Blending Roundtable

INSIDER gathered blending experts from around the natural products industry to discuss trends and specific techniques:

INSIDER:What are some of the key considerations in optimizing blending of ingredients (i.e., weight, density, solubility, etc.)?

Kauman : In addition to the considerations already mentioned in your question, add to it the concentration of one ingredient relative to other ingredients in the formulation. Ingredients that are represented in small amounts must be mixed properly in order to obtain content uniformity.

Stimfle: The key considerations in optimizing the blending of ingredients include the bulk density of the products, whether the materials are hygroscopic and the color of the materials.

Sarti : An optimal blend must be considered from the start of the formulation process. Compatible particle sizes of active ingredients and excipients are one of the most important details to get right from the beginning. If you can not manipulate the particle size of your materials in house, then sourcing of appropriate materials must be done before you proceed. Starting with the right mix of ingredients will help ensure that blend validation or verification goes smoothly and that your ingredients are properly mixed and segregation is avoided.

Overfilling the blender should also be avoided. Blenders have a proper working capacity and although it is tempting to try to fit as much as possible into a blender, without enough room to move, the blend will stay segregated. Blend fill can also impact mixing time. As part of the blend validation, or verification as required for dietary supplements, fill level must be considered. The same blend at two different fill levels may require two different mixing times. This can be verified through in process testing of the final mix, or at points during the mix.

Arizona Nutritional Supplements is also looking into certain PAT systems to further ensure blend uniformity. PAT is an initiative put forth by the FDA known as Process Analytical Technology. Although targeted at pharma, it can be applied to dietary supplement development. Using systems like NIR or Effusivity, it is possible to verify blend uniformity analytically in process. This can improve efficiency and blend consistency from batch to batch when you are dealing with natural raw materials and other inconsistencies from suppliers.

An optimal blend requires consideration of a variety of factors. With proper formulation and verification of blend times and fill levels, a high-quality, consistent dietary supplement can be produced every time.

Reingold: Blending is the most widely used process in the pharmaceutical and nutritional industry, though sometimes the least understood. The most critical parameter in blending is the raw materials and the properties that they possess. Understanding how materials flow, the density, crystal shape, moisture, cohesion properties, and the particle size can be the decisive factors that influence the blending of ingredients. Consistency and regularity in particle size will allow a better blending of solids, leading to less segregation and a more uniform blend.

Another property overlooked is blending time. Not many manufacturers run optimization trials to better understand efficient blending times. This might be an area where manufacturers can save time – i.e. a blend which might be complete in 10 minutes is blended for 25 minutes due to historical trials without optimization. Accurate sampling using standard tools (thief probes) is a key technical need for quality control and optimization of the blending process.

INSIDER:What type of overages do you encourage for dietary supplement blends? What variable parameters impact that decision?

Kaufman: Overages are established by conducting stability studies on finished products. Finished products are checked over a period of time and form the data by which the overages are calculated.

Stimpfle: As far as overages are concerned, this is something that should be discussed directly with the customer. We process a great number of different materials. The customer has more intimate knowledge of each individual ingredient.

Sarti: Use of overages in the products we manufacture is governed by several factors. The main factor is the stability of the ingredient in the formula. Our largest overages are used in probiotic products. We sample and test probiotics at several points throughout the manufacturing process in order to determine stability in manufacturing. We then conduct real time stability studies on probiotics to ensure we have a large enough overage to meet the claimed shelf life. Overages on probiotics may range from 25 percent to more than 100 percent, depending on the product. Proper storage conditions should be observed for most probiotics. Refrigeration will ensure optimal shelf-life.

Enzymes and vitamins are probably the next most sensitive if we are looking at categories. Factors such storage temperature and humidity can affect vitamin and enzyme shelf-life, which may require additional overage if going to a country with less than ideal storage conditions. Vitamin and enzyme overages range between 5 percent and 25, typically.

There are a wide range of other ingredient categories that may require overages. Antioxidants such as lutein, lycopene and others are sensitive to light and heat and may break down if not properly protected by proper packaging material, beadlet technology or storage conditions. Amino acids are fairly stable as a category, but again storage conditions and stability data should be taken into account. Minerals are the most stable dietary supplement. Little to no overage is typically needed in most mineral supplements.

Ultimately, stability of the material you are using in a particular matrix and dosage form can vary and should be studied to determine the appropriate overage. Estimates may be made on new products while implementing an appropriate accelerated stability study concurrently with a real time study. It should be studied in the appropriate packaging material as well. Keeping control of your process will also ensure overages are appropriate and ensure a product meets label claim throughout its shelf-life.

Reingold: Regulations require that the actual content of nutritional products be equal to or greater than the label claim after taking into account processing effects and shelf-life degradation.

Depending on the stability characteristics each dietary supplement will require a different overage. To minimize overages, precautions can be put in place during manufacturing to prevent environmental effects such as moisture, heat, oxidation and general degradation properties of ingredients. Another way to reduce degradation effects is the packaging and handling of the raw materials and the final product.

The best way to determine overages is to test and understand the life-cycle of the product. Running stability studies at standard (25ºC/60 percent RH) and accelerated conditions (40ºC/75 percent RH) can help formulate a robust product and market a product with a meaningful expiry date.

INSIDER:What are some methods you use to protect sensitive ingredients during the blending process?

Kaufman: For the dry bending we use a gentle low RPM blender that does not introduce unwanted heat or friction. With this method, ingredients are protected from undue stress.

Stimpfle: Each ingredient has its own individual handling criteria. This is discussed directly with the customer prior to any blending.

Reingold: When handling sensitive ingredients - procedures, protocols and training become critical. The first step is to research the ingredients that you will be using and understand how they react to different environments. This starts with general receiving of raw materials, to sampling, to weighing and mixing, to final packaging of the finished product.

Controlling the environmental conditions (temperature, relative humidity, etc.) is the key to protection. Other precautions can be utilized such as special lighting, pre-blends and order of blending. Emphasis should always be stressed on training and appreciation for the sensitivity of raw materials.

INSIDER:When selecting a method for processing, whether freeze drying or oven drying an ingredient, for example, what are the considerations that must be addressed to maximize functional outcome?

Kaufman: Freeze-drying and oven drying are totally different processes. Each one has its place. Freeze drying is typically used for a product that is first in liquid form and then needs to be converted into a powdered form. Oven drying is typically used in situations where a granulation of the ingredients is required or the ingredients need to be dried because of excessive moisture content.

Stimpfle: Once again, we perform a number of different processes, including spray drying. Each individual ingredient has its own handling considerations.

Reingold: Knowing one’s capacities and limits should be the deciding factor for selecting methods of processing. Understanding how much time will be required, the costs associated with the process, and the overall effect on the materials being manufactured can all influence the decision for the type of method selected.

INSIDER:Are you seeing increased interest in multi-ingredient blends that address certain health conditions?

Stimpfle: We are seeing increased interest in blending multiple ingredients. This is mainly due to increased specialization of individual products.

Sarti: The days of throwing in a sprinkle of 50 to 100 different ingredients into a formula are coming to end soon I think. The new FDA GMPs are really prohibitive of these types of formulations by making the costs too great. I believe the new trend will be toward specifically targeted formulations for a particular problem. Heart health continues to be a big category. This is evidenced by the move by Bayer to release a combination OTC/Dietary supplement for heart health. This formula is targeted with specific use of proven ingredients for a specific condition. More formulas like this are on the way.

Companies will have to evaluate each ingredient in a formula. Questions to ask are, “Is this ingredient truly providing a benefit?” or “Is there enough of this ingredient in the formulation to truly provide a benefit?” We are going through a major transitional period in our industry and a lot of the traditional business models will have to be reevaluated.

Multi-ingredient formulations have their place. There are synergistic combinations of herbs or other actives that can truly provide a benefit and be of help to the consumer. I think consumers are becoming more educated and are asking more questions about these formulas. We have seen an increase in awareness in consumers. They want to know more about what they are putting in their body. A “Proprietary Blend” of a large number of ingredients is less appealing to them than a carefully spelled out label that fully discloses a few appropriate ingredients to their specific condition.

Marketers and manufacturers can gain advantage in the marketplace by gaining a reputation for quality and honesty in the products they produce. If a product is formulated for a specific condition and it works for the consumer, then that will keep them coming back.

Reingold: As a contract manufacturer with a vast product listing, it is clear to CPC that the amount of combination products is on the rise. Customers are excited about the one stop product that has multiple indications. With that said, there are difficulties in bringing these types of products to market. The laboratory requirements become more challenging and understanding compatibilities of ingredients is crucial.

INSIDER:How does the use of pre-blends factor into making a top-notch full load blend?

Kaufman: Pre-blends are useful when ingredients are in small amounts relative to the entire batch. When a pre-blend is properly performed, there is a much higher assurance of ingredient content uniformity throughout the finished batch.

Stimpfle: At this point in time, we have not seen a need for pre-blends.

Sarti: Pre-blends are very important in making a quality product. It is a must to “scale-up” a material that constitutes a tiny percentage of the entire batch to a level that is appropriate to add to the full blender. Segregation of ingredients will occur without fail if one or two kilos of an active is added to a 1000 kilo batch without pre-blending the ingredient.

If the active is very small, sometimes more than one pre-blend is appropriate. Initial pre-blending can be done by hand, or in a small scale-up mixer, the second preblend can be done in a larger mixer, or possibly in the main mix without all ingredients added. It is important to check for efficiency of the pre-blend by testing the active. Folic acid and vitamin B12 are ingredients that are commonly pre-blended, even if triturations are used, which is highly recommended in most cases.

Pre-blends are also often used to mix problematic components of a formula with appropriate excipients in order to “coat” them before the remaining ingredients are added. This is not necessarily a function of blend consistency so much as a method to help processing into a capsule or tablet that runs more efficiently. This is commonly done with ingredients such as lecithin in large quantities, or Choline sources. Anything that is oily or hydroscopic could be a candidate for pre-blending with excipients such as silica or calcium silicate. This will help ensure further processing of the material goes smoothly.

Pre-blending, whether for scale up or process improvement, is an important component of proper formulation. It can improve blend and content uniformity results in analytical testing with only a small amount of extra processing. In the case of validation or verification of processes, that extra processing is worth it every time.

Reingold: Pre-blends are a necessity when working with a low dose API (active pharmaceutical ingredient) or ADI (active dietary ingredient). To enhance the distribution properties of a blend, step-wise increases in the disbursement of lower concentration ingredients will help with content uniformity.