Taking a new approach to quality control in biopharma

Dr Amit Katiyar director, Pharma Services Group within Thermo Fisher Scientific on how a new method streamlines the development and quality control of biotherapeutics. 

The biopharmaceutical industry requires robust, efficient and reliable analytical methods to demonstrate the safety and efficacy of products during the development and manufacturing of new drugs, in order to safeguard patients. As biotherapeutic molecules become increasingly complex, the methods for analysing them must also evolve. The multi-attribute method (MAM) has emerged as a new approach for analytical characterisation and testing during process development and in quality control (QC) of biopharmaceuticals.

What is MAM?

MAM is a peptide mapping approach using liquid chromatography-mass spectrometry (LC-MS). It can be used to monitor several different product quality attributes and therefore has the potential to replace multiple conventional methods including: reverse phase high performance LC; cation exchange chromatography; reduced capillary electrophoresis-sodium dodecyl sulfate (CE-SDS); and enzyme-linked immunosorbent assays (ELISA).

Why would contract organisations want to implement MAM?

To keep up with demand for new biopharmaceuticals and ever-changing regulatory requirements, pharmaceutical companies are increasingly outsourcing analytical testing to contract organisations to gain extra capacity and expertise. Several big pharmaceutical companies are already using or planning to implement MAM in process development and QC testing. Therefore, offering MAM workflows provides opportunities for contract organisations to better meet the needs of their customers.

MAM typically uses high-resolution reverse phase chromatography-MS to provide high accuracy mass data on many different quality attributes at the same time. It provides more detailed information about quality attributes compared to conventional approaches, for example, identifying changes in proteins at the amino acid level and performing site-specific relative quantitation. The high sensitivity of MAM may be particularly advantageous for biosimilar development as it could help to show the new products are comparable to reference originator biotherapeutics with greater confidence.

Performing a single method approach is more efficient and produces less waste than generating and analysing data from multiple different assays, thus saving time and money. In addition, MAM can be performed using lower sample concentrations and volumes that may not be feasible with some of the conventional methods.

MAM can be applied at different stages in the development process from cell line development to the fill-finish of the product without making any changes to the method. Using MAM for forced degradation and comparability studies helps researchers to understand the critical quality attributes and the appropriateness of the analytical method tool kit. Ahead of using MAM in QC, it is typically necessary to perform qualification and validation activities for MAM methods to ensure consistent and expected results for the method, data analysis and reporting. This continuity enables more streamlined knowledge to be transferred between teams working at different stages of the programme, which can improve collaboration and efficiency, and may give contract organisations and their customers an edge over competitors who still use conventional methods.

What challenges might a contract organisation face when implementing MAM?

Although MAM has many advantages over conventional analytical approaches, there may be some challenges in introducing the workflows into an existing laboratory infrastructure. The initial investment and ongoing maintenance costs for high resolution mass spectrometers may be a significant hurdle for many organisations, especially if they already have access to instruments suitable for the conventional approaches.

As with any new venture, building a team with the right expertise is key to success. Training programmes need to be developed to ensure users have the expertise to use MAM at different stages in process development and in QC. Contract organisations may also need to allocate time and resources into adapting their MAM workflows for diverse projects, such as the various phases of clinical trials, or to study different types of molecules.

To make full use of the large volumes of data MAM produces, users will need access to the appropriate data management and analytical software. Furthermore, it will be important for contract organisations to communicate effectively with their customers to ensure the data analysis meets their expectations and the requirements of the regulatory authorities across the globe.

MS is not currently widely used in QC and, therefore, individuals working in this space may not be familiar with MAM and other MS approaches. Since MAM offers site specific information and higher sensitivity compared to some conventional analytical methods, it could bring to light new data that may need more initial work to interpret but will ultimately provide new insights for better product development. For example, the MAM profile of a molecule may show changes that conventional methods miss.

The clinical significance of any differences between MAM data and conventional data needs to be understood before making important decisions on the direction of the product development. Therefore, while MAM workflows are being established, it is important to use orthogonal to conventional methods during the early stages of product development. During Investigational New Drug filing, it is recommended to use MAM data to support the chemistry, manufacturing and controls data acquired using conventional approaches. The data collected in the early stages of development will allow organisations to use MAM instead of conventional methods later on in the process to achieve better timelines.

Once the initial hurdles of setting up MAM workflows are overcome, contract organisations will be in a good position to offer more streamlined and higher sensitivity analytical testing to their customers.

What is the future of MAM?

Over the next four-five years, it is expected that MAM will start to replace conventional analytical approaches in biopharmaceutical process development and become more widely used in QC. The adoption will be mainly driven from the growth projected in bi-specifics, fusion proteins and other complex biomolecules. MAM may also be adopted for in-line testing of molecules during upstream and downstream operations to highlight potential issues in real-time and allow adjustments to be made during the manufacturing process, rather than having to wait until the batch harvest to determine successful product quality and yield.

While there are short-term challenges in implementing MAM, these are likely to be outweighed by the long-term benefits for contract organisations and their customers. As an LC-MS approach, MAM has the potential to replace several conventional methods for monitoring product quality attributes during the development of new biopharmaceuticals, including some LC methods, cation exchange chromatography, CE-SDS and ELISA. It has the potential to accelerate biopharmaceutical development and manufacturing and is set to become a critical tool for analytical testing.