The animal tests currently carried out according to the German and European pharmacopoeias are evaluated. The routine testing of biological medicines, excluding vaccines and pyrogen tests, is examined. The opportunities for replacing obligatory bioassays and safety tests are assessed, taking into account both pharmaceutical quality and animal welfare aspects. The aim is to encourage institutions, public authorities, and the pharmaceutical industry to investigate the importance and the necessity of the remaining tests. In addition, all parties should be encouraged to initiate integrated projects to develop, validate and establish alternative methods.
Council of Europe (1997). European Pharmacopoeia, 3rd edn. Strasbourg, France: Council of Europe.
2.
Anon. (2000). Deutsches Arzneibuch.Stuttgart, Germany: Deutscher Apotheker Verlag.
3.
Anon. (1999). Beschluss (1999/575/EG) des Rate vom 23. März 1998 über den Anschluss des Europäischen übereinkommens zum Schutz der für Versuche und andere wissenschaftliche Zwecke verwendeten Wirbeltiere durch die Gemeinschaft (ABI. Nr. L 222 vom 24.8.1999 S. 37).
4.
Van NordwijkJ. (1994). Reduction of the use of animals for quality control. Pharmeuropa6, 194–197.
Anon. (2001). Tierschutzbericht der Bundesregierung 2001.Bonn, Germany: Bundesministerium für Ernährung, Landwirtschaft und Forsten. Web site www.dainet.de/bml/Herschutz/inhalt.htm (Accessed 25.2.02).
8.
ChartonE. (1999). Hormones: the role of the European Pharmacopoeia. In Alternative to Animals in the Development and Control of Biological Products for Human and Veterinary Use, Vol. 101 (ed. BrownF., HendriksenC., & SesardicD.), pp. 159–167. Basle, Switzerland: Karger.
9.
ArtigesA. (1999). Alternatives to animals in the development and control of biological products for human and veterinary use: the role of the European Pharmacopoeia. In Alternatives to Animals in the Development and Control of Biological Products for Human and Veterinary Use, Vol. 101 (ed. BrownF., HendriksenC., & SesardicD.), pp. 29–35. Basle, Switzerland: Karger.
10.
RonnebergerH. (1976). Toxicity testing of vaccines. Proceedings of the European Society of Toxicology17, 88–94.
11.
SpieserJ.M. (1995). Reduction of the use of animals for quality control testing in the European Pharmacopoeia.Alternative Methods in Toxicology11, 471–482.
12.
WeisserK., & HechlerU. (1997). Animal Welfare Aspects in the Quality Control of Immunobiologicals: A Critical Evaluation of the Animal Tests in Pharmacopoeial Monographs, 348 pp. Nottingham, UK: FRAME.
13.
HendriksenC.F.M., GarthoffB., AggerbeckH., BrucknerL., CastleP., CusslerK., DobberlaerR., van der DonkH., van der GunJ., LefrancoisS., MilstienJ., MinorP.D., MougeotH., RombautB., RonnebergerH.D., SpieserJ-M., StolpR., StraughanD.W., TollisM., & ZigtermansC. (1994). Alternatives to animal testing in the quality control of immunologicals: current status and future prospects. The report and recommendations of ECVAM workshop 4. ATLA22, 420–434.
14.
RonnebergerR. (1993). Methoden zur Reduktion des Tierverbrauchs bei der Entwicklung und Qualitätskontrolle von biologischen Arzneimitteln. In Alternativen zu Tierversuchen in Ausbildung, Qualitätskontrolle und Herz-Kreislauf-Forschung (ed. SchöfflH., SpielmannH., GruberF.P., KoidlB., & ReinhardtC.A.), pp. 169–173. Vienna, Austria: Springer Verlag.
15.
HielscherM. (1989). Rechtliche Kriterien für die Bewertung und Anerkennung von Ersatz und Ergänzungsmethoden. In Wege zur Bewertung und Anerkennung von Alternativen zum Tierversuch (ed. BullingH., SpielmannH., & BassR.), pp. 53–58. Munich, Germany: MMV Medizin Verlag.
16.
SpielmannH., GruneB., OttT., SchnädelbachD., OlejniczakK., SchwaningM., CusslerK., MettenleiterT., & AhlR. (1998). Möglichkeiten des Einsatzes von Ersatz- und Ergänzungsmethoden zum Tierversuch bei der Entwicklung und Zulassung von Arzneimitteln. Bundesgesundheitsblatt Sonderdruck41, 422–429.
17.
ChartonE. (1999). Annual report of activities. Pharmeuropa11, 197–199.
18.
BassR. (1989). Wissenschaftliche Kriterien für die Bewertung und Anerkennung von Ersatz- und Ergänzungsmethoden im Arzneimittelbereich. In Wege zur Bewertung und Anerkennung von Alternativen zum Tierversuch (ed. BullingE., SpielmannH., & BassR.), pp. 37–45. Munich, Germany: MMV Medizin Verlag.
19.
ChartonE., & CastleP. (2001). Reduction, replacement and refinement of animal tests in the European Pharmacopoeia: recent developments for the monographs on biological substances and preparations. Pharmaeuropa13, 94–96.
20.
HartungT., AabergeI., BertholdS., CarlinG., ChartonE., CoeckeS., FennrichS., FischerM., GommerM., HalderM., HaslovK., JahnkeM., Montag-LessingT., PooleS., SchechtmanL., WendelA., & Werner-FelmayerG. (2001). Novel pyrogen tests based on the human fever reaction. The report and recommendations of ECVAM workshop 43. ATLA29, 99–123.
21.
StöckerS. (1996). Pressemitteilung PEI.Paul-Ehrlich Institute, Langen, Germany: Referat A/1. Web site http://www.pei.de/pm/1996/2_96.htm. (Accessed 2.2.02).
22.
Anon. (2001). Streichung des Tests auf anomale Toxizität für Impfstoffe. In Hightech statt Tiere (ed. Bundesministerium für Bildung und Forschung, Bundesministerium für Verbraucherschutz, Ernährung und Landwirtschaft, Bundesministerium für Gesundheit, Bundesministerium für Umwelt, Natuschutz und Reaktorsicherheit), pp. 40–42. Germany: BMBF Publik.
23.
GeigerR. (1986). Corticotrophin zur Injektion. In Kommentar zum DAB 9, Bd. 2., pp. 1341–1346. Stuttgart, Germany: Deutscher Apotheker Verlag.
24.
InouyeK., WatanabeK., & KonakaR. (1985). Separation of synthetic analogs of peptide hormones. In CRC Handbook of HPLC for the Separation of Amino Acids, Peptides and Proteins, Vol. 2 (ed. HancockW.S.), pp. 111–123. Boca Raton, FL, USA: CRC Press.
25.
HungerA. (1968). Formulierung und Analytik von ACTH Präparaten. Pharmazeutische Zeitung36, 1351–1355.
26.
StorringP.L., WitthausG., Gaines DasR.E., & StammW. (1984). The international reference preparation of tetracosactide for bioassay: characterisation and estimation of its (1–24)-corticotrophin-tetracosapeptide content by physicochemical and biological methods. Journal of Endocrinology100, 51–60.
BriançonF., DaasA., De KasteD., DollT., LarssonH.K., RaymakersH., MannionD., MaxlF., SpeiserJ-M., WindemannH., & CharltonE. (1999). Replacement of the bioassay by a liquid chromatographic assay in the oxytocin monograph. Pharmeuropa11, 301–305.
29.
KrummenK., MaxlF., & NachtmannF. (1979). The use of HPLC in the quality control of oxytocin. Pharmaceutical Technology International2, 37–43, 62.
30.
MaxlF., & SiehrW. (1989). The use of high-performance liquid chromatography in the quality control of oxytocin, vasopressin and synthetic analogues. Journal of Pharmaceutical and Biomedical Analysis7, 211–216.
31.
KrummenK., & FreiR.W. (1977). Quantitative analysis of nonapetides in pharmaceutical dosage forms by high-performance liquid chromatography. Journal of Chromatography132, 429–436.
32.
RaoP.S., WeinsteinG.S., WilsonD.W., RuijkarnN., & TyrasD.H. (1991). Isocratic high-performance liquid chromatography–photodiode-array detection method for determination of lysine- and arginine-vasopressins and oxytocin in biological samples. Journal of Chromatography536, 137–142.
33.
BuckR.H., CholewinskiM., & MaxlF. (1991). Animal test or chromatography? Validated high-performance liquid chromatographic assays as an alternative to the biological assay for ornipressin. Journal of Chromatography548, 335–341.
34.
O'HareM.J., & NiceE.C. (1979). Hydrophobic highperformance liquid chromatography of hormonal polypeptides and proteins on alkylsilane-bonded silica. Journal of Chromatography171, 209–226.
35.
HörigJ., & NerlichC. (1999). Desmopressin. In Kommentar zur Ph. Eur. NT 1998, 11. Lfg. 1999, D7. Stuttgart, Germany: Deutscher Apotheker Verlag.
36.
BuckR.H., & MaxlF. (1990). A validated HPLC assay for salmon calcitonin analysis: comparison of HPLC and biological assay. Journal of Pharmaceutical and Biomedical Analysis8, 761–769.
37.
BriançonF., DaasA., De KasteD., DuboisN., KennedyJ., Jackson MatthewsD., KleszynskiR., MaxlF., Plough LarsenL., PommaratF., SkareW., VellingJ., WardC., WindemannH., & ChartonE. (1999). Replacement of the bioassay by a liquid chromatographic assay in the calcitonin (salmon) monograph. Pharmeuropa11, 306–312.
38.
PlasC., & NunezJ. (1975). Glycogenetic response to glucagon of cultured fetal hepatocytes. Journal of Biological Chemistry250, 5304–5311.
HammerlinU., KroonR., WilhelmsenT., & SjödinL. (1996). In vitro bioassay for human erythropoietin based on proliferative stimulation of an erythroid cell line and analysis of carbohydrate-dependent microheterogeneity. Journal of Pharmaceutical and Biomedical Analysis14, 1455–1469.
41.
FukushimaY. (1981). Erythropoietin bioassay in vitro using fetal mouse liver cells (FMLC). Acta Haematologica Japonica44, 1083–1088.
42.
StorringP.L., & Gaines DasR.E. (1992). The International Standard for Recombinant DNA-derived Erythropoietin: collaborative study of four recombinant DNA-derived erythropoietins and two highly purified human urinary erythropoietins. Journal of Endocrinology134, 459–484.
43.
MuldersJ.W.M., DerksenM., SwolfsA., & MarisF. (1997). Prediction of the in vivo biological activity of human recombinant follicle stimulating hormone using quantitative isoelectric focusing. Biologicals25, 269–281.
44.
MuldersJ.W.M., WijnH., TheunissenF., MachielsenP., & JanssenP. (1999). Prediction of the in vivo biological activity of human recombinant follicle stimulating hormone using quantitative isoelectric focusing: optimization of the model. Pharmacy and Pharmacological Communications5, 51–55.
45.
HirthP., WieczorekL., & ScigallaP. (1988). Molecular biology of erythropoietin. Contributions to Nephrology66, 38–53.
46.
SasakiH., OchiN., DellA., & FukudaM. (1988). Site specific glycosylation of human recombinant erythropoietin: analysis of glycopeptides at each glycosylation site by fast atom bombardment mass spectrometry. Biochemistry27, 8618–8626.
47.
TranA.D., ParkS., LisiP.J., HuynhO.T., RyallR.R., & LaneP.A. (1991). Separation of carbohydrate-mediated microheterogeneity of recombinant human erythropoietin by free solution capillary electrophoresis. Journal of Chromatography542, 459–471.
48.
BristowA., & ChartonE. (1999). Assessment of the suitability of a capillary zone electrophoresis method for determining isoform distribution of erythropoietin. Pharmeuropa11, 290–300.
49.
WatsonE., & YaoF. (1993). Capillary elec-trophoretic separation of human recombinant erythropoietin (r-HuEPO) glycoforms. Analytical Biochemistry210, 389–393.
50.
TakeuchiM., InoueN., StricklandT.W., KubotaM., WadaM., ShimizuR., HoshiS., KozumiH., TakasaniS., & KobotaA. (1989). Relationship between sugar chain structure and biological activity of recombinant human erythropoietin produced in Chinese hamster ovary cells. Proceedings of the National Academy of Sciences, USA86, 7819–7822.
51.
GarthoffB., HendriksenC., BayolA., GoncalvesD., GrauerA., de LeeuwR., van NoordwijkJ., ParesM., PirovanoR., RiethM., RonnebergerH., SpieserJ-M., StorringP., VosbeckK., & WeichertH. (1995). Safety and efficacy testing of hormones and related products. The report and recommendations of ECVAM workshop 9. ATLA23, 699–712.
52.
LaidlerP., CowanD.A., HiderR.C., & KicmanA.T. (1997). Characteristion of human chorionic gonadotropin microheterogeneity by capillary electrophoresis: potential application for quality control in the pharmaceutical industry. Pharmaceutical Sciences3, 487–491.
53.
MorbeckD.E., MaddenB.J., & McCormickD.J. (1994). Analysis of the microheterogeneity of the gly-coprotein chorionic gonadotropin with high-performance capillary electrophoresis. Journal of Chromatography A680, 217–224.
Schmitt-RauK. (1996). Kommentar zu Urofolli-tropin. In Kommentar zum DAB 10. 3. Nachtrag 1994, 6. Lfg. Stuttgart, Germany: Deutscher Apotheker Verlag.
56.
SimoniM., WeinbauerG.F., & NieschlagE. (1993). Molecular composition of two different batches of urofollitropin: analysis by immunofluorometric assay, radioligand receptor assay and in vitro bioassay. Journal of Endocrinological Investigations16, 21–27.
57.
LecompteF., & CombarnousY. (1992). Enzyme immunoassay (EIA) for equine chorionic gonadotropine/pregnant mare serum gonadotropine (eCG/PMSG). Journal of Immunoassays13, 483–493.
58.
TiemannU., BlödowG., & BergfeldJ. (1985). Zur Ermittlung der gonadotropen Wertigkeit von Präparaten aus dem Serum tragender Stuten (PMSG). Archiv für experimentellen Veterinär-midizin39, 414–421.
59.
WichtlM. (1986). Vergleichende chemische und biologische Untersuchung von Convallaria majalisProben verschiedener Herkunft. Arzneimittelforschung17, 1277–1278.
60.
LehmannH.D., HupeJ., & SeemanD. (1992). Aggregates of cardiac myocytes as a substrate for the in vitro assessment of cardiac glycoside potency. Archiv für Pharmacologie345, Suppl. 1, R79.
61.
LehmannH.D. (1995). Alternativen zu Tierversuchen in der Qualitätskontrolle von Arzneimitteln. Pharmazie in unserer Zeit24, 10–13.
62.
LehmannH.D., HupeJ., & SeemannD. (1993). Wege zum Ersatz von Tierversuchen für die Wirkwertbestimmung von Herzglycosid-Gemischen. In Alternativen zu Tierversuchen in Ausbildung, Qualitätskontrolle und Herz-Kreislauf-Forschung (ed. SchöfflH., SpielmannH., GruberF.P., KoidlB., & ReinhardtC.A.), pp. 121–125. Vienna, Austria: Springer Verlag.
63.
SchwanigM., NagelM., DuchowK., & KrämerB. (1997). Elimination of abnormal toxicity test for sera and certain vaccines in the European Pharmacopeia.Vaccine15, 1047–1048.
64.
FriesS. (1998). Trypsin. In Kommentar zur Ph. Eur. 1997, 9. Lfg., 694 pp., T 74. Stuttgart, Germany: Deutscher Apotheker Verlag.
65.
MoserU. (1999). Prüfung auf Histamin: Prufung auf blutdrucksenkende Substanzen. In Kommentar zur Ph. Eur. 1997, 10. Lfg., Kap. 2.6.10, 2.6.11. Stuttgart, Germany: Deutscher Apotheker Verlag.
66.
StockemerJ. (1982). Bestimmung der Aminosäuren und biogenen Amine in der dunklen und hellen Muskulatur des Thunfisches mittels Amino-säureanalysator und Hochdrukflüssigkeitschroma-tographie. Zeitschrift für Lebensmittel- Untersuchung und -Forschung174, 108–113.
67.
BustoO., ValeroY., GuaschJ., & BorrullF. (1994). Solid phase extraction applied to the determination of biogenic amines in wines by HPLC. Chromatographia38, 571–578.
68.
LiaoW., PaekH., MabuniC., AngoldS., & SolimanM. (1999). Use of capillary electrophoresis with UV detection as a screening method to determine histamine in fish samples. Journal of Chromatography A853, 541–544.
69.
MahendradattaM., & SchwedtG. (1996). Histaminbestimmung in Lebensmitteln mittels Kapillarelektrophorese und HPLC im Vergleich. Deutsche Lebensmittel-Rundschau92, 218–221.
70.
SerrarD., BrebantR., BruneauS., & DenoyelG.A. (1995). The development of a monoclonal antibody-based ELISA for the determination of histamine in food: application to fishery products and comparison with the HPLC assay. Food Chemistry54, 85–91.
71.
AygünQ., SchneiderE., ScheuerR., UsleberE., GareisM., & MärtlbauerE. (1999). Comparison of ELISA and HPLC for the determination of histamine in cheese. Journal for Agriculture, Food and Chemistry47, 1961–1964.
72.
DraisciR., VolpeG., LucentiniL., CeciliaA., FedericoR., & PalleschiG. (1998). Determination of biogenic amines with an electrochemical biosensor and its application to salted anchovies. Food Chemistry61, 225–232.
73.
ThomasK., & WittmannC. (2000). Schnelltest zur Bestimmung biogener Amine in Lebensmitteln. Bioforum4, 219.
74.
MietheG., & SurmannJ.P. (2001). Determination of histamine in trypsin by capillary zone electrophoresis: a possible alternative to the bioassay?Die Pharmazie6, 461–464.
75.
MarafanteE., & BallsM. (1994). The European Centre for the Validation of Alternative Methods (ECVAM). In Alternatives to Animal Testing: New Ways in the Biomedical Sciences, Trends and Progress (ed. ReinhardtC.A.), pp. 21–25. Weinheim, Germany: VCH.
