Innovative applications of spectroscopy and chemometrics for the pharmaceutical industry

This thesis proposes innovative vibrational spectroscopy and chemometrics applications within the pharmaceutical industry from raw material warehouse to commercial finished goods. The intention is to propound optimization and/or modernization of key factors of the processes in place to deliver medicine to the patient as quickly as possible, with the highest achievable quality.Vibrational spectroscopy is a non-destructive analytical tool used for identification, as well as for quantification of (bio)-pharmaceutical compounds which can be split into two types: Raman and Near-infrared (NIR). The main difference between the two is the type of vibration and transition energies measured. In some cases, these techniques might be used in combination for chemical and physical overview of a compound.The first part of the thesis aimed to identify active pharmaceutical ingredients (API) with Raman spectroscopy. Raman manufacturers have introduced to the market handheld easy to use devices in order to deliver results within a matter of seconds. Nevertheless, developing a method prior to routine use is a mandatory step. In order to optimize and speed up this phase, a study where library transfer from a donor benchtop Raman towardsvarious Raman receiver devices was evaluated. The aim was to create a unique library of API on a lab spectrophotometer and to illustrate that a transfer to various Raman systems is possible. Consequently, library creation as well as the set-up of a device for routine measurementswould be faster avoiding the acquisition of hundreds of samples on each system, and allowing an optimizing method update strategy.The second part of the thesis aimed to evaluate residual moisture content (rMC) determination in freeze-dried (bio)-pharmaceuticals by NIR. Indeed, rMC is a critical quality attribute (CQA) for lyophilized products and is the first criterion indicating the smooth running of a process. Residual water needs to be controlled and maintained. However, new types of high potent (bio)-pharmaceuticals have been appearing on the market. Themanipulation of these products is a challenge for all pharmaceutical firms and NIR is a suitable technique for their analysis.To put it in a nutshell, a preliminary study was dedicated to understanding and optimizing a freeze-dried process using QbB and DoE principles, as well as NIR spectroscopy. The objectives were to evaluate a new freeze-dried process of a drug product currently available in liquid form, to understand the relationship between rMC and the complex interplay between excipients and lyophilization process parameters, to evaluate a robustrMC model. Using NIR and chemometric principles, the moisture content distribution was evaluated as well as to have an understanding of the differences between lyophilized runs.One of the advantages of the previous study is the possibility to select the manufacturing plant runs of interest. For instance, if two runs appeared potentially suitable, further investigation can be executed. Based on this, the study that followed is a presentation of an online application evaluation after a freeze drying process optimization. Using a NIR instrument embedded in an inspection machine, thousands of samples of a product manufactured with a reference process were measured for rMC determination. Subsequently, thousands more samples of the same product were manufactured with an optimized process. In this study, NIR was used as a final decisive tool to corroborate the results of prior development experiments.After endorsement of a freeze-dried process, the commercial manufacturing can begin. The third study is the presentation of a complete method validation applied on a commercial freeze-dried product for a quality control application. This study was also completed by some case studies in order to understand how the NIR method evolves over time.In conclusion, this work shows new elements of the versatility of vibrational spectroscopy for process understanding, process optimization, release testing, as well as accelerating method validation strategy, and proposes examples of lead time reduction using innovative strategies & tools.