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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
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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
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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
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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
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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
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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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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
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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
18
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
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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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