specifications api

8/2/2019 Specifications API

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Specifications

Active pharmaceutical substances

Author: Srikanth N

http://stabilitystudies.blogspot.com


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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


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Solubility

Very soluble < 1 volume

Freely soluble 1 to 10 volumes

Soluble 10 to 30 volumesSparingly soluble 30 to 100 volumes

Slightly soluble 100 to 1000 volumes

Very slightly soluble 1000 to 10,000 volumes

Practically insoluble > 10,000


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Identification

Discriminate between compounds of two closely related whichare 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 techniqueswhere the separation is based on different principles orcombination of tests into single procedure. HPLC/UV HPLC/MS GC/MS


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Physicochemical properties

pH of an aqueous solution,

melting point / range, and

Refractive index Particle size

Polymorphism

Isomerism Enantiomers

Chiral


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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 drugsubstance is known to be a stoichiometrichydrate.

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;


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Assay

A specific, stability-indicating procedure should beincluded to determine the content of the new drugsubstance

On Dried Basis On anhyrous Basis

In many cases it is possible to employ the sameprocedure (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 proceduresshould be used to achieve overall specificity.

For example, where titration is adopted to assay the


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Impurities

Impurities can be classified into the followingcategories:

Organic

inorganic impurities and

residual solvents


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Organic impurities

Organic impurities may be arise

Starting materials

By-products

Intermediates

Degradation products

Reagents, ligands and catalysts


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Inorganic impurities

Inorganic impurities can result from the manufacturingprocess 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 forinorganic impurities (e.g., catalysts) should be studied duringdevelopment and based on knowledge of the manufacturingprocess.

Procedures and acceptance criteria for sulfated ash / residueon ignition should follow pharmacopoeial precedents;

other inorganic impurities(pd, zn, etc.. )may be determined byother appropriate procedures, e.g., atomic absorptionspectroscopy.


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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)


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Residual solvents

Solvents to be avoided

Class I solvents

Benzene

Carbon tetra chloride

1,2-dichloroethane

1,1-dichloroethane

1,1,1-trichloroethane


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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


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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


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Listing of Impurities

In summary, the new drug substance specificationshould include, where applicable, the following list ofimpurities:

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


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Definitions

Identified Impurity: An impurity for which a structuralcharacterisation has been achieved.

Unidentified Impurity: An impurity for which a structuralcharacterisation has not been achieved and that is defined solely

by qualitative analytical properties (e.g., chromatographicretention time).

Unspecified impurity: An impurity that is limited by a generalacceptance criterion, but not individually listed with its ownspecific acceptance criterion, in the new drug substancespecification.

Specified Impurity: An impurity that is individually listed andlimited with a specific acceptance criterion in the new drugsubstance specification. A specified impurity can be either

identified or unidentified.


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Thresholds

Maximum DailyDose

ReportingThreshold

IdentificationThreshold3

QualificationThreshold

2g/day 0.05% 0.10% or 1.0 mgper day intake(whichever is

lower)

0.15% or 1.0 mgper 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 bequalified.

Identification Threshold: A limit above (>) which an impurity should beidentified.


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Polymorphic forms

Some of the drug substance exist in different crystallineforms (polymorphs) due to a different arrangement ofmolecules in crystal lattice, which thus show distinctdifferences in their physical properties.

The Some drug substances also exist in a non crystallineform( amorphous).

Polymorphism may also include solvation or hydrationproducts (also known as pseudopolymorphs) and

amorphous forms. One critical factors affecting the polymorphism is the

choice of final solvent and isolation conditions in thesynthesis.


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Polymorphic forms

Differences in these forms could, in some cases, affectthe quality or performance of the new drug products.

In cases where differences exist which have been shownto affect drug product performance, bioavailability or

stability, then the appropriate solid state should bespecified.

Physicochemical measurements and techniques arecommonly used to determine whether multiple forms

exist. Examples of these procedures are: melting point

(including hot-stage microscopy), solid state IR, X-raypowder diffraction, thermal analysis procedures (likeDSC, TGA and DTA), Raman spectroscopy, optical

microscopy, and solid state NMR.


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chiral new drug substances

Where a new drug substance is predominantly oneenantiomer, the opposite enantiomer is excluded fromthe qualification and identification thresholds given in theICH Guidelines on Impurities in New Drug Substances

Impurities. For chiral drug substances which aredeveloped as a single enantiomer, control of the otherenantiomer should be considered in the same manner asfor other impurities. However, technical limitations maypreclude the same limits of quantification or qualificationfrom being applied. Assurance of control also could begiven by appropriate testing of a starting material orintermediate, with suitable justification.


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chiral new drug substances

Assay. An enantioselective determination of the drugsubstance should be part of the specification. It isconsidered acceptable for this to be achieved eitherthrough use of a chiral assay procedure or by thecombination of an achiral assay together withappropriate methods of controlling the enantiomericimpurity.

Identity. For a drug substance developed as a singleenantiomer, the identity test(s) should be capable ofdistinguishing both enantiomers and the racemicmixture. For a racemic drug substance, there aregenerally two situations where a stereospecific identitytest is appropriate for release/acceptance testing: 1)

where there is a significant possibility that theenantiomer mi ht be substituted for the racemate, or 2


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Particle size

For some new drug substances intended foruse in solid or suspension drug products,particle size can have a significant effect on

dissolution rates, bioavailability, and / orstability.

In such instances, testing for particle size

distribution should be carried out using anappropriate procedure, and acceptancecriteria should be provided.


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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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