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It is very important to authenticate sample for estimations, when it is available. If the estimations indicate that a given impurity content is greater than 0.1% then it must be characterized as per the FDA requirements. Hyphenated methods such as gas chromatography, mass spectroscopy, or liquid chromatography, mass spectrometry or the number of other chromatographic-spectroscopic configuration are perfectly suitable for initial characterization of the impurities.
A. Spectroscopic Techniques.
B. Chromatographic Techniques.
C. Hyphenated techniques

Highly sophisticated instrumentation, such as MS attached to a GC (Gas Chromatography) or HPLC (High Performance Liquid Chromatography), are inevitable tools in the identification of minor components (drugs, impurities, degradation products, metabolites) in various matrices. Identification  and characterization of drug metabolites in biological fluids (biological analysis) by various hyphenated techniques like LC-MS,GC-MS etc which are as follows;

(1) N.M.R. The ability of NMR (Nuclear Magnetic Resonance) to provide information regarding the specific bonding structure and stereochemistry of molecules of pharmaceutical interest has made it a powerful analytical instrument for structural elucidation. The ability of NMR- based diffusion coefficient determination to distinguish between nonnumeric and dimeric substances was validated using a standard mixture of authentic materials containing both monomers and dimmers. Unfortunately, NMR has traditionally been used as a less sensitive method compared to other analytical techniques. Conventional sample requirements for NMR are on the order of 10 mg, as compared with MS, which requires less than 1 mg.

(2) M.S.(Mass spectroscopy) has an increasingly significant impact on the pharmaceutical development process over the past several decades. Advances in the design and efficiency of the interfaces, that directly connect separation techniques with Mass Spectrometers have afforded new opportunities for monitoring, characterizing, and quantification of drug related substances in active pharmaceutical ingredients and pharmaceutical formulations. If single method fails to provide the necessary selectivity, orthogonal coupling of chromatographic techniques such as HPLC-TLC and HPLC-CE (High Performance Liquid chromatography coupled with Capillary Electrophoresis), or coupling of chromatographic separations with information rich spectroscopic

Methods such as HPLC-MS or HPLC-NMR may need to be contemplated, but hopefully only as a developmenttool rather than a tool for routine QC (Quality control) use[13-25].

Various applications have been sought in the areas of drug designing and in monitoring quality, stability, and safety of pharmaceutical compounds, where they have produced synthetically, extracted from natural products or produced by recombinant methods. The applications of alkaloids, amines, amino acids, analgesics, antibacterial, anticonvulsants, antidepressant, include tranquilizers, antineoplastic agents, local anesthetics, macromolecules, steroids, miscellaneous[26].In development of Bioanalytical method ,which is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them.

Qualificationof impurities is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing impurity acceptance criteria that includes safety considerations [20].

The studies considered appropriate to qualify the impurity will depend on a number of factors, Including the patient population, daily dose, route, and duration of drug administration. The following are descriptions of methods for qualifying impurities

An impurity of drug substance covered by an ANDA (Abbreviated New Drug Application) can be qualified by comparing the analytical profiles of the drug substance with those in an approved human drug product using the same validated, stability-indicating analytical procedure (e.g. comparative HPLC studies). This approved human drug product is generally the reference-listed drug (RLD). However, the impurity profile of a different drug product, having the same drug substance, with the same route of administration and similar characteristics (e.g., tablet versus capsule) may also be used if samples of the reference listed drug are unavailable, or in the case of an ANDA submitted pursuant to a suitability petition.

The level of the identified specified impurity is adequately justified by the survey of scientific literature, no further qualification is considered necessary. An impurity which is also a significant Metabolite of the drug substance is generally considered qualified.

Toxicity studies are the least preferred method to qualify impurities. The study is used only when impurities cannot be qualified by either of the above procedures. The toxicity tests are designed to detect compounds that induce general toxic or genotoxic effects in experimental systems. If performed, such studies should be conducted on the drug product or drug substance containing the impurities to be controlled, although in toxicity studies using isolated impurities may also be used [23]

In this article, we reviewed various articles which based on several areas including sample preparation, impurity separation and detection, Impurity profiling is very important during the synthesis of drug substances and manufacture of dosage forms, as it can provide several data regarding the toxicity, safety, various limits of detection, and limits of quantitation, of various organic and inorganic impurities, usually accompany with bulk drugs and finished products. An accurate method development and validation of the procedures make the impurity profiling task easy. In this we also propose pathway for determination of impurities and acceptance criteria based on general principles of ICH guidelines. Impurity Guideline for new drug substance is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. These are types of drug substances .Which are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived from, herbal products, and crude products of animal or plant origin.

The authors are very thankful to analytical department of Guru Ramdas Khalsa Institute of Science and Technology Pharmacy Jabalpur, for providing necessary facilities and help to make this review article.

1.S. Ahuja Impurities Evaluation of Pharmaceutical, Dekker, New York, 1998.
2.S. Gorog, Identification and Determination of Impurities in Drugs, Elsevier, Amsterdam, 2000.
3.S. Ahuja k. Alsante, Handbook Of Isolation And Characterization Of Impurities In Pharmaceuticals, Academic, San Diego, CA, 2003
4.T.W. Ryan, Anal. Lett. 31 (1998) 2447.
5.Hilhorst MJ, Choice of Capillary Electrophoresis Systems for the Impurity Profiling of Drugs, JPBA, 16, 1998, 1251-1260.
6.S. Gorog, M. Babjak, G. Balogh, J. Brlik, A. Csehi, F. Dravecz, M. Gazdag, P. Horvath, A. Lauko, K. Varga, Talanta 44, 1997, 1517.
7.Vasanti S , Sulabha S; Impurity profile- A review, Drug Invention Today 2009, 1(2),81-88.
8.Rishikesh. S. Deshmukh; Impurity Profile in Pharmaceutical Substances- A Comprehensive: A Review, International Journal of Pharmacy and Biological Sciences, Volume 1, Issue 4, Oct-Dec 2011, 382-392.
9.Federal Register (2000), “International Conferences on Harmonization”, Draft Revised Guidance on Impurities in New Drug Substances, Q3A(R), 45085-90.
10.ICH Topic Q3 A (1995) Impurities Testing Guideline: Impurities in New Drug Substances, The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit.
11.Deshmukh R.S., Impurity Profile in Pharmaceutical Substances- A Comprehensive: A Review, International Journal of Pharmacy and Biological Sciences, Volume 1, Issue 4, Oct-Dec 2011, 382-392.
12.Ingale S. J., advance approaches for the impurity profiling of pharmaceutical drugs: a review, IJPLS, vol. 2, issue 7 supply: July: 2011, 955-962.
13.Ahuja S, Assuring quality of drugs by monitoring impurities, Adv. Drug Deliv. Rev. 59, 2007, 3-11.
14.Chatwal GR, Anand SK, Instrumental Methods of Analysis, Himalaya Publishing House, Mumbai, India, 5th edition , 16.
15.Pavia DL, Lampman GM, Kriz GS, Introduction to spectroscopy, 3rd edition, Thomson Learning Inc, USA, 2001, 353-354.
16.Pavia DL, Lampman GM, Kriz GS, Introduction to spectroscopy, 3rd edition, Thomson Learning Inc, USA, 2001, 13-15.
17.Ahuja S, Alsante KM, Handbook of Isolation and Characterization of Impurities in Pharmaceuticals, 1st edition, volume 5, Academic Press, United Kingdom, 2003,16
18.Pavia DL, Lampman GM, Kriz GS, Introduction to spectroscopy, 3rd edition, Thomson Learning Inc, USA, 2001, 102-103.
19.Mistry N, Impurity profiling in bulk pharmaceutical batches using 19F NMR spectroscopy and distinction between monomeric and dimeric impurities by NMR based diffusion measurements, J. Pharm. Biomed. Anal.19, 1999, 511-517.
20.John CL et al, Directly coupled HPLC-NMR and HPLC-NMR-MS in pharmaceutical research and development, JCB, 748, 2000, 233-258.
21. Gorog S, The Changing face of pharmaceutical Analysis, Trends Anal. Chem. 26(1), 2007, 12-17.
22.Ante MK et al, Application of LC-MS methodology in the development of pharmaceuticals, LC-GC Europe.1, 2002, 2-9.
23. Fiori J et al, LC-TMS for the identification of impurities in d-allethrine samples, J.Chromatogr. A.1099, 2005,149.
24.Raymond PW, Chromatographic science services, Liquid chromatography for the Analyst, 67, Marcel Dekker, New York 1994, 1.
25.Munson WH, Pharmaceutical Analysis Modern Methods, Part B, Marcel Dekker, New York 2001, 16.
26.Lohr L. L., Sharp T. R., Alsante K. M., Hatajik T D, Isolation and Identification of Process Related Impurities and Degradation Products from Pharmaceutical Drug Candidates. Part II: The Roles of NMR and Mass Spectrometry, American Pharmaceutical Review, 2001.



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