IMPURITIESIMPURITIES ImpurityImpurity :: Any component of the new drug substance Any component of the new drug substance

that is not the chemical entity defined as the new drug that is not the chemical entity defined as the new drug substance.substance.

Impurity Profi leImpurity Profi le :: A description of the identified and A description of the identified and unidentified impurities present in a new drug substance.unidentified impurities present in a new drug substance.

Degradation Product:Degradation Product: An impurity resulting from a An impurity resulting from a chemical change in the drug substance brought about chemical change in the drug substance brought about during manufacture and/or storage of the new drug during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the pH, water, or by reaction with an excipient and/or the immediate container closure system.immediate container closure system.

Degradation Profi le:Degradation Profi le: A description of the degradation A description of the degradation products observed in the drug substance or drug products observed in the drug substance or drug product.product.

Specif ied Impurity:Specif ied Impurity: An impurity that is individually An impurity that is individually listed and limited with a specific acceptance criterion in listed and limited with a specific acceptance criterion in the new drug substance specification. A specified the new drug substance specification. A specified impurity can be either identified or unidentified.impurity can be either identified or unidentified.

Identif ied Impurity:Identif ied Impurity: An impurity for which a structural An impurity for which a structural characterization has been achievedcharacterization has been achieved

Unidentif ied Impurity:Unidentif ied Impurity: An impurity for which a An impurity for which a structural characterisation has not been achieved and structural characterisation has not been achieved and that is defined solely by qualitative analytical properties that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).(e.g., chromatographic retention time).

Unspecif ied impurity:Unspecif ied impurity: An impurity that is limited by a An impurity that is limited by a general acceptance criterion, but not individually listed general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new with its own specific acceptance criterion, in the new drug substance specification.drug substance specification.

Reporting Threshold:Reporting Threshold: A limit above (>) which an A limit above (>) which an impurity should be reported. Reporting threshold is the impurity should be reported. Reporting threshold is the same as reporting level in Q2B.same as reporting level in Q2B.

Identif ication Threshold:Identif ication Threshold: A limit above (>) which an A limit above (>) which an impurity should be identified.impurity should be identified.

Qualif ication:Qualif ication: The process of acquiring and evaluating The process of acquiring and evaluating data that establishes the biological safety of an individual data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) impurity or a given impurity profile at the level(s) specified.specified.

Qualif ication Threshold:Qualif ication Threshold: A limit above (>) which an A limit above (>) which an impurity should be qualified.impurity should be qualified.

Potential Impurity:Potential Impurity: An impurity that theoretically can An impurity that theoretically can arise during manufacture or storage. It may or may not arise during manufacture or storage. It may or may not actually appear in the new drug substance.actually appear in the new drug substance.

Start ing Material:Start ing Material: A material used in the synthesis of A material used in the synthesis of a new drug substance that is incorporated as an element a new drug substance that is incorporated as an element into the structure of an intermediate and/or of the new into the structure of an intermediate and/or of the new drug substance. Starting materials are normally drug substance. Starting materials are normally commercially available and of defined chemical and commercially available and of defined chemical and physical properties and structure.physical properties and structure.

Intermediate:Intermediate: A material produced during steps of the A material produced during steps of the synthesis of a new drug substance that undergoes synthesis of a new drug substance that undergoes further chemical transformation before it becomes a new further chemical transformation before it becomes a new drug substance.drug substance.

Reagent:Reagent: A substance other than a starting material, A substance other than a starting material, intermediate, or solvent that is used in the manufacture intermediate, or solvent that is used in the manufacture of a new drug substance.of a new drug substance.

Solvent:Solvent: An inorganic or an organic liquid used as a An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in vehicle for the preparation of solutions or suspensions in the synthesis of a new drug substance.the synthesis of a new drug substance.

Enantiomeric Impurity:Enantiomeric Impurity: A compound with the same A compound with the same molecular formula as the drug substance that differs in molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image.and is a non-superimposable mirror image.

Polymorphic Forms:Polymorphic Forms: Different crystalline forms of the Different crystalline forms of the same drug substance. These can include solvation or same drug substance. These can include solvation or hydration products (also known as pseudo-polymorphs) hydration products (also known as pseudo-polymorphs) and amorphous forms.and amorphous forms.

Herbal Products:Herbal Products: Medicinal products containing, Medicinal products containing, exclusively, plant material and/or vegetable drug exclusively, plant material and/or vegetable drug preparations as active ingredients. In some traditions, preparations as active ingredients. In some traditions, materials of inorganic or animal origin can also be materials of inorganic or animal origin can also be present.present.

Extraneous Contaminant:Extraneous Contaminant: An impurity arising from An impurity arising from any source extraneous to the manufacturing process. any source extraneous to the manufacturing process.

New Drug Substance:New Drug Substance: The designated therapeutic The designated therapeutic moiety that has not been previously registered in a moiety that has not been previously registered in a region or member state (also referred to as a new region or member state (also referred to as a new molecular entity or new chemical entity). It can be a molecular entity or new chemical entity). It can be a complex, simple ester, or salt of a previously approved complex, simple ester, or salt of a previously approved drug substance.drug substance.

Impurities

Unspecif ied

Impurit ies

SpecifiedImpurit ies

Specif ied Un-Identif iedSpecif ied Identif ied

*General Acceptance

criterion *≤Identif ication threshold

*Structuralcharacterisati

on Has been achieved

*Structuralcharacterisation has

not been achieved, *e.g., “unidentif ied

A", or “unidentif ied with relative retention of

0.9”

Thresholds of Impurities in New Thresholds of Impurities in New Drug SubstanceDrug Substance

Maximum Daily Dose

ReportingThreshold

Identif ication Threshold

Qualif ication Threshold

≤ 2g/day 0.05% 0.10% or 1.0 mg per day

intake (whichever is

lower)

0.15% or 1.0 mg per day

intake (whichever is

lower)> 2g/day 0.03% 0.05% 0.05%

∴

∴

E.g. 1: The Maximum Daily Dose is 750 mga) Identification Threshold [0.10% or 1.0 mg per day intake (whichever is lower)]

750 mg → (is consider as) 100%? (How many mg is equal to) → 0.10%

0.75 mg is lower than 1.0 mg the Identification Threshold is 0.10%

b) Qualification Threshold [0.15% or 1.0 mg per day intake (whichever is lower)]

750 mg → (is consider as) 100%? (How many mg is equal to) → 0.15%

1.125 mg is greater than 1.0 mg. So calculate as per 1.0 mg

The Qualification Threshold is 0.13%

Impurity % in mg (?) =750 X 0.10

= 0.75 mg100

Impurity % in mg (?) =750 X 0.15

= 1.125 mg100

Qualification Threshold as per 1.0 mg basis in %

=100 X 1.0

= 0.13 %750

∴

∴

E.g. 2: The Maximum Daily Dose is 1500 mga) Identification Threshold (0.10% or 1.0 mg per day intake whichever is lower)1500 mg → (is consider as) 100%? (How many mg is equal to) → 0.10%

1.5 mg is greater than 1.0 mg; So calculate as per 1.0 mg

b) Qualification Threshold (0.15% or 1.0 mg per day intake whichever is lower)1500 mg → (is consider as) 100%? (How many mg is equal to) → 0.15%

2.25 mg is greater than 1.0 mg. So calculate as per 1.0 mg

The Qualification Threshold 0.066% is rounded as 0.07%

Impurity % in mg (?) =1500 X 0.10

= 1.5 mg100

Impurity % in mg (?) =1500 X 0.15

= 2.25 mg100

Qualification Threshold as per 1.0 mg basis in %

=

100 X 1.0 =

0.066 %

1500

Identification Threshold as per 1.0 mg basis in % =

100 X 1.0 =

0.066 %

1500The Identification Threshold 0.066 % is rounded as 0.07%

Maximum Daily Dose

ReportingThreshold

Identif ication Threshold

Qualif ication Threshold

1 mg – 650 mg 0.05% 0.10% 0.15%700 mg 0.05% 0.10% 0.14%750 mg 0.05% 0.10% 0.13%1000 mg 0.05% 0.10% 0.10%1250 mg 0.05% 0.08% 0.08%1500 mg 0.05% 0.07% 0.07%2000 mg – 4000 mg 0.03% 0.05% 0.05%

Identification & Qualification Thresholds of

Impurities in New Drug Substances

Thresholds of Impurities in New Drug ProductThresholds of Impurities in New Drug Product

Reporting ThresholdsMaximum Daily Dose Reporting Threshold≤ 1 g 0.1%>1 g 0.05%

MaximumDaily

Dose

Identif icationThreshold

< 1 mg 1.0% or 5 μg TDI,Whichever is lower

1mg – 10mg

0.5% or 20 μg TDI,

Whichever is lower>10 mg- 2

g0.2% or 2 mg TDI,Whichever is lower

> 2 g 0.1%

MaximumDaily Dose

Qualif icationThreshold

< 10 mg 1.0% or 50 μg TDI,Whichever is lower

10mg – 100mg

0.5% or 200 μg TDI,

Whichever is lower

>100 mg- 2 g 0.2% or 3 mg TDI,Whichever is lower

> 2 g 0.15%

E.g.1: The Maximum Daily Dose is 5 mga) Identification Threshold [0.5% or 20 μg TDI, whichever is lower]5 mg → (is consider as) 100%? (How many mg is equal to) → 0.5%

Impurity % in mg (?)

=

5 X 0.5 =

0.025 mg

1000.025 mg (25 µg) is greater than 20 µg (0.02 mg); So calculate as per 0.02 mg

Identification Threshold as per 0.02 mg basis in % =

100 X 0.02 =

0.40 %

5The Identification Threshold is 0.40%

b) Qualification Threshold [1.0% or 50 μg TDI, whichever is lower]5 mg → (is consider as) 100%? (How many mg is equal to) → 1.0%

Impurity % in mg (?)

=

5 X 1.0 =

0.05 mg

1000.05 mg is equal to 50 µg; The Qualification Threshold is 1.0%

E.g.2: The Maximum Daily Dose is 1500 mga) Identification Threshold (0.2% or 2 mg TDI, whichever is lower)1500 mg → (is consider as) 100%? (How many mg is equal to) → 0.2%

Impurity % in mg (?)

=

1500 X 0.2

=3 mg1003 mg is greater than 2 mg; So calculate as per 2 mg

Identification Threshold as per 2 mg basis in %

=100 X 2

= 0.13 %1500

The Identification Threshold is 0.13%

b) Qualification Threshold (0.2% or 3 mg TDI, whichever is lower)1500 mg → (is consider as) 100%? (How many mg is equal to) → 0.2%

Impurity % in mg (?)

=

1500 X 0.2 = 3 mg100The Qualification Threshold is 0.2%

Maximum Daily Dose

ReportingThreshold

Identification Threshold

Qualification Threshold

Unspecified impurities

Specified Identified impurities

Any other Individual impurity

Specified Unidentified impurities

1 mg -4 mg 0.1% 0.50% 1.0% 5 mg 0.1% 0.40% 1.0%10 -40 mg 0.1% 0.20% 0.5%41 – 50 mg 0.1% 0.20% 0.4%51 – 75 mg 0.1% 0.20% 0.3%76 – 80 mg 0.1% 0.20% 0.25%81 – 1000 mg 0.1% 0.20% 0.20%1250 mg 0.05% 0.16% 0.20%1500 mg 0.05% 0.15% 0.20%≥ 2000 mg 0.05% 0.10% 0.15%

Identification & Qualification Thresholds of Impurities in New Drug Product

Residual SolventsResidual SolventsClassif ication of Residual Solvents by Risk Assessment Class 1 solvents (Solvents to be avoided):Class 1 solvents (Solvents to be avoided): Known human Known human

carcinogens, strongly suspected human carcinogens, and carcinogens, strongly suspected human carcinogens, and environmental hazards. environmental hazards.

Class 2 solvents (Solvents to be l imited):Class 2 solvents (Solvents to be l imited): Non-genotoxic Non-genotoxic animal carcinogens or possible causative agents of other irreversible animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.other significant but reversible toxicities.

Class 3 solvents (Solvents with low toxic potential):Class 3 solvents (Solvents with low toxic potential): Solvents with low toxic potential to man; no health-based exposure Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per limit is needed. Class 3 solvents have PDEs of 50 mg or more per day. day.

Solvents for which No Adequate Toxicological Data was Solvents for which No Adequate Toxicological Data was found:found: However, no adequate toxicological data on which to base a However, no adequate toxicological data on which to base a PDE was found. Manufacturers should supply justification for PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products. residual levels of these solvents in pharmaceutical products.

Genotoxic Carcinogens:Genotoxic Carcinogens: Carcinogens which Carcinogens which produce cancer by affecting genes or chromosomesproduce cancer by affecting genes or chromosomes

Lowest-Observed Effect Level (LOEL):Lowest-Observed Effect Level (LOEL): The The lowest dose of substance in a study or group of lowest dose of substance in a study or group of studies that produces biologically significant studies that produces biologically significant increases in frequency or severity of any effects in increases in frequency or severity of any effects in the exposed humans or animalsthe exposed humans or animals

Modifying Factor:Modifying Factor: A factor determined by A factor determined by professional judgment of a toxicologist and applied professional judgment of a toxicologist and applied to bioassay data to relate that data safely to to bioassay data to relate that data safely to humans. humans.

Neurotoxicity:Neurotoxicity: The ability of a substance to cause The ability of a substance to cause adverse effects on the nervous systemadverse effects on the nervous system

No-Observed-Effect Level (NOEL):No-Observed-Effect Level (NOEL): The The highest dose of substance at which there are no highest dose of substance at which there are no biologically significant increases in frequency or biologically significant increases in frequency or severity of any effects in the exposed humans or severity of any effects in the exposed humans or animalsanimals

Permitted Daily Exposure (PDE):Permitted Daily Exposure (PDE): The The maximum acceptable intake per day of residual maximum acceptable intake per day of residual solvent in pharmaceutical productssolvent in pharmaceutical products

Reversible Toxicity:Reversible Toxicity: The occurrence of harmful The occurrence of harmful effects that are caused by a substance and which effects that are caused by a substance and which disappear after exposure to the substance ends.disappear after exposure to the substance ends.

Strongly Suspected Human Carcinogen:Strongly Suspected Human Carcinogen: A A substance for which there is no epidemiological substance for which there is no epidemiological evidence of carcinogenesis but there are positive evidence of carcinogenesis but there are positive genotoxicity data and clear evidence of genotoxicity data and clear evidence of carcinogenesis in rodents.carcinogenesis in rodents.

Teratogenicity:Teratogenicity: The occurrence of structural The occurrence of structural malformations in a developing fetus when a malformations in a developing fetus when a substance is administered during pregnancysubstance is administered during pregnancy

Options for Describing Limits of Class 2 Solvents Two options are available when setting limits for Class 2 solvents. Option 1: The concentration limits in ppm is calculated using equation (1) below by assuming a product mass of 10 g administered daily.

Concentration (ppm) =1000 x PDE

---- (1)dose

Here, PDE is given in terms of mg/day and dose is given in g/day. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered under Option 2.

Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product. Option 2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE. E.g.: Option 1 and Option 2 applied to acetonitrile in a drug product. The permitted daily exposure to acetonitrile is 4.1 mg per day; thus, the Option 1 limit is 410 ppm. The maximum administered daily mass of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of residual acetonitrile are given in the table.

Component Amount in formulation Acetonitri le content Daily exposure

Drug substance

0.3 g 800 ppm 0.24 mg

Excipient 1 0.9 g 400 ppm 0.36 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 728 ppm 3.64 mg

Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline.

Component Amount in formulation Acetonitri le content Daily exposure

Drug substance

0.3 g 800 ppm 0.24 mg

Excipient 1 0.9 g 2000 ppm 1.80 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 1016 ppm 5.08 mg In this example, the product meets neither the Option 1 nor the Option 2 limit according to this summation.

Reporting levels of residual solvents Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%. Only Class 2 solvents X, Y, ... are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, ...) Only Class 2 solvents X, Y, ... and Class 3 solvents are likely to be present. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%. If Class 1 solvents are likely to be present, they should be identified and quantified.

Methods for Establishing Exposure Limits PDE is derived from the no-observed-effect level (NOEL), or the lowest-observed effect level (LOEL) in the most relevant animal study as follows: If no NOEL is obtained, the LOEL may be used.

PDE =NOEL x Weight Adjustment

F1 x F2 x F3 x F4 x F5

The modifying factors are as follows: F1 = A factor to account for extrapolation between species

F1 = 5 for extrapolation from rats to humans F1 = 12 for extrapolation from mice to humans F1 = 2 for extrapolation from dogs to humans F1 = 2.5 for extrapolation from rabbits to humans F1 = 3 for extrapolation from monkeys to humans F1 = 10 for extrapolation from other animals to humans

F2 = A factor of 10 to account for variability between individuals F3 = A variable factor to account for toxicity studies of short-

term exposure F3 = 1 for reproductive studies in which the whole period of organogenesis is covered. F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents. F3 = 5 for a 3-month study in rodents, or a 2-year study in

non-rodents. F3 = 10 for studies of a shorter duration.

F4 = A factor that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used:

F4 = 1 for fetal toxicity associated with maternal toxicity F4 = 5 for fetal toxicity without maternal toxicity F4 = 5 for a teratogenic effect with maternal toxicity F4 = 10 for a teratogenic effect without maternal toxicity

F5 = A variable factor that may be applied if the no-effect level was not established

When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

The weight adjustment assumes an arbitrary adult human body weight for either sex of 50 kg.

PDE =50.7 mg kg-1 day-1 x 50 kg

= 4.22 mg day-1

12 x 10 x 5 x 1 x 1

In this example, F1 = 12 to account for the extrapolation from mice to humans F2 = 10 to account for differences between individual humans F3 = 5 because the duration of the study was only 13 weeks F4 = 1 because no severe toxicity was encountered F5 = 1 because the no effect level was determined Concentrations of gases: The equation for an ideal gas, PV = nRT, is used to convert concentrations of gases used in inhalation studies from units of ppm to units of mg/L or mg/m3. Consider as an example the rat reproductive toxicity study by inhalation of carbon tetrachloride (molecular weight 153.84)

As an example of the application of this equation, consider a toxicity study of acetonitrile in mice. The NOEL is calculated to be 50.7 mg kg-1 day-1. The PDE for acetonitrile in this study is calculated as follows:

n=

P=

300 x 10-6 atm x 153840 mg mol-1=

46.15 mg= 1.89 mg/L

V RT 0.082 L atm K-1 mol-1 x 298 K 24.45 L

PDE FOR TETRAHYDROFURAN Groups of 50 male and 50 female rats were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Identical exposures were given to groups of 50 male and 50 female mice. Under the conditions of the studies, there was some evidence of carcinogenic activity of THF in male rats due to increased incidences of adenoma or carcinoma (combined) of the kidney. There was clear evidence of carcinogenic activity of THF in female mice due to increased incidences of hepatocellular adenomas and carcinomas. No evidence for carcinogenicity was found in female rats and male mice. Using the lowest THF exposure in the most sensitive specie, the male rat at 200 ppm was used for the PDE calculation.

200 ppm =200 x 72.10

= 589.8 mg/m3 = 0.59 mg/L (residual solvent conc per liter)24.45

For continuous dosing =0.59 x 6 x 5

= 0.105 mg/L24 x 7

Daily dose =0.105 x 290 (respiratory volume)

= 71.65 mg/kg0.425 weight

PDE =

71.65 x 50

= 7.165 mg/ day =7.2 mg/da

y5 x 10 x 1 x 10 x 1

Concentration limit =7.2 x 1000

= 720 ppm10

Concentration limit =5.3 x 1000

=530

ppm10

PDE =133.58 x 50

=5.3 mg/

day5 x 10 x 1 x 5 x 5

Daily dose =0.152 x 290 (respiratory volume)

= 133.58 mg/kg0.33 weight

For continuous dosing =0.608 x 6

= 0.152 mg/L24

150 ppm =150 x 99.13

= 608.16 mg/m3 = 0.608 mg/L (residual solvent conc per liter)24.45

PDE FOR N-METHYLPYRROLIDONE (NMP) Wistar rats were exposed by inhalation to 150ppm NMP for 6 hours/day, daily from days 7-20 of gestation and were then allowed to litter. No maternal toxicity was detected and litter size was unaffected by treatment. No physical abnormalities were described. The offspring were reduced in weight, the difference being statistically significant up to week 5 after birth. A NOEL was not established.

by S.Eshwaraiah

Ref: ICH Q3A, ICH Q3B and ICH Q3C Guidelines

THE END