Forced Degradation Study-dharati

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Information about Forced Degradation Study-dharati

Published on June 22, 2012

Author: Amitsss15


Forced Degradation Study: Forced Degradation Study Prepared & Presented By : Rami Dharati M.Pharm {QA} Roll no: 04 Guided By : Mr. Jaimin Patel PowerPoint Presentation: Forced degradation studies or Stress testing studies is the process of subjecting drug compounds [ i.e Drug substance, Drug products,Placebo ] to extreme chemical and environmental conditions to determine product breakdown levels and preliminary degradation kinetics , and to identify degradant species. The current regulatory guidance documents governing forced degradation studies are very general. One of the guidance documents, Q1A (R2) – Stability Testing of New Drug Substances and Products, states: PowerPoint Presentation: “ Stress testing is likely to be carried out on a single batch of the drug substance. The testing should include the effect of temperatures ( in 10°c increments ( ie , 50°c, 60°c) above that for accelerated testing ), humidity ( ie , 75% relative humidity or greater ) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension .” PowerPoint Presentation: According to the available guidance , forced degradation studies are carried out for the following reasons/ Objectives : (1) determination of degradation pathways of drug substances and drug products; (2) discrimination of degradation products in formulations that are related to drug substances versus those that are related to non-drug substances ( eg , excipients ); PowerPoint Presentation: (3) structure elucidation of degradation products; (4) determination of the intrinsic stability of a drug substance molecule in solution and solid state; and (5) reveal the thermolytic , hydrolytic, oxidative, and photolytic degradation mechanism of the drug substance and drug product. PowerPoint Presentation: (6) To develop and validate a stability indicating method (7) To determine degradation pathways of drug substances and drug products (e.g., during development phase) (8) To identify impurities related to drug substances or excipients (9) To understand the drug molecule chemistry PowerPoint Presentation: (10) To generate more stable formulations (11) To generate a degradation profile that mimics what would be observed in a formal stability study under ICH conditions (12) To solve stability-related proble ms (e.g., mass balance) PowerPoint Presentation: Key Point to be kept in mind : The degradation products generated in the stressed samples are termed as “ potential ” degradation products that may or may not be formed under relevant storage conditions. PowerPoint Presentation: There are Different Forced Degradation Conditions used for Drug substances and Drug Products which is given in following chart- Four major forced degradation studies are : Four major forced degradation studies are Condition generally employed for forced degradation study: Condition generally employed for forced degradation study PowerPoint Presentation: [1] THERMOLYTIC DEGRADATION : Determine the Melting Point of the Analyte . Drugs for which melting point is <150°C , Stress at 70°C or about 40°C below the melting point, which ever is higher. Drugs for which melting point is >150°C , Stress the samples at 105°C . PowerPoint Presentation: THERMOLYTIC DEGRADATION : How long to stress?. What if the degradation is not achieved?. THERMOLYTIC DEGRADATION : Stress for a week time , Observe the sample. Test the sample in between. Achieve a degradation between 5 to 20%. If no degradation is achieved even after harsher stress, justification can be provided that the molecule is stable . PowerPoint Presentation: [ 2]HYDROLYTIC DEGRADATION : Drug degradation that involves reaction with water is called Hydrolysis. Degradation which is due to hydrolysis is called Hydrolytic Degradation. Hydrolysis reactions are typically Acid or Base catalyzed. If drug is hydrohobic & found to be not soluble in water, use a co-solvent to dissolve the required quantity. PowerPoint Presentation: Apart from water, Acidic and basic conditions should also be employed in order to induce potential hydrolytic reactions. As these hydrolytic stress studies are to be conducted in aqueous solutions , estimate the solubility of the drug molecule of interest in water. Two most commonly used co-solvents are Acetonitrile and Methanol . Methanol has the potential of participating in the degradation chemistry, it should be used with caution especially under acidic conditions when the compound being tested contains a carboxylic acid, ester or amide. PowerPoint Presentation: The hydrolytic degradations are recommended to be performed at a temperature of about 70°C with a reflux condenser installed to avoid the loss of evaporation and use few glass beads or porcelain pieces to avoid bumping. Typical conditions : Reflux using water/ 0.1M HCl / 0.1M NaOH for stress testing with or without co-solvent at a temperature of about 70°C. Reflux for 12 hours or until about 5 to 20% degradation is achieved or which ever is earlier. PowerPoint Presentation: HYDROLYTIC DEGRADATION : Co-solvents that are recommended for the hydrolytic stress testing studies are shown below. Acidic pH Neutral pH Basic pH Acetonitrile Acetonitrile Acetonitrile DMSO N-methyl pyrrolidine DMSO Acetic acid Diglyme Propionic acid p- Dioxane . PowerPoint Presentation: [3]OXIDATIVE DEGRADATION : one of the most common mechanisms of drug degradation. Typically oxidative degradations are to be performed at room temp (about 25°C to 30°C) in dark. Use of higher temperatures >30°C is not recommended , because the reaction rate in solution may actually be reduced at higher temp due to decrease in oxygen content of the solvent. But for some compounds, degradation may occur at higher temperature due to free radical reaction initiation. Typical stress conditions : Stress with 3% hydrogen peroxide in dark at room temperature with constant stirring. Stress for 24 hours or until about 5 to 20% degradation is achieved or which ever is earlier. PowerPoint Presentation: [4]PHOTOLYTIC DEGRADATION : Degradation that results from exposure to UV or visible light . Typical Exposure conditions : Expose the samples to 3 times to 1.2 million lux -hr visible and 200 W-hr/m 2 UV . References : FDA, “ICH: Stability Testing of New Drug Substances and Products,” Federal Register 59 (183), 48753–48759 (22 September 1994) (ICH Q1A). 2. FDA, “ICH: Draft Revised Guidance on Q1A(R ) Stability Testing of New Drug Substances and Products,” Federal Register 65 (78), 21446–21453 (21 April 2000) [ICH Q1A(R)]. References

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