What are some of the current critical issues facing the industry regarding oral dosage manufacturing?
Elizabeth Hickman, Strategic Marketing Director, Oral Drug Delivery 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 on developers to reduce development timelines and costs. We are also seeing an increasing number of smaller innovators taking molecules further into the clinic, and even to market independently, and these 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’.
Having the ability to match each customer's molecule with the right enabling 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 development milestone.
In the current competitive environment, payers require that new 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 form, regimen compliance, optimal outcomes, and total treatment cost is seen as important. This requires that the right dose design decisions are made at a suitably early phase of development, with a focus on 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, more effective manufacturing solutions that provide safe and efficacious drugs while also providing value for investors.
Outsourcing of OSD manufacturing is an important strategy. Close collaboration between supply chain partners must be part of the solution; improving efficiencies and reducing costs cannot be achieved without dialogue and understanding between suppliers, manufacturers and pharmaceutical companies. In addition, the more integrated contract service providers can be, the more likely they’ll be strategic, long-range partners for pharmaceutical companies.
Another key issue is the increasing complexity of OSD formulations. Formulation is therefore a key aspect of the overall manufacturing process – particularly new ingredients and delivery technologies. Spending money and time early on to fully understand the API and consider multiple delivery forms generally leads to success.
Many changes, therefore, are happening in OSD manufacturing, with batches becoming smaller, different chemistries being used that require new approaches and the implementation of continuous processing.
Can you tell us about some new oral solid dosage manufacturing technologies and/or processes that are helping pharmaceutical companies bring new products to market or are reviving older products?
Hickman and Savla: There are several manufacturing technologies that can help marketers manage the life cycle of their product portfolios, including orally disintegrating tablets (ODTs), modified-release, and 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, or dysphagia. ODTs resemble a “traditional” tablet, but dissolve quickly 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 is absorbed in the oral cavity. Catalent’s Zydis® fast dissolve technology takes this concept a step forward with its formulation that disperses almost instantly upon administration, requires no water with dosing and provides superior mouthfeel.
Another option in oral solid dosage manufacturing technologies is modified-release. Modified-release dosage forms can consist of coating technologies, which include tablets, softgels, beads, granules, multi-particulates, and microspheres; matrix systems; and osmotic systems. Modified release formulations have shown an increase in patient compliance, a decrease in side effects, and can also extend patent protection. These benefits demonstrate that a modified release reformulation can be a superior product when compared to the original drug.
By reformulating a drug into a controlled-release (CR) version, a company can improve product efficacy, market success, and extend patent protection. To help companies determine their optimal release profile for their drug, as well as predict the relation between dose, and drug concentration in the body and effectiveness of the treatment, Catalent has over 20 years of controlled release development expertise, and uses a decision tree built upon this experience, expertise, and capabilities, to set the quality target product profile for CR formulations and dosage forms. The choice of the best CR profile is based on drug properties (solubility, permeability, absorption window, therapeutic index, and half-life) and desired release profile. The introduction of in silico physiological-based pharmacokinetic modelling will reduce time and costs by enabling formulators to predict human pharmacokinetic profile based on in vitro and pre-clinical in vivo studies.
Sejima: There are manufacturing process technologies such as GXR conical rotor technology, which coat small particles to produce custom release profiles, taste masked API’s for use in orally disintegrating tablets for pediatric, geriatric and psychiatric patient use.
With certain therapeutic areas there is a need of self-individualized dosing for a diverse patient population. A new manufacturing technology has been developed to provide a dosage form that offers an easy and accurate dose flexibility to meet this need.
Also, 3-D printing technology has been used in drug manufacturing. Combined with GXR technology for taste masking, it will provide a unique benefit for new drug development.
Gregory: Despite oral solid dosage drugs being the oldest most popular form, OSD development and manufacturing still present many challenges and opportunities. The need for specialized processing technologies is one of the main drivers for increased outsourcing of the production of oral solid forms. Responsive and flexible CDMOs with the 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 partnerships across the supply chain.
High-throughput synthesis, solid-state technologies, spray drying, hot-melt extrusion, coprecipitation methods, nanomilling, targeted particle engineering for inhalation formulations, orally disintegrating formulations, direct-to-patient delivery for clinical trial materials, equipment sourcing, regulatory compliance, facility design, continuous manufacturing, track-and trace systems: all of these technologies and capabilites are now required to take an OSD drug from discovery through commercialization. A key driver for all of these efforts is the desire to develop oral solid dosage forms that increase patient adherence.
When a pharmaceutical company is choosing an oral solid dosage manufacturing/service provider, what questions should they ask? What qualities and expertise should an oral solid dosage manufacturer/service provider have to ensure that their clients get the best quality product?
Hickman and Savla: There are several key considerations when choosing a development and commercialization partner for a product, including the evolution of the product from early to later phases of development. It is important to consider how the partner’s capabilities will stand up to later stage requirements if the transition throughout the development phases into commercialization is to be seamless. Innovators should consider the robustness of the manufacturing process, the partner’s capacity, capabilities, their global resources if the product is to be launched internationally, and technical expertise to troubleshoot and overcome challenges prior to that launch.
Sejima: They should ask about the service provider’s expertise in formulation development, GMP manufacturing, their regulatory track record and how they set up a network of communication with the customer. Do not only focus on new product development for clinical trials, but also the capabilities and experiences taking product to approval and commercial launch.
Gregory: Increasing API complexity has created a need for innovative formulation solutions. To rapidly reach the formulation proof of concept stage, pharmaceutical companies frequently rely on outsourcing partners with extensive formulation development experience. Because the goal is commercialization, however, many sponsors prefer to work with contract development and manufacturing organizations (CDMOs) that can readily scale those proven formulations from the laboratory to GMP clinical and ultimately commercial manufacturing.
These CDMOs eliminate the risk, time and cost associated with technology transfer and the need to manage multiple suppliers. Preferred service partners also continually invest in new equipment and facilities, provide dedicated project management support with personalized service, offer real manufacturing flexibility and focus on meeting customer milestones.
Effective CDMOs also need to have a comprehensive understanding of the properties of a drug substance for OSD formulations – its solubility in solvents and buffer systems, compatibility with excipients, stability under different physiological conditions, solid-state characteristics, basic physicochemical properties, etc. This understanding is necessary to select the most effective drug-delivery system and develop an optimal drug formulation, particularly for challenging and complex compounds that suffer from poor solubility or are highly potent.
How has globalization of the pharmaceutical industry affected oral solid dosage manufacturing? How do you ensure that products manufactured meet individual country regulations?
Hickman and Savla: As well as global rises in population and the advancement in medicine for various common and rare diseases, many regions are also experiencing an increasing demographic who are able to afford proper medication. Each global market presents its own set of challenges; pharmaceutical companies and their development and manufacturing partners face many challenges when trying to commercialize products across multiple markets. Regulatory challenges and importation hurdles can impact clinical trials, commercialization, and approval processes can interfere with project timelines and regulatory submissions. Varying regulatory requirements remain an issue, as do the logistics of temperature-controlled supplies for clinical trials, serialization, and packaging.
Sejima: With globalization, some manufacturing service providers are manufacturing products for multiple countries. First, the formulation needs to be globally accepted by each country’s regulatory body – excipients needs to be tested following different countries’ requirement.
Second, the manufacturing facility needs to meet all the different regulatory agencies requirements.
The service provider should understand FDA, EMEA requirements and also follow ICH guidelines where applicable. When building new facilities, the provider needs to ensure the facility meets the regulatory requirements for the global pharmaceutical market.
What do you see as the future of oral solid dosage manufacturing?
Hickman and Savla: The key consideration is in recognizing that treatment of the patient is our primary objective. Developing and designing treatments with the patient and the indication in mind will maximize a product’s chances of success. Given that many compounds have some complicating factor, whether that be bioavailability or manufacturing issues, using the most appropriate technologies to design innovative dosage forms is the future in oral solid dosage manufacturing.
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 the large molecules will eventually make it into oral solid dosage format.
Gregory: Providers of OSD development and manufacturing services are navigating an increasingly competitive landscape. Consolidation within the pharma industry has been on the rise and is reducing the customer base for contract manufacturers. In order to simplify supplier management activities, many pharma firms are consolidating the number of suppliers with which they partner. Various market analysts have predicted that as many as 30% of existing CDMOs will be forced to exit the market in the coming years.
To survive and prevail, contract service providers must be able to provide real value and continually anticipate the changing needs of their pharma customers. The drug development process is unpredictable and the unexpected should always be expected. CDMOs that have built in flexibility will be better positioned to address the challenges that arise.
In addition, CDMOs that have expertise in pre-formulation/formulation development and are also able to provide clinical trial supplies and achieve seamless scale-up and technology transfer for commercial manufacturing will have a distinct advantage. Those CDMOs with specialized capabilities, such as the production of highly potent compounds and controlled substances, the ability to overcome the challenges posed by poorly soluble APIs and the development of innovative dosage form technologies, will be further differentiated.