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  • Impurity Profiling of Anti-Malarial Drugs
  • Photo Yash B Pokiya * Photo Vaishali V. Karkhanis

  • 1Department of Pharmaceutical Quality Assurance, A.R. College of Pharmacy & G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar
    2Department of Pharmaceutical Chemistry, A.R. College of Pharmacy & G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar
     

Abstract

Impurities are the unwanted materials which can interact with the pharmaceutical product and affects the quality of the product or the formulation. According to ICH guidelines, impurity is the part of the drug substance which affects the quality and purity of the active ingredients. Therefore, its identification and control is the major issue in the formulation industries. For the control and the limits of the impurity in the pharmaceutical dosage form, International Conference on Harmonization (ICH) formulated the guidelines for the impurity control and management. In this review, list of the sources of the impurity with their possible causes and effects with their suitable examples are given. Also, the regulatory body and guidelines involved in the detection and identification of the impurity are discussed. The article further discusses about the comprehensive information of the compendial methods and work done on the anti-malarial drugs with their possible impurities along with their structural elucidation and also the detection methods for the determination of impurity.

Keywords

Impurity, Impurity detection method, ICH, Anti-malarial class/Drugs, Degradation product

Introduction

Impurity:

The “International Council for Harmonisation and Technical Requirements for Pharmaceuticals for Human use (ICH)” presents the following definitions for impurities and impurity profile in new drug substances. An impurity is “Any component of the new drug substance that is not the chemical entity defined as the new drug substance. According to ICH Q3A (R) “Impurities in the New Drug Substance.” and ICH Q3B (R) “Impurities in the New Drug Product” a drug substance impurity is “any component of the new drug substance that is not the chemical entity defined as the new drug substance,” and a drug product impurity is “any component of the new drug product that is not the drug substance or an excipient in the drug product”.[1-3]Pharmaceutical impurities are those substances which co-exist with the API, or they may develop during synthesis or ageing of both API and formulation. The presence of these impurities even in minor amounts can influence the efficacy and safety of drug. The safety of drug is dependent not only on the toxicological properties of active drug substance itself, but also on impurities that it contains. As safety and quality of pharmaceutical products can be affected by impurities present in APIs, impurity profiling of API has started gaining wider traction. Therefore identification, isolation and quantification of impurities are an important part of drug development and regulatory assessment. In synthetic organic chemistry, it is necessary to submit qualitative and quantitative report on impurities along with API’s so that drug authorities and customer of bulk drug production can use these impurities as a reference standard. Once chemical structure of impurities is reported the reaction conditions or process of manufacturing API can be altered so as to eliminate traceable amount of an impurity to an acceptable level. Impurity profiling gives an account of impurities present in an API/ bulk/ finished products, thus it acts as a quality control tool. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products.[4] In a pharmaceutical product, an impurity is first and foremost a quality issue, since it could potentially compromise the efficacy of the drug product. Secondly, impurities also cause safety concerns. Hence, any impurity present in a drug product must be fully understood, both qualitatively (chemically) and quantitatively, and qualified, if necessary, through toxicological assessment. From a chemical perspective, pharmaceutical impurities are inevitable because no chemical reaction has 100% selectivity, and no chemical compound is “rock” stable. [5-7]

Impurity profile:

Impurity profile is “A description of the identified and unidentified impurities present in a new drug substance”. Impurity profiling is the common name of analytical activities for the detection, identification/structure elucidation and quantitative determination of organic and inorganic impurities as well as residual solvents in bulk drugs and pharmaceutical formulations. [8] In general, according to ICH guidelines on impurities in new drug products, identification of impurities below the 0.1% level is not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic. In all cases, impurities should be qualified. If data are not avail-able to qualify the proposed specification level of an impurity, studies to obtain such data may be needed (when the usual qualification threshold limits given below are exceeded). According to ICH, the maximum daily dose qualification threshold is considered as follows ? 2g/day 0. 1 % or 1 mg per day intake (whichever is lower) ? 2g/day 0.05%. [9]

Table 1: Sources of impurities:

       
            Screenshot 2024-08-30 203124.png
       
    

Impurity detection methods:

To evaluate the impurity in the synthesis of APIs, formulation of the product or in the finished product several methods are available to evaluate it includes:

•           Isolation methods

•           Separation methods

•           Characterization methods

Table 2: Impurity detection methods

       
            Screenshot 2024-08-30 203211.png
       
    

Regulatory guidelines for determination of impurities:

Monitoring and controlling of impurities imply different things. Therefore, simple terminology should be used to address questions related to impurities. The United States food and drug administration (US-FDA) has endorsed the guidelines prepared by International Conference on Harmonization (ICH). The ICH guidelines for impurities were developed with joint efforts of various regulators such as European Union (EU), Japan and United States and they help in ensuring consistent requirement of data that should be submitted to various regulatory agencies. The guidelines are not only to aid the sponsors of New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) with information that should be submitted along with their applications, but also assists FDA reviewers and field investigators in consistent implementation and interpretation of regulations.

The various regulatory guidelines are as follows:

•           ICH guidelines “Stability Testing of New Drug Substances and Products”- Q1A.

•           ICH Guidelines “Impurities in New Drug Substances”- Q3A.

•           ICH Guidelines “Impurities in New Drug Products”- Q3B.

•           ICH Guidelines “Impurities: Guidelines for Residual Solvents”- Q3C.

•           US-FDA Guidelines “NDAs- Impurities in New Drug Substances”.

•           US-FDA Guidelines “ANDAs- Impurities in New Drug Substances”.

•           Australian Regulatory Guideline for Prescription of Medicines, Therapeutic Governance Authority (TGA), Australia. [35-37]

Impurity profiling of Anti-Malarial drugs:

Malaria is the most common and important parasitic disease in humans. About three billion people in the world live at risk of contracting malaria.[1] In humans, malaria is caused by one of the five species of the genus Plasmodium: P. vivax, P. malarie, P. falciparum, P. ovale and P. knowlesi.[2] There are several drugs and their formulations available for the treatment of Malaria.

Table 3: Classification of anti-Malarial drugs:

       
            Screenshot 2024-08-30 203258.png
       
    

Table 4: Impurity profiling of compendial anti-malarial drugs:

       
            Screenshot 2024-08-30 203329.png
       
    

 

Table 5: Work done on impurity profiling of the anti-malarial drugs:

       
            Screenshot 2024-08-30 203413.png
       
    

 

CONCLUSION:

  • Impurity profiling has become the major source of the identification nowadays because of the interference of the impurity in the finished product or the prepared formulation in the pharmaceutical industry.
  • Isolation and characterization of the impurities are required for the biological and pharmacological data. Therefore, some regulatory bodies and various pharmacopoeia makes impurity profiling and monitoring mandatory.
  • This review provides information on the sources of impurity and their regulatory guidelines.
  • It aims to provide collective data on impurity profiling done on various antimalarial drugs in the past decades.
  • It also includes the impurities mentioned in the pharmacopoeias for the anti-malarial agents and their detection methods.
  • Thus, overall discussion provided above about impurity profiling of anti-malarial drugs would be of broader interest to the researchers working on the related formulations.

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Reference

  1. ICH Harmonised Tripartite Guideline, Impurities in New Drug Substances Q3A(R2), Current Step 4 version dated 2006; 6.
  2. S. Görög (Ed.), Identification and Determination of Impurities in Drugs, Elsevier, Amsterdam, 2000; 84-96.
  3. Bartos, S. Görög, Recent Advances in the Impurity Profiling of Drugs, Curr. Pharm. Anal. 2008; 215-230.
  4. Federal register International Conference on Harmonization, Draft Revised Guidance on Impurities in New Drug Substances, Q3A (R), 2000; 45085-90.
  5. FDA draft guidance: Non-clinical studies for development of pharmaceutical ingredients. 2002.
  6. ICH Q6A Specifications: Test procedures and Acceptance Criteria for New Drug Substances and New Drug products: Chemical Substances. 2000.
  7. EMEA CPMP note for Guidance on specification limits for residuals of metal Catalysis. 2002.
  8. Alsante KM, Hatajik TD, Lohr LL, and Sharp TR. Isolation and identification of process related impurities and degradation products from pharmaceutical drug candidates. Part 1. American Pharmaceutical Review. 2001; 4(1): 70-78
  9. International Conferences on Harmonization, Impurities-- Guidelines for Residual Solvents. Q3C. Federal Register. 1997; 62-67.
  10. S. Gorog, A. Lauko, B. Herényi, Estimation of impurity profiles in drugs and related materials. J. Pharma. Biomed. Ana, 1988; 6: 697-705.
  11. Muehlen, E. Impurities in starting materials and drugs. Pharmazeut. Ind, 1992; 4: 837-41.
  12. Alsante KM, Hatajik TD. Isolation of process related impurities and degradation products from pharmaceutical drug candidates. Am. Pharm. Rev., 2001; 4(10): 70-4.
  13. Connor KA, Amidon GJ, Stella VG. Chemical stability of pharmaceuticals, A handbook for pharmacists, New York, John Willey & Sons, 1986; 224-332.
  14. Khushwala P. Organic Impurities in pharmaceuticals. Pharma Info. Net, 2008; 6(4).
  15. Shah SR, Patel MA, Naik MV, Upadhyay UM. Recent approaches of impurity profiling in pharmaceutical analysis: A Review. Int. J. Pharm. Sci. Res. 2012; 3(2): 3603-17.
  16. Hoerle SL, Evans KD, Snider BG. Determination of impurities, Eastern analytical symposium, 1992; 16-20.
  17. Patil P, Vaidya I. Overview on impurity. Int. J. Pharm. Res. Scholars, 2013; 2(1): 54-65.
  18. Sapra A, Kakkar S, Narisimhan B. Sources of impurities: A Review. Int. Res. J. Pharm, 2012; 2(3): 57-9.
  19. Chatwal, GR. Pharmaceutical inorganic chemistry, Himalaya Publishing House, 1; 1991.
  20. Roy J, Patil P. Pharmaceutical impurities-A mini review. AAPS pharm Sci Tech, 2002; 3(2): 2: 1-8.
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  22. Atici EB Karl?ga B. Identification, synthesis and characterization of process related desfluoro impurity of Ezetimibe and HPLC method validations, J. Pharm. Anal, 2015; 5(6): 356-70.
  23. Roy J. Diclofenac sodium injection sterilized by autoclave and the occurrence of cyclic reaction and producing the small amount of impurity. J. Pharm. Sci., 2001; 34(2): 541-44.
  24. Vijaylaxmi R, Kumaravel S, Anbazhagan S. Scientific approaches for impurity profiling in new pharmaceutical substances and its products-An Overview. Int. J. Pharm. Chem. Sci., 2012; 1(1): 386-40.
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  31. Sutar N, Garai R, Sharma US, Sharma UK. Anthelmintic activity of Platycladusorientalis leaves extract. Int. J. Parasitol. Res., 2010; 2(2): 1-3.
  32. Parimoo P, et al, A Textbook of Pharmaceutical Analysis, CBS Publishers & Distributors, 1998; 14.
  33. Ahuja S. Chiral separations by chromatography, Oxford University Press, NY: 1997; 365.
  34. Basak AK, Raw AS, Al hakim AH, Furness S, Gill DS. Pharmaceutical impurities: Regulatory perspective for abbreviated new drug applications. Adv. Drug Deliv. Rev, 2007; 59(1): 64-72.
  35. Roy J. Pharmaceutical impurities- a mini review. AAPS pharm SciTech, 2002; 3(2): 1-8.
  36. ICH harmonized triplicate guideline: Impurities in New Drug Substances Q3A (R2), ICH steering committee, step 4 of ICH process: 2006.
  37. ICH harmonized triplicate guidelines: guideline for residual solvents Q3C (R3), ICH steering committee, and step 4 of ICH process: 2005.
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Photo
Yash B Pokiya
Corresponding author

Department of Pharmaceutical Quality Assurance, A.R. College of Pharmacy & G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar

Photo
Vaishali V. Karkhanis
Co-author

Department of Pharmaceutical Chemistry, A.R. College of Pharmacy & G.H. Patel Institute of Pharmacy, Vallabh Vidyanagar

Yash B Pokiya , Vaishali V. Karkhanis , Impurity Profiling of Anti-Malarial Drugs, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 8, 3963-3989. https://doi.org/10.5281/zenodo.13619629

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