Drug stability 2 Flashcards
what is the the rate
of reaction determined by?
- undecomposition of drug
- decomposition of drug
What are the Orders of reaction commonly encountered in drug stability studies
- Zero order
- First order
- Second order
- Pseudo first order
- Pseudo zero order
describe zero order kinetics in drug decomposition?
The decomposition proceeds at a constant rate
independent of the concentration of any of the
reactants
describe first order kinetics in drug decomposition?
Independent of the initial concentration of the reactants
describe second order kinetics of drug decomposition?
The rate is determined by the concentrations of two
reacting species
describe pseudoplastic first order and provide example?
This occurs when there is more than 1 reacting species, but the reaction appears to follow first order kinetics
e.g a large excess of one reactant
describe pseudo zero order and provide example?
This occurs when there is 1 reacting species, but the reaction appears to follow zero order kinetics
e.g an excess of the drug
Typically 10 degrees increase in temperature cause a 2 – 5 fold increase in decay
•Arrhenius -type relationship. TRUE OR FALSE?
TRUE
Why stability testing?
- Provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as
- Temperature
- Humidity
- Light
- Establish are-test period for the drug substance
- Because physical, chemical or microbiological changes might impact theefficiency and security of the final produc
What do the ICH do?
Joint initiative involving both regulators and industry as
equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines.
what are the objectives of the ICH?
create harmonisation between USA, japan and EU
What are stability testing performed on?
Drug Substances (DS) –the unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.
Drug Products (DP) –the dosage form in the final immediate packaging intended for marketing.
what are the Variables that might affect the stability of
a given API & dosage form?
1) Formulation
2) Packaging
3) Site and method of manufacture
4) Batch size
5) Batch to batch variability - the importance of process validation & quality risk
management
6) Container / labelling
7) Changes to product
what are Development studies?
- characterise compatibility with common excipients
- characterise stability profile of API
- characterise stability profile of early formulations
what are Confirmatory studies?
long term & accelerated studies on the product as it is
to be registered
what are the two types of stability testing?
- Development studies
- Confirmatory studies
what are the different stability studies at different stages?
- Stress - and accelerated testing with drug substances
- Stability on pre- formulation batches
- Stress testing on scale - up batches
- Accelerated and long term testing for registration
- On-going Stability testing
- Follow - up Stabilities
What does a regulator want to see
demonstrated in the registration dataset?
- in proposed registration formulation &
container/closure system
‒for whole of shelf life
‒at permitted extremes of storage
‒over all batches
‒ when manufactured at all registered sites (API & finished product)
‒ after any changes
Name the three international guidelines?
- ICH
- WHO
- EMA
what is product batch?
- A batch manufactured at production scale using
production equipment & in a production facility
as specified in the registration application
what is a Pilot scale batch?
A batch manufactured by a procedure “fully
representative of and simulating” full production
scale.
what is the Re -test period: API (substance)?
The period of time for which the API remains
within specification when stored under the
recommended conditions in the proposed bulk
storage container
what does API stand for?
Active pharmaceutical ingredient
what is Accelerated testing?
Studies designed to increase the rate of chemical
degradation or physical change by means of exaggerated storage conditions
what is Intermediate testing?
Studies at 30°C / 65%RH Intended for extrapolation to long term storage at 25°C
what is Stress testing?
API: Studies which elucidate intrinsic stability of
AP
what is In-use stability testing?
Establishes the “period of time during which a
multidose product can be used whilst retaining
quality within an accepted specification once the
container is opened
what is Climatic zones?
Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry
what is Bracketing?
A design in which only the extremes are tested
at all time points, eg strength, pack size, container fill
what is Matrixing?
Designs in which a selected subset of samples
is tested, eg different strengths, container
what are The risk associated with bracketing &
matrixing?
- If the results are not what you expected, you may
have insufficient data to propose an intermediate
shelf life.
-Would be risky to use bracketing & matrixing if you
do not have a good idea as to what the product’s
stability will be
Bracketing & matrixing designs are used mainly for confirmatory studies. TRUE OR FALSE?
TRUE
How can you Minimising microbiological deterioration
of non-sterile products?
- Control the microbial load of API & excipients
- Validate & monitor manufacturing conditions
- Include antimicrobial preservatives in formulations
In theory, the stability of the API is directly related to
the kinetics of the various degradation reactions. TRUE OR FALSE?
TRUE
