Impurity Profile: A Review

The subject of impurities evaluation of pharmaceutical compounds has been insufficiently addressed in scientific literature up to this time. Reasons for this shortcoming are many and varied. As a matter of fact, because of the apparent negativity attaches to the word, there is no clear definition for impurity in the pharmaceutical world. Terms such as byproduct, transformation products, degradation products, interaction products and related products are frequently used. The impurities related to residual solvents used in the preparation of pharmaceutical compounds or marketed drug products are frequently referred to as organic volatile impurities (OVI).

And the impurities related to the inert ingredients (excipients) used in the pharmaceutical formulations or pharmaceutical adjuvant used in the preparation of the marketed drug products is rarely mentioned.

It is necessary to incorporate stringent tests to control the impurities arising from different sources that are variously described, as explained above. This fact is also evident from the requirements of the federal food, drug and cosmetic act and from a large number of pharmacopoeias that provide test for the control of specific impurities. A new drug development process should include an armamentarium of physicochemical tests to fully define the purity of a pharmaceutical compound prior to performance of extensive pharmacologic and toxicological studies. This is essential to assure that the observed pharmacologic or toxicological effects are truly due to the compound of interest and not due to impurities. Further more, it is important to ensure that the product formulated for marketing does not generate any impurities during its shelf life that would cause deleterious effects.

IMPURITY PROFILE:

There is no precise definition for impurity profile. It gives an account of impurities present in it. Impurity profile of a substance under investigation gives maximum possible types of impurities present in it. It also estimates the actual amount of different kinds of impurities present in it.

IMPURITY: Any material that affects the purity of the material of interest viz. active ingredient or drug substance. The impurities are not necessarily always inferior. From the standpoint of its usage, the drug substance is compromised in terms of purity even if it contains another material with superior pharmacological or toxicological properties^.[1]

SOURCES OF IMPURITIES IN DRUG PRODUCTS:

In general, the various types of impurities that may be present in pharmaceutical substances can come from the following sources:

1. The raw materials used.
2. The method of manufacture adopted.
3. Due to the instability of product and
4. From the atmospheric contaminants ^[2]

TYPES OF IMPURITIES IN ORGANIC MEDICINAL SUBSTANCES:

Organic medicinal substances get contaminated in exactly the same manner as inorganic substances during their manufacturing processes. Since the organic substances belong to a very wide range of chemical groups and at the same time the contaminating impurities being of varied nature the task of detecting the impurities becomes a difficult job. Therefore, the contaminating impurities for organic medicinal compounds can be classified into: -

a. Inorganic impurities

b. Organic impurities

c. Contamination by chemical intermediates ^[3]

SOURCES OF IMPURITIES IN PHARMACEUTICAL CHEMICALS:

Knowledge of those impurities, which occur in pharmaceutical substances in general use, is readily from actual batch analysis and stabilities studies. Experience in the manufacture any one particular substance often shows that not all the expected impurities are present in practice.

But for a substance newly available it is important that one would be able to deduce the impurities with which it is likely to be contaminated. A list of the possible impurities can be readily compiled from knowledge of the raw materials used, the method of manufacture and the stability of the product. To these must be added impurities, which may arise from physical contamination or inadequate storage conditions.^[4]

Indian pharmacopoeia specifies qualitative, quantitative or semi quantitative tests for limiting known impurities in certain drugs. The list of few such drugs and corresponding impurities is as follows

^[5]

ICH GUIDELINES FOR IMPURITY PROFILE:

Impurities in New Drug Substances and drug products are dealt with new approaches to quantification and qualification. Regulatory requirements for the identification, quantification and control of impurities in drug substances and their formulated products are now being increasingly explicitly defined, particularly through the International Conference of Harmonization. The implications of recent are important both from their regulatory impact and the impact upon analytical technology.^[6]

This document 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

Biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation and semi-synthetic products derived there from, herbal products, and crude products of animal or plant origin are not covered under it.

IN ICH GUIDELINES IMPURITIES IN NEW DRUG SUBSTANCES ARE ADDRESSED FROM TWO PERSPECTIVES:

Chemistry Aspects includes classification and identification of impurities, report generation, setting specifications, and a brief discussion of analytical procedures; and Safety Aspects includes specific guidance for qualifying impurities that were not present in batches of new drug substance used in safety and clinical studies and/or impurity levels substantially higher than in those batches. Threshold limits are defined at or below which, qualification is not needed.

RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES:

The applicant should summarize those actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substance. This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials, which could contribute to the impurity profile of the new drug substance, and possible degradation products. This discussion may include only those impurities that may reasonably be expected based on knowledge of the chemical reactions and conditions involved. In addition, the applicant should summarize the laboratory studies conducted to detect impurities in the new drug substance.

The studies conducted to characterize the structure of actual impurities present in the new drug substance at a level greater than (>) the threshold given in Attachment 1 of ICH guidelines (e.g., calculated using the response factor of the drug substance) should be described. All specified impurities at a level greater than (>) the identification threshold in batches manufactured by the proposed commercial process should be identified analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacologic effects at a level less than or equal to the identification threshold. All impurities should be qualified as described in guide.

The registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantitation of impurities (see ICH Q2A and B guidelines for analytical validation). Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed in the registration application. Reference standards used in the analytical procedures for control of impurities should be evaluated and characterized according to their intended uses. Specifications and analytical procedures used to estimate identified or unidentified impurities are often based on analytical assumptions (e.g., equivalent detector response, etc.). These assumptions should be discussed in the registration application. Analytical results should be provided for all batches of the new drug substance used for clinical, safety, and stability testing, as well as for batches representative of the proposed commercial process. Impurities should be designated by code number all impurities at a level greater than (>) the reporting threshold should be summed and reported as Total Impurities. When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate validation information provided. Representative chromatograms should be provided.

The applicant should ensure that complete impurity profiles (i.e., chromatograms) of individual batches are available if requested.

SPECIFICATIONS FOR IMPURITIES:

The specifications for a new drug substance should include limits for impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product.

A rationale for the inclusion or exclusion of impurities in the specifications should be presented. This rationale should include a discussion of the impurity profiles observed in the safety and clinical development batches, together with a consideration of the impurity profile of material manufactured by the proposed commercial process.

QUALIFICATION OF IMPURITIES:

Qualification 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) specified.^[7]

U.S. Department of Health and Human Services, Food and Drug Administration

Center for Drug Evaluation and Research (CDER) in January 2005 has given a draft for Guidance for Industry on “ANDAs: Impurities in Drug Substances ”. This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. One can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.

CHARACTERIZATION OF IMPUITIES:

Once an impurity has been detected, it becomes necessary to estimate its content. Detect ability frequently means that a given component provides a signal at least twice that of background noise or baseline. At times the multiple is set higher for greater assurance. Initial estimation are generally done against the parent compound because in most cases the authentic sample of impurity is not available. It is important that the authentic sample should be used 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^.[9]

5. GENERAL SCHEME FOR DRUG IMPURITY PROFILING.

^[10]

Highly sophisticated instrumentation, such as mass spectra meters attached to a gas chromatography or HPLC, are inevitable tools in the identification of minor components (drugs, impurities, degradation products, metabolites) in various matrices.

NMR spectroscopy, which involves complete structure elucidation, which may require the isolation of larger components (usually by preparative HPLC). Since Mass and NMR are very expensive and in the latter case very time consuming UV rapid scanning using the diode-array detector attached to HPLC is better alternative. But the UV-HPLC method to determine impurity profile only, provi0ded the impurity is spectrophotometrically active.

Although the successful application of HPLC/diode-array UV detectors in the identification of the above mentioned minor components is restricted to those cases where the components is spectrophotometrically active and its spectrum differs sufficiently from that of the main components (parents drugs) and from other small components, this technique can be successfully used in the impurity profiling of drugs.^[11]

PURPOSEFUL DEGRADATION STUDIES:

This technique helps in identification of impurities specially of a new drug or a chemical. The substance in question is subjected to a known degradation process and the products thus obtained are identifies. As we know the degradation process (may be oxidation or hydrolysis) we have an idea what could be the degradation products. These can be listed and kept as a reference library of degradation products. Then routinely doing an impurity profile one can take help from this library and trace the nature and structure of the impurity.^[12]

{mospagebreak title=Analytical challenges}

ANALYTICAL CHALLENGES TO CURRENT METHODS AND POTENTIAL NEW METHODS:

While the threshold for identification and qualification of organic impurities is set at 0.1% for the majority of compounds, it is important to recognize that the implication is that a limit of quantification (LOQ) of approximately 0.05% will be required:

For a compound that is 98% pure, the 2% impurities could be composed of between 10 and 20 components at a level of scrutiny of 0.05%. In future, it may become essential to increase selectivity through the use of gradient separation, both in HPLC and TLC, or through the use of alternative technologies. However, gradient HPLC is the more usual technique, If single methods fail to provide the necessary selectivity, orthogonal coupling of chromatographic techniques such as HPLC-TLC and HPLC-CE, or coupling of chromatographic separations with information rich spectroscopic methods such as HPLC-MS or HPLC-NMR may need to contemplated, but hopefully only as a development tool rather than a tool for routine QC use. The further may see the significantly increased use of spectroscopic techniques for impurity measurement. NMR has shown values for stereo isomers and for process related impurity, but still does not quite show the sensitivity required. Near-infrared spectroscopy in rapidly increasing in use and can detect impurities, although more demonstrations of true validation for low levels of impurities are required.

One single method that is showing great promise in pharmaceutical analysis is capillary electrophoresis (CE). With its much increased efficiency and great variety of separation modes it may provide sufficient peak capacity, and indeed CE is finding increasing favour for pharmaceutical analysis. CE also adds speed to selectivity, and many of the concerns over the robustness and transferability of CE separations have been dispelled recently through a number of collaborative studies. Additionally, while enantiomers are outside the scope of the current ICH guidelines, there is no doubt that, when they are potential impurities, their level(s) must be controlled. CE-MECC can provide the necessary detectabilty to control enantiomers to the 0.1% level^.[13]

CONCLUSION:

Quality assurance is a vast, concept. Any new input in the form of modification of existing methods of ensuring quality is take-up in CGMP… in this sense in a dynamic process. Q.C. is a part of Q.A.

Carrying out assay of a substance with maximum possible sensitivity is the aim of Q.C. of a substance. But it is incomplete in one sense that it does not give you any account of impurities present in it. This concept leads to an area of IMPURITY PROFILING. Impurity profile of a substance under investigation gives maximum possible account of impurities present in it.

The establishment of guidelines for impurity levels in drug substances and products now provides the quality criteria for manufacturers. The key aspect is that the impurity profile of a new chemical entity must be shown to be qualified. With a qualification threshold pf 0.1%, or lower for high dose compounds, the pharmaceutical analyst must give careful thought to their analytical technology. Especially in the development phases it may be necessary to utilize methods with high selectivity, including hyphenated techniques. The importance of qualifying impurity profiles are relevant to the development scientists to ensure consideration is given to the impurities present in the batches being used in safety studies starting from limit tests for impurities, this field of impurity identification and quantitation has progressed. With newer techniques like U.V. spectroscopy with diode array detection, HPLC, GCIR, NMR, CE-MECC. This review article is an attempt to understand the concept of impurity profile and various aspects and techniques related to it.

References

1.Ahuja S: Impurities Evaluation Of Pharmaceuticals. New York: Marcel , Dekker, 1998, 1.

2.Parimoo P: A Text Book Of Pharmaceutical Analysis. New Delhi: CBS publishers and distributors, 1998, 14.

3.Parimoo P:A Text Book Of Pharmaceutical Analysis. New Delhi: CBS publishers and distributors, 1998, 20, 21.

4. Beckett AH, Stanlake JB: Practical Pharmaceutical Chemistry. New Delhi: CBS Publishers and distributors, 2002, 2.

5.I.P.1996 (Indian Pharmacopoeia-1996) Govt. of India, Ministry of Health and Family Welfare, Vol.-I, 1996 Edition, published by the Controller of Publication, Delhi.

6.Journal of Pharmaceutical and Biomedical Analysis, 14 (1995), 7-12 Cross Reference-

a. Proc. First Int. Conference on Hormonisation. P.F. D’Arey and D.W.G. Harron, Queen’s University of Belfast 1992

b. J.M Davis and J.C.Gidding, anal chem.. 55(1983)418.

c. E.Grushka, J.chromatography 316(1984)81

d. M.Martin and G.Guiochon, anal chem.. 56(1985)289.

e. C.T.Banks, J.Pharm Biomed anal 11(8)(1993)705-710

f. US Patent No-5131,998,1993

g. B.Lindgren and J.R.Martin, pharm Europa5(1)(1993)51-54

h. S.Gorog,G.Balogh and M.Gazdag, J.Pharm, Biomed.Anal

i. C.Vander Vleis,J. Pharm BIomed.Anal. 11(6)1993

j. N.W.Smith and MB.Evans

k. K.D.Altria, R.C harden,M.Hart, J.Hevizi, P.A.Hailey, J.Makewana, M.J.Portsmouth.

l. K.D.Altria and M.T. Kersey

m. J.E Noroski,D.J.Mayo and M.Moran

7. ICH Guidelines (international conference of harmonization)

8. U.S. Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER) January 2005,OGD Revision Guidance for Industry ANDAs: Impurities in Drug Substances.

9. Ahuja S: Impurities Evaluation Of Pharmaceuticals. New York: Marcel Dekker, 1998, 42.

10. International Journal - Talenta Year 2000

11. Journal of Pharmaceutical and Biomedical Analysis, 14 (1995), 7-12

Cross references -

a. Proc. First Int. Conference on Hormonisation. P.F. D’Arey and D.W.G.

Harron, Queen’s University of Belfast 1992

b. J.M Davis and J.C.Gidding, anal chem.. 55(1983) 418.

c. E.Grushka, J.chromatography 316(1984) 81

d. M.Martin and G.Guiochon, anal chem.. 56 (1985) 289.

e. C.T.Banks, J.Pharm Biomed anal 11(8)(1993) 705-710

f. US Patent No-5131, 998,1993

g. B.Lindgren and J.R.Martin, pharm Europa5 (1)(1993)51-54

h. S.Gorog,G.Balogh and M.Gazdag, J.Pharm, Biomed.Anal

i. C.Vander Vleis,J. Pharm BIomed.Anal. 11(6) 1993

j. N.W.Smith and MB.Evans

k. K.D.Altria, R.C harden,M.Hart, J.Hevizi, P.A.Hailey, J.Makewana,

M.J.Portsmouth.

l. K.D.Altria and M.T. Kersey

m J.E Noroski,D.J.Mayo and M.Moran

12. Satinder Ahuja, Hand Book of Modern Pharmaceutical Analysis. NewYork : Marcel Dekker, 2001

13. Ahuja S: Impurities Evaluation Of Pharmaceuticals. New York: Mercel Dekker, 1998, 42.

Ms. Meera S. Honrao * (M. Pharm.Quality Assurance), Assistant Professor, S.T.E.S.’s Smt. Kashibai Navale College of Pharmacy, Kondhwa(Bk), Pune, Maharashtra, India. Meera has saveral puublished papers for her credit.

*Corresponding author : hmeera@yahoo.com

Ms. Minal S. Kulkarni (M. Pharm.) Lecturer, S.T.E.S.’s Smt. Kashibai Navale College of Pharmacy, Kondhwa(Bk), Pune, Maharashtra, India.

Mr. Pramod S. Kaldate (B. Pharm.) Lecturer, S.T.E.S.’s Sinhgad Institute of Pharmaceutical Sciences (Polytechnic), Lonavala, Maharashtra, India.

Mr. Javed Akhtar Ansari.(B.Pharm.),M.C.E. Society’s Allana College of Pharmacy,Pune, Maharashtra, India