Application of Quality by Design Principles to Support Development of a Control Strategy for the Control of Genotoxic Impurities in the Manufacturing Process of a Drug Substance

Cimarosti, Zadeo; Bravo, Fernando; Stonestreet, P.; Tinazzi, Francesco; Vecchi, Orsola; Camurri, Giulio

doi:10.1021/op900242x

Cited by 42 publications

(41 citation statements)

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“…Furthermore, a Quality by Design (QbD) approach can also be applied to control GTI formation. 26 Many purification steps (i.e. crystallization, solvent liquid-liquid extraction, precipitation, distillation, column chromatography, etc.)…”

Section: Key Pointsmentioning

confidence: 99%

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

Lapanja¹,

Časar²,

Jurca³

et al. 2017

ACSi

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Mutagenic impurities (MIs) are of serious concern for pharmaceutical industry, regulatory agencies and public health. The first guideline addressing the control of genotoxic impurities (GTIs) dates back to 2006. Since then there have been several updates and refinements, which eventually resulted in the guideline, published by the International Conference on Harmonisation (ICH) in June 2014. The ICH M7 guideline, compared to previous ones, offers greater flexibility in terms of control strategies for GTIs in drug substances. More specifically, it describes a control strategy that relies on process controls in lieu of analytical testing which is based on understanding the process chemistry and process parameters that impact the levels of GTIs. This principle is adopted in the theoretical purge factor determination tool proposed by Teasdale et al. Several case studies applying the proposed theoretical purge factor determination tool were published in recent years. The results confirm the tool's good predictability of the extent to which the impurity is removed by the process. Hopefully, this approach will soon be released as an in-silico tool, generally accepted by the regulatory agencies.

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Section: Key Pointsmentioning

confidence: 99%

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

Lapanja¹,

Časar²,

Jurca³

et al. 2017

ACSi

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“…Furthermore, a quality by design (QbD) approach can contribute to better control of GTIs. 266 4.1.1. Altering the Synthesis.…”

Section: Chemical Synthetic Approachesmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

et al. 2015

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alkylation of the second nitrogen of the piperazine ring with the genotoxic reagent 4-chloro-1-bromobutane (Scheme 10). 64 APIs streams may contain genotoxic alkyl halides impurities when a reaction takes place in alcoholic solvent at reflux temperature in the presence of hydrogen halides or alkali halides and strong acids. These reaction conditions may be applied in cyclization, decarboxylation, sulfonyl cleavage, Narylation and API salt formation. Note that this list is not exhaustive. For instance, capecitabine is a chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. 65 During its synthesis, D-ribose is heated under reflux in methanol in the presence of concentrated HCI and acetone Scheme 2. O-Alkylation of Isovanillin during the Synthesis of Aliskiren Using Genotoxic 1,3-Dibromopropane Scheme 3. Use of Methyl Iodide in the Preparation of Cerivastatin Scheme 4. S-Alkylation with Methyl Iodide during the Last Synthetic Step of Lamifiban Scheme 5. S-Alkylation with Methyl Iodide during the Synthesis of Eldacimibe Scheme 6. N-Methylation with Genotoxic Methyl Iodide during the Preparation of Efegatran Scheme 7. Quaternization by Means of Methyl Iodide during Milameline Synthesis Scheme 8. Direct Use of Genotoxic 2-Iodopropane in the Synthesis of Latanoprost Scheme 9. Use of Genotoxic 2-Bromopropane and Nitrogen Mustard during the Synthesis of Mazapertine

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“…However, the available in vitro and animal data indicated that the levels at which HIV patients were exposed to EMS (maximal dose of 0.055 mg/kg/d) did not induce any risk; nevertheless, any further level was of significant concern to their safety (Elder and Snodin, 2009). Since 2007 other drugs have been reported for contamination by sulfonate impurities, such as alkyl benzene sulfonates in amlodipine besylate , dimethyl sulfate (DMS) in pazopanib hydrochloride (Liu et al, 2009), EMS and methyl methane sulfonate (MMS) in imatinib mesylate , EMS in zugrastat (Schülé et al, 2010), alkyl sulfonates in flouroaryl-amine (Cimarosti et al, 2010), and ethyl besylate in UK-369,003-26, a novel PDE5 inhibitor (Hajikarimian et al, 2010). EMS is a well-established genotoxic agent in this group which reacts with DNA producing alkylated (specifically ethylated) nucleotides.…”

Section: Genotoxic Impurities (Gis)mentioning

confidence: 99%

Genotoxic Impurities in Pharmaceuticals

Jouyban¹,

Parsa²

2012

Toxicity and Drug Testing

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Application of Quality by Design Principles to Support Development of a Control Strategy for the Control of Genotoxic Impurities in the Manufacturing Process of a Drug Substance

Cited by 42 publications

References 1 publication

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

Genotoxic Impurities in Pharmaceuticals

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