Applying QbD Principles To Develop a Generic UHPLC Method Which Facilitates Continual Improvement and Innovation Throughout the Product Lifecycle for a Commercial API

Abstract

The application of quality-by-design (QbD) principles for new chemical entities (NCEs) is highlighted in several publications. QbD, however, is rarely applied to marketed APIs. Lifecycles of existing APIs are extending. With this extension the focus on drug safety and compliance requires up-to-date knowledge of the product and its production process as over the years expectations in this respect have shifted. We applied QbD principles in order to set up an improved control strategy for the final five steps in the production route of a steroidal contraceptive, which has been produced for over 20 years within our facilities. A generic UHPLC method was developed for the quantitative analysis of the available intermediate batches which have all resulted in compliant API at full commercial scale. On the basis of the batch results, (statistically supported) specifications are proposed to create a range of proven acceptance criteria. This approach allows the application of the historical knowledge of the drug substance and its manufacturing process gained over the years to future production by exploiting the process capability of eliminating impurities and dealing with variability in the quality of the intermediates. Furthermore, it improves the process of specification setting. Generic UHPLC methods enable rapid quantitative monitoring of quality. The use of a generic UHPLC method in combination with the setup of a side-product flow scheme improves process understanding and supports chemical entity design space development. Furthermore, the use of a generic UHPLC method for multiple intermediates also offers the possibility to perform side-product tracing on the basis of retention times. A generic UHPLC method was developed according to QbD principles to create a range of proven acceptance criteria for the assay and side-product determination for the final five steps in the production route of a contraceptive API.

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method

“…A preliminary study showed that using more than 70% acetonitrile in the mobile phase eluted MF after 7 min at a pH less than 5.5, whereas baseline separation between VD and MF was not achieved. Separation quality is important; thus, the typical key response is good resolution between critical analyte peaks [ 56 , 57 , 58 ]. Similar work has been reported on different drugs in which the resolution was the only response, while buffer pH, percentage acetonitrile, and flow rate had a significant effect on the response [ 51 , 52 , 53 , 58 ].…”

“…The first-order influence of all three parameters showed a substantial effect on the separation between VD and MF ( p < 0.05), whereas the effect of all three parameters on the resolution between RE and VD was not significant, as confirmed by the p -values < 0.001 and >0.05, respectively. For the prediction of a response, a significant model is required [ 57 ]. A significant model with p < 0.05 indicates that one or more variable parameters have a significant influence on the mean response [ 59 ].…”

DEVELOPMENT OF UV SPECTROPHOTOMETRIC METHOD FOR THE DETERMINATION OF BENIDIPINE HYDROCHLORIDE BY USING QUALITY BY DESIGN (QbD) APPROACH

“…There are similar advantages of applying QbD principles to analytical methods as to manufacturing processes and product [9]. Several researchers have implemented QbD principles to analytical methods development process [10][11][12][13][14][15]. AQbD approach can be used in the development of a robust and cost-effective analytical method which is applicable at any stage of the lifecycle of the product.…”

A quality control method enhancement concept—Continual improvement of regulatory approved QC methods

“…The final step is continual improvement which can be done in the form of adjustments of the working point inside the validated MODR. A number of case studies following this approach can be found in the literature [9][10][11][12][13][14].…”