Throughout the entire drug development lifecycle, efficient and cost-effective routes to candidate drug substances with high potential for regulatory approval are established. This work involves investigation of the impact of numerous parameters on process performance (yield, selectivity, etc.) and product quality. Timely access to accurate analytical information is fundamental to completing process development projects effectively and efficiently. As a result, methods are continually evaluated and optimized as needed through all stages of the drug development lifecycle for the purposes of product characterization, or to be qualified and validated as release assays.
Analytical data on product quality and impurity identities and properties are needed to gain the detailed process knowledge necessary for determining additional parameters needed to investigate and ultimately optimize the conditions for production of the drug substance at commercial scale according to quality specifications. The data can also be used to develop predictive models of processes to facilitate scale-up and technology transfer. Consequently, both the timeliness and appropriateness of the data can have a direct impact on the efficiency of the drug development process.
To be most effective, analytical method development must not occur in isolation. Extensive interactions between analytical scientists and process development scientists and engineers are necessary to ensure that analytical methods address the specific needs of the process development group. In addition, constant, two-way exchange of data and ongoing communication on the information needs of the process development group is essential for the effective development of fit-for-purpose methods that can accelerate process development efforts.
As a CDMO that operates as an independent group within a large pharmaceutical company, GlaxoSmithKline Biopharmaceuticals offers many advantages to manu-facturers looking for a strong, stable partner with extensive experience in biologics development and commercialization and access to expansive resources, including a wide range of analytical capabilities and in-depth regulatory expertise. The Biopharmaceutical Technology — Analytical (BPT-A) group within GSK Biopharmaceuticals is a separate, additional analytical unit focused on method development and supporting process development efforts. The BPT-A group, which works in conjunction with the process development team, was formed to allow collaboration between analytical scientists and process development scientists at all stages as a means for accelerating process development efforts.
Members of the BPT-A group and process development teams work directly with one another and constantly exchange data regarding the process and analytical results. Having both teams at the same location allows for significantly reduced turnaround times and facilitates process optimization. The BPT-A group also serves as the primary analytical interface for all GSK customers.
Because the BPT-A group also works with the Quality Control (QC) department, the team has an extensive understanding of the testing required for both process development activities and commercial manufacturing, which provides a significant advantage when transitioning processes.
Supporting process development activities requires a higher level of flexibility and freedom to explore new and unconventional analytical methods than typically observed in a traditional quality control laboratory.
While the BPT-A lab at GSK Biopharmaceuticals conducts assay development, qualification, and validation work, and supports routine development testing, the team also develops a wide variety of assays / methods designed specifically to support process development activities, including optimization of processes and characterization of both products and impurities / byproducts. Method development can involve optimization of existing, but insufficient, assays or the establishment of an entirely new method when new processes are brought into the process development lab. Methods may also be modified or alternatives developed to allow the identification and characterization of new species that are generated in a process that is undergoing evaluation.
In the latter case, method development can be quite challenging, because oftentimes there are only very subtle differences in the impurities produced as a result of minor changes in process conditions. Typically, separations of biologic compounds are achieved based on size or charge heterogeneity, and often the species that need to be identified are aggregates or proteins in a denatured state. Detection and identification of such species are crucial because they can have an impact on the efficacy and safety of formulated biopharmaceuticals.
For instance, in one process development project, a new species was formed during attempts to optimize the process conditions. The species could not be separated using the existing method because it was very similar to another previously identified impurity. The lab determined that the new species was an aggregate with the same molecular weight as the known impurity but with a slightly different size radius. A new method was developed that separated the two dimers so that additional optimization studies could be conducted and process conditions identified that would avoid / minimize the generation of the new dimer.
In another example, the BPT-A team replaced an existing validated ion-exchange release method. Although inconsistency in column performance was the original reason for method redevelopment, the method was further optimized for improved detection of lysine variants on the terminus of the antibody. The improved method allowed better collaboration with the process development group to perform a full characterization of the species in order to conduct a comprehensive investigation of the process. The process development team ultimately used this method to investigate the impact of raw material choices on the levels of lysine variants generated in the process.
The flexibility of the BPT-A team at GSK Biopharmaceuticals, and its interaction with the production plant and traditional quality control group, has helped position these analytical scientists to address method development issues for more than just process development activities.
In one case, silicone was detected in a product after its container was changed. The original release size exclusion method was inadequate because the silicone peak interfered with the detection of protein-related impurities. To overcome the problem, a method was developed that bound the silicone to the chromatography column while the protein was allowed to pass through and be analyzed. Additionally, a new method for determination of the protein concentration was developed because the presence of the silicone interfered with the existing spectrometric assay. The alternative method used a reversed-phase method in combination with a calibration curve of known protein concentrations.
When analytical methods for manufacturing processes need to be improved, the BPT-A team often works in conjunction with the manufacturing team or the QC department. There was a need to replace the cuvette-based traditional A280 measurement with the SoloVPE method. The SoloVPE system utilizes a variable path length and sample absorbance at 280 nm to determine protein concentrations based on the Slope Spectroscopy® technique, which eliminates the need for a dilution step thereby avoiding the potential for human error and variation. The BPT-A team helped perform the method validation to introduce the method to the plant.
Finally, the BPT-A group is involved in method development work that must be completed in response to new regulatory requirements. When regulatory agencies identify minor chemical modifications that have the potential to appear in a specific type of biologic drug, the agency often requires the implementation of analytical methods that can detect these species. As in the case with process optimization of processes brought into GSK Biologics, in some cases, the existing method can be modified, and in others an entirely new method must be developed.
Accelerating process development activities is crucial for remaining competitive in the pharmaceutical marketplace today and requires strong collaboration with analytical method development efforts. As a contract development and manufacturing organization (CDMO) dedicated to providing advanced process development capabilities, GSK Biopharmaceuticals has established a highly experienced analytical team focused on supporting process development with the specific goal of enabling the rapid scale-up and tech transfer of biopharma partner processes.
Dr. Helmut Schneider brings more than 20 years of experience towards analytical method development for biopharmaceuticals and small molecules. For the past 12 years, he combined this experience with the management of biopharmaceutical testing in both R&D and GMP labs. Helmut’s team provides the analytical needs for process development and for moving analytical methods towards GMP testing at GSK Rockville. Helmut holds a Ph.D. in chemistry from Ludwig-Maximilians-University, Munich.