ROUNDTABLE

What are some of the current critical issues

facing the industry regarding oral dosage
Oral Solid Dosage manufacturing?
Elizabeth Hickman, Strategic Marketing Director, Oral Drug Delivery

Manufacturing Catalent Pharma Solutions; Ronak Savla, Scientific Affairs Manager

Catalent Pharma Solutions: Certain well-known drug development
challenges are impacting oral solid dose manufacturing. Notably, the
ever more complex nature of new molecules coming out of discovery
that feature one or more challenges in their bioavailability, formulation,
scalability and manufacturability. This trend is coinciding with pressures
Elizabeth Hickman on developers to reduce development timelines and costs. We are also
seeing an increasing number of smaller innovators taking molecules
Strategic Marketing Director, Oral Drug Delivery
further into the clinic, and even to market independently, and these
Catalent Pharma Solutions
companies are looking for outsourcing partners that have a broad range
of services, and have expert teams to assist in areas where the innovator
doesn’t have the resources ‘in house’.
Ronak Savla
Having the ability to match each customer's molecule with the right en-
Scientific Affairs Manage
Catalent Pharma Solutions abling technology is important, because finding the correct formulation
solutions, which are faster to scale up and less likely to fail at a later stage
of development may be critical to a product proceeding past a develop-
Yasuhiro Sejima ment milestone.

President In the current competitive environment, payers require that new

CMIC CMO USA Corporation treatments show significant real world clinical outcomes if they are
to be reimbursed, and the dose form is increasingly important in an
environment where the link between patient acceptance of the dose
Jim Gregory form, regimen compliance, optimal outcomes, and total treatment cost
is seen as important. This requires that the right dose design decisions
President and CEO
are made at a suitably early phase of development, with a focus on
UPM Pharmaceuticals
patient acceptance, convenience, and suitability to the patient’s specific
conditions (dose burden, swallowability, regimen complexity, etc.).
Industry partners must be able to support their customers with the
right input and advice to make such decisions earlier in the process,
enable that decision with the most appropriate technologies, and
provide flexible manufacturing solutions to deliver the treatment to
help patients.
Yasuhiro Sejima, President, CMIC CMO USA Corporation: Solubility/
bioavailability is still a challenge for small molecule oral drug
development. We also see increasing 505(b)2 filings using existing
drugs in new combinations for new indications. Thus API compatibility
or non-compatibility needs to be considered and can pose challenges
for formulation and delivery technology.
Jim Gregory, President and CEO for UPM Pharmaceuticals: Critical
issues facing the industry today include rising cost pressures, the
increasing expectations for patient-centric medicines and an ongoing
need to reduce time-to-market. These issues drive demand for cheaper,

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 ROUNDTABLE

more effective manufacturing solutions that provide safe and efficacious Sejima: There are manufacturing process technologies such as GXR
drugs while also providing value for investors. conical rotor technology, which coat small particles to produce custom
release profiles, taste masked API’s for use in orally disintegrating tablets
Outsourcing of OSD manufacturing is an important strategy. Close
for pediatric, geriatric and psychiatric patient use.
collaboration between supply chain partners must be part of the
solution; improving efficiencies and reducing costs cannot be achieved With certain therapeutic areas there is a need of self-individualized dos-
without dialogue and understanding between suppliers, manufacturers ing for a diverse patient population. A new manufacturing technology
and pharmaceutical companies. In addition, the more integrated has been developed to provide a dosage form that offers an easy and
contract service providers can be, the more likely they’ll be strategic, accurate dose flexibility to meet this need.
long-range partners for pharmaceutical companies. Also, 3-D printing technology has been used in drug manufacturing.
Another key issue is the increasing complexity of OSD formulations. Combined with GXR technology for taste masking, it will provide a
Formulation is therefore a key aspect of the overall manufacturing unique benefit for new drug development.
process – particularly new ingredients and delivery technologies. Gregory: Despite oral solid dosage drugs being the oldest most
Spending money and time early on to fully understand the API and popular form, OSD development and manufacturing still present many
consider multiple delivery forms generally leads to success. challenges and opportunities. The need for specialized processing
Many changes, therefore, are happening in OSD manufacturing, with technologies is one of the main drivers for increased outsourcing of the
batches becoming smaller, different chemistries being used that require production of oral solid forms. Responsive and flexible CDMOs with the
new approaches and the implementation of continuous processing. abiltiy to address the challenges and leverage the opportunities will be
successful going forward. Doing so will require the development and
application of novel technologies and the establishment of collaborative
Can you tell us about some new oral solid partnerships across the supply chain.
dosage manufacturing technologies and/or High-throughput synthesis, solid-state technologies, spray drying,
processes that are helping pharmaceutical hot-melt extrusion, coprecipitation methods, nanomilling, targeted
particle engineering for inhalation formulations, orally disintegrating
companies bring new products to market or formulations, direct-to-patient delivery for clinical trial materials,
are reviving older products? equipment sourcing, regulatory compliance, facility design, continuous
manufacturing, track-and trace systems: all of these technologies and
Hickman and Savla: There are several manufacturing technologies that capabilites are now required to take an OSD drug from discovery through
can help marketers manage the life cycle of their product portfolios, commercialization. A key driver for all of these efforts is the desire to
including orally disintegrating tablets (ODTs), modified-release, and develop oral solid dosage forms that increase patient adherence.
combination products. ODTs are a convenient dosage form suitable
for new molecules targeting certain patient populations or indications,
such as pediatric patients, patients suffering from mental health issues, When a pharmaceutical company is choosing
or dysphagia. ODTs resemble a “traditional” tablet, but dissolve quickly an oral solid dosage manufacturing/service
in the mouth and therefore do not need to be swallowed. They also have
a quick onset of action and avoid the first pass of the liver since the drug
provider, what questions should they ask?
is absorbed in the oral cavity. Catalent’s Zydis® fast dissolve technology What qualities and expertise should an oral
takes this concept a step forward with its formulation that disperses solid dosage manufacturer/service provider
almost instantly upon administration, requires no water with dosing and
provides superior mouthfeel. have to ensure that their clients get the best
Another option in oral solid dosage manufacturing technologies is mod- quality product?
ified-release. Modified-release dosage forms can consist of coating tech-
nologies, which include tablets, softgels, beads, granules, multi-particu- Hickman and Savla: There are several key considerations when choosing
lates, and microspheres; matrix systems; and osmotic systems. Modified a development and commercialization partner for a product, including
release formulations have shown an increase in patient compliance, a the evolution of the product from early to later phases of development.
decrease in side effects, and can also extend patent protection. These It is important to consider how the partner’s capabilities will stand up to
benefits demonstrate that a modified release reformulation can be a su- later stage requirements if the transition throughout the development
perior product when compared to the original drug. phases into commercialization is to be seamless. Innovators should
consider the robustness of the manufacturing process, the partner’s
By reformulating a drug into a controlled-release (CR) version, a capacity, capabilities, their global resources if the product is to be
company can improve product efficacy, market success, and extend launched internationally, and technical expertise to troubleshoot and
patent protection. To help companies determine their optimal release overcome challenges prior to that launch.
profile for their drug, as well as predict the relation between dose, and
drug concentration in the body and effectiveness of the treatment, Sejima: They should ask about the service provider’s expertise in
Catalent has over 20 years of controlled release development expertise, formulation development, GMP manufacturing, their regulatory track
and uses a decision tree built upon this experience, expertise, and record and how they set up a network of communication with the
customer. Do not only focus on new product development for clinical
capabilities, to set the quality target product profile for CR formulations
trials, but also the capabilities and experiences taking product to
and dosage forms. The choice of the best CR profile is based on drug
approval and commercial launch.
properties (solubility, permeability, absorption window, therapeutic
index, and half-life) and desired release profile. The introduction of in Gregory: Increasing API complexity has created a need for innovative
silico physiological-based pharmacokinetic modelling will reduce time formulation solutions. To rapidly reach the formulation proof of concept
and costs by enabling formulators to predict human pharmacokinetic stage, pharmaceutical companies frequently rely on outsourcing
profile based on in vitro and pre-clinical in vivo studies. partners with extensive formulation development experience. Because

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the goal is commercialization, however, many sponsors prefer to work Second, the manufacturing facility needs to meet all the different
with contract development and manufacturing organizations (CDMOs) regulatory agencies requirements.
that can readily scale those proven formulations from the laboratory to
The service provider should understand FDA, EMEA requirements
GMP clinical and ultimately commercial manufacturing.
and also follow ICH guidelines where applicable. When building new
These CDMOs eliminate the risk, time and cost associated with facilities, the provider needs to ensure the facility meets the regulatory
technology transfer and the need to manage multiple suppliers. requirements for the global pharmaceutical market.
Preferred service partners also continually invest in new equipment
and facilities, provide dedicated project management support with What do you see as the future of oral solid
personalized service, offer real manufacturing flexibility and focus on
meeting customer milestones.
dosage manufacturing?
Hickman and Savla: The key consideration is in recognizing that
Effective CDMOs also need to have a comprehensive understanding of
treatment of the patient is our primary objective. Developing and
the properties of a drug substance for OSD formulations – its solubility
designing treatments with the patient and the indication in mind will
in solvents and buffer systems, compatibility with excipients, stability
maximize a product’s chances of success. Given that many compounds
under different physiological conditions, solid-state characteristics,
have some complicating factor, whether that be bioavailability or
basic physicochemical properties, etc. This understanding is necessary to
manufacturing issues, using the most appropriate technologies to design
select the most effective drug-delivery system and develop an optimal
drug formulation, particularly for challenging and complex compounds innovative dosage forms is the future in oral solid dosage manufacturing.
that suffer from poor solubility or are highly potent. Sejima: Even though large molecule drug development is growing at
a fast rate, small molecule oral solid dosage form manufacturing will
continue to play a dominant role for new drug development. Some of
How has globalization of the pharmaceutical the large molecules will eventually make it into oral solid dosage format.
industry affected oral solid dosage Gregory: Providers of OSD development and manufacturing services
manufacturing? How do you ensure that are navigating an increasingly competitive landscape. Consolidation
within the pharma industry has been on the rise and is reducing the
products manufactured meet individual customer base for contract manufacturers. In order to simplify supplier
country regulations? management activities, many pharma firms are consolidating the
number of suppliers with which they partner. Various market analysts
Hickman and Savla: As well as global rises in population and the have predicted that as many as 30% of existing CDMOs will be forced to
advancement in medicine for various common and rare diseases, many exit the market in the coming years.
regions are also experiencing an increasing demographic who are
able to afford proper medication. Each global market presents its own To survive and prevail, contract service providers must be able to
set of challenges; pharmaceutical companies and their development provide real value and continually anticipate the changing needs of their
and manufacturing partners face many challenges when trying to pharma customers. The drug development process is unpredictable and
commercialize products across multiple markets. Regulatory challenges the unexpected should always be expected. CDMOs that have built in
and importation hurdles can impact clinical trials, commercialization, flexibility will be better positioned to address the challenges that arise.
and approval processes can interfere with project timelines and In addition, CDMOs that have expertise in pre-formulation/formulation
regulatory submissions. Varying regulatory requirements remain an development and are also able to provide clinical trial supplies and
issue, as do the logistics of temperature-controlled supplies for clinical achieve seamless scale-up and technology transfer for commercial
trials, serialization, and packaging. manufacturing will have a distinct advantage. Those CDMOs with
Sejima: With globalization, some manufacturing service providers are specialized capabilities, such as the production of highly potent
manufacturing products for multiple countries. First, the formulation compounds and controlled substances, the ability to overcome the
needs to be globally accepted by each country’s regulatory body – challenges posed by poorly soluble APIs and the development of
excipients needs to be tested following different countries’ requirement. innovative dosage form technologies, will be further differentiated.

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