This document outlines an agenda for a training workshop on pharmaceutical development with a focus on paediatric formulations being held from October 15-19, 2007 in Tallinn, Estonia. The workshop will cover various topics including pre-formulation analytical studies, stress testing APIs, the impact of impurities on API specifications, excipient compatibility studies, degradation pathways, and the role of API processing in product instability. The goal is to discuss how preformulation studies influence key decisions in API and drug product development and support establishing appropriate container closure systems and analytical methods.

1. Pharmaceutical Development
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
with a Focus on Paediatric 1 | Medicines / 15-19 October 2007

2. Pharmaceutical Development
Pre-Formulation Analytical Studies and
Impact on API & Formulation Development
Presenter: Simon Mills
Email: Simon.n.mills@gsk.com
Training Workshop on Pharmaceutical Development
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3. Outline and Objectives of Presentation
Stress Testing of API
Impact of Impurities on API Specifications
Pre-Formulation Investigations
Solid State Degradation Stability Assessment
Role of Excipients in API Instability
Hydrolysis
Oxidation
Photolysis
API Solubility/Solution-state Stability Assessment
Selection of API Drug Product Processing Methods
Degradation Issues for Combination Products
Role of API Processing in Product Instability
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4. Stress Testing of API
Deliberate forced degradation of API - serves several purposes:
To facilitate development of a ‘stability indicating’ analytical method’, e.g. HPLC
To aid in development of the first API specification
To understand the degradation pathways of the API to facilitate rational product development
To screen for possible formation of potential genotoxins
Initially performed over a short period of time (28-days) using accelerated or
stress conditions (so that reactions proceed more rapidly); target ~10%
degradation.
Typical conditions for API in solid-state might be:
80°/75%RH, 60°C/ambient RH, 40°/75%RH,
Light irradiation
Typical conditions for API in solution state might be:
pH 1-9 in buffered media
with peroxide (and/or free radical initiator)
Light irradiation
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5. Impurities: Impact on API Specification
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.
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6. Impurities: Impact on API Specification
Threshold Maximum Daily Dose of API
in Drug Product
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Threshold Limit Based on
TDI
Reporting ≤1g
1g
0.1%TDI
0.05%TDI
Identication 1mg
1mg-10mg
10mg-2g
2g
1.0%TDI or 5μg
0.5%TDI or 20 μg
0.2%TDI or 2mg
0.1%TDI
Qualification 10mg
10mg-100mg
100mg-2g
2g
1.0%TDI or 50μg
0.5%TDI or 200μg
0.2%TDI or 3mg
0.1%TDI

7. API solid-state stability study
An early indication of stability challenges for product development:
– Accelerated stability challenge but not unrealistically severe and so allows confident
extrapolation to provide an indication of API shelf-life
– Conditions less extreme than API stress testing:
• 40ºC/75%RH open vial
• 50ºC closed vial
• At least l month storage data; typically 1w, 2w, 4w, 3m (potentially supporting 12m shelf-life at RT)
• Light stability (ICH conditions); typically 1w
• HPLC analysis
• Monitor solid-state form (crystallinity) - DSC, TGA, pXRD
– Allows comparison with other versions forms of same API
– Provides a control baseline for excipient compatibility studies
– 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.
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8. 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.
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9. 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.
Considerations for the formulation scientist:
– the chemical structure of the API
– the type of delivery system required
– the proposed manufacturing process
Initial selection of excipients should be based on:
– expert systems; predictive tools
– desired delivery characteristics of dosage form
– knowledge of potential mechanisms of degradation, e.g. Maillard reaction
– There may be a preferred “A list” in your organisation
The objective of drug/excipient compatibility considerations and practical studies is
to delineate, as quickly as possible, real and possible interactions between
potential formulation excipients and the API. This is an important risk reduction
exercise early in formulation development.
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10. Excipient Compatibility Studies
One option….Binary Mix Compatibility Testing:
In the typical drug/excipient compatibility testing program, binary (1:1 or
customised) powder mixes are prepared by triturating API with the individual
excipients.
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.)
Alternatively, binary samples can be screened using thermal methods, such
as DSC/ITC. No need for stability set-downs; hence cycle times and sample
consumption are reduced. However, the data obtained are difficult to interpret and
may be misleading; false positives and negatives are routinely encountered. Also
sensitive to sample preparation.
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11. Excipient Compatibility Studies
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
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12. Excipient Compatibility Studies
Drug-excipient interactions can be studied using both approaches in a
complementary fashion. The first tier approach is to conduct short-term (1-3m)
stability studies using generic prototype formulations under stressed conditions,
with binary systems as diagnostic back-up:
Chemical stability measured by chromatographic methods
Physical stability measured by microscopic, particle analysis, in vitro dissolution methods, etc.
The idea is to diagnose any observed incompatibility from the prototype formulation work then
hopefully identify the “culprit” excipients from the binary mix data.
Hopefully, a prototype formulation can then be taken forward as a foundation for product
development.
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.
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13. 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.
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14. 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.
The addition of light absorbing agents is a well known approach to
stabilising photolabile products.
– Order of effectiveness: pigments colorants UV absorbers
However, beware variable performance between grades/sources.
e.g. Surface-treated titanium dioxide is inferior to the untreated excipient
as an opacifier.
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15. Equilibrium Solubility/Solution State Stability Tests
Vital preformulation data to enable decision-making on choice of dosage form,
excipients and processing possible and/or required. Typical studies:
– pH Solubility profile at pHs 1-10
– Solubility in bio-relevant media (SGF, FeSSIF, FaSSIF)
– Solubility in water, normal saline, IV buffers as needed
• Poorly soluble drugs may present issues for IV formulation
• Balance achieving solubility required vs. acceptable excipients for IV and their compatibility with drug
– Solubility in co-solvents, surfactants, lipids as required
– 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)
– HPLC analysis
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16. Dose/solubility ratio 250 500 1000 10000 100000
10
1
0.1
(dissolution limited)
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5000
Predicted Peff in Humans cm/sec x10-4
I
Good solubility
and permeability
II
Good permeability,
poor solubility
III
Good solubility, poor
permeability
(solubility limited absorption)
IV
Poor solubility and
permeability
BCS plot with human jejunal permeability and aqueous dose solubility ratio as
axes

17. Role of API Processing in Product Instability
High energy processes (milling, lyophilisation, granulating, roller-compaction,
drying) can introduce a degree of amorphicity into otherwise highly crystalline
material. This can lead to increased local levels of moisture and increased
chemical reactivity in these areas.
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.
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18. Selection of Product Processing
Understanding of degradation pathways of API will help to decide on most
appropriate process:
– For APIs showing severe moisture mediated degradation pathways, choose direct compression
or dry granulation
Understanding of physical properties of API will help to decide on most appropriate
process:
– For APIs showing flow issues, choose a granulation approach (wet or dry granulation)
– For APIs showing reduced crystallinity after processing e.g. milling, micronisation, etc., choose
wet granulation (presence of water will anneal (crystallise) amorphous API)
– For APIs with low melting point, choose an encapsulation approach (high speed rotary presses
will generate significant frictional forces that could melt API)
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19. Degradation Issues For Combination Products
 Objective is to minimise incompatibilities. Degradation pathways of the two APIs
could well be different, so a stabilisation strategy for API #1 could destabilise API #2.
In this situation, first intent strategy could be to prepare separate compression
blends of each individual API and compress as a bi-layer tablet
–Disadvantages: adds complexity and bi-layer rotary presses are expensive
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.
Training Workshop on Pharmaceutical Development
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20. Final thoughts
Preformulation studies are an important foundation tool early in the
development of both API and drug products. They influence….
Selection of the drug candidate itself
Selection of formulation components
API drug product manufacturing processes
Determination of the most appropriate container closure system
Development of analytical methods
Assignment of API retest periods
The synthetic route of the API
Toxicological strategy ?ANY QUESTIONS PLEASE
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