The Challenge of Managing Risks
This article will review the potential risks in deferring process development and optimization programs until after positive clinical results have been obtained. The trade-off between risk and reward is a perennial problem for almost every chemical development group. Accordingly, companies often adopt an initial short-run approach. First, develop a synthesis good enough to generate sufficient material to carry out toxicology studies and Phase I clinical trials. If the corresponding results look promising, only then optimize the process.
In practice, because many earlyphase drugs fail to meet sufficient criteria to justify further clinical investigation, this approach is often prudent. However, for those drug candidates yielding interesting clinical results, the demand for significantly larger quantities of active pharmaceutical ingredient (API) is almost immediate. If the manufacturing process is, in fact, suboptimal and cannot deliver sufficient material at the desired quality, the initial deferral of investment could lead to time delays and additional costs in later phases.
API Early-Phase Process Development
Pay Now or Pay Later
Under what circumstances should a company invest in early-phase process development?
While a variety of factors influence this decision, a few are critical: (1) if the process, particularly if linear, involves numerous chemical steps (increased risk of failure at any one step); (2) if key raw materials have limited availability or especially high cost; (3) if the purification scheme is difficult at one or more steps (e.g., chromatographic purification); (4) if yields are unacceptably low or the chemistry is difficult to scale, especially for latephase process steps or steps that must be GMP-compliant; and (5) if there are serious safety concerns.
High Risk – Paying Later
In high-risk cases, deferring the costs of early optimization can lead to losses of time and money. For example, a company decided to use an unoptimized synthesis process to prepare a few kilograms of API for a combined toxicology/Phase I study. The process was transferred to a contract manufacturing organization (CMO) on a short timeline, and production commenced after a limited laboratory evaluation.
Several steps into the scale-up run, the material failed to crystallize as it had in the laboratory. Analytical testing revealed a significant side reaction that had not been previously observed. The CMO spent the next week in the laboratory developing a purification scheme. After yet another two weeks in the kilo lab and several purification steps later, only half the desired amount of material was produced. Ultimately, the product was delivered to the formulation site six weeks late.
Managing Risk – Paying Now
While the case above seems particularly dire, every chemical development group needs to find the right balance between risk and reward in early investment decisions. Investing assets wisely in early process development could be the insurance that saves both time and money in the longer run. This decision does not commit the group to defining and developing the final process as presented in the new drug application (NDA), but it does necessitate identifying critical early-phase process steps and implementing practical trouble-shooting solutions to ensure that the process will scale successfully. Information gleaned from early process development can also be beneficial in Phase II production campaigns in which the amount of drug substance required is significantly larger and the timeline between Phase I and Phase II is often too short for extensive process optimization.
Companies also consider early-phase development from a broader financial perspective, taking into account such factors as cash flow and return on investment. The management realizes that delays in performing key studies could result in missed milestones, manufacturing cost overruns, and financial penalties assessed by the contract research organization (CRO). Similarly, they also see the wisdom in developing a comprehensive chemical development program that includes a reliable manufacturing route, readily available raw materials, a complete analytical package, and good solid-state characterization which together increase the value of the licensing package should the company decide to outlicense the drug.
Ideally, the required scientific work is carried out by a group or organization that specializes in process development and has the experience, expertise, and resources to perform the necessary tasks effectively and quickly.
Chemical and Analytical Development Group
Solvias – A Good Investment Now and Later
The chemical and analytical development (CHAD) group at Solvias has just such an extensive technology portfolio.
Moreover, Solvias has the skill and experience to utilize these tools to streamline manufacturing processes and avoid problematic synthesis steps. Available technologies include asymmetric catalysis, CX-coupling chemistry, fluorination chemistry, and complex heterocyclic chemistry. During the process chemistry phase, our scientists develop and validate analytical methods, set specifications for raw materials, chemical intermediates, and final products, and prepare reference standards. Solid-state chemists perform salt selection and polymorphism screening studies to select the optimum crystalline form. Furthermore, our chemists carry out crystallization optimization studies to improve product purity and to ensure that the desired form can be reproducibly prepared.
After collaborating with the customer to define a robust process, Solvias recommends that one or more pre-GMP scaleup batches be produced in its kilo lab.
This enables the group to verify the integrity of the implemented process improvements, to identify any remaining manufacturing issues, to assess the impact of variations in raw materials, and to prepare GMP batch records properly. The material generated from these production runs can also be used for preformulation or toxicology studies, thereby utilizing all available material. At the conclusion of the program Solvias has prepared a comprehensive technology package that is readily transferred to the client or the client’s CMO.
By outsourcing the process development program to a chemical development specialist such as Solvias, cost-saving technologies can be utilized to streamline the manufacturing route and optimize the success of the GMP production campaign.
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