Industry Experts Speak on Blending, Processing

Industry Experts Speak on Blending, Processing

Blending and processing techniques can make the difference between producing a reliable, high-quality, homogenous, shelfstable product and an inferior one that may cause poor consumer confidence and potential regulatory reprimands. Particle size, equipment requirements and bioavailability issues are primary blending and processing considerations, as are potential ingredient interactions. INSIDER conducted a question and answer session with companies providing manufacturing services to find out how blending and processing techniques ensure product consistency.

INSIDER: How important is uniformity to a finished product?

Ram Chaudhari, Ph.D., FACN, CNS, senior executive vice president, chief scientific officer at Schenectady, N.Y.-based Fortitech Inc.: It is crucial to have an even distribution of nutrients in finished products. If the final product is not homogeneous, it will not meet label declarations and will eventually fail to meet regulation requirements. In addition, consumers will not get their moneys worth.

John Blanco, president at Bridgeport, Conn.-based AnMar International:

Imagine getting a multivitamin with a stated amount of 500 mg of vitamin C, but due to a foul-up during blending, the product has less vitamin C than stated on the label. Now, the company has a problem because it has put a product into interstate commerce that is technically adulterated. This is a Food and Drug Administration (FDA) problem. Also, they would/could have a barrage of lawsuits from consumers who paid to get 500 mg of vitamin C, but were shortchanged. It is important to have a uniform product because the FDA and Federal Trade Commission (FTC) could stop all shipments and close down manufacturing until the company can prove it has resolved the problem and has corrective procedures in place.Granted, vitamin C is not too serious a problem, but when a manufacturer includes a vitamin or any active ingredient for which the level per dose is in microgram quantities, the company needs to make sure that the batch is uniformly mixed so that when a tablet or capsule is made that dose contains the quantity claimed on the level.

William Crozier, Carlo Papera and Guia Bertuzzi, Bristol, Pa.- based IMA North America Inc. and Bologna, Italy-based IMA Italy:

Uniform product content in the bulk is necessary to achieve uniformity of ingredient content in the final dosage form (sachet, tablet, capsule), which must be compliant with regulatory specifications.

Eric Barber, national sales manager, Lawrenceville, Ga.-based Valentine Enterprises Inc. (VEI):

Uniformity is a crucial factor of product quality. Proper formulation techniques, including ingredient dosing and use of appropriate processing aids, help achieve good dispersion and uniformity.

INSIDER: What blending challenges are inherent to processing ingredients of varying particle sizes?

Blanco:

You must address the question of density and particle size. If you try to blend a powder with a large granule, you will get segregation of the product due to density and particle size. Sometimes moisture, or lack of moisture, will create segregation problems and separation in your packing. Thus, the customer could never tell exactly what he or she may receive, which would lead to manufacturing problems for the finished dosage manufacturer. The challenge with a very fine ingredient is you may have to granulate or mix with another carrier to get the two different materials to blend well. Sometimes this is a problem because by either granulating or mixing with a carrier, the customer may not get the dose level desired in the final blended material. That is to say, the tablet manufacturer may not be able to get the level of active in his product at the finished weight desired. For example, suppose a formulator wanted to put 500 mg of product A in the tablet, but because of other ingredients, the level of the desired active in the blend is not high enough for the manufacturer to get the 500 mg of A from the blend. It thus becomes a question of equipment, knowledge and experience of the blending company to resolve thorny issues like this.

Chaudhari:

Critical blending is an important unit operation for processors and blenders. Due to different chemical properties, particle size and shape, nutrient blending is important to prevent ingredient segregation, which would ultimately result in a non-uniform product. That would be considered bad business practice.

Barber:

Larger particle sizes tend to settle out during the blending process, creating issues with uniformity, as well as with the taste and mouthfeel of the finished product. However, these issues can be counteracted by proper blending and processing techniques.

INSIDER: What are considerations in determining whether ingredients should be milled, dry granulated or wet granulated?

Crozier, Papera and Bertuzzi:

Ingredients should be milled when it is not possible to maintain uniform physical characteristics of ingredients. They should be dry granulated when the ingredient has a very low dosage which can be critical for the mixture. Ingredients should be wet granulated when powders are not flowable and are difficult to process on industrial scale.

Chaudhari:

The considerations in determining whether ingredients should be milled, dry granulated or wet granulated all depend upon the types of nutrients and the final product application. In addition, one has to know the chemical and physical properties of nutrients and other components of the finished product.

Blanco:

The dry granulation or wet granulation decision is a factor in the characteristics of an individual product. For example, d-calcium pantothenate does not mix well with water or alcohol. Adding a fluid to a d-cal pan powder causes a rock-solid mess. So this is a product that has to be dry granulated. Thus the chemical make-up of the product and sometimes the physical characteristics of the material lead to the decision of how to handle the ingredients.

Barber:

Milling can address issues of particle size, mouthfeel and uniformity. Dry granulation can be used to hide bitter and off tastes, and can extend shelf-life and reduce dust production. This aids in clean-up.

INSIDER: How important is blending sequencing to achieving a desirable product?

Blanco:

It really depends on the level of active. For a product that is to be in micrograms in the final dose, you need to sequentially blend up with the carrier.For example, say that you take a product like vitamin B-12 and the customer wants a 0.1-percent mixyou are putting 1 g in 1,000 g. Suppose your batch size is 1,000 kg or 1 kg in 999 kg. In order to make sure you get a uniform blend, depending on equipment, you may have to put 1 kg into 20 kg of the carrier, blend to uniform mix. This mix is then made up into the 1,000-kg batch. It is important from the point of the low dose actives desired in the final blend. Thus you want to make sure all the low-dose actives are fully contained in the final blend. The low-dose actives are usually things like vitamins D-2, D-3, B-12 and biotin.

Chaudhari:

It is extremely important to sequence nutrients during blending because of hygroscopicity and flow properties. This will help to avoid interactions and minimize segregation and/or lumping in the final product.

Barber:

Following a sequence allows the product to be more uniform in most circumstances, such as with colors and micronutrients. Some ingredients, due to physical characteristics and chemistry, may adhere to one another better, without interference from other nutrients.

INSIDER: What are important considerations in determining whether ingredients should be microencapsulated or enteric coated, and how does that impact final delivery form options?

Blanco:

Again, this depends on the release profile the manufacturer wants to achieve. It also depends on the chemistry of the active. Some actives dont like other actives in a mix and you need some way to hide one from the other. Microencapsulation can also speed release or delay release, depending on your coating. Enteric coated means you want to get the dosage form (active) past the stomach and into the intestines where they would be absorbed or taken in better by the body. Usually when a product is enteric coated, it is because the active could be affected by the stomach acid.

Barber:

Coated products can improve the taste and mouthfeel of unpleasant characteristics inherent to challenging raw materials. Microencapsulation and enteric coating may also help with the stability and shelf-life of nutrients sensitive to heat and moisture.

INSIDER: How do manufacturers avoid adverse ingredient interactions within a formula?

Blanco:

A lot of agitation. Equipment needs to be built to eliminate blind spotsplaces in the equipment where the product does not move and thus does not get mixed well.

Chaudhari:

Manufacturers have to understand the chemical forms and properties of the nutrients to be added in a given application. Depending on the given processing conditions, such as time and temperature, they can determine the appropriateness of each different form of nutrient. Based on processing steps, one can design a nutrient system to avoid interactions.

Crozier, Papera and Bertuzzi:

Usually the formulators plan the formula to avoid adverse interactions. When this is not possible, there are many actions to prevent negative interactions, including isolating ingredients with a protective coating; keeping the ingredients separated as much as possible during manufacturing and mixing them just before packaging; or packing ingredients separately and leaving the users to mix them just prior to use. Of course all the actions should not affect the active ingredient dissolution profile.

Barber:

To avoid adverse ingredient interactions, manufacturers must first adhere to strict GMPs (good manufacturing practices). They should also conduct stability tests that look at the interactions of ingredients physical characteristics in addition to nutrient levels.

INSIDER: What are key equipment requirements for blending and processing?

Crozier, Papera and Bertuzzi:

The tumbling blender is the most prevalent piece of equipment in powder mixing for pharmaceutical, food and nutraceutical products. The design of the tumbling blender is based on the concept that the bin can be removed from the drive and transported to the next step process of operation without discharging its contents into a secondary vessel. No additional containers are needed; with a single container, all the transfers in the manufacturing area are simplified to avoid tying up the production line. Furthermore, the operators are constantly protected from contact with the blender contentswhich can be hazardous.

Chaudhari:

Based on the nutrient selection for a given product, one has to choose gentle versus high shear blending equipment.Many choices are available today to accomplish proper blending. Again, choosing the proper equipment all depends on the nutrients involved and the target final application.

Barber:

Start with a working knowledge of ingredients and their chemistry and physical properties and how they interact with a mechanical environment, including friction, heat and particle size.

INSIDER: What are equipment requirements for blending and processing ingredients of comparable weight and size, versus wet or heavy ingredients?

Chaudhari:

Crystalline structure of like ingredients would help to make a homogeneous product as compared to very fine powders.The lighter the product, the more air will be incorporated into the mixture, and this will lead to uneven blending.

Crozier,Papera and Bertuzzi:

The tumbling blender is designed to handle a wide range of powders and formulas. The intermediate bulk container (IBC) shape is designed to avoid dead spots during mixing. Working capacity of the container, blender tumbling speed and mixing time are critical process parameters for achieving good mixtures.

Blanco:

For blending it could be flow. For example, silicone dioxide or tricalcium silicate can help to get materials moving better inside a mixer to achieve a better mix.

INSIDER: What is the role of processing aids in creating a desirable end-product?

Blanco:

It is a dual-edged sword. If the amount of the processing aid, such as silicone dioxide, is too high, it creates problems for the tablet manufacturer because the tablet may be too friable or may not compress well. Or the tablet could compress well but when the manufacturer opts to put 100 tablets in his bottle, he may find that they dont fit because the tablets are too bulky to fit into the jar selected by the manufacturer.

Chaudhari:

Blending aids can include lubricants, processing aids, flow agents and anti-caking agents. These are all extremely important to help the food processor to accomplish the desired results. Too much processing may cause segregation, stratification and overall uneven blendingwhich are all unacceptable. Bioavailability, however, will not be affected as long as the product is formulated correctly and taken as recommended.

Barber:

Some food processing aids can improve uniformity. Some, such as antioxidants, aid in stability and shelf-life. Others can improve formulations that use hydroscopic nutrients.