Q&A with Metrics and Recipharm: The latest oral solid dosage challenges

Discussing the latest oral solid dosage challenges and trends with John Ross, president at Metrics Contract Services & Maria Lundberg, vice president of 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.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.

Q: Different patients have different requirements when it comes to the administration of medicine. How can manufacturers adapt the formulations of OSD to adhere to specific patients’ needs?

Ross: Patients not only have different requirements regarding medicine administration; many have certain preferences. The ability to swallow a tablet or capsule is a particular consideration among paediatric and geriatric populations. Mini-tabs, which are typically regarded as having diameters of less than 4mm, offer ease of ingestion. They allow manufacturers to dose together tablets with different release profiles to achieve the desired effect. 

To achieve targeted drug delivery, manufacturers can dose mini-tabs with immediate release, delayed release, or extended release in one capsule. These can be formulated as floating devices to enable retention in the stomach for complete drug delivery. Mini-tabs can also be formulated as orally disintegrating tablets (ODTs) given the small size of the tablets, enabling faster disintegration times. ODTs are also a patient-centric drug formulation, benefiting a range of target patient populations including those who have difficulty in swallowing, experience nausea or vomiting, have had a stroke, or are bedridden. 

Formulated correctly, ODTs should disintegrate rapidly on the tongue (within approximately 30 seconds) without the need for chewing or an accompanying drink. Manufacturers can combine this dosage form with taste-masking properties to avoid bitter drug aftertaste.

Manufacturers can further assist elderly patients, who tend to need to take multiple drugs several times throughout the day, through considered dosage form design – variations in size, colour, and shape all help to address their need to be able to easily identify each product.

Lundberg: Since different patients have different needs, we need to master different technical solutions to that can be tailored to meet many different requirements. For instance, given the ageing population there are a large proportion of patients that take several different medicines on a daily basis. If a patient has a large quantity of medicines to administer, it can be difficult to remember all of them and ensure they are taken at the right times. These patients are the ones that can be helped using fixed dose combinations (FDCs) whereby patients can take one dose that contains multiple medications, which ultimately increases patient compliance.

On the other hand, the patient groups that are on the move a lot may look for an orally disintegrating tablet which can be swallowed without water. Alternatively, modified release formulations may prove very useful for patient groups that need to take medication at regular intervals as they can reduce dosing frequency. In addition, they also reduce any adverse side effects