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388 Toxicity and Drug Testing, safety topics deal with in vitro and in vivo pre clinical studies carcinogenicity testing. genotoxicity testing etc ICH 2008, The ICH initially published guidelines on impurities of drug substances and pharmaceutical. products in the late 1990s In the guidelines genotoxicity tests have been defined as in vitro. and in vivo tests designed for detecting compounds that induce genetic damage directly or. indirectly International Conference on Harmonization 1997 The ICH quality guidelines. Q3A R and Q3B R respectively address the topics of control of impurities in drug. substances and degradants in pharmaceutical products while the Q3C guideline deals with. the residual solvents However several important issues have not been addressed in the. guidelines for example the acceptable levels of impurities in drugs during development as. well as the control of genotoxic impurities Table 1 illustrates a series of thresholds described. in ICH Q3A R that trigger reporting identification and qualification requirements. Subsequently Table 2 depicts the thresholds for reporting identification and qualification. of impurities in new drug products ICH 2006 Jacobson Kram and McGovern 2007 In. addition two options for standard test battery for genotoxicity are available in the ICH S2. R1 guideline ICH 2008,Maximum daily dose,Thresholds. 2 g day 2 g day,Reporting threshold 0 05 0 03,0 10 or 1 0 mg per day intake. Identification threshold 0 05,whichever is lower,0 15 or 1 0 mg per day intake.
Qualification threshold 0 05,whichever is lower,Table 1 Threshold for APIs. i A test for gene mutation in bacteria, ii A cytogenetic test for chromosomal damage the in vitro metaphase chromosome. aberration test or in vitro micronucleus test or an in vitro mouse lymphoma tk gene. mutation assay, iii An in vivo test for genotoxicity generally a test for chromosomal damage using rodent. hematopoietic cells either for micronuclei or for chromosomal aberrations in metaphase. i A test for gene mutation in bacteria, ii An in vivo assessment of genotoxicity with two tissues usually an assay for micronuclei. using rodent hematopoietic cells and a second in vivo assay. As stated by the ICH safety guidelines S2A and S2B for compounds giving negative. results the completion of 3 test battery perform and evaluate in accordance with current. recommendations will usually provide a sufficient level of safety to demonstrate the. absence of genotoxic activity Thus any compound that produces a positive result in one or. more assays in the standard battery has historically been regarded as genotoxic which may. require further testing for risk assessment M ller et al 2006. www intechopen com,Genotoxic Impurities in Pharmaceuticals 389.
Maximum Reporting Identification Thresholds2 3 Qualification Thresholds2 3. Daily Dose1 Thresholds2 3,1 mg 1 0 or 5 g TDI,whichever is lower. 1 10 mg 0 5 or 20 g TDI,whichever is lower,10 100 mg 0 5 or 200 g TDI. whichever is lower,10 mg 1 0 or 50 g TDI,whichever is lower. 10 mg 2 g 0 2 or 2 mg TDI,whichever is lower,100 mg 2 g 0 2 or 3 mg TDI. whichever is lower, 1The amount of drug substance administered per day.
2Thresholds for degradation products are expressed either as a percentage of the drug substance or as a. total daily intake TDI of the degradation product Lower thresholds can be appropriate if the. degradation product is unusually toxic, 3Higher thresholds should be scientifically justified. Table 2 Thresholds for degradation products in new drug products Jacobson Kram and. McGovern 2007,2 2 EMEA guideline, The European Medicines Agency EMEA guideline describes a general framework and. practical approaches on how to deal with genotoxic impurities in new active substances. According to the guideline The toxicological assessment of genotoxic impurities and the. determination of acceptable limits for such impurities in active substances is a difficult issue. and not addressed in sufficient detail in the existing ICH Q3X guidance In addition the. EMEA guideline proposed a toxicological concern TTC threshold value of 1 5 g day intake. of a genotoxic impurity which is considered to be associated with an acceptable risk excess. cancer risk of 1 in 100 000 over a lifetime in most pharmaceuticals Based on the TTC value a. permitted level of an active substance can be calculated concerning the expected daily dose. Higher limits might be justified under certain conditions such as short term exposure periods. European Medicines Agency Committee for Medicinal Products CHMP for Human Use. 2006 In the context of this guideline the classification of a compound impurity as genotoxic. in general indicates that there are positive findings in established in vitro or in vivo genotoxicity. tests with the focus on DNA reactive substances that have a potential for direct DNA damage. In the absence of such information in vitro genotoxics are usually considered as presumptive. in vivo mutagens and carcinogens EMEA CHMP 2006,www intechopen com. 390 Toxicity and Drug Testing, Based on the importance of the mechanism of action and the dose response relationship in. the assessment of genotoxic compounds the EMEA guideline presents two classes of. genotoxic compounds, 1 Genotoxic compounds with sufficient experimental evidence for a threshold related.
2 Genotoxic compounds without sufficient experimental evidence for a threshold. related mechanism, Those genotoxic compounds with sufficient evidence would be regulated according to the. procedure as outlined for class 2 solvents in the Q3C Note for Guidance on Impurities. Residual Solvents For genotoxic compounds without sufficient evidence for a threshold. related mechanism the guideline proposes a policy of controlling levels to as low as. reasonably practicable ALARP principle where avoiding is not possible. On the other hand this guideline provides no advice on acceptable TTCs for drugs during. development especially for trials of short duration Jacobson Kram and McGovern 2007. The pharmaceutical research and manufacturing association PhRMA has established a. procedure for the testing classification qualification toxicological risk assessment and. control of impurities processing genotoxic potential in pharmaceutical products As most. medicines are given for a limited period of time this procedure proposes a staged TTC to. adjust the limits for shorter exposure time during clinical trials Table 3 Thus the staged. TTC can be used for genotoxic compounds having genotoxicity data that are normally not. suitable for a quantitative risk assessment Muller et al 2006. Duration of clinical trial exposure,1 1 3 3 6 6 12 12. month month month month month,Allowable Daily Intake 120 60 20 10 1 5. g day for all phases of,development,Alternative maximum level of 0 5 0 5 0 5 0 5 0 5. allowable impurity based on,percentage of impurity in API.
Table 3 PhRMA genotoxic impurity task force proposal allowable daily intake g day. for genotoxic impurities during clinical development using the staged TTC approach. 3 Genotoxic impurities GIs,3 1 Sulfonates, Sulfonate salts Figure 1 are the most frequently used compounds in pharmaceutical. developments Salt formation is a useful technique for optimizing the physicochemical. processing formulation biopharmaceutical or therapeutic properties of active. pharmaceutical ingredients APIs and sulfonate salts are widely used for this purpose. Elder and Snodin 2009 In addition to the advantages of processing sulfonate salts. possess some advantages over other salts such as producing higher melting point of the. sulfonated API This helps to enhance the stability and provide good solubility and may. have certain in vivo advantages as well For instance in contrast to other salts of strong. acids mesylates do not have a tendency to form hydrates which makes them an attractive. www intechopen com,Genotoxic Impurities in Pharmaceuticals 391. salt form for secondary processing especially wet granulation Another benefit of these salts. is their high melting point because APIs with low melting points often exhibit plastic. deformation during processing which can cause both caking and aggregation Typically an. increase in the melting point has an adverse effect on aqueous solubility owing to an. increase in the crystal lattice energies Sulfonic acid salts tend to be an exception to this rule. since they exhibit both high melting points as well as good solubility In addition as. mentioned in the literature the high solubility and high surface area of haloperidol mesylate. result in enhanced dissolution rates 2 min in pH 2 simulated gastric media which are. more rapid than the competing common ion formation Elder and Snodin 2009 Elder et al. On the other hand sulfonic acids can react with low molecular weight alcohols such as. methanol ethanol or isopropanol to form the corresponding sulfonate esters In general. sulfonic acid esters are considered as potential alkylating agents that may exert genotoxic. effects in bacterial and mammalian cell systems and possibly carcinogenic effects in vivo. thus these compounds have raised safety concerns in recent times Snodin 2006 Teasdale et. Mesyla Tosylate Besylate,Fig 1 Structures of common sulfonate salts. 3 1 1 Genotoxicity profile, Sulfonate impurities comprise the most investigated group of genotoxic impurities GIs. Initially in 2007 sulfonate impurities raised major concern when over a period of three. months March to May 2007 several thousand HIV patients in Europe were exposed to. ViraceptR nelfinavir mesylate tablets containing the contaminant ethyl methane sulfonate. EMS 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 Raman et al 2008. dimethyl sulfate DMS in pazopanib hydrochloride Liu et al 2009 EMS and methyl. methane sulfonate MMS in imatinib mesylate Ramakrishna et al 2008 EMS in zugrastat. Sch l 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 MMS an analog of EMS is a genotoxic. compound both in vitro and in vivo The international agency for research on cancer IARC. has classified EMS and MMS in group 2B and 2A respectively Snodin 2006 Gocke et al. www intechopen com,392 Toxicity and Drug Testing, Gocke et al 2009a reviewed both in vivo and in vitro genotoxicity carcinogenicity general.
toxicity and the effects on reproductive and embryo fetal development of EMS They. reported that the genotoxic effects induced by EMS were observed in viruses phages. bacteria fungi plant insect and mammalian cells In another study the induction of gene. mutations at the hprt locus and the induction of chromosomal damage were examined as. evidenced by the formation of micronuclei in human lymphoblastoid cells It was found that. the lowest dose inducing a positive response was 1 40 g ml and a no observed effect level. NOEL could be defined at 1 2 g ml Also no toxicity was observed at doses up to 2 5. g plate This observation is in strong contrast to the largely linear dose response observed. in the previous studies As a result of in vivo assays for the induction of DNA damage EMS. is distributed rather uniformly over the body and induces similar levels of DNA damage in. the various organs Also EMS is clastogenic in all test systems The minimal dose of EMS. applied in these studies was either 50 mg kg or 100 mg kg In the majority of studies the. dose response relationships appeared sub linear and a threshold below 50 mg kg appeared. possible Gocke et al 2009a demonstrated that EMS in various gene mutation tests such as. induction of hprt lacZ and dlb 1 mutations in mice was mutagenic The carcinogenicity of. EMS was confirmed in several animal models In another study three methanesulfonates. and three benzenesulfonates were tested by micronucleus and Yeast deletion recombination. DEL assays It was observed that all six substances produced positive responses in the tests. Sobol et al 2007,3 2 Alkyl halides and esters, Owing to their electrophilic nature alkylating agents can introduce lesions at nucleophilic. centers of DNA Drug salt formation includes strong acid base interactions in the presence. of alcohols and can form impurities such as alkyl halides As salt formation is a common. method in drug formulation processes alkyl halides exist as impurities in several drugs. Sobol et al 2007 Elder et al 2008a,3 2 1 Genotoxicity profile. The nucleophilic attack mechanisms of alkylating compounds determine their reactivity. against DNA The SN1 mechanism leads to O alkylation O 6 methylguanine which is. mutagenic but not clastogenic whereas the SN2 mechanism leads to N methylation which is. clastogenic and not mutagenic In this group it seems that bromo compounds are more. reactive as compared to chloro compounds Sobol et al 2007 Snodin 2010. Genotoxic Impurities in Pharmaceuticals Abolghasem Jouyban 1 and Hamed Parsa 2 1Drug Applied Research Center and Faculty of Pharmacy 2Tuberculosis and Lung Disease Research Center Tabriz University of Medical Sciences Tabriz Iran 1 Introduction Genotoxic compounds induce genetic mutation s and or chromosomal rearrangements and can therefore act as carcinogenic compounds McGovern an d

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