QPS Human Mass Balance Presentation

In 10 stepsHuman Mass Balance Study

09 October 2014 1Confidential

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

HMB Study at QPS

AbbreviationsEC = 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


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

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 groupIf required, all documents can be written by QPS


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.


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.


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.


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.


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.


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


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


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


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.


HMB Study at QPS

Campus of the University Medical Center Groningen


Clinical Pharmacology Unit

Isotope Laboratory

Radiopharmacy

Clinical Trial Pharmacy

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

HMB Study at QPS

Functions Involved – Roles & Responsibilities (cont.)

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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

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QPS Human Mass Balance Presentation

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