Much has been written about the “new bottleneck” in drug research and development. Advances in genomics, combinatorial chemistry and high through-put screening have all contributed to an explosion of new biological targets and new drug leads. In order to keep pace with these new scientific developments and evaluate the usefulness of potential drug compounds more efficiently, a number of companies in the pharmaceutical and biotechnology industries have turned to contract chemistry R&D providers.

Albany Molecular Research, Inc. (AMRI) is one such provider, offering lead discovery and optimization to scale-up and commercial manufacturing problem solving, as well as several drug discovery platform technologies. Although each of these services meets very different technical requirements, they all require good communication between the client/customer and contractor/service provider for successful completion. The chemical development and synthesis areas are rich with examples of the importance of teamwork and communications. These projects often have intense needs and constrained timelines. Products from these projects are usually starting materials for other projects and significant cost and resources are committed in anticipation of delivery, requiring close coordination of efforts. Successful projects and customer relationships all possess the same common denominators. The following discussion draws on our experience in chemical development, but the central ideas apply to all projects.

Throughout all projects, the sponsor and provider should carefully manage communication. For chemical development projects, the client may engage 20-30% of its human resources managing the interface with the contractor, instead of carrying out the activity internally. Clients need to consider not only the technical abilities of a contractor, but also the contractor’s ability to communicate progress effectively. Efficient communication by the service provider may reduce the customer’s resource commitment by 80% (a manpower leverage of 5:1) or more, allowing the efficient outsourcing customer to deploy its resources on many more projects and giving the customer a tremendous advantage over its competitors. Conversely, much of the outsourcing advantage is lost if the interface between client and service organization is inefficient (a manpower leverage of only 3:1). Worse, if communications are poor, objectives are often not met and outsourcing fails to provide any advantage for the customer.

Like a newspaper article, the information that must be conveyed from the client to the contractor follows the old journalism checklist: “Who?” “What?” “When?” “Where?” “Why?” and “How?” It is obvious that the contactor needs to know what the client wants to be accomplished, when the client wants it completed and under what constraints the client wants it done. These are the project deliverables. Unlike a newspaper article, which looks at a snapshot in time, the deliverables must be communicated continually between the two organizations during the course of a project. Effective communication ensures that the contractor understands the deliverables.

Answering the question of “Why?” leads to value-added results. If the contractor understands the customer’s needs—the “why” of the deliverables—then the two parties can address many issues efficiently during a project. Understanding, however, can only come from an effective exchange between client and contractor.

This exchange is needed through every stage of a project. At the inquiry stage, where speed of response is very important, the service provider must understand not only the requirements of the project but also the nature of the bid needed. For example, sometimes the client is looking only for a budget quote; other times, the client requires a detailed proposal. During the bid and contract stage of a project, the client and contractor must maintain a clear dialogue with regard to project requirements and the capabilities of both parties.

Only through effective communication can a fair contract be negotiated that accurately and specifically defines the expectations of both parties. Once the contract is awarded, the client and contractor should each name an ombudsman who will serve as a primary contact for their respective organizations. These ombudsmen should not be the only individuals communicating, nor should they even be the ones doing the most communicating. They ensure that the right people from each organization are in communication at the right time during the course of the project. An ombudsman serves as the voice of the other party within an organization and does a great deal to cultivate a true partnership. The ombudsman is always looking for feedback, both internally and externally, to continue to ensure that the expectations of the contract are being met.

Factors for Success
The most successful projects, those that exceed expectations, are the ones in which the client’s organization is intimately involved during the execution phase. A spirit of partnership between the organizations is allowed to develop and shows itself in four common characteristics:

• Taking ownership of a client’s project

• Clarifying expectations at every stage of a project

• Communicating progress efficiently

• Communicating trouble without delay

Taking Ownership
Taking ownership of a project occurs when a customer-focused culture is instilled in a contractor’s organization. When a contractor owns the project, the focus is no longer on just meeting requirements communicated from the client, but on meeting an internal standard of excellence and applying experience and skills from many areas to the project stemming from an understanding of the reasons for the requirements. This leads to value-added results.

Scenario 1
As an example, our company recently contracted with the National Institute on Drug Abuse (NIDA) to produce the b-isomer of a drug substance (see Scheme 1). In the course of the synthesis, we also generated a small percentage the a-isomer. Because the company’s scientists understood that the a-isomer might be needed as a standard, they also purified the undesired isomer, rather than just disposing of it as a process waste stream.

Scenario 2
In another case, NIDA contracted with AMRI for the preparation of the D1 agonist SKF-77,434 (see Scheme 2). During the course of the project, we isolated a higher melting point compound, which had been purified from pooled laboratory lots. Differential scanning calorimetry (DSC) and IR analysis showed that the compound was a high melting polymorph, distinct from the cGMP lot, and previously unknown to the investigators. This polymorph was interesting for formulation studies and potentially valuable as a new composition of matter.

Clarify Expectations

The goals and the conditions under which a research project are conducted are rarely static. Priorities of the client can change, imposing new conditions on a project. New information developed as a direct consequence of the work can cause a change in emphasis. As a result, good project management requires a continual clarification of expectations.

Scenario 1
To illustrate, AMRI began a project to produce clinical supplies for a new drug candidate, with analytical methods supplied by the customer. It became clear very early in the project that the methods were not working correctly. AMRI’s analytical chemists showed the problems to the customer and made some suggestions for improvement. After some discussion, it was decided that our Analytical Services group would devise and validate improved methods before proceeding further with the project. The methods development and validation effort was concluded within two weeks. The project was completed successfully and on time.

Scenario 2
As another example, AMRI’s client had licensed a drug candidate from its inventor and was contracted to produce several kilograms for pre-clinical and clinical evaluation. The synthetic route was practical, but the procedure exhibited unanticipated problems on scale-up. In the first step, reactants A and B were mixed neat and reacted to produce C as a low-melting solid mass. During scaleup of the first step to 50 g, an intense exotherm drove the reaction mixture from ambient to 190°C in two minutes. The product C was not produced cleanly and required silica gel column chromatography purification. In scaling up the second step, the acylation of purified C was carried out at room temperature and resulted in by-products due to excessive acylation. Since both AMRI and the customer did not originally expect significant process development, AMRI scientists communicated these unanticipated hurdles to the client and recommended that a limited process development effort be undertaken. The client agreed and the procedures were modified. In the first step, reactant A was dissolved in a solvent and a solution of reactant B added during several hours of controlled temperature conditions. Product C crystallized cleanly from the reaction solvent. In the second step, the acylation temperature was reduced to -20°C and afforded pure API. As a result of the focused development effort, the client received 50% more API at the end of the campaign as well as improved procedures, all of this being accomplished within the original budget. This process was later transferred to a chemical production facility with only minor modifications and used to produce the API at large scale. The decision to carry out process development paid big dividends in the end.

Communicating Efficiently
Data presentation is critical to the success of a project. No one has time to wade through raw data. The data must be presented in an efficient format, one that the customer can easily understand. Many clients have a standard form they prefer, which is best for efficient communications, because the clients are familiar with their own format and can extract the needed data with little trouble. AMRI has developed a general report format based on interactions with more than 135 clients involving more than 850 projects since the company’s inception. Each project has an optimum frequency of status reporting. If reports are too frequent, they are disjointed: the customer needs to refer to several previous reports to gain a sense of perspective. If reports are too infrequent, information may be lost and the client may not have adequate opportunity to provide feedback on progress. Generally, we have observed that weekly contact is best, although the most effective frequency is established on a project-by-project basis. This is not a “one size fits all” business.

In today’s fast-paced, high-tech environment, the client and provider have many choices regarding how they communicate. These choices commonly include courier, telephone, fax, secure e-mail, teleconference, videoconference and meetings. These media have three different characteristics: degree of interaction (the immediacy and richness of the contact), capacity (roughly defined as the product of the volume of information and the target audience) and time efficiency. In practice, a mix of “low interaction” and “high interaction” media seems to work well, particularly if one chooses the mix to have complementary capacity and time efficiency attributes. As an example, one of AMRI’s customers was coordinating a project to supply different segments of a drug candidate with three other contractors. The overall project was in tremendous flux: supply requirements increased tenfold and shipping points changed frequently. Efficient communications were essential to success. AMRI sent a progress report by fax (high efficiency, low interaction, low capacity) every Thursday afternoon. This gave the client enough time to review the report before the Friday morning videoconference (low efficiency, high interaction, high capacity). The Friday morning session could be spent making decisions for the coming week’s work, an activity best reserved for high interaction media, instead of reporting and discussing results. A note on phone courtesy, especially important to the contractor: If either party seeks to make contact, every effort should be made to return the call within 24 hours. If the client calls seeking information and the result is “radio silence,” this may be construed as “big trouble.”

Communicating Trouble
Outsourcing partners may encounter difficulties during the course of any project. Effective communications can often blunt the adverse effects of these difficulties on the overall outcome of the project. Anticipating, communicating and addressing a problem should be a standard process. Waiting until a crisis develops and then handling the situation in an ad hoc manner is a recipe for failure. When a problem first presents itself, don’t wait for a miracle to happen, hoping that it will all just go away; confront the difficulty head-on. Gather the details together and inform the customer, communicating only the facts without comment. Once the customer understands the situation, propose an action plan. Discuss the proposed plan and arrive at a final solution with the customer. Capture the plan in writing (memories of verbal discussions are volatile and rarely precise). Be certain both sides understand the change. Execute the plan and communicate progress frequently. For example, one of our clients had a tough end-of-year deadline. The vendor informed us that a raw material delivery would likely be late, adversely impacting the company’s promise to deliver by year’s end. AMRI informed the customer and proposed using an alternative vendor that could not deliver all of the needed material, but could at least ship a large portion of the requirement by the deadline. The parties devised a new schedule of deliveries that kept the customer supplied with product and without interruptions. In this event, we were right to be worried. The original source of material was very late, but the client’s needs were met without delays.

Conclusion
A process of teamwork and communication between the client and contractor is important to good project management in all stages. The efficiency of communication is critical to the client’s leverage of internal resources. Communications between the organizations are made much more effective if both the client and contractor appoint an ombudsman to act as the principal contacts for a project. The four factors of success are characteristics of a partnership between the client and the contractor. Following these factors may well lead to the formula for success for pharmaceutical and biotechnology companies looking for a competitive advantage in their chemistry research and development efforts.

Harold Meckler, Ph.D., is vice president of science and technology at Albany Molecular Research, Inc. (AMRI). Kenton Shultis is vice president of operations and a founder of the American Advanced Organics division of AMRI.