ABSTRACT
Several regulatory guidelines [1-10] recommend quantitative exposure limits of impurities or toxic chemicals This chapter provides a collection of tables with the recommended and calculated exposure limits that are relevant to impurities and genotoxic impurities, to serve as a systematic reference Different terminologies are used to describe the quantitative exposure limits by regulatory authorities, and some of the terms are listed in Table 31 for comparison
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q3A guideline Impurities in New Drug Substances [1] recommends reporting, identification, and qualification thresholds in drug substances, as shown in Table 32 The threshold values depend on the maximum daily dose (MDD) In Table 33, calculated values of the impurity thresholds are shown based on the MDD, in percentage or in milligrams as appropriate
The ICH Q3B guideline Impurities in New Drug Products [2] recommends reporting, identification, and qualification degradation product thresholds in drug products, as shown in Table 34 The threshold values depend on the MDD In Table 35, calculated values of the degradation product thresholds are shown based on the MDD, in percentage or in milligrams as appropriate
The ICH Q3C guideline Impurities: Guideline for Residual Solvents [3] classifies solvents by risk assessment and recommends concentration limits based on permitted daily exposure (PDE) and daily dose The concentration limits recommended
References 175
TABLE 3.2 ICH Q3A: Thresholds of Impurities in New Drug Substances
TABLE 3.1 Terminologies Used to Describe Quantitative Exposure Limits by Regulatory Authorities
TABLE 3.3 ICH Q3A: Impurity Thresholds Based on Maximum Daily Dose
TABLE 3.4 ICH Q3B: Thresholds for Degradation Products in New Drug Products
TABLE 3.5 ICH Q3B: Degradation Product Thresholds Based on MDD
are shown in the ICH Q3C section of Chapter 1 Two options are described for setting limits for class 2 solvents The concentration limit is calculated from PDE and administered daily dose (equation follows), and option 1 is based on a 10 g daily dose:
=
× Concentration(ppm)
1000 PDE(mg/day)
Dose(g/day)
No further calculation is necessary to use option 1 concentration limits, provided that the daily dose does not exceed 10 g Products that are administered in doses greater than 10 g/day should be considered under option 2 Using option 2, PDE (in milligrams per day) can be used with the known MDD and the aforementioned equation to determine the concentration of residual solvent allowed in a drug product Such limits are considered acceptable provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum Concentration limits for class 2 solvents, shown in Table 36, were calculated using option 2 with PDE and MDD values
Inorganic impurities can result from the manufacturing process, and they are normally known and identified Inorganic impurities include reagents, ligands, catalysts, heavy metals, and inorganic salts The United States Pharmacopeia (USP) General Chapter 232 recommends permissible daily exposure (PDE) for elemental impurities [9], as shown in Table 37 The European Medicines Agency (EMA) guidelines on the specification limits for residues of metal catalysts [8] classify metals into one of the following three classes:
Class 1 metals: metals of significant safety concern Known or suspect human carcinogens, or possible causative agents of other
significant toxicity Class 2 metals: metals with low safety concern
Metals with lower toxic potential to man They are generally well tolerated up to exposures that are relevant to the context of the guidelines They may be trace metals required for nutritional purposes, or they are often present in foodstuff or readily available nutritional supplements
Class 3 metals: metals with minimal safety concern Metals with no significant toxicity Their safety profile is well established
They are generally well tolerated up to doses that are well beyond the doses relevant to the context of the guidelines Typically, they are ubiquitous in the environment or the plant and animal kingdoms
Table 38 shows the recommendation of maximum acceptable limits of metal residues as described in the EMA guideline It should be noted that an adult body weight of 50 kg was used in the PDE considerations of this EMA guideline
The USP and EMA guidelines include the concentration limits of metals based on a 10 g MDD Both the USP and EMA guidelines state that the option 2 approach (as described earlier for class 2 solvents in ICH Q3C) is acceptable, which determines the concentration limit based on PDE and MDD values As can be seen in
TABLE 3.6 Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
TABLE 3.6 (Continued ) Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
TABLE 3.6 (Continued ) Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
TABLE 3.6 (Continued ) Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
TABLE 3.6 (Continued ) Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
TABLE 3.6 (Continued ) Concentration Limits (in Parts per Million) for Class 2 Solvents Based on Option 2, ICH Q3C, [PDE (mg/day)]
Tables 37 and 38, the metals included in the two guidelines do not match and some of the recommended PDE values differ between the two guidelines (eg, the oral daily dose PDE for nickel is 500 µg/day according to the USP, whereas the oral PDE is 300 µg/day according to the EMA) Concentration limits (in parts per million) based on MDD values were calculated using PDE values recommended by either USP or EMA guidelines and are shown in Table 39 International efforts to harmonize the guidances for elemental impurities are in progress, and the step 2 version of the ICH Q3D guideline for elemental impurities is currently available The permitted daily exposures recommended in the ICH Q3D draft guideline are shown in Table 310 as reference
A threshold of toxicological concern (TTC) was developed to establish a common exposure level for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects [4,11] This TTC value was estimated to be 15 µg/ person/day The TTC, originally developed as a “threshold of regulation” at the Food and Drug Administration (FDA) for food-contact materials, was established based on the analysis of 343 carcinogens from a carcinogenic potency database (CPDB) and was repeatedly confirmed by evaluations expanding the database to more than 700 carcinogens The probability distribution of carcinogenic potencies has been used to derive an estimate of a daily exposure level of most carcinogens, which would give rise to less than a 1 in 106 (1 × 106) upper-bound lifetime risk of cancer (“virtually safe dose”) Further analysis of subsets of high-potency carcinogens led
TABLE 3.7 Elemental Impurities for Drug Products, UPS 232
to the suggestion of a 10-fold lower TTC (015 µg/day) for chemicals with structural alerts that raise concern for potential genotoxicity However, for the application of a TTC in the assessment of acceptable limits of genotoxic impurities in drug substances, a value of 15 µg/day, corresponding to a 10−5 lifetime risk of cancer, can be justified as for pharmaceuticals a benefit exists It should be recognized that the methods on which the TTC value is based are generally considered very conservative since they involved a simple linear extrapolation (LE) from the dose giving a 50% tumor incidence (TD50) to a 1 in 106 incidence, using TD50 data for the most sensitive species and the most sensitive site (several worst-case assumptions)
Acceptable genotoxic impurity levels during clinical development are recommended in the FDA draft guideline [6] The most pragmatic approach to calculate acceptable short-term exposures to known genotoxic carcinogens is to linearly extrapolate the short-term exposure from the acceptable lifetime exposure or virtually safe dose The acceptable daily intakes (ADIs) (also termed “acceptable qualification thresholds” in the FDA guideline) of genotoxic impurities during clinical development are shown in Table 311, based on the LE approach The impurity threshold exposures for exposure durations of up to 12 months are based on a 10−6 cancer risk level (015 µg/day for lifetime exposure), since these trials often include healthy subjects for whom there is no expected health benefit and the efficacy of the drug may still be uncertain The values are derived from a LE from the
TABLE 3.8 Class Exposure and Concentration Limits for Individual Metal Catalysts and Metal Reagents, EMA
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The EMA Committee for Medicinal Products for Human Use agrees with the use of a staged TTC (sTTC) concept during clinical development, as described
TABLE 3.10 Permitted Daily Exposures for Elemental Impurities,a ICH Q3D Draft Guideline
in the EMA Q&A document on genotoxic impurities [5] The allowable daily intake (ADI) values are shown in Table 311 in comparison with the FDA guideline The concentration limits (in parts per million) calculated using MDD and ADI (“acceptable daily intake” according to the FDA, and “allowable daily intake” according to the EMA) values for genotoxic and carcinogenic impurities are shown in Table 312
TTC is a pragmatic risk assessment tool that can be used to assess the likelihood of toxic effects of a particular level of exposure to a chemical, in the absence of chemical-specific toxicity data [11] The TTC concept reduces unnecessary extensive toxicity testing and safety evaluations, and it enables focused use of limited resources (time, animal use, cost, and expertise) on substances with greater potential risks to human health Application of the TTC principle would set priorities for toxicity testing and could be used to indicate analytical data needs It is considered a preliminary step in safety assessment The TTC values were derived after the evaluation of over 700 compounds extracted from the Gold carcinogenic potency database (also known as the “Gold database”) [12,13], as described in Chapters 15, 16, 17, and 18
The CPDB was developed by Gold and others [12,13], and it is publicly available on the Internet The database includes Ames test results and TD50 and target sites on 1547 compounds currently TD50 is defined as “chronic dose-rate in mg/kg body wt/day which would induce tumors in half the test animals at the end of a standard lifespan for the species” or more precisely “dose-rate in mg/kg body wt/day which, if administered chronically for the standard lifespan of the species, will halve the probability of remaining tumorless throughout that period”
TABLE 3.11 Comparison of the sTTC Values in FDA and EMA Guidelines
TABLE 3.12 Genotoxic Impurities Concentration Limits (in Parts per Million) Based on MDD and ADI
Selected compounds from the CPDB [12] that are pharmaceutically relevant are presented in Table 313 These compounds include possible raw materials, reagents, catalysts, solvents, by-products, intermediates in drug substance synthesis, pharmaceutical agents, or compounds that would provide guidance on genotoxicity as a representative of chemical functionality When a compound contains HCl in the salt form, HCl is omitted from the structure for simplicity of presentation in Table 313 When there are several compounds with similar structures (such as positional isomers) in the CPDB, the compounds with the most potent TD50 values are presented in Table 313 Generally, compounds that have either positive mutagenicity results or TD50 values (in rats and/or mice) are chosen Some pharmaceutically relevant compounds that show no mutagenicity are included to serve as references for risk evaluation purposes
Three structural classes were mentioned as high-potency carcinogens (cohort of concern) in EMA and FDA guidelines, that is, aflatoxin-like, N-nitroso, and azoxy compounds The compounds that belong to the three classes are noted as “highpotency carcinogens” in Table 313
For mutagenic compounds with TD50 data, a compound-specific acceptable exposure was calculated based on the rodent carcinogenicity potency data (TD50) in Table 314, using the simple LE procedure employed to derive the TTC At TD50, one in two animals will develop cancer over its lifetime The cancer risk of 1 in 105 is then calculated by dividing TD50 by 50,000, corresponding to the LE from a 1 in 2 to a 1 in 100,000 risk of cancer This is the LE method used to derive the TTC from the TD50 values of the compounds in the CPDB [11] An example of the LE calculations for ethylene oxide is shown in Note 4 of the ICH M7 step 2 document [7] and is repeated here It should be noted that the ICH M7 draft guideline is under development and is subject to change
ICH M7 Step 2 Note 4: Example of linear extrapolation from the TD50 It is possible to calculate a compound-specific acceptable intake based on rodent
carcinogenicity potency data such as TD50 values (doses giving a 50% tumor incidence equivalent to a cancer risk probability level of 1:2) Linear extrapolation to a probability of 1 in 100,000 (ie, the accepted lifetime risk level used) is achieved by simply dividing the TD50 by 50,000 This procedure is similar to that employed for derivation of the TTC
Calculation example: Ethylene oxide TD50 values for ethylene oxide according to the Carcinogenic Potency database
[12] are 213 mg/kg body weight/day (rat) and 637 mg/kg body weight/day (mouse) For the calculation of an acceptable intake, the lower (ie, more conservative) value of the rat is used
To derive a dose to cause tumors in 1 in 100,000 animals, divide by 50,000:
213 mg/kg ÷ 50,000 = 042 µg/kg
To derive a total human daily dose,
×042 µg/kg/day 50 kg Body Weight = 213 µg/person/day
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Hence, a daily lifelong intake of 213 µg ethylene oxide would correspond to a theoretical cancer risk of 10−5 and therefore be an acceptable intake when present as an impurity in a drug substance
The human body weight of 50 kg was used in the calculation to yield more conservative exposure limits, even though 60 kg body weight was used to derive the TTC of 15 µg/day [11] For reference, the TTC value of 15 µg/day corresponds to 0025 µg/kg/day using 60 kg body weight (60 kg body weight was used to derive the TTC), which then corresponds to a TD50 of 125 mg/kg/day The step-by-step calculations are as follows:
= =(15 µg/day)/60 kg 0025 µg/kg/day 0000025 mg/kg/day
To convert 1 in 105 to 1 in 2, multiply by 50,000:
( ) × =0000025 mg/kg/day 50,000 125 mg/kg/day Therefore, the 15 µg/day TTC corresponds to the TD50 value of 125 mg/kg/day
This LE method is very conservative [11], as several conservative assumptions were made to derive the TTC value from TD50 values of compounds in the CPDB These conservative assumptions include the following:
• Establishment of the dose giving a 50% tumor incidence (TD50) using data for the most sensitive species and the most sensitive site
• Based on a selected subset of the database containing 730 carcinogenic substances, which had adequate estimates of the TD50 following oral dosage
• Simple LE from the TD50 to a 1 in 106 incidence • The approach assumes that all biological processes involved in the gen-
eration of tumors at high dosages are linear over a 500,000-fold range of extrapolation
• Simple linear low-dose extrapolation is conservative because the possible effects of cytoprotective, DNA repair, apoptotic, and cell cycle control processes on the shape of the dose-response relationship are not taken into account
• All of the compounds were analyzed assuming that there is no threshold in the dose-response relationship
It should be noted that the 10−6 lifetime risk of cancer was used for the derivation of TTC, which was originally developed for food-contact materials (in the diet) Considering the existence of pharmaceutical benefits, a 10−5 lifetime risk of cancer is justified for pharmaceuticals
Due to the nature of the databases used to derive the TTC values, the TTC approach would not normally be applied to the following cases [11]:
• Heavy metals, such as arsenic, cadmium, lead, and mercury, because of the concern of accumulation
• Compounds with extremely long half-lives that show very large species differences in bioaccumulation, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structural analogs
• Proteins
Table 314 illustrates the calculation of LE based on TD50 for selected compounds from the CPDB The calculated LE values shown in Table 314 are for the 10−5 acceptable lifetime cancer risk In other words, these values are related to daily exposure throughout a person’s lifetime (70 years) In cases where the treatment duration is less than lifetime, including clinical development, higher exposures could be justified [7] by the analogy of the sTTC concept [5,6]
The LE values presented in Table 314 could be used for the preliminary compound-specific risk assessment purpose and for the analysis and control of genotoxic and carcinogenic impurities in pharmaceutical development
The solvents that are included in both the ICH Q3C guideline [3] and the CPDB [12] are compared in Table 315 For class 2 and class 3 solvents, the permitted daily exposure values from ICH Q3C are presented ICH Q3C does not explicitly state the PDE for class 1 solvents The PDE values of class 1 solvents were backcalculated from the concentration limits based on a 10 g daily dose in Table 315 for comparison purposes only The simple LE values from TD50 were calculated using the same procedure as in Table 314 It is clear that the vast majority of the solvents show lower LE values (calculated from TD50) than PDE (calculated from the noobserved-effect level [NOEL] in ICH Q3C) This illustrates the conservativeness of the LE method
Table 316 shows LE values and PDE values for metals included in EMA [8] and USP [9] guidelines and in the CPDB [12], for comparison purposes only The values were calculated using the same procedure of simple LE from TD50 as in Table 314 PDE values were obtained from either USP or EMA guidelines For the majority of the metals that have both PDE and TD50 values, the LE values calculated from TD50s are lower than PDEs The only two exceptions are lead (as lead acetate in the CPDB) and arsenic (as trimethylarsine oxide in the CPDB) The TTC approach was considered to be not applicable to heavy metals, such as arsenic, cadmium, lead, and mercury, due to the concern of accumulation [11] Again, this comparison demonstrates that the LE method from TD50 is very conservative
There are several regulatory guidelines with recommended quantitative exposure limits This chapter summarizes and compares the exposure limits that are relevant to impurities and genotoxic impurities in drug development Calculation procedures of acceptable exposures are discussed, and the calculated values are presented in a tabular format to be used as an essential and versatile reference
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