The Role of QTPP and QbD in Pellets Manufacturing

In pharmaceutical formulation, the primary objective is to develop drug products that meet desired quality standards while ensuring consistent quality control measures from raw material testing to final product testing. Although standard quality control tests are crucial in determining product quality at the post-manufacturing stage, these tests alone are insufficient to guarantee the overall quality of the product. Recognising this gap, the US FDA introduced the Quality by Design (QbD) concept in 2009.

QbD emphasises a proactive approach to product development by identifying and mitigating potential risks that could affect the drug product’s quality, safety, and efficacy. Central to this approach is the establishment of a Quality Target Product Profile (QTPP), which outlines the key characteristics that ensure the final product meets its intended quality requirements.

What is Quality by Design (QbD)?

Quality by Design (QbD) is defined as a systematic approach to drug development that begins with predefined objectives and focuses on product and process understanding through sound science and quality risk management. It starts by defining a set of quality requirements known as the Quality Target Product Profile (QTPP). The QTPP serves as a prospective summary of the key quality attributes a drug product must possess to ensure its desired quality, safety, and efficacy.

Within the QTPP, Critical Quality Attributes (CQAs) are identified, which include any physical, chemical, biological, or microbiological properties that must be controlled within an appropriate range to ensure product quality. CQAs are determined by the combination of Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs).

Critical Quality Attributes (CQAs) = Critical Material Attributes (CMAs) + Critical Process Parameters (CPPs)

• Critical Material Attributes (CMAs) refer to the properties of input materials, including active pharmaceutical ingredients (API), excipients, or other materials that significantly impact product quality.
• Critical Process Parameters (CPPs) are parameters related to the manufacturing process, particularly those linked to equipment and unit operations, that can alter the quality of the drug product if not properly controlled.

CMAs and CPPs in Pellets Manufacturing

Pellets manufacturing involves several stages: seal coating, drug loading, sub-coating, enteric coating, and over-coating. Below, we discuss how CMAs and CPPs play a critical role in these stages:

1. Seal Coating:

• CMAs: Seal coating is typically performed on core inert spheres to reinforce them and prevent pellet breakage during fluidisation in fluid bed coaters. Common materials for seal coating include Povidone K-30, Hydroxypropyl Cellulose, or Hydroxypropyl Methylcellulose (HPMC 3cps or 5cps) used at concentrations of 3-5%. Exceeding 5% can lead to issues such as spray gun clogging, causing the formation of lumps during fluidisation.
• CPPs: The critical parameters here are the pellet bed temperature and the inlet blower speed. The seal coating solution is usually water-based, so drying is crucial. The ideal pellet bed temperature should be between 40°C and 45°C, achieved by maintaining the inlet air temperature between 45°C and 55°C.

2. Drug Loading:

• CMAs: Drug loading can involve solutions, dispersions, or suspensions. The solution is prepared by dissolving the binder in a solvent, followed by the API. Particle size distribution (PSD), solid content, and solvent system (aqueous, alcoholic, or hydro-alcoholic) are critical factors. Improper particle size or solid content can result in uneven coating and rough pellet surfaces.
• CPPs: Important process parameters include inlet temperature, spray nozzle diameter, bed temperature, and blower speed. The bed temperature varies depending on the solvent system: 40-45°C for aqueous, 28-32°C for non-aqueous, and 30-35°C for hydro-alcoholic coatings. The choice of air distribution plate, based on pore size and number, also impacts coating efficiency.

3. Enteric Coating, Over Coating, and Sub Coating:

• CMAs: The critical attributes here are the solubility and nature of the coating materials, as they determine how well the coating will perform in its intended environment.
• CPPs: The process parameters, such as those within the fluid bed coater, must be carefully controlled to ensure uniform coating and consistent drug dissolution. These parameters vary depending on the coating material and must be optimised for each formulation to ensure reproducibility and product quality.

Establishing a Quality Target Product Profile (QTPP) in pellets manufacturing is essential for ensuring product quality, safety, and efficacy. By identifying and controlling Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) at every stage of production, pharmaceutical companies can develop robust products that meet regulatory standards. The integration of QbD principles into the manufacturing process provides a comprehensive understanding of potential risks, leading to more efficient processes and consistent product quality.

anish pharma specialises in state-of-the-art pellet manufacturing equipment, including fluid bed processors and tablet coaters, designed to optimise coating processes while ensuring uniformity, efficiency, and regulatory compliance. With a focus on innovation and quality by design (QbD), anish pharma is dedicated to helping pharmaceutical companies achieve superior product quality and operational excellence.