HOW TO DEFINE THE SCOPE OF A CHEMICAL PROCESS DEVELOPMENT

The development of chemical processes intended to the manufacturing of Active Pharmaceutical Ingredients (APIs) is usually oft-overlooked when the whole Drug Discovery and Development is told or even taught. For an innovator pharma companies, it is generally initiated concurrently to lead-optimization but it is faded behind the significance, duration and cost of clinical trials.

It is an activity essential for innovators but also for those companies devoted to the manufacturing of generics APIs. If they aim for a piece of cake of a complex and ravenous market, they should develop a competitive production process (in-house or under a contract development) to be ready when the original patent had expired, even before if a paragraph IV challenge is possible.

Chemical Process Development is an essential activity for innovators as well as for generic APIs manufacturers

Regardless who the development promoter was, the main target is the same: to get a process which allow the production of an API under the strict regulatory and quality demands of the pharmaceutical industry.

The chemical development is usually managed as a project itself, with its typical triple restriction: time, cost and scope. Time and cost are estimated, monitored and controlled in a similar way to any other project but, how could it be defined the scope of this particular projects?

First and foremost, it is necessary to define which the deliverable is. It is neither a product nor a service but a chemical process whose precise execution provides the desired product. Regarding the own chemical process (and simplifying) the deliverable is not more than a recipe, a set of instructions which thorough execution allows to transform at an industrial scale a molecule into a new one within an specified quality requirements. In this sense, the scope can be determined by a set of conditions which should be accomplished by the deliverable. The casuistry of each development is assorted, but here you can find a proposal of which these conditions should be.

1.- Safety. The chemical process must be designed and developed to be inherently safe. If it is not possible, any risky situations should be foreseen and the needed preventive actions implemented to guarantee the safety of the process. It is necessary to include a detailed risk assessment as part of the development itself, and it will be always on the top of the project backlog.

2.- Quality of the obtained API. The way in which the quality requisites are fixed differs from New Chemical Entities (NCE) to generic compounds. For generic compounds, the target quality is usually well known. However, for NCE the specifications of the final API should be proposed by the innovator and discussed case by case with the corresponding regulatory agencies. When in doubt, a good recommendation is to aim ICH guidelines.

3.- Robustness. A process which lead to a variable and unpredictable outcome will not be useful. A set of operations which triggers a different result each time they are executed cannot be considered as a process in the strict sense. They are questionable from an efficiency perspective but in addition, they are not acceptable within the GMP guidelines of the pharmaceutical industry. The robustness is naturally linked with the idea behind the process validation. The absence of robustness can affect to safety, quality, cost, … in fact to any other scope requirement.

A good understanding of the process behavior, the consequences of deviations in the process parameters and a strict control of critical process parameters, is the only way to ensure the robustness of a process. A current trend is to use a Quality by Design approach to face new developments, which is also very useful to support the validation stage.

Process knowledge and understanding is the key to get a robust process 

4.- Cost. The manufacturing cost of the API could be a minor relevance factor for innovators but it is critical for generics manufactures; if it is not competitive, you will be out of the market. The design of process all in all can be determined and conditioned by the target cost: the cheaper the product the more the limitations for the process.

The manufacturing cost should include cost of raw materials, as well as plant costs, labor costs and any other indirect ones allocable according to the costs calculation system of each production site. Notice that the manufacturing cost depends not only on chemical yields but also on batch sizes and on the own manufacturing site.

5.- Regulatory Environment. Ultimate extent of any API development is to validate the process under the cGMP, which, by the way, are usually marked by the FDA.

In this context, it is convenient to define as earlier as possible, preferably at the beginning, the starting material, the synthetic steps to validate and the manufacturing process. The overall development of the process may be considerer as an essential part in guaranteeing the validation. As it was mentioned above, QbD approach endorses the validation as long as it provides a broader knowledge of the process within the design space.

Notice, that manufacture under GMP rules implies to have a full Quality Assurance System implemented in all the departments involved: production, quality control, wharehouse, etc.. In this sense, the requests for R&D departments are becoming more strict.

6.- Operational requirements. The process will be carried out in a particular facility and on a specific scale. Many time these issues are improperly ignored until the late stages of the process development. The process chemist must have into account where the product will be produced and anticipate the equipment, features and facility needs as soon as possible. Sometimes the process requires to be adapted to the facilities (common in multiproduct plants) and in other cases the facilities are adapted or even, specifically designed for that process. At this point, a close collaboration between process chemists and engineers is essential to maximize efficiency rates.

Plant adaptation vs process adaptation

How to measure these requirements and how to ensure their compliance will be topic of future articles, as long as this one shows to be interesting to you, the reader.

The conditions shown here can be the main common goals for chemical process intended to the API manufacturing but each single project has distinctive features that must be evaluated in order to establish the scope properly. Regardless which of they were, try to defined all of them at the beginning of the project, preferably at the kick-off meeting (if it exists).

Facundo Andina (facundo.andina@gmail.com)

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