. 21 days at 70100C, pH 1.7 buffer solution

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Additional studies that examined the leaching of DEHP from plastic bags under static conditions were as follows. Kambia et al. (46) studied the leaching of DEHP from TPN bags by parenteral emulsions and found that 0.2 0.7 mg of DEHP leached from such bags over the course of 1 week of storage at 4C. Kim et al. report that up to 85 mg of DEHP is extracted from PVC bags by admixed Taxol over 24 h of ambient temperature contact (47). These authors note that the DEHP release is of similar magnitude in the drug vehicle (Cremophor EL and dehydrated ethanol). Demore et al. report that intraveneous etoposide solution leaches up to 25 g/mL of DEHP from plasticized PVC bags (100-mL size) over 24 h of ambient temperature storage (55). Finally, several authors investigated the migration of phthalates and alternate plasticizers from PVC materials other than medical products. Shen reported the migration of eight different phthalates from 25 kinds of plastic products for food use (7). Munksgaard studied the leaching of phthalates from denture soft lining materials by an aqueous saliva simulant (8). Shoff studied the relative migration of several PVC plasticizers including phthalates, citrates, and phosphonium-based ionic liquids (56). Tactical and Strategic Issues Related to Extractables/Leachables Investigations As the topic of leachables and extractables has matured, publications related to the strategic and tactical aspects of performing leachables/extractables assessments have appeared. For example, manuscripts by Zhang et al. (11), Norwood et al. (61), Kauffman (62), and Wang (63) discuss analytical strategies and techniques applicable to the discovery, identication, and quantitation of leachables and extractables. Numerous authors, including Green (64), Bennan et al. (65), Cardona (66), and Goldstein et al. (67) consider the issue of leachables and extractables in the context of biopharmaceutical applications of plastic packaging, containment, and processing materials and/or systems. Northup (68) and Osterberg (69) have considered the toxicological or biological impact of extractables and leachables. Both Hansen (70) and Jenke (71) have considered the need to, and implications of, linking extractables from plastic materials to leachables that are present in nished drug products. Recently, Jenke et al. (36) have proposed an approach to assessing the leachables impact of a change in the composition of the solution-contact plastic materials. 202

Regulatory guidelines or standards that have been recently published include 1. Guideline on Plastic Immediate Packaging Materials, by the European Medicines Agency (72). 2. Establishment of Allowable Limits for Leachables Substances (medical devices), by the Association for the Advancement of Medical Instrumentation (AAMI) (73). 3. Chemical Characterization of Materials, by the AAMI (74). Recent publications also include those that deal with the processing of leaching from a theoretical perspective. For example, publications that consider the theoretical aspects of mass transport in packaging systems (e.g., migration of leachables) include manuscripts by Linseem et al. (75), Scholler et al. (76), Marin (77), and Tehrany and Desobry (78). Two recent publications by Jenke and associates address the issue of the utility of simulating solvents in extractable/leachables investigations (35, 79). Finally, Piotrowska (80) has recently complied a review related to the issue of toxic components of food packaging materials. It is relevant to pharmaceutical applications to the extent that leachables is an issue to both the food and pharmaceutical industry and to the extent that materials used in food applications are similar to materials used in pharmaceutical applications. References 1. Jenke, D. Extractable leachable substances from plastic materials used in pharmaceutical product containers/devices. PDA J. Pharm. Sci. Technol. 56(6), 332 (2002). 2. 3.1.3 Polyolens. In the European Pharamcopoeia, 4th ed. Council of Europe: Strasbourg, 2001, 242. 3. Moskovkin, A. S. Chromatographic-mass spectrometric determination of toxic substances liberated from polymeric materials. Journal of Analytical Chemistry. 57, 507 (2002). 4. Sajiki, J., and Yonekubo, J. Leaching of bisphenol A (BPA) to seawater from polycarbonate plastic PDA Journal of Pharmaceutical Science and Technology

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14. Kawahara, T., Nomura, Y., Tanaka, N., Teshima, W., Okazaki, M., and Shintani, H. Leachability of plasticizer and residual monomer from commercial temporary restorative resins. J. Dentistry 32, 277 (2004). 15. Stoffers, N. H., Linssen, J. P. H., Franz, R., and Welle, F. Migration and sensory evaluation of irradiated polymers. Radiat. Phys. Chem. 71, 203 (2004). 16. McNeal, T. P., Komolprasert, V., Buchalla, R., Olivo, C., and Beglay, T. H. Effects of ionizing radiation on food contact materials. In ACS Symposium Series #875, 2004, 214. 17. Franz, R. and Welle, F. Effect of ionizing radiation on the migration behavior and sensory properties of plastic packaging materials. In ACS Symposium Series #875, 2004, 236. 18. Kao, Y. H., Bender, J., Hagewiesche, A., Wong, P., Huang, Y., and Vanderlann, M. Characterization of lter extractables by proton NMR spectroscopy: studies on intact lters with process buffers. PDA J. Pharm. Sci. Technol. 55(5), 268 (2001). 19. Helmroth, I. E., Bekhuis, H. A. M., Linssen, J. P. H., and Dekker, M. Direct measurement of additive migration from low-density polyethylene as a function of space and time. J. Appl. Poly. Sci. 86, 3185 (2002). 20. Marand, A., Karlsson, D., Dalene, M., and Skarping, G. Extractable organic compounds in polyurethane foam with special reference to aromatic amines and derivatives thereof. Anal. Chim. Acta 510, 109 (2004). 21. ORiordan, T. C., Voraberger, H., Kerry, J. P., and Papkovsky, D. B. Study of the migration of active components of phosphorescent oxygen sensors for food packaging applications. Anal. Chim. Acta 530, 135 (2005). 22. Landy, P., Nicklaus, S., Semon, E., Mielle, P., and Guichard, E. Representativeness of extracts of offset paper packaging and analysis of the main odor-active compounds. Journal of Agricultural and Food Chemistry. 52, 2326 (2004). 203

23. Michelsen, V. B., Lyre, H., Skalevik, R., Tveit, A. B., and Solheim, E. Identication of organic eluates from four polymer-based dental lling materials. European Journal of Oral Sciences. 111, 263 (2003). 24. Tou, J. S., Kostelc, J. G., Sclittler, M. R., and Violand, B. N. Isolation and identication of the major extractable impurity from Dowex 1 2 resin. Org. Process Res. Dev. 7, 750 (2003). 25. Sidwell, J. Examination of extractables from plastic and rubber components of medical products by GC-MS and LC-MS. 3rd International Conference on Polymers Used in the Medical Industry, Medical Polymers 2003, 2003, 51. 26. Quinto-Fernandez, E. J., Perez-Lamela, C., and Simal-Gandara, J. Analytical methods for foodcontact materials additives in olive oil simulant at sub-mg kg 1 level. Food Additives and Contaminants 20, 678 (2003). 27. Skjevrak, I., Brede, C,, Steffensen, I., Mikalsen, A., Alexander, J., Fjekdal, P., and Herikstad, H. Non-targeted multi-component analytical surveillance of plastic food contact materials: Identication of substances not included in EU positive lists and their risk assessment. Food Additives & Contaminants 22, 1012 (2005). 28. Bouma, K. and Schothorst, R. C. Identication of extractable substances from rubber netting used to package meat products. Food Additives & Contaminants 20, 300 (2003). 29. Shen, H. Simultaneous screening and determination of eight phthalates in plastic products for food use by sonication-assisted extraction/GC/MS methods. Talanta 66, 734 (2005). 30. Sidwell, J. Research on extractables from foodcontact rubber compounds using GC/MS and LC/MS based techniques. Paper 16 in RubberChem 2002, 3rd International Rubber Chemicals, Compounding and Mixing Conference, Munich, Germany, 2002, 117. 31. Postaire, E., Cohen, J., Paul, J., Fournier, G., Corvazier, M., Jehenne, G., Raichvarg, D., and Man, N. Characterization and identication of 204

substances isolated from dialyzer extracts. Articial Organs 12, 471 (1988). 32. Lygre, H., Hol, P. J., Solheim, E., and Mo, G. Organic leachables from polymer-based dental lling materials. Eur. J. Oral Sci. 107, 378 (1999). 33. Jenke, D., Poss, M., Story, J., Odufu, A., Zietlow, D., and Tsilipetros, T. Development and validation of chromatographic methods for the identication and quantitation of organic compounds leached from a laminated polyolen material. J. Chromatogr. Sci. 42, 388 (2004). 34. Jenke, D. R., Jene, J. M., Poss, M., Story, J., Tsilipetros, T., Odufu, A., and Terbush, W. Accumulation of extractables in buffer solutions from a polyolen plastic container. Int. J. Pharm. 297, 120 (2005). 35. Jenke, D., Odufu, A., and Poss, M. The effect of solvent polarity on the accumulation of leachables from pharmaceutical product containers. European Journal of Pharmaceutical Sciences. 27, 133 (2006). 36. Jenke, D., Swanson, S., Edgcomb, E., Couch, T., Chacko, M., Garber, M. J., and Fang, L. Strategy for assessing the leachables impact of a material change made in a container/closure system. PDA J. Pharm. Sci. Technol. 59(6), 360 (2005). 37. Jenke, D., Poss, M., Sadain, S., Story, J., Smith, W., and Reiber, D. Identication of caprolactam oligomers and related compounds in aqueous extracts of Nylon-6. J. Appl. Polym. Sci. 95, 1262 (2005). 38. Thompson, D., Parry, S. J., and Benzing, R. Neutron activation analysis for the determination of contaminants in food contact materials. J. Radioanal. Nucl. Chem. 195, 209 (1995). 39. Thompson, D., Parry, S. J., Benzing, R. The validation of a method for determining the migration of trace elements from food packaging materials into food. J. Radioanal. Nucl. Chem. 217, 147 (1997). 40. Skrzydlewska, E., and Balcerzak, M. Determination of traces of toxic elements in laminated plasPDA Journal of Pharmaceutical Science and Technology

tic food packaging materials by inductively coupled plasma time-of-ight mass spectrometry (ICP-TOFMS). Chemia Analityczna 48, 909 (2003). 41. Zucchi, O. L. A. D., Moreira, S., Salvador, M. J., and Santos, L. L. Multielement analysis of soft drinks by x-ray uorescence spectrometry. J. Agric. Food Chem. 53, 7863 (2005). 42. Aston, D. S. J. and Parry, S. J. A radiotracer technique for the migration of inorganic contaminants into dry food from packaging made from recycled paper and board. J. Radioanal. Nucl. Chem. 263, 81 (2005). 43. Fordham, P. J., Gramshaw, J. W., Crews, H. M., and Castle, L. Element residues in food contact plastics and their migration into food simulants, measured by inductively-coupled plasma-mass spectrometry. Food Additives & Contaminants 12, 651 (1995). 44. Pavanetto, F., Genta, I., Conti, B., Modena, T., and Montanari, L. Investigation on the contribution of raw materials and of the primary container on aluminum, cadmium and lead contamination of large-volume parenteral solutions. Pharmaceutical Technology, 5th International Conference 2, 435 (1989). 45. Bohrer, D., Nascimento, P. C., Binotto, R., and Becker, E. Inuence of the glass packing on the contamination of pharmaceutical products by aluminum. Part II. Interaction container-chemicals during the heating for sterilization. Journal of Trace Elements in Medicine and Biology. 17, 107 (2003). 46. Kambia, K., Dine, T., Gressier, B., Bah, S., Germe, A., Luyckx, M., Brunet, C., Michaud, L., and Gottrand, F. Evalution of childhood exposure to di(2-ethylhexyl) phthalate from perfusion kits during long-term parenteral nutrition. Int. J. Pharm. 262, 83 (2003). 47. Kim, S. C., Yoon, H. J., Lee, J. W., Yu, J., Park, E., and Chi. S. Investigation of the release behavior of DEHP from infusion sets by paclitaxelloaded polymeric micelles. Int. J. Pharm. 293, 303 (2005). Vol. 60, No. 3, MayJune 2006

48. Loff, S., Subotic, U., Reinicke, F., Wischmann, H., and Brade, J. Extraction of di-ethylhexylphthalate from perfusion lines of various material, length and brand by lipid emulsion. Journal of Pediatric Gastroenterology and Nutrition 39, 341 (2004). 49. Tanaka, M., Kawano, K., Hanawa, T., Suzuki, M., and Nakajima, S. Leaching mechanisms of di-(2ethylhexyl) phthalate from polyvinyl-chloride tube during the administration of enteral nutrition. Journal of Pharmaceutical Science and Technology, Japan. 62, 146 (2002). 50. Hanawa, T., Endoh, N., Kazuno, F., Suzuki, M., Kobayashi, D., Tanaka, M., Kawano, K., Morimoto, Y., Nakajima, S., and Oguchi, T. Investigation of the release behavior of diethyl phthalate from polyvinyl chloride tubing for intravenous administration based on HC060. Int. J. Pharm. 267, 141 (2003). 51. Hill, S. S., Shaw, B. R., and Wu, A. H. B. Plasticizers, antioxidants, and other contaminants found in air delivered by PVC tubing used in respiratory therapy. Biomed. Chromatogr. 17, 250 (2003). 52. Bagel-Boithias, S., Sautou-Miranda, V., Bourdeaux, D., Tramier, V., Boyer, A., and Chopineau, J. Leaching of diethylhexyl phthalate from multilayer tubing into etoposide infusion solutions. American Journal of Health-System Pharmacy. 62, 182 (2005). 53. Loff, S., Kabs, F., Subotic, U., Schaible, T., Reinecke, F., and Langbein, M. Kinetics of diethylhexyl-phthalate extraction from polyvinylchloride-infusion lines. JPEN 65, 305 (2002). 54. Nakamura, Y., Nakazawa, K., Ohmori, S., Kawano, K., Shinichirou, N., and Kitada, M. Investigation of the involvement of a surfactant in the leaching of diethylhexyl phthalate from administration sets. Iryo Yakugaku 30, 180 (2004). 55. Demore, B., Vigneron, J., Perrin, A., Hoffman, A., and Hoffman, M. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous etoposide solution. Journal of Clinical Pharmacy and Therapeutics. 27, 139 (2002). 205

56. Schoff, H. W., Rahman, M., and Brazel, C. S. Leaching and migration resistance of phosphonium-based ionic liquids as PVC plasticizers: comparative study of traditional phthalate and citrate plasticizers with ionic liquids. Polymer Preprints 45, 295 (2004). 57. Wang, Q. and Storm, B. K. Migration of additives from poly(vinyl chloride) (PVC) tubes into aqueous media. Macromol. Symp. 225, 191 (2005). 58. Welle, F. Migration of radiolysis products from radiation-sterilized plastics. Pharmazeutische Industrie 67, 970 (2005). 59. Caner, C. and Harte, B. Effect of high-pressure processing on the migration of antioxidant Irganox 1076 from polypropylene lm into a food simulant. J. Sci. Food Agric. 85, 39 (2005). 60. Meng, P. and Li, L. Analysis of styrene dimer and trimer in polystyrene food packing materials by GC/MS. Hecheng Shuzhi Ji Suliao 21, 15 (2004). 61. Norwood, D. L., Nagao, L., Lyapustina, S., and Munos, M. Application of modern analytical technologies to the identication of extractables and leachables. American Pharmaceutical Review. 8, 78 (2005). 62. Kauffman, J. S. Identication and risk-assessment of extractables and leachables. Pharmaceutical Technology. Analytical Methods 2006, S14 (2006). 63. Wang, Q. Selection of analytical techniques for pharmaceutical leachables studies. American Pharmaceutical Review. 8, 38 (2005). 64. Green, S. Extractables and leachables: a biopharmaceutical perspective. American Pharmaceutical Review. 8, 24 (2005). 65. Bennan, J., Bing, F., Boone, H., Ferandez, J., Seely, B., van Deinse, H., and Miller, D. Evaluation of extractables from product-contact surfaces. BioPharm International. 17, 1 (2002). 66. Cardona, M. and Blosse, P. Liquids handling. Guidelines for selecting sterilizing lters. Chem. Eng. Prog. 101, 34 (2005). 67. Goldstein, A., Schieche, D., Hartner, J., Samavedam, R., Wilkinson, L., and Manocchi, A. Dis206

posable systems in biopharm production design, compliance and validation methods. American Pharmaceutical Review. 8, 60 (2005). 68. Northup, S. J. Assessing the biological safety of extractable and leachables chemicals in pharmaceutical and medical products. American Pharmaceutical Review. 8, 38 (2005). 69. Osterberg, R. E. Potential toxicity of extractables and leachables in drug products. American Pharmaceutical Review 8, 64 (2005). 70. Hansen, K. J. Developing a correlation between extractables & leachables in MDIs and DPIs. Drug Delivery Technology 5, 66 (2005). 71. Jenke, D. R. Linking extractables and leachables in container/closure applications. PDA J. Pharm. Sci. Technol. 59(4), 265 (2005). 72. Guideline on Plastic Immediate Packaging Materials. European Medicines Agency. EMEA/ CVMP/205/04. 5/19/05. 73. ISO/FDIS 10993-17:2002Biological Evaluation of Medical DevicesPart 17: Establishment of Allowable Limits for Leachables Substances. Association for the Advancement of Medical Instrumentation (AAMI). 11/27/02. 74. ISO/FDIS 10993-18 (draft)Biological Evaluation of Medical DevicesPart 18: Chemical Characterization of Materials. Association for the Advancement of Medical Instrumentation (AAMI). In draft. 75. Linssen, J. P. H., van Willige, R. W. G., Dekker, M. Packaging-avor interactions. In Novel Food Packaging Techniques; CRC Press: Boca Raton, FL, 2003; pp 144 171. 76. Scholler, D., Vernaud, J. M., Bouquant, J., Vergallen, H., and Feigenbaum, A. Safety and quality of plastic food contact materials. Optimization of extraction time and extraction yield, based on arithmetic rules derived from mathematical description of diffusion. Application to control strategies. Packaging Technology and Science 16, 209 (2003). 77. Marin, A. Polymer additives: physical aspects of their behavior in polymers. Recent Research DePDA Journal of Pharmaceutical Science and Technology

velopments in Applied Polymer Science 1, 567 (2002). 78. Tehrany, E. A. and Desobry, S. Partition coefcients in food/packaging systems: a review. Food Additives & Contaminants 21, 1186 (2004). 79. Jenke, D., Odufu, A., and Poss, M. The effect of solvent polarity on the accumulation of leachables

from pharmaceutical product containers. European Journal of Pharmaceutical Science. 27, 133 (2006).

80. Piotrowska, B. Toxic components of food packaging materials. In Toxin in Food, Dabrowski, W. M., Sikorski, E., Eds., CRC Press: Boca Raton, FL, 2005; pp 313333.

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