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Complementary methodology of stability tests for cosmetics products according to ANVISA- BRAZIL(Vol.3)
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| 작성일 | 2019-06-18 | 조회수 | 6,674 |
| 원문 | 한국보건산업진흥원 | ||
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(3) Complementary methodology of stability tests for cosmetics products according to ANVISA- BRAZIL.pdf(282.29KB)Complementary methodology of stability tests for cosmetics products according to ANVISA- BRAZIL – Volume 3 (final)
□ Abstract
The proposal of this article is to expresses Anvisa's understanding about the description of complementary methodologies required by ANVISA for the registration of cosmetics in Brazil. This is the tird one of a series of 3 complementary papers.
1. Introduction
Stability studies are aimed at evaluating the capacity of a product maintain the same organoleptic, physical- chemical, microbiological characteristics as well as its safety and effectiveness. Thus the stability study must be seen as a necessary requirement for the product’s quality guarantee and not merely as a requirement of the regulatory agency.
In Brazil, it’s responsibility of the National Health Surveillance Agency – Anvisa/MS to regulate, inspect and control the production and the commercialization of cosmetic products, in order to offer safe products and with quality, on the market; contributing in this way towards the protection of the population’s health.
2. Organoleptic Tests
Parameters are offered that make it possible to evaluate, immediately, the state of the study sample, using comparative analysis, with the aim of verifying alterations such as: phase separation, precipitation and turbidity allowing the primary recognition of the product. A reference sample must be used, recently elaborated, or a sample of the product, stored at an adequate temperature, in order to avoid changes in the organoleptic properties.
2.1 Appearance
The sample characteristics are visually observed, verifying if there were any macroscopical modifications in comparison with the standard established.
The appearance can be described as: granular, dry dust, moist dust, crystalline, paste, gel, fluid, viscous, volatile, homogeneous, heterogeneous, transparent, opaque, milky, etc.
The sample can be classified according to the following criteria:
· normal, without alteration;
· slightly separated, slightly precipitated or slightly turbid;
· separated, precipitated or turbid.
2.2 Color
The methods used to verify color are many; the most used being the visual and spectrophotometric methods.
Visual
The color of the sample is compared with the established standard in a flask with the same specification. The used light sources can be white, natural or in special chambers with many types of light sources.
The sample of the product can be classified according to the following terms:
· normal, without alteration;
· slightly modified;
· modified;
· intensively modified.
Spectrophotometric
The sample of the product under study, either pure or in solution is submitted to scanning analysis by spectrophotometry in the visible light band and its spectrum is compared to the reference spectrum. Variations in the intensity of the band (hyperchromic and hypochromic) indicate alterations in the intensity of the color or even modification of the coloring material.
2.3 Odor
The odor of the sample is compared with the established pattern directly, by smelling it. The sample can be classified according the following criteria:
· normal, without alteration;
· slightly modified;
· modified;
· intensively modified.
2.4 Flavor
The flavor of the sample is compared with the established standard, directly by tasting it. The sample can be classified according to the following criteria:
· normal, without alteration;
· slightly modified;
· modified;
· intensively modified.
3. Physical-ChemicalTests
The physical-chemical evaluations allow the formulator to detect future problems that can affect the stability and the quality of the product.
3.1 Hydrogen Ion Potential – Ph
The methods used for the verification of the pH value of the samples are:
colorimetric calibration: using universal indicators, and prepared ranges of buffer solutions and indicators. Presents low sensitivity. Small variations in acidity or alkalinity in the formulations are hardly observeable. potentiometric calibration: a pH meteris used (pedometer) and the value is measured by the potentialdifference
found between two electrodes immersed in the study sample. It is important to use an electrode suitable for the type of formulation being analyzed.
Both methods above lead to numerical results easily interpreted.
3.2 Volatile Materials
A measured quantity of the sample, analytically weighed, is submitted to drying in an oven heated to 105°C until it attains a constant weight.
The difference in the mass of the sample before and after the test shows the quantity of the mass of the formulation that will be volatilized under such conditions and this is usually expressed as a percentage. This method offers numerical results, easily interpreted.
3.3 Water Content
Many methods are used for the quantitative determination of water in a finished product, the most common being: Gravimetric Method, Distillation Method in Dean & Stark apparatus and the Karl-Fischer Titration Method. These methods produce numerical results, easily interpreted.
3.4 Viscosity
Viscosity is a variable that characterizes a system in its rheological aspect. The evaluation of this parameter helps to determine if a product presents the appropriate consistency or fluidity and can indicate if stability is adequate and thus gives an indication of the product’s behavior over a period of time.
The most frequent methods used in determining the viscosity of a fluid use, viscosimeters of the capillary or rotating type or with orifices. Such methods supply numerical results, easily interpreted.
3.5 Analysis of Particle Distribution by Size
The analysis of the profile of the particle distribution curve, during the stability period, makes it possible to accompany the microscopic behavior of the particles in suspension, highlighting instability phenomena.
Different factors both in the formulation itself and in the manufacturing process, affect particle formation and
consequently particle dimensions, notably the following: the preparation method, the quantity of mechanical energy introduced in the system, the viscosity differences among the phases and the type and quantity of emulsifier used.
Most of the equipments used for this analysis are based on the principle of dispersion or diffraction of laser light. The laser beam goes through the cell that contains the sample, and the particles disperse the light in beams that depend on: the wavelength, the optical properties of the sample and the particle dimension. After the analysis, the results, with the dimensions of the particles detected are extrapolated to apply to the entire population of particles in the sample.
The method offers numerical results, easily interpreted, in which the concentration, dimension and particle shapes can be evaluated.
3.6 Centrifuging
The force of gravity acts on the sample making the particles move within it.
The centrifuging test produces stress in the sample, simulating an increase in the force of gravity and increasing the mobility of the particles thus anticipating possible instabilities. These changes may appear in the form of precipitation, separation of phases, caking, or coalescence among others.
The sample is centrifuged at a standardized temperature, time and speed. Afterwards, the sample is visually evaluated.
3.7 Density
This is the ratio between the mass of a substance and the volume that it occupies, and generally for the liquids, it is determined using the pycnometer or the densimeter. In the case of liquids or semi-solids this parameter can indicate the incorporation of air or the loss of volatile ingredients.
For determining the (apparent) density of powders, a test tube and a balance are used. The apparent density is related to the capacity of the recipient.
It is important to avoid overflow or an apparent lack of product in the recipient that holds it, because the declared weight may be within the specified limits, but the consumer will have the impression that some of the product is missing.
3.8 Granulometry
In the product there are particles/drops of varying diameters. The proportion of particles outside the specified limits can influence in the appearance, in the performance and in the color of the product. For this kind of test, the following methods can be used:
· sifting: silk screen siftersare used with standardized mesh, to specifythe size of the particles;
· laser diffraction: used to evaluate very small-sized particles.
3.9 Electrical Conductivity
Uses measurement of the passage of electric current through the medium being evaluated using conductivity meters. The alteration of the electrical conductivity of disperse systems can indicate instabilities. An increase in conductivity may be related to coalescence and a decrease to aggregation.
3.10 Spectrum Photometry
Ultraviolet/Visible (UV/Vis): the absorption of light by a substancein the ultraviolet/visible range of the spectrum depends on the electronic structure of the molecule. Through the incidence of light energy on the sample, a spectrum is obtained that is used to obtain a graph plotting absorption/transmission against wavelength or frequency. The height (intensity) of the peaks (spikes) on the plotted line may be altered by changes in the concentration of the substance. This analysis can be used for identifying and dosing substances.
Infrared (IR): spectrum-photometry in the infrared (IR) frequencies is a technique widely used for identifying compounds as it is a method that is both fast and sensitive. It permits the identification of the substance by comparing its absorption bands with those of standardized chemicals. In contrast with the few spikes that can be observed in the UV/Vis range, the spectrum in the infrared frequencies offers many absorption bands generating a set of information about the chemical structure of the analyzed substance.
3.11 Chromatography
Chromatographic methods are used to identify and quantify the ingredients. The evaluation of a formulation component, over many time intervals, reveals its stability profile under the specified conditions. The following
methods can be mentioned: Slender Layer Chromatography (SLC), Liquid and High Efficiency Chromatography (LHEC) and Gas Chromatography (GC).
4. Microbiological Tests Applied to Stability Studies
The cosmetic products must be produced, stored, transported and distributed in a safe way, and must comply with Resolution 481/99. The presence of water and organic components in the formulation favors the growth of microorganisms. In some cases, this affects the structure of the additive agents, influencing the stability of the product and this justifies a microbiological evaluation of the product.
With the development of Good Manufacturing Practices, it is understood that the microbiological quality of a cosmetic must not depend exclusively on the system of preservatives. However, as their use is indispensable, the choice of the additives must be adequate in order to be effective. Besides, it must be considered that the additives may be partially or totally inoperative thus leaving the product without the hoped for protection. Therefore, effectiveness tests for the additives must be an essential part of the safety data of the cosmetic products. These tests are aimed at determining the type of additive and the minimum effective concentration necessary to assure satisfactory protection of the product from the moment of manufacture until its final use by the consumer.
4.1 Challenge Test of the Preservative System
The challenge test of the additive or preservative system consists in purposely contaminating the product with specific microorganisms and evaluating the sample at defined time intervals with the objective of evaluating the effectiveness of the preservative system necessary to the protection of the product.
The used of additives must be in conformity with that established in Resolution 162/01 and its updated versions. For a wider approach, the test must be done in at least two phases: the first after the definition of the formula of the product; and the second, after the end of the stability testing and/or the test for formulation compatibility with the containing material.
The analysis methods are described in the official compendium and orientation guides for cosmetic
microbiological analysis and effectiveness tests of additive systems(Pharmacopeias, ABC Microbiology Guide, Guideline of CTFA, among others).
5. Specifications for the Liberation of Produced Batches
If, at the moment of manufacture, a batch presents specifications close to the established limits for the product, then certainly a slight change may lead to the transgression of these limits and the occurrence of non- conformity that can reduce the time that the product maintains itself suitable for using.
With the aim of maintaining the expiry date projected for the product, it is desirable that two specifications be established: one denominated “Liberation Specification” to be adopted an the moment of manufacture, and the other denominated “Shelf Life Specification”, which characterizes the product over the period of its useful life. During the time the product is being stored under market conditions, its specifications can vary within the limits established by the liberation Specifications and the Shelf Life Specifications, and this is especially true for those parameters for which the product has lower stability.
Figure 1 exemplifies the possibility of establishing, a variation range of ± 5% of the nominal value of a certain parameter as a liberation Specification; and a variation range of ± 10% as a Shelf Life Specification.
6. Conclusion
This was the third and last paper in the series of articles on stability of cosmetic products according to ANVISA (BRAZIL). In this way, following the technical recommendations listed in the three articles, the company will have a strong technical dossier, meeting the expectations of the regulatory agency in case of favorable results.
Anyway, it is worth remembering that ANVISA offers several channels of communication with companies (telephone, internet and face-to-face meeting) in order to assist in the design of the studies, prior to the submission of the dossier by the companies. This helps minimize possible requirements, which slow down the product registration process in Brazil and generate more costs for companies.
Reference
BRASIL. ANVISA. Agência Nacional de Vigilância Sanitária. Guia de Estabilidade para Produtos Cosméticos, publicada em http://portal.anvisa.gov.br/ em maio de 2004.
[BRAZIL, ANVISA - Brazilian Health Surveillance Agency. Cosmetic Product Stability Guide published in http://portal.anvisa.gov.br/ in 2004, may].
□ Profile
Priscilla Viana Palhano Lima was Manager of Regulatory Affairs and Special Projects of the Brazilian public laboratory. He was directly in charge of the legal compliance of technology transfers with foreign companies from France, Poland, the United States and South Korea. He has experience in dossier analysis and elaboration of Partnership for Productive Development projects for the Ministry of Health. She is currently a consultant in Regulatory Affairs and Project Management of Partnership Projects for Productive Development for the Ministry of Health. Priscilla is the founder of the Argo Consulting company that promotes consulting in the areas of regulatory affairs, business development, project management international partnerships and technology transfers in partnership with MM Assessoria Industrial company.
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