Tackling challenges in the development of fixed-dose combinations

Developing fixed-dose combinations (FDCs) is becoming a popular lifecycle-management (LCM) strategy for pharmaceutical companies seeking to maximize the value of their products. “The development of FDCs is driven by factors, such as the patent expiry of major blockbuster drugs, stiffer competition from generic drugmakers, and a drought in the pharmaceutical R&D pipeline,” Anil Kane, PhD, executive director and global head of formulation sciences at Patheon, noted in an interview with Pharmaceutical Technology. Reformulating and combining drugs that have been proven to be safe and effective into FDCs represents an essential strategy for drug-development companies to realize maximal commercial returns in a faster way than developing new molecular entities, which could be a lengthy, expensive, and high-risk endeavor. FDCs can benefit patients through the potential increase in efficacy, the synergistic effect of a potentially lower dose, and the convenience in terms of administration and compliance. Combination drugs also offer an opportunity for intellectual property and exclusivity. Kane spoke to Pharmaceutical Technology about the challenges in the development of FDCs and discussed how to integrate quality-by-design (QbD) in the manufacturing process of FDCs.

PharmTech: What factors must formulation scientists consider when developing FDCs?

Kane: The main challenge usually involves product formulation and manufacturing issues. Two or more active ingredients in the FDCs have to be physically and chemically compatible along with their excipients. It is important to ensure that these active ingredients do not generate new impurities or raise new drug-drug interactions.

Individual drug dose differential can pose formulation and processing challenges when combined in a single-unit dosage form. Physicochemical properties and stability of each of the drug in an FDC will define the formulation approaches to maintain stability during the shelflife of the combined drug product. For example, the hygroscopicity of one active drug substance can influence the stability of the other drug in the combination product unless they are completely separated by way of multiple techniques.

The particle size distribution of a low-dose drug and the distribution of the second high-dose drug can affect the content uniformity of one and flow and processability of the other for a single two-layer tablet. If the active drugs are incompatible with each other, they would need to be formulated in a single pill using a number of different options, such as multilayer tablets, compression-coated tablet, multiparticulates in capsules, combinations of coated and uncoated beads, or pellets of one placed with a powder of another active.

Innovative formulation strategies also require new analytical procedures to accurately assess product quality. Additionally, the packaging of an FDC product may need to be re-considered based on the criticality of the multiple actives and their stability profile in combination.

PharmTech: Can you describe the manufacturing process of FDCs?

Kane: We adopt a decision tree for formulating two or more drugs as FDCs (see Figure 1). Depending on the formulation strategy adopted, the manufacturing of an FDC can be as simple as mixing the two or more active drug substances (provided they are physically and chemically compatible and stable) with excipients required for encapsulation, or tableting and compression followed by coating or encapsulation.

The manufacturing process is more complex with bilayer, three-layer, or tablet-in-a-tablet manufacturing. This could involve multiple granulations and compressing these layers using suitable multilayer tablet presses or a special press for tablet in a tablet. Minitablets can be manufactured using conventional tablet presses with specialized tooling and multiple minitablets containing different components of the FDC can be encapsulated in a capsule.

The manufacturing process of FDCs as multiparticulates could involve beads or pellets prepared using an extrusion spheronization process and a second active drug layering. An alternative is to have multiple layers loaded onto nonpareil sugar or cellulose beads. In general, if a high drug loading is required, an extrusion process is preferred to manufacture pellets and the second active drug can be layered using an active coating process. For low drug loading, layering onto sugar or cellulose beads is feasible. The beads or pellets of different population containing different active drug substances can then be filled into a hard-shell capsule.

PharmTech: How do you integrate QbD into the manufacturing process of FDCs?

Kane: It is important to integrate principles of QbD into the development and manufacturing process for all products, especially the complex processes of FDCs. The critical quality attributes (CQAs) for FDCs will be similar to single-ingredient drug products. The only additional complexity will be impact of two or more active drug substances on the potency, impurities, dissolution of individual drugs, and content uniformity of each active especially where there is a big dose differential among the active drugs. The drug-drug interaction in-vivo are additional attributes to be considered for FDCs.

The critical process parameters (CPPs) are similar to individual single-drug products as well. The CPPs become more complex when the impact of physicochemical properties of multiple ingredients on the manufacturing unit process affects the processability and the quality parameters. Properties such as hygroscopicity and particle size distribution play a key role in the ability to process the FDC’s to meet the target product profile (TPP). Depending on the final identified target dosage form and the method of manufacture, the CPPs could be different (e.g., roller compacted granules of Drug A + a direct blend of Drug B with excipients compressed as a bilayer tablet). The formulator needs to understand the process by a systematic design of experiments conducted to evaluate the impact of processing parameters to meet the quality specifications. QbD in development of FDCs becomes more critical as it involves study of the impact of multiple actives and process understanding to formulate and manufacture a robust FDC product.

About the Author
Adeline Siew is the scientifc editor for Pharmaceutical Technology.