Studied by 3 people
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>
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
define “expiration date”
time period during which the product is known to be stable and after which the drug product cannot be used
What USP chapter describes stability testing?
USP <1191>
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
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)
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
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
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
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.
What are examples of stability analysis tests that focus on physical properties?
hardness
appearance/description (uniformity of dosage units)
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)
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
What are examples of stability analysis tests that focus on therapeutic properties?
dissolution
What are examples of stability analysis tests that focus on toxicological properties?
impurity tests
What does subpart G in 21 CFR 211 cover?
Packaging and Labeling Control
What does 21 CFR 211.137 in subpart G cover?
expiration dating
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.
What does subpart I in 21 CFR 211 cover?
laboratory controls
What does 21 CFR 211.166 in subpart I cover?
stability testing
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.
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)
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
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
What is the minimum expiration date time frame for OTC products?
3 years
What supplies/products are exempt from expiration dating?
Phase 1, 2, and 3 clinical supplies
When are (initial) stability studies required to be performed?
concurrent to clinical trials
(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!!
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
What broad factors can affect stability?
environment
excipients/internal
packaging/containers
What are examples of environmental factors that could affect stability?
temperature
humidity
light
oxygen
pH
What are examples of internal/excipient factors that could affect stability?
water
peroxides
free radicals
pH
What are examples of packaging factors that could affect stability?
bottles (glass vs. HDPE)
blisters
drums
What are examples of mechanisms of degradation?
hydrolysis
oxidation
isomerization
photochemical
polymerization
polymorphic changes
Describe the degradation pathway of hydrolysis
drug molecule interacts with water and breaks down
When aspirin drug molecules interact with water, what are the degradation products?
salicylic acid + acetic acid
What functional groups are most susceptible to hydrolysis/reacting with H2O?
esters
amides
lactones
Describe the degradation pathway of oxidation
reaction with O2
also knows as dehydrogenation (loss of hydrogen)
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
Describe the degradation pathway of isomerization
change in optical or geometric isomers
What are examples of drugs prone to experiencing the degradation pathway of isomerization?
tetracycline
cephalosporins
docetaxel
Describe the photochemical degradation pathway
molecule degrades when exposed to light
What are examples of drugs prone to experiencing the photochemical degradation pathway?
ascorbic acid
hydrocortisone
nifedipine
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
What are examples of drugs prone to experiencing the degradation pathway of polymerization?
ampicillin
morphine — this specifically forms dimers
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
What is an example of a drug susceptible to degrading via polymorphic changes?
ritonavir
Describe the morphine degradation pathway (possible degradation products)
morphine-N-oxide
pseudomorphine
apomorphine
What is the issue with pseudomorphine?
the dimer will not metabolize and therefore stay in the body, leading to increased toxicity
What is the issue with morphine-N-oxide?
the N-oxide structural group has genotoxicity
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
What are the types of stability studies?
stress stability testing
long-term (at room temperature)
accelerated stability testing
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
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
What is another name for stress stability testing?
forced degradation studies
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
What is the goal of stress stability testing?
carried out on the drug substance in order to understand the degradation pathway of the API
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
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
How much degradation is stress stability testing trying to obtain?
5-15% degradation of the API substance
Which stability test is the main tool to predict stability problems?
stress stability testing (forced degradation studies)
Which instrument is used to determine the amount of impurities in a drug substance or a drug product?
HPLC
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
What forced degradation stability studies are specifically performed on solid drug substances?
photolytic
thermal/humidity
What forced degradation stability studies are specifically performed on solution/suspension drug substances?
acid/base hydrolysis
oxidation
What forced degradation stability studies are specifically performed on solid drug products?
photolytic
oxidation
thermal
thermal/humidity
What forced degradation stability studies are specifically performed on solution/suspension drug products?
photolytic
thermal
oxidation
What are the USP assay specifications? (what range do the results need to be within)
95.0-105.0%
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
What do the results of accelerated stability testing allow?
the development of an expiration date
(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
How were the studies of accelerated stability testing designed? (why?)
to increase the chemical degradation or physical change
(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.
What are the time intervals for accelerated stability testing?
Typically 0 (duh), 1, 3, and 6 months.
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.
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!)
What kind of capsules contain a lower moisture content?
hypromellose (HPMC) capsules [~6%] versus gelatin [~14%]
What are examples of primary packaging?
HDPE bottles & caps
glass bottles
blisters
pharmacy vials
ampoules
syringes
plastic tubes
fiber drums (lined with plastic bags)
Define “primary packaging”
materials that directly enclose and protect a pharmaceutical product, ensuring its integrity and stability
IT TOUCHES THE PRODUCT
What does “HDPE” stand for?
High-Density Polyethylene
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
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
(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
What are examples of secondary packaging?
cartons (paper, fiber)
Define “secondary packaging”
materials that provide additional protection and branding for primary packaged products, often facilitating storage and transport
When primary and secondary packaging come together, what is that called?
container closure system
What kinds of packaging are container closure systems made of?
primary + secondary packaging
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)
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
What instrument is used to set the seal on containers? What kind of heating does it utilize?
Enercon Cap sealer — utilizes induction heating
What are examples of liner combinations?
one piece liner
two piece liner
higher barrier version
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)
What are the criteria for determining a good seal?
visual
mechanical pressure (squeeze)
shipping
What is the procedure of adding a seal to a bottle using an Enercon instrument?
apply the correct amount of torque onto the cap to ensure it is closed properly
electromagnetic field from the instrument reacts with foil to generate heal, sealing it
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
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.
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)
Typically, how big are desiccant package canisters?
0.5g — 3g
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
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
![<p>hypromellose (HPMC) capsules [~6%] versus gelatin [~14%]</p>](https://knowt-user-attachments.s3.amazonaws.com/fc7139d9-db23-4566-9c6f-f971eff7916b.png)
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