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ExcipientFest 2017

Update On Novel Excipient Qualification Program

Dave Schoneker Nigel Langley 1

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FDA Critical Path Innovation Meeting

Novel Excipient Qualification Program

IQ/IPEC-Americas Novel Excipient Working GroupFriday 10 March 20173:00 PM – 4:30 PM ET

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Our Organizations

• International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) http://iqconsortium.org• Technically-focused organization of industrial pharmaceutical and

biotechnology companies with a mission of advancing science-based standards and regulations for pharmaceutical and biotechnology products worldwide

• International Pharmaceutical Excipients Council (IPEC-America) http://ipecamericas.org/• Industry association that develops, implements, and promotes

global use of appropriate quality, safety, and functionality standards for pharmaceutical excipients and delivery systems

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IQ/IPEC Americas Novel Excipients Working Group in attendance:

William P. Beierschmitt Research Fellow Drug Safety R&D Pfizer

Lorrene A. Buckley Sr. Research Fellow Toxicology & Drug Disposition Eli Lilly and Company

Thiago Carvalho Sr. Research Investigator Bristol Myers Squibb

Mitchell Friedman Global Development Lead Takeda

Keith Horspool Material & Analytical Sciences Boehringer Ingelheim

Nigel Langley Director Global Technical Marketing & Technical Service

BASF Corporation

Raja Mangipudy DSE & DSE Therapeutic Area Head CV/Virology BMS

Jeffrey Pitt Senior Product Stewardship ManagerDow Pharma & Food Solutions

Andrew Prpich Sr. Scientist Drug Product Design Pfizer Corporation

Eric Schmitt Director Formulation Sciences Abbvie

David Schoneker Director of Global Regulatory Affairs Colorcon

Philip Sherratt Sr. Principal Scientist Toxicology Celgene

Evan Thackaberry Assoc. Director & Therapeutic Area LeaderGenentech

IQ/IPEC Americas Novel Excipients Working Group remote participants:

Shobha N. Bhattachar Small Molecule Design & Development Eli Lilly Company

Stefan Schulte Regulatory Toxicology Chemicals II BASF

Katherine Ulman Global Regulatory Compliance (retired) Dow Chemical Corporation

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Agenda Topics• Determination/classification of novel excipients

• Reasons for and benefits of novel excipients• Patient perspective

• Product Applications

• Technology/Supply needs

• Evolution of novel excipients

• Definition of novel excipients and types of novel excipients

• Challenges to the development of novel excipients• Pharma

• Excipient developer

• Anecdotes on impact

• Proposed non-clinical safety packages• Description of base case for NCE excipients and

• potential variations based on excipient types (with example materials)

• Proposed steps in a potential qualification process

• Summary and Questions/Discussion

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Reasons for and benefits of novel excipients: Patient Perspective

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Access to new medical entities to treat unmet needs – see Product requirements

Patient-centric products : Address specific needs for pediatrics and geriatrics

Palatability, ease of swallowing, ability to dose titrate, alternative dosage forms

Improved compliance. Controlled release to reduce frequency of administration and extend duration – e.g. depot injections

Different product options – alternative routes of delivery

Improved ease-of-use/use. Reformulationof products improve product characteristics – no need to take with food, no need for refrigeration andto improve safety profiles (replace older excipients e.g. solvents)

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Product ApplicationsEnabling Delivery of poorly soluble oral products. Current portfolio at least 10X less soluble than portfolios in the 1980s.

Overcoming current challenges with biologics – highly concentrated, high viscosity formulations, aggregation, stability. Alternatives to more complex and costly wearable infusion devices

Delivering important parenteral products. Increased solubility up to 5000-7000 fold.

Injectable ocular controlled release. Duration increase from days to years. By 2020 ~ 5 million people will have impaired vision due to age-related macular degeneration and diabetic macular edema.

Addressing future challenges - for drug targeting (e.g. cancer), peptide/protein delivery and for delivery of recombinant nucleic acids

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Technology/Supply Need

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Improved product processing for more challenging complex formulations

Enable more efficient and effective alternative processing – Continuous Manufacture. Improved material properties key to future success

Potential to facilitate more futuristic dosage form fabrication techniques such as 3D printing. Current interest in exploring the technology as a potential means to deliver “precision medicines”

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Evolution of New Excipients

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Increased “Design for Purpose”

Increased Functionality

Extending product options

Improving manufacture

Enabling new therapies

Novel Excipients will generally have better knowledge and

better characterization

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Novel Excipients – DefinitionUS FDA

A material or a composition that has not been previously used in an approved drug product in the US (i.e. not listed in FDA Inactive Ingredient Database (IID)) for the intended route and level of administration.

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Types of Novel Excipients• New Chemical Entities (NCE)

• A modified excipient (generally polymers of the same family with varying chain length/molecular weight/substitution).

• A new co-processed excipient made from two or more previously approved excipients.

• Previously used excipient which is employed in a new route of administration or patient population.

• Excipient used in an approved drug product but at higher level of use than has been previously listed in the IID.

• Approved food use/cosmetic use ingredient 11

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Why aren’t we innovating? Pharma Challenge• Industry has no way to know if a novel excipient

is acceptable for use early in development.

• No data available prior to NDA approval –accessibility only after the NDA.

• In the face of uncertainty there is limited incentive to use and it is easy to turn new excipient innovations away/down .

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New Excipient Development Process -Excipient Developer Challenge

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Identification & Identificatioselection of polymer class • ~ 1,000

polymers synthesized

Optimization of selected polymer class to identify 2 to 3 candidates (MW and degree of substitution)

Toxicology Toxicologystudies • based on US

FDA Novel excipients Guidance

Prior t to launch • ~ 7 years

TOTAL OF 15 YEARS!

Development /Launch Timelines (years)

NDA testing/submission

/approvalCommercial

sales

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Anecdotes – Pharma – drugs failing, excipient supplier –novel excipients stalled, at huge risk regarding future investment

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Nonclinical safety assessment: data requirements are proportional to “degree of newness”

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NCEA

mou

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ety

Dat

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Degree of Newness

Co-processed (IID) ExcipientsIID Excipients

New Grade of an Existing Family

Chemically Modified Excipients

New Use of an Existing Excipient*

* Higher level of use and/or different route of delivery

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Safety Assessment Considerationsfor New/Novel Excipients• No human or nonclinical experience (publically available).

• “De novo” safety assessment required (as for a NCE).

• A “base package” of nonclinical studies could support a potential “qualification process” to enable early clinical use of a novel excipient.

• Consistent with regulatory guidance and 3R concepts• ICH: M3(R2), S2, S5, S7A, S10• FDA guidances, Nonclinical studies for safety evaluation of:

Pharmaceutical excipients & Reformulated drug products / products intended for administration by alternate route

• Nonclinical data and interpretation thereof used to justify the “context of use” for the novel excipient in early development (eg, limitations on patient populations, duration of use, maximum dosage)

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Proposal: A “base” nonclinicalsafety assessment packageInitial assessment would include the following:

• In silico QSAR evaluations of genetic toxicity,

• Genotoxicity: bacterial reverse mutation, chromosomal aberration (eg. in vivo micronucleus),

• Repeated dose toxicity: 30-day studies, two appropriate species (rodent/non-rodent) by the intended route of clinical administration,

• Safety Pharmacology: CNS, respiratory, CV (including hERG),

• ADME studies (to characterize toxicokinetics &metabolism),

• Pilot embryo-fetal development studies (rodent, rabbit),

• Phototoxicity assessment (per ICH S10),

• Route-specific bridging studies (for non-oral excipients).

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Nonclinical safety assessment:New/novel excipients (cont’d)

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• Longer term non-clinical safety requirements for new excipients would still be required based on the information needed to support the later clinical program and the marketed product.

• Such data could be added to the initial qualification.• As for the Biomarker Qualification Process, it might be

possible to add data from longer term nonclinical studies to broaden COU (context of use) recommendations for materials that undergo the “excipient qualification process”

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Other Types of New/Novel Excipients (Non-NCE)• The current system presents hurdles for the use of these Non-

NCE types of New/Novel excipients as well

• Many of these excipients could provide significant value to patients and the industry (e.g. new manufacturing )

• In most cases, a significantly reduced amount of new safety information typically needs to be generated to support the intended uses

• Once developed, it is very difficult to get a sponsor to utilize these excipients

• Many years can go by without anyone including these excipients in a new drug product even though they would provide significant product quality benefits 19

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Excipient Innovation –Co-processedStarCap® 1500• unique co-processed (spray-dried)

mixture of corn starch and pregelatinized starch.

• inert free-flowing with disintegration and dissolution properties independent of media pH.

• Individual ingredients currently used in oral solid dosage forms (and bulk foods). No additional components due to co-processing.

• Co-processing yields better physical properties versus a simple blend.

• Launched in 2007 with DMF detailing analytical studies and tox bridging arguments.

• No current U.S. NDA or ANDA approval (10 years); however, approved in EU and other countries!

20NOTE: of the approx. 25 co-processed excipients launched, regulatory acceptance has been mixed

no new covalent bonds

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Excipient Innovation – Variation

• AFFINISOL™ HPMC HME = hypromellose • Designed for amorphous solid dispersions via hot-melt extrusion (HME) • No current US NDA or ANDA approval (3 years) 21

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Excipient Innovation - Variation

220

4

8

12

16

20

24

28

32

16 18 20 22 24 26 28 30 32

% H

ydro

xypr

opyl

Subs

titu

ion

% Methoxyl Substitution

P-Series

HPMC HME28-day tox study in rats

Impurity profileJ-Series

USP 1828[IID oral max]

K-SeriesUSP 2208

[IID oral max]

E-SeriesUSP 2910

F-SeriesUSP 2906

Methylcellulose

2 ADME 7 Acutes9 Irritation/sensitization17 Repeat Dose (<1 year)1 Carcinogenicity2 ICH 4.1.3 1 Genetox3 human studies

FDA Food division approved HPMC substitutions in gray shade; 20 g/day

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Safety assessment considerations for different types of novel Excipients• Same qualification paradigm applies to all types of excipients

• New uses of existing materials (eg, new routes, durations, target populations …)

• Co-processed existing materials• Materials with high structural similarity to (i.e. variants of) existing

materials (e.g., polymers)

• Nonclinical safety testing needs would vary, depending on the data and experience already available for established comparable materials.

• Approach• Clarify what is known (experience) as it relates to proposed setting• Identify information gaps• Identify alternative sources of relevant/appropriate information• Conduct “bridging” studies, as needed (nonclinical, clinical)

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Data requirements are proportional to the “degree of newness”

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NCE

Am

ount

of S

afet

y D

ata

Degree of Newness

Co-processed (IID) ExcipientsIID Excipients

New Grade of an Existing Family

Chemically Modified Excipients

New Use of an Existing Excipient

The data package needed is a case-by-case decision depending on what is known, the context of use, and identified or toxicological hazard

HPMC HME

StarCap1500

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Proposed process• Sponsor submits request to FDA for novel excipient qualification

for the intended route of administration and level of use• Provide rationale for proposed safety package

• When appropriate include independent expert review

• FDA assembles appropriate committee of experts to perform the review and collaborate with sponsor to determine appropriate submission package

• Sponsor submits all appropriate information to support intended use

• FDA expert committee reviews submission package as it relates to intended use to determine acceptability for qualification

• FDA generates summary report of findings and provides to Sponsor

• If excipient qualified for intended use, then FDA adds excipient and intended use information to a published list on FDA website

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Next Steps/Conclusions/Summary• The proposed novel excipient qualification process is a critical

step towards incentivizing and sustaining investment in innovative new materials

• Regulatory recognition of these important new materials early in development will encourage more widespread consideration of their application for: enabling new modalities, improving product performance and supporting new manufacturing processes

• The novel excipient qualification non-clinical safety packages will be designed to support a specific context of use in early clinical programs

• Review by FDA and communication of information on novel excipients across the industry will prevent additional redundant, repeat, non-clinical studies & reduce animal use

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Questions

• Is the FDA willing to support an initiative to develop a Novel Excipient Qualification Process as outlined?

• What can IQ/IPEC-Americas do in support of FDA to facilitate the development of such process?

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Meeting Outcome and Feedback

• Very positive engagement with the FDA ( ~ 40 attendees).

• A high level of interest shown.

• A follow up meeting is in the process of being arranged.

• It has been communicated that this topic will be given high priority by the agency.

Stay tuned for further updates !

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