UGA PMCY 4510 - Exam 2 Material (contains some Exam 1 stability cards)

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412 Terms

1

Define “stability”

the ability of the drug substance or drug product to retain the same properties and characteristics that it possessed at the time of its manufacture

supported by USP <1191>

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2

define “shelf-life”

time interval a drug product remains with approved specifications when stored under defined conditions on the label before it may begin to degrade in quality

<p>time interval a drug product remains with approved specifications when stored under defined conditions on the label before it may begin to degrade in quality</p>
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3

define “expiration date”

time period during which the product is known to be stable and after which the drug product cannot be used

<p>time period during which the product is known to be stable and after which the drug product cannot be used</p>
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4

What USP chapter describes stability testing?

USP <1191>

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5

Why is stability testing needed?

  • to establish a retest period for an active substance

  • to establish a commercial expiration date for a drug product

  • to determine specifications and control limits for batch/lot release

  • to select appropriate storage conditions and container closure system

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6

What are things that stability studies required for?

  • drug substance (API)

  • clinical development (IND, Phase 1/2/3)

  • clinical/pivotal batches / registration batches

  • commercial/marketed product (QC)

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7

What are the criteria of stability studies?

  • physical — appearance, palatability, suspensibility

  • chemical — API retains its chemical integrity and labeled potency

  • microbiological — sterility or resistance to microbial growth

  • therapeutic — effect remains unchanged

  • toxicological — no toxic impurities or degradation

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8

Define “pivotal batch”

a batch of a drug product used in later-stage clinical trials (phase III) that provides critical (pivotal) data for regulatory submissions, demonstrating the product's safety and efficacy.

produced under processes that closely resemble the full commercial-scale manufacturing process

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9

Define “registration batches”

Batches of a drug product manufactured for submission to regulatory authorities to demonstrate consistency, quality, and compliance with specifications

can be phase III or final batches

produced under full commercial-scale manufacturing processes and need to meet the specifications that will be used for commercial production

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10

What is the difference between pivotal batches and registration batches?

sometimes can be considered the same, sometimes!

Pivotal batches: are used in phase III clinical trials to provide critical data for regulatory submissions

Registration batches: are manufactured to demonstrate consistency and quality for regulatory compliance.

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11

What are examples of stability analysis tests that focus on physical properties?

  • hardness

  • appearance/description (uniformity of dosage units)

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12

What are examples of stability analysis tests that focus on chemical properties?

assay (goal is to make sure the labeled amounts stays within the specifications)

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13

What are examples of stability analysis tests that focus on microbiological properties?

  • water content determination (goal is to make sure the product is not at risk for microbiological growth)

  • sterility test

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14

What are examples of stability analysis tests that focus on therapeutic properties?

dissolution

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15

What are examples of stability analysis tests that focus on toxicological properties?

impurity tests

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16

What does subpart G in 21 CFR 211 cover?

Packaging and Labeling Control

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17

What does 21 CFR 211.137 in subpart G cover?

expiration dating

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18

According to 21 CFR 211.137, what is the purpose of expiration dating?

To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in § 211.166.

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19

What does subpart I in 21 CFR 211 cover?

laboratory controls

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20

What does 21 CFR 211.166 in subpart I cover?

stability testing

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21

According to 21 CFR 211.166, what is the purpose of stability testing?

There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates.

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22

How are the drug products manufactured every year tested? (describe the plan)

are tested based on a statistical plan that considers the total number of batches manufactured (with FDA’s agreement)

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23

What is the minimum expiration date time frame for marketed products?

24 months (more is preferred) — desired for all pharmaceutical dosage forms to allow enough time for manufacture, packaging, testing, distribution, and consumption by patient

Having an expiration of 24 months will allow ~18 months before the expiration date that patients can benefit from the drug product

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24

If the product is meant to be reconstituted, what should the labeling include about expiration dating?

expiration information for both reconstituted and unreconstituted drug products

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25

What is the minimum expiration date time frame for OTC products?

3 years

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26

What supplies/products are exempt from expiration dating?

Phase 1, 2, and 3 clinical supplies

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27

When are (initial) stability studies required to be performed?

concurrent to clinical trials

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28

(T/F) Even though solid dosage forms are multi-component and multi-phase, their stability is fairly straightforward since it depends on the API.

False — their (in)stability is also complex!!

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29

What factors can affect formulation design?

  • DRUG & EXCIPIENT

    • Chemical structure

    • Impurity profile

    • Physical form

    • Moisture content

    • Particle size

    • Surface area

    • Morphology

  • FORMULATION

    • Drug to excipient ratio

    • Processing method

    • Mixing/milling

    • Powder packing

  • ENVIRONMENT

    • Temperature

    • Relative humidity

    • Packaging

    • Light

    • Oxygen

<ul><li><p>DRUG &amp; EXCIPIENT</p><ul><li><p>Chemical structure</p></li><li><p>Impurity profile</p></li><li><p>Physical form</p></li><li><p>Moisture content</p></li><li><p>Particle size</p></li><li><p>Surface area</p></li><li><p>Morphology</p></li></ul></li><li><p>FORMULATION</p><ul><li><p>Drug to excipient ratio</p></li><li><p>Processing method</p></li><li><p>Mixing/milling</p></li><li><p>Powder packing</p></li></ul></li><li><p>ENVIRONMENT</p><ul><li><p>Temperature</p></li><li><p>Relative humidity</p></li><li><p>Packaging</p></li><li><p>Light</p></li><li><p>Oxygen</p></li></ul></li></ul><p></p>
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30

What broad factors can affect stability?

  • environment

  • excipients/internal

  • packaging/containers

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31

What are examples of environmental factors that could affect stability?

  • temperature

  • humidity

  • light

  • oxygen

  • pH

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32

What are examples of internal/excipient factors that could affect stability?

  • water

  • peroxides

  • free radicals

  • pH

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33

What are examples of packaging factors that could affect stability?

  • bottles (glass vs. HDPE)

  • blisters

  • drums

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34

What are examples of mechanisms of degradation?

  • hydrolysis

  • oxidation

  • isomerization

  • photochemical

  • polymerization

  • polymorphic changes

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35

Describe the degradation pathway of hydrolysis

drug molecule interacts with water and breaks down

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36

When aspirin drug molecules interact with water, what are the degradation products?

salicylic acid + acetic acid

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37

What functional groups are most susceptible to hydrolysis/reacting with H2O?

  • esters

  • amides

  • lactones

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38

Describe the degradation pathway of oxidation

reaction with O2

also knows as dehydrogenation (loss of hydrogen)

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39

How does the addition of antioxidant excipients prevent degradation, and what are some examples of antioxidant excipients?

Antioxidant excipients prevent degradation by scavenging free radicals and inhibiting oxidation reactions

EX: sodium bisulfite, ascorbic acid, vitamin E

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40

Describe the degradation pathway of isomerization

change in optical or geometric isomers

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41

What are examples of drugs prone to experiencing the degradation pathway of isomerization?

  • tetracycline

  • cephalosporins

  • docetaxel

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42

Describe the photochemical degradation pathway

molecule degrades when exposed to light

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43

What are examples of drugs prone to experiencing the photochemical degradation pathway?

  • ascorbic acid

  • hydrocortisone

  • nifedipine

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44

Describe the degradation pathway of polymerization

a process where small molecules combine to form larger, more complex molecules, often leading to changes in the drug's properties

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45

What are examples of drugs prone to experiencing the degradation pathway of polymerization?

  • ampicillin

  • morphine — this specifically forms dimers

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46

Describe the degradation pathway of polymorphic changes

a process where a drug exists in multiple crystalline forms, leading to variations in solubility, stability, and bioavailability

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47

What is an example of a drug susceptible to degrading via polymorphic changes?

ritonavir

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48

Describe the morphine degradation pathway (possible degradation products)

  • morphine-N-oxide

  • pseudomorphine

  • apomorphine

<ul><li><p>morphine-N-oxide</p></li><li><p>pseudomorphine</p></li><li><p>apomorphine</p></li></ul><p></p>
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49

What is the issue with pseudomorphine?

the dimer will not metabolize and therefore stay in the body, leading to increased toxicity

<p>the dimer will not metabolize and therefore stay in the body, leading to increased toxicity</p>
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50

What is the issue with morphine-N-oxide?

the N-oxide structural group has genotoxicity

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51

What is the issue with apomorphine?

Apomorphine can cause severe nausea and vomiting, limiting its therapeutic use

typically used for animals to prevent ingestion of poisons

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52

What are the types of stability studies?

  • stress stability testing

  • long-term (at room temperature)

  • accelerated stability testing

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53

What are the accepted temperature and relative humidity ICH/FDA standards for long-term stability testing?

performed at the ICH/FDA accepted standard of 25C & 60% relative humidity

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54

What are the accepted temperature and relative humidity ICH/FDA standards for accelerated stability testing?

performed at the ICH/FDA accepted standard of 40C & 75% relative humidity

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55

What is another name for stress stability testing?

forced degradation studies

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56

What is the difference between stress stability testing and accelerated stability testing?

Stress stability testing: involves subjecting a drug substance to extreme conditions to observe its degradation

Accelerated stability testing: evaluates both the drug substance’s and drug product's stability under elevated temperature and humidity conditions

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57

What is the goal of stress stability testing?

carried out on the drug substance in order to understand the degradation pathway of the API

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58

Under what possible conditions is stress stability testing conducted under?

  • extremes of pH — EX: 1 (very acidic), 10 (very basic)

  • temperature “freeze/thaw transport studies”

  • oxygen

  • photostability

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59

Which stability test is used in order to develop a stability-indicating analytical method?

stress stability testing — it is able to detect the API, impurities, and degradation products

<p>stress stability testing — it is able to detect the API, impurities, and degradation products</p>
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60

How much degradation is stress stability testing trying to obtain?

5-15% degradation of the API substance

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61

Which stability test is the main tool to predict stability problems?

stress stability testing (forced degradation studies)

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62

Which instrument is used to determine the amount of impurities in a drug substance or a drug product?

HPLC

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63

What analytical method is used for stability testing? What happens if there are major impurity peaks?

  • HPLC or UPLC combined with UV detection

    • UV is more for quantification

  • Liquid chromatography combined with mass spectrometry is used for identifying the peaks and determining the molecular weight of the impurity

major impurity peaks are synthesized for accurate quantitation

<ul><li><p><strong>HPLC </strong>or UPLC combined with UV detection </p><ul><li><p>UV is more for <u>quantification</u></p></li></ul></li><li><p>Liquid chromatography combined with mass spectrometry is used for identifying the peaks <u>and determining the molecular weight of the impurity</u></p></li></ul><p></p><p><em>major impurity peaks are synthesized for accurate quantitation</em></p>
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64

What forced degradation stability studies are specifically performed on solid drug substances?

  • photolytic

  • thermal/humidity

<ul><li><p>photolytic</p></li><li><p>thermal/humidity</p></li></ul><p></p>
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65

What forced degradation stability studies are specifically performed on solution/suspension drug substances?

  • acid/base hydrolysis

  • oxidation

<ul><li><p>acid/base hydrolysis</p></li><li><p>oxidation</p></li></ul><p></p>
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66

What forced degradation stability studies are specifically performed on solid drug products?

  • photolytic

  • oxidation

  • thermal

  • thermal/humidity

<ul><li><p>photolytic</p></li><li><p>oxidation</p></li><li><p>thermal</p></li><li><p>thermal/humidity</p></li></ul><p></p>
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67

What forced degradation stability studies are specifically performed on solution/suspension drug products?

  • photolytic

  • thermal

  • oxidation

<ul><li><p>photolytic</p></li><li><p>thermal</p></li><li><p>oxidation</p></li></ul><p></p>
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68

What are the USP assay specifications? (what range do the results need to be within)

95.0-105.0%

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69

Why is stress testing conducted at 40C and 75% RH?

To evaluate the stability of drug products under accelerated conditions that mimic long-term storage.

6 months under these conditions = 24 months of room temperature stability

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70

What do the results of accelerated stability testing allow?

the development of an expiration date

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71

(T/F) Since stress stability testing only uses the API (drug substance), accelerated stability testing only uses the final drug product.

False — accelerated stability testing uses both the drug substance and drug product

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72

How were the studies of accelerated stability testing designed? (why?)

to increase the chemical degradation or physical change

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73

(T/F) Unlike stress stability testing, accelerated stability testing is not always predictive.

True — keep in mind, BOTH are required to be performed to ensure comprehensive stability assessment.

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74

What are the time intervals for accelerated stability testing?

Typically 0 (duh), 1, 3, and 6 months.

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75

What is the Arrhenius equation?

A formula that relates the rate of a chemical reaction to temperature, predicting how reaction rates increase with temperature changes.

<p>A formula that relates the rate of a chemical reaction to temperature, predicting how reaction rates increase with temperature changes. </p>
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76

When can the Arrhenius model be applied to a reaction as a predictive model?

any process that is accelerated by heat

(keep in mind, not all degradation mechanisms are accelerated by heat!)

<p>any process that is accelerated by heat </p><p>(keep in mind, not <em>all </em>degradation mechanisms are accelerated by heat!)</p>
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77

What kind of capsules contain a lower moisture content?

hypromellose (HPMC) capsules [~6%] versus gelatin [~14%]

<p>hypromellose (HPMC) capsules [~6%] versus gelatin [~14%]</p>
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78

What are examples of primary packaging?

  • HDPE bottles & caps

  • glass bottles

  • blisters

  • pharmacy vials

  • ampoules

  • syringes

  • plastic tubes

  • fiber drums (lined with plastic bags)

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79

Define “primary packaging”

materials that directly enclose and protect a pharmaceutical product, ensuring its integrity and stability

IT TOUCHES THE PRODUCT

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80

What does “HDPE” stand for?

High-Density Polyethylene

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81

Why does the size of the bottle matter?

depending how much you fill it up with the drug product, there could be a lot of headspace

more headspace = more oxygen = more exposure to oxygen = possibly more degradation

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82

How do you choose what size of bottle to use?

GOAL IS TO BE AROUND ¾ FULL

Consider the volume of the drug product and what number of tablets/capsules to include in each container

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83

(T/F) When determining what is the primary packaging for powder-filled drums, the primary package is only the plastic bag liner.

False — it is BOTH the plastic bag liner AND the fiber drum

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84

What are examples of secondary packaging?

cartons (paper, fiber)

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85

Define “secondary packaging”

materials that provide additional protection and branding for primary packaged products, often facilitating storage and transport

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86

When primary and secondary packaging come together, what is that called?

container closure system

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87

What kinds of packaging are container closure systems made of?

primary + secondary packaging

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88

Define “container closure system”

the sum of packaging components that together contain and protect the dosage form (including the secondary packaging, like the outer carton)

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89

What is the difference between primary and secondary packaging?

Primary packaging: is the first layer of packaging that directly contains the product

Secondary packaging: is the outer layer that groups multiple primary packages for protection or branding

<p><strong>Primary packaging:</strong> is the first layer of packaging that directly contains the product</p><p><strong>Secondary packaging:</strong> is the outer layer that groups multiple primary packages for protection or branding</p>
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90

What instrument is used to set the seal on containers? What kind of heating does it utilize?

Enercon Cap sealer — utilizes induction heating

<p>Enercon Cap sealer — utilizes induction heating</p>
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91

What are examples of liner combinations?

  • one piece liner

  • two piece liner

  • higher barrier version

<ul><li><p>one piece liner</p></li><li><p>two piece liner</p></li><li><p>higher barrier version</p></li></ul><p></p>
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92

How do you select the proper liner for induction sealing? (what is the rationale)

determined by level of protection needed for stability of the product based on how sensitive it is to the environment (ex: humidity/moisture)

<p>determined by level of protection needed for stability of the product based on how sensitive it is to the environment (ex: humidity/moisture)</p>
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93

What are the criteria for determining a good seal?

  • visual

  • mechanical pressure (squeeze)

  • shipping

<ul><li><p>visual</p></li><li><p>mechanical pressure (squeeze)</p></li><li><p>shipping</p></li></ul><p></p>
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94

What is the procedure of adding a seal to a bottle using an Enercon instrument?

  1. apply the correct amount of torque onto the cap to ensure it is closed properly

  2. electromagnetic field from the instrument reacts with foil to generate heal, sealing it

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95

What is the key factor that differentiates high density PE bottles from low density PE bottles?

the permeability of the bottle —> impacting the Moisture Vapor Transmission Rate

HDPE prevents moisture from coming in

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96

What is the Moisture Vapor Transmission Rate (MVTR)?

A measure of the rate at which moisture vapor passes through a material, indicating its barrier properties.

<p>A measure of the rate at which moisture vapor passes through a material, indicating its barrier properties. </p>
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97

What needs to be considered when looking at the package headspace of HDPE bottles?

the amount of room for moisture and oxygen coming in from the environment during packaging (too much is bad)

<p>the amount of room for moisture and oxygen coming in from the environment during packaging (too much is <u>bad</u>)</p>
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98

Typically, how big are desiccant package canisters?

0.5g — 3g

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99

What are the possible roles of desiccants in packaging, and which is the most important and what does it protect against?

  • MOISTURE ADSORBERS — absorb free water in the packaged headspace or any that enter via MVT more quickly than the drug product

    • in order to protect against hydrolytic or enzymatic degradation

  • oxygen-scavenging agents

  • humidity control agents

  • aroma-releasing agents

  • odor-adsorbing agents

<ul><li><p><mark data-color="yellow" style="background-color: yellow; color: inherit">MOISTURE ADSORBERS — absorb free water in the packaged headspace or any that enter via MVT more quickly than the drug product</mark></p><ul><li><p><mark data-color="yellow" style="background-color: yellow; color: inherit">in order to protect against hydrolytic or enzymatic degradation</mark></p></li></ul></li><li><p>oxygen-scavenging agents</p></li><li><p>humidity control agents</p></li><li><p>aroma-releasing agents</p></li><li><p>odor-adsorbing agents</p></li></ul><p></p>
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100

What specific solid oral dosage form are desiccants not used with?

capsules — the desiccant would make the capsules too brittle

capsules need to have a certain amount of moisture

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