Things You Should Know Final

8/3/2019 Things You Should Know Final

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Topical Dermatological Formulation Development

Put your molecule in good hands.

Things You Should Know


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Formulation Development o Topicals is Dierent Pg 1

Developing a Target Product Profle is Important Pg 2

How to Select the Topical Dosage Form Pg 3

Defnition o a Successul Formulation Pg 4

The Need or Multiple Excipients Pg 5

The Formulation Development Process Pgs 6-7

Challenging Analytical Method Development Pg 8

Prototype Screening Using In Vitro Skin Penetration Studies Pg 9

Selection o The Lead Formulation Pg 10

Clinical Manuacturing, Tech Transer & Scale Up Pg 11

About Dow Pgs 12-13

Dermatological Product Development Flowchart Back Cover

Things You Should Know


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There are important issues to consider as you contemplate develop-

ment o a topical dermatological product. You may already have

experience with oral or parenteral products, but there are challenges

and issues which are unique to development o topical ormulations.

A topical ormulation must be aesthetically pleasing, in addition to

being both physically and chemically stable, and this may require

numerous excipients. The ormulation must allow or optimal

penetration o the drug into the skin, a complex tissue. Skin pH is

approximately 5.5; thus the pH o the ormulation may change ollow-

ing application to the skin. This brochure is based on our experience

and exclusive ocus at Dow Pharmaceutical Sciences in developing

topical dermatological ormulations since 1977.

Formulation Development o Topicals is Dierent

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The frst step in a successul topical ormulation program is todevelop a Target Product Profle, describing the key desired product

attributes. The profle will include the intended therapeutic indication,

the preerred dosage orm (cream, gel, ointment, spray, e.g.), the

anticipated product strength (% active pharmaceutical ingredient or

API), the desired release profle and skin penetration goals, packaging,

target shel lie, and the desired cosmetic/aesthetic properties. While

not true or orals and parenterals, the cosmetic elegance o a topicalormulation (i.e., eel, color, scent, spreadibility, absorbability, etc.) is

o great importance in topical dermatologic products and is oten key

to the success o the product. The ease and/or speed with which a

topical product can be rubbed in, or avoidance o a greasy or sticky

eel, or example, can be key. Managing these actors is one o the arts

o topical ormulation development.

Pg 2

Developing a Target Product Profle is Important

Intended Therapeutic Indication

Preerred Dosage Form

Anticipated Product Strength

Desired Release Profle and Skin Penetration Goals

Cosmetic/Aesthetic Properties

Target Shel Lie


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Flexibility regarding dosage orms enhances the chance o success

or development o a stable and elegant ormulation. During early

development, the target product profle is oten refned based on

solubility, stability and/or compatibility data, as these data may

determine the dosage orm. I the API is amenable to dierent dosage

orms rom a solubility and stability standpoint, the dosage orm may

which ormulation allows or optimal penetration o the API to the

the therapeutic indication. I all dosage orms developed are similar

in their stability and skin penetration characteristics, the dosage

orm may ie selected based on compatibility with the disease state,

cosmetic properties, consumer testing and marketing considerations.

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How to Select the Topical Dosage Form


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Deinition o a Successul Formulation

A successul topical dermatological ormulation can be considered

to be one that satisies the target product proile and is 1) physically

and chemically stable (adequate shel lie), 2) releases API rom the

ormulation and delivers it into the skin as required or the target

indication, 3) is cosmetically elegant and acceptable to patients,4) contains only excipients that are necessary, FDA-approved or

acceptable rom a regulatory perspective, and acceptable or the

disease state, 5) is easy to apply and compatible with the desired

packaging, and 6) can be manuactured with a process that is

scalable to commercial levels. There are challenges during almost

every development program. It is important to be able to anticipate

problems, prevent them where possible, and to understand how tocorrect those that do occur.

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Unlike oral and parenteral dosage orms, topical dermatologicalormulations oten require many excipients. Each excipient should

be justifed by unction and need. Those that may have activity or

the disease state or that could inuence the vehicle eect (thereby

reducing chances o clinical success) should be avoided. A novel

excipient should not be used i an older, well-characterized, inactive

ingredient which is listed on the FDA Inactive Ingredients Database

would work just as well. I a novel excipient is used, it is probablethat FDA will require additional saety data, which will increase the

nonclinical study burden (time and cost). Solvents, preservatives,

antioxidants, suractants and other agents are used to overcome

solubility, stability, or skin penetration challenges and are selected

based on the physiochemical properties o the API. Cosmetic elegance

necessary or patient acceptance and compliance may require

additional excipients. With so many excipients, interactions may

occur with each other or with the API, ultimately resulting in odor,

discoloration, loss o viscosity, or loss o potency. In addition, it is also

important to select well-characterized excipients whenever possible,

in order to avoid uture issues with variability.

The Need or Multiple Excipients

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Dow Pharmaceutical Sciences has developed a ormulation

development process which has proved to be very successul or

our clients. A team rom our Formulations, Analytical Sciences,Drug Delivery, and Project Management groups (with consultation

rom Nonclinical Toxicology, and Regulatory & Clinical Aairs) work

together to custom design ormulations based on the physio-

chemical properties o the API, with one eye on the desired cosmetic

attributes required or the clinical indication and the other on potential

regulatory considerations.

Pre-ormulation studies are conducted initially and orm the basis

or rational ormulation design. The solubility o the API in dierent

solvents (water, water miscTe p-


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Based on this data, multiple dierent prototype ormulations based

on dierent solvent and excipient systems are developed. This is done

in order to minimize the need or additional ormulation developmentat a later stage. Each topical dosage orm has its special challenges.

For example, emulsions (creams and lotions) can be thermodynamic-

ally unstable lat96(elo(der t)5.9(o)-separrmula. A varie.9(ot)-9 o(der t)echniquesns) ca.9(.)9.9( )]TJ


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Topical ormulations oten contain multiple excipients and

preservatives, as well as potentially low levels o API, sometimes making

the development o stability-indicating and impurity-tracking methods

challenging. The semisolid environment can accelerate degradation or

other reactions. Rates o degradation can vary signifcantly based on

the ormulation matrix. Extractions can also present challenges dur-

ing topical ormulation development. An API method must oten be

modifed in order to be appropriate or assay o a topical ormulation

containing the API. R&D methods can be developed, qualifed or GLP

nonclinical studies, and then validated as appropriate or GMP supplies

or Proo o Concept (POC) clinical studies in a step-wise ashion, as

needed or the particular stage o development. Full validation can

then be completed at Phase III.

Challenging Analytical Method Development

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In vitro penetration studies are used to screen prototypes to ensure

that the API is released rom the ormulation and penetrates the

target tissue as required or your clinical indication. A ormulation

optimized or drug penetration is more e cient and requires lower

concentrations o API, thus reducing cost o goods. This can also result

in a product o lower irritation potential, and maximum opportunity

or clinical e cacy. At Dow, human abdominal skin rom elective

surgery rom a single donor is used or these studies. This provides test

results superior to cadaver skin and avoids donor-to-donor variation.

Multiple prototypes can be compared in one study using Diusion Cell

Systems (Franz Static or Bronaugh Flow-Thru, depending on desired

study design).

Prototype Screening Using In Vitro Skin Penetration Studies

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A lead ormulation is selected based on the chemical and physical

stability data rom accelerated stability studies, on in vitro skin

penetration data, on the assessment o cosmetic elegance and

aesthetic properties, and on results o animal e cacy testing that

may be conducted (dependent on availability o predictive animal

models).

In topical dermatological product development programs, it ispreerable that the lead ormulation selected or non-clinical and

clinical studies be very close to the fnal commercial ormulation.

Signifcant ormulation changes made later in development will likely

trigger the need or bridging studies or an FDA request to repeat

potentially expensive and time consuming non-clinical studies.

Thereore, i optimization o the ormulation (beyond minor changes)

is considered necessary, it should be conducted at this stage, prior toentering into potentially costly GLP nonclinical studies.

Selection o the Lead Formulation

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During ormulation development a process should be developed

which will later allow the ormulation to be scaled up to large batch

sizes at a commercial manuacturing site. With topical ormulations,

the manuacturing process can inuence both stability and product

perormance. When a ormulation is transerred to a commercial

manuacturer, depending on the type, size and mixing capacity o the


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Experience With Many Indications and Dosage Forms

Since 1977, Dow has ocused exclusively on topicals and has developed

more Rx topical ormulations than any other company in the world.

Most projects are or NCEs which can be di cult to ormulate. From

this ocused experience we understand the issues and challenges

and we know how to lead you through the process. By working with

Dow, you gain access to all our experience and this provides your best

chance or success. While other companies may provide dermatological

ormulation development services, most do not have the same ocus

on topicals, wealth o experience and history o success.

Dow has developed topical ormulations or psoriasis, acne, atopic

dermatitis, actinic keratosis, rosacea, wrinkles, ungal inections,womens health, topical pain, wound healing, warts and other

dermatological conditions. A range o disease-compatible dosage

orms are developed as part o our ormulation process, so we have

considerable experience developing aqueous and non-aqueous gels,

ointments, creams, lotions, oams, sprays, shampoos, solutions, and

suspensions.

Topical Dermatological Formulation Experience

About Dow

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Each year we develop ormulations or 20-25 new clients, including

many start-ups. We understand the needs o small and large comp-

anies. Dow clients come rom the USA, Europe, Australia, Canada,

China, Israel, Japan, and Taiwan. Several clients are now selling

products ormulated at Dow including ClindagelTM, Clobex SprayTM,

Cutivate LotionTM, Desonate GelTM, MetroGel 1%TM, ZianaTM and AcanyaTM

to name a ew.

All services needed to progress your topical ormulation through

development, testing, manuacturing, labeling and delivery to clinical

sites are available at our acility in Petaluma, Caliornia. Coordinated

by a Dow project manager, in one location you have a ull team ospecialists to provide ormulation development and optimization, in

vitro skin penetration studies, analytical method development and

validation, scale-up and process development, stability, manuacturing

o toxicology and clinical supplies, labeling and distribution to your

clinical sites, and regulatory support. Our goal is to save you time and

to provide your best chance or success.

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Experience Working With a Broad Range o Clients

Everything You Need in One Location


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Dow Pharmaceutical Sciences, Inc.

1330 Redwood Way

Petaluma, CA 94954-1169

Tel: 707.793.2600www.dowpharmsci.com

2009 Dow Pharmaceutical Sciences, Inc. All rights reserved.

Drug Discovery

API Selection

API Synthesis

Pre-FormulationStudies

Selection oLead Formulation

Conduct o GLPTox Studies

Preparation andSubmission o IND

TopicalFormulation

Development

RegulatoryConsulting orIND-EnablingTox Studies

Manuacture oGLP Supplies or

Tox Studies

Screening(stability & in vitrotissue penetration

studies)

Manuacture andLabeling o GMP

Supplies(PhI and PhII)

Conduct oPhase II (Other)Phase I (Saety)

clinical trials

GMP Manuactureo Phase III

RegistrationBatches

Tech Transer toCMO (commerical

manuacturer)

Phase IIIClinical Trials

Manuacturing oCommercial Product

DowCapabilities

Dermatological Product Development Flowchart

Submission oNDA & Approval

Documents

Things You Should Know Final