Successful Development a Generic Anabolic Steroid Where Others Have Failed.

Project Background

Cedarburg Pharmaceuticals undertook the development of a generic anabolic steroid pharmaceutical under an exclusive arrangement with a mid-sized generic company. Although this anabolic steroid has been off patent since 1981, a generic version has not appeared due to the difficulty of its synthesis. We concluded a novel approach was required and sought to achieve the following to meet this client's needs:

Cedarburg Pharmaceuticals will be the exclusive manufacturer for this generic product upon FDA approval, which is expected to be the first to the market.

Project Results -Overview

A process to manufacture a synthetically difficult steroid was developed and validated, including all analytical methodology. The latter included methods for assaying potency and impurities, the latter of which is a stability indicating method, and all related Q7A specification tests.

The finalized process was successfully validated in our kilo lab to provide commercial quantities of this potent API. A drug master file (DMF) has been submitted to the FDA in support of our customer's ANDA. Due to the continued growth of the market for the API, the process has been scaled up to our pilot plant, where further validation batches have now been completed.

Project Approach

After searching the published literature, we undertook the development of this generic steroid using a patent-free, unique synthetic approach. A team of synthetic and analytical chemists was assembled to carry out this work, which included developing our own analytical methodology and reference standards. Monthly project meetings were held with the generic company, which included technology transfer of our analytical methods to their drug product manufacturer.

Project Results - In-Depth

The initial starting commercial steroid proved to give too many impurities during the early stages of the synthesis. An alternate commercially available steroid was considered, which proved be the starting material of choice. The viability of the proposed route was demonstrated, but safety concerns of one of the reagents resulted in abandoning this procedure prior to scale up. Two other methods were investigated for this synthetic transformation. One of these procedures was clearly superior and was successfully scaled up in the kilo lab. This procedure involved a technology that was new to us. Our staff quickly mastered this technology, which now has expanded the synthetic tools we have to offer our customers.

New analytical methods needed to be developed for the API and all isolated intermediates, including in-process controls. This was a challenging endeavor since the API lacked a strong UV chromophore. Similarly, all impurities had to be controlled to low levels, identified and independently synthesized. This effort involved a wide array of analytical tools, including infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR, both H1 and C13) and mass spectroscopy either alone or coupled with prior HPLC purification. During the early stages of development for this generic drug, issues of particle size and crystal morphology (polymorphism) also needed to be addressed. Internal studies, combined with outside companies with expertise in particle size analysis and X-ray spectroscopy, resulted in reproducible conditions for the final physical characteristics.

The finalized process was successfully validated in Cedarburg's kilo lab to provide commercial quantities of this potent API. A drug master file (DMF) has been submitted to the FDA in support of our customer's ANDA. Due to the continued growth of the market for the API, the process has been scaled up to Cedarburg's pilot plant, where further validation batches have now been completed.

Working closely with our generic customer, a process to manufacture a synthetically difficult steroid was developed and validated, including all analytical methodology. The latter included methods for assaying potency and impurities, the latter of which is a stability indicating method, and all related Q7A specification tests. Cedarburg Pharmaceuticals will be the exclusive manufacturer for this generic product upon FDA approval, which is expected to be the first to the market.

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