Solid Dose Pharmaceuticals to Remain Strong

Oral Solid Dosage Forms Raise the Bar On Pharma Standards

The oral route has for long been the most common and convenient of the different delivery routes. Oral Solid Dosage Forms (tablets and capsules) are among the most widely used and convenient drug delivery modalities. After more than a century of development, the process, equipment, and technology may be produced in a non-sterile environment, and the method, tools, and techniques are well defined and known.

As one would expect from a dynamic vertical like pharmaceuticals, there have been rapid and innumerable innovations that are taking place under the gamut of OSD. With API’s becoming more jumbled, it becomes pretty critical that the solid dosage forms become compliant with their attributes with no room for any fall out. Because OSD’s inherent nature is patient centric, their ability to adapt to innovations, be they technological or otherwise, is far easier. As formulations have become increasingly varied and are susceptible to external forces, having a full-proof OSD makes sense, and this can be possible only when there is a complete thrust given to the technological realm that goes into it.

Keeping this in mind, World Pharma Today recently put the OSD’s existence in the era we are in, on the table of industry leaders and the elements that encircle it to make it more relevant, and the replies that we have received show a lot more intent and promise, and to an extent, dependence on its success.

Here is a detailed interview that took place between the editor of WPT and the executives from various organisations on the existence, relevance, and future of the OSD’s.

Q&A on Solid Dose Pharmaceuticals to Remain Strong

Contributor:
Yogesh D. Sadhale
Director, Pharmaceutical Development
Metrics Contract Services

Q1. What OSD manufacturing capabilities are currently in-demand? Do you foresee this shifting in the next 3-5 years?

Ans. Many of today’s drug development strategies seek to avoid parenteral administration and sponsors continue to be motivated to develop critical medicines in OSD forms because of patient and payer benefits. Although most biologic medicines are parenteral, and because of their efficacy, the demand for external capacity to process and finish large-molecule medicines will continue to grow but likely not to surpass the demand for OSD contract development and manufacturing services.

Many of these APIs require sophisticated formulation and manufacturing solutions to enhance bioavailability and dose control in the gastrointestinal tract. External partners with well-developed capabilities, capital equipment and experience to formulate and process these kinds of active ingredients will remain in high demand for the foreseeable future.

For the most part, pharma contract development and manufacturing organizations are working hard to help drug developers unknot problematic side effects and other patient-centered issues like dose frequency, compliance and the size of the individual dose.

Patient-centricity is now firmly at the forefront of drug development across

Rx, Gx and OTC products. The great thing about OSD forms is that they are inherently patient centric to begin with. Much, if not all of recent OSD technology development has been prompted by this overarching goal. Health care systems and patients have made it clear that if a jab can be avoided, it should, and that despite the potential for more risk and higher development costs, the extra expense is worth it because it serves both patient and payer interests best.

Q2. Complex APIs are increasingly becoming the norm, what strategies are you implementing to overcome solubility and bioavailability challenges?

Ans. Developing poorly soluble drugs for oral administration can be challenging and expensive. If the pandemic has proven anything, it’s that parenteral drugs like vaccines can be developed, approved and brought to market faster because there are fewer steps to finishing a liquid drug product.1 For solids, the chemistry can be more complex, with process and preparation of batches very labor intensive.

Depending on the demands of API chemistry, manufacturing the finished form may require more steps, and require longer lead times to create a validatable compliant commercial scale process. But ultimately, what the patient prefers are tablets and capsules and so developing precision formulations that solve the specific insolubility challenges of the molecule will continue to be remain a strategic development goal that we help our OSD clients reach.

Q4. What recent OSD technologies or methods might be proving extra capable of improving a given OSD’s therapeutic performance as well as challenges surrounding patient centricity?

Ans. Drug developer’s needs are changing and they are demanding even greater access to advanced dose form manufacturing techniques like amorphous solid dispersions (ASDs) and multiple unit pellet system (MUPS). These technologies have made a great impact on the efficient, effective delivery of problematic actives through the GI tract for example.

Pharma will continue to innovate technically to meet advanced drug development and manufacturing challenges. However, one piece of “technology” that has been missing from this toolkit until more recently is the human being. The emphasis on treating the patient as opposed to treating the disease has prompted drug developers to send development in new directions and that includes the contract partners they engage. Pharma’s developers are demanding solutions and new ways to improve the efficacy and patient centricity of their drug products.

Q5. Are there any new OSD technologies that you are excited about that may revolutionize the industry in the coming years? What challenges do these technologies aim to solve?

Ans. Osmotic pump tablets are another example of a technology developed to deliver actives more effectively. Coated with a semi-permeable membrane, the tablet is breached in one location by a laser-drilled port. Water permeates through the membrane, dissolving excipients in the core and thus raising the internal pressure. The raised pressure in the core causes the contents to be forced through the laser-drilled port at a constant rate.

Osmotic pump technologies offer several therapeutic and patient-centered benefits:

• Zero-order drug release (i.e., drug is released at the same rate over a given period of time)
• The drug release rate is independent of the gastric pH
• The release rate from the delivery system is not affected by the presence of food (i.e. no food effect)
• High degree of in-vitro/in-vivo correlation with these kind of delivery systems
  Single daily doses are achievable

Pfizer CentreOne offers two commercially viable osmotic technologies: Swellable Core Technology (SCT) and an Extrudable Core System (ECS). What is exciting about all these OSD technologies and processing techniques is the fact that they are increasingly well understood by pharma’s commercial manufacturing partners and consequently are constantly being put to work to deliver complex and often potent compounds to patients successfully.

Q&A on Solid Dose Pharmaceuticals to Remain Strong

Contributor:
Peter Kruger
Head of Strategic Marketing
Recipharm

Q1. What OSD manufacturing capabilities are currently in-demand? Do you foresee this shifting in the next 3-5 years?

Ans. The oral solid dose (OSD) market is growing rapidly at the moment, and is expected to be worth $926 billion by the end of 2027 from $493 billion in 2017, with a CAGR of 6.5% . As a result, contract development and manufacturing organisations (CDMOs) are seeing rising demand for comprehensive development support from OSD projects, from discovery to commercial manufacture.

Demand is increasing for support in handling highly potent active pharmaceutical ingredients (APIs), including sex hormones, corticosteroids and controlled substances. This is due to the rapid growth in the use of HPAPIs in drug development. In fact, the global market is expected to be worth USD 38.84 billion by 2028, expanding at a CAGR of 8.4% from 2021 to 2028 . With this in mind, we can expect HPAPI manufacturing capabilities to continue to be in demand for the foreseeable future.

Q2. Complex APIs are increasingly becoming the norm, what strategies are you implementing to overcome solubility and bioavailability challenges?

Ans. The HPAPIs increasingly being used in drug development pose particular development and manufacturing challenges. Not only are they highly potent – posing an environmental health and safety issue – they also often have low solubility that must be overcome in order to develop a commercially viable and therapeutically effective formulation.

Poorly soluble APIs require specialist technology and special excipients to overcome solubility and associated bioavailability challenges. Adding further complexity is the fact that no two APIs are alike – there is no one-size-fits-all technology or formulation approach to enhancing solubility successfully.

Nevertheless, in most cases, holding to the principles of Quality by Design (QbD) and Design of Experiments (DoE) is still the most important measure that should be taken by a product sponsor’s CDMO partner. These can help lay a systematic groundwork for identifying a solubilisation approach that is not only effective, but also scalable to ensure commercial viability of the finished formulation.

In addition, it is crucial to manufacture these HPAPIs under high-containment conditions and processing operational controls. Specialised operator training with the level of containment based on occupational exposure limits is another prerequisite to ensure compliance. With HPAPI production expected to grow in the coming years, achieving health and safety goals while optimising manufacturing efficiency will be a challenge that we are committed to overcome for our customers.

Q3. OSDs continue to be relevant within the pharma landscape. Are there other routes of administration that you feel will become more predominant in the future? What makes OSD so attractive as a route of administration?

Ans. Parenteral products, such as vaccines, are perennially attractive for developers and we can expect demand for the route to grow in the coming years. There are some key reasons for this. Parenterals can be developed, approved and commercialised faster than OSD products, especially when poorly soluble HPAPIs are involved. As there is no need to address bioavailability issues for parenterals, there are fewer steps to finishing a liquid drug product .

Nevertheless, OSD is being increasingly favoured by pharmaceutical companies, due to the inherent patient experience benefits offered compared with parenteral. Patients continue to prefer their medication in tablet and capsule forms, as they are easier and more pleasant for them to self-administer, especially outside a clinical setting. As such, the benefits of OSD outweigh the costs .

Q4. What recent OSD technologies or methods might be proving extra capable of improving a given OSD’s therapeutic performance as well as challenges surrounding patient centricity?

Ans. One key example of OSD technology that is growing in demand is modified release (MR) formulation development and manufacturing, which is on the rise as a means of reducing dosage frequency or creating fixed-dose combination drugs.

These benefits can help significantly enhance patient centricity, as they reduce the number of tablets that a patient needs to take per day, cutting the risk of missed doses and helping to optimise adherence.

Capsules have particular advantages when it comes to manufacturing MR products effectively and efficiently, as they allow the use of pellet technology to achieve the required release control profile. Using pellets can also allow versions of the same product with differing strengths to be created efficiently without the need for separate production lines.
Another advantage of capsule technology is that they do not need coating as is often required for tablets containing drugs with a bad taste (a common property with many drugs, which can make patients reluctant to take their medication, with patient compliance consequences). This can help optimise manufacturing efficiency without impacting on the experience of the patient taking the drug.

Q5. Are there any new OSD technologies that you are excited about that may revolutionise the industry in the coming years? What challenges do these technologies aim to solve?

Ans. As discussed earlier, the use of pellet technology in capsules offers many advantages for enhancing the performance of OSD products while optimising manufacturing efficiency, and it should be used more than it is now. It is highly efficient and convenient for drug formulators looking to manufacture MR products and fixed dose combination drugs.

Pellets allow the easy adjustment of an OSD product’s strength and release profile, and it is straightforward to combine different APIs to create new fixed dose combination products as needed.

As such, pellet technology is a flexible approach that can significantly enhance drug innovation all while optimising development and manufacturing efficiency for drug formulators.

Q&A on Solid Dose Pharmaceuticals to Remain Strong

Contributor:
Deirdre Whelan
Director of Operations for Pfizer CentreOne
Pfizer CentreOne

Q1. What OSD manufacturing capabilities are currently in-demand? Do you foresee this shifting in the next 3-5 years?

Ans. Many of today’s drug development strategies seek to avoid parenteral administration and sponsors continue to be motivated to develop critical medicines in OSD forms because of patient and payer benefits. Although most biologic medicines are parenteral, and because of their efficacy, the demand for external capacity to process and finish large-molecule medicines will continue to grow but likely not to surpass the demand for OSD contract development and manufacturing services.¹

Many of these APIs require sophisticated formulation and manufacturing solutions to enhance bioavailability and dose control in the gastrointestinal tract. External partners with well-developed capabilities, capital equipment and experience to formulate and process these kinds of active ingredients will remain in high demand for the foreseeable future.

For the most part, pharma contract development and manufacturing organizations are working hard to help drug developers unknot problematic side effects and other patient-centered issues like dose frequency, compliance and the size of the individual dose.

Patient-centricity is now firmly at the forefront of drug development across

Rx, Gx and OTC products. The great thing about OSD forms is that they are inherently patient centric to begin with. Much, if not all of recent OSD technology development has been prompted by this overarching goal. Health care systems and patients have made it clear that if a jab can be avoided, it should, and that despite the potential for more risk and higher development costs, the extra expense is worth it because it serves both patient and payer interests best.

Q2. Complex APIs are increasingly becoming the norm, what strategies are you implementing to overcome solubility and bioavailability challenges?

Ans. Developing poorly soluble drugs for oral administration can be challenging and expensive. If the pandemic has proven anything, it’s that parenteral drugs like vaccines can be developed, approved and brought to market faster because there are fewer steps to finishing a liquid drug product.1 For solids, the chemistry can be more complex, with process and preparation of batches very labor intensive.

Depending on the demands of API chemistry, manufacturing the finished form may require more steps, and require longer lead times to create a validatable compliant commercial scale process. But ultimately, what the patient prefers are tablets and capsules and so developing precision formulations that solve the specific insolubility challenges of the molecule will continue to be remain a strategic development goal that we help our OSD clients reach.²

Q3. What recent OSD technologies or methods might be proving extra capable of improving a given OSD’s therapeutic performance as well as challenges surrounding patient centricity?

Ans. Drug developer’s needs are changing and they are demanding even greater access to advanced dose form manufacturing techniques like amorphous solid dispersions (ASDs) and multiple unit pellet system (MUPS). These technologies have made a great impact on the efficient, effective delivery of problematic actives through the GI tract for example.

Pharma will continue to innovate technically to meet advanced drug development and manufacturing challenges. However, one piece of “technology” that has been missing from this toolkit until more recently is the human being. The emphasis on treating the patient as opposed to treating the disease has prompted drug developers to send development in new directions and that includes the contract partners they engage. Pharma’s developers are demanding solutions and new ways to improve the efficacy and patient centricity of their drug products.

Q4. Are there any new OSD technologies that you are excited about that may revolutionize the industry in the coming years? What challenges do these technologies aim to solve?

Ans. Osmotic pump tablets are another example of a technology developed to deliver actives more effectively. Coated with a semi-permeable membrane, the tablet is breached in one location by a laser-drilled port. Water permeates through the membrane, dissolving excipients in the core and thus raising the internal pressure. The raised pressure in the core causes the contents to be forced through the laser-drilled port at a constant rate.

Osmotic pump technologies offer several therapeutic and patient-centered benefits:

• Zero-order drug release (i.e., drug is released at the same rate over a given period of time)
• The drug release rate is independent of the gastric pH
• The release rate from the delivery system is not affected by the presence of food (i.e. no food effect)
• High degree of in-vitro/in-vivo correlation with these kind of delivery systems
• Single daily doses are achievable

Pfizer CentreOne offers two commercially viable osmotic technologies: Swellable Core Technology (SCT) and an Extrudable Core System (ECS). What is exciting about all these OSD technologies and processing techniques is the fact that they are increasingly well understood by pharma’s commercial manufacturing partners and consequently are constantly being put to work to deliver complex and often potent compounds to patients successfully.

References:

1. www.frontiersin.org/articles/10.3389/fphar.2021.618411/full
2. www.nature.com/articles/d41586-020-03626-1
3. www.pubmed.ncbi.nlm.nih.gov/8451252/

Q&A on Solid Dose Pharmaceuticals to Remain Strong

Contributor:
Brittany L. Hayes, Ph.D.
Director, Global Highly Potent & Oncology Platform
CordenPharma International

Q1. What OSD manufacturing capabilities are currently in-demand? Do you foresee this shifting in the next 3-5 years?

Ans. One of the requests that we see frequently is minitablets or pellets in capsules. This dosage form is easily adjusted for higher and lower dosage strengths by adding more or less minitablets or pellets. It is also a good dosage form for pediatrics (or geriatrics) because you can open up the capsules and sprinkle the contents into food. For highly potent APIs, coated tablets have been the dosage form of choice for several years. This is based on safety aspects to prevent the patients or employees in hospitals from having direct contact to the API in the tablets.

Additionally, 70-90% of APIs in development are highly insoluble and suffer from bioavailability issues. This trend will increase over the next few years, requiring efficient strategies or technologies to solve this issue. Demand has increased for technologies such as spray drying, hot melt extrusion, and nanomilling or micronization.

Q2. Complex APIs are increasingly becoming the norm, what strategies are you implementing to overcome solubility and bioavailability challenges?

Ans. In the last 10 years, CordenPharma has seen more and more complex APIs entering clinical Phase I. The complexity is mainly solubility/bioavailability driven. In order to overcome these issues, CordenPharma is working on an early-stage concept between API development and Drug Product development for First-in-Human clinical studies. We are installing this early-phase platform at the CordenPharma Liestal, Switzerland and CordenPharma Plankstadt, Germany sites. The Liestal site will conduct solid-state characterization, polymorph, salt screening, and biopharmaceutical characterization of the API (e.g. solubility testing, small-scale dissolution testing). And, in Plankstadt, we will be installing small-scale equipment for spray drying, hot melt extrusion, nanomilling, and micronization. We will then be able to prepare small-scale prototypes in our R&D laboratory for animal studies. Further development and scale-up for clinical studies can then be conducted in larger scale GMP equipment in Plankstadt, or one of our other facilities in the network.

Q3. OSDs continue to be relevant within the pharmalandscape. Are there other routes of administration that you feel will become more predominant in the future? What makes OSD so attractive as a route of administration?

Ans. I believe that OSDs will continue to be a predominant route of administration within the pharma landscape. Many patients prefer swallowing tablets and capsules versus injections or infusions. They can also be sent home with these medications, instead of having to go into hospitals for administration of treatments. In addition, they are generally more simple, stable, flexible, and more cost-effective dosage forms to manufacture.

Q4. What recent OSD technologies or methods might be proving extra capable of improving a given OSD’s therapeutic performance as well as challenges surrounding patient centricity?

Ans. One key methodology that improves both therapeutic performance and is patient-centric is a modified release dosage form. Modified release drug products enable drug release over a defined period of time, or at specific locations within the GI tract for prolonged or targeted drug delivery. This allows for less frequent dosing, which can increase patient compliance, resulting in fewer side effects by reducing peaks and troughs in blood levels. This is a huge therapeutic advantage for patients if the debilitating effects of a disease appear quickly once the drug concentration falls out of the therapeutic window.

Newer technologies that will be interesting to see how they progress in our industry are 3D printing and digital/eHealth dosage forms. And, of course continuous manufacturing. Together with PAT tools, this is suitable for development, clinical manufacturing, and small-scale commercial manufacturing.

Q5. Are there any new OSD technologies that you are excited about that may revolutionize the industry in the coming years? What challenges do these technologies aim to solve?

Ans. 3D Printing is very interesting. It is currently still in an early development phase and is a slow process (compared to conventional drug product manufacturing technologies), but it can create personalization of dose and specific combinations of APIs. It will be highly challenging from a regulatory standpoint.

Conclusion

The needs of drug developers are changing, and they are seeking even more complex dosage form production procedures. Another example of a technology capable of delivering abilities more effectively is osmotic pump tablets. By 2028, the global market is estimated to be worth USD 38.84 billion, with a CAGR of 8.4% from 2021 to 2028. With this in mind, HPAPI manufacturing capabilities are likely to be in high demand for the coming years. The fact remains that the advantages of OSD’s outweigh the cost, which is involved in its research, technological upgrade, and tweaks. Pharmaceutical firms are increasingly favouring OSD over injectables because of the inherent patient-centred benefits it provides. Patients continue to favour tablet and capsule forms of medication because they are better and easier to self-administer, particularly outside of a clinical setting. The oral solid dose (OSD) market is estimated to reach $926 billion by 2027, up from $493 billion in 2017, a 6.5% CAGR. CDMOs are witnessing an increased demand for OSD development help for their projects. 

With all these facts that make the OSD’s imprint thicker, their growth at a brisk pace can never be ruled out throughout this decade.