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Project Challenge

As a follow-up to a successful project (developing an active pharmaceutical ingredient (API) for depression and anxiety), we were again retained by a major pharmaceutical company to undertake two new projects. This entailed:

In its earlier work for the emerging pharmaceutical company, the development work not only was successful in meeting all the client's requirements but, additionally, a previously unobserved impurity was identified in the client's reference standard. This earlier API was acquired by a major pharmaceutical company, who contracted with us to continue this project.

For this new work, the first objective was to complete the 2 kg synthesis under cGMP conditions as quickly as possible in order for the major pharma company to begin its development program. This effort also involved scaling up of a process modification for the first time. During this scale up in Cedarburg's kilo laboratory, areas for improvement were identified for later development and process improvements were to be developed where time permitted.

For the larger 20 kg synthesis, the goals were targeted to scaling up the synthetic process for pilot plant manufacturing. Specifically, these goals were:

Project Approach

A joint development team was formed with this major pharma company and our chemical development and analytical staffs. Since this project was on the "fastest development timeline" their project manager had seen, it was agreed the teams would meet weekly and project updates were to be e-mailed the previous day. It was also decided it would be prudent to target making 30 kg of API due to the length of the synthesis and its first scale up into the plant reactors. Each step was to be done in duplicate again to minimize the risk.

Project Results - Overview

For the two-kilogram synthesis, the project lasted eleven weeks and delivered 2.3 kg of GMP API on schedule, which met all of the customer's specifications. Improvements were made on several key steps, which resulted in the overall yield increase from 46% to 55%.

For the larger 20 kg synthesis, it was not possible to avoid the thermolysis procedure (second objective) and initially these caused delays in the timeline. As a result, the customer asked us to expedite the synthesis by undertaking only one batch per step (two equally sized campaigns). The thermolysis problems were solved and 6.3 kg were delivered. All of the plant yields either met or exceeded our expectations with one exception.

The problem step in the first pilot plant campaign was collaboratively resolved. With a few modifications, this step was successfully demonstrated in the pilot plant. A total of 18.3 kg was produced in the second campaign (24.6 kg overall).

Project Results - In Depth

As noted earlier, for the two-kilogram synthesis, the project lasted eleven weeks and delivered 2.3 kg of GMP API on schedule, which met all of the customer's specifications. Improvements were made on several key steps, which resulted in the overall yield increase from 46% to 55%. Despite this success, a chromatographic purification step for the API was still necessary. Elimination of this procedure became a goal of the larger 20 kg synthesis.

Upon completion of the above synthesis, a contract for 20 kg of cGMP API was obtained from the customer. The original nine-step synthesis became thirteen steps as it was found necessary to purify several intermediates in order to insure optimal results in the subsequent steps. The first objective was successfully completed in that crystalline intermediates were obtained or it was demonstrated that an intermediate could be used in the subsequent step without isolation.

It was not possible to avoid the thermolysis procedure (second objective) and initially this caused delays in our timeline. As a result, the customer asked Cedarburg to expedite the synthesis by undertaking only one batch per step (two equally sized campaigns). The thermolysis problems were solved and 6.3 kg was delivered. All of the plant yields either met or exceeded our expectations with one exception. Due to an equipment limitation, one of the later steps would not go to completion. Efforts to continue the synthesis resulted in partial decomposition of this intermediate and lowered the amount delivered (52% yield obtained versus 85% expected). Collaboration with the customer's development team resulted in the elimination of the chromatography step (third objective).

The problem step in the first pilot plant campaign was also collaboratively solved. The customer had previously looked at alternatives for this step, but too much purity was formed. Soon after our Scale-Upproblem appeared, we solved this issue and transferred their procedure to Cedarburg. With a few further modifications, this step was successfully demonstrated in the pilot plant. A total of 18.3 kg was produced in the second campaign (24.6 kg overall).

Strong customer interaction, an experienced process development staff, production flexibility, and problem solving expertise resulted in a satisfied customer, whose development program stayed on schedule.

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