Synthesis of Radiolabelled Compounds for Clinical Studies

Atzrodt, Jens; Derdau, Volker; Loewe, Claudia

doi:10.1007/978-3-319-56637-5_12-1

Cited by 7 publications

(8 citation statements)

References 64 publications

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“…Peptides can be labelled with radioactive 14 C to track the passage of the biomolecule through a biological system. 6 The manufacture of these 14 C-peptides is custom made to the clients' requirements, with regard to the position of the labelled amino acid. The requested labelled amino acid may have a single 14 C-label or multiple 14 C-labels.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of carbon‐14–labelled peptides

Dell'Isola

Brown

Jones

et al. 2019

Labelled Comp Radiopharmac

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Carbon‐14 (14C)–labelled active pharmaceutical ingredients (APIs) and investigational medicinal products (IMPs) are required for phase 0/I to phase III mass balance and micro‐dosing clinical trials. In some cases, this may involve the synthesis of 14C‐labelled peptides, and the analysis can be performed by accelerated mass spectrometry (AMS). The 14C‐peptide is typically prepared by the solid‐phase peptide synthesis (SPPS) approach using custom‐made glassware for the key coupling steps. Further modification of the purified 14C‐peptide can then be performed.

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Section: Discussionmentioning

confidence: 99%

Synthesis of carbon‐14–labelled peptides

Dell'Isola

Brown

Jones

et al. 2019

Labelled Comp Radiopharmac

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“…Based on the ICH Guidelines Q3A ‘ Impurities in New Drug Substances ’ and Q6A ‘ Specifications in New Drug Substances ’ the limit for an unspecified impurity (related substance) in drug substances for phase I/IIa/IIb is set at 0.1%, the same threshold being valid for the diluted radioactive drug substance (rDS). Assuming that the hrDS forms less than 10% of the rDS, even in a worst‐case scenario with a single 1% impurity in the hrDS, dilution would result in only 0.1% impurity in the final rDS (see Scheme ) …”

Section: Methodsmentioning

confidence: 99%

“…Assuming that the hrDS forms less than 10% of the rDS, even in a worst-case scenario with a single 1% impurity in the hrDS, dilution would result in only 0.1% impurity in the final rDS (see Scheme 1). 12 This argument was accepted by our local German authorities, and thus for oral drugs when hrDS forms less than 10% of the rDS, only the purification and dilution steps have to be executed as a formal GMP process. Only in the rare cases were hrDS makes up more than 10% of the rDS does an additional GMP covalent bond modification step become necessary.…”

mentioning

confidence: 99%

Conception, realization and qualification of a radioactive clean room lab facility dedicated to the synthesis of radiolabeled API for human ADME studies

Loewe

Atzrodt

Reschke

et al. 2016

Labelled Comp Radiopharmac

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The human absorption, distribution, metabolism and elimination study administering radiolabeled drugs to human volunteers is an important clinical study in the development program of new drug candidates. The manufacture of radiolabeled Active Pharmaceutical Ingredients is covered by national drug laws and may come within the scope of regulatory GMP requirements. Additionally, authorities may request an appropriate environmental zoning to minimize the risk of microbiological contaminations particularly during the synthesis of radiolabeled Active Pharmaceutical Ingredients intended for parenteral application. Thus, a radioactive clean room lab facility in line with both GMP and radiation safety regulations was installed and the environmental zoning validated by appropriate testing of technical parameters and microbial and particle monitoring. The considerations detailed in this paper cover only GMP aspects related to the synthesis of radioactive drug substance. The subsequent, final formulation step in the overall process for manufacturing of radioactive drug product for any kind of administration is not within the scope of this paper. Under these qualified and controlled environmental conditions, we are now in a position to provide radiolabeled drug substances for all kinds of drug administration including both po and iv.

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“…Although the radioactive dose utilized in a microtracer study is low enough to fall within range of normal background variation, administration of radioactive drugs at pharmacological cold dose levels still requires an appropriate CMC dataset. Clinical studies involving radioactive dose administration require approval by a special ethics committee as well as submission and approval of Investigational New Drug Application (IND, US) or Investigational Medicinal Product Dossier (IMPD, EU) (Atzrodt et al 2017). Regulatory requirements related to Good Manufacturing Practices (GMP) for radiolabeled drugs are not clearly defined.…”

Section: Introductionmentioning

confidence: 99%

CMC development of [14C]-labeled sotorasib for the conduct of microtracer human ADME study

et al. 2023

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Human absorption, distribution, metabolism, and excretion (hADME) studies of new drugs are required for global regulatory filings. Recent advances in high sensitivity analytical technologies have enabled microtracer hADME studies wherein very low radioactive doses can be administered to healthy volunteers to study drug pharmacokinetic profile. Microtracer hADME studies are advantageous to accelerate study timelines during drug development. However, there are limited examples in peer-reviewed journals that highlight the key chemistry, manufacturing, and control (CMC) development challenges and requirements for enabling these clinical microtracer hADME studies. The current manuscript summarizes the CMC activities, risk assessment, and mitigation strategies that were put in place and executed to enable and accelerate the microtracer hADME study of [14C]-labeled sotorasib (AMG 510, compound 1). Sotorasib is a first in class KRASG12C inhibitor used to treat non-small cell lung cancer (NSCLC) in patients with a KRASG12Cmutation (Canon et al., Nature 575:217–223, 2019). The key CMC activities included the synthesis of low nanocurie [14C]-labeled AMG 510 drug substance, development of a drug-in-bottle (DIB) formulation, use of simulation software to predict absorption profiles, associated drug substance and drug product analytical control strategies development, and the utilization of accelerator mass spectrometry (AMS) as a CMC tool enabling low radioactive strength formulation analysis.

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Synthesis of Radiolabelled Compounds for Clinical Studies

Cited by 7 publications

References 64 publications

Synthesis of carbon‐14–labelled peptides

Synthesis of carbon‐14–labelled peptides

Conception, realization and qualification of a radioactive clean room lab facility dedicated to the synthesis of radiolabeled API for human ADME studies

CMC development of [14C]-labeled sotorasib for the conduct of microtracer human ADME study

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