CASE STUDY 4:
cGMP Analytical Release Testing of a Cytotoxic Drug, as Well as Other Analytical and Bioanalytical Services
A small biopharma company had a molecule entering clinical trials for an oncology indication in Europe and in the US. The regulatory authorities in one European country requested that they conduct genotoxicity testing on the drug substance and drug product before initiating the trial.
The testing revealed a genotoxic impurity in the API as well as the drug product. Further examination revealed that the impurity arose during API manufacturing, requiring a modification to the API manufacturing process as well as the development and validation of a highly sensitive analytical method that could be used for in-process and release testing to quantify levels of the impurity that is structurally similar to the parent compound.
Although it was determined that the impurity arose from API manufacturing, they wanted the release test to be used for both the API as well as drug product. Additionally, because the clinical trial was placed on hold, there was a particular urgency to the work and the client needed the method developed as quickly as possible, with the highest degree of scientific rigor and quality assurance.
The company had not ever worked with Wolfe Laboratories before, but had a long track record with several large, international CROs. They first approached their existing vendors to develop the methods, but they were not satisfied that these vendors would be able to satisfy all aspects of the project demands. After evaluating a number of organizations, they selected Wolfe Laboratories.
The drug molecule and its process impurity are structurally similar. The drug is highly unstable and therefore, all aspects of the manufacturing process were controlled for temperature and oxygen exposure, leading to an exceedingly expensive manufacturing process that yielded small batch sizes. The client company could only provide very small quantities for testing so sample handling was a critical component of release test.
An HPLC-MS method was developed that permitted identification and quantitation of the impurity at the levels of quantitation, while also meeting the regulatory demands.
Sample stability was a key issue, due to the lability of the drug and its process impurity as well as the extremely limited amount of sample that could be provided. Processes were established that allowed stable storage should re-testing be necessary.
While the method was being validated, Wolfe Laboratories worked with the API manufacturer to evaluate the impurity levels in various pilot lots. When the manufacturer was ready to prepare cGMP lots, Wolfe Laboratories had completed the cGMP method validation, and the client company was able to move ahead with their program. The client routinely has Wolfe Laboratories perform this release test.
Based on the success of this initial analytical project that had layers of technical, regulatory and logistical complexity, the client then decided to work with Wolfe Laboratories to develop analytical methods to support both CMC programs as well as bioanalytical methods to support ADME programs for several compounds in their pipeline.