Preformulation Studies Who

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Training Workshop on Pharmaceutical Development

with a Focus on Paediatric Medicines / 15-19 October 20071|

Training Workshop onPharmaceutical Development withfocus on Paediatric Formulations

Tallink City Hotel

Tallinn, Estonia

Date: 15 - 19 October 2007

Pharmaceutical Development


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Pharmaceutical Development

Pre-Formulation Analytical Studies and

Impact on API & Formulation Development

Presenter: Simon Mills

Email: [email protected]


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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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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 overa short period of time (28-days) using accelerated orstress conditions (so that reactions proceed more rapidly); target ~10%

degradation.

Typical conditions for API in solid-state might be: 80/75%RH, 60C/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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Impurities: Impact on API Specification

The allowable level of any given impurity or impurities that are permitted in API/drug product, withoutexplicit 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 reportingthreshold is defined as the level that must be reported to regulatory agencies to alert

them to the presence of a specified impurity. Theidentificationthreshold is defined as the level that requires analytical identification of a specified

impurity.

Finally, the qualificationthreshold is defined as the level where the specified impurity must besubjected 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 inabsolute terms as the total allowable amount, whichever is lower.


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Threshold Limit Based on

TDI

Maximum Daily Dose of API

in Drug Product

Threshold

0.1%TDI

0.05%TDI

1g

>1g

Reporting

1.0%TDI or 5g

0.5%TDI or 20 g

0.2%TDI or 2mg

0.1%TDI

2g

Identication

1.0%TDI or 50g

0.5%TDI or 200g

0.2%TDI or 3mg

0.1%TDI

2g

Qualification

Impurities: Impact on API Specification


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API solid-state stability study

An early indication of stability challenges for product development:

Accelerated stability challengebut not unrealistically severe and so allows confidentextrapolation to provide an indication ofAPI shelf-life

Conditions less extreme than API stress testing:

40C/75%RH open vial

50C 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 thisearly stability study may become unrepresentative of final selected API version & form.


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API degradation pathways

Hydrolysis and Oxidation are the most common pathways for API degradation in thesolid-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 ofdegradation increases with temperature. Extrapolation of accelerated temperaturedata to different temperatures, e.g. proposed storage conditions, is common practice(e.g. using Arrhenius plots) but we must be mindful of the pit-fallsthe influence ofthe various degradation pathways and mechanisms can change with temperature.

It is well understood that pH, particularly extremes, can encourage hydrolysis of APIwhen ionised in aqueous solution. This necessitates buffer control if such a dosageform is required. pH within the micro-environment of a solid oral dosage form canalso impact on the stability of the formulation where the API degradation is pHsensitive; through understanding the aqueous pH imparted by typical excipients, aprudent choice can overcome this issue.


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Excipients:API Interaction

Whereas excipients are usually biologically inactive, the same cannot be said froma chemical perspective. Excipients, and any impurities present, can stabiliseand/or destabilise drug products.

Considerations for the formulation scientist:

the chemical structure of the APIthe type of delivery system required

the proposed manufacturing process

Initial selection of excipients should be based on:

expert systems; predictive toolsdesired 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 isto delineate, as quickly as possible, real and possible interactions betweenpotential formulation excipients and the API. This is an important risk reductionexercise early in formulation development.


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Excipient Compatibility Studies

One option.Binary Mix Compatibility Testing: In the typical drug/excipient compatibility testing program, binary(1:1 or

customised) powder mixesare 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 samplescan 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 andmay be misleading; false positives and negatives are routinely encountered. Also

sensitive to sample preparation.


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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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Drug-excipient interactions can be studied using both approaches in acomplementary 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 vitrodissolution methods, etc.

The idea is to diagnose any observed incompatibility from the prototype formulation work thenhopefully identify the culprit excipients from the binary mix data.

Hopefully, a prototype formulation can then be taken forward as a foundation for productdevelopment.

Can apply statistical models(e.g. 2nfactorial design) to determine the chemicalinteractions in more complex systems such as prototype formulations, with a viewtowards establishing which excipients cause incompatibility within a given mixture.



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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 inoxygen 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 toyield 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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Photolysis and the Role of Excipients

Sunlight (both in the UV and visible regions) may degrade drug productsand excipients; and consequently photolabile APIs can raise many

formulation (& phototoxicity) issues.

The addition of light absorbing agents is a well known approach tostabilising 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 excipientas an opacifier.


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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 50C up to 7 days

in bio-relevant media at 37C up to 24 hours

Light Stability (ICH)

HPLC analysis

250 500 1000 10000 100000/ l bili i 5000


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250 500 1000 10000 100000Dose/solubility ratio

10

1

0.1

5000

Predicted

PeffinHumansc

m/secx10-4

I

Good solubilityand permeability

II

Good permeability,poor solubility

III

Good solubility, poor

permeability

IV

Poor solubility and

permeability

BCSplot with human jejunal permeability and aqueous dose solubility ratio as axes

(dissolution limited)

(solubility limited absorption)


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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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Selection of Product Processing

Understanding of degradation pathways of API will help to decide on mostappropriate 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 appropriateprocess:

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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Degradation Issues For Combination Products

Objective is to minimise incompatibilities. Degradation pathways of the two APIscould well be different, so a stabilisation strategy for API #1 could destabilise API #2.

In this situation, first intent strategy could beto prepare separate compression blendsof 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 acapsule product, along with the powder blend from the second API

Disadvantage are that capsule size could be large, it requires specialisedencapsulation equipment to fill tablets and blend process is more complex andexpensive

If however, simplicity and cost are significant issues, look to produce a commonblend (particle size of APIs should be similar), and by understanding of degradationpathways stabilise the blend and compress or encapsulate.


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Final thoughts

Preformulation studies are an important foundation tool early in thedevelopment 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?

Documents

Preformulation Studies Who