Introduction
Many biopharma companies will often have multiple active projects on their outsource managers’ desks, and larger pharmaceutical companies routinely utilize multiple contractors for a variety of functions. For the current discussion, we will limit the situation to multiple contractors working on the same API project. Even within these limits, the permutations are almost innumerable. Thorough planning before the first contractor is chosen sets the foundation and attentive project management to fine tune the plan as information is gathered will avoid many potential pitfalls. Establishing a team environment with your contractors based on trust and respect creates an atmosphere of cooperation which will conserve resources in the short term and provide long term benefits from the quality of the completed project. Constant and consistent communication not only between the client and the contractors but also among the contractors is essential to maximize productivity of the team. Making the effort to develop a well functioning team will also pay dividends when things don’t go as planned. Leveraging the combined talent and expertise of your entire contractor team will result in quicker and more innovative solutions to unforeseen challenges. Organized information storage and well written final reports that include both the successful path as well as the unproductive dead ends not only support the project as it unfolds but also provide learning points that will improve the process for future production runs. We will examine a hypothetical situation to illustrate the general operating principles that minimize the challenges and maximize the potential for success.
Scope and Plan
It is critical to have a firm grasp on the master plan for the development of your API. This plan will in turn set the key parameters that will dictate the choice of contract partners. At this point the functional details that define the key tasks are the main focus. These key tasks will set much of the timeline; the important management principle at work here collates the multiple tasks and sets them into a realistic timeline. The critical path is established and the tasks that can be done in parallel should present themselves. Before any work begins, investing time with all the team members, both internal and external, to define the resources needed for each task provides the details that set your budget and form the elements of your timeline.
For our hypothetical case study, consider a small to medium biopharma company with discovery chemistry and pharmacology that also has limited scale up laboratory capabilities. They have capacity to produce one kilogram batches of their current API and have successfully scaled up the synthesis to provide GLP material for the IND enabling studies. The IND has been filed and plans are to be made for the Phase 1 clinical trials. The corporate strategy calls for sufficient cGMP API to be manufactured in North America to supply the North American clinical studies. The target amount is 25 kgs, which will support the clinical trials, the polymorph studies, and the solid formulation development.
First and foremost, the protection of intellectual property with appropriate patent activity is critical. Secondly, all legal documents such as confidentiality agreements (CDA), master service agreements (MSA), and statement of work (SOW) must be carefully and thoughtfully prepared to safeguard both the client and the contractors. While it is beyond the scope of this article, as well as my expertise, to completely cover these two important topics, when utilizing multiple CRO/CMO resources, careful consideration with expert legal counsel must be made to properly prepare and execute CDA’s that cover more than two-way sharing of information and to insure that all intellectual property is protected.
The key strategy is to foster strong and trusting relationships with your contract colleagues. It is important to remember that the CRO or CMO that works with you wants your project to succeed; they have as much pride in their contribution to your project as you would if you were doing it yourself, and a successful outcome is their best advertisement for securing future work from you and from others. When a CRO/CMO is treated with respect and trust, they become a more perfect extension of your company, and their dedication to the project at hand increases the value of their work.
CRO/CMO Strategy
While some large service contractors exist that have broad capabilities and could provide a single source scenario for our hypothetical study, this may not be the most practical solution for a number of reasons. Location, special chemistry needs, or highly active compounds could all lead to multiple contractors providing the best solution for your project. However, even when a large single contract organization is engaged, many of the principles discussed here can be applied, as you will be working with many scientists in various departments.
For our case study, we need a CMO to manufacture the API, a CRO to carry out the polymorph studies, a CRO to study solid formulations, and a CRO to validate the analytical method. In addition, stability studies will need to be initiated; typically the API CMO or the analytical development CRO has the capability to perform this function as well. One management style suggests that all these activities can be conducted independently and the client can act as both the central repository of information as well as the filter to decide which information might be shared. In my experience, when contractors are treated as trusted colleagues and allowed to share information at a basic scientist-to-scientist level, the quality of the expected results improves and the ability to handle unexpected challenges becomes more effective. After all, if all of these functionalities were being carried out by internal resources, the team meetings would often include members from all the functions to support the overall progress of the project. The goal is to manage your outsourced API project so that the same degree of cooperation and scientific interaction is maintained.
Since establishing CDA’s with multiple parties can present legal challenges and take longer to prepare and execute, careful consideration must be made in choosing which parties to include. In our working scenario, establishing a relationship between the API CMO, the analytical development CRO, and the polymorphism CRO offers great advantages. As the CMO develops the chemistry for scale-up, improvements in the analytical process can be applied to the chemistry work to insure that impurities are not hidden behind other peaks, intermediates are properly quantified, and analytical sample analysis run times are streamlined. In some synthetic schemes, a starting material, intermediate, or reagent may present a particular analytical challenge due to lack of a suitable HPLC chromaphore or sampling challenge; having your analytical CRO backing up the API CMO analytical group can solve problems before they spoil a production run. As the polymorph CRO charts the crystalline characteristics of your API, they can work in step with the API CMO to insure that the desired polymorph is cleanly and efficiently produced by the manufacturing process. A change in recrystallization solvent made by the API CMO that improves both the purity and yield of your final product as well as the environmental friendliness of your process can also change the polymorph obtained. Other processes such as drying, milling, and storage can also affect the polymorph obtained. The ability of these two contractors to freely exchange samples will make the entire process run more smoothly, and many polymorph CRO’s can develop polymorph specific processes and provide technology transfer to the API CMO to make sure that the correct polymorph is reproducibly produced.
Likewise, having your analytical CRO, polymorph CRO and solid dosage form CRO connected at a scientific level presents certain synergistic advantages. As the solid form CRO carries out the excipient/API stability studies, transferring the methodology developed by the analytical CRO can save a great deal of analytical development time. The method may not be suitable for use as is, but it will certainly provide a significant head start. Some solid form techniques such as grinding the excipients and the API together can also have an effect of the polymorph; working with the polymorph CRO can monitor this potential problem.
Secure and Central Data Storage
In order for information to be readily available, a central electronic location must be established. There are many ways to achieve this end: a secure SharePoint can be set up on a company server or a cloud-based data file may be created. Your company resources and policies will dictate the method that you will use; whatever platform is chosen, this will be critical to both your short- and long-term success. Organization of the data is also of paramount importance. Folders need to have distinct descriptive labels, and sub folders will often need to be created to keep the contents of a particular folder sorted and available. For example, ‘API analytical’ may initially seem like a good name, but remember that you will have analytical data from multiple steps and multiple batches. In order to be able to retrieve key information a week, month, or year later requires more description. Within the ‘API analytical’ folder you should have ‘[batch number] process analytical’, ‘[batch number] final analytical’, ‘[batch number] CoA’ and so forth. While it is possible to create too many folders, this is unlikely to be the case. As the data in the central file accumulates, you need to monitor the shape it takes. Although any API project will have similar data categories, each project will have some unique characteristics—don’t be afraid to create a unique filing system to manage these characteristics. In my experience, one of the most valuable sections of the data file is also the most difficult to successfully manage. This is the preliminary results folder. As the various contract functions are developing new information a nd sharing it, initial results will lead to conclusions that are then modified by subsequent data. It is important to maintain that thread of development for the current interactive team environment to thrive, but at some point, the overriding or final conclusions must be retained and the interim postulates removed or very clearly marked. Two years from now, when you have questions that need answering, if you have to go back and read all the documents to re-create the thread to re-connect with the final results, you will be frustrated with the amount of time spent figuring out something you thought you already knew.
Critical Communication
Throughout the entire project, clear communication is absolutely mandatory. From setting initial expectations, roles, and responsibilities through discussing results—especially in case of problems— communication is the central platform that will support all activity. Before the first contractor has been approached, high quality technology transfer documents and internal goal setting will give your project a firm foundation. When writing contracts, communication of technical details and time line requirements develops trust and mutual agreement on realistic goals and costs. During the project work, regular team meetings with detailed minutes that are posted on the central data site insure that progress is shared and that problems are dealt with before they become critical. As the team dynamic forms, encouraging the contractors to communicate directly when appropriate will increase efficiency; the only caveat is that as the client, you must insist that you are copied on all such communications. Not only is it imperative that you keep up with the latest results, but it is your responsibility to document the information and post any key information on the central web site. And when the project has been successfully completed, comprehensive final reports from all participants, which should include discussions of the challenges faced and potential solutions and improvements as well as the work that was accomplished provide an invaluable archive that will be re-examined when the next phase of the project is initiated.
Iron Fist and Velvet Glove
Establishing a relationship built on trust and respect between the client and the contractors and among the contractors leverages the skill and talent of each individual against the project at hand. Creating an environment of teamwork instead of a mercenary mentality unlocks the full capabilities of the contract organization and results in a job done correctly, not one that is just completed. Ultimately, however, you are responsible for the project. Your leadership style should balance your authority to make decisions and hold all team members accountable with your ability to listen to suggestions, evaluate alternate options and to choose the best path forward. Quite often, the contract organizations that you have chosen as partners have collectively decades of experience; taking their advice on key aspects of the project gives you the best chance of a successful outcome. Yet once a decision is made, it must be clear that it is your decision, and not that of the contractor. No plan is ever perfect, and when something doesn’t work in the laboratory the way it was drawn up on the white board, the client cannot blame the individual or group of contractors that proposed the solution, unless gross misconduct is clearly evident. You learn what you can from the unexpected result, regroup, and with continued teamwork and communication, formulate a new course of action and move forward.
Conclusion
When multiple contractors are engaged for the development of a new API, an already complex task takes on an additional level of challenges. With careful planning and tireless communication, a team of dedicated contract organizations can be brought together to take on the project in an environment of respect and cooperation. Proper management of roles and responsibilities and a careful balance of authority and enablement provide the perfect condition for synergistic application of diverse expertise and extensive experience towards the successful completion of the task at hand. It takes a bit more effort to establish this type of working relationship, but the increased probability of a positive outcome is well worth it.
Jeff Marra received a BS in Chemistry from Clarkson University and his PhD in Organic Chemistry from Colorado State University. After 12 years of industrial process R&D, and 15 years spent managing the outsourcing of research and development compounds, and more recently the outsourcing of API compounds for Purdue Pharma LP, the author is exploring to find the next interesting opportunity.