Originally published on 12/10/2018 at Tablets & Capsules Solid Dose Digest, and appears in the December edition of Tablets & Capsules Solid Dose Digest newsletter
By Ed Scholtz
What criteria should my company use to select an outsourcing partner that can help us reach the formulation proof-of-concept stage more rapidly?
The application of advanced high-throughput technologies to accelerate drug discovery has led to more-complex and challenging-to-formulate active pharmaceutical ingredient (API) candidates in the drug development pipeline. Also, the growing emphasis on patient-centric drug delivery solutions and improved medication adherence has created a need for drug products designed with patients' needs in mind. In addition to increasing complexity, pharmaceutical companies are facing mounting pressure to reduce the costs and time required for drug development.
After the pharmacological activity of the API, formulation can have the largest impact on a new drug product's ultimate performance. The proof-of-concept stage of formulation links the API to the final drug formulation that patients will use. This stage involves considering API properties and challenges and accounting for the desired dosage form. Formulators perform testing and work to optimize the process and the composition to deal with challenges that the API provides. Ultimately, they allow pharmaceutical companies to achieve their desired dosage forms and move forward with the development process.
Developing an optimal formulation and drug delivery system requires a comprehensive understanding of the properties of the API in question, including:
- BCS classification, to examine its solubility in solvents and buffer systems and its permeability;
- Compatibility with excipients;
- Stability under different physiological conditions;
- Solid-state characteristics; and
- Basic physicochemical properties.
These properties determine how the API will behave in the body, how it will interact with different types of excipients and other ingredients in the final formulation, and what its processability will be.
The work performed at this proof-of-concept stage has a direct impact on the safety and efficacy of the final drug product. Successful completion of this stage also helps to minimize problems at later development stages, which can lower overall project costs and shorten timelines.
CRO or CDMO for the Proof of Concept Stage?
The increasing complexity of APIs and the need for specialized drug delivery systems is leading many pharmaceutical companies to look to outsourcing partners to help them rapidly reach the formulation proof-of-concept stage.
Choosing the right formulation partner isn't easy. Numerous partnering options are available, including contract research organizations (CROs), which are focused only on a drug product's early development phases, and contract development and manufacturing organizations (CDMOs), which can support projects through the entire development and commercialization cycle.
CROs have expertise in discovery services and the ability to conduct testing to determine the properties of an API candidate. They typically don't have manufacturing experience or capabilities or extensive knowledge about final drug products, dosage forms, and the commercialization process. They also can't provide any technology transfer that may be necessary to move a formulation project beyond the early developmental stage.
CDMOs understand the work required to carry a project from the proof-of-concept stage through scale-up for clinical studies, and ultimately, commercial manufacture.
Pharmaceutical companies with strong scale-up and commercialization expertise may prefer a CRO, while those with some preformulation capabilities but little experience with technology transfer and scale-up process might prefer a CDMO. Emerging and smaller pharmaceutical firms with limited resources that rely heavily on outsourcing partners for most aspects of the drug development process also tend to prefer CDMOs, as do larger firms wanting to simplify their supply chains.
Whatever the extent of your needs, the company you choose must have extensive formulation-development experience given that your goal is to commercialize new drug products and get them into the hands of patients as quickly as possible.
Because CDMOs have experience with manufacturing, they understand that the proof-of-concept stage occurs in the context of an overall project, with commercialization as the end goal. Close cooperation between analytical and development groups allows a CDMO to engineer an optimized formulation/ delivery technology that can be directly scaled to GMP clinical and commercial production.
Make sure that the CDMO you are considering has the skill and capacity:
- To assess the scalability and manufacturability of the formulation from the start. The equipment train has to be fully scalable from preclinical to clinical and commercial stages. You should also look at the CDMO's reputation, regulatory history, and financial stability.
- To evaluate the specific needs of the patient population and design formulations and systems with convenience and ease of use in mind. Identify whether the CDMO provides a panel to assess patient needs based on an evaluation study. For instance, if the drug product is a pediatric medication, does it need to be an orally disintegrating product for ease of ingestion? These panels can design the dose around the target patient population.
- To remove your need to manage multiple suppliers. A full-service CDMO will include preclinical; clinical; commercial; analytical—micro, raw materials, product testing, method development, and stability; packaging; and other supportive services.
- To take a project from proof of concept all the way through commercialization and to eliminate the risk, time, and cost associated with technology transfer. It's key to determine that a CDMO has staff with the expertise needed to undertake all steps of the process. These include processing labs, preclinical labs, clinical labs, and commercial capabilities. It's also important to understand the CDMO's processes governing how it transfers information from one scale to the other. It is equally important to assess the experience of the staff. Does the CDMO have a technical scientific staff, technology-transfer staff, validation and qualification group, and analytical group, and does it provide metrology to support manufacturing and analytical work?
The best CDMO partners also recognize that they must complete the proof-of-concept stage rapidly and cost-effectively. Make sure that the CDMO you are considering has:
- Experience with many different API chemistries and the ability to perform the key analyses required to characterize the API. You must understand the services that you are outsourcing. Leverage the experience of the CDMO to address any issues with the characteristics of the API. For instance, if the API is photo- or moisture-sensitive, does the company have experience in dealing with those challenges?
- The expertise to select only the preformulation studies necessary to fully characterize the API. You must know what properties other entities are evaluating, from the API vendor to the dosage-form vendor, and what the dosage-form vendor must identify.
- Extensive knowledge and the ability to determine the dosage form and formulation technologies and drug delivery systems with the greatest potential to provide a safe, stable drug product with high efficacy.Identify the expertise of the CDMO and the API type to determine whether the CDMO has experience in the dosage form that interests you, such as oral disintegrating or bi-layer.
- The facilities, equipment, and available capacity throughout the lifetime of each project. It is essential to perform a thorough capacity evaluation and create an allocation plan in addition to determining full scalability. This will ensure that not only is the right equipment on-site but also that it's available according to the project's timelines.
- A willingness to collaborate on all aspects of each project and to make long-term commitments as well as a track record of success, financial stability, and the ability to adapt to a project's changing needs. You will need an on-site visit to get to know the leaders of the company. It's important to get a sense of the CDMO's capabilities, the way in which they manage projects, and the company's culture. You must also identify specific equipment needs and decide who assumes financial responsibility if the project needs additional equipment. Also, is the relationship a partnership? Will it include profit sharing? Is the CDMO willing to invest in the product? Will the CDMO iteratively develop the project, or will you determine everything in the beginning with a comprehensive contract?