Late-stage API Development, Manufacturing, and CMO Relations

Summary

Late-stage Development and first manufacture represent critical phases for a new API. Outsourcing these complicated tasks adds an additional layer of complexity. Chemistry that has been of secondary importance becomes the highest priority and faces the challenge of first multi-kilogram synthesis. A successful program requires a comprehensive plan with carefully crafted goals and a flexible approach to deal with the unique challenges that will undoubtedly surface. Successful execution requires an open, communicative relationship with a capable CMO that can cope with unforeseen delays and subsequent changes in the plan.
Introduction

Late-stage API development exposes the chemistry of your compound to intense scrutiny for the first time. Each API will present unique challenges and no CMO, regardless of experience, will be able to anticipate them all. The plan needs to allow for process chemistry development and successful scale-up demonstration. Analytical support must evolve with the chemistry. Goals must be carefully designed to achieve the plans yet allow for flexible creativity to deal with unforeseen hurdles. The client must be willing to defer to an experienced CMO and the CMO must be willing to lead when the client is inexperienced. Frequent, appropriate, transparent communication is essential to establish a strong functional relationship. If properly nurtured and maintained, this relationship can withstand the inevitable adversity. The details that warrant this stage of development are different for every compound and at every company or collaboration, yet for the process to be successful, there are central elements that must be addressed. A plan needs to be developed that clearly defines and prioritizes key parameters using realistic and practical considerations. The chemistry must be examined and tested at appropriate scale. An appropriate CMO needs to be chosen based upon a complex formula of capability, availability and an intensely unscientific criterion often termed “fit.” What follows is a general discussion that will hopefully illuminate this murky situation.

Chemistry Development

Late-stage API development probes the chemistry of your compound just as its biology has been tested to reach this stage of the drug discovery process. Your API has been through a labyrinth of in vitro and in vivo testing to determine how it behaves in every imaginable physiological system. Efficacy, side effects, metabolic disposition, off-target activity, chronic exposure and multi-species variations have all been examined under the proverbial microscope. The chemistry that produced the material for all these tests has been secondary; the clichés used are “good enough at this stage,” “additional resources for process chemistry are not yet justified,” and “just manage the impurity profile.” Then you attend a planning meeting, the timelines for development are revealed and there in the middle is “10Kg API campaign” and suddenly, the API chemistry is aligned along the critical path. This translates to intense activity for the team responsible for supplying the API which requires a well-orchestrated plan of action.

Developing chemistry from the bench to the pilot plant takes a unique skill set and is the first key decision point regarding the choice of the appropriate CMO. If you have chemists with the proper experience and that possess the necessary equipment, your plan must include the resources needed to allow a reasonable in-house scale-up route to be developed. If you do not have these capabilities, then either a separate CRO needs to be identified that can provide a working process or a CMO that also does process development must be found. This is the first major challenge for the communication ability of your outsourcing staff and their ability to establish and nurture a relationship. The strengths and gaps of both the client and the potential CRO/CMO need to be candidly evaluated in order to choose the right contractor to create a strong collaboration. Considering the overall risk involved to develop a new drug, any reticence that inhibits your ability to establish an honest and open relationship with your new CRO/CMO must be overcome. Critical self-analysis and thorough evaluation of the CRO/CMO are the first steps towards creating a relationship that will survive the rigors of chemistry development and first manufacture of the API.

Creation of an appropriate strategy with realistic goals for the new process chemistry development and API manufacture 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 have a huge impact. Any unusual circumstances such as high potency, cytotoxicity, exotic or high-energy chemistry, particular morphology or specific formulation will affect the plan. The amount of API to be manufactured drives many of the subsequent activities and should be one of the first decisions made. The scale is determined by two factors: the dosage levels and the overall API supply strategy. The dosage levels are determined from the efficacy, toxicology and other pharmacological data; translating these results into amount of API needed takes knowledge and experience 2012that your CRO/CMO may have if you do not. The supply strategy comes from your company culture, history and resources. You may decide to first prepare a GLP batch for IND enabling studies, and if successful, then a GMP batch for the first-in-man studies. The GMP batch may be sized to supply only the Phase I studies or to support both Phase I and II studies. Making a GMP batch large enough to support the initial IND studies and the Phase I and II studies is also a viable option. Each strategy has its risks and benefits, and each company must weigh these options carefully. Regardless of your choice, it must be made prior to process chemistry development. The level of development and sophistication of the chemistry process needed to prepare a 2Kg GLP batch will often be different than that needed to prepare a 40Kg GMP batch. While the 2Kg GLP development strategy must look forward to the much larger GMP batch, the final goals, and therefore the resources applied, will be different. For example, with a chiral molecule, supercritical fluid chromatography separation of a racemic mixture may be fully appropriate for the GLP and Phase I GMP, while it is likely that development of an enantioselective process would be needed before preparing enough API to support phase II trials and the solid dose formulation development. The entire strategy, however, shifts dramatically for a highly potent API which could reduce your API needs by ten-fold, and requires a CMO with special capabilities or a CRO with strong process skills and appropriate Kilo Lab.

Analytical Process Support

The analytical component of early stage API development 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 PKDM work from initial enabling toxicology studies in animals to the human studies. Waiting to develop the analytical method until IND filing can reduce resource allocation, but it can also reduce the effectiveness of the chemistry development process. Without a robust analytical method, chemistry reaction by-products can go undetected during initial development which may result in re-evaluation of some of the process steps in later stages of development. If this occurs during the final scale-up research immediately prior to first manufacture, significant delays can be realized. Like the chemistry, the analytical development will be unique for every API. Especially with improvements in analytical methodology, inexperienced clients may under-appropriate resources for analytical development. 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.

For many clients, outsourcing the analytical development needs to be part of the planning strategy. There are CRO’s that specialize in analytical development, and many CMO’s have a capable analytical department. Some CMO’s 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.

Establishing, Nurturing and Maintaining a Relationship

Relationships with CMO’s 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.

When initial negotiations with a CRO/CMO begin, viewing your project from their perspective will help the relationship start with mutual understanding. Remember that the contractor puts their reputation on the line with every new project they undertake. They also have a business model; it may differ from yours, but it still relies on long-term sustainability and ultimately must be profitable. The contractor gains little, if anything, from leaking your confidential information or misleading you 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; we all gather at the same conferences year after year and we all share our experiences, good and bad. It doesn’t take long for a series of negative experiences with one contractor to become common knowledge.

When initially engaging a CMO, it is important to have a 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 guessing 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 doesn’t feel 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 doesn’t immediately communicate an unforeseen problem with the client that may affect the timeline until it’s too late, the CMO loses trust with the client.

When Things Go Wrong

If the CMO misses a project milestone due to timing or poor yields, it’s not due to lack of effort. It’s due to an unforeseen occurrence. When the client makes a late change in the goals, it’s not to make the CMO look bad or to try and get more for the agreed upon fee. It’s 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 scale-up 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.

Scientific Communication

Once the project overview has been agreed upon, the next key factor involves the technology transfer. A comprehensive report is absolutely mandatory; the more relevant information included only increases the chances for success. The tech transfer must be more than a proud client showing off how well they managed to prepare the first 500g or 1Kg of the API. It should also include all the missteps, abandoned synthetic pathways and failed reactions. If it took 25 tries to achieve the desired yield and minimize a certain by-product, then include a table with all the pertinent variables and results, not just the final conditions. If a reaction only works well in a particular solvent or selected temperature range, include these results as well. If there is mechanistic or engineering theory for why a particular rate of addition, stoichiometry or reaction vessel is used, put it in there. All of these parameters can have a large affect on the process as it goes from the known scale to larger scale, and your CMO will know how to utilize much of this information to prepare a more accurate bid as well as streamline the development of your API manufacture.

Scientist-to-scientist communication is another key aspect of the technology transfer. Managers and project leaders have important roles to play, but when it comes to putting chemicals in flasks, the best way to accurately convey the full extent of the information is for the scientists to talk. Without the scientists communicating directly, describing the synthetic process is much like one person trying to tell another person about a book or movie that was described to them by someone else. For example, it may say in the technology transfer document that “the reaction was maintained at 0°C during addition of [reagent].” But when the scientists discuss the reaction face-to-face in detail, the difference between using an ice/water bath to maintain the temperature and needing a Dry Ice/acetone bath because the energy released is so great can greatly impact the process scale-up. I believe that the bench scientists from both the client and the CMO should be intimately involved in the negotiation process and in establishing the working relationship.

In my opinion, the best technology transfer goes beyond the written documents. When I am primarily responsible for this stage of the program, I like 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 try all the process steps at scale in a parallel fashion. This allows them to see the chemistry first hand in an efficient manner. After this, a meeting between the client and CMO chemists will generate information that is incredibly beneficial to the positive outcome of the process scale-up.

Summary

Developing a synthetic process for API scale-up for the first time is an extremely challenging exercise, and engaging a CMO to undertake this task increases the complexity exponentially. To successfully negotiate the formidable sequence of events necessary to produce the proper amount of API with the proper specifications, a comprehensive strategy, a detailed plan, and a realistic timeline need to be developed. To implement the plan, strong client/contractor collaboration needs to be established through trust and understanding, and maintained by copious and never ending communication.