Alternative Preservatives

SCC Ontario Education Day

R. Nunez/ Lonza Inc./ Sept. 2006

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Outline Why Preservatives?

Conventional Alternatives

Preservatives Today: Where are we? Preservative Trends Global Regulatory Overview Conventional Preservatives Profiles

Alternative Preservative Approaches Ingredients with Antimicrobial Activity Other Preservative Alternative Approaches

Conclusions

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Why Preservatives By Definition, Used to Prevent Growth of Microorganisms in a

Cosmetic product… A substance intentionally added to a cosmetic product for the

primary purpose of inhibiting the development of microorganisms.

Help Prevent Microorganism Growth During Manufacturing…But Not a Substitute for GMP

Primarily Designed to Prevent Microorganism Growth After Product Sale to Consumers

Therefore… Preservatives Must be Toxic to Microorganisms but Be Safe for Humans

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Without Preservatives

Risky Business

Product Spoilage, Recalls

Health, Infection Issues

Formulating Without a “Safety Net”

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With Preservatives

Preserved Formulations

Low Cost “Insurance”

Tradeoff between Preservation and Formulating Issues

Need Preservative Potency, Compatibility and Stability

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Cosmetic Preservatives History

Pre-1900: Sodium Benzoate, Phenol, Cresol 1920’s: Parabens, Formaldehyde 1940’s: Alcohols, Phenoxyethanol 1960’s: Staph Outbreak from Hospital Hand Lotions -

Changed Attitude towards Preservatives 1960’s: Formaldehyde Studies, Concerns 1970’s: Imidazolidinyl Urea, DMDMH, Bronopol 1970’s: FDA Surveyed Cosmetics, Found 24%

Contaminated 1980’s: Diazolidinyl Urea, Isothiazolinones 1990’s: Blends Introduced, e.g. DMDMH/ IPBC 2000’s: Blends, Naturally-Derived Today: Acute Perception Issues, Fragmented Market

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What Preservatives Do We Use Today?

2003 2001

Methylparaben 7161 6893

Propylparaben 5809 5621

Butylparaben 2326 2174

Imadazolidinyl Urea 2038 2025

Ethylparaben 1725 1451

Phenoxyethanol 1670 1480

DMDM Hydantoin 993 943

Diazolidinyl Urea 725 701

MCI/ MI 699 595

Quaternium-15 516 505

Triclosan 451 462

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“Conventional” Preservative Takeaways

All These Commonly Used Preservatives have Limitations

All are Classified as “Conventional” Preservatives and Are Approved by Regulatory Bodies Globally

All Have Been Used for Many Years…..Long Histories and Experiences

All Have Been Found to be Safe and Effective for Use as Directed

And Many are Under Some Sort of Pressure

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Why “Alternative” Approaches?

Attempt to Meet Varied Real and Perceived Needs

Address an Increasingly Fragmented and Confusing Cosmetics Preservatives Market

Address Customer and Retailer Perception Issues

Simplify Formulating – Less Raw Materials/ Testing Required

Allow Global Use of Simplified Systems

However…..

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Is the Perfect “Alternative” Preservative Possible?

Water Soluble

Colorless and Odorless

Cost-Effective

Widely Compatible

Globally Approved

Available for Use Today…..

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Why Is It So Difficult? Regulatory Barriers

Few Ingredients Acceptable in All Regions

Formulation Barriers No Single Technology Works in All Types of Products

New Preservative Molecules Unlikely Due to Cost, Time and Data Requirements vs. Market Size INCI-Listed, Multi-functional Approaches are Best Bets

“Alternatives” Effectiveness… Are They Potent Enough? Can They Replace “Conventional” Approaches?

Preservatives Today: Where Are We?

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What Drives Preservative Choice? Formulation Type

Effectiveness in the Formulation

Use Cost in the Formulation

Preservative Safety / Perception / Acceptance

Compatibility / Stability with Other Ingredients

Global Regulatory Approvals

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Today’s Preservative Trends Regulatory Changes Driving Preservative Choices

Many Traditional Materials Being Challenged Increase in Restrictions, Perception Issues

Increase Preservative System “Safety” But… Maintain Efficacy Ensure Formulation Compatibility

More Preservative Studies, Publications, “Pressures”

Naturally-Derived and Blended Preservatives, Use of Potentiators

Confusing Array of “Alternative” Preservative Approaches

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Global Regulatory Overview (1) NAFTA

Widest Range of Approved Preservatives Parabens, Formaldehyde Donors, Isothiazolinones, Acids,

Alcohols, etc.

Europe Positive List, Difficult Approval Process,… Plus Green Groups Close to NAFTA in General, But More Constraints Most Preservative “Controversies” Start in Europe

Japan Positive List, Longest and Most Difficult Approval Process No Formaldehyde Donors, Other Constraints

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Global Regulatory Overview (2)

Other Countries Brazil, Australia, Korea, China Many Driven by US or Europe Gets Complicated……Seek Regulatory Assistance

Conventional Preservatives Profiles

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Parabens Profile

Target Organisms: Fungi Mode of Action: Nutrient Transport Applications: Rinse-offs, Leave-ons Wide Global Acceptance, Long Use History Typically Blended (methyl, propyl, butyl, ethyl) / Combined with

Bactericides Recent Controversy – Study Results, Perception Issues Formulating Tips

Low Water Solubility Polysorbates/ PE pH range: 3.5 – 6.5 0.1 – 0.8% as Active

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Formaldehyde Releasers Profile

Target Organisms: Bacteria Mode of Action: Denatures Proteins Applications: Rinse-offs, Most Leave-ons Limited Approval in Japan Imidazolidinyl Urea, Diazolidinyl Urea, DMDM Hydantoin,

Quaternium-15 Recent Controversy: Gas vs. Liquid Formaldehyde measurement Formulating Tips

Highly Water Soluble High Temperatures, Reducing Agents pH range: 3 - 10 0.1 – 0.5% as Product

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Alcohols Profile

Target Organisms: Bacteria Mode of Action: Denatures Proteins Applications: Rinse-offs, Leave-ons Wide Global Acceptance Phenoxyethanol, Benzyl Alcohol, Ethyl Alcohol, Usually Combined

with Fungicides Formulating Tips

Highly Water Soluble May Impact Viscosity May Add Odor pH range: 3 - 10 0.5 - 1% as Active

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Isothiazolinone Profile

Target Organisms: Bacteria and Fungi Mode of Action: Disulfide Linkage With Cell Wall Proteins Applications: Rinse-offs, Some Leave-ons Wide Global Acceptance (BIT has Limited Approvals) Chloromethlyisothiazolinone, methylisothiazolinone,

benzisothiazolinone – CMI/ MI Most Common Blend Formulating Tips

Sensitizations Issues Add at <50°C Primary Amines, Sulfites pH range: 2 - 8 Up to 15 ppm Active R/O

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Acids Profile

Target Organisms: Fungi Mode of Action: Denatures Proteins Applications: Rinse-offs, Leave-ons Wide Global Acceptance Sorbic, Benzoic, Salicylic, Dehydroacetic, Boric, Citric (and salts) Typically used in combination with a bactericide Formulating Tips

Low Water Solubility (acid forms) Add at <50°C Primary Amines, Sulfites pH range: <6 Up to 0.5% as Free Acid

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IPBC Profile

Target Organisms: Fungi Mode of Action: Nucleophilic Reaction with Thiols, Amines in Cell Applications: Rinse-offs, Leave-ons Wide Global Acceptance Available in Surfactant, Water or Solid Carriers – not sold as 100% Typically used in combination with a bactericide Recent Controversy: EU Dosage Levels and Applications Formulating Tips

Low Water Solubility Reducing Agents pH range: Up to 9 0.05 – 0.1% as Active

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Other Conventional Preservatives Bactericides

Benzalkonium Chloride Benzethonium Chloride Chlorophenesin Methyldibromo Glutaronitrile Sodium Hydroxymethylglycinate Thimersal Triclosan Triclocarbon

Fungicides Glutaral Zinc Pyrithione Zinc Oxide

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Top Global Choices

Goal: Broad Spectrum, Global As Possible Blends Acids – Benzoic, Citric, Dehydroacetic, Salicylic, Sorbic Alcohols – Phenoxyethanol, Benzyl, Ethyl Formaldehyde Donors – Imidazolidinyl Urea, DMDMH, DI Isothiazolinones – MI, CMI Parabens – Methyl, Propyl, Butyl, Ethyl Many Blends are Patented or Proprietary

Phenoxyethanol + IPBC Formaldehyde Donors + IPBC Phenoxyethanol + Parabens Acids + Alcohols + Quats

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Examples of Blended Preservative Systems

Pert Shampoo (P&G) CMI + MI

Herbal Essences Shampoo (Clairol / P&G) DMDMH + IPBC

Nivea Visage Cream (Beiersdorf) Phenoxyethanol + Diazolidinyl Urea

Plenitude Facial Lotion (L’Oreal) Imidazolidinyl Urea + Parabens

Head-to-Toe Baby Cleansing Cloths (J&J) Phenoxyethanol + Parabens + Citric Acid

Alternative Preservative Approaches

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Alternative Approaches Alternative Ingredients

Naturals Glycols Glycerins Antioxidants Surfactants Potentiators

Alternative Non-Ingredient Approaches Water Activity pH Adjustment Raw Material Specifications Plant GMP Package Design

A cosmetic Ingredient is NOT a Preservative if: It’s NOT on Europe’s Positive List It’s NOT on Japan’s Positive List It has an INCI Name Claiming Another Function It Helps Create a More Hostile Formulation Environment

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Create a Self-Preserving Environment

Use Ingredients and Essential Oils that have Antimicrobial Properties but are NOT classified as Preservatives

Create an Environment that is Unfavorable to Microbial Growth either through

substituting alternative chemistries lowering water activity changing pH increasing alcohol, surfactant, other ingredient levels

Ensuring that the product is manufactured under GMP conditions Use a Package that minimizes introduction of microbes into mass Minimize incoming ingredient bioload

Alternative Ingredients with Antimicrobial Activity

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Natural Ingredients

Many on the market Used in Combinations or with Traditional Preservatives

Addresses Growing Natural Trend, but Difficult to Execute

Typically Have Multi-Functionality and INCI Listed

Often have Odor, Color and Allergen Issues

Tend to be Organism-Specific, not Broad Spectrum

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Natural Ingredients (2)

Grapefruit Seed Extract Bactericide Activity may be due to Other Ingredients introduced during

processing

Gluconolactone Bactericide Moisturizer

Tea Tree Oil Bactericide Humectant

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Natural Ingredients (3)

Usnic Acid Mostly Gram positive Bactericide May impart blue color to products

Neem Seed Oil Bactericide May impart color and odor to products

Other Oils and Extracts Cinnamon, eucalyptus, lavender, lemon, rosemary, thyme,

honeysuckle…..

Challenge Test, Ensure Compatibility

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Glycols

Possess Humectancy and Potentiation

Propylene, Butylene Glycol (6.0%) Improves solubility and product stability Reduces oil/water partitioning Assists in preservation, lowers water activity

Hexylene, Pentylene Glycol (2.0%) Preservation Efficacy

Caprylyl Glycol (1.0%) Preservation Efficacy

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Caprylyl Glycol

Some Broad Spectrum Activity

Often used in Combination with Phenoxyethanol, Other Preservatives

Wide Global Approval

Compatible with Most Formulation Types

Some reports of Irritation when used in combination with other glycols

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Ethylhexylglycerin

Similar to Other Glycerins Activity against most Gram Positive Species Lowers Water Activity

Often used in Combination with Phenoxyethanol

Wide Global Approvals

Compatible with Most Formulation Types

Some reports of Irritation when used in combination with other ingredients

Good Humectant Properties

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Antioxidants

BHA, BHT, Propyl Gallate, t-Butyl Hydroquinone, Tocopherol All Provide Varying Benefits, Mainly as Formulation Stabilizers

Sodium Sulfites Technically are Preservatives Strong Reducing Agents Stabilizer for Other Ingredients

Sodium Erythorbate Isomer of Vitamin C Strong Reducing Agent GRAS, wide use in food industry

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Other Ingredients with Antimicrobial Activity

Lauricidian Surfactant Effective Against Gram Positive Bacteria Sometimes combined with Lactic Acid and EDTA

Biosurfactants Activity against Pseudomonas

Fragrances and Fragrance Mixtures

Enzymes, Phospholipids, Mono-Esters

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Potentiators: Multifunctional EDTA

Chelating Functionality Improves Preservative Performance

Has Activity against Pseudomonas

Helps Prevent Resistance to Antimicrobials

Helps Stabilize Color and Fragrance, Control Fading

Other Chelators/ Potentiators Include: HEDTA, DTPA, Etidronic Acid

Other Preservative Alternative Approaches

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Water Activity

Definition: A measure of water’s energy status in a system, aw. “Bound” water is not available for microorganism growth.

Microorganisms need “free” water within a product to survive and proliferate

Water activity and not water content is a better measure of the free water

Pure water has aw of 1.0, typical shampoo 0.96

Goal: lower water activity = less preservative!

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Water Activity Requirements

0.95 - 1.0 Gram Negatives

0.90 - 0.95 Staphylococci

0.87 - 0.90 Common Yeast

0.80 - 0.87 Common Mold

0.65 - 0.75 Xerophilic Mold

0.60 - 0.65 Osmophilic Yeast

Therefore…lower aw, create a more hostile microbe

environment

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Water Phase pH

Knowing the optimum pH for each of your preservatives is important in using preservatives effectively

Extreme pH’s can have an inhibitory affect on bacteria, yeast and mold

By using a combination of pH and Water Activity control, you are creating an environment which is hostile to microbial growth

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Water Phase pH Impact on Preservatives

Methyl Paraben Optimum pH 3.5 - 6.5 Generally poor activity >7.0

Organic Acids Optimum pH <6.0 Generally poor activity >7.0

Phenoxyethanol, Formaldehyde Releasers Not affected by pH

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Raw Material Specifications

Ensure that incoming raw materials are as clean as possible to minimize bioburden

Recommended <100 cfu per gram

Ensure that the water system is checked frequently and is free of bacteria

Consider it a critical “raw material” with specifications Beware of biofilm buildup in your holding tank, pipes and

valves Use hot water when possible

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Good Manufacturing Practice (GMP)

Ensure that the manufacturing tanks and filling lines are properly cleaned and sanitized

All transfer lines and storage tanks are properly cleaned and sanitized

That stored product is tested before filling and that partial drums are not returned to the warehouse

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Product Package Design

Package design can play a big role in minimizing contamination once in the hands of the consumer

It can act as a physical barrier to the external environment

Examples include: One way valves Pressurized components Airless tubes, sealed tops Unit dose packaging

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Conclusions

The Cosmetic Preservative Market Will Continue to Fragment

Regulations and Perception Will Continue to Drive Conventional Preservative Choices, Particularly as More Studies are Published

There is No Conventional or Alternative Preservative “Holy Grail”. The Market Will Mix and Match Preservatives to Meet Product Needs.

“Alternative Approaches” Should Focus on Creating as Hostile and Self-Preserving an Environment as Possible

There are Many Alternative Ingredients Available in the Market, as Reviewed. Most Have Unique, But Limited, Applicability.

There are Many Non-Ingredient Approaches Possible, Such as Water Activity Reduction, Which Can be Used Widely to Improve the Self-Preserving Environment

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Acknowledgements

My Thanks to the Following Colleagues and Groups forTheir Input and Support in Creating this Presentation

Lonza Teammates: Carl Cappabianca, Crystal Arlea

David Steinberg: Steinberg & Associates

Steve Schnittger: Estee Lauder

SCC Ontario Chapter

The CTFA Microbiology Committee