Alternative Preservatives

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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
  ManufacturingBut 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
• 1920s Parabens, Formaldehyde
• 1940s Alcohols, Phenoxyethanol
• 1960s Staph Outbreak from Hospital Hand Lotions
  - Changed Attitude towards Preservatives
• 1960s Formaldehyde Studies, Concerns
• 1970s Imidazolidinyl Urea, DMDMH, Bronopol
• 1970s FDA Surveyed Cosmetics, Found 24
  Contaminated
• 1980s Diazolidinyl Urea, Isothiazolinones
• 1990s Blends Introduced, e.g. DMDMH/ IPBC
• 2000s 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?

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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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Todays 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 ComplicatedSeek Regulatory Assistance

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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 lt50C
• 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 lt50C
• Primary Amines, Sulfites
• pH range lt6
• 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 (PG)
• CMI MI
• Herbal Essences Shampoo (Clairol / PG)
• DMDMH IPBC
• Nivea Visage Cream (Beiersdorf)
• Phenoxyethanol Diazolidinyl Urea
• Plenitude Facial Lotion (LOreal)
• Imidazolidinyl Urea Parabens
• Head-to-Toe Baby Cleansing Cloths (JJ)
• Phenoxyethanol Parabens Citric Acid

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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
• Its NOT on Europes Positive List
• Its NOT on Japans 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

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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

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Other Preservative Alternative Approaches
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Water Activity

• Definition A measure of waters 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
• Thereforelower 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 pHs 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 gt7.0
• Organic Acids
• Optimum pH lt6.0
• Generally poor activity gt7.0
• 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 lt100 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
  for
• Their 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