Section 2 - Expiration Dating Flashcards
What is accelerated testing?
Studies that are used to increase the rate of chemical or physical degradation by using exaggerated storage conditions
What is the purpose of accelerated testing?
To determine kinetic parameters in order to predict a tentative expiration dating period
Accelerated testing is often used synonymously with _____ testing
Stress
What is an expiration date?
A date placed on the label of a drug product that designates the date through which the product will remain within specifications
How long will a product be good for if the expiration date only includes a month and a year?
Until the last day of the month
What is stability?
The capacity of a product to remain within specifications established to ensure its identity, strength, quality, and purity
What is primary stability data?
Data on a product stored under labeled storage conditions in container-closure to be used
What is supportive stability data?
Data other than primary stability data
What are 2 examples of supportive stability data?
- Accelerated studies
- Published stability data
What is one drawback to stability studies at labeled storage conditions?
Time consuming
Are stability studies at labeled storage conditions required?
Yes, but tentative permission may be given to market a product with the expiration date predicted from accelerated testing
How can expiration dates be predicted from accelerated testing?
Using the Arrhenius plot to predict from high temperature data the rate of product breakdown to be expected at actual storage conditions
What are the steps to an accelerated stability test?
Samples are held at elevated temperatures and sampled at timed intervals for chemical analysis
How is the data from an accelerated stability test used?
To assign a rate order, which is then used to calculate appropriate rate constants using linear regression analysis
What is the y-axis for an Arrhenius plot?
Log of the rate constant
What is the x-axis for an Arrhenius plot?
The inverse of temperature in absolute degrees
Data generated from the linear regression of the Arrhenius equation allows for _____
The calculation of the rate constant at room temperature, and from this t90
What type of dose forms is the Arrhenius plot best for?
Solution
Why shouldn’t the Arrhenius plot be used for solid dose forms?
They will experience changes in moisture, which may influence stability
Why shouldn’t the Arrhenius plot be used for suspensions containing polymorphic materials or solvates?
May undergo changes at elevated temperatures
What are 2 examples of an adverse event that can happen during the Arrhenius plot experiment?
- Some materials may undergo phase transitions at elevated temperatures
- pH may change with temperature
What can happen to oxygen levels with increasing temperature?
They may drop
What happens as extrapolated points become further from the actual data points?
Range of error increases
What is the range for activation energy for an accelerated stability test?
10-30 kcal/mole
What happens to an accelerated stability test if the rate is limited by diffusion or a photochemical process?
The test may not be valid
What happens to an accelerated stability test if the product decomposes due to freezing, agitation, or microbial contamination?
The test is not valid
Should you use an accelerated stability test for suppositories and ointments? Why?
No because they contain protein drugs or suspending agents, which causes them to undergo a phase transformation
What are examples of physical tests that can be done to products?
- Tablet disintegration or dissolution
- Emulsion droplet size
- Suspension particle size
- Sedimentation rate
For drug stability work, what must the method of analysis be?
Stability-indicating and validated
What must be distinguished for drug stability work?
Active drug from breakdown products and excipients
What is the most commonly used analytical method?
High-pressure liquid chromatography (HPLC)
What are examples of validation criteria?
- Selectivity
- Accuracy
- Precision
- Linearity
- Range and sensitivity
- Robustness
What is selectivity/specificity?
Ability of the method to detect and quantify the analyte in the presence of excipients, degradation products, and metabolites
What should be done if the mechanism of decomposition is known the degradation products are available?
They should be chromatographed
What should be done if degradation products are not available?
A procedure of forced degradation could be used
What happens in forced degradation?
The drug is exposed to severe conditions which will result in degradation and the product of the process is used in the chromatography in place of the authentic sample
What is accuracy?
The closeness of the test result obtained by the method to the true value
What are the criteria for acceptance of accuracy?
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?
The degree of agreement among individual test results
What are the criteria for precision testing?
Must be done by using a minimum of 9 determinations and the values should not exceed a relative standard deviation of 3-5%
What is linearity?
The ability of the method to generate test results or responses which are directly proportional to the concentration of the analyte within a given range
How is the range for linearity determined?
It is the upper and lower levels of analyte that have been shown to have suitable levels of accuracy and precision
How can linearity be established?
By using a minimum of 5 concentrations within the range
What can be used to test the relationship between assay response and concentration?
Regression analysis
What does sensitivity involve determining?
The lowest concentration where linearity, accuracy, and precision are all within the accepted limits
What is robustness?
Ability of the method to remain unaffected by small variations in method parameters
What does robustness provide an indication of?
Reliability and durability of the assay
What is the expiration dating guideline for non-sterile compounded solid or non-aqueous liquid dose forms prepared from
a commercially available dose form?
25% of the remaining expiration date of the commercial product or 6 months, whichever is earlier
What is the expiration dating guideline for non-sterile compounded solid or non-aqueous liquid dose forms prepared from bulk ingredients?
Use actual labeled expiration dates of the components, so the one with the shortest dating will be the limiting factor; maximum of 6 months
What is the expiration dating guideline for non-sterile compounded aqueous-based formulations prepared from ingredients in solid form?
- 14 days in the fridge
- 30 days if preserved
What is the expiration dating guideline for all other non-sterile compounded products?
Up to 30 days or the intended duration of use, whichever is earlier
What is the expiration dating guideline for non-sterile compounded products that are literature sourced?
The published dating may be used provided it is shorter than that of any of the components used
What is the expiration dating guideline for sterile compounded products?
Depends on risk of microbial contamination and physicochemical stability considerations (low, medium, or high)
What is the expiration dating guideline for low risk sterile compounded products prepared using commercially made sterile products and devices?
- Room temperature - 48 hours
- Fridge - 14 days
- Freezer - 45 days
What is the expiration dating guideline for medium risk sterile compounded products prepared using commercially made sterile products and devices?
- Room temperature - 30 hours
- Fridge - 7 days
- Freezer - 45 days
What is the expiration dating guideline for high risk sterile compounded products made from non-sterile starting material?
- Room temperature - 24 hours
- Fridge - 3 days
- Freezer - 45 days
What are examples of low risk sterile compounded products?
- Reconstitution of an antibiotic
- Withdrawal of all or part of a solution and dilution by adding to an IV vehicle
What is the criteria for a low risk sterile compounded product?
All materials used are commercially made and is one dose for a specific patient
What is the criteria for a medium risk sterile compounded product?
Multiple doses are prepared or complex mixtures
What is an example of a medium risk sterile compounded products?
Parenteral nutrition solution
What is an example of a high risk sterile compounded products?
A preparation of a product not commercially available using USP grade drug dissolved in water for injection, filtered for particulates, packaged into vials, and sterilized by autoclaving
What is the Q10 method?
A method for estimating temperature effects on reaction rates
What does Q10 mean?
The factor the rate constant increases for a 10 C temperature increase
Is Q10 dependent on reaction order?
No
What is the equation for Q10?
t90(T2) = t90(T1) / Q10 ^ (delta T/10)
What does an expiration date specify?
The only date that the manufacturer guarantees the full potency and safety of the drug
What is normally the maximum expiration date?
5 years from the time of manufacture
What is the manufacturer required to provide in regards to testing for expiration dates?
The test results for the duration of the expiration date they have assigned the product
Do a product need to be tested until it is no longer viable?
No
What does “stored under defined conditions” mean?
That if the packaging is opened or the storage conditions were different from label directions, the expiration date has been compromised
What is beyond-use dating?
- The time period within which the medication should be used up
- Normally one year from date the prescription was filled
Is the beyond-use date longer than the expiration date?
No, significantly shorter
What are beyond-use dates based on?
The assessment of risk, not on science
What is an appropriate beyond use date for an antibiotic prescribed for a 10 day period?
14 days b/c the medication should be used up by then
Why shouldn’t people store medications in the bathroom?
Temperature changes and humidity from showers can damage medications
What percentage of the labeled quantity of active ingredient must a product contain in order to be useable?
90-95%
What are the 3 most common routes of chemical degradation?
1) Hydrolysis
2) Oxidation
3) Photolysis
What are 3 less common routes of chemical degradation?
1) Racemization
2) Maillard reaction
3) Formation of Schiff bases
What does hydrolysis do to a drug?
Decomposes the drug through a reaction with water acting as a nucleophilic agent by attacking electrophilic sites in the drug
What are the most common functional groups involved in hydrolysis reactions?
Carboxyl derivatives
What is the functional group susceptible to hydrolysis in acetaminophen?
Amide
What is the functional group susceptible to hydrolysis in penicillin?
Lactam
What is the functional group susceptible to hydrolysis in atropine?
ester
What is the functional group susceptible to hydrolysis in warfarin?
Lactone
What is oxidation strongly influenced by?
Light, metal ions, and oxygen
The majority of oxidation reactions are ____ which means _____
- Free radical reactions
- They can occur spontaneously
What usually happens to the products of oxidation reactions?
They are conjugated, which results in changes to colour and odor
What is the downside to oxidation reactions in drugs?
Can cause the product to be unfit even though only a small percentage of the product has decomposed
What is the functional group susceptible to oxidation in steroids?
Phenols
What is the functional group susceptible to oxidation in isoproterenol?
Catechol
What is the functional group susceptible to oxidation in methimazole?
Thiols
How can you prevent hydrolysis?
- Remove water
- Add propylene glycol
How can you prevent oxidation?
- Remove oxygen
- Add antioxidants
- Protect from light
Which physical properties must a product retain in order to be useable?
- Appearance
- Palatability
- Uniformity
- Dissolution
- Suspendability
What are the potential problems to physical stability?
- Polymorphism
- Vaporization
- Aging
- Adsorption
What is polymorphism and what can it cause?
- Difference in internal crystal structure
- Solubility and melting temperature differences leading to caking of suspensions or altered bioavailability
What are 2 drugs that can be lost through vaporization?
Nitroglycerin and ibuprofen
What type of aging can occur in tablets?
Hardening, which can alter disintegration/dissolution properties
What is an example of adsorption?
Drug lost to packaging materials for IV solutions in PVC plastic
How can you protect microbiological stability?
- Packaging must retain its integrity
- Antimicrobial preservatives must retain their effectiveness
Can accelerated studies be used to determine an expiration date?
Nope, can only be used for approximations of shelf life and nature of the product degradation
What is the criteria for long-term stability studies?
- Must be done at controlled storage temperatures and humidity levels in the final packaging
- Must be done on a minimum of 2 batches of product
Testing is for ______ aspects of the product
Chemical, physical, and microbiological
Is stability testing a requirement for compounded preparations?
No
How are expiration dates derived for compounded products?
- From literature
- Guidelines in USP chapters 795 and 797
What are the 6 things that need to be considered when assigning an expiration or beyond use date?
- Nature of drug and its degradation kinetics
- Dose form and product packaging
- Storage conditions and presence of preservatives
- Expected length of therapy
- Expiration date of similar commercial products
- Published literature
What does USP chapter 795 say about the beyond use date for water containing oral compounded preparations?
Beyond use date of no longer than 14 days when stored at controlled cold temperature
What does USP chapter 795 say about the beyond use date of water containing topical, dermal, or mucosal liquid or semisolid compounded preparations?
Beyond use date of no longer than 30 days
What does USP chapter 795 say about the beyond use date of non-aqueous compounded preparations?
- Beyond use date of no longer than the earliest expiration date of any ingredient, or 6 months, whichever is earlier
- For a preparation using a commercially prepared dose form (tablet or capsule), 25% of the remaining expiration date or 6 months, whichever is earlier
What is the maximum expiration date?
5 years from the time of manufacture
What are the risks associated with using expired drug products?
- Formation of toxic degradation products (unusual)
- Loss of potency (especially nitroglycerin, insulin, and liquid antibiotics)
