OSD SUPPLEMENT

Discussing the latest oral solid dosage challenges and trends with two leading players in the industry.

Quick Questions with John Ross, president at Metrics Contract Services & Maria Lundberg, vice president Product Development at Recipharm.

Q: Can you outline the key challenges and growth opportunities that have happened in the OSD market recently?

ROSS: The major challenge for the market lies in the misalignment of installed capacity compared with the contemporary needs to produce today’s OSD drug products.

Many large-scale installations that were used for producing blockbuster drugs, for example, simply do not fit or fulfil the requirements for producing most new drug products. The rising demand for orphan drugs and personalised medicine requires smaller scale batch sizes. Companies will have to invest substantially to remediate or retrofit legacy equipment and sites; alternatively, they can choose to work with more niche contract partners.

The growth in highly potent active pharmaceutical ingredient (HPAPI) programmes is seeing an increased need for installed contained operations. Regulatory controls concerning HPAPIs have become more stringent, requiring companies to rely on engineering controls rather than simply standard work practices and personal protective equipment (PPE) to keep workers safe. Installing contained equipment, such as isolators, bag-in/bag-out filters and split butterfly valves, requires significant investment.

As the number of poorly soluble and poorly bioavailable APIs in development continues to rise, so too do the challenges for formulation scientists trying to develop pharmaceutical dosage forms. It is these qualities that contribute to poor attrition rates of drugs in development, which translates into longer development times to formulate new products and delays in getting them to market. Companies need to invest in installing solutions that enhance solubility and bioavailability properties of new drugs; for example, multi-particulate drug delivery, spray drying, hot melt extrusion, and extrusion spheronization.

Controlling impurities in APIs and drug products remains a critical issue for the industry. Greater evaluation and understanding of impurities — such as trace metals or nitrosamine — in APIs and drug products can be achieved by installing appropriate analytical instrumentation and expertise.

LUNDBERG: While oral solid dose (OSD) products may seem unfashionable compared with the steep increase in new biopharmaceutical products, they remain extremely popular. There are many reasons why OSD forms remain the strongest in the market, most notably for their effectiveness, patient-friendly nature, and ability to extend product lifecycles by implementing extended, controlled, and rapid release formulations. However, there are, of course, many challenges to overcome when developing these different formulations.

Importantly, advances in formulation technology are aiding patient compliance.

One of the main hurdles in the market is ‘user-friendliness’. Oral formulations are user friendly in the sense that swallowing things is natural to humans. However, it is crucial to ensure that swallowing is not unpleasant for the patient, due to the size, taste, or odour of the product. The challenge for OSD products is to maintain their advantage as other dosage forms such as parenteral products advance, leading to increased cost competitiveness and user friendliness.

Q: Do you think there have been any recent advances in technology that have impacted the quality of the OSD market?

ROSS: Oral solid dosage forms still represent the largest (in terms of numbers) and remain the most popular dosage form in the pharmaceutical industry today. They also account for the greatest number of new drug approvals each year.

Several advances in technology are helping drug formulators to bring the benefits of OSD administration to molecules that previously had to be delivered by other means or could not be tolerated well in legacy formulations. There has been an increase in more complex molecules in an attempt to deliver targeted therapies. Developing such molecules with a modified release profile is enabling them to be made into OSD forms.

Importantly, advances in formulation technology are aiding patient compliance. Long-acting formulations result in once-a-day dosages, which are particularly helpful to those patients who forget to take their medication or find it difficult to manage dosage frequency. The growth in fixed-dose combinations and reformulations of injectable drugs to oral delivery is also testament to their benefit in enhancing patient compliance and/or patient experience.

Mini-tablets have in recent times shown their enormous potential as a patient-friendly drug delivery system, particularly for paediatric populations. These single- or multiple-unit oral dosage forms offer versatility of route of administration across varied patient populations and highly precise dosing options.

LUNDBERG: The industry has continued to see growing interest in precision medicine and products that are tailored for smaller groups of patients. One of the most notable advances in technology is 3D printing, which allows for a high degree of individual adaptation of the medicine. However, several issues regarding quality assurance and cost may limit the use of 3D printing in the future.

The most important advances may be less conspicuous. Adapting conventional manufacturing technology, making it more flexible and allowing smaller batches may be particularly useful. Pellet technology and mini-tablets are examples of conventional manufacturing technology that allows a high degree of flexibility as it is easy to combine different pellets and/or mini-tablets to achieve combinations of different drugs in different doses and different release rates.

It is likely that in the future, more and more patients will demand control over their own medication. Packages and devices that communicate with the likes of smartphones or tablets make it possible to track dosing and increase compliance may also become increasingly common.

Q: How has Covid-19 impacted OSD drug development?

ROSS: The current coronavirus pandemic has impacted OSD drug development less than the injectable drugs space. It has, however, spurred on the numerous additional OSD therapeutics in consideration for symptomatic relief or accelerated recovery, such as antivirals. Government funding has been far more prevalent for sponsors however such contracts bring additional obligations and requirements.

Although the pursuit of non-Covid therapies has remained largely unchanged, clinical trial processes have been adversely affected. For example, the availability of patients and patient monitoring due to social distancing policies have been challenging. In some cases, where funding sources have been affected, drug development programmes have been delayed or even stopped as a corporate cash preservation action.

LUNDBERG: The Covid-19 pandemic has had a relatively limited impact on OSD development. Of course, throughout the pandemic there has been a lot of focus on vaccines and parenteral dosage forms. However, that does not change the basic fact that oral administration, in the cases where it is feasible, is the most convenient and economical administration route. While the resulting vaccine is unlikely to be an OSD the medication in circulation to treat secondary symptoms for example, antibiotics, will remain in this format.

Four key considerations addressing the challenges for oral dosing with minitablet dispensing innovations.

Tough pill to swallow

Author: BJØRN KNUD ANDERSEN - director, Front-End Innovation and Head Technology Accelerators and IPR, Phillips-Medisize, a Molex company

When it comes to orally dosing solid tablets and/or capsules, certain patient populations such as paediatrics, geriatrics and oncology may find it a tough pill to swallow – quite literally. These patients often need highly flexible oral dosing based on their age, weight, body surface area or other variables. Alternative liquid dosing such as syrups pose some disadvantages, including the need for refrigeration, poor taste (especially for children) and the possibility of microbial contamination. Minitablets provide an easier to swallow alternative. However, the need to depend on the patient or caregiver’s ability to accurately handle and count the minitablets for the correct dose presents its own set of challenges. Most current systems rely on volumetric measuring principles using a syringe plunger to fill the cavity with minitablets, which can be imprecise.

How can the industry better meet the unique oral dosing needs of these special patient populations? Let’s explore some of the newer evolutions in device design, and where future innovation is headed. Here are four key considerations:

1. ELIMINATE GUESSWORK

There should be zero room for error. Newer minitablet dispensing innovations eliminate guesswork and enable patients and caregivers to more

In the future, such minitablet dispensing devices have the potential to be part of the growing connected health ecosystem.

accurately and reliably administer the exact number of minitablets needed per dose. One example is a dispenser that mounts directly on a standard Ø38 mm tablet bottle neck and can be used with minitablets ranging from ~2.0–2.5 mm diameter. It can be integrated/ co-packaged directly with the bottle or supplied separately to help meet the growing needs of patients who require consistent, customised oral dosing.

With the dispenser positioned directly on the bottle, only counted and dispensed minitablets come into contact with the outside environment. The patient simply unscrews the child-resistant bottle cap, mounts the dispenser onto the bottle and repositions the cap. When it’s time to dispense medication, the user inverts the bottle to shake the minitablets into the dispenser metering chamber, which has a transparent lid. The user then turns the bottle back upright and shakes it gently. The correct number of minitablets automatically fall into the indentations on the dosage disc (one per indentation) and the rest shake off and drop back into the bottle. After visually confirming that there’s a minitablet in each hole and therefore the count is correct, the user rotates the transparent metering chamber lid and pours the minitablets onto a spoon, food or other option.

2. MINIMISE CONTAMINATION

RISK

The risk of contamination is heightened these days and minitablet dispensing innovations can reduce this possibility. The type of dispenser design described earlier helps to avoid situations where the medication could incur unnecessary environmental or surface exposure. It prevents any potential contamination that could occur if patients poured the minitablets into their hand or onto a countertop, counted out the ones needed, and returned the excess back into the bottle. With this design, the user can adjust the dispenser to the desired minitablet count between one and 20. This “set and forget” approach requires the patient to pre-set the dispenser dosing disc only once. However, the setting can easily be changed if the medication dosage needs to be adjusted at any point during treatment.

3. INCORPORATE PATIENT-

FRIENDLY FEATURES

Added design flexibility makes oral dosing dispensers particularly attractive to global pharmaceutical companies who continuously seek new ways to help ensure that patients are adhering to their medication regimens. While pharmaceutical and medical device manufacturers are making positive strides to address unique dosing needs, the industry will benefit from even more innovations that take into account human factors engineering (HFE) early in the design. The features of minitablet dispensing devices must be further validated to test child resistance and senior friendliness, as well as the need to accommodate other tablet dimensions and bottle formats.

4. INTEGRATE CONNECTIVITY

In the future, such minitablet dispensing devices have the potential to be part of the growing connected health ecosystem. Integrating a low-cost connectivity electronics module into the dispenser could make it possible to detect tablet metering, dispensing activity and other patient behaviours – thereby helping to monitor and support medication adherence from afar. This is especially important as remote patient monitoring and telehealth become more popular.

CONCLUSION

For special patient populations with customised oral dosing needs where minitablets are the best option, innovative dispensers offer a promising solution. Patients and caregivers can experience improved accuracy in counting tiny pills without requiring a new or different bottle. At the same time, the container minimises the risk of contamination. The ability to add connectivity in the future will help encourage medication adherence.