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Preservation of Personal Care Products A Microbiologist’s View

Deidre L. MitchellDevelopment Manager MicrobiologyUnileverTrumbull, CT

PCPC Microbiological WorkshopOctober 26, 2011

Presentation Objectives

• Purpose of a preservative• Impact of pH, temperature and water activity on

preservative requirements for a product formulation• Impact of formulation ingredients on preservatives• Preservative Challenge Testing• Other considerations impacting preservative selecti on

(Regulatory and Public Relations (PR)• Consumer Use• Distribution

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Purpose of a Preservative

� Preservatives are essential ingredients added to a product to prevent and/or minimize the growth of microorganisms.

� Preservatives are added to products to protect the quality and consumer safety for the intended shelf life of a product.

� Note: Preservatives should be used with consideration for the intended consumer. � Preservatives have long been recognized as skin sensitizers.1

� Ultimately, Preservatives are essential to protect the quality of the product and safety of the consumer.

1 Meyandier, JM. Meyandier J, Colmas A et al. Allergie aux conservateurs. Ann Dermatol Venerol 1982; 109:1017-23

Key Points on Preservatives

� Preservatives will reduce any incidental contamination.

� Preservatives are not intended to compensate for poor manufacturing practices.

� It must be recognized that despite adequate product preservation and the following of cGMP’s, personal care products are NOT immune to microbiological exposure.

� Success is a combination of robust preservation in combination with good manufacturing processes.

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The Ideal Preservative

� Globally acceptable� No negative public relation issues (PR)� Wide pH compatibility� Broad spectrum activity (bacteria, yeast, mold)� Cost effective� Safe and non-irritating at minimal use levels� Easy to incorporate into product formulations� Synergy with co-preservatives to reduce concentration of

preservatives needed

Preservative Mechanisms of ActionPreservatives are not selective like antibiotics, t hey attack many sites on the cell membrane ….

Ref. Principles and Practice of Disinfection, Preservation and Sterilization, Third Edition, Blackwell Science LTD, London, UK, 1999, p.272

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Factors Affecting Microbial Growth

Bacterial growth & survival are affected by:

Physical Conditions� pH

� Temperature

� Water activity (a w)

� Nutrition

� Presence/absence of antimicrobials or preservativesEnvironment

Importance of pH

pH Influence� Molds prefer acidic pH � Bacteria prefer neutral/alkaline pH� Note: Some Gram negative organisms can tolerate an

acidic pH (i.e.Burkholderia cepacia can grow at pH 3)� Extremes of pH can be self-preserving (i.e pH < 2.0 or

greater than 10.5)

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pH – Personal Care Products

1 2 3 4 5 6 7 8 9 10 11 12 13 14

No Chemical Preservative Required

Chemical Preservative Required

ShampooSkin Cream

Hair Conditioner

Hair GelsFacial Cleansers

Body Wash

Water Activity and Preservation

What is It? ”Water available for microbial growth”� Not the percentage of water in a formulation

The higher the aW the greater the potential risk of microbial contamination

� Water activity measurements can be used to provide direction as to how to best preserve a product

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Water Activity (aw) and Potential for Growth

Water Activity pH Level ProblemOrganism

ProductExamples

0.98-1.0 5-9 Gram Positives and Gram Negatives

Shampoos and Emulsions

0.95-0.97 5-9 Gram Positives and Gram Negatives, PseudomonadsLimited

Eye area products

0.95-0.97 < 5.5 Gram Positives and Gram Negatives, PseudomonadsLimited

Hair Conditioners

0.70-0.80 5-9 Mold and Yeast Some Talcs

0.65-0.70 5-9 Osmotolerant Yeast Some Anti-Perspirants

0.60-0.65 5-9 Osmotolerant Molds

Below 0.60 5-9 None

Ref. Daniel K. Brannan, Cosmetic Microbiology, A Practical Approach, Second Edition, Taylor and Francis, New York London, 2006, page 50.

Application of Water Activity Values

Water Activity (a w)< Typical Product Type Preservative Requirement Based on Water Activity Only

0.90-1.0 ShampoosFoam/Bath/Shower ProductsHair ConditionersCreams and LotionsOil-in-Water Emulsions

Anti-bacterial3 and Anti-fungal4

preservative required

0.8-0.90 Water in Silicone EmulsionsConcentrated Liquids (Typically > 40% active)

Unlikely to require an anti-bacterial preservative, may require an anti-fungal preservative

< 0.60 High alcoholic deodorants Preservative not required

3 Aw 0.90-0.94 - Inconsistency in literature for Gram Negative bacteria.

4 Many preservatives have antibacterial and some antifungal activity (i.e. Isothiazolinones/Formaldehyde) It does not imply that an antifungal agent (i.e. Parabens/Glycacil) is always required.

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-10 0 10 20 30 40 50 60 70 80 90 100°C

Psychrophiles

Mesophiles

Thermophiles

Yeasts

Molds

Temperature

Body temperature- most human pathogens grow best at 37oC

Other Ingredients Impacting Preservation

Positive Ingredients

�Alcohol (i.e. Ethanol > 20% level required to be self-preserving)

�Chelating agents – Disodium EDTA�Active Ingredients - (i.e. Salicylic Acid, Triclosan, Zinc

Pyrithione)Potentially Negative Ingredients

�Quality of Raw Materials – Increased demand on Preservative

�Growth Promoting - Natural Extracts/Glucose�Certain ingredients can inactivate preservatives, such

as, sunscreens, anionics, and starch.

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Importance of Chelating Agents

• EDTA can improve the performance of some preservatives against microorganisms. �Believed to weaken cell envelope by removing

magnesium ions�May permit preservative to enter cell more easily and

attack cellular target

�Chelating agents can improve efficacy of preservatives against Gram negative organisms such as B.cepaciaand P.aeruginosa.

• Recommend incorporating a chelating agent into product formulation to strengthen the preservative system.

AddEDTA

AddEDTA

LPS of outer membrane Inner membrane

calcium and magnesium ions stabilize the outer and i nner membranes of Gram negative cells

- this helps protect them from preservatives

EDTA chelates calcium and magnesium which destabili zes the cell membranes

- helping preservatives to attack the cell

EDTA WILL NOT WORK IN FORMULATIONS WITH HIGH LEVELS OF Ca or Mg

How EDTA Enhances Preservative Activity

Normally LPS excludes preservatives but up to 40% of LPS molecules lost following EDTA treatment

Loss of Ca/Mg increases repulsion between negatively charged phospholipids - making it easier for preservatives to enter the cell

Preservative Preservative

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Preservative Selection – Additional Considerations

�Legal Restrictions

�Company Restrictions

�PR Restrictions

Preservative Selection – Legal

Approvals Documentation

European Union (EU) Pre-approves preservatives and publishes a positive list known as Annex VI

China Hygienic Standard for Cosmetics (version 2007/01) issued by China Ministry of Health (MOH).

Canada Publishes a hotlist of ingredients that are either prohibited or restricted

Japan Publishes a positive list (restrictive and classifies approvals based on the end use of the cosmetic

United States FDA has a list of prohibited or severely restricted ingredients

Microbiologists need to be aware of the restrictions on preservativesWhen providing recommendations to Chemists/Formulators!

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Preservative Selection - Legislation

May require additional testing (i.e. Shelf life jus tification)• Europe : Period After Opening (PAO) – Requires that

all cosmetics with a shelf life of < 30 months must have a best used by date on the label.

• US (FDA Regulations) – All cosmetics need not be sterile but they must not contain microorganisms that are pathogenic and the density of non-pathogenic must be low in the product formulation and remain at low levels for the anticipated product shelf life.

• Products must be tested for microbiological quality before being released to the trade.

• Products must be tested for preservative efficacy during the product development process.

Preservative Selection – Public Relations (PR)

� Every preservative is fighting some degree of public scrutiny!

� All preservatives have a restriction/issue somewhere in the world!

� Based on level (dose) restrictions, product type (rinse off, leave on, baby categories, mucous membrane), even differences within a chemical family (isothiazolinones, parabens)

� Microbiologists should consult with Regulatory to be aware of the latest views on the preservatives they are recommending to Formulators.

� The legal and regulatory landscape is constantly changing so be “aware”.

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Preservative Selection Compatibilities – pH and Temperature of Addition

Preservative pH Temperature

Parabens 3-8 Add at emulsification temperature (75-80°C) to water phase

Benzoic Acid < 5.5 Typically added to water phase and added early to facilitate mixing

DMDM Hydantoin 3-9 Stable up to temperatures of 80°C*At temperatures exceeding 80°C, preservative will break down and release formaldehyde

MCI/MI < 9.0 Add in cool down phase< 50°C

Phenoxyethanol 3-10 Often added with Fragrance, Stable up to 85°C

Ref. David Steinberg, Preservatives for Cosmetics, Second Edition, Allured Publishing, 2006

MCI/MI – Methylchloroisothiazolinone and Methylisothiazolinone

Ingredients that have an Impact on PreservationIngredients that have an Impact on Preservation

Preservative Absorbers� Kaolin� Silica� Talc� Titanium Dioxide

Preservative In-activators�Cellulose gum�Alkaline pH�Lecithin�Over-heating�Non-ionics e.g.. Polysorbates�Xanthan gum

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Preservative Neutralizers and In-activators

Preservative Neutralizers and In-activators

Parabens� Lecithin, Non-ionic surfactants, polysorbate, gums,

alkaline pH, polyethylene glycolAlcohols

� Gums, non-ionic surfactants, especially TweensMCI/MI

� Bisulfites, secondary amines, strong nucleophiles� ZPT is not compatible with MCI/MI

Phenolic and Chlorophenolic Compounds� Polysorbate 80, Non-ionic surfactants, proteins� Carboxymethylcellulose, polyethylene glycols,� lecithin

Organic Acids� Neutral -> Alkaline pH, non-ionic surfactants, CaCl2,

Tweens� Formaldehyde Donors

� Incompatible with Parsol 1789

Preservative Neutralizers and In-activators

Preservative Neutralizers and In-activators

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Preservative Selection - Stability

Temperature• Is it stable for life time of product?

• Take account of countries it will be used in• Is it stable for distribution?

• Take account of distribution, especially if global or into hot tropical regions

UV Stability• Does preservative need to be UV stable

• Transparent Packaging

Preservative Selection - Partitioning

The preservative must be active in the aqueous phase of a formulation to be microbiologically effective and functional.

Some preservatives can partition between the aqueous and oil phase leaving a sub-optimal amount in the aqueous phase.

Preservatives with a preference for oil phasePhenoxyethanol, Benzyl Alcohol, Benzoic acid and Parabens

Preservative challenge testing is critical to demon strate effectiveness

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Preservative Selection - Cost

What is the most cost effective way to ADEQUATELY preserve the formulation?• Do NOT over preserve• Do NOT operate at the cliff edge

Never chip away at preservative levels to achieve c ost savings!

Preservative Selection - “Factory History/Standards”

� Need to consider where the product will be manufactured

� High risk products should NOT be made on plants with poor hygiene standards

� Consider any historical “in-house” bugs

� If known “in-house” bugs, consider incorporating them into challenge test inoculum as a separate pool

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Sub Lethal Levels of Preservative

Microorganisms are populations of individual cells• A small number of cells will be a little more resistant to

preservatives then the rest of the population.

It is extremely important that a sub lethal level o f preservative is not used in a formulation• Sub lethal levels select for the less susceptible organisms

increasing the risk of a contamination problem. • i.e. selects for organisms that are expressing resistance traits • e.g. using too low a level of formaldehyde donor can select resistant

microbes that express high levels of formaldehyde dehydrogenase)

• Can lead to growth of resistant microbes in a product and can lead to failure of the preservative, even if it is subsequently used at the correct dosage levels (because microbes have become resistant).

Consumer Use - Key Points

How is product used by the Consumer? (Habits/Practices/Frequent Abuse!)

• What are the risks of introducing contamination by the consumer?

• Creams - Direct Consumer Contact with Product

• Dilution of Product with Water

• Environmental contamination risk

• Is a Broad Spectrum Preservative Required?• Confirm choice by preservative challenge test• Confirm ability of formulation to resist contamination by

running consumer use studies (i.e. novel formats, low water personal care products, high risk formulas)

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Consumer Use

Restricted Access Packaging (i.e. Eye Creams Packag ed in Tubes): Low introduction of contamination during use• Low level dust from air

Shampoo: Water enters product during use in shower• Design of Packaging and Packaging Closures

Important ConsiderationsSkin Creams: Consumer touches product in primary

container during use• Design of Packaging and Packaging Closures

Important Considerations • Wide mouth jars present increased risk

Increasing Demand

On form

ula preservative system

Real Life Experience

Formulation needs a preservative until determined otherwise

If not sure it needs a preservative, it needs preservation

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Microbiologist “Thought Process”

1. Does formulation require a preservative?

2. If yes, use knowledge/experience to design an appropriate preservation system for the product• Type Preservative (required spectrum of control)• Level of Preservative

• Avoid using sub lethal levels

3. Validate your choice in a challenge test

Do NOT over Preserve but do NOT operate at the clif f edge. The challenge is getting the balance right!

Preservative Challenge Testing/Evaluation

Challenge Testing: What are the objectives?• Assess the preservative capacity of a formulation• Simulate the risk (repeat inoculation recommended ) of

contamination during;• Manufacturing

• Product Shelf Life

– Can perform preservative analytical tests to confirm preservative stability and efficacy

Recommend contacting supplier for method/advice

• Consumer (normal) use

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Challenge Tests - Limitations

Can be a very good tool to differentiate between preservative systems

Can the test predict how formulation will behave in the manufacturing or under consumer use?

Microbiologist should consider the following: • Potential for dilution in use• Consumer instructions for use

• i.e. consumer instructed to dilute with water prior to use• Design of Final Packaging • Limited number of microorganisms tested

– In nature, organisms exist as a mixed biofilm

Microbiologists need to be aware of limitations!

Common Statement

During an Incident - “But the product passed a challenge test”

Response - “All products in production should have passed a challenge test”

Preservation alone does not ensure microbiological quality

No preservative protects a product against a substa ntial failure in GMPs

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Distribution

• If global supply chain, consider hygienic risk of extended distribution channels

• If shipping product across tropical areas, the risk of contamination to primary or secondary packaging will increase

• Assess hygiene risk if product is distributed in shipping containers

Other Points to consider include:• Stability of preservative system (temperature dependent)

within the distribution system• Risk of mold growth on pallets

Distribution - Mold

� Materials made of cellulose are vulnerable to mold growth.

� Mold growth is favored in damp, high humidity conditions. � These conditions can occur in distribution or while the

product is stored in the consumers home. � The design of the product itself can also result in a local

high humidity environment.

Top side of paper cartridge

Mold growth on PE laminate

Bottom of papercartridge

Bottom of primarycontainer

Mold growth around the edgeof PE laminated paper

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Summary of Preservative Selection Parameters

EfficacyTarget ConsumerCostWater Activity and Formula pHFormula Compatibility and StabilityFactory Hygiene StatusPackagingRegulatory RequirementsPublic Relations IssuesSensitive Skin etc… – Mildness ClaimsChelating Agent AdditionProcessing – Temperature restrictions

In Conclusion

Successful preservation of personal care products involves knowledge of:

� Formulation and ingredients, including pH� Ability of the unpreserved base to support the grow th

and replication of microorganisms � Regulations and PR issues about the preservatives

under consideration� Target consumer and consumer use habits� Manufacturing facility where the product will be ma de� Intended life cycle of the product, including distr ibution

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Thank you for your attention

Contact Information:

Deidre L. Mitchell

Email: deidre.mitchell@unilever.com

Telephone: 203-381-5377