Role of Critical material attributes in Formulation of Pharmaceutical Pellets

Critical material attributes are defined as the physical, chemical, biological, or microbiological properties or characteristics of a material that should be used within an appropriate limit or in a specified range or distribution to ensure the desired quality of the product. In other words, these are the properties of the raw materials used in pharmaceutical pellet manufacturing. All pharmaceutical formulations, including different types of dosage forms, mainly depend on the type of raw materials used in the formulations and the process parameters maintained during product manufacturing to achieve the desired product quality. Nowadays, pelletized drug delivery is gaining paramount importance in therapeutics due to their narrow particle size range, prevention of dose dumping, and suitability as a route of administration for low-dose drugs.

Impact of Critical Material Attributes (CMAs) at Each Stage of Pellet Manufacturing:

1. Core Spheres Manufacturing

Generally, the core spheres are manufactured with sucrose, microcrystalline cellulose, or tartaric acid powder, alone or in combination with starch.

Critical Material Attribute (CMA):
The CMA in core sphere manufacturing is the concentration of starch used in sucrose, microcrystalline cellulose, or tartaric acid spheres. Generally, up to 8% starch concentration is advisable. If the concentration of starch is very low, the spheres will lack sufficient binding strength. If the concentration of starch is very high, microbial growth may occur, as starch is more prone to microbial contamination due to its high moisture content.

2. Seal Coating

Critical Material Attribute (CMA):
This coating is performed over the core spheres. The excipients used in this stage are polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC). The CMA here is that these binders should be applied at a concentration resulting in a 3–5% weight gain on the core spheres. At this concentration, they help achieve the desired round shape of pellets and increase the strength of the cores, preventing them from becoming friable during further coatings.

For polyvinylpyrrolidone, the preferred grade is K-30, as its viscosity ranges from 27–32 cps. If higher-viscosity grades like K-60 or K-90 are used, the seal coating process becomes difficult, and spray gun choking may occur during solution spraying. The same applies to hydroxypropyl methylcellulose: the preferred grade is E5, with a viscosity range of 3–6 cps, and higher-viscosity grades such as E15 or K100 should be avoided.

3. Drug Loading

Critical Material Attribute (CMA):
This coating is applied over the seal coat. At this stage, the active pharmaceutical ingredient (API) should be dissolved or dispersed in a suitable binder solution along with a lubricant and plasticiser. The concentration of the binder solution plays a major role in drug coating. The binder solution should be applied to achieve approximately 5–7% weight gain. The desired drug release profile may be altered if the binder concentration increases. The solid content of the solution should be maintained at up to 20%.

If the solid content or binder concentration is too high, improper spraying, spray gun choking, or lump formation may occur. Conversely, if the concentration is too low, there will be greater drug powder loss and filter bag blockage. Hence, the optimum concentration of the binder solution and the solid content are critical material attributes.

4. Enteric Coating

Critical Material Attribute (CMA):
This coating is applied over the drug-loaded pellets. It is a crucial stage in pellet manufacturing, as most pellet formulations are controlled-release dosage forms designed to release the drug at intestinal pH. Commonly used polymers include HPMC phthalate 50, HPMC phthalate 55, Eudragit L30D55, Eudragit L100, and Eudragit S100.

The CMA here involves selecting the appropriate excipient based on the target site pH where drug release is required. For example, to achieve drug release at pH 5.0 and above in the intestine, HPMC phthalate 50, HPMC phthalate 55, or Eudragit L30D55 should be used at the required concentrations to meet the desired drug release profile. For drug release at pH above 6.0, Eudragit L100 is appropriate, and for pH above 7.0, Eudragit S100 should be used.

There is no strict limit for the concentration or weight of the functional excipient applied; the coating weight may go up to 80–100% w/w or even higher, depending on the formulation requirements.

5. Overcoating

Critical Material Attribute (CMA):
This coating is applied over the enteric coating. Since most pellet formulations are controlled, sustained, or delayed-release forms intended to release the drug in the intestine, the dosage form must withstand gastric pH during transit. Generally, the gastric residence time of any dosage form or food is about 2 hours. To protect the formulation during this period, a pH-independent overcoat is applied as the topmost layer of the pellet dosage form.

A good example is ethyl cellulose coating at 3–5% weight gain over the enteric-coated pellets, which provides protection against drug release at stomach pH and enables release in the intestine. The most important factor is the concentration of the ethyl cellulose coating. If the concentration is too high, it will retard drug release at all pH levels and time points. If the concentration is too low, there is a risk of more than 10% drug release at stomach pH. As per regulatory guidelines, the drug release at stomach pH should be less than 10% for enteric-coated formulations.

The critical material attributes, such as the excipients (binders, plasticisers, lubricants, functional polymers), solvents, and their concentrations used at each coating stage, play a significant role in pharmaceutical pellet manufacturing.

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