Specifications on Drug Substances

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Specifications :

1 Specifications Active pharmaceutical substances Author: Srikanth N http://stabilitystudies.blogspot.com

Description or appearance :

2 Description or appearance State of the drug substance Solid – amorphous or crystalline Liquid – viscous / clear / hazy Color of the drug substance Foreign matter Black particles, lumps etc…

Solubility :

3 Solubility Very soluble < 1 volume Freely soluble 1 to 10 volumes Soluble 10 to 30 volumes Sparingly soluble 30 to 100 volumes Slightly soluble 100 to 1000 volumes Very slightly soluble 1000 to 10,000 volumes Practically insoluble > 10,000

Identification :

4 Identification Discriminate between compounds of two closely related which are likely to be present Identification should be of specific or confirmatory specific for new drug substance IR spectroscopy Confirmatory UV, HPLC ( RT) etc… However the use of two chromatographic techniques where the separation is based on different principles or combination of tests into single procedure. HPLC/UV HPLC/MS GC/MS

Physicochemical properties :

5 Physicochemical properties pH of an aqueous solution, melting point / range, and Refractive index Particle size Polymorphism Isomerism Enantiomers Chiral

Water content / LOD :

6 Water content / LOD Water content ( % w/w or w/v) This test is important in cases where the new drug substance is known to be hygroscopic or degraded by moisture or when the drug substance is known to be a stoichiometric hydrate. The acceptance criteria may be justified with data on the effects of hydration or moisture absorption. however, a detection procedure that is specific for water (e.g., Karl Fischer titration) is preferred. In some cases, a Loss on Drying procedure may be considered adequate;

Assay:

7 Assay A specific, stability-indicating procedure should be included to determine the content of the new drug substance On Dried Basis On anhyrous Basis In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities. In cases where use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. For example, where titration is adopted to assay the drug substance, the combination of the assay and a suitable test for impurities should be used

Impurities :

8 Impurities Impurities can be classified into the following categories: Organic inorganic impurities and residual solvents

Organic impurities :

9 Organic impurities Organic impurities may be arise Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts

Inorganic impurities:

10 Inorganic impurities Inorganic impurities can result from the manufacturing process Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal) The need for inclusion of tests and acceptance criteria for inorganic impurities ( e.g., catalysts ) should be studied during development and based on knowledge of the manufacturing process. Procedures and acceptance criteria for sulfated ash / residue on ignition should follow pharmacopoeial precedents; other inorganic impurities(pd, zn, etc.. )may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy.

Residual solvents :

11 Residual solvents Broadly residual solvents are classified as Solvents to be avoided ( class I) Solvents to be limited ( class II) Solvents with low toxic potential ( class III)

Residual solvents :

12 Residual solvents Solvents to be avoided Class I solvents Benzene Carbon tetra chloride 1,2-dichloroethane 1,1-dichloroethane 1,1,1-trichloroethane

Residual solvents :

13 Residual solvents Solvents to be limited Class II solvents ACC Acetonitrile -410 ppm Chlorobenzene -360 ppm Chloroform- 60 ppm MDDC Methanol -3000 ppm Dichloromethane-600 ppm Dimethylformamide -880 ppm Cyclohexane -3880 ppm HMT Hexane -290 ppm 2-methoxyethanol -50 ppm Toluene -890 ppm MNS Methylbutylketone-50 ppm Nitromethane- 50 ppm Sulfolane -160 ppm

Residual solvents :

14 Residual solvents Solvents with low toxic potential Class III solvents Ethanol, acetic acid, acetone,1-butanol, 2-butanol Isopropyl alcohol, DMSO, ethyl acetate Ethyl ether

Listing of Impurities :

15 Listing of Impurities In summary, the new drug substance specification should include, where applicable, the following list of impurities: Organic Impurities Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than (  ) the identification threshold Total impurities Residual Solvents Inorganic Impurities

Definitions :

16 Definitions Identified Impurity : An impurity for which a structural characterisation has been achieved. Unidentified Impurity : An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). Unspecified impurity : An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification. Specified Impurity : An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified.

Thresholds :

17 Thresholds Maximum Daily Dose Reporting Threshold Identification Threshold3 Qualification 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% Reporting Threshold: A limit above (>) which an impurity should be reported. Qualification Threshold : A limit above (>) which an impurity should be qualified. Identification Threshold : A limit above (>) which an impurity should be identified.

Polymorphic forms:

18 Polymorphic forms Some of the drug substance exist in different crystalline forms (polymorphs) due to a different arrangement of molecules in crystal lattice, which thus show distinct differences in their physical properties. The Some drug substances also exist in a non crystalline form( amorphous ). Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs ) and amorphous forms. One critical factors affecting the polymorphism is the choice of final solvent and isolation conditions in the synthesis.

Polymorphic forms:

19 Polymorphic forms Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In cases where differences exist which have been shown to affect drug product performance, bioavailability or stability, then the appropriate solid state should be specified. Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist. Examples of these procedures are: melting point (including hot-stage microscopy), solid state IR, X-ray powder diffraction , thermal analysis procedures (like DSC, TGA and DTA ), Raman spectroscopy, optical microscopy, and solid state NMR.

chiral new drug substances :

20 chiral new drug substances Where a new drug substance is predominantly one enantiomer, the opposite enantiomer is excluded from the qualification and identification thresholds given in the ICH Guidelines on Impurities in New Drug Substances Impurities. For chiral drug substances which are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities. However, technical limitations may preclude the same limits of quantification or qualification from being applied. Assurance of control also could be given by appropriate testing of a starting material or intermediate, with suitable justification.

chiral new drug substances :

21 chiral new drug substances Assay. An enantioselective determination of the drug substance should be part of the specification. It is considered acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an achiral assay together with appropriate methods of controlling the enantiomeric impurity. Identity . For a drug substance developed as a single enantiomer, the identity test(s) should be capable of distinguishing both enantiomers and the racemic mixture. For a racemic drug substance, there are generally two situations where a stereospecific identity test is appropriate for release/acceptance testing: 1) where there is a significant possibility that the enantiomer might be substituted for the racemate, or 2) when there is evidence that preferential crystallization may lead to unintentional production of a non-racemic mixture.

Particle size:

22 Particle size For some new drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bioavailability, and / or stability. In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided .

Microbial limits:

23 Microbial limits There may be a need to specify the Total count of aerobic microorganisms Total count of yeasts and molds Absence of specific objectionable bacteria Staphylococcus aureus Escherichia coli Salmonella Pseudomonas aeruginosa

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