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Regulatory requirements-Chiral drugs.pptx

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Regulatory requirements-Chiral drugs.pptx

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There is a trend in pharmaceutical industry towards the development of chiral drugs. Several factors have
influenced this trend in the pharmaceutical industry towards the development of the chiral drugs to provide more
potent selective and specific drugs. Over 1/3 rd of the marketed drugs worldwide are chiral and the regulators now
only will approve new chiral drugs in the single enantiomer form and even then insists on full profiling of the role
of the individual enantiomers invivo. The importance of chirality lies not only in the product development but in
the area of analytical and bioanalytical method development. Development of chiral analytical method/bioanalytical methods as per regulatory requirements requires a series of selection process to get the adequate resolution and quantification. Selection of compatible mobile phases and stationary phase that suits the particular need is very important. This presentation gives a brief description of chiral products, excipients followed by
functions and effects of its chiral forms. This presentation also describes the case studies of the chiral quantification in bioanalytical and analytical methods and their applications.

There is a trend in pharmaceutical industry towards the development of chiral drugs. Several factors have
influenced this trend in the pharmaceutical industry towards the development of the chiral drugs to provide more
potent selective and specific drugs. Over 1/3 rd of the marketed drugs worldwide are chiral and the regulators now
only will approve new chiral drugs in the single enantiomer form and even then insists on full profiling of the role
of the individual enantiomers invivo. The importance of chirality lies not only in the product development but in
the area of analytical and bioanalytical method development. Development of chiral analytical method/bioanalytical methods as per regulatory requirements requires a series of selection process to get the adequate resolution and quantification. Selection of compatible mobile phases and stationary phase that suits the particular need is very important. This presentation gives a brief description of chiral products, excipients followed by
functions and effects of its chiral forms. This presentation also describes the case studies of the chiral quantification in bioanalytical and analytical methods and their applications.

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Regulatory requirements-Chiral drugs.pptx

  1. 1. CHIRALITY IN PHARMACEUTICAL PRODUCT DEVELOPMENT: A REGULATORY PERCEPTIVE Kishore Kumar Hotha., PHD
  2. 2. INTRODUCTION WHAT IS CHIRALITY IMPORTANCE FOR DRUG DESIGN IMPACT ON TODAY PORTFOLIO POTENTIAL ADVANTAGES DIFFERENCES REGULATORY REQUIREMENTS Pharmacokinetics Toxicity Stability Labeling
  3. 3. WHAT IS CHIRALITY Chirality is a property of asymmetry related to three- dimensional structure. Human hands represent a special illustration of chirality because they are related to each other by a reflection: they are non-super imposable mirror images of each other. Hands are chiral because there is no way to rotate the left hand so that it looks like the right hand .In chemistry, stereo isomers are molecules that have the same molecular formula or atomic composition, but which are arranged differently in space.
  4. 4. IMPORTANCE FOR DRUG DESIGN Enantiomers of compounds can react differently in the body, with greatly helpful or harmful outcomes “Many molecules are chiral, and their unique handedness has both intricate and dramatic influences on how they interact with biological systems.”
  5. 5. IMPORTANCE FOR DRUG DESIGN Molecular chirality is a fundamental phenomenon that plays an important role in biological processes. A wide range of biological and physical functions are generated through precise molecular recognition because enzymes, receptors and other natural binding sites within biological systems interact with different enantiomers in decisively in different ways As a result of such chiral recognition, drug enantiomers may differ in their pharmacokinetic handling and their pharmacological and/or toxicological profiles
  6. 6. Importance For Drug Design German drug maker Chemie Grünenthal introduced thalidomide, under the name Contergan, to the German market on Oct. 1, 1957 It was a sedative to treat insomnia as well as to reduce nausea associated with pregnancy. By 1960, the drug was in more than 20 countries in Europe and Africa. On Nov. 18, 1961, the German paper Welt am Sonntag reported on a study finding that pregnant women who had been taking thalidomide were giving birth to babies with gross deformities. "By November 27, Grünenthal had pulled the drug off the market, blaming the sensationalism of the press"
  7. 7. IMPACT ON TODAY’S GENERIC PORTOFOLIO Today it is often easier to submit single enantiomeric chiral drugs rather than racemic chiral drugs Old racemates are often reassessed as single enantiomers Synthesis, separation and analysis of chiral compounds has advanced greatly, and is highly sought
  8. 8. Potential advantages of single enantiomer products Less complex, more selective Pharmacodynamic profile Potential for an improved therapeutic index Less complex pharmacokinetic profile Reduced potential for complex drug interactions Less complex relationship between plasma concentration and effect
  9. 9. SOME DIFFERENCES • “the mean daily dose … was reduced by approximately one third compared to the racemate” • “the cardio toxicity of the drug appears to be predominantly associated with the (R)-enantiomer” • “significantly reduced negative isotropic effect (approximately half) was observed with the single enantiomer compared to the mixture” • “between 130 and 160 fold more potent than the (R)- enantiomer” • “faster onset of action, reduction of side effects and improved tolerability profile” • “the S-enantiomer being effectively inactive”
  10. 10. REGULATORY REQUIREMENTS Applications for drug products that contain an enantiomer or racemic drug substance should include a stereo chemically specific identity test and/or a stereo chemically selective assay method. The choice of the controls should be based upon the product's composition, method of manufacture and stability characteristics.
  11. 11. REGULATORY REQUIREMENTS STABILITY The stability protocol for enantiomeric drug substances and drug products should include a method or methods capable of assessing the stereo chemical integrity of the drug substance and drug product. However, once it has been demonstrated that stereo chemical conversion does not occur, stereo selective tests might not be needed
  12. 12. REGULATORY REQUIREMENTS Pharmacology The pharmacologic activity of the individual enantiomers should be characterized for the principal pharmacologic effect and any other important pharmacological effect, with respect to potency, specificity, maximum effect, etc.
  13. 13. REGULATORY REQUIREMENTS Pharmacology The pharmacologic activity of the individual enantiomers should be characterized for the principal pharmacologic effect and any other important pharmacological effect, with respect to potency, specificity, maximum effect, etc.
  14. 14. REGULATORY REQUIREMENTS Pharmacokinetic profile To monitor in vivo inter conversion and disposition, the pharmacokinetic profile of each isomer should be characterized in animals and later compared to the clinical pharmacokinetic profile obtained in phase 1
  15. 15. REGULATORY REQUIREMENTS Toxicology It is ordinarily sufficient to carry out toxicity studies on the racemate. If toxicity other than that predicted from the pharmacologic properties of the drug occurs at relatively low multiples of the exposure planned for clinical trials. The toxicity study where the unexpected toxicity occurred should be repeated with the individual isomers to ascertain whether only one enantiomer was responsible for the toxicity.
  16. 16. REGULATORY REQUIREMENTS Toxicology If toxicity of significant concern can be eliminated by development of single isomer with the desired pharmacologic effect, it would in general be desirable to do so. The agency would be pleased to discuss any cases where questions exist regarding the definition of "significant toxicity."
  17. 17. REGULATORY REQUIREMENTS • LABELING The labeling should include a unique established name and a chemical name with the appropriate stereo chemical descriptors.
  18. 18. REGULATORY REQUIREMENTS IMPURITY LIMITS It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants on the compound tested preclinical that is intended for use in clinical trials. The maximum allowable level of impurity in a stereoisomeric product employed in clinical trials should not exceed that present in the material evaluated in nonclinical toxicity studies.
  19. 19. CURRENT CHIRAL METHODS: COST AND TIME • SEPARATION • Preparative chiral chromatography • Cheaper despite waste • Applicable to most small chiral molecules • Crystallization of diastereomeric salts • SELECTIVITY • Chiral pool • A lot of catalysis • Enantioselective processes • Conversion of enantiomers “Speed is essential, and you don’t always have the luxury of trying to come up with the best synthesis”
  20. 20. CURRENT CHIRAL METHODS:APPROACH Enantiomeric supply and absolute configuration Detector response and racemization potential Instrumentation and flexibility of the application Chiral derivatization reaction, diastereomer confirmation and stability Stereo selective kinetics of diastereomers formation (kinetic resolution) Chromatography, separability and elution order
  21. 21. CONCLUSION Chiral drugs are very important, in terms of efficacy and applications in the human body, but they are not a universal solution, and there are still many risks in their development. “Nature has a way of knowing how to make things work. Reactions often run in a catalytic mode, and material use, energy, and waste are minimized. Many molecules are chiral, and their unique handedness has both intricate and dramatic influences on how they interact with biological systems.”
  22. 22. THANK YOU

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