KLPresentation (Alain KHAIAT)

8/6/2019 KLPresentation (Alain KHAIAT)

1/93

The ASEAN Cosmetic Directive

andWhat it means ?

Efficacy and Quality requirements

Alain KHAIAT, PH.D.

Vice President R&D Johnson & Johnson Asia Pacific

EU Senior Expert on Post Marketing Surveillance


2/93

Article 8: Product Information Package (Dossier)

Under General provisions, to keep the products

technical and safety information readily accessible to the

regulatory authority

To be kept at address specified on the product label

To be available in national language of, or languageeasily understood by, the regulatory authority



3/93

Product Information Package (contd)

Product formula (qualitative & quantitative)

(Name & Code & Name of supplier of perfume composition)

Raw material and product specifications

Method of manufacture complying with GMP

(ASEAN Guidelines)

Safety assessment of finished product & ingredients

Existing data on undesirable effects of product

Supporting data on claimed benefits

Cosmetic

GMP


Product safety

evaluationProduct

Efficacy


4/93

Methods of Analysis

To be made available to the regulatory authority upon

demand

Methods used by the manufacturer to check

ingredients against the Certificate of Analysis

Criteria for microbial content of products and chemicalpurity of ingredients & methods for checking compliance

to these criteria



5/93

New responsibilities for the

industry

Safety evaluation

Product information

GMP and Quality requirements


6/93

New responsibilities (Safety evaluation)

Need to be satisfied that the product will not cause

damage to human health under normal or reasonably

foreseeable conditions of use (art.3)

Need to retain product & ingredient assessmentsresults in product information package

Some questions to ask

> What are the specific responsibilities? Safety evaluation guidelines

> How to conduct safety evaluation of product? Tests to conduct? In-house? Out-sourcing?

> How to obtain safety assessment results from supplier?

> How to analyze these safety assessment results?

> Any requirements for safety assessor or layout of documents?


7/93

New responsibilities (Product information)

To be kept on premises of company marketing the

product

Readily available to regulatory authority


> What information to obtain from supplier? And how?

> When will regulatory authority ask to see information?


8/93

New responsibilities (GMP)

All manufacturers to comply to Cosmetic GMP

ASEAN Guidelines for Cosmetic GMP:

General guideline for manufacturers to develop

internal quality management system and procedure


> How to gain awareness of the requirements?

> How to build up expertise? Internal training? Employ experts?Consultants?

> Costs of building up GMP program?


9/93

Product Safety


10/93

Approach for formulating Safe

Skin Care productsReview of ingredients to minimize known irritants and sensitizers

Elimination of unnecessary ingredients

Stability evaluation of ingredients as formulated

Utilization ofin vitro method to predict final formulation skin and eyeirritation

Utilization ofin vivo methods to predict final formulation skinirritation and sensitization, considering weather conditions and casualUV exposure

If needed, utilization of sensitive skin panel to confirm result ofin

vitro and in vivo testing, considering weather conditions and casualUV exposure

Premarket monitored consumer large scale testing

Postmarket monitoring of consumer responses and adverse eventreporting

From Harry Cosmetology 8th edition, page 765


11/93

Primary- Cumulative Irritation:

To determine the irritation potential of topical

product left on skin.

Sensitization (RIPT):

To determine the potential of a product to causeallergic contact response.

Photo-toxicity:

To assess the potential of ingredients to causelocalized irritant reactions when exposed to sunlight

Photosensitization:

To determine the potential of a product to cause

allergic contact response when exposed to sunlight.

Testing for SafetyTesting for Safety


12/93

Cumulative Irritation

25 volunteers

Occlusive patch applied for 24 hours for 3 weeks

RIPT - Predictive testing for skin sensitizers

100 - 200 volunteers

48 hr Patches - 3 weeks (10 patches)

Rest period - 2 weeks

Challenge 48hr at new skin site.

Safety TestingSafety Testing


13/93

Phototoxicity20 volunteers

1 dose

0, 24, hr exposure & patchesRead @ 48, 72 hr

Photoallergy25 volunteers, fair skinned

Induction phase twice/week for 3 weeks. Reading& irradiated 24 hrs after patching

Rest period 2 weeks

Challenge phase Patch at new skin site. Read @

24, 48, 72 hrs

Safety TestingSafety Testing


14/93

EYE MILDNESSEYE MILDNESS


15/93

Ocular SafetyOcular Safety

Suggested Test Criteria

Transepithelial Permeability

(TEP)

MDCK CellsCorneal Epithelium

MDCK cells grown to confluenceTight junctions between cells form an impermeablebarrierDye marker will not cross undamaged cell layer

In-vitro Screening: EC50 TEP Rating

2.20 or higher PASS

1.8 - 2.19 Borderline

1.79 or lower FAIL

EC50 = test product concentrationwhere 50% of the max amount ofdye to leak through the barrier into

the lower well.


16/93

Required Tests Criteria

In-Vivo Test:

Human Ocular Irritation Test Stinging at time of instillation

Which is not statisticallyhigher than sterile water control

Panel of 10 subjects Supervised by an ophthalmologist Subject focus on any minor discomfort

in their eyes after application of warmedtest products.

Measures sting, lacrimation, irritation

One eye receives a 10% concentration ofthe test substance and the other eye receivesdistilled water

When 5 subjects (or more) experiencelarger responses on test product than towater, the test product will generally failto be non irritating to the eye

Ocular SafetyOcular Safety


17/93

EfficacyT

esting


18/93

MOISTURIZATIONMOISTURIZATION


19/93

MoisturizationMoisturizationTest Subjects:Test Subjects:

Female adults, usually 20 to 55 yrs oldFemale adults, usually 20 to 55 yrs old

In good health, no allergy to cosmeticsIn good health, no allergy to cosmetics

Normal to Dry skinNormal to Dry skin


20/93

MoisturizationMoisturizationTest Design:Test Design:

Base size of 10 to 20Base size of 10 to 20

RandomizedRandomized

ControlControl untreated skin and/or benchmarkuntreated skin and/or benchmark


21/93

MoisturizationMoisturizationTest Site:Test Site:

4cm x 8cm rectangle on volar forearm4cm x 8cm rectangle on volar forearm

Usually 2 test sites per armUsually 2 test sites per arm

Product Usage:Product Usage:

0.1mL per test site0.1mL per test site


22/93

MoisturizationMoisturizationBefore the test:Before the test:

No leaveNo leave--on products 24 hours beforeon products 24 hours before

No caffeinated drinks 1 hour beforeNo caffeinated drinks 1 hour before

3030--minute acclimatization to roomminute acclimatization to room

conditionsconditions


23/93

MoisturizationMoisturizationInstrumental Evaluations:Instrumental Evaluations:

Baseline, 1, 4, 8, (12), (24) hoursBaseline, 1, 4, 8, (12), (24) hours

SkiconSkicon ConductanceConductance

TewameterTewameterTEWLTEWL

Visioscan Surface roughnessSurface roughness


24/93

MoisturizationMoisturizationSuccess Criteria:Success Criteria:

Increase in conductance vs. baselineIncrease in conductance vs. baseline

Higher increase vs. control/benchmarkHigher increase vs. control/benchmark

Reduction in TEWL vs. baselineReduction in TEWL vs. baseline

Higher reduction vs. control/benchmarkHigher reduction vs. control/benchmark


25/93

MoisturizationMoisturizationOther Considerations:Other Considerations:

For washFor wash--offproducts, need to do longeroffproducts, need to do longer

term studies e.g. 2 weeksterm studies e.g. 2 weeks


26/93

Claim:Claim: Moisturizes, hydratesMoisturizes, hydratesSuggested Tests/Data

Instrumental Skicon (based on

conductance) Corneometer (based on

capacitance)

TEWAmeter

Criteria

Increase in parameter

versus baseline, untreated

skin or benchmark (0, 2, 4,

6, 8, 24 hours, weeks)

Criteria

Decrease in trans-epidermal

water loss versus baseline,

untreated skin or

benchmark (0, 2, 4, 6, 8, 24hours)


27/93

Claim:Claim: Prevents symptomsPrevents symptoms

of dry skinof dry skin

Suggested Tests/Data

Derm Assessment Dryness

Scaling

Erythema

Instrumental Skicon/Corneometer

T

EWAmeter Erythema Index

Digital Photography

Self-Assessment

Irritation

Criteria

Improvement in grading vs.baseline, untreated skin or

benchmark

Improvement in parametervs. baseline, untreated skinor benchmark

Improvement in grading vs.baseline, untreated skin orbenchmark


28/93

Claims related to productsClaims related to products

which treat orpreventwhich treat orprevent

Acne and PimplesAcne and Pimples


29/93

Reaches deep downinto pores

Contains ablackheadfightingingredient

Preventsfutureblackheads

Oil Free

Wontoverdryyour skin

Removes oil, dirtand make-up

Non-comedogenic

Longlasting oilcontrol


30/93

Acne

Acne

Test Subjects:Test Subjects:

Female adults, usually 20Female adults, usually 20--35 yrs old35 yrs old


Mild to Moderate AcneMild to Moderate Acne


31/93

AcneAcne

Test Design:Test Design:


DoubleDouble--Blind, RandomizedBlind, Randomized

ControlControl vehicle and/or benchmarkvehicle and/or benchmark


32/93

AcneAcne

Test Site:Test Site:

Whole faceWhole face


Normal or habitual useNormal or habitual use

Usually 2x dailyUsually 2x daily


33/93

AcneAcne

During the study:During the study:

Use of skin care products with activeUse of skin care products with active

ingredients NOT allowedingredients NOT allowed


34/93

AcneAcne

Clinical Evaluations:Clinical Evaluations:

Baseline, 1, 2, 4, 8 weeksBaseline, 1, 2, 4, 8 weeks

Overall Acne Severity (Cooks GradingOverall Acne Severity (Cooks GradingScale)Scale)

Lesion CountLesion Count papules, pustules, open &papules, pustules, open &

closed comedonesclosed comedones


35/93

AcneAcne

Instrumental Evaluations:Instrumental Evaluations:

SkinskanSkinskan inflammationinflammation

DRSDRS erythemaerythema

PRIMOSPRIMOS size & elevationsize & elevation

PhotographyPhotography overall improvementoverall improvement


36/93

AcneAcne

Success Criteria:Success Criteria:

Improvement vs. baselineImprovement vs. baseline

Better improvement vs. vehicleBetter improvement vs. vehicleBetter improvement vs. benchmarkBetter improvement vs. benchmark

Other Considerations:Other Considerations:

Inclusion of safety assessment e.g. erythema,Inclusion of safety assessment e.g. erythema,

edema, dryness, scalingedema, dryness, scaling


37/93

Claim:Claim: Helps treat and preventHelps treat and prevent

pimples and blackheadspimples and blackheads


Theproduct contains a

keratolytic agent

Self assessment (150-based

consumer research)

Instrumental Measures and

Derm assessment.

Criteria

E.g. Salicylic Acid 0.5-2.0%

Statistically significant results vsbaseline/control/ benchmark

Digitalphotography. Numericalcount of lesions, DermatologicalGrading (versus visualstandards).


38/93

Example of Dermatologist Grading Scale:

Modified Cooks Grading scale


39/93

Claim:Claim: Keeps pores uncloggedKeeps pores unclogged


Theproduct contains a

keratolytic agent,

exfoliant or absorbent.

Self assessment (150-

based consumerresearch)

Criteria

E.g. Salicylic Acid, AHA,

Benzoyl Peroxide,

Polyethylene, Silica,

Kaolin.

Statistically significant

results vs baseline/control/benchmark


40/93

Claim:Claim: OilOil--FreeFree


Theproduct does not

contain any ingredient

that would beconsidered an oil.

Criteria

The CTFA/INCI

ingredient listing for

each ingredient doesnot contain the word

oil.


41/93

Claim:Claim: Reduces skin rednessReduces skin redness

Required Tests/Data

Derm assessment

and Instrumentation

Criteria

Grading on Erythema

Scale (0-none to 4-

severe)

Chromameter a-value,

Mexameter Erythema

Index, DigitalPhotography (before

and after)


42/93

Claim:Claim: AntiAnti--bacterialbacterial


Theproduct contains

ingredients with

proven anti-bacterialactivity againstp.acnes

(propionibacterium

acnes)

Criteria

Effective dosage levels

of anti-bacterial agent,

e.g. Salicylic Acid 0.5-2.0%, Triclosan 0.1%.

A 10% solution of the

product should be able

to inhibitp. acnes.


43/93

Oil ControlOil Control


Female teens, usually 13Female teens, usually 13--19 yrs old19 yrs old


Normal to Oily skinNormal to Oily skin


44/93




DoubleDouble--Blind, RandomizedBlind, Randomized

ControlControl vehicle and/or benchmarkvehicle and/or benchmark


45/93



Forehead and/or nasoForehead and/or naso--labial foldlabial fold





46/93


Before the study:Before the study:

No leaveNo leave--on products 24 hours beforeon products 24 hours before

Face must be cleansed 4 hours beforeFace must be cleansed 4 hours before

No caffeinated drinks 1 hour beforeNo caffeinated drinks 1 hour before

3030--minute acclimatization to roomminute acclimatization to room

conditionsconditions


47/93



Baseline, 1, 2, 4, 8 weeksBaseline, 1, 2, 4, 8 weeks

SebumeterSebumeter sebum level (sebum level (QQg/cmg/cm22))

SebufixSebufixpixels of sebumpixels of sebum

PhotographyPhotography shine/glare on the faceshine/glare on the face


48/93



Reduction in sebum vs. baselineReduction in sebum vs. baseline

Higher reduction vs. vehicleHigher reduction vs. vehicle

Higher reduction vs. benchmarkHigher reduction vs. benchmark


49/93



Inclusion of safety assessment e.g.Inclusion of safety assessment e.g.

erythema, edema, dryness, scalingerythema, edema, dryness, scaling


50/93

Claim:Claim: Oil ControlOil Control


Sebum Reduction

Sebutape

Sebumeter

Self assessment (150-based

consumer research)

Lipase Analysis via HPLC

Criteria

Chromatographic analysis

of sebum (baseline, and at 2,

4, 6 and 8hrs).

Skin sebum levels

Statistically significant data

vs. baseline/control/

benchmark

A statistical significant

reduction in triglycerides

and fatty acids.


51/93

Claim:Claim: Deep cleanses to remove oilDeep cleanses to remove oil

and impuritiesand impurities


Self assessment

(150-based consumer

research)

Sebutape, Sebumeter

Criteria


results vs. baseline/control/

benchmark

The % change in sebum

after washing with water

versus washing with test

product.


52/93

Claims related toClaims related to

Sunscreen ProductsSunscreen Products


53/93

Protects againstskin aging UVArays

Protects againstskin burning UVBrays

Fights damagingfree radicals Oil-Free

Non-comedogenic(wont clogyour pores)

Recommended by

dermatologists

SPF 45

Waterproof

Sweatproof


54/93

Claim:Claim: Sun Protection FactorSun Protection Factor

SPF 15, 30, 45SPF 15, 30, 45

Required Tests/Data

US FDA Sun

Protection Factor

Method(Australia uses their

own method.)

Criteria

20 person test. Males

and Females. Fair

skinned Type I, II,and III.


55/93

Claims:Claims: Broad Spectrum Protection,Broad Spectrum Protection,

Protects against skinProtects against skin--aging UVA rays,aging UVA rays,

Protects against skinProtects against skin--burning UVB raysburning UVB rays.Required Tests/Data

Spectrophotometric

Analysis

(300-400nm)

Criteria

The product must not

transmit more than

10% UV radiation atany wavelength

between 320-360nm.


56/93

Claim:Claim: Waterproof for x hoursWaterproof for x hours

Required Tests/Data

US FDA Immersion

Test

Criteria

SPF rating after the

prescribed immersion

time.


57/93

Claims:Claims: Protects against /Protects against /

fights damaging free radicalsfights damaging free radicals


This type of claim

relates to specific

ingredients with anti-oxidant functions.

In-vitro antioxidant,

anti-ozone, anti-pollution activity

Criteria

An effectiveconcentration ofVitamin E, C, AA2G,BHT, Lycopene etc.

No changes in skin

markers with productwhen exposed topollutants


58/93

FAIRNESSFAIRNESS


59/93

LighteningLightening




Preferably with slight to moderate dark skinPreferably with slight to moderate dark skin

tonetone


60/93




DoubleDouble--Blind, RandomizedBlind, RandomizedControlControl vehicle and/or benchmarkvehicle and/or benchmark


61/93








62/93






63/93



Baseline, 4, 8, 12 weeksBaseline, 4, 8, 12 weeks

Overall FairnessOverall FairnessOverall EvennessOverall Evenness

Spot LighteningSpot Lightening

SallownessSallowness


64/93



ChromameterChromameter L* (white), a* (red), b*L* (white), a* (red), b*

(yellow)(yellow)MexameterMexameter melanin, erythemamelanin, erythema

DRSDRS melanin, hemoglobinmelanin, hemoglobin

PhotographyPhotography overall improvementoverall improvement


65/93




Better improvement vs. vehicleBetter improvement vs. vehicle

Better improvement vs. benchmarkBetter improvement vs. benchmark


Inclusion of safety assessment e.g. erythema,Inclusion of safety assessment e.g. erythema,edema, dryness, scalingedema, dryness, scaling


66/93

Claim:Claim: Lightens skinLightens skin


Derm assessment Overall Fairness

Criteria

Change in grading using a

standard scale versusbaseline, vehicle or

untreated skin

0 (lightest) to 9 (darkest) scale

Scale developedper subject


67/93


Instrumental Chromameter L-value

Mexameter MelaninIndex

Diffuse ReflectanceSpectroscopy

Digital Photography PixelLuminosity Value

Self assessment

(150-base consumerresearch

Criteria

Change in parameter versusbaseline, vehicle or untreated

skin

Statistically significant resultsvs. baseline/control/ benchmark

Claim:Claim: Lightens skinLightens skin


68/93


Derm assessment Age Spots / Sun spots

Mottled Hyperpigmentation

Instrumental Mexameter Melanin Index



Criteria


standard scale versusbaseline, vehicle, untreated

spot or adjacent skin

Change in parameter

versus baseline, vehicle,

untreated spot or adjacent

skin

Claim:Claim: Reduces dark spots andReduces dark spots and

other hyperpigmentationother hyperpigmentation


69/93


Solar UV Simulation

Self assessment

(150-base consumerresearch)

Criteria

Reduction in colorpost-

treatment ofUV-irradiated skin

Statistically significant results vs

baseline/control/ benchmark

Claim:Claim: Reduces dark spots andReduces dark spots and

other hyperpigmentationother hyperpigmentation


70/93


Derm assessment Overall Evenness

Instrumental

Chromameter L-value

Mexameter MelaninIndex



Criteria


standard scale versus baseline,

vehicle or untreated skin

Lower std. dev. in parameter

versus baseline, vehicle or

untreated skin

Claim:Claim: Evens skin toneEvens skin tone


71/93


Self assessment


Criteria


results vs. baseline/control/benchmark

Claim:Claim: Evens skin toneEvens skin tone


72/93


Derm assessment

Overall Fairness

Instrumental

Chromameter L-value Mexameter Melanin

Index


Digital Photography Pixel

Luminosity ValueSolar UV Simulation

Self assessment


Criteria

No change in grading using astandard scale versus baseline oruntreated skin even with sunexposure

No change in parameter versusbaseline or untreated skin evenwith sun exposure

No change in color ofpre-treated skin when irradiated withUV



Claim:Claim: Prevents darkeningPrevents darkening


73/93


Derm assessment Sallowness

Instrumental Chromameterb-value

Digital Photography

Self assessment


Criteria


standard scale versus baseline,

vehicle or untreated skin

Change in parameter versus

baseline, vehicle or untreated

skin



Claim:Claim: Reduces sallownessReduces sallowness


74/93


Derm assessment Overall Radiance

O

verall Clarity

Self assessment


Criteria


standard scale versusbaseline, vehicle or

untreated skin

Statistically significantresults vs baseline/control/

benchmark

Claim:Claim: Makes skin more radiantMakes skin more radiant

Boosts skin clarityBoosts skin clarity


75/93

Required Tests/Data

Instrumental Video Camera (dead skin

cells)

Optical 3D Measurement

(roughness)

Digital Photography Pixel

Luminosity Value

Fluorescence Technique

Criteria

Change in parameter

versus baseline, vehicle oruntreated skin

Claim:Claim: Makes skin more radiantMakes skin more radiant

Boosts skin clarityBoosts skin clarity


76/93

Required Tests/Data

In-vitro

Reaction of melanomacells with the specificingredient

Reaction of tyrosinase withthe specific ingredient

Skin Penetration Study

Cadaver Skin

Criteria

Reduction in melanoma cells or

tyrosinase

Ingredient still to be detected by

HPLC below epidermis level

Claim:Claim: Proven whiteningProven whitening

ingredient, deposits to the skiningredient, deposits to the skin


77/93


Instrumental Viscoelastic Measurements

(Cutometer)

Collagen/ElastinOrientation (Reviscometer

)

Optical 3D

Measurement

Fluorescence /

Microscopy

Criteria

Change in parameter

versus baseline, vehicle oruntreated skin

Claim:Claim: Firms skinFirms skin


78/93

AntiAnti--AgingAging



In good health, no allergy to cosmeticsIn good health, no allergy to cosmeticsVisible wrinkles, hyperpigmentationVisible wrinkles, hyperpigmentation


79/93




DoubleDouble--Blind, RandomizedBlind, RandomizedControlControl vehicle and/or benchmarkvehicle and/or benchmark


80/93








81/93






82/93



Baseline, 4, 8, 12 weeksBaseline, 4, 8, 12 weeks

WrinklesWrinklesLaxityLaxity

HyperpigmentationHyperpigmentation

SallownessSallowness


83/93



CutometerCutometer -- elasticityelasticity

PRIMOSPRIMOS -- wrinkleswrinklesPhotographyPhotography overall improvementoverall improvement


84/93




Better improvement vs. vehicleBetter improvement vs. vehicle

Better improvement vs. benchmarkBetter improvement vs. benchmark


Inclusion of safety assessment e.g. erythema,Inclusion of safety assessment e.g. erythema,

edema, dryness, scalingedema, dryness, scaling

Cl iCl i R d i klR d i kl


85/93


Instrumental Profilometry (Replicas)

Optical 3D Measurement

Criteria

Change in parameter


untreated skin

Claim:Claim: Reduces wrinkles,poreReduces wrinkles,pore

size or scar depthsize or scar depth

Cl iCl i W th lW th l


86/93


Instrumental Thermal Imaging

Laser Doppler BloodPerfusion

Criteria

Change in parameter


untreated skin

Claim:Claim: Warms, soothes, calms,Warms, soothes, calms,

enhances blood circulationenhances blood circulation


87/93

Product Quality

GMP Guidelines conformance

Analysis of Raw Material

Microbiological control ofproducts


88/93

GMP

GMP Guidelines conformance:while GMPcertification is no longer a requirement (decisionof ACC May 05), self-declaration of conformance

is mandatory asw

ell as:The method of manufacture complying with the GMP

practice as laid down in the ASEAN Guidelines (appendixVI);

Theperson responsible for manufacture or importation into

the market must possess adequate knowledge orexperience in accordance with the legislation and practiceof the Member State which is the place of manufacture orimportation


89/93


90/93

Quality

Products made before January 1st, 2008 which do

not conform can remain on the market until

January 1st, 2011 i.e. no recall

All productsput in the market after January 1st,

2008 must be in total compliance


91/93

What will happen next?

Implementation by 1st Jan 2008


92/93


93/93

THANK YOU

Documents

KLPresentation (Alain KHAIAT)