Preservation of Personal Care Products A Microbiologist s View

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Preservation of Personal Care Products A Microbiologist s View PCPC Microbiological

Mitchell Development Manager Microbiology Unilever Trumbull, CT Presentation Objectives

requirements for a product formulation Impact of formulation ingredients on preservatives

1 Preservation of Personal Care Products A Microbiologist s View PCPC Microbiological Workshop October 26, 2011 Deidre L. Mitchell Development Manager Microbiology Unilever Trumbull, CT 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 selection (Regulatory and Public Relations (PR) Consumer Use Distribution 1

2 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: 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. 2

3 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 Action Preservatives are not selective like antibiotics, they 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 3

4 Factors Affecting Microbial Growth Bacterial growth & survival are affected by: Physical Conditions ph Temperature Water activity (a w ) Nutrition Environment Presence/absence of antimicrobials or preservatives 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) 4

ph Personal Care Products Hair Gels Facial Cleansers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Shampoo Skin Cream Body Wash Hair

Water available for microbial growth Not the percentage of water in a formulation The higher the a W the greater the

5 ph Personal Care Products Hair Gels Facial Cleansers Shampoo Skin Cream Body Wash Hair Conditioner No Chemical Preservative Required Chemical Preservative Required Water Activity and Preservation What is It? Water available for microbial growth Not the percentage of water in a formulation The higher the a W 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 5

6 Water Activity (a w ) and Potential for Growth Water Activity ph Level Problem Organism Gram Positives and Gram Negatives Gram Positives and Gram Negatives, Pseudomonads Limited < 5.5 Gram Positives and Gram Negatives, Pseudomonads Limited Product Examples Shampoos and Emulsions Eye area products Hair Conditioners Mold and Yeast Some Talcs Osmotolerant Yeast Some Anti- Perspirants Osmotolerant Molds Below 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 Shampoos Foam/Bath/Shower Products Hair Conditioners Creams and Lotions Oil-in-Water Emulsions Water in Silicone Emulsions Concentrated Liquids (Typically > 40% active) Anti-bacterial 3 and Anti-fungal 4 preservative required Unlikely to require an antibacterial preservative, may require an anti-fungal preservative < 0.60 High alcoholic deodorants Preservative not required 3 Aw 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. 6

Temperature Thermophiles Mesophiles Psychrophiles Body temperature- most human pathogens grow best at 37 o C -10 0 10 20 30 40 50 60 70 80 90 100 C Yeasts Molds Other Ingredients Impacting

7 Temperature Thermophiles Mesophiles Psychrophiles Body temperature- most human pathogens grow best at 37 o C C Yeasts Molds 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. 7

8 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.cepacia and P.aeruginosa. Recommend incorporating a chelating agent into product formulation to strengthen the preservative system. How EDTA Enhances Preservative Activity Preservative Preservative calcium and magnesium ions stabilize the outer and inner membranes of Gram negative cells - this helps protect them from preservatives LPS of outer membrane Add EDTA EDTA chelates calcium and magnesium which destabilizes the cell membranes - helping preservatives to attack the cell Inner membrane Add EDTA 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 EDTA WILL NOT WORK IN FORMULATIONS WITH HIGH LEVELS OF Ca or Mg 8

9 Preservative Selection Additional Considerations Legal Restrictions Company Restrictions PR Restrictions Preservative Selection Legal Microbiologists need to be aware of the restrictions on preservatives When providing recommendations to Chemists/Formulators! Approvals European Union (EU) China Canada Japan United States Documentation Pre-approves preservatives and publishes a positive list known as Annex VI Hygienic Standard for Cosmetics (version 2007/01) issued by China Ministry of Health (MOH). Publishes a hotlist of ingredients that are either prohibited or restricted Publishes a positive list (restrictive and classifies approvals based on the end use of the cosmetic FDA has a list of prohibited or severely restricted ingredients 9

10 Preservative Selection - Legislation May require additional testing (i.e. Shelf life justification) 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. 10

11 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, MCI/MI Methylchloroisothiazolinone and Methylisothiazolinone Stable up to 85 C Ref. David Steinberg, Preservatives for Cosmetics, Second Edition, Allured Publishing, 2006 Ingredients 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 11

12 Preservative Neutralizers and In-activators Parabens Lecithin, Non-ionic surfactants, polysorbate, gums, alkaline ph, polyethylene glycol Alcohols Gums, non-ionic surfactants, especially Tweens MCI/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 Preservative Neutralizers and In-activators Neutral -> Alkaline ph, non-ionic surfactants, CaCl 2, Tweens Formaldehyde Donors Incompatible with Parsol

13 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 phase Phenoxyethanol, Benzyl Alcohol, Benzoic acid and Parabens Preservative challenge testing is critical to demonstrate effectiveness 13

14 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 cost 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 14

15 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 of 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) 15

16 Consumer Use Restricted Access Packaging (i.e. Eye Creams Packaged 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 Considerations Skin 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 formula preservative system Real Life Experience Formulation needs a preservative until determined otherwise If not sure it needs a preservative, it needs preservation 16

17 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 cliff 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 17

18 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 substantial failure in GMPs 18

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

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.

19 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. Mold growth around the edge of PE laminated paper Mold growth on PE laminate Bottom of paper cartridge Bottom of primary container Top side of paper cartridge 19

20 Summary of Preservative Selection Parameters Efficacy Target Consumer Cost Water Activity and Formula ph Formula Compatibility and Stability Factory Hygiene Status Packaging Regulatory Requirements Public Relations Issues Sensitive Skin etc Mildness Claims Chelating Agent Addition Processing 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 growth 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 made Intended life cycle of the product, including distribution 20

21 Thank you for your attention Contact Information: Deidre L. Mitchell Telephone:

The Good, The Bad & The Ugly: Formulation Tips for Traditional Preservatives. Personal Care Products Council Microbiology Seminar

The Good, The Bad & The Ugly: Formulation Tips for Traditional Preservatives Personal Care Products Council Microbiology Seminar October 24, 2013 Chuck Jones The Dow Chemical Company Lest You Think Preservative