Excipient Co processing Technologies - ipecamericas.org · excipient‐like performance to the overall formulation ... – Handbook of Pharmaceutical Excipients ... PROSOLV SMCC MCC,

ExcipientFest Americas 2013 April 30th

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Excipient Co‐processing Technologies

Intelligent Combinations to Meet Current & Future Needs

Joseph ZeleznikManager, Technical & Regulatory Affairs

MEGGLE USA, Inc.

Merriam‐Webster Online Dictionary– Entry: ex∙cip∙i∙ent– Pronunciation: ik‐'si‐pE‐&nt– a usually inert substance (as gum Arabic or starch) that forms a

vehicle (as for a drug)

21 CFR 210.3(b)(8) [FDA]– any component other than an active ingredient

40 CFR 63.1251 [EPA]– means any substance other than the active drug or product which

has been appropriately evaluated for safety and is included in adrug delivery system to either aid the processing of the drugdelivery system during its manufacture; protect, support, orenhance stability, bioavailablity, or patient acceptability; assist inproduct identification; or enhance any other attribute of theoverall safety and effectiveness of the drug delivery system duringstorage or use.


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They are multi‐functional materials that provideexcipient‐like performance to the overall formulationwithout complex processing.

Not all excipient experts and companies subscribe tothis view:– Marketing construct– Who would use low‐performance excipients?

Opinions have altered in recent years.It is now recognized by many in the pharma and excipient industries that co‐processing can and often does create synergy– Performance greater than the parent ingredients alone or simply blended

– De facto increasing formulation functionality• High performance


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How many excipients are there?– Handbook of Pharmaceutical Excipients• > 300 entries

– Handbook of Pharmaceutical Additives• > 1800 entries

– National Formulary• > 350 entries

While there is considerable overlap in the three references, some additives/excipients are unique to the individual referencesMultiple variants through technical gradesFew co‐processed excipients make the list

Acquisitions & mergers– Large pharma (innovator and generic) and nutritional companies are in acquisition mode• Global in nature• > 1,300 mergers and acquisitions of pharmaceutical assets and pharmaceutical companies♦ ~$700 billion in value

• Acquisitions fulfill needs♦ Expand market penetration♦ Diversify therapeutic base♦ Increase shrinking pipeline♦ Change company direction♦ Enter new markets


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Teva Acquired RatiopharmNovartis Acquired BMS ConsumerBarr Acquired PlivaJ&J (McNeil) Acquired Pfizer ConsumerSandoz Acquired EonPfizer Acquired WyethWarner Chilcott Acquired P&G ConsumerMerck Acquired Schering PloughTeva Acquired BarrPfizer Acquired KingNBTY Acquired Leiner

Acquisitions & mergers– Large pharma (innovator & generic) and nutritional companies are in acquisition mode

– Dosage form manufacturers are not alone• Excipient manufacturers undergoing consolidation


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Colorcon Acquired NP PharmRhodia Acquired Albright & WilsonInnophos Acquired RhodiaJ. Rettenmaier Acquired Penwest ExcipientsWR Grace Acquired SynthetechDow Acquired Wolff CellulosicsJ. Rettenmaier Acquired DemacsaDMV Acquired AvebeKerry Acquired SheffieldDMV/Fontera Merges DFE formedDFE Acquires Brahmar Cellulose Innophos Acquires Kelatron


– Dosage form manufacturers are not alone– What’s next?• Consolidation is ongoing• Cross‐market sector acquisition

– Associated implications• Facility closings• Down‐sizing• Resource reallocation• Outsourcing• Cost containment• New start‐ups


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Expertise from consolidation victims or “cast‐aways”Start‐ups vary in size and focus–Many are small• May be one person in a laboratory• Others are small group

– Some are virtual• Rely on others’ expertise to realize product development and commercialization• Good a managing and coordination activities


– Dosage form manufacturers are not alone– This is the tip of the iceberg– Associated implications– Result

• greater reliance on suppliers for solutions♦ Excipient suppliers are no exception


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API challenges continue to increase– Not that it was ever easy

Medium dose APIs are fewer and fewer– Low dose APIs may present uniformity concerns

– High dose APIs challenge excipient performance

API challenges continue to increase– Not that it was ever easy

Medium dose APIs are fewer and fewerShift in BCS class creating challenges– Solubility/bioavailability

Drives the need for new excipients

40%

5%

30%

70%

24%5%

6%20%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2000 2010

Approvals Breakdown by BCS

Class IV

Class III

Class II

Class I


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API drives excipient choices and needsDo currently available excipients meet all the challenges?– NO!– The challenges change constantly– Excipient combinations are used to maximize functional performance• MCC and Lactose is a classic combination

– Complex processing in combination with excipients applied to overcome deficiencies• Significant cost added to product development and manufacture

Combinations through co‐processing– Using existing excipients• Lactose/MCC

• Lactose/Powdered cellulose• Starch/Lactose• MCC/CSD

• Many others

– Co‐processing has become mainstream for excipient suppliers

– Functionality tailored to dosage form• Does this make sense in the long term?


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The above table omits more than a dozen others

Product Composition Manufacturer Applications

Cellactose 80Lactose, powdered cellulose MEGGLE

DC, RC, and/or Capsule fillMicroceLac 100 Lactose, MCC

Avicel DG MCC, DCPFMC Biopolymer

Avicel HFE‐102 MCC, Mannitol

PROSOLV SMCC MCC, SiO2 JRS PHARMADC, RC, and/or Capsule fill; some WG

PanExcea MHC300G

MCC, HPMC, Crospovidone

Mallinkrodt‐Baker

DC, RC with disintegrant functionalityLudipress

Lactose, XL‐PVP, soluble povidone

BASF

StarLac Lactose, starch MEGGLE

The above table omits more than a dozen others

Product Composition Manufacturer Applications

PharmaBurst Mannitol, Sorbitol SPI Pharma ODT

PROSOLV ODTMCC, CSD, Mannitol, Fructose, XLPVP

JRS PHARMA ODT

LudiFlashMannitol, XL‐PVP, PVA‐PEG copolymer

BASF ODT

RetaLac Lactose, HPMC MEGGLE CR tablet formulations

PROSOLV EASYtab 1 MCC, CSD, SSG, SSF JRS PHARMASelf‐lubricating/self‐disintegrating DC/RC


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Combinations through co‐processing

Benefits– Existing excipients widely accepted– Co‐processing does not chemically alter parent ingredients

– Attempts to exploit parent material attributes

– Synergistic combination• Intelligent combinations

♦ Co‐processed combination better than simple blend of parent ingredients

Combinations through co‐processing

Benefits

Issues– Need to verify performance enhancement

– Can limit formulator flexibility• Fixed concentrations

– Changes formulation approach• Creates a need for training/education


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Pharmaburst™ (SPI Pharma)– Parent ingredients• Sorbitol• Mannitol

– Synergy through co‐processing• Compaction• Disintegration

– Performance increased over simple blending of individual ingredients

Pharmaburst™

Cellactose 80 (MEGGLE)– Composition• 75% α‐lactose monohydrate, Ph.Eur., NF, JP• 25% powdered cellulose, Ph.Eur., NF, JP

–Manufacturing process• Co‐spray‐drying

– Physical characteristics• Binary composition• Mono‐particulate


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Synergy is established through co‐processing– Cellactose® 80 compacts better than the admixture comprising the individual ingredients

0

50

100

150

200

250

0 50 100 150 200 250 300

Breaking force [N]

Compression pressure [MPa]

Breaking Force as a Function of Compression Pressure

Tablettose 80

Tablettose 80/VIVAPUR 102 blend (75:25)

Cellactose 80

Synergy is established through co‐processing– Cellactose® 80 improves blending and CU over traditional excipients

MCC Type 200

Sorbitol

Cellactose 80

0

20

40

60

80

100

1.7 3.5 5 10

% Adhered

Initial glyburide content

Glyburide Adherence as a Function ofInitial Glyburide Content and Substrate


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Pharmaburst™Cellactose 80RetaLac (MEGGLE)• Parent ingredients

♦ Lactose monohydrate♦ Hypromellose K4M

• Synergy through co‐processing♦ Flow» Blending

♦ Compaction• Simplifies formulation development• Reduces reliance on processing

♦ DC versus WG• Reduces need for auxiliary binders

RetaLac possesses superior compaction properties

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 50 100 150 200 250 300 350 400 450

Tensile strength [MPa]

Compression pressure [MPa]

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

RetaLac lot L1004 A4020



Physical admixture 1




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From where will the next excipient generation come?What features/benefits are being explored?What will the impact be?What are the obstacles faced?What about existing excipients and technologies?Where will excipient supplier and pharma converge?

From where will the next excipient generation come?– New chemical entities• Possible, but unattractive, and happening nonetheless

♦ Regulatory hurdles make NCEs difficult» Toxicity required

♦ Cost prohibitive♦ Acceptance challenging

– Current materials from other industry segments• Food industry• Cosmetic industry

– Intelligent excipient combinations/modifications• Combinations of existing excipients• Additional specialty grades offering more than the parent material

– Collaborations• Academia• Industry


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From where will the next excipient generation come?What features/benefits are being explored?– Functional improvements– Pharmacokinetic enhancements• Bioavailability

♦ Solubility♦ Permeability

From where will the next excipient generation come?What features/benefits are being explored?What will the impact be?– Supplier/User partnerships• Tailored technologies• Co‐development


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From where will the next excipient generation come?What features/benefits are being explored?What will the impact be?What are the obstacles faced?– Development costs– Manufacturing infrastructure– Industry acceptance• Including regulatory• No one wants to be the first to use a new technology• FEAR!

♦ “The pharmaceutical industry is notoriously conservative. We all want to be first to be second.”

From where will the next excipient generation come?What features/benefits are being explored?What will the impact be?What are the obstacles faced?What about existing excipients and technologies?– They are here to stay for the foreseeable future• Existing materials are known and understood• Generics rely on current materials to “match” innovators• Many companies do not wish to embrace new excipients

♦ Fear FDA rejection due to “unknown”, new excipients


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From where will the next excipient generation come?What features/benefits are being explored?What will the impact be?What are the obstacles faced?What about existing excipients and technologies?Where will excipient supplier and pharma converge?– Building excipient qualities into APIs• Functional characteristics• Streamline drug product manufacture

API/excipient co‐processing– Several excipient companies and universities exploring API/excipient combinations through a variety of processes• Co‐milling• Co‐drying• Nano‐sizing• Others

Thin film applicationsMolecular dispersionsCrystal engineeringAdvances in catalysis– Choosing API polymorphs– Isomer selection

Excipient choices and technologies play critical role in formulation development and API delivery


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API/excipient co‐processingGoals– Reduce development time and costs– Customize API delivery– Enhance bioavailability– Improve stability– Streamline manufacturing– Raise quality standards– Improve patient compliance

API/excipient co‐processingGoalsPathway– Understand current technology assets and limitations• Exploits the assets, if possible• Reduce or eliminate limitations

– Dialog with pharmaceutical companies• Understand industry’s general or specific needs

♦ This is likely API specific

– Use existing materials if possible to avoid hurdles


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API/excipient co‐processingGoalsPathwayRegulatory perception– Clarity in identity– Monograph position– GRAS status– Discern co‐processing versus simple blending

Soluble lubricant that does not adversely affect compression or dissolution– Will this require co‐processing?

The “universal” tableting excipient– Self lubricating, self disintegrating, freely flowing, directly compressible powder having excellent blending and loading properties.

Possibly something else?– Excipients for improved bioavailability• Increased solubility

• Enhanced permeability

• These already exist, but additional excipients in this class are still needed


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You should go away believing that co‐processed excipients are here to stay

Used properly, they will facilitate significantly improved dosage form development with simpler manufacturing processes

Key to any development is open communication between pharma and excipient producers– “Many new excipients are a solution looking for a problem.”– The relationship should not be adversarial– Collaborative efforts are needed for true success

A pathway or process is needed for new excipient approval independent of drug product approval– Reduces/eliminates the fear of using new excipients– Improves overall acceptance of new ingredients

Documents

Excipient Co processing Technologies - ipecamericas.org · excipient‐like performance to the overall formulation ... – Handbook of Pharmaceutical Excipients ... PROSOLV SMCC MCC,