From Proof of Concept Commercialization

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By Shabbir T. Anik, PhD and Colin M. Minchom, PhD

Biotech companies usually face significant time pressures to initiate clinical trials. Under these circumstances, it is important to select a contract service provider that has the ability to develop fast-into-human formulations for proof of concept studies. Once proof of concept has been established, a contract service provider must be able to rapidly advance the drug-development program through to Phase II and Phase III studies.

A structured approach to selecting a contract supplier is recommended, since “choosing well” is very important to the ongoing success of the development program. Success is also contingent on managing the relationship effectively once the development work is underway. This article will discuss attributes to look for in a service provider and suggest ways to effectively manage outsourced dosage-form development projects.

Selection Criteria: People and Premises
During the selection process, both the expertise and experience of the service provider’s scientific staff and the suitability of its facilities must be evaluated relative to the specific dosage-form needs of the project.

When evaluating a contract service provider’s scientific team, a number of important organizational attributes must be considered. The organization must be large enough, with enough critical mass and collective experience to ensure organizational learning in the fundamentals of drug development. For example, members of the scientific team must have 10 to 15 years of experience in formulation and analytical development and possess knowledge of a broad range of dosage forms, including the dosage form under consideration. Their experience must allow them to understand the formulation and analytical requirements at various stages of development. An understanding of the drug-development process beyond the technical aspects, along with experience in the commercialization of formulations, is critical.

The scientific staff must be prepared to provide the client with a formulation-development strategy, including the pros and cons, in support of proof of concept and the ultimate development program. In addition to these technical abilities, the scientific team must have a client-service orientation, meaning that team members should be focused on meeting the needs of their clients.

The service provider must recognize its limitations and be willing to decline the project if the provider does not have the required experience.

Similarly, there are several important criteria that must be considered when evaluating a service provider’s facilities. First, dedicated formulation development facilities are necessary and must be engineered for the safe handling and disposal of new molecular entities (NMEs) for which the safety profile is not fully defined. A contract service provider must have a history of handling high potency or unknown hazard molecules. The facilities must be constructed with appropriate air-handling and material-handling systems for such compounds. To ensure safety, separate areas for handling both high- and low-potency compounds must be available. Such facilities allow formulation development to begin early in the drug-development process when safety data for the NMEs are not yet available.

Second, small-scale equipment ranging from bench-top (gram scale) to 15 kilograms is essential. Quantities of drug substance are usually in short supply during preclinical and Phase I dosage-form development. Small-scale equipment allows a contract service provider to make the best use of limited amounts of NME and provides the flexibility to investigate more formulations early on.

Third, the equipment should be scalable to that used in the pilot plant and in commercial operations. Once proof of concept is established, it is imperative that the early development work is scalable to enable the manufacture of supplies for larger clinical studies. Development work performed at gram scale does not provide the wherewithal to supply clinical studies. Rather, it provides the information necessary to develop a scalable formulation in pilot equipment in a GMP environment. When little or no thought is given to transfer or scale-up, or when the equipment to be used for clinical supply is not known, the timeline for supply of clinical materials is lengthened. However, when scalable equipment is available, seamless transfer from development to clinical supply is achieved.

One way to quickly develop fast-into-human formulations is through the use of non-GMP areas for investigative development. Information from such work is fully acceptable as supportive data for a regulatory submission. It must be stressed, however, that although GMP rules are not strictly followed in a non-GMP facility, the principles of good laboratory and documentation practices must be applied to such development work or there is risk of failure during transfer to clinical-trial manufacture.

Selection Criteria: Integrated Services
A tactical approach to outsourcing has served some biotech companies in the past. However, the hard and soft costs associated with the transfer of a project among several third-party providers, either through parallel processing or at different stages of the drug-development process, often result in this approach being more costly. In addition, the total project time is lengthened as each party is brought up to speed.

An integrated supplier can provide a seamless transfer through the drug product-development process to commercialization. The reduction in technical transfers means a shortened development time. For example, in moving from formulation development to scale-up, three months can be added to a development program if a company changes service providers at that juncture. The transfer of analytical methods from a third party alone can add four to eight weeks to a program. These transfers also translate to increased costs, particularly if feasibility or process-development work must be repeated because of equipment changes.

With an integrated supplier, a biotech company is more apt to be successful in ensuring that the manufacturing process is scalable. The likelihood of successfully completing a pre-approval inspection also increases. Regulatory authorities like to see a rationale for the formulation and a development report that includes process development and scale-up with all of the associated analytical results. Having all of this information available at one site with the same personnel to explain the entire development program is a significant advantage. In the end, having fewer players results in cleaner paperwork and a simpler audit trail for the inspector to follow.

Selection Criteria: Business Processes
It is important to understand the processes that the service provider uses in the overall management of the project. A sample quotation will provide an idea of how the work is scoped and priced. A project team approach is essential for the successful execution of the project and must be discussed with the provider prior to placing the work. As with most development work, changes to the original plan will occur as information on the drug is generated. Since changes of scope resulting in increased costs often become a contentious issue, it is essential to reach an agreement of how these will be managed.

Managing the Relationship through Regular, Effective Communication
After selecting an appropriate service provider, a biotech company should ensure that there are well-organized project team structures and processes in place to manage the relationship on an ongoing basis. Effective communication between the service provider and the client is absolutely critical to the success of the relationship. Communication needs to take place at many levels — the team level, direct scientific contact, the executive level and the business and financial level. Individual players, roles, responsibilities and decision flows should be documented, so there is no confusion about which tasks are being performed by whom, and who is on the project team.

There should be clear communication from the beginning of the process, starting with the initial briefing of your needs. It is critical at this stage to articulate the amount of risk you are willing to accept for the project. The service provider will then design programs that fit the project brief and your risk tolerance, identifying and communicating the inherent risks in the design. Recognize that there is a need to balance adequacy of formulation with speed to clinical trial. This is always a balancing act and assumes a new dynamic when a third-party service provider is involved. We have seen cases, for example, in which leaving out pre-formulation excipient interaction studies at the client’s request has resulted in stability problems, additional costs and time delays later in the process.

Key performance indicators should be established and meetings held periodically between the service provider and client. Whether they are weekly, monthly or quarterly, regular assessments are important. Honest, frequent and constructive feedback is of great value in improving performance and cementing the relationship.

From Proof of Concept to Commercialization . . . Successfully
To meet their development objectives, biotech companies must partner with contract service providers that can rapidly and inexpensively generate and select the right formulation for proof of concept. Once this milestone has been successfully achieved, the emphasis shifts to developing an efficacious, scalable formulation to provide additional clinical supplies and, ultimately, a commercial product. The degree to which biotech companies will be successful in outsourcing their development programs will depend on their ability to: 1) identify service providers with the right resources to meet their needs, and 2) implement measures to effectively manage the on-going relationship.

Shabbir T. Anik, PhD is executive vice-president of Pharmaceutical Development Services and chief scientific officer for Patheon Inc. (Mississauga, ON). Colin M. Minchom, PhD is Patheon’s group director of PDS Operations, Toronto Region. Patheon is a leading provider of drug-development and manufacturing services to the international pharmaceutical industry. Exclusively focused on outsourcing, Patheon serves 150 clients through its network of 11 facilities in Canada, the United States and Europe, employing 3,800 people. In addition to providing commercial manufacturing services for about 700 products, Patheon is currently providing dosage-form development services for 102 of its clients’ new products. For more information, please call 1-888-PATHEON or visit Patheon’s Web site at www.patheon.com.