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Pharmaceutical industry “borrowed” ingredients from other industries – Food – Cosmetic – Industrial

Ingredients adapted to a “fit for use” model.

APIs allowed the “fit for use” strategy to work… – …that has all changed… – …APIs pose more challenges

There has been a shift to “designed for purpose” – Ingredients designed specifically for the pharmaceutical

industry to meet formulation development and manufacturing challenges.

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1960s & 1970s: – Co-processing initially used in food industry to

improve stability, solubility, gelling…

Early to mid 1980s: – MCC and CaCO3 (Vitacel)

Late 1980s: – Lactose and cellulose powder (Cellactose®80) – Lactose and MCC (MicroceLac® 100)

1990s: – Strong increasing number of co-processed products

• Pharma: ♦ Excipients (StarLac®), APIs

• Food applications: ♦ Fat substitutes ♦ Flavor enhancement

2000 and beyond – The trend continues (RetaLac® & CombiLac®)

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Co-processed Excipients:

Positioning Compared to Other Excipients

4

New chemical entity (NCE) Challenging due to regulatory approval

New chemical grade of an existing excipient

Co-Processed Excipients Two or more compendial /non-compendial excipients, ratios of componants may vary, physically modified properties, not achieved by physical mixing,

Excipient Mixtures

Single Monographed Excipients

Acceptance Level

5

Two or more compendial or non-compendial excipients with varying composition Designed to physically modify functional properties, not achieved by physical mixing – “high energy input“ Without significant chemical change – Proven by suitable techniques: SEM, FTIR, GC, NIR … No limitations with regard to co-processing methods, or state – New CPEs can be obtained by:

• New chemical excipients (NCEs) • New grades of existing materials • New combinations thereof

http://ipec-europe.org/uploads/ipeccompositionguidefinal.pdf 6

A physical combination of individual established pharmacopeial excipients

Must be distinguishable (measureable) in at least one non-performance-related attribute from the corresponding physical admixture

No formation of a covalently bonded entity

Components must have USP NF monographs

… are the result of a typical manufacturing process as: – Spray-drying, high-shear dispersion, granulation,

melt-extrusion

http://www.usp.org/USPNF/submitMonograph/subGuide.html 7

High Performance Co-Processed Excipient

Define/Identify Desired Functional Performance

Selection Process Excipients Composition

Choose Appropriate Manufacturing Process

Assess Functional Performance Compare to Physical Mixture

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Co-spray-drying – StarLac ®, Avicel HFE-102,

Cellactose, Ludipress®, PROSOLV SMCC, MicroceLac®

Co-crystallization, co-precipitation – Sugartab®, Di-Pac®

Spray agglomeration – RetaLac®

Granulation, dry (RC) – Nutab®

Granulation, melt – Calcium phosphate &

glyceryl behenate

Extrusion – Pharmaburst®

Co-milling – Calcium silicate,

Confectioner’s sugar

Co-Attrition – Avicel® DG 500

http://www.usp.org/USPNF/submitMonograph/subGuide.html 9

Excipients specifically designed for pharmaceutical industry with “value added” performance

Co-processing typically is the incorporation of one excipient into the particle level of another. – Creation of an integrated, engineered particle – Not separable at a particulate level (“engineered

particles“)

Performance cannot be achieved through simple blending of components

Mostly understood: physical “particle design” of mono-, to oligomeric excipient systems

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Thermodynamic or Physical state may change Molecular level: – Crystal lattice

• Polymorphism & pseudo-polymorphism • Amorphous state, …

Particle level: – Morphology/shape – Size – Porosity – Dual compaction mechanism

• Plastic deformation • Brittle fracture

– Component homogeneity

Bulk level: – Particle size distribution

• Fewer fines – Bulk & tapped density – Hygroscopicity

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Functional performance synergies – Complementary

• Performance beyond simple mixtures of individual components

– Balancing • Enhance desired properties • Minimize/eliminate limitations

Less performance variation

Quality by Design (QbD) – QbD drives the need for CPEs – CPEs simplify QbD

Convenient – Reduced testing

• less different excipients, less paper work, less equipment needed)

– Easier scale-up • less variability

– Better handling

Efficient, cost effective – Fewer excipients needed

during development & manufacture

– Decreased use levels – Lower cost in use – Streamlined processes

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41%

36%

16%

7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Taxes

R&D

COGS

S&GA

Raymond H. Scherzer April 2002

Sales: > $ 300 billion

Costs: ~ $250 billion

Manufacturing Costs

Personnel $22.5 Bn 24%

Operations $22.5 Bn 24%

Raw

Materials

$45 Bn 49%

Excipients $1-2 Bn

?

~2%

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Flow: – Uniform dosage mass

• Tablets and capsules – Enhance blending

• Blend uniformity • Content uniformity

Compaction – Increased compactibility

• Improved hardness profiles • Less friability • Increased dilution potential

– Decreased lubricant sensitivity

Hydration: – Faster disintegration – Reproducible dissolution

Stability enhancement – Heat & moisture

exposure reduced or eliminated • DC processes favored

Others? – Solubility/wettability? – Permeability?

Functional performance enhancement results

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CPEs available > 114 Number of different components used > 72 Excipients most commonly co-processed – Unmodified cellulose (MCC &

powder cellulose): 35 – Lactose: 27 – Mannitol: 9 – CaCO3: 8 Frequently used manufacturing methods – Co-spray dried: 28 – Co-agglomerated: 7 – Co-precipitated/crystalized: 7

77%

18%

5%

BinaryTertiaryQuartinary +

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Cellactose ® 80 – Co-spray-dried

• 75% α-Lactose lonohydrate ♦ Ph.Eur./USP-NF/JP

• 25% Powdered cellulose ♦ Ph.Eur./USP-NF/JP

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17

96979899

100101102103104105

Re

lati

ve t

he

op

hyl

ine

co

nte

nt

[%]

Uniformity as a Function of Blend Composition Powder Blend containing Theophylline [1%]

RetaLac®

(co-processsed) Physical

admixture

RetaLac® – Uniform integrated

structure – Spheroidal shape

• Improved flow • Better blending

PAM • Discrete

particles • Various

sizes & shapes • Poor

flow

RetaLac® – Spray-agglomerated

• 50% α-Lactose Monohydrate ♦ Ph.Eur./USP-NF/JP

• 50% HPMC, co-processed ♦ Ph.Eur./USP-NF/JP ♦ 2208 type – K4M

» ca. 4000 mPa s

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 100 200 300 400 500

Ten

sile

str

engt

h [

MP

a]

Compression pressure [MPa]

RetaLac lot L1004 A4020

RetaLac lot L1021 A4020

RetaLac lot L1033 A4020

Physical admixture 1

Physical admixture 2

Physical admixture 3

Tensile Strength as a Function of Compression Pressure RetaLac versus an Admixture Comprising Tablettose 80 & Hypromellose K4

StarLac® – Co-spray-dried

• 85% a-Lactose Monohydrate ♦ Ph.Eur./USP-NF/JP

• 15% Corn Starch, co-processed ♦ Ph.Eur./USP-NF/JP

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Co-processed: Immediate dispersion PAM: No dispersion after 10 min.

Co-processed excipient versus simple mixture of individual components – Simple blend combining 50% HPMC (K4M) & 50% lactose

monohydrate – Co-processed system integrating 50% HPMC (K4M) & 50% lactose

monohydrate • RetaLac®

Agitation in cold water

(http://www.meggle-pharma.de/de/produkte-und-leistungen/produkte/produktuebersicht/retalac-coprocessed-)

PAM: No dispersion after 10 min. Co-processed: Immediate dispersion

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CombiLac® – Co-spray-dried

• 70% α-Lactose Monohydrate ♦ Ph.Eur./USP-NF/JP

• 20% MCC ♦ Ph.Eur./USP-NF/JP

• 10% Corn starch ♦ Ph.Eur./USP-NF/JP

– Multi-functionality • Flow • Compaction • Hydration

♦ Disintegration

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Fixed ratio of individual components – Excipient manufacturer can be flexible; ratios can

be altered

Proprietary position/supply chain security – Second production site often exists – Price policy

• CPEs can be more expensive than traditional excipients • Significant price increase upon acceptance/use

FEAR – Newness

• Regulatory uncertainties • Lack of official acceptance

♦ Few CPEs are monographed » USP/NF has greatest number of CPE monographs

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USP/NF has greatest number of CPE monographs – Manufacturers are encouraged to develop and submit draft CPE

monographs

Ph.Eur. has few CPE monographs, but they do exist – EDQM prefers to define individual component quality of medicinal

products rather than mixtures

JP treats CPEs as premixes – no monographs exist

Numerous CPEs listed on FDA’s IID – CPEs may be listed as separate components due to competition – Typical for CPEs to have DMF

• DMF can be referenced in submission for review

IPEC together with IQ consortium – Novel excipients working group

• IQ and IPEC are currently exploring regulatory pathways for the use of novel excipients

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Single, traditional excipient mixtures

1+1 = 2

1+1+1 = 3

1+1+…+1 = n

n

i=1

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Co-processed excipient

1+1 2

1+1+1 3

1+1+…+1 n

n

i=1

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Need for new excipients to overcome challenges presented by new APIs – Excipient perception transitioning from “inert and cheap” to “high

functionality”

CPEs are a logical consequence of QbD – They ensure product quality, reduce variability – Designed performance characteristics to meet current and future

challenges

Novel/new excipients will play be critical role for new therapies – Few NCE excipients introduced due to regulatory hurdles and costs – This makes CPEs attractive to pharmaceutical industry – Independent excipient assessment/approval process by regulators needed

• Expedite industry acceptance and use

Emerging trends towards “tailor made“ excipients – Requires greater pharma-excipient trust and collaboration – Communication critical for success – Rules for cross-disciplinary strategies will have to be established

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