What Is The Importance Of Blend Uniformity In The Pharmaceutical Industry
In the pharmaceutical manufacturing process for solid dosage forms, powder blending has always been a challenging operation. If the compounds in the formulation are not adequately blended the uniformity of the final product will be adversely affected which, of course, will have a direct impact on the performance of the business. Since every product is based on its own unique mixture of raw materials, the selection of the equipment used for blending and the blending process is dependent on the starting materials. The type of mixer or blender used will influence the flow behaviour of the final mixture, as will the particle sizes and shapes of each of the starting materials.
Overview of the blending process and equipment
The equipment used to blend pharmaceutical powders are generally either fixed shell blenders (e.g., impeller mixers, ribbon or screw mixers), or rotating shell blenders (e.g., drum , cross-flow, double cone, and twin-shell). Fixed shell blenders have an internal rotating impeller or paddle and provide a continuous shearing force to the particles, shuffling the particles to mix them up. The high shear force can also break up agglomerates of powder particles. Rotating shell blenders rely on the altogether gentler mixing of the particles as they slide or roll together. On a large scale a concrete mixer is an example of a rotating shell blender.
The choice of blender is influenced by the particle size, shape, morphology and density of the active and excipient ingredients that are to be mixed. In all types of blender, the material can stratify with large coarse particles settling on the bottom of the blender vessel. The ability to mix uniformly and not stratify can be affected by the mixing time, the speed of the blender, the flow rate and volume of material to be blended. All such process parameters will affect the final product and care should be taken throughout the blending process to maintain constant blending parameters. Unfortunately there is no simple method available that will determine blend uniformity during the actual mixing process. It is not simply a matter of blending for a long time, as this can actually have a negative effect on the uniformity of the blended material, causing ingredients to segregate or de-mix. Mixing time should therefore be adjusted according to the formulation and experience of the operator to achieve the required level of blended uniformity. Active materials may be added in small quantities throughout the mixing process to help improve blending uniformity.
Guidelines have been given by the US Federal Drug Agency for checking the uniformity of blends.
The size of the particles or granules can also affect the physical appearance of the product. Tablet dissolution is affected by the particle size of the active ingredient.
Overblending can also affect the product as it can cause the ingredients to de-mix. Over blending results to the active ingredient segregating from other materials and can show the results of the blend uniformity limits. It is therefore important to check the mixing time.
The size and shape of the particles or granules plays an important role in the mixing process. Particles that are of similar sizes will mix most easily. A difference between the particles sizes of the active and excipient ingredients can cause de-mixing of the ingredients. Stickiness of the particles can also affect the blending - excipients that are more sticky than the active ingredient will be more difficult to blend. The particles of very fine powders may become electrostatically charged and are best avoided.
Blend Uniformity Analysis
The US FDA issues draft guidance for industry Blend Uniformity Analysis in 1999 that was withdrawn in 2002. Further proposals were tabled by the International Society for Pharmaceutical Engineering. There is ongoing discussion about the correct methods of sampling materials to ensure that adequate blending is achieved. The FDA guidelines defined in “process dosage unit sampling and assessment” as “the process of collecting a representative sample by selecting units deliberately from various identified locations within a lot or batch, or from various phases or periods of a process to obtain a sample dosage unit that specifically targets locations throughout the compression/filling operations that have a higher risk of producing failing results in the finished product uniformity of content”. By collecting several samples at any one time from a single location enables some variability to be assigned to the sample that can be used to assess the uniformity of blending. The FDA proposed that sample results should all be within 10.0% of the mean to meet an adequate level of blending. Analysis is only necessary when the active ingredient is 50mg or greater and when the dosage contains more than the 50% active ingredient. To meet the target FDA homogeneity the blend is only analyzed to check for the uniformity of the active contents to ensure that it complies with the limit of 85 to 115% or 75 to 125% of the target strength for individual units.
The blending process is a GMP activity and needs to be assessed carefully as samples placed on a vibrating surface, for example, can cause segregation of particles which can lead to errors in the analytical data.
The Impact on Tablets
If there is non-uniformity in the blend of materials that are submitted for tabletting, then issues will become apparent when manufacture is carried out on either a rotary pill press or a single station pill press.
The first issue you may notice is that of inconsistent tablet weights. This issue can be caused by a number of things but as long as the tablet press is getting an accurate and constant fill for every tablet then this issue could well be caused by an inconsistently blended mix.
The next issue that may become apparent is inconsistent punch pressure. If the tablet press has a digital display then this will indicate the compressive pressure for every tablet that is produced. The machine parameters will be set to give an optimum pressure. If the machine operates with compressive forces very different from the set level, the effect may be caused by issues such as damaged tooling or running out of mix in the hopper. However if it is neither of these is the case, then it could be that an inconsistent or non-uniform mixture has caused the issue.
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