title: Large-scale manufacturing of GMP-compliant anti-EGFR targeted nanocarriers: production of doxorubicin-loaded anti-EGFR-immunoliposomes for a first-in-man clinical trial.
abstract: We describe the large-scale, GMP-compliant production process of doxorubicin-loaded and anti-EGFR-coated immunoliposomes (anti-EGFR-ILs-dox) used in a first-in-man, dose escalation clinical trial. 10 batches of this nanoparticle have been produced in clean room facilities. Stability data from the pre-GMP and the GMP batch indicate that the anti-EGFR-ILs-dox nanoparticle was stable for at least 18 months after release. Release criteria included visual inspection, sterility testing, as well as measurements of pH (pH 5.0-7.0), doxorubicin HCl concentration (0.45-0.55 mg/ml), endotoxin concentration (<1.21 IU/ml), leakage (<10%), particle size (Z-average of Caelyx ± 20 nm), and particle uptake (uptake absolute: >0.50 ng doxorubicin/μg protein; uptake relatively to PLD: >5 fold). All batches fulfilled the defined release criteria, indicating a high reproducibility as well as batch-to-batch uniformity of the main physico-chemical features of the nanoparticles in the setting of the large-scale GMP process. In the clinical trial, 29 patients were treated with this nanoparticle between 2007 and 2010. Pharmacokinetic data of anti-EGFR-ILs-dox collected during the clinical study revealed stability of the nanocarrier in vivo. Thus, reliable and GMP-compliant production of anti-EGFR-targeted nanoparticles for clinical application is feasible.
authors.affiliation: Department of Oncology and Department of Biomedicine, University and University Hospital, Basel, Switzerland. Electronic address: andreas.wicki@usb.ch.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.affiliation: Department of Oncology and Department of Biomedicine, University and University Hospital, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Ritschard
authors.affiliation: Hospital Pharmacy, University Hospital, Basel, Switzerland.
authors.forename: Uli
authors.initials: U
authors.lastname: Loesch
authors.affiliation: Hospital Pharmacy, University Hospital, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deuster
authors.affiliation: Department of Oncology and Department of Biomedicine, University and University Hospital, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
authors.affiliation: Department of Hematology and Oncology, Cantonal Hospital, Aarau, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D002986:Clinical Trials as Topic / Q000592:standards*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis*; D016503:Drug Delivery Systems / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D019983:Guideline Adherence / Q000592:standards*; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis
chemical_list: D004337:Drug Carriers; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D066246:ErbB Receptors
keywords: Cholesterol (CID: 5997); Cysteamine hydrochloride (CID: 9082); DSPC (distearoyl phosphatidylcholine) (CID: 94,190); Doxorubicin (CID: 31,703); EGFR; Erbitux (SID 495,888); GMP production; Immunoliposomes; Nanocarrier; PEG2000 DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) (CID: 406,952); Phase I clinical trial; Targeted therapies