title: Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP.
abstract: BACKGROUND
  Rhenium-188-HEDP ((188)Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of (188)Re-HEDP.
  
  
  METHODS
  A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing.
  
  
  RESULTS
  With 2ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24h resulted in acceptable radiochemical purity. Complexation for 30min at room temperature, at 60°C and at 100°C generated appropriate and stable products. A complexation time of 10min at 90°C was too short, whereas heating 60min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5°C resulted in notable decomposition.
  
  
  CONCLUSIONS
  Two boundary tests, an elution volume of 9ml and a heating time of 10min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals.
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands. Electronic address: r.lange@meandermc.nl.
authors.forename: Rogier
authors.initials: R
authors.lastname: Lange
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ter Heine
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Toon
authors.initials: T
authors.lastname: van der Gronde
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Selles
authors.affiliation: Department of Nuclear Medicine, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: de Klerk
authors.affiliation: Department of Internal Medicine and Medical Oncology, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Haiko
authors.initials: H
authors.lastname: Bloemendal
authors.affiliation: Department of Clinical Pharmacology & Pharmacy, VU University Medical Centre, Amsterdam, The Netherlands; Department of Radiology & Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Hendrikse
mesh_terms: D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D012968:Etidronic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011786:Quality Control; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C101598:rhenium-186 HEDP; D012968:Etidronic Acid
keywords: ICH Q8; Preparation; Proven acceptable ranges; Quality by design; Quality control; Rhenium-188-HEDP; Therapeutic radiopharmaceutical