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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