How characterization of How characterization of excipient physical and excipient physical and

chemical properties helps chemical properties helps build quality into drug productbuild quality into drug product

Dr Brian A CarlinDr Brian A Carlin

FMC BioPolymerFMC BioPolymer

ExcipientExcipient

Excipient \Ex*cip"i*ent\, n. 1. An exceptor. [R.] 2. (Med.) An inert Excipient \Ex*cip"i*ent\, n. 1. An exceptor. [R.] 2. (Med.) An inert or slightly active substance used in preparing remedies as a or slightly active substance used in preparing remedies as a vehicle or medium of administration for the medicinal agentsvehicle or medium of administration for the medicinal agents

Excipient \Ex*cip"i*ent\, a. [L. excipients, -entis, p. pr. of exipere. Excipient \Ex*cip"i*ent\, a. [L. excipients, -entis, p. pr. of exipere. See Except, v. t.] Taking an exception. See Except, v. t.] Taking an exception.

Exceptor \Ex*cept"or\, n. [L., a scribe.] One who takes exceptions.Exceptor \Ex*cept"or\, n. [L., a scribe.] One who takes exceptions.

Does characterization of excipient Does characterization of excipient physical and chemical properties help build physical and chemical properties help build

quality into drug product?quality into drug product?

Definition of Quality?Definition of Quality? Compliance with specificationsCompliance with specifications

• Drug product, raw materialsDrug product, raw materials ConsistencyConsistency Processability, yieldProcessability, yield Functionality, utilityFunctionality, utility PATabilityPATability

>70% perform additional functionality or >70% perform additional functionality or processability testingprocessability testing• 76% to determine excipient suitability76% to determine excipient suitability• 66% always for the excipient66% always for the excipient• >50% for oral solutions. >50% for oral solutions. • 87% for solid oral dosage forms. 87% for solid oral dosage forms.

Quality NOT by Design?Quality NOT by Design?

““About 25% of the time drug product About 25% of the time drug product manufacturers test excipient suitability for manufacturers test excipient suitability for processing, using experimental processing, using experimental (laboratory) scale batches, or pilot scale (laboratory) scale batches, or pilot scale manufacturing batches. This was higher manufacturing batches. This was higher than expected.”than expected.”

“An excipient's functionality can only be assessed in the context of a particular formulation and manufacturing process”

RC Moreton Pharmaceutical Technology, May 2004

Functionality transcends the excipientFunctionality transcends the excipient

Application dependent (why do you add it?)Application dependent (why do you add it?)

Formulation dependent (effect of other ingredients)Formulation dependent (effect of other ingredients)

Process dependent (application may be process-Process dependent (application may be process-specific)specific)

Trade-off (competing formulation objectives)Trade-off (competing formulation objectives)

Multi-functional excipientsMulti-functional excipients

Diverse Materials BaseDiverse Materials Base Chemical Synthesis*Chemical Synthesis* Mining of MineralsMining of Minerals Harvesting of VegetationHarvesting of Vegetation Formulated Products Formulated Products BiotechnologyBiotechnology Genetic ModificationGenetic Modification Animal By-ProductsAnimal By-Products

*Often less defined than single low mol wt entities*Often less defined than single low mol wt entities

Pharmacopoeial compliance of Pharmacopoeial compliance of limited relevancelimited relevance

Primarily safety and purity focusedPrimarily safety and purity focused

Mainly chemical with some limited physical characterisationMainly chemical with some limited physical characterisation

Functionality Related Characteristics (FRCs) in European Functionality Related Characteristics (FRCs) in European PharmacopoeiaPharmacopoeia

IPEC opposed to inclusion of functionality in monographs but IPEC opposed to inclusion of functionality in monographs but supportive of USP proposal for general chapters on supportive of USP proposal for general chapters on Compactability, Lubrication & DisintegrationCompactability, Lubrication & Disintegration

Physical testing a necessary but insufficient guarantee of Physical testing a necessary but insufficient guarantee of functionalitiesfunctionalities• Grade specificationGrade specification

Variable Raw Material + Fixed Variable Raw Material + Fixed Process = Variable ProductProcess = Variable Product

Raw Material

s

Process

Product

Control

Variable Raw Material + (Anti)variable Variable Raw Material + (Anti)variable Process = Constant ProductProcess = Constant Product

Raw Material

s

Process

Product

Control (Anti-phase)

PAT

Questions/IssuesQuestions/Issues

Holistic definition of QualityHolistic definition of Quality User/Supplier collaborationUser/Supplier collaboration FDA 21FDA 21stst century cGMP initiative (PAT) century cGMP initiative (PAT) Functionality testing and specificationFunctionality testing and specification Sourcing higher specification Sourcing higher specification

materialsmaterials Tailored excipientsTailored excipients