Drug Stability & Stability Testing - Part 2

Question 1

API

Answer 1

Active Pharmaceutical Ingredient

Question 2

FPP

Answer 2

Finished Pharmaceutical Product

Question 3

GMP

Answer 3

Good Manufacturing Practices

Question 4

ICH

Answer 4

International Conference on Harmonization

Question 5

MA

Answer 5

Marketing Authorization

Question 6

RH

Answer 6

Relative Humidity

Question 7

Reaction Energetics: Thermodynamics Reaction Rates: Kinetics

For the reaction:
DRUG [D] → DEGRADATION PRODUCT [P]
The rate of reaction can be determined by..

Answer 7

following (un-decomposed) drug [D] or decomposition product [P]:

rate of reaction = −𝑑[𝐷] / 𝑑𝑡
rate = k [D]x

= 𝑑[𝑃] / 𝑑𝑡

Question 8

– Zero order

Answer 8

Differential equation
- d [A] / dt = k [A] 0 = k
Integral equation
[A] = [A]0 – k t

The decomposition proceeds at a constant rate independent of the concentration of any of the reactants

Question 9

First order

Answer 9

Differential equation
- d [A] / dt = k [A]
Integral equation
In [A] = [A]0 – k t

Half life:
• The time taken for half of the reactant to decompose
• Independent of the initial concentration of the reactants (only for 1st order!)

The rate of reaction is determined by a single concentration term:
−𝒅[𝑫] = k1[D] 𝒅𝒕
Which integrated at t = 0 and rearranged to give a linear relationship can be found expressed as:
t = 𝟐.𝟑𝟎𝟑 log a - 𝟐.𝟑𝟎𝟑 log (a-x) 𝒌𝒌
Where a = [A]0
a-x = [A]t (so x refers to amount degraded)

Question 10

Second order

Answer 10

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 → degradation products
- 𝒅[𝑨] / 𝒅𝒕 = k[A][B]
Which integrated at t=0 and rearranged to give a linear relationship can be expressed as:
t = 𝟐.𝟑𝟎𝟑/𝒌(𝒂−𝒃) log (𝒃/𝒂) + 𝟐.𝟑𝟎𝟑/𝒌(𝒂−𝒃) log (𝒂−𝒙)/ (𝒃−𝒙)
Where:
a = [A]0
b = [B]0 and x = amount of drug degraded

Question 11

When does Pseudo first order occur

Answer 11

• 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
– e.g. water or oxygen frequently in great excess and their concentrations will essentially remain constant

Question 12

When does Pseudo zero order occur

Answer 12

• This occurs when there is 1 reacting species, but the reaction appears to follow zero order kinetics
– E.g. an excess of the drug.
– E.g. hydrolysis of a suspension (e.g. aspirin) – drug concentration in solution is kept constant (saturated solution maintained).
System follows pseudo zero-order as long as suspension, then follows pseudo first order.

Question 13

Determining rate orders

Answer 13

• Determine experimentally the amount of drug decomposed at various intervals
– substitute the data in to the integrated equations for zero, first and second order reactions
• Determine the one which produces the most consistent value for k at a range of time points
– or represent data graphically according to the linear equations
• Determine which one produces a straight line

Question 14

Drug degradation

Answer 14

• Hydrolysis
• Oxidation
• Photolysis
• Trace metal catalysis
• Isomerisation

All affected by temp

Question 15

Temperature and Arrhenius type relationship

Answer 15

Typically 100C increase in temperature causes a 2 – 5 fold increase in decay
• Arrhenius-type relationship
log k = logA - 𝑬𝒂/
𝟐.𝟑𝟎𝟑 𝑹𝑻
• Reaction rate can then be calculated at any given temperature and a prediction of shelf life obtained.
• Below 500C

Question 16

Half-lives and shelf lives for zero order

Answer 16

Integrated rate equation: c = c0 – k0t
Units of k: conc. x time -1
Half-life t1⁄2: 0.5 𝑐0/ 𝑘0
Shelf-life t90: 0.1 𝑐0/ 𝑘0

Question 17

Half-lives and shelf lives for first order

Answer 17

Integrated rate equation: logc0 – 𝑘1𝑡/ 2.303
Units of k: time -1
Half-life t1⁄2: 0.693/ 𝑘1
Shelf-life t90: 0.105/ 𝑘1

Question 18

Temperature Effects on Activation energy Ea

Answer 18

Relationship to k Units of k: log k = log A - 𝐸𝑎/ 2.303 𝑅𝑇

Typical values
Min: 10 kcal/mol
Max: 25 kcal/mol

Question 19

ICH is carried out in which regions

Answer 19

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.

Question 20

Stability Studies are performed on..

Answer 20

• 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.

Question 21

Variables that might affect the stability of a given API & dosage form

Answer 21

1) Formulation
2) Packaging
3) Site and method of manufacture
– API
– Finished product
4) Batch size
5) Batch to batch variability
– the importance of process validation & quality risk management
6) Container / labelling 7) Changes to product

Question 22

Stability studies at different stages

Answer 22

1. Stress- and accelerated testing with drug substances
2. Stability on pre-formulation batches
3. Stress testing on scale-up batches
4. Accelerated and long term testing for registration
5. On-going Stability testing
6. Follow-up Stabilities

Question 23

Stability testing - 2 studies

Answer 23

Development studies
‒ characterise compatibility with common excipients
‒ characterise stability profile of API
• e.g susceptibility to acid, base, light, oxygen etc
‒ characterise stability profile of early formulations
• especially susceptibility to heat, humidity & light

Confirmatory studies
‒ long term & accelerated studies on the product as it is to be registered
‒ in practice: design now largely dictated by ICH guidelines

Question 24

What does a regulator want to see demonstrated in the registration dataset?

Answer 24

The product maintains relevant quality
characteristics within the acceptable range:
‒ 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

Question 25

Terminology – adapted from ICH | Define production batch

Answer 25

A batch manufactured at production scale using production equipment & in a production facility as specified in the registration application

Question 26

Terminology – adapted from ICH | Define pilot scale batch

Answer 26

A batch manufactured by a procedure “fully representative of and simulating” full production scale. For tablets & capsules, this means 100,000 units or 1/10th of production scale, whichever is larger

Question 27

Terminology – adapted from ICH | Define re-test period: API

Answer 27

‒ The period of time for which the API remains within specification when stored under the recommended conditions in the proposed bulk storage container ‒ “After this period, the batch should be retested for compliance with specifications & then used immediately” [if in compliance]

Question 28

Terminology – adapted from ICH | Define Accelerated testing

Answer 28

Studies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditions

Question 29

Terminology – adapted from ICH | Define Intermediate testing

Answer 29

‒ Studies at 30°C / 65%RH, | ‒ Intended for extrapolation to long term storage at 25°C [provided that 25°C is appropriate for the market in question]

Question 30

Terminology – adapted from ICH | Define Stress testing

Answer 30

– API: Studies which elucidate intrinsic stability of API. Normally during development. Normally more stressful than ‘accelerated’ testing. – Finished product: Studies of effect of ‘severe’ conditions. E.g. freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture-permeable containers.

Question 31

Terminology – adapted from ICH | Define In-use stability testing

Answer 31

– 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” – ICH 2000 • For example: – Liquids that are reconstituted prior to use – Effervescent tablets in a moisture-proof container (e.g. aluminium screw-cap tube) – Ophthalmic products (especially with respect to preservative efficacy)

Question 32

Terminology – adapted from ICH | Define Climatic zones

Answer 32

– 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 – Zones (Futscher & Schumacher 1972): • I Temperate (21oC / 45%RH) • II Subtropical (25oC / 60%RH with possibly high RH) • III Hot & dry (30oC / 35%RH) • IV Hot & wet (30oC / 70%RH)

Question 33

Terminology – adapted from ICH | Define Reduced study designs

Answer 33

– Bracketing • A design in which only the extremes are tested at all time points, eg strength, pack size, container fill – Matrixing • Designs in which a selected subset of samples is tested, eg different strengths, container/closure systems, batches

Question 34

The risk associated with bracketing & matrixing

Answer 34

* 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. * Consequently: Bracketing & matrixing designs are used mainly for confirmatory studies.

Question 35

Drug Substance | Stability

Answer 35

• At least 3 primary batches: Minimum of pilot scale – same synthetic route, same method of manufacture that simulates production process Quality representative of production scale material Container/closure system simulate commercial pack Test appropriate physical, chemical, biological, microbiological attributes • Continue studies on 3 production scale batches through re-test period • Further studies to a total of at least 3 production scale batches • If no data on production scale batches, place first 3 production scale batches on store

Question 36

Drug Substance | Data at submission

Answer 36

``` • Data at submission: – 6 months 400C ± 20C / 75% ± 5% RH – 6 months 300C ± 20C / 65% ± 5% RH – 12 months 25oC ± 20C / 60% ± 5% RH or 30oC ± 2oC / 65% ± 5% RH ``` • if designed for refrigerated storage: – Long term: 12 months 50C ± 30C – Accelerated: 6 months 250C ± 20C / 60% ± 5% RH • if designed for storage frozen: – 12 months -200C ± 5oC – Short term excursions supported by 50C ± 30C or 250C ± 20C • Forced degradation and Photostability testing

Question 37

Drug Product | Stability

Answer 37

• At least 3 primary batches: ‒ Same formulation and market packaging ‒ Manufacturing process simulates production process • At least two pilot scale batches • Where possible different batches of active substance • Test each strength & container size unless bracketing / matrixing used • Test appropriate physical, chemical, microbiological, biological attributes, preservative content, functionality • Stability commitments ‒ Continue studies on 3 production scale batches ‒ Further studies to at least 3 production scale batches ‒ Place first 3 production scale batches on store

Question 38

Drug Product | Data at submission

Answer 38

• Data at submission: ‒ 6 months 400C±2oC / 75%±5% RH ‒ 6 months 300C±2oC / 65%±5% RH ‒ 12 months 250C±2oC / 60%±5% RH or 300C±20C / 65%±5% RH • Significant change ‒ 5% change in assay – or failure to meet potency criteria ‒ any degradation product exceeding acceptance criteria ‒ failure to meet acceptance criteria unless justified

Question 39

Minimising microbiological deterioration of non-sterile products

Answer 39

• Control the microbial load of API & excipients • Validate & monitor manufacturing conditions • Include antimicrobial preservatives in formulations ‒ N.B.: Normally only bacteriostatic & not bactericidal

Question 40

Statistical estimation of shelf life ICH 2003

Answer 40

“Where the data show so little degradation & so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis but only to provide a justification for the omission”

Question 41

Statistical estimation of shelf life ICH 2000

Answer 41

“An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence interval for the mean curve intersects the acceptance criterion”

Question 42

Estimation of shelf life ICH 2003

Answer 42

* “Any evaluation should consider not only the assay but also the degradation products & other appropriate attributes” * “Where appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance”

Question 43

Shelf life - conclusions

Answer 43

* In theory, the stability of the API is directly related to the kinetics of the various degradation reactions. * However, the relevant physico-chemical equations are strictly applicable only when a single reaction occurs by a single mechanism. * Because medicines are usually mixtures of substances and may be in the solid state, these theoretical models cannot be relied upon as predictive tools.

Question 44

Psuedo – zero order

Answer 44

k0 = k1 x solubility