coprocessed excipient workshop (drs revisions) bac rcm …avicel cl611 fmc coattrited, cospray dried...

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IPEC-Americas Co-processed

Excipients Workshop 1-4pm April 29th 2013

Brian Carlin

Dave Schoneker Chris Moreton

1 Co-processed Excipients Workshop Apr 29th 2013

Abstract •  Greater use of co-processed excipients is a logical outcome of

Quality by Design, whereby tailored combinations of physical properties are provided, beyond what can be achieved by simple blends of the components. The ratios of the components may vary depending on the desired performance.

•  The International Pharmaceutical Excipient Council (IPEC) definition of a co-processed excipient is “a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change”. The absence of chemical change presents a much lower regulatory burden for adoption than the introduction of a new chemical entity.

Co-processed Excipients Workshop Apr 29th 2013 2

Abstract •  However the description new, or novel, applied to a physically co-

processed entity often raises inappropriate perceptions of onerous regulatory hazard, leading to avoidance and inability to improve the material science consistent with QbD.

•  The United States Pharmacopoeia (USP) encourages development of monographs for co-processed excipients and IPEC is drafting a guideline to facilitate development and adoption of co-processed excipients.

•  The safety, QbD, technical and regulatory aspects of co-processed excipients, as addressed in the draft IPEC guideline, will be reviewed and discussed


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Co-Processed Excipients (CoPEs) Workshop Overview

•  CoPEs vs “regular” Excipients (Carlin) –  Definition –  Technological benefits of Co-processing –  Why CoPEs are the Future –  Regulatory aspects

•  IPEC CoPE Guideline (Moreton) •  IPEC New Excipient Safety Evaluation

Procedure (NESEP) to support CoPE safety evaluation (Schoneker)

•  Wrap-Up

Co-processed Excipients

Definitions, regulatory implications and QbD

Professor Brian A Carlin Director Open Innovation, FMC BioPolymer

Chair IPEC Americas QbD & Excipient Composition Committees [email protected]

www.ipecamericas.org 5

Where do CoPEs fit in?

•  Existing “Single” Excipients •  Mixtures or Blends of Existing Excipients •  CoPEs

– Physical synergistic combination only – No chemical change, else:-

•  New Chemical Grade of Existing Excipient •  New Chemical Entity Excipients (NCEs)

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Single (label-) Entity Excipients

•  One primary component – the nominal excipient

•  May contain other components – Concomitant components – Residual processing aids – Additives

Multiple Excipient Mixtures or Blends

•  Simple physical mixtures or blends of two or more compendial or non-compendial excipients by means of a low- to medium-shear process where the individual excipients are mixed together without significant chemical change*

•  For mixtures or blends of solids the individual excipients remain physically separate at a particulate level (“unengineered particles”)

•  Miscible liquids or solutions mix at molecular level. Suspensions and emulsions generally require co-processing if not self-dispersing

*Excluding incidental in-situ salt formation

CoPEs (IPEC definition)

•  Combination of two or more compendial or non-compendial excipients using a mfg. process –  designed to physically modify their properties in a manner not

achievable by simple physical mixing, a composite. AND –  without significant chemical change*

•  Co-processing methods may include: –  Granulation, spray drying, melt extrusion, milling, etc.

•  Ratios of components may vary depending on performance •  For solid-solid CoPEs the individual excipients may remain

separate within a particle but not separable at a particulate level (“engineered particles”)

•  Liquid & semi-solid CoPEs have supramolecular structure

*Excluding incidental in-situ salt formation Note: USP will only monograph CoPEs with compendial components

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Co-processing Methods Process Pharma Excipient

Roller Compaction Predominantly Batch, common

Rare. Agglomeration only, no synergy?

Wet Granulation Predominantly Batch, common

Less common, not continuous/large scale

Extrusion Spheronization Hot Melt Extrusion

High shear continuous mixing (wet/melt)

Spray Drying Less common, Batch Dominant granulation technology, continuous, particle size control

Co-Crystals APIs Often co-spray dried

Co-processing is at the higher energy end of a continuum of processing methods

Multiple Component “Unprocessed*”

• Simple powder or liquid blends • Low energy input

Continuum

• Ordered mixing? • Co-grinding?

Multiple Component (Co)Processed

• Composites • Significant energy input* • Functional synergy?

*Co-processing often the same processes used for single component excipients or formulations

Examples of CoPEs

12

Name Supplier Ingredients % ManufactureSucrose 97Dextrin 3Dextrose 92Maltose 4Maltodextrin 4β Lactose 95Lactitol 5Sucrose 93Invert sugar 7Mannitol 70-97Sorbitol 3-30Sucrose 95-98Invert sugar 2-5

PVAP-T Colorcon PVAP 90 TiO2 incorporatedTitanium Dioxide 10 in PVAP manuf.

DMV

JRS

SPI

Dipac

Emdex

Pharmatose DCL40

SugarTab

Compressol S (Pharmaburst)

MegaTab Paulaur Cocrystallised

Spray Crystallised

Cocrystallised

Melt Extrusion

Domino

JRS

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Examples of CoPEs

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Name Supplier Ingredients % Manufacture Xanthan Locust Bean Gum Calcium Sulphate Filler Lactose 96.5 PVP 3.5 α Lactose monohydrate 85 Maize Starch 15 Xylitol 96.5 Polydextrose 3.5 Xylitol 98 SCMC 2 Corn Starch 85-95 Pregelatinised Starch 5-15 Fructose 95 Starch 5

TimerX

Colorcon

SPI

Endo Granulate

Advantose FS

Spray dried compound

Granulate

Granulate

Co-spray dried

Codried

Ludipress

Starlac 100

Xylitab 100

Xylitab 200

StarCap 1500

BASF

Meggle

Danisco

Danisco

Examples of CoPEs

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Name Supplier Ingredients % Manufacture Mannitol 90 PVA latex solids 5 Crospovidone 5 MCC HPMC Crospovidone α Lactose monohydrate 75 Cellulose 25 Calcium Carbonate 70 Sorbitol 30 α Lactose monohydrate 75 MCC 25 α Lactose monohydrate 85 Maize Starch 15

Starlac 100 Meggle Spray dried compound

Formaxx EMD Coprocessed (unique process)

Microcelac 100 Meggle Spraydried mixture

PanExcea MHC 333G

Covidien Granulated

Cellactose 80 Meggle Spray dried compound

Ludiflash BASF Granulated

Microcrystalline Cellulose: Application-specific Co-processing

15

Name Supplier Ingredients % ManufactureMCC 90Mannitol 10MCC 98Colloidal Silicon Dioxide 2MCC 85Guar 15MCC 75DiCalcium Phosphate 25MCC 89Carmellose Sodium 11MCC 89Carmellose Sodium 11MCC 85Carmellose Sodium 15

Avicel CL611 FMC Coattrited, CoSpray Dried

JRS

FMC

Avicel RC591 FMC Coattrited, CoSpray Dried

Avicel RC581 FMC Coattrited, Bulk Dried

Avicel DG FMC CoSpray Dried

CoSpray Dried

CoSpray Dried

CoSpray Dried

Avicel HFE

ProSolv

Avicel CE15

FMC

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New or Novel Excipients (IID)

•  Generally, excipients not listed in the FDA Inactive Ingredient Database (IID)* are new or novel •  http://www.accessdata.fda.gov/scripts/cder/

iig/index.cfm

• CoPEs may not be listed as such in the IID, possibly as separate components

•  IPEC supporting FDA upgrade of IID

*IID listing is not an approval but the excipient is“likely to be deemed safe for use in other products that involve use under similar circumstances, but the Agency may ask that the database be brought up to current standards in relation to even that “similar” use”.

Are CoPEs New or Novel?

•  For a chemically unmodified* combination of ingredients with precedence of use:

Components Not novelProcesses Not novelComponent Combinations Not novelPhysical Form NovelFunctionality/Utility Novel*Hence IPEC definition:- “without significant chemical change”

Newness in terms of Patient Safety

•  In this guidance, the phrase new excipients means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.

Ref: FDA Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients 2005

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Regulatory Aspects of Co-processing

•  Perceived regulatory barriers outweigh reality

•  Pharmacopoeial listing minimizes barriers to adoption

•  Silicified MCC and Ethylcellulose Dispersion Type B are recent monographs in NF31.

•  Avoidance inconsistent with 21st century cGMP risk based approach – Clarity around stakeholder expectations needed to facilitate broader usage and lower risk of delay

•  Put into context: •  Essentially chemically unchanged •  Processing similar to that of single excipients in pharmaceutical products

19

USP CoPE Monograph Guideline

•  Proposal (PF) 35(4)(2009) •  Response to comments (PF) 37(3)(2011)

– Combination excipients in which covalent bond formation takes place not covered

– Guideline currently limited to solid CoPEs – Liquid products may be addressed in the

future.


CoPE Monograph Eligibility

•  Combination of pharmacopeial excipients* •  Must be distinguishable—in at least one non–

performance-related property—from the admixture obtained by physically mixing the corresponding constituent excipients in the same proportions.

•  Must be included in an FDA-approved drug application, have a GRAS designation, or be under special consideration by Council of Experts.

*legal consequence of the status of USP–NF under the US Federal Food Drug and Cosmetic Act


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Differentiating CoPE from mix

•  A mix of the components will not quantitatively exhibit one or more characteristics of the CoPE.

•  Characteristics distinguishing the CoPE from a physical mix must be measurable without separation of the individual components of the CoPE.

•  Individual excipient components in a physical admixture are not modified in order to change their inherent thermodynamic or physical states before being mixed.

•  In a CoPE the inherent thermodynamic or physical state of the individual excipient components may be changed before or during mixing and/or processing.


Differentiating CoPE from mix

•  Characteristics distinguishing CoPE from mix must be inherent, demonstrably measurable, and quantitatively different in CoPE before incorporation into the finished drug product. –  No monograph without acceptable distinguishing

analytical test! •  For quantification of the individual components (but

not for the purpose of differentiating from mix) the components may be separated before quantification.


No chemical change

•  No covalently bonded chemical entity is formed when the individual ingredients are combined to form the CoPE.

•  The absence of the formation of covalent bonds between individual ingredients in the co-processed excipient must be analytically demonstrated over the proposed shelf life or retest period of the coprocessed excipient.


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NF components only •  Individual ingredients in CoPE must have USP–NF

monographs, or at least monograph proposals must be published in PF as part of in-process revision.

•  This does not necessarily imply that those individual ingredients must demonstrably meet monograph specifications in USP–NF before being co-processed. –  may not be possible because one or more individual

component(s) of the co-processed excipient may not be isolated before co-processing.

•  CoPE cannot be considered for monograph in NF if its production or manufacture involves incorporation of a noncompendial ingredient.


Monographed Co-processed Excipients (NF26/NF31)

•  Ammonio Methacrylate Copolymer Dispersions alkalinising & antimicrobial preservative

•  Microcrystalline Cellulose & Carboxymethylcellulose Sodium co-attrited

•  Silicified Microcrystalline Cellulose •  Ethyl Acrylate & Methyl Methacrylate CoPolymer Dispersion

suitable emulsifier •  Ethylcellulose Aqueous Dispersion

Ethylcellulose, Cetanol, Sodium Lauryl Sulfate •  Ethylcellulose Dispersion Type B

Ethylcellulose, plasticizers, stabilizers, and glidants •  Methacrylic Acid Copolymer Dispersion (Methacrylic Acid and Ethyl Acrylate Copolymer

Dispersion ) suitable surfactant

•  Polyvinyl Acetate Dispersion suitable surface active agents and stabilizers

•  Compressible Sugar starch, maltodextrin, or invert sugar, and suitable lubricant

•  Confectioners Sugar Co-ground starch sucrose (>95%)

•  Sugar Spheres 62.5-91.5% sucrose, chiefly starch, colour permitted

26

Technological Benefits of Co-processing

•  Synergy –  Functionality not achievable with corresponding blend

•  Complementary –  Balancing properties eg. brittle/plastic

•  Convenience –  One ingredient replaces several

•  Consistency in Performance –  Variability which exists in individual component properties can

be minimized through engineering for specific pharmaceutical functionalities

•  Quality by Design –  CoPEs will be a key to building improved quality into products

and processes –  Excipients designed for purpose

27

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Avoid risk from CoPE Unknowns

• True variability of specified attributes including ratio of components

• Continuous manufacture • Process capability

• dictates composition range • Unspecified excipient attributes • Functionality/Performance • Early discussion with supplier!

CoPE vs Components

•  CoPEs expressed as single components in a manufacturing formula may not meet the guideline

•  Should reviewers extend this manufacturing requirement to other formulae in MAA?


CPMP/QWP/486/95 re: Section 3 Manufacturing Formula

CoPEs are designed for Functionality/Performance

•  Microcrystalline Cellulose and Carboxymethylcellulose Sodium NF (Avicel RC/CL) –  contains NLT 75.0% and NMT 125.0% of the labeled

amount of carboxymethylcellulose sodium


0.1000 1.000 10.00 100.0 1000shear rate (1/s)

1.000E-3

0.01000

0.1000

1.000

10.00

100.0

vis

co

sit

y (

Pa

.s)

Mixture of MCC(1.35%)+CMC(0.15%)SDMC 1.5%Avicel RC 591 1.5%

0.1000 1.000 10.00 100.0 1000shear rate (1/s)

1.000E-3

0.01000

0.1000

1.000

10.00

100.0

vis

co

sit

y (

Pa

.s)

CMC 0.15%MCC 1.35% Avicel RC 591 1.5%

Zhao G, Kapur N, Carlin B, Selinger E, Guthrie J. Int J Pharmaceutics 415 (2011) 95-101

Visc

osit

y Pa

.s

Shear Rate s-1

1.5% Avicel RC591 1.5% Avicel RC591

1.5% Co-spray dried

1.5% Mix

0.15% SCMC

1.35% MCC

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In-house v Outsourced Wet Granulation?

•  Avicel DG –  Microcrystalline Cellulose 75% –  Dicalcium Phosphate 25% –  Co-spray dried –  Synergy in recompactability for Roller Compaction

•  MCC/DCP blends widely used in Roller Compaction & Wet Granulation

•  Consider differences between the proposed use (as CoPE) and the prior use.


Why single out CoPEs?

•  Magnesium Stearate NF –  “a compound of magnesium with a mixture of

solid organic acids, and consists chiefly of variable proportions of magnesium stearate and magnesium palmitate.”

–  Acceptance criteria: NLT 40% for the stearate peak. The sum of the stearate and palmitate peaks is NLT 90% of the total peak areas of all the fatty acids.

–  Anhydrate, mono- & di- hydrates within LOD –  Multiple manufacturing processes-

•  Precipitation, direct reaction, fusion,


CoPEs are the future •  Physical mixtures of excipients have lowest data

burden but offer little added functionality. •  CoPEs offer additional functionality with a moderate

level of supporting data.

NCE

Am

ou

nt

of S

afe

ty D

ata

Degree of Newness

Co-processed (IID) Excipients

IID Excipients Mixtures of IID Excipients

Chemically Modified Excipients

Non-IID Excipients

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How do we minimise the regulatory burden on new CoPEs?


PJ Brucat // University of Florida www.chem.ufl.edu/~itl/2041_u98/lectures/lec_m.html

Reg

ula

tory

Bur

de

n

Existing Excipients New CoPEs

New IID IPEC CoPE Guideline

IPEC NESEP USP

IPEC-Americas Co-processed Excipients Guide

Dr. R. Christian Moreton FinnBrit Consulting, Waltham, MA

[email protected]


Disclaimers

•  The IPEC-Americas Guide for Co-processed Excipients is still in preparation (a work in progress).

•  The ideas and concepts presented during these next several slides should not be taken as definitive; many of the draft provisions may, and probably will, change before the Guide is finalized.

•  Until the final Guide is published, these slides should not be taken to represent the official policy of IPEC-Americas, or any other organization with which I am associated.

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Outline

•  Co-processed excipients •  Why? •  A brief introduction to the Guide •  The likely content of the Guide •  Some details on the different sections as

they apply to excipient manufacturers •  Some details as they apply to excipient

users •  In summary

Definition of a Co-processed Excipient

“A co-processed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change. However in some instances, formation of necessary components may occur, such as in-situ salt formation. Many different co-processing methods may be used, including standard unit operations such as granulation, spray drying, melt extrusion, milling etc. The choice for a specific application will depend on the materials used, their form (e.g. whether dry powders or liquid) and the specific physical properties desired. Likewise the ratios of the components may vary depending on the desired performance.”

(IPEC Excipient Composition Guide - https://ipecamericas.org/ipec-store)

Why develop an IPEC-Americas Guide for Co-processed Excipients?

•  Co-processed excipients represent a convenient and economic way to develop new excipient functionalities.

–  Developing new chemical excipients (NCEs) takes a long time, and is expensive and uncertain.

–  The patent exclusivity period may well have expired before there is a positive return on the investment.

•  There are still uncertainties concerning co-processed excipients, particularly in the context of QbD:

–  Test methods •  To confirm the composition of the co-processed excipient •  Stability indicating methods, if possible

–  Stability –  Safety bridging –  Process validation/qualification –  Provision of samples

•  For evaluation •  To allow incorporation of the co-processed excipient into the Design of Experiments

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Economics of New Chemical Excipients

Moreton, R.C., Drug Dev. Ind. Pharm., (1996), 22, (1), 11 - 23.

IPEC-Americas Co-processed Excipient Guide

•  In some ways this Guide is a first for IPEC-Americas in that: –  It does not address a specific regulatory or

compendial issue per se, –  It is not a guide that is potentially applicable

to all excipients, rather –  It is a Guide that provides advice on how to

address technical, safety and regulatory concerns relating to the development and commercialization of co-processed excipients.

Likely content of the draft Guide*

Preamble 1. Introduction 2. Co-processed excipients 3. Co-processed excipient

manufacturers 3.1 Co-processed excipient

development 3.2 Co-processed excipient

specification 3.4 Analytical method

development 3.5 Composition profile 3.6 Stability 3.6 Safety concerns 3.7 Bridging studies

3.7.1 IPEC-Americas’ New Excipient Safety Evaluation Procedure

3.8 Manufacturing issues 3.9 Consistency 3.10 Regulatory issues 3.11 Provision of samples 3.12 Pharmacopeia monograph

4. Co-processed excipient users 4.1 What advantages does the co-

processed excipient offer? 4.2 What are the disadvantages? 4.3 How good is the technical data

package? 4.4 Is the safety/toxicology

package acceptable? 4.5 How straightforward will the

regulatory filing be? 4.6 Supply 4.7 Consistency

*Note: This layout is provisional and may change as the Guide is developed.

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For the Excipient Manufacturer

Try to anticipate the User’s questions!

Co-processed Excipient Development

•  First find your synergy/niche: –  Without some form of advantage for the customer, there is no point! –  Advantages can be in:

•  Manufacturing performance •  Convenience/handling •  In vivo performance

•  Work out what is required to address the commercial need, and how to get there.

•  Determine the limits of acceptability. –  Performance vs. composition –  Composition profile –  Define the manufacturing space (QbD for the co-processed excipient)

•  Are there any other applications for which the co-processed excipient may have advantages?

–  ProSolv® (Silicified Microcrystalline Cellulose) was originally developed for wet granulation, but was later found to have superior direct compression performance compared to conventional Microcrystalline Cellulose.

Co-processed Excipient Specification

•  The specification(s) will be based on the performance goal(s) –  What is required to address the unmet need(s)? –  What needs to be controlled to ensure that the

performance will be consistent (CPPs, CRMAs)? •  What is needed to properly control the co-processed

excipient for routine use; i.e. what is the Control Strategy for the co-processed excipient? –  In-process controls vs. finished product testing

•  Chemical tests vs. sensors •  Physical tests vs. sensors •  Microbiological tests vs. precautions

–  Packaging requirements, including labeling and environmental controls.

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Analytical methods •  We need to be able to confirm that the composition is within

acceptable limits: –  A stability indicating method is desirable and preferred. –  Some excipients do not have assay methods; for other excipients,

the assay methods are not stability indicating –  Very often we have to resort to physical methods which may, or

may not, be adequate to assess stability. •  Even if we simply use the results from in-process monitoring to

release the excipient, we will still need methods suitable for finished product testing for the customer. –  Such methods will be important for the eventual development of

a pharmacopeia monograph for the co-processed excipient. •  There are examples of co-processed excipients that have NF

monographs, and these monographs can give guidance on what methods should be considered for a new co-processed excipient.

Composition Profile •  Composition profile will comprise:

–  Composition profiles of the individual components. –  Quantitative composition of the co-processed

excipient. –  Absence of other, potentially undesirable

components. •  Possibly indicative of unforeseen degradation, i.e. one

component has an adverse effect on another component.

•  We may not test or declare the composition of every lot, but we do need to be aware of what it should be, and what, if anything, is changing with time.

Co-processed Excipient Stability

•  As with any excipient we need to show adequate stability.

•  With co-processed excipients, there are some further considerations: –  How ‘stable’ is the interaction between the

components that creates the performance benefit? –  Are there any new degradant peaks created:

•  From an interaction between one of the main components and minor components from the other excipient?

•  From an interaction between minor components from two different component excipients?

•  Are the new degradants likely to be absorbed from the GIT, transdermally, etc?

•  Are any of the new degradants potentially genotoxic?

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Safety concerns •  A new co-processed excipient is ‘new’! •  For any new excipient the Regulatory

Agencies will have concerns. •  So how do we address them for a new co-

processed excipient? –  We most likely will not need to resort to animal

studies for a new co-processed excipient, since, by definition, we are not generating any new covalently bonded compounds.

–  There are other types of ‘bridging’ studies that may be more appropriate.

–  We do need to demonstrate that we have not created any new covalently bonded materials.

Bridging studies •  How to demonstrate that we have not formed any new covalently

bonded materials? •  We can use spectroscopic methods, e.g:

–  1H NMR, 13C NMR –  FT-IR –  NIR –  Raman –  etc.

•  However, we must anticipate changes associated with e.g. hydrogen bonding, and/or ionic interactions, and possibly hydrophobic interactions.

•  Using the ProSolv® example (a co-processed mixture of Microcrystalline Cellulose NF and Colloidal Silicon Dioxide NF), the investigations were undertaken by a leading academic research group and the data were published in a premier peer-reviewed journal:

–  Tobyn MJ et al., (1998) Int. J. Pharm, 169, 183 – 194.

Manufacturing issues

•  Batch manufacture vs. continuous processing

•  How robust is our process – Performance vs. composition profile – What is the inherent variability in our

process and raw materials, and how do these translate to co-processed excipient variability?

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Consistency •  What is our inherent variability?

–  It will depend on the type of excipient and its intended use.

•  The excipient manufacturer can only assess performance relative to the model systems it has used to assess the viability of the co-processed excipient during development.

•  We can use process capability indices, etc. However, formal validation of a continuous process may not be feasible. –  We can also use continuous process verification

(that we continue to operate within the established manufacturing space).

Regulatory issues

•  For the US market, the excipient manufacturer is strongly advised to submit a Type 4 DMF for the new co-processed excipient. –  This will simplify any regulatory filings in the US

until a USP-NF monograph is issued. •  If a safety data package is required and

available, this should be submitted as a Type 5 DMF.

•  Letters of access will be required for both DMFs.

Provision of samples •  Most co-processed excipients are offered for sale as

fixed combinations. •  As such, the samples typically available will comprise

that same fixed combination. However, there may be some minor variability.

•  Be careful when providing samples other than for the commercially available fixed combination: –  It is likely, particularly in the context of Quality-by-Design,

that customers will ask for samples to be supplied comprising different ratios of the nominal component excipients.

–  Be aware of any contractual obligations should such samples be ultimately preferred by the User.

•  Manufacturing lot size vs. customer usage •  Logistics •  Continuity of supply

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Pharmacopeia monograph •  Why submit a proposal for a pharmacopeia monograph?

–  It simplifies the regulatory issues. •  The different pharmacopeias have different approaches to co-

processed excipients. •  In all cases, the pharmacopeias will only accept proposals for full

monographs once an excipient has been included in an approved product in that country or region.

•  The USP-NF now has the possibility to develop a pending monograph. –  Once complete, the monograph is held (pending) until a product is approved,

and then it can be issued very quickly. •  The Ph Eur has stated that they will not accept monograph proposals

for co-processed excipients that are still subject to patent protection, i.e. sourced from a single manufacturer.

•  If the co-processed excipient contains a non-monograph excipient, it cannot be accepted as a monograph proposal until a monograph proposal has been accepted for the non-monograph excipient.

For the Excipient User

Maintain a professional skepticism!

What advantages does the Co-processed Excipient offer?

•  The reason(s) that a new co-processed excipient would be tried is because there exists in the User’s opinion an unmet need, e.g: – Manufacturing – Handling convenience –  In vivo performance

•  Does the co-processed excipient meet the User’s unmet need? –  In all respects? – Partially?

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What are its disadvantages?

•  There is no perfect excipient! – Every excipient has beneficial properties – Every excipient has limitations

•  What are the limitations for the User’s application? – Stability? – Manufacture of the finished dosage form? –  In vivo performance

How good is the Technical Data Package?

•  The Manufacturer will have tested the new co-processed excipient. –  Performance can only be assessed in

applications: •  They will likely have used model drugs and formulations

to assess the co-processed excipient.

•  How relevant are the model drugs and formulations to the User’s proposed application? –  Drug solubility (BCS classification?) –  Unit dose –  Drug loading –  Manufacturing method

Is the Safety/Toxicology package acceptable?

•  Is the co-processed excipient such that simple bridging to the safety data for the individual component excipients will suffice? –  How has this been demonstrated?

•  If simple bridging studies are not sufficient, what further safety testing has been done?

•  What were the results? •  Have these results been assessed by

independent experts? (e.g. IPEC-Americas’ NESEP)

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How straightforward will the regulatory filing be?

•  Is a Type 4 DMF available for CMC data (US)? •  Is a Type 5 DMF available for safety data (US)? •  Is a CEP available for BSE/TSE (Europe)? •  Is a CEP available for excipients having a monograph in the Ph Eur

(Europe)? •  For many co-processed excipients inclusion in an IND, NDA or ANDA

should not be an issue. •  The Common Technical Document has sections dealing with

monograph and non-monograph excipients. •  If the co-processed excipient does not have a pharmacopeia

monograph, then include it with the non-monograph excipients, even if all the component excipients have monographs.

•  In the US, remember the FDA’s IID. –  Make sure that its use in the co-processed excipient in the User’s application

does not exceed the maximum level for the intended route of administration given in the IID.

–  If the level in the IID is exceeded, then a safety assessment will be required (see IPEC-Americas NESEP).

Supply

•  For a new co-processed excipient, what is the Manufacturer’s capacity for this excipient/grade in the context of the User’s projected requirements? –  Short term – Medium term –  Long term

•  For an existing co-processed excipient (simply a new application), we still need to ask the same questions.

•  Written supply commitments/contracts!

Consistency

•  The Manufacturer will have tested several different batches of the excipient using model formulations.

•  There is no guarantee that the model formulations will be relevant to the User’s formulation.

•  It is up to the User of the co-processed excipient to confirm that it is suitable for its intended application, and that the inherent variability is acceptable.

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Which type of variability applies to our application?

Batch number/Time of output

Raw material parameter

* * *

64

Raw Material Variability: Acceptable

Raw material Parameter

Raw material batches

65

Raw Material Variability: Possibly acceptable



66

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Raw Material Variability: Impossible limits



67

In Summary •  The IPEC-Americas’ Co-processed excipient

Guide is in preparation. •  A summary of the possible content of the

Guide has been provided; however, this may change before the Guide is finalized.

•  There are obligations on the part of the Manufacturer and the User. –  The manufacturer must try to anticipate the

User’s questions. –  The User should maintain a professional

skepticism. •  Communication will be key!

Thank you!

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Co-processed Excipient Safety Assessment

Total Excipient Control (TEC)

Opportunities to Minimize the FEAR

David R. Schoneker

Director of Global Regulatory Affairs – Colorcon Vice Chair – Maker & Distributor Relations – IPEC-Americas

[email protected]


What is Total Excipient Control (TEC)

•  TEC will utilize all of the existing IPEC guidelines, programs and proposals to build an overall control system

•  TEC covers the controls needed from the time an excipient manufacturer thinks of marketing a chemical as an excipient to the pharmaceutical industry to the time the patient takes the drug product containing the excipient.


What is TEC and how to combine TEC Elements

•  This Total Excipient Control system involves three main areas of control:

•  Excipient Design Controls would include how design criteria are set to meet the requirements for the intended use taking Quality by Design into account.

•  Excipient Safety involves the information which has been developed to support the safe use of the excipient in the intended application at the expected daily dose for a patient.

•  Excipient Manufacturing Process Control and Distribution is the area of control traditionally covered by GMPs, Auditing, QC testing, Information Sharing and Supply Chain Security.


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TEC Elements

Excipient Design (QbD, Specs, Stability, Validation, etc.)

Excipient Safety (Toxicology, Precedence of Use)

Excipient Mfg. Process Control and Distribution (GMP, QA, Supply Chain)

TEC

Co-processed Excipients

designed for purpose

IID Improvements

NESEP

Safety Assessment of CoPEs

•  Detailed analytical studies to confirm absence of chemical reaction/degradation due to co-processing.

•  Types of studies will depend on chemistry of excipients and potential for reaction during co-processing.

•  Bridge to safety data on the previously studied individual components

•  Toxicological expert opinion, if necessary •  Abbreviated safety studies, if necessary •  Option for IPEC NESEP •  Submit data to FDA in Drug Master File

Less Toxicology in absence of chemical changes

•  The better the chemical evidence for no reaction or degradation the less risk that abbreviated safety studies will be required

•  Safety assessment must still be made even if relying on chemistry argument of no reaction/degradation to bridge to existing data on the individual excipients.

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Existing Situation •  No process exists for excipient safety to be

independently reviewed outside of the FDA drug approval process (NDA)

•  Confusion exists about the “level of newness”. Would extensive safety data be required by regulators for co-processed excipients

•  Pharmaceutical users are cautious to use co-processed excipients due to perceived risks of delays

•  This results in difficulties for excipient suppliers trying to introduce co-processed excipients into the marketplace AND minimizes the potential for QbD benefits by users!!!

Degree of Newness – Data Requirements

•  Physical mixtures of excipients have lowest data burden but offer little added functionality.

•  CoPEs offer additional functionality with a moderate level of supporting data.

NCE

Am

ou

nt

of S

afe

ty D

ata

Degree of Newness

Co-processed (IID) Excipients

IID Excipients Mixtures of IID Excipients

Chemically Modified Excipients

Non-IID Excipients

New or Novel Excipients (IID)

•  Generally, excipients not listed in the FDA Inactive Ingredient Database (IID) are new or novel – INCLUDES CoPEs •  http://www.accessdata.fda.gov/scripts/cder/

iig/index.cfm

• CoPEs may not be listed as such in the IID, possibly as separate components – NOT A CORRECT WAY TO DO THIS!!!

•  If the actual CoPE is not listed as an entity itself, then, by definition it is new or novel

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Novel Excipients (P.4.6)1 CTD “Novel excipients are excipients used for the first time in a human

drug product in the United States or by a new route of administration. Any novel excipient should be identified and its specification included in this section of the application (P.4.6).”

“Additionally, full details of manufacture, characterization, and controls, with cross-references to supporting safety (nonclinical and/or clinical) data, should be provided. The information should provide the same level of detail as that provided for a drug substance, and according to the drug substance format (guidance will be provided in the forthcoming drug substance guidance). This detailed information should be provided in A.3 unless the information is provided in an appropriately referenced DMF.”

1Guidance for Industry, Drug Product, Chemistry, Manufacturing and Controls Information, U.S Dept. of Health and Human Services, FDA, CDER, CBER, January 2003

Novel Excipients (Appendix A.3.)1 CTD

“Novel excipients are excipients used in the United States for the first time in a human drug product or by a new route of administration. The chemistry, manufacturing, and controls information for a novel excipient should be provided in the same level of detail and in the same format as the information provided for a drug substance (see the forthcoming drug substance guidance).”

“The suitability of the novel excipient for the intended route of administration should be discussed. Cross-references to supporting safety (nonclinical and/or clinical) data should be provided. Information to support safety can include, for example, references to FDA’s regulations, Food Chemical Codex, citations or supporting toxicology data provided in the application (include study numbers).”

1Guidance for Industry, Drug Product, Chemistry, Manufacturing and Controls Information, U.S Dept. of Health

and Human Services, FDA, CDER, CBER, January 2003

FDA Published Statements •  “There is a common misperception that once an

excipient is used in an approved product (i.e. listed on IIG) it is automatically assumed by the agency to be safe for use in any product thereafter that involves the same route of administration and level of exposure”

•  “If an excipient was used in a previously approved product (excipients are never “approved” themselves), it is likely to be deemed safe for use in other products that involve use under similar circumstances, but the Agency may ask that the database be brought up to current standards in relation to even that “similar” use.”

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FDA Published Statements

•  “Any attempt by the manufacturer to justify a proposed human exposure to an excipient by discussing prior use of the excipient should consider differences between the proposed use and the prior use.”

•  Reference: Toxicity of Excipients-A Food and Drug Administration Perspective, R. Osterberg and N. See. International Journal of Toxicology, 2003.

84

FDA’s Expectation for ANDAs (1): Excipient Safety

•  QbR question: Does any excipient exceed the FDA inactive ingredient database (IID) limit for this route of administration calculated based on maximum daily dose? If so, please justify or qualify. –  FDA Guidances:

•  Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, May 2005

•  Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products (draft), Match 2012

–  FDA Detects High Levels of Peroxide in Crospovidone Issuing a Drug Safety Advisory on 10/21/2010 http://www.fda.gov/drugs/drugsafety/ucm230492.htm

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Current Situation

•  Numerous IPEC-Americas member companies and other companies have experienced a significant increase in the number of Refuse to File letters received since late 2010.

–  Impact of FDA OGD’s new SRS nomenclature used in the IID and how an excipient’s precedence of use is determined and used at time of filing by OGD.

–  Full Toxicology studies have been requested to justify typical uses of common excipients………ICH Q9??

–  Industry was not informed of FDA OGD’s change in requirements…………….until Refuse to File letters were received??

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IID SRS Nomenclature - Changes and Impact

•  Inconsistencies exist in naming of materials (common, generic, brand and monograph names, etc.). SRS Nomenclature was introduced in 2011

•  Several industry issues resulted due to IID listing changes, e.g.:

–  Some listings of “un-like” products have merged - e.g. polyethylene oxide and polyethylene glycol

–  Some listings have disappeared - e.g. dimethicone for Transdermals

–  Maximum use levels for many listings have changed or are not being accepted by reviewers – e.g. hypromelloses vs. specific grades

–  Based on changes to IID listings and a higher number of “deficiency” or “Refuse to File letters”, the generic industry is confused about which excipients can be used, and at what levels

•  IPEC-Americas met with FDA OGD in December 2011 to discuss improvements needed and submitted a detailed Backgrounder document to provide examples of problems and recommendations

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Meeting Outcome

•  FDA and IPEC-Americas agreed to meet quarterly and develop meeting minutes which will be made available to the public (via the FDA web site) to provide information to potential sponsors and other interested persons. –  Minutes from all quarterly meetings, the December 2011 meeting

slides and the Backgrounder Document have been posted on FDA web site: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm

•  Much progress has been made which is detailed in the posted minutes. Last quarterly meeting was on March 1, 2013

•  A short-term IID spreadsheet approach is being worked out to include all grades for a family of excipients and clarify which Max. Potency level can be applied to all grades in that family. (Initial priorities: Hypromellose and Polyethylene Oxide)

Different viscosity & substitution “family” of polymers with same toxicology profile

Inac%ve(Ingredient' Route;(' dosage(form' CAS#' UNII' Max(Potency'

HPMC(–Hypromellose/hydroxypropyl'methylcellulose'chemical'composi>on'differences'are'dis>nguished'only'by'type,'which'is'defined'in'compendia'monographs,'and'are'based'on'methoxy'and'hydropropoxy'content.''Viscosity'is'a'physical'parameter'used'to'differen>ate'grades'within'a'type.'

Hypromelloses'ORAL' Capsule,'sustained'

ac>on'3NXW29V3W

0'670.04'mg'

Hypromellose'2208'(15000'mPa.s)'

ORAL' 'Capsule,'sustained'ac>on,'hard'gela>n'

Z78RG6M2N2'

2.771'mg'

Hypromellose'2208'(15000'mPa.s)'

ORAL' Tablet,'sustained'ac>on' Z78RG6M2N2'

480'mg'

Hypromellose'2208''(60000'mPa.s)' ORAL' Tablet,'extended'release' 2F7T07H9ZD' 175'mg'

Hypromellose'2208'(80000'–'120000'mPa.s)'

ORAL' Tablet,'extended'release' 9004653' VM7F0B23ZI' 54'mg'

Hypromellose'2910'(15000'mPa.s)' ORAL\21' Tablet' 288VBX44JC' 0.75'mg'

Hypromellose'2910'(15000'mPa.s)' ORAL' Tablet,'enteric'coated'

par>cles' 288VBX44JC' 445'mg'

Hydroxypropyl'methylcellulose'2906' ORAL' Tablet,'film'coated' 9004653' Pending' [none]'

Hydroxypropyl'methylcellulose'2906' ORAL' Tablet' 9004653' Pending'' 50'mg'

Current(Precedence(of(Use(Limit((based(on(Safety(data)'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

670.04'mg'

What can be done to assess the safety of a CoPE for an

intended use/level and support the use of CoPEs not

listed in the IID?

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Independent Evaluation: the IPEC New Excipient Safety Evaluation Procedure

•  Excipient manufacturers submit dossiers in DMF format to independent expert committee who evaluates:-  Newness  Bridging arguments  Safety and analytical data and rationale for co-

processed excipient safety

•  FDA/global health authority would consider results during drug registration  Retain authority to approve final drug product

•  Positive appraisal from independent expert committee

limits risk of FDA rejection of drug based on excipient  Could encourage innovation & minimize risk for

pharmaceutical company

Excipient Expert Committee Objectives

•  Evaluation limited to safety for specific intended uses and exposure levels  Use FDA criteria (US) and ICH Safety

Evaluation Criteria (ex-US) as basis for review  Level of “Newness” is determined to evaluate

the level of data needed  Include composition profile and analytical

data in evaluation  CMC safety issues other than composition

should be evaluated separately (e.g. IPEC/GMP audit)

Recent Use of the IPEC NESEP & NF Monograph

•  Ethylcellulose Dispersion – Type B –  New draft NF Monograph for a complex type of liquid

co-processed excipient

–  Plasticized Ammoniated Ethylcellulose Dispersion – different formulation and manufacturing process than Ethylcellulose Aqueous Dispersion NF

–  Contains Oleic acid and either MCT or DBS

–  Forms Ammonium Oleate during processing which reverts back to Ammonia and Oleic acid upon coating

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Recent Use of the IPEC NESEP - NF Monograph

•  Ethylcellulose Dispersion – Type B (cont.) – USP Expert Committee used concepts of

PF Stimuli Article on Co-processed Excipients (PF 35 [4] July-Aug. 2009) when evaluating this draft monograph

•  First liquid co-processed excipient to be evaluated using these concepts

•  Resulted in a flexible approach to allowing for the use of multiple plasticizers within the same monograph for different grades


•  Ethylcellulose Dispersion – Type B (cont.) –  Product had already been in commercial use for

years (listed in IID) but higher levels of use and slightly different grades were needed

–  IPEC NESEP was utilized to assess the additional toxicology data (90 day sub-chronic study & genotox) that had been developed on one grade and analytical studies performed on all grades to understand what chemistry occurs in the process to support the safety bridging argument why further tox studies were not needed


•  Ethylcellulose Dispersion – Type B (cont.) –  IPEC NESEP Expert Committee provided a report

to support significantly higher levels of use than already listed in the IID for oral applications based on the tox and analytical data

–  Report also supported slight modifications to the Oleic acid used in the formulation – animal vs. vegetable grade

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Recent Use of the IPEC NESEP – Co-processed Excipient

•  Co-processed Polyvinyl acetate phthalate – TiO2 (PVAP-T) –  TiO2 incorporated intimately into the PVAP (NF) polymer

matrix during the mfg. process

–  IPEC NESEP was utilized to assess the existing toxicology data that had been developed for PVAP (NF) itself and the detailed analytical studies and minor tox studies performed on PVAP-T to demonstrate that no chemistry occurs in the process used to produce PVAP-T

–  Acute and genotox studies were performed on PVAP-T to provide some basic tox information on the PVAP-T itself and submitted for IPEC NESEP review with dossier


•  Co-processed Polyvinyl acetate phthalate – TiO2 (PVAP-T) –  This analytical assessment and minor set of tox

studies supported the safety bridging argument why further significant tox studies were not needed

–  IPEC NESEP Expert Committee provided a report to support the use of PVAP-T in drugs for oral applications based on the existing tox data on PVAP and the analytical/tox data on PVAP-T


•  StarCap 1500 –  Corn Starch and Pregelatinized Corn Starch are co-

processed together to form a unique material with enhanced properties not achievable by using a simple mixture

–  IPEC NESEP was utilized to assess the limited toxicology data that existed for each component individually, historical human use information of each component and the detailed analytical studies and minor tox studies performed on StarCap 1500 to demonstrate that no chemistry occurs in the process used to produce StarCap 1500

–  Acute and genotox studies were performed on StarCap 1500 to provide some basic tox information on the StarCap 1500 itself and submitted for IPEC NESEP review with dossier

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•  StarCap 1500 –  This analytical assessment and minor set of tox

studies supported the safety bridging argument why further significant tox studies were not needed

–  IPEC NESEP Expert Committee will be providing a report shortly to support the use of StarCap 1500 in drugs for oral applications based on the existing limited tox data on each starch component and the analytical/tox data on StarCap 1500

New IPEC Concepts •  Initial discussions have taken place with USP

concerning the use of the “pending standards” approach for new monographs for excipients (including co-processed excipients) which have gone through the IPEC NESEP

•  IPEC Safety Committee plans to submit a proposal to USP to consider this approach during 2013.

•  Could encourage innovation and reduce fear to use these materials the first time in a drug

Conclusion •  Very few new chemical entities (NCEs) will be introduced

as new excipients

•  Co-processed excipients are the trend to introduce new functionalities and minimize variability with minimum data burden

•  Risk assessment should be on a case by case basis

•  IPEC New Excipient Safety Evaluation Procedure should be used for co-processed excipients to reduce regulatory uncertainties

•  IPEC is developing a guideline on Co-processed excipients to further clarify an appropriate approach

coprocessed excipient workshop (drs revisions) bac rcm …avicel cl611 fmc coattrited, cospray dried...

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