Leading oral solid dosage (OSD) form contract development and manufacturing organizations (CDMOs) are rapidly expanding their capabilities as active pharmaceutical ingredients (APIs) with complex chemistries are becoming the norm.

Solubility and thereby bioavailability of most of the APIs entering clinical phase I are getting increasingly complex in recent years, show studies.

“With over 80% of current pipeline candidates, poorly soluble APIs dominate today’s global R&D pipeline,” says Neil Jones, chief commercial officer at Aenova, a global CDMO headquartered in Starnberg, Germany. “These compounds cannot be formulated as a standard immediate-release tablet, since the API cannot be absorbed in the intestine due to its low aqueous solubility.”

Aenova, partner of choice for large-volume manufacturing, identifies bioavailability enhancement of poorly soluble APIs and patient-centric drug design as the two key areas having the greatest potential where the need for advancement is the highest.

Keeping this in view, the CDMO is bolstering capabilities for more complex and difficult-to-manufacture formulations, particularly in novel technologies to improve the bioavailability of APIs.

Over the last two years, Aenova has continued investing in capabilities such as controlled release (MUPS or encapsulated mini tablet systems), hot melt extrusion (HME), specialized excipient particle design to improve solubility and disintegration, and low- or micro-dosed capsules, across many of its 14 manufacturing sites.

Quotient Sciences, which announced the completion of an expansion of its early-phase formulation development capabilities for OSDs at its Nottingham, UK, facility last February, provides another example. With this latest investment, the CDMO has expanded its high containment laboratory capacity to support oral drug programs including immediate release, modified release tablets and multi-particulate dosage forms for highly potent compounds.

Similarly, Piramal Pharma Solutions upgraded OSD capabilities to 4.5 billion from 3 billion doses with a new production block at the Pithampur site in the state of Madhya Pradesh, India in May 2022. V Block includes aqueous and non-aqueous wet granulation (high shear, top spray, and bottom spray); direct, mono, and bilayer compression, aqueous and non-aqueous coating and bottle packaging technologies.

Not so long ago, heeding to the increasing demand for drug substance manufacturing, particle engineering, and drug product manufacturing, Hovione announced in a November 2021 press release that it was expanding its industrial facilities in Portugal, Ireland, and New Jersey by around 25% investing $170 million.

Seeing the urgency of the problem, which is getting exacerbated by the increasing complexity of molecules in recent years, a growing number of OSD contract service providers have started adding bioavailability enhancement services, while providers of specialized formulations services and other CDMOs including Hovione, Thermo Fischer Scientific, Lonza, and Catalent have broadened bioavailability services portfolios as part of a one-stop-shop approach, show reports.

Industry observers maintain that the capabilities to unknot molecule-specific insolubility problems and develop formulations having precise delivery mechanisms will remain a strategic development goal that CDMOs help their OSD clients reach.

Solution for solubility

Molecules with poorly soluble chemistries present a challenge and often require resource-intensive, sophisticated formulation solutions to enhance their bioavailability/absorption as they enter the gastrointestinal tract.

CDMOs say that drug developers’ needs are changing and they are demanding even greater access to advanced dose form manufacturing techniques like amorphous solid dispersions (ASD) and multiple-unit pellet system (MUPS).

ASDs and lipid-based systems are among the key technologies to enable oral bioavailability of poorly soluble APIs.

ASDs are produced using HME or spray drying technology. In this technique, poorly soluble APIs are converted into an amorphous dispersion by dissolving the API and a polymer excipient in an organic solvent and evaporating the solvent with heated gases.

Whereas lipid-based systems are designed to tackle the solubility and bioavailability problems of poorly water-soluble drugs.

On the delivery front, MUPS has made a great impact on the efficient, effective delivery of problematic APIs. A flexible approach, pellet technology allows the easy adjustment of an OSD product’s strength and release profile, and it is simple and easy to combine different APIs to create new fixed-dose combination products as needed.

Osmotic pump tablets are another advancement currently employed by some CDMOs to deliver APIs more effectively. The release of actives from these systems is osmotically controlled and is independent of gastric fluids to a large extent.

Reports say that CDMOs integrating such technologies to add skill sets for addressing bioavailability issues can have a transformative impact.

Patient experience at forefront

Even as specialized capabilities and know-how to formulate complex APIs are increasingly in demand, patient-centered issues like dose frequency, compliance and the size of the individual dose remain the key goal of OSD development.

Drug makers continue to favor OSDs as patients and even healthcare systems are looking if a jab can be avoided and embrace the inherently patient-centric OSDs.

CDMOs say the number of sponsoring firms that come seeking strategies to develop the product in the OSD forms, avoiding the parenteral route, is increasing by the day.

“Serving as a more patient-centric alternative to parenteral administration, we see the rise of OSD forms for treating different chronic diseases such as cardiovascular diseases, diabetes, as well as cancer as a key trend in the pharma industry,” says Rajesh Vooturi, head of formulations R&D at Aurigene Pharmaceutical Services Limited, a wholly owned subsidiary of Dr. Reddy’s Lab, Hyderabad.

The high prevalence of chronic diseases requiring long-term treatment with oral medications is one of the key factors that account for the OSD market to remain significant. Treatments for these conditions increasingly harness highly potent active pharmaceutical ingredients (HPAPIs) with poorly soluble chemistries.

Also, “based on the trends of the past few years, one could see a clear transition from conventional OSD formulations toward innovative drug delivery systems,” says Vooturi.

The advancements, he explains, are essentially focused on improving the patient’s quality of life. Specifically, enhanced dosage forms would help improve patient compliance and adherence to dosage regimens. Some of the examples include taste improvement of bitter drugs; reduction of side effects associated with conventional dosage forms by converting into a sustained release system or site-specific drug delivery systems; providing improved bioavailability through ASDs; conversion of injectable dosage forms to oral solution or modified release capsule dosage forms to avoid frequent injections; and poly-pill systems providing fixed dose combination specific to a certain disease.

Aurigene provides end-to-end services to customers right from discovery phase formulations up to commercial scale manufacturing of a wide variety of OSD dosage forms, says Vooturi.

In concurrence, Florent Bordet, chief scientific officer at Aenova, says, “Patient-centric OSD solutions are emerging, since they offer significant benefits in the therapeutic performance of drug products and patient experience.”

Orally disintegrating tablets (ODTs) offer a good example. Such tablets “melt” in the mouth and consequently offer the highest convenience in dose administration and can improve onset and therapeutic efficacy. ODTs overcome problems such as dysphagia in pediatric and geriatric patient populations.

“ODTs require sophisticated formulation concepts depending on the API physiochemistry and pharmacology characteristics,” says Bordet. “Aenova is offering a broad range of formulation solutions paired with long-standing experience in the field.”

When it comes to advanced formulation concepts, partnering with expert CDMOs that offer a broad range of technologies and making use of their expertise is key to advancing new molecules and superior drug products to the market.

Consistently high demand

As mentioned, formulating poorly soluble drugs for oral administration can be expensive and may require longer lead times.

However, Vooturi of Aurigene Pharmaceutical Services maintains that while parenteral drugs are often easier to develop and can be brought to market faster, the patient-centricity of OSDs means that they are worth the additional time and financial investments.

The benefits of OSD outweigh the costs because tablet and capsule forms are easier to self-administer, especially outside a clinical setting.

Large segments of patients prefer oral medications over other forms of administration, such as injections or infusions, due to convenience, ease of administration, and familiarity. Moreover, OSD formulations are used to deliver a wide range of therapeutics, including small molecules, which are still the primary modality for many diseases despite the overarching impact of modern-day large molecule therapeutics.

Industry leaders are of the view that even though the top-selling large-molecule drugs are “ready to dominate the pharma market” as more targeted therapeutic options, they are unlikely to beat the demand for OSDs which remain the mainstay of drug delivery.

“Tablets continue to be the preferred dosage form worldwide due to their ease of use,” says Jones of Aenova.

Aenova expanded its high-volume solids site in Tittmoning further in December 2023 with an investment of around €20 million aimed to increase capacity by 2 to 3 billion packaged tablets in the final expansion stage. Consistently high demand is driving the continuing investment in the CDMO’s largest plant for solid oral dosage forms with a capacity of around 10 billion tablets and capsules per year, according to the company.

“Many medicines commonly used worldwide are available in tablet form and these markets need to be supplied. Customers and patients need their medicines urgently, on time, in budget and to the right quality. Aenova plans to meet this growing demand via the expansion of the CDMO’s Oral Solid Dose Center of Excellence in Tittmoning, Germany,” says Jones, explaining the rationale behind Aenova’s huge volume upgrade for OSDs.

The global OSD contract manufacturing market size was estimated at $36.5 billion in 2023 and is projected to grow at a CAGR of 5.97% from 2024 to 2030, according to a report by Grand View Research.

Asia Pacific region is expected to have the largest CAGR. Operating in the market with very low prices has aided China and India in controlling the OSD CMO market, show reports.
Obviously, orally administered tablets and capsules—the most convenient drug delivery modality with a long history of successful use—continue to dominate in the pharmaceutical industry and external partnering shows no signs of slowing down. 

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Soman Harachand is a pharmaceutical journalist based in Mumbai and a regular contributor to Contract Pharma. He can be reached at harachand@gmail.com.