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Photostability
Light can affect drugs, causing chemical changes ICH Q1B guidance spells out how to do photostability tests Light sources
Combination of visible and UV light
Procedure
Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter Standards given identical exposure, but protected by light barrier such as aluminum foil
Temperature Extremes
Studies are typically done in increasing 10C increments (40C, 50C, 60C, etc.) until significant degradation is observed Freeze/Thaw studies
Particularly important for proteins and other biomolecules Example: insulin forms aggregates on freezing
Oxidation
Typically done by placing the drug substance in aqueous solution with hydrogen peroxide Goal is significant degradation
Can identify degradants Determine whether protective packaging is required Determine if an antioxidant should be considered for the drug product formulation
pH Extremes
Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10. Can be complicated by limited solubility of the drug substance under different pH conditions Again, the goal is significant degradation
Determine degradants Decide if the molecule will survive passage through the stomach
Is enteric coating necessary? Should the drug be given by injection?
Degradation Reactions
Oxidation
Thiols (R-SH) form disulfides (R-SS-R) Alcohols (RCH2-OH) form aldehydes (RHC=O) and acids (RC02H) Amines (R3N) can form amine oxides (R3N+O-)
Hydrolysis
Usually caused by high or low pH Esters (RCO2R ) form acids and alcohols (RC02H + R OH) Amides (RCONHR ) form acids and amines (RC02H + R NH2)
Accelerated Stability
Stability study run under more stressful conditions than expected for long term storage Different from stress studies in that the goal is to get a quick understanding of what may be expected from a Accelerated Conditions long term study Long-term conditions
Room temperature (2530C) Refrigerated (5 3C) Freezer (-20C 5C) 40C/75%RH 25C/60%RH 5 3C
But it is essential to have some method available to evaluate the results of stress studies Thus, stability studies and analytical method development work together
Start with drug substance molecule and separately synthesized possible degradants to determine method effectiveness
Phase II
Goal is to determine dosing and get a limited sense of the effectiveness of the drug By this point in drug development there is usually more stability data available for the drug substance New routes of synthesis of the drug substance can lead to different patterns of change on stability due to the presence of different impurities, especially metals Stability data for the drug product in a formulation that should be the same or close to the intended commercial formulation is obtained Stability is obtained concurrently with clinical studies Failures on stability must be investigated promptly and appropriate action taken, possibly including recalling the drug from clinical sites.
Freeze/thaw
important if the drug product is at risk for experiencing temperatures <0C
Intermediate conditions: 30C/75%RH if 25C used for long-term and significant change occurs
Stability of Comparators
Comparators are used in clinical trials to test the new drug against standard therapy For a blinded trial, the comparator must be disguised, typically by overencapsulation The blinded comparator must be studied on stability Dissolution Degradation If compendial methods are not available, tests must be developed Shelf-life for comparator cannot exceed manufacturers expiration date
Stability of Placebos
Placebos must be evaluated on stability Appearance is the only attribute that needs to be tested If the appearance changes over time, the blinding of a study may be broken Placebos can be given a long shelf-life based on available data; if the color doesnt change over 12 months, it is not likely to change over 36 months
Create a Quality Agreement that clearly spells out expectations on both sides
Summary
Stability studies play a central role in drug development
Permit understanding of the molecule Essential for developing analytical methods, selecting packaging and storage conditions for drug substance and drug product