Blending Trace Ingredients

For commercial-scale, GMP manufacturing of tablets and capsules, homogeneity of the powder blend is crucial. “Pharmaceutical manufacturers require high-volume precision blending of formulations on equipment that provides batch-to-batch consistency and repeatable results,” says Gregg Muench, vice-president of business development at Gemco. Pharmaceutical Technology spoke with Muench about best practices for meeting these challenges.

Primary challenges

PharmTech: What are the primary challenges seen with blending trace ingredients (< 1%) into powder blends?

Muench (Gemco): The blending of several solid ingredients is easier and more uniform if the ingredients are approximately the same size. It is more difficult to create precise blends with trace ingredients (< 1%) that are vastly dissimilar in size and density. In some cases, this scenario might require doing multiple key blends in a time-consuming and costly process.

It is essential to achieve results within blend uniformity requirements for every batch, whether the formula is predominantly active ingredients and several excipient ingredients, or predominantly excipient ingredients with very small amounts of active ingredient. Homogeneity is very important because finished products are only as good as how well they are blended.

One of the primary challenges of trying to blend trace materials occurs when not enough consideration is given to the shape, size, and density of the particles. Is the particle round, a sphere, shaped like a rod or cone, or irregular? If the shape of the particles is not taken into consideration, the distribution of the active ingredients can be poor. Also, if the sizes of the particles are vastly different, it can be a challenge as well.

Particle analyzing equipment is typically used to look at the shapes and sizes of each particle as well as how it is distributed through the entire batch. At that point, it is possible to decide what to do if a particle is too large or will not blend well.

If disparity of particle sizes is too great, an agitator bar can be installed in the equipment that helps resize and disburse the particles through micro-mixing. The agitator bar is the ‘great equalizer’ that can bring particles to a similar size and take off the rough edges so they sufficiently blend together.

If the trace elements are in liquid form, it is important to evenly coat the particles without over- or under-wetting the material. When using liquid-based ingredients, the pharmaceutical manufacturer needs to consider other factors as well, such as the proper feed rate, nozzle size, and blending speed.

When dealing with active ingredients, particularly at trace levels below 1%, it is even more critical to ensure that each particle gets just the precise amount of coating so that the patient will get the proper dose. Spray coatings are also often used to control time-release of active ingredients. So, the coating must be properly applied to control the material’s dissolution properties.

Static electricity can also effect mixing and is too often ignored. Static charges may cause powders to clump or stick to the blender walls. To resolve issues with static, it is best to install a static arrestor on blender shafts and properly ground the machine.

Current blending equipment

PharmTech: What are the current equipment options for creating homogeneous blends with trace ingredients?

Muench (Gemco): Traditionally, there are many types of blending equipment, such as plow, ribbon, and paddle mixers, that use blades or paddles to push material. However, most of these are inefficient and require adding extra ‘key blend’ steps to adequately deliver homogeneous blends with trace ingredients. A key blend is used to mix minor percentages of active ingredients together prior to blending with the rest of the batch. Key blends are generally required when the blending process is inefficient and the entire bed of material is not fully mixing. By creating a homogenous batch of the minor ingredients first, it can be more easily mixed with the rest of the material. However, this method adds processing steps, and each key blend must be analyzed for quality control purposes.

Blade or paddle mixers are limited to moving the material within the confines of their active area. The mechanics force the material bed outward, leaving dead spots inside the vessel where material moves more slowly or remains stationary. Also, because these units are stationary, they have one stationary port at the bottom of the machine. This port has a long neck, which isolates the material from any processing force during mixing [and] creates a pocket, or ‘dead zone,’ where material can be trapped. Operators often need to empty the dead space in the neck and manually reintroduce it back into the top of the mixer, which means some portions of the mix will receive more additive than others. Such mixers cannot accommodate blends with 7% or less of any one ingredient.

Another issue lies in the positioning of the intensifier bars or fluidization zones. These intensifier bars should ideally be located in the mixing zone, where every particle passes through. Many times, however, traditional mixers have their intensifier bars in dead zones. When this happens, the material will not be fluidized properly, and active ingredients will not be incorporated throughout the batch.

Traditional mixers tend to require higher quantities of additives to achieve the desired concentration in the blend. Because additives initially contact only a small portion of the material when added, they get quickly absorbed into the material bed, [which may require] increasing the percentage of additives to ensure the proper concentration is achieved in each sample.

To address the deficiencies of traditional mixers, a growing number of pharmaceutical manufacturers use tumble blending. As a low-impact processing technique for handling sensitive or abrasive solids, tumble blending is commonly used to create precise pharmaceutical blends that contain trace ingredients (< 1%) that are vastly dissimilar in size and density.

To eliminate dead spots, tumble blenders apply even turbulence in all corners of the mix through a combination of macro and micro blending, which can eliminate the need for key blends and produce a better distribution of active ingredients. Macro blending is achieved by rotating the shaped vessel, allowing the material bed to fall away from the vessel’s walls. Tumble blender vessel shapes are engineered to create a repeatable pattern in which the entire bulk material moves to form a homogenous mixture. The blender moves at a precise speed, with the vessel wall at a precise angle, so that the material cascades over itself. There is no additional force from paddles, plows, or spiral ribbons-just gravity. 

During rotation, micro mixing (if needed) simultaneously proceeds via agitator blades located in the mixing zone center of the vessel, where fine processing in the material transpires. This design allows for a gentle, repeatable pattern that preserves the product’s physical characteristics. Together, the macro and micro mixing evenly expose each particle to six times more active blending per revolution than traditional mixers [based on equipment geometry differences].

Impact of blender shape

PharmTech: How do different tumble blender shapes affect blending?

Muench (Gemco): Slant cone, double cone, and V-shape are the most popular tumble blender shapes. Among these shapes, the slant cone blends better and faster than the other two. Slant cone blenders are also more versatile when it comes to loading capacities and offer increased mixing efficiency when compared to other tumble blender configurations.

Production-size blenders must be integrated with the work area and procedures; loading, room space, and cleaning often affect what shape is best for the job. Given this, in specifying tumble blender shapes, some characteristics of the three most popular shapes are important to keep in mind.

Slant cone:

• No sensitivity to loading sequence

• Lower head room clearance required

• Faster mixing

• Dual automatic loading/discharging port options

• Largest mixing zone

• Greatest range of batch sizes.

The slant cone’s mixing action allows for more flexibility because it moves powder more efficiently. Operators do not have to adhere to strict procedures to make this blender work; the shape makes up for operator differences in procedures.

V-shape:

• High head room required

• More floor space required

• Recommended loading/discharge is through valve only

• Smallest mixing zone

• More difficult to clean

• Very small range of batch sizes.

The V-shape is a good general-purpose blender for batch sizes that will not change. It is often used in the pharmaceutical market.

Double cone:

• Lower head room clearance required

• Dual automatic loading/discharging port options

• Most compact use of floor space

• Second largest mixing zone

• Good range of batch sizes

• Easy to clean.

The double cone shape is versatile and can fit bigger batch sizes into the same square footage than other shapes. Automatic loading and discharging ports are in-line, which saves more plant floor space. Cleaning and maintenance are still simple.

Best practices

PharmTech: What are some best practices for optimizing blending parameters?

Muench (Gemco): Optimizing blending parameters for specific applications often involves research and development, trial and error, as well as mathematical calculations. Critical parameters that can be varied include batch size, blend time, and agitator speed.

Validating the repeatability of the blender is crucial when qualifying it as a piece of equipment for any particular process. To avoid wasting resources through excessive trial and error, it is also important to do some feasibility research and development blending.

For instance, pharmaceutical manufacturers need to evaluate the raw materials to find potential problems and issues that may need to be resolved before even attempting a blend. Often, this involves particles of different shapes and sizes, as discussed in the first question. These sorts of issues should be resolved during feasibility studies before going to trials or validation. Adequate preparation at this stage can avoid blending problems down the road.

PharmTech: Can you use computer modeling to determine optimal blend parameters?

Muench (Gemco): Generally, computer modeling is used more when mixing liquids. Liquids flow in known patterns that can be visually represented in computer modeling. Computer modeling is not often used when blending solids because the movement and flow of solids is not as predictable. This limitation may change in the future as computer processing power and computer modeling continue to improve.

When performing R&D tests on new products for a blender sample, computer modeling may be useful in following a FDA sampling regimen. According to the FDA Guidance for Industry: Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment, stratified sampling is the process of sampling dosage units at predefined intervals and collecting representative samples from specifically targeted locations in the compression/filling operation that have the greatest potential to yield extreme highs and lows in test results. These test results are used to monitor the manufacturing process output that is most responsible for causing finished product variability. The test results can be used to develop a single control procedure to ensure adequate powder mix and uniform content in finished products (1).

Generally, the physical sampling process entails taking samples every 30 seconds for five minutes. This approximates how the blend comes together and gives a ‘snapshot’ picture of the blend. 

Vacuum tumble-drying

PharmTech: How does vacuum tumble-drying work, and what is it most appropriate for?

Muench (Gemco): In addition to tumble blending, a growing number of pharmaceutical manufacturers are finding that vacuum tumble-drying equipment offers advantages. Usually, tumble blenders can do both tumble blending and vacuum tumble-drying.

Most pharmaceutical powders contain solvents or free radicals that need to be removed to dry them effectively. Traditionally, to dry such powdered product, manufacturers use tray dryers, where wet material is laid in thin layers on multiple racks of heated trays. This method, however, can lead to uneven drying as heat is applied. Also, volatile material may be trapped on bottom layer particles as a crust forms on the top layer of material.

As a solution, advanced vacuum tumble-drying equipment can resolve such issues and speed drying while reducing cost. Vacuum tumble-drying equipment can use gas purging in addition to heat application. In addition, dynamic vacuum tumble-drying dries powder energetically as it rotates inside the vessel, which dries the powder faster, more evenly, with less labor, and is particularly helpful in reducing residual organic solvents.

Tumble drying can also be employed when a liquid is used to put an active ingredient on a pharmaceutical powder. Generally, the pharmaceutical manufacturer would blend in the active ingredient with a carrier, such as alcohol, which is sprayed on the particles. Vacuum tumble-drying helps remove the alcohol. As the powder tumbles in the blender, the cold powder moves out to the heated walls of the blender. The heat vaporizes the alcohol while it is drying. The material has to be moved so it does not burn against the wall and leave the colder materials in the middle.

Reference

1. FDA, Draft Guidance for Industry: Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment, October 2003 (withdrawn on August 7, 2013).

Article Details

Pharmaceutical Technology
Vol. 43, No. 8
Pages: 26–29

Citation

When referring to this article, please cite it as J. Markarian, "Blending Trace Ingredients," Pharmaceutical Technology 43 (8) 2019.