Excipient VariabilitySources, Importance and Potential

Impact

Chris Moreton, Ph.DPast Chair IPEC-Americas

Partner – FinnBrit Consultingconsulting@finnbrit.com

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Presentation Outline

• Background• Why excipient variability is important• How excipient variability can arise• Options for addressing excipient

variability

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The Objective• To manufacture robust medicines that deliver

the drug to the patient:– In the required amount (content and assay).– At the optimum rate necessary to achieve the

desired therapeutic benefit (in vivo dissolution).– Consistently:

• Within lots (blend uniformity for all components).• Between lots (validated manufacturing process).

– For the shelf life of the product (stability).• At the same time, the development process

has to be efficient.

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Components of a medicinal product

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Why is excipient variability important?

• Excipients are important components of drug products.

• Excipient variability may impact drug product variability.– But excipients are not the only sources

of drug product variability• API and process parameters may also be

sources of product variability.

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Excipient Variability

• There is inherent variability in everything:– Excipients are no exception.

• Why is it important?– It can contribute to product variability.

• But it is not the only potential source of product variability!

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Excipient Variability

• We can sometimes see the effect of excipient variability in failed batches, but

• We cannot always control excipient variability adequately

• Why?– How does excipient variability arise?

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Sources of Excipient Variability

• Many excipients are natural products, or derived from natural products.

– Source of feedstock (crop)• Species/varietal• Soil composition• Use of fertilizer

– Weather is changeable• Conditions during the growing season• Conditions during harvesting• Conditions during transportation to the processing site• Conditions during storage of the crude feedstock• Conditions during processing• Conditions during packaging, storage and distribution

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Sources of Excipient Variability

• Even for synthetic materials:– There is a misconception that synthetic or

semi-synthetic materials are less variable than natural products• It depends on the chemical processing

– Single phase or multiphase, etc.

– Most synthetic materials are derived from crude oil or gas which varies with location of the well:• Content of sulfur• Content and range of heavy metals• Distribution of the different organic components

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Sources of Excipient Variability

• Manufacturing process– Scale of manufacture

• Excipients frequently manufactured using continuous processing.

– Location of manufacturing site• Different scale of manufacture at different sites.

– Alternate processes used by different manufacturers.• Anti-oxidant vs. inert gas blanket

– Normal wear and tear of the equipment train• Supply chain

– Type of transportation– Duration– Storage conditions en route

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Excipient Variability

• We have to accept that there will be variability.

• We need to come to terms with it.• Options may include:– Designing more robust formulations to

cope with variability• QbD will help

– Using processing end-points to compensate for materials variability.

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What is a Robust Formulation?

• A formulation that is able to accommodate the typical variability seen in:– API– Excipients– Processes

Without compromising the manufacture, stability, performance or any other attribute of the product critical to the patient’s care or well being.

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Formulation variability– a Simplistic View

σσσσ 2Process

2Excipients

2Active

2Product

BulkActiveDrug

Variability

ExcipientsVariability

ProcessVariability

ProductVariability

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Formulation variability– a Wrong View

σσσσ 2Process

2Excipients

2Active

2Product

BulkActiveDrug

Variability

ExcipientsVariability

ProcessVariability

ProductVariability

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In reality!

BulkActiveDrug

Variability

ExcipientsVariability

ProcessVariability

ProductVariability

σσσσσ2

nsInteractio

2

Process

2

Excipients

2

Active

2

Product

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Interactions in Product Manufacture

• Interactions include:– Powder – Powder– Powder – Liquid– Powder – Equipment– Liquid – Equipment

• For each unit process

– Powder – Operator– Liquid – Operator– Equipment – Operator– etc.

• For each component

σσσσ

σσσσσ

2(n)n Interactio

2(2)n Interactio

2(1)n Interactio

2nsInteractio

2nsInteractio

2Process

2Excipients

2API

2Product

.......

:Where

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Which type of variability applies to our application?

Batch number/Time of output

Raw materialparameter

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Raw Material Variability

Raw materialParameter

Raw material batches

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Raw Material Variability: Acceptable

Raw materialParameter

Raw material batches

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Raw Material Variability:Possibly acceptable

Raw materialParameter

Raw material batches

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Raw Material Variability:Impossible limits

Raw materialParameter

Raw material batches

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Conclusions

• Excipient variability is important.• There is inherent variability in

excipients arising from a variety of possible sources.

• Designing product formulations and setting excipient specifications that do not allow for the inherent variability of the excipient is a recipe for disaster.

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Thank you!

We will now answer Questions.

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