SIAM

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STABILITY INDICATING ASSAY METHOD:

STABILITY INDICATING ASSAY METHOD PRESENTED BY YAJNESH PAI 1 st YR M.PHARM QA DEPT. 1

DEFINITION :

DEFINITION A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product. 2

DEFINITION :

DEFINITION A Validated Quantitative Analytical Method that can detect the changes with time in Physical, Chemical or Microbiological properties of the Drug Substance and Drug Product and that are specific so that the contents of Active Ingredients, Degradation Products and other components of interest can be accurately measured without interference. A stability-indicating method accurately measures the active ingredients, without interference from degradation products, process impurities, excipients or other potential impurities. 3

CLASSIFICATION:

CLASSIFICATION Stability Indicating Assay Method (SIAM) is classified into two types: SPECIFIC SIAM SELECTIVE SIAM SPECIFIC SIAM : A method that is able to measure unequivocally the Drug in the presence of all degradation products, excipients and additives to be present in the formulation. B. SELECTIVE SIAM : A method that is able to measure unequivocally the Drug and all degradation products in the presence of Excipients and Additives expected to be present in the formulation. 4

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES Forced degradation ( FD ) study is a process in which the natural degradation rate of a pharmaceutical product is increased by the application of an additional stress. FD studies : i ) Help to identify reactions that cause degradation of pharmaceutical product, ii ) Are part of the development strategy and an integral component of validating analytical methods that indicate stability and detect impurities which are formed during manufacture, storage , or use and their properties are different from the desired product with respect to activity, efficacy and safety, iii ) Are designed to generate product-related variants and develop analytical methods to determine the degradation products formed during accelerated and long term stability studies. Any significant degradation product should be evaluated for characterization and quantization for its potential hazard. 5

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES In general, stressing values anywhere between 5% to 20% degradation of the drug substance have been considered as reasonable and acceptable for validation of chromatographic assays . However, for small pharmaceutical molecules for which acceptable stability limits of 90% of label claim is common, Pharmaceutical scientists have agreed that approximately 10% degradation is optimal for use in analytical validation . The ICH guidelines elaborate on stability testing of API’s and drug products in order to determine storage conditions, retest period, maximum expiring dating period of drug products, correct packaging to protect the product and transport conditions. These guidelines recommend the conduct of long term stability studies ( 25˚C ± 2˚C/60% RH ± 5% or 30˚C ± 2˚C/65% RH ) for 12 months, intermediate stability studies (30˚ C ± 2˚C/65% RH ± 5% RH) for 6 months and accelerated stability study ( 40˚C ± 2˚C/75% RH ± 5% RH) for minimum 6 months duration. 6

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES The main causes of Degradation are Heat Humidity Solvent pH Light encountered during manufacture, isolation, purification, drying , storage, transportation, and/or formulation. 7

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES The major routes of degradation of any drug substance include Hydrolysis Oxidation Heat Photolysis 8

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 1. Hydrolytic condition Hydrolysis is one of the most common degradation chemical reactions over wide range of pH. Hydrolysis is a solvolytic process in which drug reacts with water to yield breakdown products of different chemical compositions . Water either as a solvent or as moisture in the air comes in contact with pharmaceutical dosage forms is responsible for degradation most of the drugs. For example, aspirin combines with water and hydrolyzed to salicylic acid and acetic acid. 9

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 10

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 2 . Oxidative condition Many drug substances undergo autoxidation i.e . oxidation under normal storage condition and involving ground state elemental oxygen. Therefore it is an important degradation pathway of many drugs. 11

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 12

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 3 . Thermal condition In general, rate of a reaction increases with increase in temperature. Hence , the drugs are susceptible to degradation at higher temperature. Many APIs are sensitive to heat or tropical temperatures. For example, vitamins, peptides , etc. Thermal degradation involves different reactions like pyrolysis, hydrolysis, decarboxylation, isomerization , rearrangement and polymerization . 13

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES Effect of temperature on thermal degradation of a substance is studied through Arrhenius equation: K= Ae -Ea/RT where k is specific reaction rate, A is frequency factor, Ea is energy of activation, R is gas constant(1.987 cal/deg mole ), T is absolute temperature. 14

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES Thermal degradation study is carried out at 40˚C to 80 ˚C. The most widely accepted temperature is 70˚C at low and high humidity for 1-2 months. High temperature (> 80˚C) may not produce predictive degradation pathway. The use of high-temperatures in predictive degradation studies assumes that the drug molecule will follow the same pathway of decomposition at all temperatures . This assumption may not hold true for all drug molecules. 15

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 4 . Photolytic condition Exposure of drug molecules may produce photolytic degraded products. The rate of photodegradation depends upon the intensity of incident light and quantity of light absorbed by the drug molecule. Photolytic degradation is carried out by exposing the drug substance (in solid as well as in the solution form) or drug product to a combination of visible and UV light. The most commonly accepted wavelength of light is in the range of 300-800 nm to cause the photolytic degradation. 16

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 17

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES Identification of Degradation Products The unknown impurity that are observed during the analysis, pharmaceutical development , stress studies and formal stability studies of the drug substances and drug product by using various chromatographic techniques like Reversed Phase High Performance Liquid Chromatography (RP-HPLC), Thin Layer Chromatography (TLC), Gas Chromatography (GC ), Capillary Electrophoresis (CE ), Capillary Electrophoresis Chromatography (CEC) and Super critical Fluid Chromatography (SFC). The RP-HPLC is most widely used analytical tool for separation and quantifying the impurities and it is most frequently coupled with UV detector. 18

FORCED DEGRADATION STUDIES:

FORCED DEGRADATION STUDIES 19

PARAMETERS:

PARAMETERS A SIAM must be – Validated (demonstrate that it is suitable for its intended use) Specific (resolution of active from related substances, peak purity) Reproducible Quantitative Able to monitor a change in the chemical, physical and microbiological properties of drug product over time. 20

PARAMETERS:

PARAMETERS The demonstration of specificity and the ability of the method to monitor a change in the chemical properties of the drug over time, invariably calls for a forced degradation (stress testing) study to be done on the drug substance and drug product. Forced degradation on the drug substance and product will also provide the following information : (1) Determination of degradation pathways of drug substances and drug products. 21

PARAMETERS:

PARAMETERS ( 2) Discernment of degradation products in formulations that are related to drug substances versus those that are related to non-drug substances (eg. excipients). ( 3 ) Structure elucidation of degradation products. ( 4) Determination of the intrinsic stability of a drug substance molecule in solution and solid state. ( 5) Reveal the thermolytic, hydrolytic, oxidative and photolytic degradation mechanism of the drug substance and drug product. 22

EXAMPLE:

EXAMPLE 23

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DEVELOPMENT OF SIAM:

DEVELOPMENT OF SIAM A Systematic approach for the development of SIAM includes : Critical study of Drug structure to assess the likely decomposition route(s). Collection of information on physicochemical properties. Stress (forced decomposition) studies. Preliminary separation studies on stress samples. Final method development and optimization. Identification and Characterization of degradation products and preparation of standards. Validation of Stability Indicating Assay Method. 25

SIAM DEVELOPMENT:

SIAM DEVELOPMENT STEP 1. Generation of Degraded Samples for testing Selectivity of the Method : Stress tests should generate representative samples to assess drug substance and drug product stability. Provide information about possible degradation pathway and demonstrate the stability indicating power of the analytical procedures applied . 26

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Determination of the following parameters aid in SIAM DVPT Limit of Quantification ( LoQ ) Limit of Detection ( LoD ) These limits should be closely related to the Reporting, Identification and Qualification of degradation products, as stated in ICH Q3B (R2 ). These thresholds are determined either as percentage of drug substance or total daily intake (TDI) of degradation product. 27

SIAM DEVELOPMENT:

SIAM DEVELOPMENT 28

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Information like aqueous solubility, pH versus solubility profile, excipients compatibility studies , etc. all information that enable full assumption of the knowledge of the product, will help to ensure that best (more appropriate) condition a re chosen for developing a SIAM , like those related to the forced degradation design. 29

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Overstressing / Understressing Care should be taken in order to avoid overstressing or understressing samples, which may lead to non representative or non-purposeful degradation . Hence, the use of a properly designed and executed forced degradation study will generate representative samples that will help to ensure that resulting method reflects adequately long-term stability. Changing conditions to harsher or softer levels, can be applied, when too little or too much degradation are obtained. 30

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Photostability Testing Photostability tests should follow ICH requirements : i ) Tests on the drug substance; ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ; iii) Tests on the drug product in the immediate pack; and if necessary ; iv) Tests on the drug product in the marketing pack. 31

SIAM DEVELOPMENT:

SIAM DEVELOPMENT The extent of drug product testing should be established by assessing whether or not acceptable change has occurred at the end of the light exposure testing as described in the Decision Flow Chart for Photostability Testing of Drug Products . Design of forced degradation test should consider the previous knowledge of the substance or product being tested , since photoreactivity is wavelength dependent and degradation pathways can be different for UV and visible ranges (case by case basis). It is recommended to use artificial sources of irradiation, like ID65 and specific filters to guarantee the exposure above 320 nm. 32

SIAM DEVELOPMENT:

SIAM DEVELOPMENT 33

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Step 2: Method Development (Manipulating and evaluating Selectivity / Specificity) Liquid chromatography is the most appropriate technique for developing/validating a SIAM . The use of diode-array-detector and additionally mass spectrometers gives best performances. The goal is to manipulate selectivity by changing mobile phase composition, wavelength of detection and pH. Columns mechanically strong, with high efficiency and that which operate over an extended pH range, should be preferred. 34

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Acidic compounds are more retained at low pH; while basic compounds are more retained at higher pH (neutral compounds are unaffected). At traditionally used pH values (pH 4 - 8), a slight change in pH would result in a significant shift in retention. Type of chromatography used (e. g. HPLC or GC) and arrangements/ detectors (GC/FID, GC/MS , LC/DAD or LC/MS) are certainly useful tools. For HPLC, different modes of chromatography can be used (normal or reversed phase, ion par). To monitor compounds without light absorption in UV/Vis region, Light Scattering Detector (LSD) coupled to HPLC is a powerful tool. 35

SIAM DEVELOPMENT:

SIAM DEVELOPMENT The use of HLPC coupled to diode-array detectors (DAD) in the achievement of peak purity usually give reasonable results, mainly related to reliable determination of the main active ingredient. It is possible to guarantee no co-elution with degradation peaks and other impurities. DAD detectors can be limited on occasion the more similar the spectra, and the lower the relative absorbance, the more difficult it can be to distinguish co-eluted compounds . MS can provide unequivocal peak purity information, exact mass, structural and quantitative information depending upon the type of instrument used . MS is also a very useful tool to track peaks to selectivity manipulations in method development. 36

SIAM DEVELOPMENT:

SIAM DEVELOPMENT The determination of each degradation product is a critical work mainly when ICH thresholds are reached. This may trigger additional investigations about the drug product, so it is recommended to dedicate all analytical tools and expertise available in this step of method development . 37

SIAM DEVELOPMENT:

SIAM DEVELOPMENT Step 3: Method validation For assay procedures, that are intended to measure the analyte present in a given sample, typical validation items should be considered: Accuracy Precision (repeatability and intermediate precision ) Specificity Detection and Quantitation Limits Robustness Linearity Range 38

CONCLUSION:

CONCLUSION The stability profile needs to be established for drug product to assure safety, efficacy and quality. The results coming from these studies can support formulation and packaging. The know-how coming from stress tests are useful to reduce time and money, related to the drug and final product development , giving the possibility of forecasting analytical problems. 39

REFERENCES:

REFERENCES www.fda.gov Shein -Chung Chow. Statistical design and Analysis of Stability Studies. Pg no.9 FDA Guidance for Industry. Analytical Procedures and Methods Validation (draft guidance),August 2000. www.ich.org 40

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