Fixed-Dose Combinations

Fixed-dose combination (FDC) formulations have gained popularity as a strategy to obtain supplementary patent protection and minimize generic exposure of mature brands. Pharmaceutical Technology spoke to Stefania Barzanti, marketing manager at IMA Active division, about the challenges and considerations in the formulation and manufacturing process of FDCs.

PharmTech: What are the advantages of FDCs?

Barzanti (IMA Active) : The success of FDCs is the result of two concurrent needs: on one side, there is the need of welfare systems to contain healthcare costs, and on the other side, the need for pharmaceutical companies to optimize products lifecycle and exploit the potential of their existing product portfolio. An aging population and an increase in chronic diseases are setting a challenge to welfare systems concerning the sustainability of growing healthcare costs. Cost containment is probably the most important driver in the current pharmaceutical market but it must be pursued without affecting health outcomes.

FDCs can be used either to combine different actives in one single dosage or to achieve a precise release profile of a specific active (e.g., combining an immediate-release with an extended-release formulation). At the same time, FDCs can reduce the frequency of administration and improve the pharmacokinetics of the drug, therefore, resulting in less side effects. FDCs are more convenient for patients and encourage compliance and adherence with their medications. In addition, they allow product differentiation and containment of generic exposure for mature pharmaceutical products.

PharmTech: Can you describe the formulation and manufacturing process of FDC dosage forms?

Barzanti (IMA Active) : In terms of formulation, the first challenge is to bring together different pharmacokinectics and target release profiles, and this, of course, becomes more complex with higher number of active drugs. However, from the manufacturing point of view, one of the most common challenges is represented by the combination of two chemically incompatible actives that have to be kept separated but included into a single dosage form. This issue is particularly crucial for layered tablets, where sometimes, an intermediate placebo layer has to be created to avoid any interaction. Constant check and frequent replacement of the scraper blade are also importance in order to avoid the mixing of the different powders comprising the various layers.

A second and extremely relevant issue is represented by the control of the single dosages. In a layered tablet, the single layers can be sampled and checked individually but it is not possible to check them separately in the final complete unit dose.

During the last four to five years, we have seen a growing interest for hard gelatin capsules, especifically for FDC products. On a capsule filler, different ingredients can be easily combined inside the same capsule shell simply adding a dosing unit. Besides powder, different product forms can also be dosed, including pellets and minitablets, small tablets or capsules, softgel or liquids, and semi-solids. There are technologies available for in-line check of each single unit produced by the machine.

PharmTech: FDC tablets are often more expensive than their components and provide less flexibility in dosing options, what are your thoughts on this?

Barzanti (IMA Active) : The total cost should also include the subsequent manufacturing phases up to the final packaging. In any case, the final cost reduction from the increased patients compliance and better use of medicines makes FDCs beneficial when considering the cost aspect from a global standpoint. It is, however, true that flexibility in dosing options is reduced, and it becomes more difficult to have fine tuning of the medication prescription to the needs of a specific patient. Careful evaluation of the pros and cons should drive the choice between the different solutions on the basis of a patient-centric approach that considers lifestyle needs and the medical condition.

PharmTech: In your opinion, how successful is the current FDC market and what is the future of this type of dosage form?

Barzanti (IMA Active) : I see FDCs as one of many opportunities present on the market to innovate oral solid dosage forms together with the growing interest for multiparticulate formulations and new drug delivery solutions. The overall aim is to make a better use of existing product portfolios through optimization of plasma concentration of APIs, improved bioavailability, enhanced therapeutic effect as well as minimization of side effects. FDCs can be especially useful to support long-term concurrent therapies in patients affected by chronic diseases that are related to each other. I believe the current aging population is a driver for growth for this type of oral solid dosage form.