Small Molecule

Long Live OSD

The industry’s oldest drug form proves it’s here to stay

By Karen Langhauser, Chief Content Director

With more than a century of safe, effective usage, oral solid dose products are a proven pharmaceutical market mainstay. Despite the increasing number of biologics and even parenteral small molecule drugs, OSD remains dominant in the market.

This is not to say the dosage form is without challenges. With many traditional blockbuster oral solid dose products now off-patent, next-generation OSD products, such as high potency drugs and personalized medicines, necessitate smaller volumes of production, with shorter lead times. A trend toward more regionalized manufacturing also means smaller production volumes. These factors, combined with a more intense pressure to control costs, and improve operational efficiencies and quality standards, boils down to this: OSD manufacturers need a more modular, flexible process.

On the innovation front, 2016 saw the percentage of solid dose new molecular entities approved by the FDA slip from 53 to 32 percent. The sector may already be mounting a comeback though, as 5 of the 7 already approved NMEs in 2017 are tablets.

This novel drug approval number does not include generic approvals - a category where OSD is still the dosage form of choice. With the large number of OSD drugs losing patent protection, generic solid dose products have stepped in, poised to compensate for future decline in OSD NMEs. There were 630 ANDA approvals and 183 tentative approvals in 2016 (the highest number in history), with 73 of them being first-time generic drug approvals. About 70 percent of these first-time generic approvals were solid dosage products.

With all areas of pharma firmly invested in oral solid dose products, the dosage form surely isn’t fading away any time soon - and yet it continues to be challenged to stay competitive in a changing pharma market. What follows is a discussion of how the industry’s most stable drug form is innovating and evolving to stay relevant.

OSD OVER INJECTABLES
Consultants at NNE pharma engineering point to an emerging trend in biopharmaceuticals whereby manufacturers are choosing to formulate biopharma products in oral solid dosage forms, rather than as injectables. The familiar, accessible OSD format promotes increased patient compliance.

One example is in oncology. The global market for cancer drugs has recently reached an annual sales value of $100 billion. OSD oncology drugs are much more common now than even five years ago, and oral drugs are increasingly making up a larger proportion of the oncology drug costs.

The three oncology approvals in 2017 - Kisqali, Xermelo and Revlimid - are all oral dosage products.

Already familiar with the containment issues surrounding highly potent, toxic products, OSD manufacturers are well-positioned to handle oncology drugs. Equipment manufacturers are offering assistance with solutions that prioritize containment for manufacturing oncology drugs. Advances in solubility enhancement technologies, such as spray-dried dispersions, are enabling faster dissolution and enhanced bioavailability in OSD products, allowing them to compete in a space previously dominated by injectables.

CONTINUOUS CONTINUES
Although definitely not a new concept, a decade ago, continuous manufacturing was somewhat of a theoretical discussion in the pharmaceutical industry. Batch production had a long history of success under its belt, and many in the industry questioned such a huge paradigm shift.

During a recent panel discussion at Interphex 2017, Fernando Muzzio, distinguished professor of chemical and biochemical engineering at Rutgers University, made the following analogy: “People in the early 1900s asked ‘why do we need cars when we have so many horses?’”

Today, as OSD manufacturers are realizing the critical need for a more flexible, efficient process, the continuous process - which itself is also evolving - is shaping up to be an important tool.

“Continuous manufacturing has gained and continues to gain traction. It is the biggest ‘hot button’ for OSD right now,” says OSD subject matter expert, Dave DiProspero.

While both biopharma and OSD are playing in the continuous manufacturing space, OSD has the power of concrete examples and FDA approvals in its corner. Vertex has been using a continuous manufacturing process for cystic fibrosis drug, Orkambi, since its approval in July 2015. Janssen made history last year by getting the first FDA approval for a manufacturer’s production method change from “batch” to continuous manufacturing for its HIV tablet, Prezista. Most recently, Eli Lilly took home two 2017 ISPE Facility of the Year awards for the drugmaker’s three replicate operational continuous Oral Solid Dosage production facilities.

Initially viewed as a solution best suited for high volume, new products, continuous manufacturing is proving to have broader applicational benefits.

Janssen proved that continuous manufacturing is not just for new products. “Continuous manufacturing opens the door for increased efficiency and quality, which can decrease the manufacturing costs for new and existing products. The solution really has the potential to work both ways,” confirms DiProspero, who is a senior consultant for CRB Consulting Engineers.

A trend toward continuous operations will significantly affect the OSD sector in several ways:
Facility Costs: The overall amount of facility space and utility costs required are greatly reduced when the manufacturing process is continuous. While the traditional OSD batch process necessitates a series of unit operations, with each of those units generally in its own process suite, a continuous process links everything together. This means processors can dispense, blend, granulate, dry compress and coat in a single train of equipment, in one space.

“Facility space changes are huge with continuous manufacturing - sometimes by as much as a factor of ten - greatly reducing facility costs,” says DiProspero.

Output Flexibility: Traditionally, continuous manufacturing was seen as a solution ideal for high-volume products - but that pendulum, according to DiProspero, is swinging.

Continuous means output can easily vary. With pharma’s more traditional batch process, key pieces of OSD equipment, such as high sheer granulators or fluid beds, are generally sized to accommodate a specific volume of tablets/capsules. Often, several sizes of the same equipment are needed to cover a wide range of outputs. With continuous manufacturing, output becomes solely a function of how long the plant runs the equipment train. The same equipment and the same process can be used, regardless of the volume of final product needed.

A recent ORC International survey, sponsored by Patheon, found that a majority of pharmaceutical companies had either overestimated or underestimated demand for new drugs by up to 25 percent, with some reporting instances of forecasts being off by more than 50 percent - a pricey miscalculation in batch manufacturing. Continuous manufacturing allows plants to cover a full range of volumes, using less APIs - and adjust according to demand.

Speed to Market: Once thought of an inevitable part of the product lifecycle of every drug, scale-up is time-consuming, meticulous and expensive. Continuous manufacturing can, in many scenarios, eliminate the time and risk associated with scale-up. In many applications of CM, the equipment used to test and develop a product is the same equipment used to commercially manufacture the product.

Additionally, the numerous stops and starts involved in batch processing in terms of product transfers and testing are also eliminated in continuous manufacturing. CM both enables and necessitates the application of process analytical technology (PAT) for on-line monitoring and control in real-time - which can simultaneously increase production speed and product quality. Production time can realistically go from months to days.

BATCH LIVES ON
So why isn’t the entire oral solid dose sector jumping onboard the continuous train? The industry continues to debate how to apply - and whether or not it’s even necessary to apply - continuous manufacturing broadly across all oral solid dosage products.

Part of it has to do with a change in philosophy. The pharma industry has grown comfortable looking to its equipment suppliers for equipment expertise. But in order to maximize the benefits of continuous manufacturing, drugmakers will need to assume responsibility for the entire drug manufacturing process - process design especially.

“What makes something more conducive to continuous manufacturing and what makes it not so good is important to understand. I really like the potential for continuous manufacturing. I just don’t want anyone to think it is a simple matter of different equipment. Fixing the challenges requires formulation and process adjustments to make it a success,” says OSD industry vet, Michael Tousey, CEO of Techceuticals.

One challenging example Tousey gives is that of continuous operation of tablet compression to film coating. Many tablets are not capable of being successfully coated continuously from tablet compression because of the energy and time required for a tablet to settle and stabilize before coating is applied. Some tablets continue to change and settle over a 48-hour period, while others only require six hours, for example. Coating a changing tablet immediately can lead to defects.

From the equipment side, Ed Godek, process technology manager for Glatt Air Techniques, agrees that continuous manufacturing takes equipment to the next level. “We are seeing a lot of interest in our continuous manufacturing lines. Equipment manufacturers’ biggest challenge now is not so much supplying the hardware, but rather providing a fully integrated system. CM demands that we learn exactly what’s going on from a chemical engineering standpoint.”

He adds that many drug manufacturers are buying equipment, and attempting to bring the integration aspect in-house, rather than relying on vendors. But still, forward-thinking vendors in the CM space continue to bring much-needed support. Glatt, which has been working in the continuous manufacturing space in the non-pharma sector for almost 40 years, is doing its part to help pharma transition. The company offers CM expertise, workshops, as well as two technology centers in Germany boasting full continuous manufacturing lines. Customers can utilize these CM lines to run trials and work through the integration details of a system.

Continuous manufacturing means the roll of the process engineer will become vital. It’s here that many experts, including those on the “Continuous Manufacturing Opportunities Keep Expanding in Pharma” panel at Interphex 2017, point out pain points in the CM transition: the industry simply lacks process engineers. Recent feedback from Hays recruiting firm pointed out the surging need for permanent process engineers in pharma, with many pharma companies specifically looking to make permanent hires, rather than consultants, to encourage development of an intimate knowledge of individual products.

CDMOs PLAY A ROLL
Some question the efficiency of continuous manufacturing given the economies of scale in the pharma industry. If it is truly possible to realize an 80 percent reduction in manufacturing time (an estimate given by Janssen after converting its Puerto Rico plant), what do manufacturers do with idle continuous processing lines?

This scenario seemingly creates an opportunity for CDMOs to get in the game, sharing their continuous manufacturing capacity across multiple customers. And yet, contract organizations historically tend to a take a more demand-based approach to CapEx spending, driven by customer projects. In 2015, U.K.-based CDMO Aesica collaborated with a key customer to manufacture a product using what the company claimed to be the first semi-continuous processing line and technology installed at a CDMO. The line delivers continuous flow, from the wet granulation stage, through to tablet compression.

More recently, CDMO Hovione announced that a state-of-the-art facility for continuous manufacturing will be installed in its New Jersey site, expected to be operational by the end of 2017. The facility is being designed mainly to support the future manufacturing of Vertex’s approved medicines, however spare capacity will be offered to third parties. According to the company, the facility will allow the continuous production of tablets by means of direct compression, dry granulation or wet granulations modes.

Patheon, on the other hand, is seemingly not content waiting for big pharma to take the lead in continuous manufacturing. The CDMO is currently completing work on its continuous manufacturing suite in Greenville, North Carolina, which is expected to come online later this year. Patheon’s continuous manufacturing line will use modular components to perform dry granulation, wet granulation, tableting and capsule filling. The modular design will allow equipment to be switched out as desired, speeding changeovers and adding flexibility to the process. Importantly, Patheon will take responsibility for the integration aspect - designing and developing the supervisory control system.

MIDDLE GROUND
It’s important to consider that it’s not always all-or-nothing when it comes to continuous manufacturing. Currently, oral solid dose products are being manufactured in what can be considered a “semi-continuous” manner on a daily basis. Parts of the process, such as tableting, milling and blending, have seen much success executed in a continuous mode.
In fact, numerous continuous manufacturing experts who spoke at Interphex 2017, including Eric Jayjock, director of continuous manufacturing, Patheon, and Jay Jones, VP, Delavau, spoke to the benefits of a gradual implementation. A manufacturer could, for example, start by adding continuous granulation, and use this as a stepping stone to develop the knowledge necessary to push the entire process continuous.

Additionally, drug manufacturers are specifically looking to regulators for concurrence that batch and continuous OSD processes can coexist, sometimes at different locations, with slightly different formulations. Merck, for example, has specified the importance of both production methods operating in parallel. The company plans to file the continuous manufacturing approach as an additional manufacturing scheme to its already-approved batch process, rather than as a full changeover from batch to continuous.

The close consideration and exploration of the continuous manufacturing process - whether fully adopted or not - will have positive effects on the oral solid dose sector. Variability is more visible in continuous manufacturing than it is in batch. Continuous considerations will force the industry to closely examine consistency in common variables, such as raw materials. Potentially gone are the days of wasteful trial and error, as change ushers in a more advanced use of on-line measurement, process modeling and control.

As the OSD sector pushes itself to gain a more precise understanding of the important characteristics of equipment and products, this overall enhancement in process understanding will result in higher quality, more evolved oral solid dose products.