MANUFACTURING IN MANUFACTURING IN COSMETICS COSMETICS

FROM THE LABORATORY TO FROM THE LABORATORY TO FULL PRODUCTIONFULL PRODUCTION

November 6, 2007

Eugene M. Frank, PH.DSR V.P. RAANI CORPORATION

BEDFORD PARK, IL

OUTLINE OF PRESENTATION• TYPES OF COSMETIC PRODUCT FORMS

• COSMETIC R&D LABORATORY & EQUIPMENT FOR FORMULA PREPARATION.

• STABILITY & TESTING PARAMETERS.

• PILOT SCALEUP OF COSMETIC FORMULATIONS AND ASSOCIATED PARAMETERS.

• MANUFACTURING IN THE PLANT ENVIRONMENT

• SUMMARY

COSMETIC PRODUCT FORMS

• Selection of a proper product form is important in order to achieve the criteria of marketing and technical attributes desired in the final system.

• One must balance the desired consumer perceived benefits with the technical ability in the formula to deliver such benefits.

SOLUTIONS• These are the simplest forms of cosmetic products. Are characterized

as liquid systems in which all of the constituents are soluble.

• Solutions can be water or oil based systems and are easy to manufacture as they usually consist of utilizing a single mixing vessel where the main diluents is added and then mixing in one ingredient after another.

• In most cases heating and/or cooling are not required to achieve a homogenous solution ; the only thing needed is adequate mixing of the components.

• Even though solutions are easy to produce from a manufacturing perspective, they do possess the downside of offering little functionality. Many functional cosmetic ingredients have limited or no solubility in water and require other product forms.

CREAMS

• Most cosmetic cream formulations are emulsions which are defined as a heterogeneous system composed of an immiscible liquid dispersed as droplets in another liquid.

• Emulsified cream products can be O/W or W/O systems depending on the continuous phase.

• Most (75 % +) of cosmetic creams are of the OIL-IN-WATER type with an oil phase ranging from 10%-25%. Typical products that use creams are Shaving products , Skin care, Antiperspirants, etc.

• Most cream formulations of cosmetic products are well perceived by the consumer and have aesthetic appeal.

• However, since this dosage form is an emulsion they are inherently unstable and proper stability testing must be done in the lab before releasing for actual manufacturing on a large scale.

LOTIONS• This is the type of product form that is used in applications, where a less viscous dosage form

is desired from a rheological perspective. They can be defined as thin creams.

• As these products are also emulsions in nature they are less greasy to the touch and are lighter in texture to the consumer.

• From a manufacturing perspective lotions are easier to produce as they are less viscous and heating and cooling times are lessened.

• From a rheological perspective, it is important to remember that lotions are less stable thermodynamically from creams because the higher viscosity of a cream will slow down the natural destabilizing forces.

• Examples of products that utilize the lotion form are :– Skin and Facial Lotions– Hair Conditioners– Moisturizing Cleansers

OINTMENTS AND PASTES• This type of product form is utilized when there is a desire for a formula to be extra viscous

in consistency.

• They are thicker than creams and can be total anhydrous systems or contain a very low amount of water. Most are heavy or greasy as they contain lanolin, petroleum and mineral oil as the main constituents.

• It is important to note that since this product form are essentially oil based systems, they present few stability issues ( outside of rancidity or lipid oxidation ) and do not have microbiological contamination issues.

• Because of their high viscosity or thickness, problems in manufacturing can arise especially in compounding and filling.

• Examples of products that are ointments in nature are :– Hair Pomades– Medicated Skin Products– Ethnic Hair Treatment Items

SUSPENSIONS• This product form is related to emulsions, are usually water-based formulations which

contain larger, often visible products suspended throughout.• They can range in viscosity and this type of product form offer a unique visual effect

to the consumer not observed in other cosmetic products.

• By means of suspensions one can deliver non compatible ingredients.• From a stability perspective, suspensions usually contain either an inorganic thickener

or structurizing polymer which “lock” the particles in place. This counteracts instability such as Van Der Waals or hydrophobe/ lipophobe interactions

• Production of suspensions is generally easier than producing emulsions as separate mixing kettles are rarely required.

• Examples of suspensions are :– (encapsulated emollients) – Sunscreen lotions with titanium dioxide or zinc oxide– Calamine lotion– Antiperspirant sticks

GELS• This product form can be defined as clear, shear thinning formulations. They are

composed usually of water or alcoholic solutions gelled or thickened with specific gelling agents such as natural gums, acrylic polymer or cellulosic type polymers.

• There is a special type of gel system which can be made called a micro emulsion or “RINGING” gel that vibrates or rings when you tap the container.

• In the manufacturing process large scale production is complicated by their high viscosity. AIR entrapment is common place during this manufacturing mode and careful mixing is required to avoid this from happening.

• Examples of gels include:• Shower Gels• Shaving Gels• Toothpastes• Ethnic “Shine” Hair Products (Microemulsion)

STICKS• This is a product type which can be used to deliver insoluble materials

such as fragrances, pigments, emollients and specific active ingredients.• They are usually opaque but can, in some cases, be formulated as clear

products.• Sticks can be made as a sodium stearate type or as a pure stick from high

melting point ingredients such as waxes, hydrogenated oils and esters.• Stick formulations have good stability profiles as their solid structure

inhibits most destabilizing processes.• Examples of stick personal care products are:

• Deodorant sticks• Antiperspirant sticks• Hair styling sticks• Lipsticks

POWDERS• Powders present the simplest form of a solid dosage form. They consist of

solid raw materials blended together in a fine mixture.• Common ingredients that are utilized in the formulation of powders include:

• Talc• Starch• Titanium dioxide• Silicates• Powders are a relatively stable product form and during the

manufacturing process involving specialized mixing equipment, it becomes critical to avoid contamination with water.

• Examples of powder personal care products are:• Baby powders• Anti-fungal powders• Body talc

AEROSOLS• In contrast to the product forms discussed earlier, aerosols depend more on the

packaging for their existence than the ingredients.• Aerosols are composed of a concentrate solution that is filled into a metal can

after being pressure-filled with a propellant that is hydrocarbon or freon based.• In compounding the active materials are mixed with the solvent and then this

concentrate is filled into the can. The propellant is added and the can is sealed.• Stability issues are primarily of can corrosion and can be prevented by adding

corrosion inhibitors to the formula with high water contents.• Examples of aerosol personal care products are :

• Shaving creams• Hair sprays• Aerosol antiperspirants & deodorants• Feminine deodorant products

COSMETIC R&D LABORATORY

• The development of aesthetic and chemically stable personal care formulations has its origin in the research and development department.

• The development of such formulations and the ultimate manufacturing and production can be visualized in the product development “ CASCADE” of steps as follows :

• Formulation “ BRAINSTORMING”• Prototype development and panel testing.• Formula optimization and selection for desirable

aesthetic/ marketing parameters.• Stability testing of lab prepared samples.

•Pilot scale-up and production of formula with appropriate stability testing.

•Intermediate sized experimental batch and appropriate stability testing.

•Selection of proper processing equipment for full production-sized run.

•Process evaluation and validation.

•What are the needs in the way of equipment for the research and development laboratory in order to help begin the “product development cascade” of events?

BASIC LABORATORY EQUIPMENT

• Mixer-stirrers either electric or air driven equipped with both propeller and sweep ( simulated) shafts to simulate production processing equipment.

• Viscometer capable of determining viscosity of very fluid liquid systems to thick viscous creams and ointments.

•Ph meter for assessing specific acidity or alkalinity of a formulation.

•Heating device ( hot plate or mantle) for preparation of formulations requiring thermal energy.

•Refrigerator and/or oven for minimum stability testing of formulations.

OPTIONAL LABORATORY EQUIPMENT

• Centrifuge for additional analytical and stability testing.• Cone penetrometer for relative “ HARDNESS” of creams,

gels, ointments etc.• Analytical instrumentation in conjunction with quality

assurance lab equipment for advanced needs.

• IR spectro photometer• HPLC• UV-visible Spectro photo meter• Specific claim substantiation equipment ( EX-Instron)• Lab homogenizer

STABILITY PARAMETERS AND TESTING• Formulations in R&D routinely examine product stability using various

procedures.• It is rarely possible to predict long term stability of any product, even

after repeated examinations of the formula during and after exposure to artificially created stress conditions.

• Typical stress conditions used by formulators in the hope that product performance and appearance are not adversely affected during the projected product shelf life include:

• Heating• Freezing• Centrifugation

• Within the cosmetic industry, shelf life projections are based on the formulators assessments of stability data in contrast to much more rigorous analytical testing that is found in the pharmaceutical industry.

• Cosmetic products may exhibit instability due to chemical changes of the individual chemical components or the presence of undesirable micro-organisms.

• If one examines the various product forms discussed earlier in this presentation, creams and lotions that are emulsions by definition possess the greatest potential for stability problems during the shelf- life of the product.

• Cosmetic formulations, especially emulsions dosage forms, are thermodynamically unstable systems. They obey the basic laws of physical chemistry and tend to revert to states of lowest free energy. (I.e.- oil and water phases).

EMULSION INSTABILITY TYPES• CREAMING

• Separation into two or more layers having different phase concentrations and different particle size distributions.

• Encountered in primarily fluid ( low viscosity) emulsions and usually can be minimized by reducing droplet size. Will not occur if both phases have the same density.

• EMULSION BREAKDOWN• Usually preceded by a sequence of physical processes,

flocculation and coalescence, and can be caused by:

• Electrolytes

• Micro-organisms

• pH

• Temperature extremes

• Mechanical stresses

• Must monitor stability samples rigorously to determine extent of above physical processes

• INVERSION:

– Defined as the change from one type of emulsion form to another with the “FLIP” of the continuous phase.

– Rare, but can occur in certain types, of o/w systems. Example Borax / Beeswax upon loss of water)

PREDICTIVE COSMETIC STABILITY TESTING OF

EMULSIONS– Cosmetic stability testing, in general has to do with the

primary concerns of physical appearance and the products use characteristics.

– Review of main parameters for emulsion instability:

• TEMPERATURE

– Rule of thumb assumes three months storage at a temperature between 37 degree C and 45 degree C

– with no evidence of separation should guarantee stability of the formula at room temperature ( 25-30 degree Celsius) for one year.

– Above rule is based on principles of the arrhenius equation which may not be valid for emulsions.

– Based on the above it is an accurate point to state that stability testing of emulsions should not be based solely on high temperature testing.

• RHEOLOGY

– Formulators utilize the examination of rheological change as a predictive tool to assess emulsion stability.

– This type of stability testing includes the use of viscometers and/or cone or needle penetrometers.

• STABILTY OF ACTIVES IN COSMETICS

– Testing of drug ( active) constituents in emulsions using the Arrhenius equation requires storage at two temperatures at which chemical decomposition may occur. The wider the separation between the temperatures the more reliable is the analysis.

– The tendency of emulsions to separate at elevated temperatures may have effects on drug solubility and can alter reaction rates.

• PARTICLE SIZE

• Particle size measurement of the disperse phase in an emulsion requires careful interpretation.

– A continuous increase in particle size should result in emulsion instability unless the preparation is very viscous.

SUMMARY OF ACCEPTED GUIDELINES FOR ACCELERATED

STABILITY TESTING

CONDITION TYPE OF ASSESSMENT 25°c ± 2°c One year

30 °c ± 2°c One year ( Equivalent to R.T)40 °c ± 2°c Six monthsFreeze/ thaw Cycle repeatedly between 4 °c and

40 °c or 45 °c .LIGHT TESTING

Fluorescent One to two weeks ( or longer).Xenon One to two weeks. Ultraviolet One to two weeks. Daylight One year.

SHAKING One week at 30°c or 40°c.

CENTRIFUGATION One or two hours.

OTHER TESTING

PILOT SCALEUP OF COSMETIC FORMULATIONS

• It is not unusual for a formula which has been successfully developed in the R&D lab to exhibit different characteristics when it is transferred to production. As the formula is transferred from a small, laboratory-scale apparatus to large-scale production equipment, a difference in condition is experienced.

• Process Scale-up involves:

– The successful duplication of a formulation’s primary physical characteristics over a specific range of increasing batch sizes.

– The successful duplication of a formulation’s primary physical characteristics over a variety of manufacturing equipment.

• Upon successful scale-up you can trouble shoot:

– Manufacturing issues

– Formulation issues

– Equipment issues

– Raw material issues

GOALS OF SCALE-UP

• Batch Reproducibility

• Quick startup in manufacturing.

• Increased profit to company.

REASONS FOR SCALE-UP

TRADITIONAL REASONS:

– Right first time production batches

– Quicker to market for company

– Less downtime

• NEW REASONS:

– Lower emulsifier levels

– Requires higher mechanical energy

– Better designed equipment with $ savings.

Scale-up technique involves R&D pilot batches which require time and patience on the part of the formulator.

WHAT IS THE RATIONALE FOR PILOT EQUIPMENT?

• For preparation of scaled-up versions of specific R&D formulations intermediate in size between laboratory ( 1-2 kg) and production ( 1000-2000 gallon) batches.

• Applicable for the following product types:– Emulsions including creams and lotions

– Suspensoid systems including gels and sticks.

– Non-Suspensoid systems and miscellaneous product types.

• Useful for stability test data analysis in tandem with that which is obtained from laboratory batches

• Additionally, equipment can be utilized for small-sized production batches which could not be manufactured utilizing normal processing kettles.

• In summary the overall benefits of formulation scale-up in the cosmetic industry are as follows:

– Provides a smoother transition of manufacturing procedures from the laboratory to the plant environment.

– One can obtain fewer failures on first-time production batches.

– From an efficiency perspective, one can realize a quick production start-up with less scrap and rework.

MANUFACTURING IN THE PLANT ENVIRONMENT

• In our previous discussion of scale-up we examined the overall reasons and benefits for pilot batches and procedures as they relate to cosmetic formulations.

• It is generally believed that scale-up is am engineering function. In essence, it is a dual function between the formulator and the process team in the plant.

• As the given formulation is guided through the scale-up stages for plant production there are number of key areas that become critical to the overall process:

– Mixing

– Heat transfer

– Mass transfer

• Without going into detailed engineering equations regarding mixing criteria the key points to consider in the plant setting for this procedure are

– Impeller dimensions and types– Impeller speed– Impeller diameter to tank diameter referred to as the O/T

ratio.– Turnover rate ( number of batch turnovers per unit time)– Flow profile based on the impeller and vessel

configuration and batch loading.

• Heat transfer variables primarily involve:– Heat transfer medium– Heating and cooling rates– Maximum and minimum temperatures

• Lastly, mass transfer primarily is concerned with phase transfer rates.

• It is important to understand that not all products react adversely with bench-to-production variations. There are many products robust enough to withstand all but the most extreme variation.

PROCESS ROBUSTNESS

• Within the pharmaceutical industry there is a term that is used which can be transferred to personal care manufacturing. That term is called PROCESS ROBUSTINESS.

• ROBUSTINESS is defined as “ the ability of a manufacturing process to tolerate the expected variation of raw materials, operating conditions, process equipment, environmental conditions and human factors.”

• In order to develop a robust manufacturing process there are six steps which need to be followed:

– Team formation– Define the process– Prioritize experiments

– Analyze measurement capability– Identify functional relationships– Confirm critical quality attributes and critical process parameters.

• Creating a system that facilitates increased process understanding and leads to process robustness benefits the manufacturer through quality improvements and cost reduction.

• Information about the process setting and key relationships are communicated to manufacturing. Upon transfer, manufacturing begins to verify R&D’s information on process robustness through process monitoring and data analysis. Both general and process specific improvement activities help manufacturing attain and maintain its goals.

RHEOLOGICAL CONSIDERATIONS AND

BATCH PROCESSING• Definition of basic concepts:

– Rheology- Study of the flow of matter.

– Viscosity- The measure of the matter’s resistance to the flow.

– Rate of shear- The measure of movement of matter depending on force applied.

– Viscosity= Shear stress/ rate of shear

• Emulsions are systems where the viscosity varies with the rate of shear. This is in contrast with typical Newtonian systems where viscosity is independent of the rate of shear.

• Emulsions can also exhibit:

– Thixotropic properties- viscosity decreases with shear time.

– Rheopectic properties- viscosity is a function of duration of the applied stress; viscosity increases with shear time ( rare in emulsion systems).

PROCESSING PARAMETERS AND PROBLEMS

• FACTORS INFLUENCING VISCOSITY

1. Temperature of various processing steps

– Individual phases before emulsification

– Phases upon combination

– Cooling water temperature

– Blend pumped out of process vessel.

– Blend at filling point.

•

2. Mechanical work

– Shear of mixing

– Homogenization or milling

– Transfer work ( pipes, values, nozzles, etc)3. Time factors

• Heating period• Cooling period• Mixing period

– All factors do not operate independent of each other. Ex-reducing mixing speed to minimize shear thinning results in decreased cooling efficiency.

MIXING EQUIPMENT AND IMPLICATIONS

• Extremely critical parameter for emulsion systems.

• In a highly thixotropic emulsion with a high yield value, avoid a small propeller as only a small portion of fluid near the propeller would move. A larger diameter propeller ( paddle type) would ensure for better mixing.

• Flow to fluid shear ratio is the term used in engineering to judge mixing requirements.

• In an emulsification process, a high shear level ( high speed mixer) is needed, while in heat transfer steps, such as heating and cooling, high flow ( low speed mixer) is desirable.

• A proper combination of the above two mixing procedures will yield the desired processing result.

EFFECTS OF VISCOSITY ON PROCESSING CONDITIONS

• Product viscosity can directly influence the mixing and cooling rate.

• In a high viscosity emulsion, the heat transfer efficiency is lower and, therefore, so is the rate of cooling.

• Similarly, a high viscosity product or a shear thickening product can cause both pumping and filling problems under production conditions.

• AIR ENTRAPMENT is common in high viscosity products. This is dependent on :

– Amount of air “trapped” during processing and filling.

– Amount of air escaping after entrapment.

– A shear thinning system tends to aerate much easier than either Newtonian or shear thickening formulations

• Solutions for de-aeration include:

– Gentle heating.

– Impeller size and / or speed adjustment.

– Varying pumping procedure.

– Use of vacuum deaerator such as a versator.

PUMPING VARIABLES DURING PROCESSING

• Critical equipment for proper processing and filling of cosmetic type formulations.

• Two basic types of pumps used for cosmetic processing:

1. SHARE POSITIVE DISPLACEMENT TYPEDiaphragm--- Good for liquid, low shearGear--- Impart high shear

Moyno--- Impart low to medium

2. Centrifugal type

Works on principle of conversion of contrifugal force into pressure. This type of pump will not function at very high pressure or viscosities.

COOLING CONDITIONS DURING PROCESSING

• This is critical in emulsions, as rate of cooling affects the final viscosity. Some products require slow cooling, while others require “ FORCED COOLING” through use of a water jacket.

• Temperature and seasonal factors can impact cooling time in non-air-conditioned environments. Use of a chiller may be essential.

PROCESS VALIDATION CONCEPTS

• DEFINITION-establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting pre-determined specifications and quality attributes.

• TWO BROAD TYPES OF VALIDATIONProspective--- That done for a new product or revised manufacturing conditions.

Retrospective--- That done for a product already in distribution.

• Fundamental concept is documentation of protocols and/or procedures so as to identify the “KEY” areas which require special attention.

• Similar in format to a total quality assurance standard operating procedure ( SOP) with special emphasis placed on particular areas such as :

• Gauge calibration

• Preventive maintenance

• Statistical analysis

• Emphasis of process validation is on prevention which is identical with the concept of quality management.

PROCESS EQUIPMENT OVERVIEW

SUMMARY• This presentation has attempted to provide an overview of the

development, testing, scale-up and manufacturing of personal care and cosmetic products.

• Emphasis has been placed on the importance of scale-up techniques and the use of proper equipment, especially regarding emulsions, to manufacture these type of formulations.

• Preparation is the “KEY TO SUCCESS” in any endeavor in life, be it business or personal in scope. The same philosophy holds true in the successful manufacturing of cosmetic products.