1. How characterization of excipient physical and chemical properties helps build quality into drug product Dr Brian A Carlin FMC BioPolymer

2. Excipient Excipient \Ex*cip"i*ent\, n. 1. An exceptor. [R.] 2. (Med.) An inert or slightly active substance used in preparing remedies as a vehicle or medium of administration for the medicinal agents Excipient \Ex*cip"i*ent\, n. 1. An exceptor. [R.] 2. (Med.) An inert or slightly active substance used in preparing remedies as a vehicle or medium of administration for the medicinal agents Excipient \Ex*cip"i*ent\, a. [L. excipients, -entis, p. pr. of exipere. See Except, v. t.] Taking an exception. Excipient \Ex*cip"i*ent\, a. [L. excipients, -entis, p. pr. of exipere. 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 physical and chemical properties help build quality into drug product?

3. Definition of Quality? Compliance with specifications Compliance with specifications Drug product, raw materialsDrug product, raw materials Consistency Consistency Processability, yield Processability, yield Functionality, utility Functionality, utility PATability PATability >70% perform additional functionality or processability testing >70% perform additional functionality or processability 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.

4. Quality NOT by Design? “About 25% of the time drug product manufacturers test excipient suitability for processing, using experimental (laboratory) scale batches, or pilot scale manufacturing batches. This was higher than expected.” “About 25% of the time drug product manufacturers test excipient suitability for processing, using experimental (laboratory) scale batches, or pilot scale manufacturing batches. This was higher 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

5. Functionality 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- specific) Process dependent (application may be process- specific) Trade-off (competing formulation objectives) Trade-off (competing formulation objectives) Multi-functional excipients Multi-functional excipients

6. Diverse Materials Base Chemical Synthesis* Chemical Synthesis* Mining of Minerals Mining of Minerals Harvesting of Vegetation Harvesting of Vegetation Formulated Products Formulated Products Biotechnology Biotechnology Genetic Modification Genetic Modification Animal By-Products Animal By-Products *Often less defined than single low mol wt entities

7. Pharmacopoeial compliance of limited relevance Primarily safety and purity focused Primarily safety and purity focused Mainly chemical with some limited physical characterisation Mainly chemical with some limited physical characterisation Functionality Related Characteristics (FRCs) in European Pharmacopoeia Functionality Related Characteristics (FRCs) in European Pharmacopoeia IPEC opposed to inclusion of functionality in monographs but supportive of USP proposal for general chapters on Compactability, Lubrication & Disintegration IPEC opposed to inclusion of functionality in monographs but supportive of USP proposal for general chapters on Compactability, Lubrication & Disintegration Physical testing a necessary but insufficient guarantee of functionalities Physical testing a necessary but insufficient guarantee of functionalities Grade specificationGrade specification

8. Variable Raw Material + Fixed Process = Variable Product Raw Materials Process Product Control

9. Variable Raw Material + (Anti)variable Process = Constant Product Raw Materials Process Product Control (Anti-phase) PAT

10. Questions/Issues Holistic definition of Quality Holistic definition of Quality User/Supplier collaboration User/Supplier collaboration FDA 21 st century cGMP initiative (PAT) FDA 21 st century cGMP initiative (PAT) Functionality testing and specification Functionality testing and specification Sourcing higher specification materials Sourcing higher specification materials Tailored excipients Tailored excipients