2005 ANNUAL SCIENTIFIC SEMINAR 367 Test methods and guidelines, such as the CTFA Guideline for Determination of Preservative Adequacy in Cosmetics, provide guidance in many areas of PET testing. Some of the guidance includes: • Personnel qualifications • Importance of Manufacturing GMPs • Factors to consider when designing preservative systems • Importance of testing formulations during development • Importance of using microbiologically acceptable raw materials • Use of an unpreserved formula as a control to determine the need for preservation • Stability testing of preservative systems • Testing of product in final packages after storage Similarly, the COLIPA Microbiological Testing Guidelines on Microbial Quality Management (MQM) note that the function of preservatives is consumer protection and prevention of spoilage during normal and reasonably foreseeable product use, that preservatives should not be used in lieu of good production hygiene, and that preservative selection should be chosen by microbiological challenge tests during product development. The Guideline states that packaging should be designed to restrict contamination and to avoid condensation of water from the product on the inner surface. Inactivation of preservative systems by the container and diffusion through it should be considered. Unlike the CTF A Guidelines and the compendia! methods, the Colipa Guidelines do not specify acceptance criteria. Thus, interpretation of adequacy of the preservative system is determined by review of the challenge test data, packaging, and intended consumer use. The recommendations from each of the methods will be discussed, and compared, including the challenge organisms, media, differences, and acceptance criteria - both time of exposure and reductions observed - will be highlighted. The differences between "compendia!" tests for drug products, standard test methods, and association guidelines will be reviewed. For example, the CTFA Guideline notes that the criteria are "minimal criteria". Manufacturers should understand that the preservative system of the formula, packaging, and consumer use must be evaluated in determining the preservative requirements of each product.
368 JOURNAL OF COSMETIC SCIENCE PRESERVATION - LEARNING FROM THE BASICS Donald S. Orth, Ph.D. Neutrogena Corporation, Los Angeles, CA 90045 Preservative efficacy testing is performed on aqueous cosmetics and drugs to determine the minimum effective concentration of one or more preservatives required for adequate control of contamination. Products are satisfactorily preserved if they meet appropriate acceptance criteria and if they are packaged properly. 1his presentation discusses the advantages of the linear regression method, acceptance criteria, the preservative system concept, use of the principles of preservation to reduce the need for chemical preservatives, and the use of a miniaturized system for preservative efficacy testing without counting colonies. PreseITative Efficacy Test Methods Several methods of preservative efficacy testing are used in different countries, including US Pharmacopoeia (USP), European Pharmacopoeia (EP), The European Cosmetic, Toiletry and Perfumery Association (COLIPA), Japan Cosmetic Ingredient Association (JCIA), and rapid procedures such as the Linear Regression Method. Advantages of the Linear Regression Method Several factors need to be considered when selecting the method of preservative efficacy testing used. These include reliability, time required for testing to be completed, labor and material costs, acceptance criteria, compliance with regulations or corporate guidelines, and environmental impacts of testing. The linear regression method offers several advantages, as follows: Quantitative - The rates of microbial death are expressed numerically in D-values. The D-value is the time required for a 90% decrease ( 1-log reduction) in the population of test organisms. The rationale for use of D-values is that every organism has a characteristic rate of death when subjected to any lethal treatment. Reliability - A method must be reliable or it is not worth using. The reliability of any test method depends on precision, sensitivity and accuracy. In microbiological testing, the precision generally depends on the skill and care used by the analyst. In the linear regression method, the correlation coefficient is used as an indicator of precision and is used to demonstrate the 'goodness of fit' of the data to the regression in this method. 1b.is allows a statistical control of each set of data. The linear regression method allows reliable determination of whether a product is satisfactorily preserved when appropriate recovery systems, culture conditions and acceptance criteria are used. Acceptance Criteria - It s possible to set meaningful guidelines for accepting or rejecting a product based on the performance of its preservative system because the linear regression method provides a quantitative measure of the rate of die-off of test organisms. Selection of appropriate acceptance criteria is key to successful preservation of a product. Rigorous criteria generally are desirable because they minimize the likelihood of product contamination during manufacturing and during use by the consumer. They minimize the Phoenix Phenomenon (i.e., rebound of organisms after initial testing reveals no organisms present). A preservative system with D-values no greater than 30 hr (e.g., about a 6-log reduction in 7 days) for gram negative bacteria has a greater safety factor than one with D-values of 56 hr (e.g., 3-log reduction in 7 days). Target acceptance criteria for topical products are: • D-value of 4 hr for pathogens/opportunistic pathogens • D-value of 28 hr for non-pathogens, yeasts and molds • Bacteriostatic or slowly bactericidal for Bacillus spp. spores. Time Needed to Complete Testing - The linear regression method is rapid because it uses rigorous acceptance criteria. Testing for pathogens may be completed within three days tests for nonpathngenfc bacteria, yeasts and molds may be completed within two weeks.
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