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Pharmaceutics Year 2 > Section 2 - Expiration Dating > Flashcards

Section 2 - Expiration Dating Flashcards

1
Q

What is accelerated testing?

A

Studies that are used to increase the rate of chemical or physical degradation by using exaggerated storage conditions

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2
Q

What is the purpose of accelerated testing?

A

To determine kinetic parameters in order to predict a tentative expiration dating period

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3
Q

Accelerated testing is often used synonymously with _____ testing

A

Stress

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4
Q

What is an expiration date?

A

A date placed on the label of a drug product that designates the date through which the product will remain within specifications

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5
Q

How long will a product be good for if the expiration date only includes a month and a year?

A

Until the last day of the month

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6
Q

What is stability?

A

The capacity of a product to remain within specifications established to ensure its identity, strength, quality, and purity

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7
Q

What is primary stability data?

A

Data on a product stored under labeled storage conditions in container-closure to be used

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8
Q

What is supportive stability data?

A

Data other than primary stability data

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9
Q

What are 2 examples of supportive stability data?

A
  • Accelerated studies

- Published stability data

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10
Q

What is one drawback to stability studies at labeled storage conditions?

A

Time consuming

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11
Q

Are stability studies at labeled storage conditions required?

A

Yes, but tentative permission may be given to market a product with the expiration date predicted from accelerated testing

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12
Q

How can expiration dates be predicted from accelerated testing?

A

Using the Arrhenius plot to predict from high temperature data the rate of product breakdown to be expected at actual storage conditions

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13
Q

What are the steps to an accelerated stability test?

A

Samples are held at elevated temperatures and sampled at timed intervals for chemical analysis

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14
Q

How is the data from an accelerated stability test used?

A

To assign a rate order, which is then used to calculate appropriate rate constants using linear regression analysis

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15
Q

What is the y-axis for an Arrhenius plot?

A

Log of the rate constant

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16
Q

What is the x-axis for an Arrhenius plot?

A

The inverse of temperature in absolute degrees

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17
Q

Data generated from the linear regression of the Arrhenius equation allows for _____

A

The calculation of the rate constant at room temperature, and from this t90

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18
Q

What type of dose forms is the Arrhenius plot best for?

A

Solution

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19
Q

Why shouldn’t the Arrhenius plot be used for solid dose forms?

A

They will experience changes in moisture, which may influence stability

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20
Q

Why shouldn’t the Arrhenius plot be used for suspensions containing polymorphic materials or solvates?

A

May undergo changes at elevated temperatures

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21
Q

What are 2 examples of an adverse event that can happen during the Arrhenius plot experiment?

A
  • Some materials may undergo phase transitions at elevated temperatures
  • pH may change with temperature
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22
Q

What can happen to oxygen levels with increasing temperature?

A

They may drop

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23
Q

What happens as extrapolated points become further from the actual data points?

A

Range of error increases

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24
Q

What is the range for activation energy for an accelerated stability test?

A

10-30 kcal/mole

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25
Q

What happens to an accelerated stability test if the rate is limited by diffusion or a photochemical process?

A

The test may not be valid

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26
Q

What happens to an accelerated stability test if the product decomposes due to freezing, agitation, or microbial contamination?

A

The test is not valid

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27
Q

Should you use an accelerated stability test for suppositories and ointments? Why?

A

No because they contain protein drugs or suspending agents, which causes them to undergo a phase transformation

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28
Q

What are examples of physical tests that can be done to products?

A
  • Tablet disintegration or dissolution
  • Emulsion droplet size
  • Suspension particle size
  • Sedimentation rate
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29
Q

For drug stability work, what must the method of analysis be?

A

Stability-indicating and validated

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30
Q

What must be distinguished for drug stability work?

A

Active drug from breakdown products and excipients

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31
Q

What is the most commonly used analytical method?

A

High-pressure liquid chromatography (HPLC)

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32
Q

What are examples of validation criteria?

A
  • Selectivity
  • Accuracy
  • Precision
  • Linearity
  • Range and sensitivity
  • Robustness
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33
Q

What is selectivity/specificity?

A

Ability of the method to detect and quantify the analyte in the presence of excipients, degradation products, and metabolites

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34
Q

What should be done if the mechanism of decomposition is known the degradation products are available?

A

They should be chromatographed

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35
Q

What should be done if degradation products are not available?

A

A procedure of forced degradation could be used

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36
Q

What happens in forced degradation?

A

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

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37
Q

What is accuracy?

A

The closeness of the test result obtained by the method to the true value

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38
Q

What are the criteria for acceptance of accuracy?

A

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

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39
Q

What is precision?

A

The degree of agreement among individual test results

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40
Q

What are the criteria for precision testing?

A

Must be done by using a minimum of 9 determinations and the values should not exceed a relative standard deviation of 3-5%

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41
Q

What is linearity?

A

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

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42
Q

How is the range for linearity determined?

A

It is the upper and lower levels of analyte that have been shown to have suitable levels of accuracy and precision

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43
Q

How can linearity be established?

A

By using a minimum of 5 concentrations within the range

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44
Q

What can be used to test the relationship between assay response and concentration?

A

Regression analysis

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45
Q

What does sensitivity involve determining?

A

The lowest concentration where linearity, accuracy, and precision are all within the accepted limits

46
Q

What is robustness?

A

Ability of the method to remain unaffected by small variations in method parameters

47
Q

What does robustness provide an indication of?

A

Reliability and durability of the assay

48
Q

What is the expiration dating guideline for non-sterile compounded solid or non-aqueous liquid dose forms prepared from
a commercially available dose form?

A

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

49
Q

What is the expiration dating guideline for non-sterile compounded solid or non-aqueous liquid dose forms prepared from bulk ingredients?

A

Use actual labeled expiration dates of the components, so the one with the shortest dating will be the limiting factor; maximum of 6 months

50
Q

What is the expiration dating guideline for non-sterile compounded aqueous-based formulations prepared from ingredients in solid form?

A
  • 14 days in the fridge

- 30 days if preserved

51
Q

What is the expiration dating guideline for all other non-sterile compounded products?

A

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

52
Q

What is the expiration dating guideline for non-sterile compounded products that are literature sourced?

A

The published dating may be used provided it is shorter than that of any of the components used

53
Q

What is the expiration dating guideline for sterile compounded products?

A

Depends on risk of microbial contamination and physicochemical stability considerations (low, medium, or high)

54
Q

What is the expiration dating guideline for low risk sterile compounded products prepared using commercially made sterile products and devices?

A
  • Room temperature - 48 hours
  • Fridge - 14 days
  • Freezer - 45 days
55
Q

What is the expiration dating guideline for medium risk sterile compounded products prepared using commercially made sterile products and devices?

A
  • Room temperature - 30 hours
  • Fridge - 7 days
  • Freezer - 45 days
56
Q

What is the expiration dating guideline for high risk sterile compounded products made from non-sterile starting material?

A
  • Room temperature - 24 hours
  • Fridge - 3 days
  • Freezer - 45 days
57
Q

What are examples of low risk sterile compounded products?

A
  • Reconstitution of an antibiotic

- Withdrawal of all or part of a solution and dilution by adding to an IV vehicle

58
Q

What is the criteria for a low risk sterile compounded product?

A

All materials used are commercially made and is one dose for a specific patient

59
Q

What is the criteria for a medium risk sterile compounded product?

A

Multiple doses are prepared or complex mixtures

60
Q

What is an example of a medium risk sterile compounded products?

A

Parenteral nutrition solution

61
Q

What is an example of a high risk sterile compounded products?

A

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

62
Q

What is the Q10 method?

A

A method for estimating temperature effects on reaction rates

63
Q

What does Q10 mean?

A

The factor the rate constant increases for a 10 C temperature increase

64
Q

Is Q10 dependent on reaction order?

A

No

65
Q

What is the equation for Q10?

A

t90(T2) = t90(T1) / Q10 ^ (delta T/10)

66
Q

What does an expiration date specify?

A

The only date that the manufacturer guarantees the full potency and safety of the drug

67
Q

What is normally the maximum expiration date?

A

5 years from the time of manufacture

68
Q

What is the manufacturer required to provide in regards to testing for expiration dates?

A

The test results for the duration of the expiration date they have assigned the product

69
Q

Do a product need to be tested until it is no longer viable?

A

No

70
Q

What does “stored under defined conditions” mean?

A

That if the packaging is opened or the storage conditions were different from label directions, the expiration date has been compromised

71
Q

What is beyond-use dating?

A
  • The time period within which the medication should be used up
  • Normally one year from date the prescription was filled
72
Q

Is the beyond-use date longer than the expiration date?

A

No, significantly shorter

73
Q

What are beyond-use dates based on?

A

The assessment of risk, not on science

74
Q

What is an appropriate beyond use date for an antibiotic prescribed for a 10 day period?

A

14 days b/c the medication should be used up by then

75
Q

Why shouldn’t people store medications in the bathroom?

A

Temperature changes and humidity from showers can damage medications

76
Q

What percentage of the labeled quantity of active ingredient must a product contain in order to be useable?

A

90-95%

77
Q

What are the 3 most common routes of chemical degradation?

A

1) Hydrolysis
2) Oxidation
3) Photolysis

78
Q

What are 3 less common routes of chemical degradation?

A

1) Racemization
2) Maillard reaction
3) Formation of Schiff bases

79
Q

What does hydrolysis do to a drug?

A

Decomposes the drug through a reaction with water acting as a nucleophilic agent by attacking electrophilic sites in the drug

80
Q

What are the most common functional groups involved in hydrolysis reactions?

A

Carboxyl derivatives

81
Q

What is the functional group susceptible to hydrolysis in acetaminophen?

A

Amide

82
Q

What is the functional group susceptible to hydrolysis in penicillin?

A

Lactam

83
Q

What is the functional group susceptible to hydrolysis in atropine?

A

ester

84
Q

What is the functional group susceptible to hydrolysis in warfarin?

A

Lactone

85
Q

What is oxidation strongly influenced by?

A

Light, metal ions, and oxygen

86
Q

The majority of oxidation reactions are ____ which means _____

A
  • Free radical reactions

- They can occur spontaneously

87
Q

What usually happens to the products of oxidation reactions?

A

They are conjugated, which results in changes to colour and odor

88
Q

What is the downside to oxidation reactions in drugs?

A

Can cause the product to be unfit even though only a small percentage of the product has decomposed

89
Q

What is the functional group susceptible to oxidation in steroids?

A

Phenols

90
Q

What is the functional group susceptible to oxidation in isoproterenol?

A

Catechol

91
Q

What is the functional group susceptible to oxidation in methimazole?

A

Thiols

92
Q

How can you prevent hydrolysis?

A
  • Remove water

- Add propylene glycol

93
Q

How can you prevent oxidation?

A
  • Remove oxygen
  • Add antioxidants
  • Protect from light
94
Q

Which physical properties must a product retain in order to be useable?

A
  • Appearance
  • Palatability
  • Uniformity
  • Dissolution
  • Suspendability
95
Q

What are the potential problems to physical stability?

A
  • Polymorphism
  • Vaporization
  • Aging
  • Adsorption
96
Q

What is polymorphism and what can it cause?

A
  • Difference in internal crystal structure

- Solubility and melting temperature differences leading to caking of suspensions or altered bioavailability

97
Q

What are 2 drugs that can be lost through vaporization?

A

Nitroglycerin and ibuprofen

98
Q

What type of aging can occur in tablets?

A

Hardening, which can alter disintegration/dissolution properties

99
Q

What is an example of adsorption?

A

Drug lost to packaging materials for IV solutions in PVC plastic

100
Q

How can you protect microbiological stability?

A
  • Packaging must retain its integrity

- Antimicrobial preservatives must retain their effectiveness

101
Q

Can accelerated studies be used to determine an expiration date?

A

Nope, can only be used for approximations of shelf life and nature of the product degradation

102
Q

What is the criteria for long-term stability studies?

A
  • 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
103
Q

Testing is for ______ aspects of the product

A

Chemical, physical, and microbiological

104
Q

Is stability testing a requirement for compounded preparations?

A

No

105
Q

How are expiration dates derived for compounded products?

A
  • From literature

- Guidelines in USP chapters 795 and 797

106
Q

What are the 6 things that need to be considered when assigning an expiration or beyond use date?

A
  • 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
107
Q

What does USP chapter 795 say about the beyond use date for water containing oral compounded preparations?

A

Beyond use date of no longer than 14 days when stored at controlled cold temperature

108
Q

What does USP chapter 795 say about the beyond use date of water containing topical, dermal, or mucosal liquid or semisolid compounded preparations?

A

Beyond use date of no longer than 30 days

109
Q

What does USP chapter 795 say about the beyond use date of non-aqueous compounded preparations?

A
  • 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
110
Q

What is the maximum expiration date?

A

5 years from the time of manufacture

111
Q

What are the risks associated with using expired drug products?

A
  • Formation of toxic degradation products (unusual)

- Loss of potency (especially nitroglycerin, insulin, and liquid antibiotics)

Pharmaceutics Year 2 (17 decks)

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