Facilitating Rapid Introduction of New Chemical Entities: Part 1
By David Johnston, President, Oread Laboratories
This two-part article by Oread CEO David Johnston discusses, from a contract manufacturer's perspective, how pharmaceutical companies can speed up introduction of new chemical entities.
Introduction
What Is Preclinical Development?
Discovery Support
Active Pharmaceutical Ingredient (API)—Synthesis, Characterization, and Qualification
References
Introduction (Back to Top)
Over the last decade, the quest for accelerated drug discovery and development, as well as for rapidly introducing new chemical entities (NCEs), has become the major focus throughout the international pharmaceutical industry. On the discovery front, the advent of combinatorial chemistry, and the ability to rapidly screen molecules, has greatly increased the number of potential drug candidates that might be considered for development. This increase in potential candidates to fill the pipeline has, of course, also increased the need for refined decision-making to insure that only the optimal candidates get the benefit of full development resources. The International Conference on Harmonization (ICH) has further facilitated the development process in defining areas where a single guideline on areas of pre-clinical and clinical development might be mutually acceptable, thus improving the efficiency of the global approval process. When combined with gains in efficiency within the regulatory review processes, this has resulted in significant reduction in the times taken to review and approve drugs within the U.S. and the European Union. With the streamlining of the regulatory process, the emphasis has now shifted to examining ways to accelerate the remaining rate determining steps in the process.
What Is Preclinical Development? (Back to Top)
Traditionally, preclinical drug development might have been (very narrowly) defined as only those safety studies needed before beginning the clinical evaluation of a drug candidate. These studies were completely separated from the discovery process and would commence only after a candidate had been formally nominated for acceptance as a drug development candidate. Today, preclinical activities may be considered in a broader sense, i.e. as everything which needs to be completed before the drug candidate is moved on to the next phase of clinical development. Using this broader definition, one would include chemical development, analytical chemistry, formulation development, bioanalytical support, drug metabolism, and pharmacokinetics, as well as the regulatory and quality assurance functions.
In today's paradigm, preclinical development provides a continuous level of integrated support services, interfacing early on with discovery, to identify drug development candidates. The process then continues through the entire development process, culminating in the approval of a marketing application.
With the continuing change of strategy within the major pharmaceutical companies to focus resources on their internal core competencies, i.e. discovery and marketing, there are additional needs for contract preclinical and clinical resources throughout the discovery-development continuum. These needs can be met either through the use of discrete services or through contract pharmaceutical development organizations as fully aligned partners in achieving drug development goals. The work being outsourced can cover the full spectrum of preclinical development activities. Ideally, where these activities are in different scientific disciplines, the processes should take place in parallel, or with smooth handoffs and feedback mechanisms between each other. In the case where multiple outsource providers are used, this becomes even more of an issue, and the likelihood of delays and missed handoffs become much higher, resulting in delayed entry into the clinic, delayed marketing applications, and ultimately millions of dollars in lost sales for a potential new drug.
For all pharmaceutical companies, integration of the pre-clinical development activities offers opportunities to shrink the development timeline and to move as rapidly as possible from the identification of a lead development candidate to decision-making in the development process, to performing clinical trials. In many ways, it is informative to consider the preclinical development process as an interlocking jigsaw of activities where the interfaces of the activities provide opportunity for accelerating development as a whole. If pieces of the jigsaw are missing, then time will be lost in transferring information and technology between discrete preclinical disciplines.
Discovery Support (Back to Top)
The discovery process, from the definition of a therapeutic target through the process of creating and evaluating leads, has recently been discussed (Reference 1). The number of potential candidates for development has never been greater, and the need for a highly efficient and effective selection process is key, if the optimal candidates are to be progressed into development. Several components can be usefully applied to identify the optimal candidate for full development. These considerations may start with the long-term viability and potential cost of the synthesis of the drug candidate, which may eliminate a few candidates. At the same time, it is important to recognize that the general pharmaceutical properties of the lead molecules being rank ordered may differ very significantly. The application of aspects of the pre-formulation screening studies mentioned later in this article could help identify those molecules that stand the best chance of producing an optimally bioavailable formulation. A broad range of in vitro tests can be applied to identify properties, including metabolic profile, toxic potential, permeability, and absorption.
Genomics and bioinformatics can also aid in the development candidate selection. The use of human fluid and tissue samples with defined clinical history through time has been helpful in calibrating diagnostic tools for disease states. It would seem reasonable that these same samples will have a significant role to play in the development of therapeutic agents in the future.
Active Pharmaceutical Ingredient (API)—Synthesis, Characterization, and Qualification (Back to Top)
While it is obvious that very little preclinical development can be performed without the API, the lack of availability of this material is often the rate-determining factor in the progress of a development program. The chemistry manufacturing and control (CMC) activities begin with the synthesis of the first lots of drug substance produced outside of the research or discovery operation. During the Drug Product Development Cycle, the molecule(s) that is responsible for the therapeutic action in the body must be synthesized many times. Scales that began with milligram quantities in discovery, grow to the 1–10 kilogram scale in early development and move on to the tens and eventually hundreds of kilogram scale as the later stages of development progress towards commercialization.
Recognizing that the synthetic pathway chosen to make the target molecule in discovery is unlikely to be suitable for scale-up, or in the distant future for commercialization, two key activities will be initiated at the discovery development interface.
First, the final purification step needs to be developed so that it can produce test material of consistent physical and chemical quality and with a well-defined impurity profile. Second, the synthesis needs to be scaled up to produce the quantities needed for the early portion of the drug development cycle, i.e. to yield 500g to 5kg. For the next stage of development, this process will be scaled up to the 50kg scale and beyond. The control of the quality of the drug substance arising from these early synthetic efforts ensures that the data generated in the early safety studies will be relevant to the materials included in the first dosage forms to be dosed in human studies. This control is insured by very close collaboration of the Chemical Development and the Pharmaceutical Chemistry group, which will develop and validate analytical methods for both in-process and final control of the API.
The capacity limitations found in many major pharmaceutical companies in the early stages of development, where 5–50kg quantities are needed, is mirrored in the contract pharmaceutical industry, where relatively few companies can produce quantities of API from laboratory scale through pilot plant scale with the application of appropriate pharmaceutical cGMPs. Close integration of these early chemical development studies with the early efforts by the Pharmaceutical Chemistry groups to characterize the physical chemical properties and impurity profile of the API allows the process development to progress more quickly while providing a solid basis for rational process development.
The physical characteristics of the material produced, including the particle size, crystallinity, hydration state, and the possibility of polymorphism, need to be carefully evaluated. Alongside this, there will be studies to evaluate other critical factors such as solubility (over a range of pHs), partition coefficient, and stability in the solid state under stress conditions. The ability of these solid state properties to influence how the drug behaves during the isolation step in the synthetic process, during processing to dosage forms, and ultimately on the bioavailability of the drug make them a key part of early studies. Where significant issues are identified, other studies as to the impact on processability of API in the drug product manufacturing process, safety, and efficacy may be needed before moving ahead with development.
The nature of the impurity profile needs to be carefully assessed, taking due account of the International Conference on Harmonization (ICH) guidelines. An important feature to note is that, as the development cycle progresses, the synthesis of the API is scaled up and evolves, with the result that there can be subtle changes in both the physical and chemical nature of the drug substance including the impurity profile.
Each of these changes needs to be carefully assessed as to whether they can impact the safety and/or efficacy of the product. This can result in re-evaluating some aspects of the toxicology package and/or the pharmacokinetic properties of the "new" API following formulation. This evaluation can also require the independent synthesis of process-related impurities. Similarly, in separate studies the liability of the API to be degraded will be evaluated under a variety of stress conditions and this potential degradation profile will also be used to define optimal isolation and storage conditions.
The close relationship between the Pharmaceutical Chemistry and Chemical Development divisions facilitates the acceleration of the drug development process in this area. This qualification of a drug product candidate for use in humans involves an assessment of the integrated information available from all of the pre-clinical studies. This includes the chemistry, manufacturing, and controls (CMC), in conjunction with the safety pharmacology, drug metabolism and pharmacokinetics, and drug safety studies. The information obtained during these early experiments will allow the rapid development of preliminary specifications that will define the key characteristics of the drug development candidate.
End of Part 1. To read Part 2, click here.
- JM Graham, "Contract Research Organizations—A Move into Discovery?", European Pharmaceutical Contractor May 1998, 46-50.
For more information: David Johnston, President, Oread Laboratories, 1501 Wakarusa Dr., Lawrence, KS 66047-1803. Tel: 785-749-0034. Fax: 785-749-1882.