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PSF > Drug Stability & Stability Testing - Part 2 > Flashcards

Drug Stability & Stability Testing - Part 2 Flashcards

1
Q

API

A

Active Pharmaceutical Ingredient

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2
Q

FPP

A

Finished Pharmaceutical Product

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3
Q

GMP

A

Good Manufacturing Practices

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4
Q

ICH

A

International Conference on Harmonization

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5
Q

MA

A

Marketing Authorization

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6
Q

RH

A

Relative Humidity

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7
Q

Reaction Energetics: Thermodynamics Reaction Rates: Kinetics

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

A

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

rate of reaction = βˆ’π‘‘[𝐷] / 𝑑𝑑
rate = k [D]x

= 𝑑[𝑃] / 𝑑𝑑

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8
Q

– Zero order

A

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

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9
Q

First order

A

Differential equation
- d [A] / dt = k [A]
Integral equation
In [A] = [A]0 – 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:
βˆ’π’…[𝑫] = k1[D] 𝒅𝒕
Which integrated at t = 0 and rearranged to give a linear relationship can be found expressed as:
t = 𝟐.πŸ‘πŸŽπŸ‘ log a - 𝟐.πŸ‘πŸŽπŸ‘ log (a-x) π’Œπ’Œ
Where a = [A]0
a-x = [A]t (so x refers to amount degraded)

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10
Q

Second order

A

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
- 𝒅[𝑨] / 𝒅𝒕 = k[A][B]
Which integrated at t=0 and rearranged to give a linear relationship can be expressed as:
t = 𝟐.πŸ‘πŸŽπŸ‘/π’Œ(π’‚βˆ’π’ƒ) log (𝒃/𝒂) + 𝟐.πŸ‘πŸŽπŸ‘/π’Œ(π’‚βˆ’π’ƒ) log (π’‚βˆ’π’™)/ (π’ƒβˆ’π’™)
Where:
a = [A]0
b = [B]0 and x = amount of drug degraded

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11
Q

When does Pseudo first order occur

A

β€’ 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

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12
Q

When does Pseudo zero order occur

A

β€’ 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.

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13
Q

Determining rate orders

A

β€’ 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
β€’ 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
β€’ Determine which one produces a straight line

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14
Q

Drug degradation

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

All affected by temp

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15
Q

Temperature and Arrhenius type relationship

A

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

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16
Q

Half-lives and shelf lives for zero order

A

Integrated rate equation: c = c0 – k0t
Units of k: conc. x time -1
Half-life t1⁄2: 0.5 𝑐0/ π‘˜0
Shelf-life t90: 0.1 𝑐0/ π‘˜0

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17
Q

Half-lives and shelf lives for first order

A

Integrated rate equation: logc0 – π‘˜1𝑑/ 2.303
Units of k: time -1
Half-life t1⁄2: 0.693/ π‘˜1
Shelf-life t90: 0.105/ π‘˜1

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18
Q

Temperature Effects on Activation energy Ea

A

Relationship to k Units of k: log k = log A - πΈπ‘Ž/ 2.303 𝑅𝑇

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

19
Q

ICH is carried out in which regions

A

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.

20
Q

Stability Studies are performed on..

A

β€’ Drug Substances (DS)
– the unformulated drug substance that may subsequently
be formulated with excipients to produce the dosage form.

β€’ Drug Products (DP)
– the dosage form in the final immediate packaging intended for marketing.

21
Q

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

A

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

22
Q

Stability studies at different stages

A
  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
23
Q

Stability testing - 2 studies

A

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

24
Q

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

A

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

25
Q

Terminology – adapted from ICH

Define production batch

A

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

26
Q

Terminology – adapted from ICH

Define pilot scale batch

A

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

27
Q

Terminology – adapted from ICH

Define re-test period: API

A

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

28
Q

Terminology – adapted from ICH

Define Accelerated testing

A

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

29
Q

Terminology – adapted from ICH

Define Intermediate testing

A

β€’ Studies at 30Β°C / 65%RH,

β€’ Intended for extrapolation to long term storage at 25Β°C [provided that 25Β°C is appropriate for the market in question]

30
Q

Terminology – adapted from ICH

Define Stress testing

A

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

31
Q

Terminology – adapted from ICH

Define In-use stability testing

A

– Establishes the β€œperiod of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened”
– ICH 2000
β€’ 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)

32
Q

Terminology – adapted from ICH

Define Climatic zones

A

– 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):
β€’ I Temperate (21oC / 45%RH)
β€’ II Subtropical (25oC / 60%RH with possibly high RH)
β€’ III Hot & dry (30oC / 35%RH)
β€’ IV Hot & wet (30oC / 70%RH)

33
Q

Terminology – adapted from ICH

Define Reduced study designs

A

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

34
Q

The risk associated with bracketing & matrixing

A
  • 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.
35
Q

Drug Substance

Stability

A

β€’ 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
β€’ Continue studies on 3 production scale batches through re-test period
β€’ Further studies to a total of at least 3 production scale batches
β€’ If no data on production scale batches, place first 3 production scale batches on store

36
Q

Drug Substance

Data at submission

A 
β€’ Data at submission:
– 6 months 400C Β± 20C / 75% Β± 5% RH
– 6 months 300C Β± 20C / 65% Β± 5% RH
– 12 months 25oC Β± 20C / 60% Β± 5% RH or 30oC Β± 2oC /
65% Β± 5% RH

β€’ if designed for refrigerated storage:
– Long term: 12 months 50C Β± 30C
– Accelerated: 6 months 250C Β± 20C / 60% Β± 5% RH

β€’ if designed for storage frozen:
– 12 months -200C Β± 5oC
– Short term excursions supported by 50C Β± 30C or 250C Β± 20C

β€’ Forced degradation
and Photostability testing

37
Q

Drug Product

Stability

A

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

38
Q

Drug Product

Data at submission

A

β€’ Data at submission:
β€’ 6 months 400CΒ±2oC / 75%Β±5% RH
β€’ 6 months 300CΒ±2oC / 65%Β±5% RH
β€’ 12 months 250CΒ±2oC / 60%Β±5% RH or 300CΒ±20C / 65%Β±5% RH

β€’ Significant change
β€’ 5% change in assay – or failure to meet potency
criteria
β€’ any degradation product exceeding acceptance criteria
β€’ failure to meet acceptance criteria unless justified

39
Q

Minimising microbiological deterioration of non-sterile products

A

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

40
Q

Statistical estimation of shelf life ICH 2003

A

β€œWhere 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”

41
Q

Statistical estimation of shelf life ICH 2000

A

β€œAn 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”

42
Q

Estimation of shelf life ICH 2003

A
  • β€œAny evaluation should consider not only the assay but also the degradation products & other appropriate attributes”
  • β€œWhere appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance”
43
Q

Shelf life - conclusions

A
  • 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.
44
Q

Psuedo – zero order

A

k0 = k1 x solubility

PSF (11 decks)

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