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■ The allowable level of any given impurity or impurities that are permitted
in API/drug product, without explicit non-clinical safety testing, are
defined by ICH Q3A/B.
■ The amounts of impurities that are allowable are based on the total daily
intake of the drug product.
■ There are separate limits (or thresholds) for reporting, identification and
qualification of API impurities.
■ The reporting threshold is defined as the level that must be reported to
regulatory agencies to alert them to the presence of a specified impurity.
>1g 0.05%TDI
>2g 0.1%TDI
>2g 0.1%TDI
– Important to bear in mind that API development is ongoing so API batch used in this
early stability study may become unrepresentative of final selected API version & form.
Training Workshop on Pharmaceutical
7 | Development
API degradation pathways
Hydrolysis and Oxidation are the most common pathways for API degradation in the
solid-state and in solution
Photolysis and trace metal catalysis are secondary processes of degradation
Temperature affects each of the above chemical degradation pathways; the rate of
degradation increases with temperature. Extrapolation of accelerated temperature
data to different temperatures, e.g. proposed storage conditions, is common practice
(e.g. using Arrhenius plots) but we must be mindful of the pit-falls – the influence of
the various degradation pathways and mechanisms can change with temperature.
It is well understood that pH, particularly extremes, can encourage hydrolysis of API
when ionised in aqueous solution. This necessitates buffer control if such a dosage
form is required. pH within the micro-environment of a solid oral dosage form can
also impact on the stability of the formulation where the API degradation is pH
sensitive; through understanding the aqueous pH imparted by typical excipients, a
prudent choice can overcome this issue.
■ Can apply statistical models (e.g. 2n factorial design) to determine the chemical
interactions in more complex systems such as prototype formulations, with a view
Training Workshop
towards on Pharmaceutical
establishing which excipients cause incompatibility within a given mixture.
12 | Development
Oxidation and the Role of
Excipients
Oxidation is broadly defined as a loss of electrons in a system, but it can
be restated as an increase in oxygen or a decrease in hydrogen content.
Oxidation always occurs in tandem with reduction; the so-called REDOX
reaction couple.
Oxidation reactions can be catalysed heavy metals, light, leading to free
radical formation (initiation). Free radicals then react with oxygen to form
peroxy radicals, which react with the oxidative substrate to yield further
complex radicals (propagation), finally the reaction ceases (termination).
Excipients play a key role in oxidation; either as a primary source of
oxidants, trace amounts of metals, or other contaminants.
E.g. Peroxides are a very common impurity in many excipients,
particularly polymeric excipients. They are used as initiators in
polymerisation reactions, but are difficult to remove.
Training Workshop on Pharmaceutical
13 | Development
Photolysis and the Role of
Excipients
Sunlight (both in the UV and visible regions) may
degrade drug products and excipients; and
consequently photolabile APIs can raise many
formulation (& phototoxicity) issues.
– Solution Stability:
• pH buffers at 25C and 50°C up to 7 days
• in bio-relevant media at 37°C up to 24 hours
• Light Stability (ICH)
10 I II
(dissolution limited)
Good solubility Good permeability,
and permeability poor solubility
III IV
Good solubility, poor Poor solubility and
permeability permeability
0.1
BCS plot with human jejunal permeability and aqueous dose solubility ratio as axes
Alternatively, could compress one of the APIs and over-encapsulate this into a
capsule product, along with the powder blend from the second API
– Disadvantage are that capsule size could be large, it requires specialised
encapsulation equipment to fill tablets and blend… process is more complex and
expensive
If however, simplicity and cost are significant issues, look to produce a common
blend (particle size of APIs should be similar), and by understanding of degradation
pathways stabilise the blend and compress or encapsulate.