Drug Stability & Stability Testing - Part 2 Flashcards
(44 cards)
API
Active Pharmaceutical Ingredient
FPP
Finished Pharmaceutical Product
GMP
Good Manufacturing Practices
ICH
International Conference on Harmonization
MA
Marketing Authorization
RH
Relative Humidity
Reaction Energetics: Thermodynamics Reaction Rates: Kinetics
For the reaction:
DRUG [D] β DEGRADATION PRODUCT [P]
The rate of reaction can be determined by..
following (un-decomposed) drug [D] or decomposition product [P]:
rate of reaction = βπ[π·] / ππ‘
rate = k [D]x
= π[π] / ππ‘
β Zero order
Differential equation
- d [A] / dt = k [A] 0 = k
Integral equation
[A] = [A]0 β k t
The decomposition proceeds at a constant rate independent of the concentration of any of the reactants
First order
Differential equation
- d [A] / dt = k [A]
Integral equation
In [A] = [A]0 β k t
Half life:
β’ The time taken for half of the reactant to decompose
β’ Independent of the initial concentration of the reactants (only for 1st order!)
The rate of reaction is determined by a single concentration term:
βπ
[π«] = k1[D] π
π
Which integrated at t = 0 and rearranged to give a linear relationship can be found expressed as:
t = π.πππ log a - π.πππ log (a-x) ππ
Where a = [A]0
a-x = [A]t (so x refers to amount degraded)
Second order
Differential equation
- d [A] / dt = k [a] 2
Integral equation
1/[A] = 1/[A]0 + k t
The rate is determined by the concentrations of two reacting species
A + B β degradation products
- π
[π¨] / π
π = k[A][B]
Which integrated at t=0 and rearranged to give a linear relationship can be expressed as:
t = π.πππ/π(πβπ) log (π/π) + π.πππ/π(πβπ) log (πβπ)/ (πβπ)
Where:
a = [A]0
b = [B]0 and x = amount of drug degraded
When does Pseudo first order occur
β’ This occurs when there is more than 1 reacting species, but the reaction appears to follow first order kinetics
β e.g. a large excess of one reactant
β e.g. water or oxygen frequently in great excess and their concentrations will essentially remain constant
When does Pseudo zero order occur
β’ This occurs when there is 1 reacting species, but the reaction appears to follow zero order kinetics
β E.g. an excess of the drug.
β E.g. hydrolysis of a suspension (e.g. aspirin) β drug concentration in solution is kept constant (saturated solution maintained).
System follows pseudo zero-order as long as suspension, then follows pseudo first order.
Determining rate orders
β’ Determine experimentally the amount of drug decomposed at various intervals
β substitute the data in to the integrated equations for zero, first and second order reactions
β’ Determine the one which produces the most consistent value for k at a range of time points
β or represent data graphically according to the linear equations
β’ Determine which one produces a straight line
Drug degradation
- Hydrolysis
- Oxidation
- Photolysis
- Trace metal catalysis
- Isomerisation
All affected by temp
Temperature and Arrhenius type relationship
Typically 100C increase in temperature causes a 2 β 5 fold increase in decay
β’ Arrhenius-type relationship
log k = logA - π¬π/
π.πππ πΉπ»
β’ Reaction rate can then be calculated at any given temperature and a prediction of shelf life obtained.
β’ Below 500C
Half-lives and shelf lives for zero order
Integrated rate equation: c = c0 β k0t
Units of k: conc. x time -1
Half-life t1β2: 0.5 π0/ π0
Shelf-life t90: 0.1 π0/ π0
Half-lives and shelf lives for first order
Integrated rate equation: logc0 β π1π‘/ 2.303
Units of k: time -1
Half-life t1β2: 0.693/ π1
Shelf-life t90: 0.105/ π1
Temperature Effects on Activation energy Ea
Relationship to k Units of k: log k = log A - πΈπ/ 2.303 π π
Typical values
Min: 10 kcal/mol
Max: 25 kcal/mol
ICH is carried out in which regions
EU, Japan and USA.
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.
Stability Studies are performed on..
β’ Drug Substances (DS)
β the unformulated drug substance that may subsequently
be formulated with excipients to produce the dosage form.
β’ Drug Products (DP)
β the dosage form in the final immediate packaging intended for marketing.
Variables that might affect the stability of a given API & dosage form
1) Formulation
2) Packaging
3) Site and method of manufacture
β API
β Finished product
4) Batch size
5) Batch to batch variability
β the importance of process validation & quality risk management
6) Container / labelling 7) Changes to product
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
Stability testing - 2 studies
Development studies
β characterise compatibility with common excipients
β characterise stability profile of API
β’ e.g susceptibility to acid, base, light, oxygen etc
β characterise stability profile of early formulations
β’ especially susceptibility to heat, humidity & light
Confirmatory studies
β long term & accelerated studies on the product as it is to be registered
β in practice: design now largely dictated by ICH guidelines
What does a regulator want to see demonstrated in the registration dataset?
The product maintains relevant quality
characteristics within the acceptable range:
β in proposed registration formulation & container/closure system
β for whole of shelf life
β at permitted extremes of storage
β over all batches
β when manufactured at all registered sites (API & finished product)
β after any changes