new guidelines multiple and key topics stakeholders; about ... · ratios of components may vary...

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International Pharmaceutical Excipients Council Collaborative solutions for excipient industry stakeholders

Multiplestakeholders;one objective.

New Guidelines and Key Topics

aboutCo-processed

ExcipientsDave Schoneker

Vice Chair – Maker & Distributor Relations – IPEC Americas

[email protected]

Copyright © 2015, All Rights Reserved IPEC-Americas 2

Why Co-processed Excipients?

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.

Engineered or Designed for Purpose!

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Copyright © 2015, All Rights Reserved IPEC-Americas

Types of Excipients

Existing “Single” ExcipientsMixtures or Blends of Existing Excipients Co-Processed Excipients (CoPEs) Physical synergistic combination only No chemical change

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 Residual solvents or residual moisture

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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 (“un-engineered 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

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CoPEs (IPEC definition)

Combination of two or more compendial or non-compendialexcipients (using a manufacturing 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 made from compendial components6

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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 involves the same processes used for single component excipients or formulations

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Examples of CoPEs

Name Supplier Ingredient % Manufacture

ProSolv JRS Microcrystalline cellulose , MCC 98 Co-spray driedColloidal Silicon Dioxide 2

PVAP-T ColorconPolyvinyl acetate phthalate, PVAP 90 TiO2 incorporated

in PVAP manufactureTitanium dioxide 10

Ludipress BASF Lactose 96.5Polyvinylpyrrolidone, PVP 3.5

Starlac 100 Meggle a Lactose monohydrate 85 Spray dried compoundMaize starch 15

Xylitab 100 Danisco Xylitol 96.5 GranulatePolydextrose 3.5

Xylitab 200 Danisco Xylitol 98 GranulatePolydextrose 2

StarCap 1500 Colorcon Corn starch 85-95 Co-spray driedPregelatinized starch 5-15

Advantos FS SPI Fructose 95 CodriedStarch 5

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New or Novel Excipients (IID)

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

x.cfm

• CoPEs are sometimes not listed as such in the IID, but may be listed as separate components

• IPEC-Americas supports FDA upgrade of IID –current Issues with the RTR Guidance

* 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”.

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Are CoPEs New or Novel?

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

*Hence IPEC definition:- “without significant chemical change”

Components Not novelProcesses Not novelComponent combinations Not novelPhysical form NovelFunctionality/utility Novel

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Newness in Terms of Patient Safety

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

“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.”

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Regulatory Aspects of Co-processing

However, the perceived regulatory barriers outweigh reality Pharmacopoeial listing minimizes barriers to adoption once there is a

precedence of use Silicified MCC and Ethylcellulose Dispersion Type B are recent

monographs from NF31. Avoidance is 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 – analytical data can provide proof• Processing similar to that of single excipients in pharmaceutical products• Safety data not typically be needed

Cannot simply treat a CoPE as if it were a mixture…it is a unique entity which should be assessed on it’s own…...when first used CoPEs are “Novel Excipients”

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Monographed Co-processedExcipients (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 and sucrose (>95%) Sugar Spheres - 62.5-91.5% sucrose, chiefly with starch, color permitted


Technological Benefits of Co-processing

Synergy Functionality not achievable with corresponding blend

Complementary Balancing properties e.g. 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 are key to building improved quality into products and processes

in the future Excipients designed for purpose

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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

Regu

lato

ry B

urde

n

Existing ExcipientsNew CoPEs

New IID IPEC CoPE GuidelineIPEC NESEPUSP


IPEC-Americas Co-processed Excipients Guide

To be published by Mid - 2015

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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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Content of the Guide

Preamble1. Introduction2. Co-processed excipients3. Co-processed excipient manufacturers

3.1 Co-processed excipient development

3.2 Co-processed excipient specification

3.4 Analytical method development3.5 Composition profile3.6 Stability3.6 Safety concerns3.7 Novel co-processed excipients &

patient safety3.7.1 Safety Bridging3.7.2 IPEC-Americas’ New Excipient

Safety Evaluation Procedure

3.8 Manufacturing issues3.9 Regulatory Affairs3.10 Quality by Design3.11 Provision of samples3.12 Pharmacopeia monograph

4. Co-processed excipient users4.1 Co-processed excipient technical

data package4.2 Regulatory & Safety4.3 Excipient Manufacture4.4 Fitness for Purpose4.5 Supply

5. Summary

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Analytical Methods

A supplier needs to be able to confirm that the composition is within acceptable limits - considerations: 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 a supplier simply uses the results from in-process monitoring to release the excipient, they 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.

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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.

A supplier may not test or declare the composition of every lot, but they need to be aware of what it should be, and what, if anything, is changing with time.

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Co-processed Excipient Stability

As with any excipient a supplier needs 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 what safety concerns should a supplier address for a new co-processed excipient? Most likely a supplier will not need to resort to animal studies

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

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

A supplier does need to demonstrate that they have not created any new covalently bonded materials.

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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

ount

of S

afet

y D

ata

Degree of Newness

Co-processed (IID) Excipients

IID ExcipientsMixtures of IID Excipients

Chemically Modified ExcipientsNon-IID Excipients

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Bridging Studies

How to demonstrate that new covalently bonded materials have not been formed?

Can use spectroscopic or other analytical methods, e.g: 1H NMR, 13C NMR FT-IR NIR Raman, etc.

However, associated changes with e.g. hydrogen bonding, and/or ionic interactions, and possibly hydrophobic interactions must be anticipated.

Using ProSolv® as an 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.

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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, only if necessary. Option for IPEC-Americas? New Excipient Safety

Evaluation Procedure (NESEP). Submit data to FDA in Drug Master File (U.S.).

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Less Toxicology Data needed 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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Independent Evaluation: the IPEC-Americas 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

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Recent Use of theIPEC NESEP – Co-processed Excipient

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-Americas 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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Recent Use of theIPEC NESEP – Co-processed Excipient

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 has provided a report 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.

This report has been supplied to customers for use in the regulatory submissions.

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New Concepts

IPEC-Americas is working with the IQ Consortium to develop a new process for an independent evaluation of the safety of new excipients and new co-processed excipients.

The team is working to: Develop a process for an independent review of the

excipient for a specific intended use and exposure level – not part of the drug approval.

Meet with the FDA to discuss the concept of an independent review process.

Expand this thinking to other countries once established in the U.S.

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Summary

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.

The regulatory assessment of Co-processed excipients should be based on the unique new CoPE. CoPE’s cannot simply be treated like a mixture.

Risk assessment should be on a case by case basis.

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

IPEC-Americas new Co-processed Excipient Guide can be helpful to develop appropriate supporting information for the use of a CoPE.

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Questions?

Thanks to Brian Carlin & Chris Moreton

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new guidelines multiple and key topics stakeholders; about ... · ratios of components may vary...

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