Introduction
Like chess, which is easy to learn but difficult to master, engaging a CMO for API manufacture is a straightforward process yet delivering the proper amount of API on time, on budget and within specifications presents challenges. With each API comes a distinct set of requirements, and with each CMO comes a distinct set of capabilities. Making a match that results in harmonious collaboration and successful API manufacture is a task that is difficult to master.
CMO Selection
The first strategic step to effective CMO utilization starts with CMO selection. The chemistry that shapes your API must also influence your choice of CMO. As each synthetic scheme contains unique elements, there is no general formula to follow. Two brief illustrative examples will demonstrate the thought process; ultimately, familiarity with your chemistry needs and thorough investigation of CMO capabilities should guide your decision.
In one example, a 16-step synthesis that introduces a chiral center at step six will be considered. In this instance, the corporate culture mandates that the API be manufactured in North America, which is also the location of the clinical trial, to minimize the risks of API supply disruption. The CMO capabilities that make a good match for this project would include: offshore connections for the eight-step synthesis of the cGMP starting material, the culture to work with another CRO/ CMO with the expertise to effectively introduce the chiral center, and the transparent project management skills to handle these challenges. In another instance, a scheme that contains a cryogenic step as well as a step that utilizes an energetic reagent such as sodium azide or hydrazine will be introduced. Obviously, the CMO must have these capabilities or have demonstrated successful sub-contracting with key suppliers of key technology.
Other factors include the CMO’s size, financial history, and availability. This article will not try to include every variable but rather aim to emphasize that effective utilization of a CMO begins with a thorough understanding of your process and any unique requirements. Careful evaluation of potential CMO partners that match your needs in order to make an appropriate choice is the first and most important step; a mismatch at this juncture will likely result in multiple delays in later stages.
Technology Transfer
The most effective way to improve the efficiency of API manufacture, once an appropriate CMO has been chosen, is to invest in a robust technology transfer. Whether the synthetic scheme was developed internally or by a CRO, thorough documentation of the entire process is essential. The technology transfer must not only include how well the first 500g or 1Kg of the API was prepared, it should also include all the missteps, abandoned synthetic pathways and failed reactions. If, for example, it took 25 experiments to achieve the desired yield and minimize a certain byproduct, then a table with all the pertinent variables and results should be included, not just the final conditions. If a reaction only works well in a particular solvent or selected temperature range, these results should also be included. If a mechanistic or engineering theory exists for why a particular rate of addition, stoichiometry or reaction vessel is used, this should be included as well. All of these parameters can have a large effect on the process as it progresses from the known scale to the larger scale, and the CMO will understand how to utilize much of this information to prepare a more accurate bid as well as streamline the development of the API manufacture.
Having additional information at the beginning of a project, such as the potency of the API, the known or calculated biological effects of key intermediates, and the potential sources for raw materials and reagents, may also improve the efficiency of the CMO. The activity of your API and the potential adverse side effects from overexposure along with any known or suspected toxic or biologically active intermediates must be communicated early and completely. This information can have a profound effect on equipment and personnel resources the CMO commits to your project. Any information that is not communicated properly that leads to a change in protocol will also likely lead to a delay. Some clients seem to assume that a CMO maintains a comprehensive knowledge of every single compound and reagent that is available on a commercial scale and can immediately order any amount for overnight delivery. Unfortunately, this is not the case. If a cost of goods analysis has already been performed or a particular class of compounds or a specific type of reagent has been utilized, the cheapest high quality supplier with inventory in stock may have been discovered. Sharing the raw material and reagent supply information can save the CMO a great deal of time, effort, and resources.
Scientist-to-scientist communication is another important aspect of the technology transfer. Managers and project leaders have crucial roles to play, but when it comes to putting chemicals in reactors, the best way to accurately convey the full extent of this information is for the scientists to talk. Without the scientists communicating directly, describing the synthetic process is inefficient. For example, it may say in the technology transfer document that “the reaction was maintained at 0°C during addition of [reagent]”. However, when the scientists discuss the reaction face-to-face in detail, the difference between using a 0°C set point to maintain the temperature and needing a -20°C set point because the energy released, can greatly impact the process scale-up.
The best technology transfer goes beyond the written documents. An extremely effective strategy is to provide the CMO with 100g quantities of all the stable reaction intermediates and a 5g to 10g sample of the final product along with copies of the pertinent chromatographic and NMR data. This gives the CMO the opportunity to explore the process steps at scale in a parallel fashion, allowing them to see the chemistry first-hand in an efficient manner. After this, a meeting between the CMO chemists and the chemists who developed the process chemistry will generate information that is incredibly beneficial to the positive outcome of the process scale-up.
Analytical Process Support
The analytical component of API manufacture supports the overall process in many important ways. Ultimately, an analytical method must be developed that resolves all components present in the synthetic process. This is a requirement for the chemistry portion of the CMC and for the stability studies. The analytical method also supports the pharmacokinetics and drug metabolism (PKDM) work from initial enabling toxicology studies in animals to the human studies. While most API manufacturing projects will already have a robust validated analytical method for the final product, many projects do not have a robust in-process analytical package. For some reactions, taking an aliquot and analyzing by HPLC may be sufficient and provide all the necessary information to monitor the progress of that reaction. Many reactions, however, may require an in-process analytical procedure that is different from the API analytical method. An early stage intermediate may not have a UV chromaphore, so HPLC with UV detection may need to be replaced by gas chromatography with thermal conductivity, flame ionization detector or mass selective detection. Many intermediates do not have the same molar absorptivity; in some cases the difference may be sufficiently significant to cause misinterpretation of the HPLC data.
Although not common, reaction sampling can sometimes alter the profile of the sample and give misleading results. Radical changes in compound polarity or solubility of the process intermediates will challenge the most advanced separation technology and experienced analytical chemists. The presence of chirality, which is becoming more prevalent, adds an additional level of analytical complexity. The investment of the necessary resources to thoroughly understand each step of the API manufacturing process will minimize time consuming unexpected results that arise from poorly designed in-process analytical protocols. For many clients, outsourcing the analytical development needs to be part of the planning strategy. Some CROs specialize in analytical development, and many CMOs have a capable analytical department. Other CMOs are very capable at receiving a transferred analytical method, but not as experienced at developing one. The more closely the analytical development parallels the chemistry development, the easier the analytical method validation and the higher the confidence level will be with the process chemistry. Communication of the analytical needs when initially engaging a CMO for first manufacture will greatly reduce later problems.
Clearly-established Goals and Strategy
A fully developed manufacturing plan with realistic goals for API manufacture must be in place prior to engaging a CMO. Creation of an appropriate strategy must take into account a wide range of variables. The amount to be produced, the ultimate phase of drug development that needs to be supported, and the location of the manufacture of the drug product are among the most important. Whatever strategy the API and company culture inspires, it needs to be clearly communicated to the CMO prior to contract finalization. Effectively sharing a strategy with the CMO during the initial negotiations will greatly improve the quality of the contract specifications. Clearly defined goals and expectations will provide the clarity and confidence the CMO needs to move ahead efficiently from contract negotiation, equipment decisions, resource allocations, raw material and reagent purchase, and even manufacturing schedules. Any deviations or indecisiveness by the client will hinder the CMO as they implement plans to execute the strategy and will likely result in delays.
Establishing and Nurturing a Relationship
A strong relationship with the CMO manufacturing the API is the most powerful tool to minimizing delays once the reactors are filled with chemicals. Relationships with CMOs are not radically different from individual personal relationships. The main differences are the legal contracts; the confidentiality agreement and the master service agreement are essential to properly manage corporate risks. Once established, however, these legal agreements should be utilized more as a safety net than as a guide to day-to-day operations. Frequent and honest communication along with sincere formation of a collaborative atmosphere help to form a strong relationship that will handle the rigors of manufacturing an API within specifications and the desired timeline.
When initial negotiations with a CMO begin, viewing a project from the CMO’s perspective will help the relationship begin with mutual understanding. The contractor puts their reputation on the line with every new project they undertake.
They also have a business model; it may differ from the sponsor’s, but it still relies on long-term sustainability and ultimately must be profitable. The contractor gains little if anything from leaking the sponsor’s confidential information or misleading the sponsor regarding their capabilities, capacity or availability. If they initially underbid and then add charges later or botch up the process in any way, their reputation suffers negatively. The world of contract API manufacture is a small one. A series of negative experiences with one contractor can quickly become common knowledge.
When initially engaging a CMO, it is important to share the vision of the ultimate goal. The most effective relationship is a true collaboration where the two partners interact with transparent communication. A client and CMO relationship should resemble a partnership more than a customer buying a service. The CMO takes on risk when they agree to manufacture a new API; the resources required to fulfill the contractual obligations are not entirely quantifiable. The fundamental uncertainties involved in any API scale-up, especially the first one, require the CMO to make certain estimates regarding resource allocations. When the CMO prepares a quote, the uncertainty generated by unresolved variables can make it challenging to balance the ability to cover their costs without overcharging the client. They want your project to succeed for your reasons as well as theirs. The relationship between client and contractor works best when both sides view it as a mutually beneficial alliance where the agreed upon goals and milestones will lead to successful API production. If the client unknowingly pushes the CMO to an extremely aggressive timeline and the CMO is not comfortable enough with the relationship to point out the high potential for missing the deadline, the relationship is set up for failure. If the CMO does not immediately communicate an unforeseen problem with the client that may affect the timeline until it is too late, the CMO loses trust with the client. In both cases, unexpected delays may occur that could have been avoided by building a genuine relationship with the CMO from the start.
When Things Go Wrong
And believe me, they will. If the CMO misses a project milestone due to timing or poor yields, it is not due to lack of effort. It is due to an unforeseen occurrence. When the client makes a late change in the goals, it is not to make the CMO look bad or to try and get more for the agreed-upon fee. It is due to some new data that changes their strategy. The relationship between the client and the CMO must not only take these potential events in stride, but it should also anticipate them. Again, communication is the best tool to handle these problems, followed closely by respect and understanding. If a particular step in the synthetic scheme appears risk intensive to the CMO, they must point that out to the client so it can be worked into the initial project bid. If the client is waiting for the results from a key study that will affect their ultimate strategy in a way that may change the amount of API needed or the level of a known impurity, they should inform the CMO before final project specifications are set. If these changes cannot be resolved in a single contract, setting up more than one contract or a staged contract may be most advantageous. The initial process scaleup investigation can be set up as the first stage, while the ultimate amount or purity specification could be put into a later contract once the determining factors have been resolved. By expecting problems and developing a strong relationship with the CMO, the unavoidable unforeseen challenges will have a minimum impact on the timeline. Careful consideration of potential problems and incorporation of these into the contract will align expectations, help develop realistic timelines and potentially reduce delays.
Conclusion
API manufacture is a complex undertaking with an almost endless number of variables. Engaging a CMO also presents significant challenges and resource requirements. Combining the two with the expected outcome of successful API manufacture by a CMO requires an organized and concerted effort. Prior to engaging a CMO, the chemistry details and the scope of the project need to be well-defined and completely understood. The choice of an appropriate CMO must reflect all of these chemistry and project parameters, and the communication of them to the CMO must be comprehensive. Establishing a strong collaborative relationship with the CMO will facilitate the entire process and effectively reduce the resolution time of unforeseen challenges. From initial project genesis and CMO selection through technology transfer and API manufacture, constant attention and communication is required to insure efficient project management. When diligence in planning is combined with comprehensive communication and a sincere collaborative relationship with a CMO, effective API manufacture is the most likely outcome.
Jeff Marra Received a B.S. in Chemistry from Clarkson University and a Ph.D. in Organic Chemistry from Colorado State University. He worked at The Dow Chemical Company for 11 years and Lonza US primarily in process development of industrial antimicrobials. For the past 15 years he has worked at Purdue Pharma L.P. in drug discovery, process development and outsourcing management.