“ort ve ae wapeting if Accordance wip ‘ational/regional requirements, The statement should be based on it the stabil the drug substance. Where applicable, specific instructions shoulg be i alt for drug substances that cannot tolerate freezing. Terms such as “ambient oh “room temperature” should be avoided. A re-test period should be derived displayed on the container label if, from the stability information, and g Telest date appropriate. AAD OORT iss (Q1B) SELECTION OF BATCHES Data from stability studies should be Provided on at least Product. The primary batches should be of the same form: container closure system as proposed for marketing. CONTAINER CLOSURE SYSTEM secondary drug product outside its imm; ia TESTING FREQUENCY For iy ae Se frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months ‘over the first year, every 6 nionths over the second year, and annually thereafter through the proposed shelf life » At the accelerated storage condition, a minimum of three time points, including the initial and final time points (eg., 0, 3, and 6 months), from a 6month study is recommended. Where an expectation (based on development experience) exists that results from accelerated testing are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including. a fourth time point in the study design. * * When testing at the intermediate storage condition is called for result of a significant change at the accelerated storage condition, a minimum Of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12- a | month study is recommended. seer + Reduced designs, ie., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, cam be applied, if justified. iT SOURCES coats “Yources described below may be used for photostability testing. The applicant ‘either maintain an appropriate control of temperature to minimize the effect of erature changes or include a dark control in the same environment unless | For both options 1 and 2, a pharmaceutical manufacturer/applicant may distribution specification of the light source manufacturer. AP eouite that is designed to produce an output similar fo the D65/1D65: a such as an artificial daylight fluorescent lamp combining visible and ee outputs, xenon, or metal halide lamp. D65 is the internationally recogr ized outdoor daylight as defined in ISO 10977 (1999), D5 is the equiv see cee dard | standard. For a light source emitting signin radiation below 320 nm, - ‘ate filter(s) may be fitted to eliminate such radiation. r46 ia |<] Concise course Paro Option 2 For option 2 the same sample should be exposed to both ultraviolet lamp. 1. A cool white fluorescent lamp designe ing. a spect that specified in ISO 10977(1993) ; and 2. A near UV forescent ame, Sa s nm. distribution from 320 nm to 400 nm with a maximum nee oT a aed ne 370 nm, a significant proportion of UV should be in both bancis © s 400 nm. the cool white fluorescent and near .d to produce an output similar tg PROCEDURE : eg ‘ F hould be exposed £0 light providing an overall For confirmatory studies, samples shot een integrated near ultraviolet a he illumination of not less than 1.2 million lux @ " energy of not less than 200 watt hours/square meter to allow direct comparisons to roduct. tbe made between the drug substance and drug pr , ‘ ‘ + Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained, oF for the appropriate duration of time when conditions have been monitored using calibrated radiometers /lux meters. + If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to ‘evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample. | STORAGE CONDITIONS In general, a drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. The long term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. ‘ the assessment period of the registration appl d si Tequested. General case Condition is as follows: oh i © Long term® (12 months): 25°C + 2°C/6 RH « Intermediate**(6 months): 30°C + 2°C/65 * Accelerated (6 months): 40°C + 2°C/75!-_ on omminGien 47 Mirae ajeisup tothe applicant to decide whether long term stability studies are performed at 25 = 19¢/60% RH 25% RH or 30°C £2°C/65% RH 5% RH. wef 30°C # 2°C/65% RH * 5% RH is the long-term condition, there is no intermediate condition. 4 iHlong-term studies are conducted at 25°C + 2°C/60% RH :5% RH and “significant change” sccars at any time during 6 months’ testing at the accelerated storage condition, addition testing at the intermediate storage condition should be conducted and evaluated n significant change criteria. The intial application should include a minimum of 6 mor Gata from a 12- month study at the intermediate storage condition. In general, “significant change” for a drug product is defined as: ‘A.5% change in assay from its initial value; or failure to meet the acceptance cri potency when using biological or immunological procedures, ‘Any degradation product's exceeding its acceptance criterion; Failure to meet the acceptance criteria for appearance, physical atts functionality test (e.g., color, phase separation, resuspendibility, caking, delivery per actuation); however, some changes in physical attributes (eg suppositories, melting of creams) may be expected under accelerated con appropriate for the dosage form: © Failure to meet the acceptance criterion for pH; or Failure to meet the acceptance criteria for dissolution for 12 dosage products packaged in impermeable containers ensitivity to moisture or potential for solvent loss is not a conce ackaged in impermeable containers that provide a permanent b cisture or solvent. Thus, stability studies for products stored in i | be conducted under any controlled or ambient humidity conditi ‘products packaged in semi-permeable containers s-based products packaged in semi-permeable containers should be al water loss in addition to physical, chemical, biological, and micro This evaluation can be carried out under conditions of low relative hunidie ‘below, Ultimately, it should be demonstrated that aqueous-based drug products rnd low relative humidity environments. ° Je containers can withsta can be developed and reported for non-aqueous, solvent-