Alternative Preservatives

1. SCC Ontario Education Day Alternative Preservatives R. Nunez/ Lonza Inc./ Sept. 2006

2. 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

3. 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

4. Without Preservatives • Risky Business • Product Spoilage, Recalls • Health, Infection Issues • Formulating Without a “Safety Net”

5. With Preservatives • Preserved Formulations • Low Cost “Insurance” • Tradeoff between Preservation and Formulating Issues • Need Preservative Potency, Compatibility and Stability

6. 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

7. 20032001 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 What Preservatives Do We Use Today?

8. “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

9. 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…..

10. Is the Perfect “Alternative” Preservative Possible? • Water Soluble • Colorless and Odorless • Cost-Effective • Widely Compatible • Globally Approved • Available for Use Today…..

11. 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?

12. Preservatives Today: Where Are We?

13. 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

14. 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

15. 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

16. Global Regulatory Overview (2) • Other Countries • Brazil, Australia, Korea, China • Many Driven by US or Europe • Gets Complicated……Seek Regulatory Assistance

17. Conventional Preservatives Profiles

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. Other Conventional Preservatives • Bactericides • Benzalkonium Chloride • Benzethonium Chloride • Chlorophenesin • Methyldibromo Glutaronitrile • Sodium Hydroxymethylglycinate • Thimersal • Triclosan • Triclocarbon • Fungicides • Glutaral • Zinc Pyrithione • Zinc Oxide

25. 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

26. 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

27. Alternative Preservative Approaches

28. 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

29. 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

30. Alternative Ingredients with Antimicrobial Activity

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. Other Preservative Alternative Approaches

41. 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!

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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