IMPURITIES IN IMPURITIES IN NEW DRUG NEW DRUG PRODUCTSPRODUCTS

Q3B(R2)Q3B(R2)ICH- dated 2 June 2006

Provides guidance for registration applications on Provides guidance for registration applications on the content and qualification of impurities in new the content and qualification of impurities in new drug products produced from chemically drug products produced from chemically synthesized new drug substances.synthesized new drug substances.

This guideline is complementary to the ICH Q3A(R) guideline “Impurities in New Drug Substances”

This guideline addresses only those impurities in This guideline addresses only those impurities in new drug products classified as degradation new drug products classified as degradation products of the drug substance or reaction products products of the drug substance or reaction products of the drug substance with an excipient and/or of the drug substance with an excipient and/or immediate container closure system.immediate container closure system.

Impurities present in the new drug substance need not be monitored or specified in the new drug product unless they are also degradation products.

Not covered in this guideline: biological/biotechnological products, peptides, fermentation products and semi-synthetic

products, herbal products. Impurities arising from excipients present in the

new drug product . Extraneous contaminants .

The applicant should summarize the degradation products observed during manufacture and/or stability studies of the new drug product.

It should be based on sound scientific appraisal of potential degradation pathways in the new drug product and impurities arising from the interaction with excipients and/or the immediate container closure system.

A justification should be provided for exclusion of those impurities that are not degradation products (e.g., process impurities from the drug substance and impurities arising from excipients).

Any degradation product observed in stability studies conducted at the recommended storage condition should be identified when present at a level greater than (>) the identification thresholds.

When identification of a degradation product is not feasible, a summary of the laboratory studies demonstrating the unsuccessful efforts to identify it should be included .

Degradation products present at a level lesser than the identification threshold generally not need to be identified. However, analytical procedures should be developed for those degradation products that are suspected to be unusually potent.

ANALYTICAL PROCEDURESANALYTICAL PROCEDURES The registration application should include

documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products.

In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products.

this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.

The quantitation limit for the analytical procedure should be less than the reporting threshold.

Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard or to the response of the new drug substance itself.

Differences between the analytical procedures used during development and those proposed for the commercial product should also be discussed.

REPORTING DEGRADATION REPORTING DEGRADATION PRODUCTSPRODUCTS

Analytical results should be provided in the Analytical results should be provided in the registration application for all relevant batches of the registration application for all relevant batches of the new drug product used for clinical, safety, and new drug product used for clinical, safety, and stability testing, as well as batches that are stability testing, as well as batches that are representative of the proposed commercial process.representative of the proposed commercial process.

Any degradation product at a level greater than the reporting threshold and total degradation products observed in the relevant batches of the new drug product, should be reported with the analytical procedures indicated.

Degradation products should be designated by Degradation products should be designated by code number or by an appropriate descriptor, e.g., code number or by an appropriate descriptor, e.g., retention time.retention time.

If a higher reporting threshold is proposed, it If a higher reporting threshold is proposed, it should be fully justified.should be fully justified.

All degradation products at a level greater than All degradation products at a level greater than (>) the reporting threshold should be summed and (>) the reporting threshold should be summed and reported as total degradation productsreported as total degradation products..

For each batch the documentation should include:

Batch no., strength, and size Date of manufacture Site of manufacture Manufacturing process Immediate container closure Degradation product content, individual and total Use of batch (e.g., clinical studies, stability studies) Reference to analytical procedure used Batch number of the drug substance used in the

new drug product Storage conditions for stability studies

Chromatograms with peaks labelled from representative batches, including chromatograms from analytical procedure validation studies and from long-term and accelerated stability studies, should be provided.

LISTING OF DEGRADATION LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONSPRODUCTS IN SPECIFICATIONS

The specification for a new drug product should The specification for a new drug product should include a list of degradation products expected to include a list of degradation products expected to occur during manufacture of the commercial occur during manufacture of the commercial product and under recommended storage product and under recommended storage conditionsconditions..

Stability studies, knowledge of degradation pathways, product development studies, and laboratory studies should be used to characterise the degradation profile.

Those individual degradation products with specific acceptance criteria included in the specification for the new drug product are referred to as "specified degradation products" in this guideline.

Specified degradation products can be identified or unidentified.

In summary, the new drug product specification should include, where applicable, the following list of degradation products: Each specified identified degradation product Each specified unidentified degradation product Any unspecified degradation product with an

acceptance criterion of not more than (≤) the identification threshold

Total degradation products.

QUALIFICATION OF QUALIFICATION OF DEGRADATION PRODUCTSDEGRADATION PRODUCTS

Qualification is the process of acquiring and Qualification is the process of acquiring and evaluating data that establishes the biological safety evaluating data that establishes the biological safety of an individual degradation product or a given of an individual degradation product or a given degradation profile at the level(s) specified. degradation profile at the level(s) specified.

The applicant should provide a rationale for The applicant should provide a rationale for establishing degradation product acceptance criteria establishing degradation product acceptance criteria that includes safety considerationsthat includes safety considerations..

The level of any degradation product present in a The level of any degradation product present in a new drug product that has been adequately tested new drug product that has been adequately tested in safety and/or clinical studies would be in safety and/or clinical studies would be considered qualified.considered qualified.

Degradation products could be considered qualified at levels higher than those administered in safety studies based on a comparison between actual doses given in the safety studies and the intended dose of the new drug product.

Reporting ThresholdsReporting Thresholds

Maximum Daily Dose Threshold ≤ 1 g 0.1% > 1 g 0.05%

Identification ThresholdsIdentification Thresholds

Maximum Daily Dose1 Threshold < 1 mg 1.0% or 5 μg TDI,

whichever is lower 1 mg - 10 mg 0.5% or 20 μg TDI,

whichever is lower >10 mg - 2 g 0.2% or 2 mg TDI,

whichever is lower > 2 g 0.10%

TDI =total daily intake of the degradation product.

Qualification ThresholdsQualification Thresholds Maximum Daily Dose Threshold < 10 mg 1.0% or 50 μg

TDI, whichever is lower

10 mg - 100 mg 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%

IMPURITIES: GUIDELINE FOR IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS -Q3C(R4)RESIDUAL SOLVENTS -Q3C(R4)

Current Step 4 version dated February 2009Current Step 4 version dated February 2009

The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.

Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible

Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.

Therefore, the solvent may sometimes be a critical parameter in the synthetic process. However, the content of solvents in such products should be evaluated and justified.

ICH Q3CICH Q3C ICH Q3C guides in determining, on a safety basis, ICH Q3C guides in determining, on a safety basis,

acceptable residual solvent levels for intake by use acceptable residual solvent levels for intake by use of the term ‘‘permitted daily exposure’’ (PDE).of the term ‘‘permitted daily exposure’’ (PDE).

This Guidance classifies residual solvents used in This Guidance classifies residual solvents used in the synthesis and processing into four categories. the synthesis and processing into four categories. The Guidance recommends that The Guidance recommends that

Class I solvents be avoided. These include benzene, Class I solvents be avoided. These include benzene, carbon tetrachloride, 1,2-dichloromethane,1,1-carbon tetrachloride, 1,2-dichloromethane,1,1-dichloroethane, and 1,1,1-trichloroethane. dichloroethane, and 1,1,1-trichloroethane.

Class II solvents that should be limited because of Class II solvents that should be limited because of their inherent toxicity either by calculation of their inherent toxicity either by calculation of concentration (PPM) or by PDEconcentration (PPM) or by PDE

Class 3 solvents with low toxic potential Class 4 solvents with no safety data.

Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected

human carcinogens, and environmental hazards. Benzene - Carcinogen Carbon tetrachloride -Toxic and environmental

hazard 1,2-Dichloroethane - Toxic 1,1-Dichloroethene - Toxic 1,1,1-Trichloroethane - Environmental hazard

Class 2 solvents: Solvents to be limited Non-genotoxic animal carcinogens or possible

causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.

PDE (mg/day) Acetonitrile 4.1 Chlorobenzene 3.6 Chloroform 0.6 Cyclohexane 38.8 1,2-Dichloroethene 18.7

Pyridine 2.0 Toluene 8.9 Hexane 2.9 Methanol 30.0 1,1,2-Trichloroethene 0.8 Xylene 21.7 Methylbutyl ketone 0.5 Methylcyclohexane 11.8 N-Methylpyrrolidone1 5.3 Nitromethane 0.5 Pyridine 2.0 200 Sulfolane 1.6 Tetrahydrofuran2 7.2

Solvents in Class 3 (shown in Table 3) may be regarded as less toxic and of lower risk to human health. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals.

However, there are no long-term toxicity or carcinogenicity studies for many of the solvents. It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification.

Class 3 solvents: Solvents with low toxic potential

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 day.

Acetic acid , Heptane, Acetone, Ethanol, 1-Pentanol , Ethyl acetate, 1-Propanol , Ethyl ether, 2-Propanol

Ethyl acetate Ethyl ether Ethyl formate Propyl acetate Formic acid Cumene 2-Methyl-1-propanol Dimethyl sulfoxide Pentane

Class 4 solvents :Solvents for which No :Solvents for which No Adequate Toxicological Data was FoundAdequate Toxicological Data was Found

1,1-Diethoxypropane , Methyl isopropyl ketone, 1,1-Dimethoxymethane,Methyltetrahydrofuran 2,2-Dimethoxypropane, Petroleum ether Isooctane , Trichloroacetic acid Isopropyl ether, Trifluoroacetic acid

It is only necessary to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used to produce the drug product.

If the calculation results in a level equal to or below that recommended in this guideline, no testing of the drug product for residual solvents need be considered.

If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount..

Drug product should also be tested if a solvent is used during its manufacture.

Options for Describing Limits of Class 2 Options for Describing Limits of Class 2 SolventsSolvents

Option 1: Concentration (ppm) =1000 x PDE/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 .

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 as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product.

Analytical ProceduresAnalytical Procedures Residual solvents are typically determined using

chromatographic techniques such as gas chromatography. Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application.

If only Class 3 solvents are present, a non-specific method such as loss on drying may be used.

Validation of methods for residual solvents Validation of methods for residual solvents should conform to ICH guidelines Text on should conform to ICH guidelines Text on Validation of Analytical ProceduresValidation of Analytical Procedures

Reporting levels of residual solvents The supplier might choose one of the following as

appropriate: 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.

ANALYTICAL METHOD ANALYTICAL METHOD DEVELOPMENTDEVELOPMENT

Analytical methods employed for detection and quantification of impurities should be sufficiently sensitive to measure low levels of impurities.

There are a great variety of methods used for monitoring impurities. The primary requirement for such techniques is the capacity to differentiate between the compounds of interest. This requirement frequently necessitates utilization of separation methods in combination with a variety of detectors

Separation Methods The following methods can be used for separation

of impurities and degradation products: Capillary electrophoresis (CE) Chiral separations Gas chromatography (GC) High-pressure liquid chromatography (HPLC) Supercritical fluid chromatography (SFC) Thin-layer chromatography (TLC)

The nature and complexity of the separation problem determines which method should be used. The primary goal of a good separation method is resolution of all impurities of interest.

Capillary electrophoresis is an effective technique in situations where very low quantities of samples are available and high resolution is essential. Its relatively lower reproducibility is the principal difficulty of this procedure.

Gas chromatography is an extremely useful technique for quantification. It can afford the desired resolution, selectivity, and ease of quantification.

The chief limitation, however, is that the sample must be volatile or must be made volatile by derivatization.

This technique is very practical for organic volatile impurities (OVI).

High-pressure liquid chromatography is often referred to as high performance liquid chromatography today.. The applications of this very effective technique have been significantly expanded for the pharmaceutical chemist by the use of a variety of detectors such as fluorescence, electrometric, MS, and so forth.

Supercritical fluid chromatography (SFC) offers some of the advantages of GC in terms of detection and of HPLC in terms of separations, in that volatility of the sample is not of paramount importance.

SFC is generally performed in the normal phase (NP) mode, and often NP-TLC or NP-HPLC methods can be readily adapted to SFC methods. Because of the similarity to HPLC in the chromatographic measurement process, this technique can be used to accurately quantify nonpolar impurities of the sample of interest.

Thin-layer chromatography coupled with densitometric detection is a highly sensitive method for quick assessment of the purity of various compounds

High-performance TLC (HPTLC) is an improved version of TLC that uses stationary phases of decreased thickness and lower particle size, providing improved resolution over shorter elution distances.

TLC can resolve a large range of compounds by employing a variety of different plates and mobile phases. Limited resolution ,detection, and ease of quantification are the main problems associated with this method.

Spectroscopic MethodsSpectroscopic Methods The following spectroscopic measurement

techniques have been used for characterizing impurities; most of these are very useful as detectors for chromatographic methods:

Ultraviolet (UV) Infrared (IR) Raman spectroscopy Mass spectrometry (MS) Nuclear magnetic resonance (NMR)

Ultraviolet spectrophotometry coupled with diode array detectors, is capable to obtain sufficient simultaneous information at various wavelengths to assure greater reliability.

Infrared spectrophotometry (IR) affords specific information on some functional groups. However, low-level delectability is difficult.

Raman spectroscopy is based on the measurement of scattered electromagnetic radiation resulting from the irradiation of matter. Specifically, when a material is irradiated with a strong monochromatic light source (e.g., laser), difference in vibrational energy between the scattered beam and incident beam that is measured.

Raman spectroscopy is an extremely powerful tool in characterizing the presence of polymorphs

Mass spectrometry (MS) provides excellent structural information, and, based on the resolution of the instrument, it may be an effective tool for differentiating molecules with small differences in molecular weight

Nuclear magnetic resonance spectroscopy (NMR) provides reasonably detailed structural information on a molecule and is an extremely useful method for characterization of impurities. Its use as a quantitative method is limited.

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