QPS Human Mass Balance Presentation
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The document outlines the procedure for conducting human mass balance (HMB) studies at QPS, emphasizing its extensive experience and favorable regulatory environment in the Netherlands. The process consists of ten steps, including ethics committee submission, preparation, administration of radiolabeled investigational medicinal products, and the management of radioactive human excreta. Each step is supported by detailed descriptions of responsibilities and procedures to ensure compliance with health and safety regulations.
QPS Human Mass Balance Presentation
- 1. Human Mass Balance Study In 10 steps 09 October 2014 Confidential 1
- 2. HMB Study at QPS Reasons why our Clients recommend performing a HMB Study at QPS QPS has extensive experience and expertise with the conduct of human mass balance studies (references will be provided upon request). The favorable regulatory environment in the Netherlands makes conducting human mass balance studies at QPS an excellent choice. The option of using QPS also as a preferred provider for the necessary preclinical radiolabeled study package (i.e. tissue distribution study in rats using quantitative whole-body autoradiography, dosimetry calculation, mass balance / excretion study in rats, and metabolite profiling, identification, and radio-quantitation study) enables QPS to transfer the knowledge obtained from preclinical studies smoothly to the human mass balance study in the Netherlands. Smooth knowledge transfer from preclinical to clinical becomes particularly important when metabolism pathways are complex and ensuring sample integrity becomes critical. In addition, sponsors can take advantage of the fact that QPS uses a by QPS qualified and state of the art radiopharmaceutical facility (Selcia, UK) with a governmental Manufacturer’s/GMP license for the (individual) preparation of 14C-labeled IMPs. Because of these outstanding radiopharmaceutical facilities, the availability of only the 14C-labeled drug substance is sufficient to carry out human mass balance studies at QPS. 09 October 2014 Confidential 2
- 3. HMB Study at QPS Abbreviations EC = Ethics Committee CA = Competent Authority CPU = Clinical Pharmacology Unit CTP = Clinical Trial Protocol IB = Investigator’s Brochure IMP = Investigational Medicinal Product IMPD = Investigational Medical Product Dossier ICF = Informed Consent Form PI = Principal Investigator UMCG = University Medical Center Groningen QP = Qualified Person 09 October 2014 Confidential 3
- 4. HMB Study at QPS In 10 Steps Step 1: Ethics Committee & Competent Authority Submission Step 2: Receipt and Release of 14C-labeled IMP Step 3: Individual Drug Preparation of 14C-labeled IMP Step 4: Transport and Drug Administration of 14C-labeled IMP Step 5: Collection, Sample Processing and Transport of blood and Human Excreta Step 6: Return and Destruction of 14C-labeled IMP Step 7: Measurement of the 14C-Radioactivity in blood and Human Excreta Step 8 Follow up of Measurement of the 14C-Radioactivity in Human Excreta Step 9: Determination of the total 14C-Radioactivity Recovery Rate Step 10: Disposal of 14C-labeled Human Excreta 09 October 2014 Confidential 4
- 5. HMB Study at QPS Step 1 – Ethics Committee & Competent Authority Submission The application process for a radioactive phase I trial in the Netherlands is essentially the same as for any other non-radioactive phase I trial QPS CPU and Isotope lab are located in the same building and have a permanent license to work with 14C, 3H and other isotopes Written EC and CA approval is routinely obtained within 14 days after submission of the Clinical Trial Application (CTA). Submission documents as part of the Clinical Trial Application are: Clinical Trial Protocol (CTP) Investigator’s Brochure (IB) Investigational Medical Product Dossier (IMPD) Informed Consent Form (ICF) Human Dosimetry Calculation which is done by QPS DMPK group If required, all documents can be written by QPS 09 October 2014 Confidential 5
- 6. HMB Study at QPS Step 2 - Receipt and Release of 14C-labeled IMP Radiopharmacy is located at the premises of the University Medical Center Groningen. QPS CPU is located at the same premises at a distance of approximately 200 meters. QPS has a permanent contract with the Radiopharmacy 14C-labeled IMP is sent from the Sponsor or UK facility (Selcia) to the Radiopharmacy 14C-labeled IMP is placed in quarantine at the Radiopharmacy until release by QP (QPS QP). 14C-labeled IMP is entered in IBC-606 (fully automated & validated Isotope Book Keeping System) of the Radiopharmacy. 09 October 2014 Confidential 6
- 7. HMB Study at QPS Step 3 – Individual Drug Preparation of 14C-labeled IMP Per study subject drug preparation of 14C-labeled study medication is done by the UMCG Radiopharmacist and the QPS Pharmacist. Individual Drug Preparation Forms are prepared by the Clinical Trial Pharmacy of QPS – documents are reviewed by the Radiopharmacy and the Sponsor. Label specifications are prepared according to GMP Annex 13 by the Clinical Trial Pharmacy – documents are reviewed by the Radiopharmacy and Sponsor. Labels are printed (without batch number) by the Clinical Trial Pharmacy. Unique batch numbers will be added in handwriting on the labels during each individual drug preparation. 09 October 2014 Confidential 7
- 8. HMB Study at QPS Step 4 – Transport and Drug Administration of 14C-labeled IMP 14C-labeled study medication, prepared on a per subject basis, is picked up from the Radiopharmacy and transported in a closed Perspex transport box to QPS’s CPU (i.e. the place where drug administration takes place) by Clinical Trial Pharmacy personnel. Administration of the 14C-labeled study medication is always done in the presence of the Authorized User and the PI or a designated Research Physician. Circumstances are essentially the same as for any other non-radioactive phase I trial. Additional hygienic measures are used to prevent radioactive contamination of the CPU. 09 October 2014 Confidential 8
- 9. HMB Study at QPS Step 5 – Collection, Sample Processing and Transport of Radioactive Human Excreta All necessary steps to ensure sample integrity (based on experience obtained from preclinical studies) will be taken during sample collection, sample processing, storage, and shipping to either QPS Isotope laboratory for radioactivity counting or DMPK for metabolic profiling. Selection of samples for metabolic profiling are done by DMPK based on radioactivity levels per sample Collection of blood, urine, feces and expired air takes place in the CPU. Processing of collected blood, urine, expired air and feces samples (i.e. homogenization and aliquoting) takes place in the dedicated Isotope laboratory within the CPU Volunteers are discharged from the clinic after at least 85 % (or more if the study protocol requires to do so) of the total dose of radioactivity has been recovered in the excreta from the volunteer. Radioactive human excreta and/or aliquots, not needed for radioactivity counting, remain stored in the CPU Isotope laboratory until shipment or destruction. 09 October 2014 Confidential 9
- 10. HMB Study at QPS Step 6 - Return and/or Destruction of 14C-labeled IMP Returned/(partially) used 14C-labeled study medication is picked up from the CPU (i.e. the place where drug administration takes place) and transported in a closed Perspex box back to the Radiopharmacy by Clinical Trial Pharmacy personnel. Returned/(partially) used 14C-labeled study medication, if any, is stored in a closed Perspex box in a locked cabinet in the Radiopharmacy until approval for destruction has been received from the Sponsor. Returned /(partially) used 14C-labeled study medication is considered and handled as radioactive waste for which the Dutch guidance on radioactive health and safety applies. 09 October 2014 Confidential 10
- 11. HMB Study at QPS Step 7 – Measurement of the 14C-Radioactivity in Human Excreta After samples have been processed in the CPU, all necessary further sample preparations prior to the actual measurement of 14C-radioactivity are done by laboratory technicians from QPS own Isotope laboratory who are GLP trained. They work in accordance with the particular Assays Instruction(s) as required by the Bioanalytical Protocol of the concerned study. The measurement of 14C-radioactivity in human study samples is performed on a beta-counter (Tricarb 2500) in the same Isotope laboratory. Measurements include so called “quick counts” to verify subject’s discharge criteria from the CPU as well as all counting for the entire mass balance determination 09 October 2014 Confidential 11
- 12. HMB Study at QPS Step 8 – Follow up of Measurement of the 14C-Radioactivity in Human Excreta Results of radioactivity counting are evaluated by our own DMPK group. They will select samples from the appropriate matrixes for metabolite identification/profiling Selected samples will be shipped from the Isotope laboratory Results are described in analytical reports whereas the appropriate PK evaluations will be carried out and reported by our PK group 09 October 2014 Confidential 12
- 13. HMB Study at QPS Step 9 – Determination of the total 14C-Radioactivity Recovery Rate Determination of the total 14C-radioactivity recovery rate is done by the Statistics Department of QPS using validated excel sheets. The total recovery rate from urine, feces and expired air samples will be calculated during the last 24-hour interval of hospitalization on the basis of quick count determinations. This percentage of 14C-radioactivity recovery will be used as the discharge criterion for the volunteer in the clinic. The 14C-radioactivity recovery from all human excreta at all sampling times and intervals will be documented in a validated excel sheet. PK on total radioactivity will be calculated by QPS Pharmacokineticist Results will be reported in a Clinical Study Report 09 October 2014 Confidential 13
- 14. HMB Study at QPS Step 10 – Disposal of Radioactive Human Excreta All radioactive human excreta collected during mass balance studies will be treated as radioactive waste and handled according to the Dutch guidance on radioactive health and safety. 09 October 2014 Confidential 14
- 15. HMB Study at QPS Campus of the University Medical Center Groningen Clinical Pharmacology Unit Isotope Laboratory Radiopharmacy Clinical Trial Pharmacy 09 October 2014 Confidential 15
- 16. HMB Study at QPS Functions Involved – Roles & Responsibilities Functions Physical Location & Affiliation Roles & Responsibilities Synthesis Laboratory Selcia, UK Synthesis of radiolabeled IMP, GMP quality Radiopharmacy UMCG Radiopharmacy Receipt and Release of 14C-labeled IMP Individual Drug Preparation of 14C-labeled IMP Return and/or Destruction of 14C-labeled IMP Clinical Trial Pharmacy QPS Clinical Trial Pharmacy Transport of 14C-labeled IMP Individual Drug Preparation Forms Label Specifications according to GMP Annex 13 Clinical Pharmacology Unit QPS Clinical Pharmacology Unit Drug Administration of 14C-labeled IMP Sample Collection and Processing of Radioactive Human Excreta (blood, urine, feces and expired air) Isotope Laboratory QPS Isotope Laboratory Processing of Radioactive Human Excreta Sample preparation and actual radioactivity counting 09 October 2014 Confidential 16
- 17. HMB Study at QPS Functions Involved – Roles & Responsibilities (cont.) Functions Physical Location & Affiliation Roles & Responsibilities DMPK QPS DMPK Sample selection for metabolic profiling Metabolic profiling and reporting of results PK QPS PK Pharmacokinetic evaluation and reporting on parent compound and metabolites, if applicable Statistics QPS Biometrics Department Determination of the total 14C-Radioactivity Recovery Rate 10-10-14 Confidential 17
- 18. Contact Corporate Office Delaware Technology Park 3 Innovation Way, Suite 240 Newark, DE 19711 info@qps.com Tel: + 1 302 369 5601 www.qps.com 09 October 2014 Confidential 18