3.5 Product Stability Testing

Product Stability Testing

Presented by

Ian Lyle (Port Sunlight)

Chadaporn Kusumarn (Shanghai)

Topics to be covered

Why do we do stability testing?

Stability test protocols & procedures

Factors that can affect product stability

Real life examples

Data recording





Real life examples

Data recording

Stability – Why Bother?

World class brands are built on world class quality products.

If consumers experience low quality products (thin, separated, malodour etc) they will be unlikely to buy them again + it will affect their perception of the brand and their expectations of other products within the brand.

Regulatory requirements in some regions (e.g. EU requires 30 months shelf life for cosmetic products, during which they must remain safe and fit for use)

Stability – Why Bother? The role of the product design team is to deliver consumer

preferred products that meet well defined physical performance standards and specifications.

The product must be able to be manufactured so that it maintains its appearance and performance profile under a range of conditions that it could realistically expect to experience during its life. During shipping Warehouse storage Consumer handling

The purpose of stability testing is to ensure that a new or modified product meets the intended physical, chemical and microbiological quality standards as well as functionality and aesthetics when stored under appropriate conditions

Factory to Consumer

Very Cold!

Very Hot!

From factory to consumers’ homes our products are subject to a range of temperatures during storage in warehouses and transportation in trucks.

They can then sit on a shelf in a shop for up to 2 years!

Long way!





Real life examples

Data recording

Stability Testing

Our Stability Protocols are broken down into two main categories of testing:

General long term shelf life stability. Guidelines for this are well documented by the IFSCC, COLIPA

and ICH

Short-term stress testing May require a series of several short tests that range from days to

weeks Light Stability Temperature Cycling Freeze/Thaw Not as well documented and can vary from region to region Dependent on SC conditions as well as weather extremes

Industry Guidelines Industry Guidelines published by IFSCC and COLIPA suggest that

stability be completed across a range. The range suggested is 4, 25, 37 and 45C although some of the temperatures and ranges can be varied.

The FDA in the USA bases their guidelines for Drug Expiration Dating on the ICH Guidelines. The temperatures cited in the ICH Guidelines are based primarily on a Global Climate Survey conducted by W. Grimm which was an extensive study that included warehouse temperatures, extremes, average temps and the number of days particular cities in various regions were above the Mean Kinetic Temperature.

Since 45C covers the worst case scenario for Long Term Product Stability Testing and is in wide use throughout Unilever, the range suggested in the COLIPA , IFSCC and ICH Guidelines are reasonable to recommend.

Stability of a Cosmetic Product

Whether conducted in real time or under accelerated conditions, tests should be done in order to assure: stability and physical integrity of cosmetic

products under appropriate conditions of storage, transport and use

chemical stability microbiological security compatibility between the contents and the

container.

Designing Stability Tests

The design of the stability test/protocol is dependent on the objective of the test.

As an example we may be interested in one or more of the following objectives: assessment of the product contents assessment of the product-container compatibility comparison of a newly modified formula to an

existing stable product new manufacturing process new container changes in raw material supply or specification

Stability Protocol Overview

2 day Reference RT Control for

Accelerated Stability

(Pilot Batch)

Fragrance Support

StandardAccelerated

Stability(Pilot Batch)

Stress Testing

Time 4o C 2o C 25o 2o C 37o 2o C 45+ 2 C 50 C

INITIAL P,C,M

1 Week P,C

4 weeks P P,C P,C,M

8 weeks P P,C P,C

12 weeks13 Weeks for OTC

P P,C,M P P,C

P – Physical Characteristics (Color, Odor, Appearance)C – Chemical/Physical Characteristics (pH, Viscosity, %Actives)M – Microbiological Requirement

Sample Requirements:

Micro Requirements 6 (2 each at Initial, 45 & 1 mo, 25 & 3 mo)Chemical/Physical 12 (1 at each pull point indicated above)

Signs of Physical Instability “Cracking” within the formulation Phase separation

e.g. Creaming, Sedimentation Colour change

Yellowing very common when formulation contains amine Odour

Significant difference from control, base odour not covered

Some attributes such as pH, viscosity and micro have well defined numerical specification ranges, but others are more vague (“compare with standard”)

Currently there are no fixed standards for what are acceptable and unacceptable changes in physical characteristics – it is up to the judgment of individual formulators.

Category workshop planned in 2007 to begin to define common reference points for these

Example: SE Asia Grading Scale1) Sign of Separation

SCORE DESCRIPTION

0 OK 1 10% Cracking in shampoo texture 2 20% Cracking in shampoo texture 3 30% Cracking in shampoo texture 4 40% Cracking in shampoo texture 5 50% Cracking in shampoo texture or more

2) Phase Separation

SCORE DESCRIPTION

0 OK 1 0.1 cm. of transparent level on top 2 0.2 cm. of transparent level on top 3 0.3 cm. of transparent level on top 4 0.4 cm. of transparent level on top 5 0.5 cm. of transparent level on top or more

Sign = 1Sep = 1

Sign = 2Sep. = 2

Sign = 3Sep = 4

Sign = 4Sep = 3

Signs of Physical Instability

Shampoo samples scored according to SE Asia scale:

When to do stability testing

Stability testing of the formulation (CUC) should be started as soon as possible during product development, even if the full formulation is not yet defined. This should allow early identification of any fundamental issues that need to be resolved as part of the product development process.

Final stability testing must be done on final full scale manufactured product in the final pack (CU) according to the defined life test protocols and results recorded in a database for reference.

At the final stability stage there should be no intrinsic stability issues due to the base formulation. At this stage you should be looking for any unexpected interactions between fragrance, formulation and pack.

Project Execution

Global Charter Gate

IdeasFeasibility

Capability

Charter sign-on

Global Idea

Contract sign-on

Regional Launch Gate

1. Project Brief -

Technical Section

4. Design Lock

Lab/Pilot scale

stability proven

5. Specification

Lock

Full scale manufacture

stability proven

1

Launch

43 5

3. Concept

Lock

2.Charter -Technical

section

2

Ongoing stability evaluation Final stability

GlobalContract Gate

4 5

At Spec lock – final stability must be complete (full scale manufacture product in final pack) with final ingredient and product specifications in InterSpec





Real life examples

Data recording

Factors affecting stability

Ingredient chemistry New ingredient (or more often a sub-component or impurity)

Specification definition Inadequate processing

e.g. incomplete hydration of polymers such as Jaguar and Carbopol can lead to increasing viscosity over time

Hydrolysis of ingredients e.g. DLSS hydrolysis leads to production of laureth-3 which

increases viscosity Change in fragrance Fault in packaging

e.g. pinholes in aerosol can lining leading to corrosion New packaging (material and colour) Sunlight (for transparent packs)

Formulation Chemistry

DI Water Carbopol Slurry (2%)

SLES-1 (25%)Guar C13S

Sodium Hydroxide (50%) DLSS (32%)

GlycerinPolyox WSR 308Methocel 40-202

CAPB (28%)Euperlan KE 3795

Si macro emulsionTetrasodium EDTA (39%)

FragranceKathon CG DMDM Hydontoin

Sodium Chloride (20%) PPG-9

(Euperlan KE 3795 contains SLES-1EO and CAPB)

What are the emulsifiersused in the silicone emulsion?What else is in Euperlan, apart from EGDS?How might these additives affect stability of the product?

In order to solve any instability problems with your formulation it is critical that you understand the basic chemistry associated with the key ingredients.

By understanding the potential interactions between ingredients you can begin to generate technical hypotheses for the cause of the instability.

e.g. Dove shampoo formulation

The SLES Iceberg

OH

OOH

OO

OH

OOH

nn=3-12

Ethylene Oxide

Sulphur Trioxide

OSO3Na

Non ethoxylated material

OOSO3Na

nn=3-12

NaOH

OO

OSO3Na

OH

OH

OOH

OO

OH

OOH

nn=3-12

Ethylene Oxide

Sulphur Trioxide

OSO3Na


OOSO3Na

nn=3-12

NaOH

OO

OSO3Na

OH

OH

OOH

OO

OH

OOH

nn=3-12

Ethylene Oxide

Sulphur Trioxide

OSO3Na


OOSO3Na

nn=3-12

NaOH

OO

OSO3Na

OH

Non-ethoxylated materialUnsulphated material

Distribution of EO unitsDistribution of alkyl chain lengths

SLES 1EO is not a single pure molecule

It is a cocktail of a mixture of small amounts ofa variety of residual feedstock and by-products

+ NaCl? Citric acid? NaSO4?

Pack & Fragrance Interactions

Product stable in glass container

Product in whitePP Bottle - stable

Product in white PE Bottle - unstable

Product in colouredPP Bottle - unstable

Simple changes in packaging & fragrance can lead to changes in stability e.g. colour and odour

Product with new fragrance in glass

container - unstable

Effect of minor change in fragrance

Effect of change in plastic composition

Effect of change in plastic dye

Effect of moving from glass to plastic

Effect of Processing

Definedformulation& order of addition


Bench scale Pilot plantFull scale manufacture


Stable Stable Unstable

Making a product in the factory is very different from making it on the bench. Simply increasing the scale and changing equipment can impact on factors such as final microstructure which can impact on product stability.

Beware hidden modifications in processing (e.g. temp, mixing times etc).





Real life examples

Data recording

Sunsilk Volume Combing Cream

● New Sunsilk Volume range launched in Europe Jan 2004 (Project Einstein); combing cream had “ultra low fat” conditioner base with performance superior to Kerastase.

● Storage testing done on samples from lab and pilot scale production; no main plant trial done.

● At first production in Bydgoszcz, product viscosity was at lower end of spec, did not build normally, and separation observed after 1-2 weeks.

● Fortunately, First Production routinely held in quarantine and product spec had both “fresh” and “equilibrium” viscosities

● Crisis Team formed to find resolve issue and minimise launch delay

● Product had to be reformulated to make more robust to variation in mixing intensity. Consumer test had to be repeated: fortunately results were good!

AMET Dove Atlas Viscosity

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

VİS

.

DAY

RMD 029 (VİS.)0

RT

37

45

50

Stability problemSignificant increase in viscosity of shampoos with 6/4/3 surfactant base over time at high storage temperatures

Hydrolysis of DLSS in 6/4/3

DLSS (Disodium Laureth-3 Sulphosuccinate) surfactant in 6/4/3 base is prone to hydrolysis under low pH conditions.

Hydrolysis leads to production of Laureth-3 and a decrease in pH

Laureth-3 is incorporated into miceller structure of surfactant base leading to development of longer wormlike micelles that lead to significant increase in product viscosity

R O CH2CH2 OONa

O SO3

O

Na

[ ]n R O CH2CH2 OH[ ]

n

+

Na

ONa

O SO3

O

HO

Increasing 6/4/3 viscosity

Loss of DLSS

Impact of fatty alcohol, acid, and DLSS consumption on micelle shape. (Dickinson, 2004)

6/4/3 Viscosity instability solution Inclusion of 2% NaCl (much higher than normal ca. 0.5%) to

thicken shampoo and then viscosity adjusted via addition of PPG.

High salt level means that micelles are closer to their maximum growth capacity when the shampoo is made.

End results – hydrolysis still occurs but impact of increased level of fatty alcohol on viscosity is significantly reduced by higher salt level. (i.e. Formulation is now more robust.)

Increasing salt level to 2% or above keepsformulation viscosity stable at high temp.

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

0 1 2 3 4 5

Weeks at 49oC

Vis

cosi

ty (

cP)

))

2.2 wt% NH4Cl

0.2 wt% NH4Cl

Stabilising 6/4/3 Shampoos

Key learning points

Key delivery from CTC is stable products under all relevant handling and storage conditions

Rigorous stability testing procedures are key to ensuring the integrity of our products

We have well defined stability evaluation protocols – better global definition of acceptable vs unacceptable results to be agreed later this year.

Understanding the chemistry of formulations is key to finding the technical cause of any instability and identifying a solution

Cause of instability can range from molecular chemistry of a specific ingredient to the way in which the whole product was manufactured – detailed knowledge of product ingredients and manufacture is critical.





Real life examples

Data recording

Contact:Rob Waight (Ext. 3219)

Data Recording

Details and results of stability testing must be recorded

In Port Sunlight the plan is to do this using FReg

FReg and Stability TestingWhat are we doing now?Links to FReg:

FormulationsIngredientsEquipment

How it might activitiesbe used:ModellingSample tracking

Aid to help schedule

Documents

3.5 Product Stability Testing