2 Expiration

Question 1

What is accelerated testing?

Answer 1

Studies to increase the rate of chemical or physical degradation by using exaggerated storage conditions.
Used to determine kinetic parameters in order to predict a tentative expiration dating period and synonymously with stress testing.

Question 2

What is an expiration date?

Answer 2

A date place on the label of a drug product that designates a date through which the product will remain within specifications to the last day of the month stated.

Question 3

What is stability?

Answer 3

The capacity of a product to remain within specifications to ensure its identity, strength (potency), quality and purity.
Studies are time consuming

Question 4

What is primary stability data?

Answer 4

The data on a product stored under labelled conditions in the container-closure to be used.

Question 5

What is supportive stability data?

Answer 5

Data other than primary stability data such as accelerated studies and published stability data.

Question 6

Can a product with a predicted expiration date be marketed?

Answer 6

Tentative permission may be given with a date predicted by accelerated testing.
Prediction can be made through use of an Arrhenius plot.

Question 7

What is the accelerated stability approach?

Answer 7

A two step process where samples are held at elevated temperatures and sampled for chemical analysis at timed intervals.
Rate order is assigned and rate constants are calculated.

Question 8

What are the differences between the linearized equations of zero, first and second order reactions?

Answer 8

Zero order is already the equation of a line (y=mx+b)
First order has logs in it
Second order has fractions (inverse)

Question 9

In what situations is the Arrhenius plot useful for and not useful for?

Answer 9

Very successful for solutions
Solid dose forms (moisture), suspensions containing polymorphic materials or solvates (high temperatures), materials with phase transitions at elevated temps and pH changes, oxygen levels drop with increasing temperature.

Question 10

What some limitations of stability studies?

Answer 10

Methods only valid when degradation is a thermal phenomenon with an activation energy between 10-30 kcal/mol. (can’t be used if rate is limited by diffusion or photochemical process or it decomposes due to freezing, agitation or microbial contamination)
Products containing protein drugs or suspending agents (suppositories, ointments) which may undergo phase transformation.

Question 11

How must real time testing be done?

Answer 11

Under probable storage conditions and sometimes under light and moisture stress.
Done on a continuous basis.

Question 12

What kind of physical testing of products is done?

Answer 12

Done as appropriate for the product.

Tablet disintegration or dissolution, emulsion droplet size, suspension particle size, sedimentation rate, etc.

Question 13

What are some important things to think about before using the analytical method?

Answer 13

The method of analysis must be stability indicating and must be validated (selectivity, accuracy, precision, linearity, range, sensitivity, robustness).
Important that active drug is distinguished from breakdown products and excipients.

Question 14

What is an example of an analytical method?

Answer 14

High pressure liquid chromatography (HPLC)

Question 15

What is selectivity or specificity?

Answer 15

The ability for an analytical method to detect and quantify the analyte in the presence of excipients, degradation products and metabolites.
In HPLC, there should be no interfering peaks on the chromatogram.
If the mechanism of decomposition is known and the degradation products are available, they should be chromatographed. If not, forced degradation should be used.

Question 16

What is accuracy?

Answer 16

The closeness of the test result obtained by the method to the true value.
Determined by reference standard or comparison of the results obtained by the method to those of a second well characterized method.
Recovery values should be 100 +/- 2% at each concentration over the range of 80-120% of the target.

Question 17

What is precision?

Answer 17

The degree of agreement among individual test results for multiple replicates of a sample.
Testing done using minimum 9 determinations and values should not exceed 3-5% relative standard deviation.

Question 18

What is linearity?

Answer 18

The ability of the method to generate test results or responses which are directly proportional to the concentration of the analyte at a given range.
Regression analysis can be used.

Question 19

What is robustness?

Answer 19

The ability of the method to remain unaffected by small variations in method parameters.
Provides an indication of the reliability and durability of the assay.

Question 20

What is the expiration date for a solid or non-aqueous liquid dose form prepared from a commercially available dose form?

Answer 20

25% of the remaining expiration date of the commercial product or 6 months, whichever is earlier.

Question 21

What is the expiration date of a solid or non-aqueous liquid dose form prepared from bulk ingredients?

Answer 21

Whatever the actual labelled expiration dates of the components are. The one with the shortest dating will be the limiting factor. Max 6 months.

Question 22

What is the expiration date of aqueous based formulations prepared from ingredients in solid form (dissolved or suspended)?

Answer 22

14 days in the fridge or 30 days if preserved.

Question 23

What is the expiration date of all other formulations?

Answer 23

Up to 30 days or the intended duration of use by patient, whichever is earlier.

Question 24

What is the expiration date if a formulation was published?

Answer 24

If the pharmacist judges that the study was properly designed and executed, the published date may be used. Provided it is shorter than that of any of the components used to prepare the product.

Question 25

What are low risk sterile compounded products?

Answer 25

Products prepared using commercially made sterile products and devices.
Reconstitution of an antibiotic, withdrawal of all or part of the solution and dilution by adding it to an IV vehicle.
All materials are commercially made and this is one dose for a specific patient.

Question 26

What are medium risk sterile compounded products?

Answer 26

Products prepared using commercially made sterile products and devices.
But multiple doses are prepared or complex mixtures (parenteral nutrition) are being made.

Question 27

What are high risk sterile compounded products?

Answer 27

A product is being made from a non-sterile starting material.
Preparation of a product which is not available commercially using USP grade drug dissolved in water for injection, filtered for particulates, packaged into vials and then sterilized by autoclaving.

Question 28

What is the expiration dating for low risk sterile compounded products?

Answer 28

48 hours at room temperature.

14 days in the fridge and 45 days when frozen.

Question 29

What is the expiration dating for medium risk sterile compounded products?

Answer 29

30 hours at room temperature.

7 days in the fridge and 45 days when frozen

Question 30

What is the expiration dating for high risk sterile compounded products?

Answer 30

24 hours at room temperature.

3 days in the fridge and 45 days when frozen.

Question 31

What is the Q10 method of shelf life estimation?

Answer 31

A convenient but approximate method for estimating temperature effects on reaction rates.
Q10 is the factor the rate constant increases for a 10 degree celsius temperature increase. May be 2, 3 or 4.
Ea is assumed to be constant, independent of reaction order.

Question 32

Does the expiration date really mean that the drug is only “good” for that period of time?

Answer 32

No. It is just the date that guarantees the full potency and safety of the drug. Drug companies are not required to test a drug until it is no longer viable.
Generally is 5 years max.

Question 33

What is beyond use dating?

Answer 33

When packaging has been opened, or in storage conditions different from label directions, the expiration date has been compromised.
Usually 1 year from when prescription was filled or may reflect time period within which all the medication should be used.
Based on assessment of risk.

Question 34

Where should drugs be stored?

Answer 34

Away from children and pets in a dark area where the temperatures are cool and stable.
Caps and lids securely in place.

Question 35

What is a chemical stability guideline?

Answer 35

In order to be useable, the product must contain 90-95% of the labelled quantity of active ingredient.

Question 36

What are primary amines incompatible with?

Answer 36

Saccharides due to a Maillard reaction

Question 37

What are esters incompatible with?

Answer 37

Basic components due to ester hydrolysis

Question 38

What are carboxyl groups incompatible with?

Answer 38

Divalent ions due to the formation of an insoluble salt

Question 39

What is alcohol incompatible with?

Answer 39

Oxygen due to the oxidation to an aldehyde

Question 40

What is sulfhydryl incompatible with?

Answer 40

Oxygen due to dimerization

Question 41

How can we slow the rates of chemical reactions?

Answer 41

Reduced temperature, buffering to a specific pH

Question 42

How can we prevent oxidation?

Answer 42

By the removal of oxygen, addition of antioxidants and protection from light.

Question 43

What is aging?

Answer 43

The hardening or softening in tablets that can occur in tablets and change disintegration/dissolution properties.
Ostwald ripening

Question 44

What is the industry’s responsibility in regards to expiration dates?

Answer 44

Must provide experimental data regarding products stability to the regulatory bodies.

Question 45

Is stability testing required for compounded preparations?

Answer 45

Not required.

But expiration dates may be derived from literature.

Question 46

What is the beyond use date for water containing oral formulations?

Answer 46

Not later than 14 days when stored at a controlled cold temperature.

Question 47

What is the beyond use date for water containing topical/dermal/mucosal liquid or semisolid formulations?

Answer 47

No later than 30 days.