How does blending nutraceuticals differ from mixing pharmaceutical products? 

Banaszek: Nutraceuticals production straddles the interface of food and pharmaceuticals manufacturing—two markets which themselves share plenty of overlap. Pharmaceutical customers often specify higher polish on product contact surfaces as well as exterior finishes that are more aesthetically pleasing. Their control systems often include features for running specific recipes and securely storing batch data. 

Muench: Based on FDA Label Claims and requirements for nutraceuticals versus pharmaceuticals, the two can be very similar. The products likely diff er the most in the validation processes for material, formulation, process, and equipment. 

Nutraceuticals tend to have larger batches and operation workflows, thus “Total Room Usage” must be considered for speed, safety, efficiency and consistency. Load time, mixing and/or drying time, discharge time and cleaning time are all critical material handling performance indicators, particularly in high-volume, scalable campaigns. It is applicable to all campaigns, however, tumble mixers and dryers, for example, provide the greatest overall optimization of room usage from load to mix/dry to unload and clean (and repeat). 

Given the materials contained within a mix, pharmaceuticals are typically much more stringent; changes made in any of the above typically require re-validation. Nutraceuticals typically do not. For example, a nutraceutical batch of a diff erent size, made in properly “scaled” equipment, with the same formula with regard to ratios or proportions, will remain consistent and repeatable with no requirement for validation other than typical QC/QA (Quality Control/Quality Analysis) analytical analysis. 

When choosing process equipment to develop your formulations, it’s important to ensure the equipment comes with a validation package and experts on staff to help execute these documents. 

What’s the biggest consideration in blending nutraceuticals to meet GMP standards? 

Banaszek: Well-designed blending equipment supports good manufacturing practices by making it easy for operators to clean and maintain their machines. This starts with proper mixer selection because, in reality, most products can be made in a number of mixing equipment and through a variety of manufacturing methods. Take the time and due diligence to identify the best mixing strategy. Once the right mixer is selected, it can then be optimized for sanitation: high polish on stainless steel surfaces; interchangeable mix vessels; sanitary fittings and valves that can be quickly taken apart for thorough cleaning; drain ports; easy access to the agitators; CIP spray nozzles; etc. On the controls side, the appropriate control system provides electronic soft start, overload protection and other features that help prevent premature wear and mechanical failure. Maintenance and calibration schedules can also be pre-programmed into PLC recipe controls, so operators are less likely to overlook such procedures. 

Muench: Mixing equipment that can provide batch-to-batch consistency and/or repeatability with traceability. Your formulation may be perfect, but if the mixing equipment isn’t designed properly, your desired results will not be achieved. Nutraceuticals come in many forms. 

How does blending needs change for products that come as powders versus, say, capsules? How can you ensure consistency when blending nutraceuticals? 

Banaszek: Again, proper mixer selection is the starting point. The right mixing equipment will create the product exactly to specifications and do so consistently. When blending all dry ingredients, the bulk density, batch capacity, the properties and relative ratio of raw materials must be discussed with the mixer manufacturer. If certain ingredients tend to form undesirable lumps, the shear intensity required to break down those lumps is an important consideration. For example, tumble blenders are routinely used for gentle mixing of free-flowing solids. Turning at relatively low speeds, the V-shaped or double-cone vessel systematically splits and recombines the batch with each revolution with highly predictable results. For some formulations though, this blending action is too gentle. Switching to a ribbon blender—a higher shear device due to its double-ribbon agitator turning at higher tip speeds—could eliminate lumps and shorten batch times. More stubborn agglomerates may require high-speed chopper blades installed on the ribbon blender’s sidewall or cover. 

As for liquid and semi-solid applications (such as emulsions, syrups, slurries, pastes, gels and dough), viscosity is a main parameter for mixer selection, in addition to shear. Viscosity often dictates the overall mixer design—including blade geometry, diameter and speed. A wide range of mixer options is available: single-shaft low-speed agitators and high-speed dispersers, high shear rotor/stator devices, multi-shaft mixers and planetary mixers. Finally, consider efficient transfer of the finished product from the mixer. Will the product flow by gravity or will it need to be pumped or pushed out of the mixing vessel? 

Muench: Close scrutiny/quality control of raw ingredients as well as using well-designed/engineered equipment with significant/accurate controls and automation. 

As unpopular as the technique may be, “take the human out of the equation.” 

Highly automated equipment will not only give you the consistency when mixing, but will provide you batch records with time stamps, graphs, and other helpful documents to learn about your batch. 

When should you consider blending your own nutraceuticals, versus using a contract manufacturing organization? 

Banaszek: Based on our experience, using a contract manufacturer is useful for gaining processing know-how and quickly scaling up when there’s a surge in demand. Partnering with the right toller gives newcomers a chance to strike while the iron is hot. In-house blending requires a larger investment in production space, capital equipment and skilled staff, but does allow for greater control over quality and consistency. 

Muench: Some mixing equipment manufacturers even have their own testing and processing facilities to ensure scale-up and production produces the desired blend before investing in the equipment. This is particularly helpful to smaller organizations producing their own products. As the COGs (Cost of Goods) either as a function of quality or capacity exceed required margins, it may be time to look for CMOs (Contract Manufacturing Organization) help. 

What are some of the most difficult nutraceutical ingredients you’ve blended? Why were they challenging? 

Banaszek: Minerals, in a dry state, can form agglomerates in a liquid batch with low-speed, low-shear agitation. So do cellulosic thickeners, natural gums and starches. The challenge is to generate a homogenous mixture and expose as much surface area of the additive particles as possible. To achieve this mechanically, the batch must be subjected to ample shearing energy as the powders are being incorporated. Some oils, like flax seed, require emulsification at lower temperatures to prevent polyunsaturated fats from oxidizing. Botanical extracts are also heat sensitive and must be kept in a “Goldilocks” zone during manufacturing. If the temperature is too high, the extracts will degrade and lose their potency. It’s therefore important to balance shear, mix time and external heating/cooling. 

Capsule shell materials, some meat substitutes, soft chews, and other gel-like substances commonly require processing in a closed system, vacuum-rated mixer designed for accurate temperature control and efficient agitation at viscosities well over 100,000 cps. Depending on the viscosity range and shear requirement, multi-shaft mixers and planetary mixers are typically utilized for such high-end applications. Vacuum processing capability allows removal of air from the product, resulting in a smooth, air-free gel. Teflon scrapers constantly exchange materials from the sidewalls and bottom surfaces of the mix vessel, promoting batch homogeneity and accelerating heat transfer.

Muench: Kava & Saint John’s Wort. 

Typically, with a spray-dried extract, the activity levels can vary significantly from drum to drum. The QC function here then becomes extremely significant, and the formulation based on these varying activity levels can become challenging. 

How do you test scalability from a small batch to industrial production? 

Banaszek: Scaling up from a laboratory or pilot plant operation requires that the physical and chemical properties of the product are duplicated at the full-scale plant level. It further requires that the desired outcome is produced within a reasonable amount of time. (See Scaling Up box)

Muench: We are fortunate that GEMCO industrial mix and dry equipment tends to be extremely scalable. 

Regardless of this, as a matter of GEMCO’s testing and tolling partner, Advanced Powder Solutions’ (APS), own internal processes, within the limits of the formulation and process design, the first three batches produced are considered “validation batches”. If found to be consistent and repeatable across these three, the product is “released” for commercial processing. 

What kinds of quality control should blenders do to ensure the best mixed, most consistent product? 

Banaszek: The right mixer will yield repeatable viscosity, density, particle or droplet size distribution, color, texture, stability and accurate dosage. 

Muench: The equipment needs to be able to produce uniform results every single time. Depending on which material(s) you are mixing, use a uniform chemical or active assay based on a standard pattern. Consider uniformity in color and/or physical consistency based on a standard pattern. Look for even and consistent, overall particle distribution. 

Aim for good particle size distribution. Flow characteristics are also important—especially critical for capsule technology. The list goes on…

SCALING UP Christine Banaszek: 

• Invest in a scalable laboratory mixer that is available in industrial size models. While there are many mixer options that suffice for R&D—including magnetic stirrers and kitchen mixers—many of these devices are not scalable equipment and will require extra time and resources for experimentation once the product graduates to production scale. 
• Maintain tip speed and agitator geometry. Account for longer mixing and heating times due to the unavoidable decrease in surface area to volume ratio and/or horsepower per unit volume. 
• Perform mixer testing using your own raw materials and simulate your actual operating conditions as close as possible. Renting equipment for in-house trials at your facility is another option. To obtain reliable data for scale-up, a good rule of thumb is to test on a mixer that is no smaller than 10% of the capacity you are looking to scale up to. 
• Determine the quantity of full and partial batches that can be made on a particular mixer model to accommodate fluctuations in product demand. 
• Scaling up to a larger mixer with a change-can design can further increase throughput and equipment utilization by enabling semi-continuous processing. For instance, a single mixer may be supplied with multiple interchangeable vessels that cycle through a sequence of charging, mixing, discharging and cleaning. 
• If scale-up calculations point to a prohibitively large mixer size, consider alternative mixer technologies that can potentially supplement or even replace your current mixing procedure and accomplish the same end point in a fraction of the time. Examples include switching from a saw-tooth disperser to a rotor/stator mixer to improve dissolution rates, installing a solids induction system to accelerate powder wet-out and dispersion, utilizing an ultra-high shear mixer to finish emulsions much faster than a traditional rotor/stator, and other solutions that depend on the specifics of a particular application. By significantly reducing cycle time, you can work with more manageable batch sizes and still achieve the desired output volume per day or shift.