Expiration Dating Flashcards
What is the definition of accelerated testing?
Studies to increase the rate of chemical or physical degradation by using exaggerated storage conditions
Purpose to determine kinetic parameters in order to predict a tentative expiration dating period
Often used synonymously with stress testing
What is the definition of expiration date?
Date placed on a label of a drug product that designates date through which the product will remain within specifications
If the date includes only a month and a year, product will meet specifications to last day of the month
What is the definition of stability?
Capacity of product to remain within specifications established to ensure its identity, strength (potency), quality and purity
What is the definition of primary stability data?
Data on product stored under labeled storage conditions in container-closure to be used
What is the definition of supportive stability data?
Data other than primary stability data such as accelerated studies on published stability data
Why is accelerated testing important?
Stability studies at labeled storage conditions are time consuming. Although they are required, tentative permission may be given to market a product with the expiration date predicted from accelerated testing.
How are expiration dates predicted?
The prediction of expiration dates is accomplished through the use of an Arrhenius plot to predict from high temperature date the rate of product breakdown to be expected at actual storage
Describe the accelerated stability approach
It is a two step process where samples are held at elevated temperatures and sampled at timed intervals for chemical analysis. From this data, a rate order can be assigned and appropriate rate constants are calculated using linear regression analysis
Arrhenius plots fro predicting stability are usually quite successful with solution dose forms but more uncertain when applied to other systems. Explain.
Solid dose forms will experience changes in moisture which may influence stability
Suspensions containing polymorphic materials or solvates may undergo changes at elevated temperatures
Some materials may undergo phase transition (i.e., change of state) at elevated temperatures and pH may change with temperature
Oxygen levels may drop with increasing temperature
In these situations, the Arrenhenius relationship may not be linear so some products are unsuitable for accelerated studies
If a study is designed and conducted well, good approximations of shelf life can be obtained but there are a number of limitations:
Methods are only valid when degradation is a thermal phenomenon with an activation energy between 10-30 kcal/mole. If the rate is limited by diffusion or photochemical processes, this test may not be valid. If a product decomposition is due to freezing, agitation or microbial contamination, the test is not valid
Products containing protein drugs or suspending agents, products such as suppositories and ointments which may undergo a phase transformation may be unsuitable for this type of testing
How is real-time testing done?
Real-time testing must be done under probable storage conditions and sometimes under light or moisture stress.
Why is physical testing done? When is physical testing of products done?
Physical testing of products is done as is appropriate for the product, i.e., tablet disintegration or dissolution, emulsion droplet size, suspension particle size and sedimentation rate, etc.
For drug-stability work, what is important with regards to the method of analysis?
The method of analysis must be stability-indicating and must be validated. It is important that the active drug is distinguished from breakdown products and excipients. High-pressure liquid chromatography (HPLC) is the most commonly used method.
What is included in validation criteria?
Selectivity and sensitivity, accuracy, precision, linearity, range, and robustness
What is selectivity and sensitivity with regards to the method of analysis?
The ability of the method to detect and quantify the analyte in the presence of excipients, degradation products and metabolites. For HPLC there should be no peaks in the chromatogram which will interfere with the analyte
If the mechanism of decomposition is known and the degradation products are available, they should be chromatographed. If they are not available, a procedure of forced degradation could be used
What is accuracy with regards to the method of analysis? How is it determined?
The closeness of the test result obtained by the method to the true value. It is determined by replicate injections of reference standard or comparison of the results obtained by the method to those of a second well characterized method.
What are the criteria for acceptance of accuracy?
Criteria for acceptation of accuracy are that the recovery values should be 100 +/- 2% at each concentration over the range of 80-120% of the target comparing the measured value to the true value
What is precision with regards to the method of analysis?
The degree of agreement among individual test results for multiple replicates of a sample
Precision testing is done using minimum of nine determinations and the values should not exceed a relative standard deviation (RSD) of 3-5%
What is linearity with regards to the method of analysis?
The ability of method to generate test results or responses which are directly proportional to the concentration of the analyte within a given range.
Regression analysis can be used to test the relationship between assay response and concentration
What is robustness with regards to the method of analysis?
The ability of the method to remain unaffected by small variations in method parameters
It provides an indication of the reliability and durability of the assay
What are the expiration dating guidelines for solid or non-aqueous liquid dose forms prepared from commercially available dose forms (non-sterile compounded products; USP 795)?
25% of the remaining expiration date to the commercial product or 6 months (whichever is earlier)
What are the expiration dating guidelines for solid or non-aqueous dose forms prepared from bulk ingredients (non-sterile compounded products, USP 795)?
Use actual labeled expiration dates of the components therefore the one with the shortest dating will be the limiting factor. Therein a maximum of six months however.
What are the expiration dating guidelines for aqueous-based formulations prepared from ingredients in solid form (dissolved or suspended) (non-sterile compounded products, USP 795)?
14 days in the fridge or 30 days if preserved
What are the expiration dating guidelines for all other non-sterile compounded products?
Up to 30 days or the intended duration of use by the patient, whichever is earlier
