Training Workshop on
Pharmaceutical Development
with focus on Paediatric
Formulations
Tallink City Hotel
Tallinn, Estonia
Date: 15 - 19 October 2007
Training Workshop on Pharmaceutical Development
1 | with a Focus on Paediatric Medicines / 15-19 October 2007
Pharmaceutical Development
Presenter:
Simon Mills
Email:
Simon.n.mills@gsk.com
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.
The identification threshold is defined as the level that requires analytical identification of a specified
impurity.
Finally, the qualification threshold is defined as the level where the specified impurity must be subjected
to non-clinical toxicological testing to demonstrate safety.
Threshold limits are defined as a percentage of the total daily intake (TDI) of the drug product, or in
absolute terms as the total allowable amount, whichever is lower.
Reporting
1g
0.1%TDI
>1g
0.05%TDI
<1mg
1.0%TDI or 5g
1mg-10mg
0.5%TDI or 20 g
10mg-2g
0.2%TDI or 2mg
Identication
>2g
Qualification
0.1%TDI
<10mg
1.0%TDI or 50g
10mg-100mg
0.5%TDI or 200g
100mg-2g
0.2%TDI or 3mg
>2g
0.1%TDI
Excipients:API Interaction
Whereas excipients are usually biologically inactive, the same cannot be said from
a chemical perspective. Excipients, and any impurities present, can stabilise
and/or destabilise drug products.
These powder samples, usually with or without added water and occasionally
compacted or prepared as slurries, are stored under accelerated conditions and
analysed by stability-indicating methodology, e.g. HPLC.
(The water slurry approach allows the pH of the drug-excipient blend and the role
of moisture to be investigated.)
However, the binary mix approach takes time and resources and.it is well
known that the chemical compatibility of an API in a binary mixture may differ
completely from a multi-component prototype formulation.
An alternative is to test prototype formulations. The amount of API in the blend
can be modified according to the anticipated drug-excipient ratio in the final
compression blend.
Platform prototypes can be used for specific dosage forms, e.g. DC vs. wet gran tablets
There is better representation of likely formulation chemical and physical stability
However, this is a more complex system to interpret
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
towards establishing which excipients cause incompatibility within a given mixture.
Dose/solubility ratio
10
250
500
1000
5000
I
Good solubility
and permeability
10000
100000
II
(dissolution limited)
Good permeability,
poor solubility
III
IV
0.1
BCS plot with human jejunal permeability and aqueous dose solubility ratio as
axes
Training Workshop on Pharmaceutical Development
16 | with a Focus on Paediatric Medicines / 15-19 October 2007
With some materials, ball milling causes irregularity, surface faults and
imperfections in crystals. The degree of crystal damage can be directly correlated
with the energy of the milling process.
Final thoughts
Preformulation studies are an important foundation tool early in the
development of both API and drug products. They influence.